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Michael R

Mechanisms of CR-Associated Impaired Glucose Tolerance

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All:

Pinged by a diligent contributor to and reader of the Forums, I'm reposting some material I've previously posted in the Archives, since it's clear they won't be resurrected any time soon and since the issue is hot at the moment on the more practially-oriented side in a thread initiated by Tasbin (welcome Tasbin! And welcome back Sirtuin! I'd thought you'd left us — not for the grave ;)xyz: just for other discussion groups).

Reduced Circulating IGF-1 and the "CR Triad": Impaired Beta-Cell Maintenance/Renewal?
So as most folks will know, many models of reduced IGF-1 signaling slow the degenerative aging process (albeit to varying magnitudes and degrees of convincingness). This evidence includes the existence numerous rodent "longevity mutants" with low IGF-1 signaling, amongst rodents and recently apparently amongst humans with exceptional familial longevity. Part of this data is the mostly compelling evidence of a role for reduced circulating IGF-1 in mediating at least some of the anti-aging effect of CR — particularly its protection against cancer.

So the lack of such a reduction in most people on CR in the WUSTL CR Society subjects — indeed, the finding of HIGH IGF-1 in most of us -- was a disconcerting piece of evidence that seemed to point against the human translatability of the anti-aging action of CR into humans.

Experimental dietary manipulation proved that what was going on was that in humans, consuming substantially more than the RDA of protein (which many of us were at that time) blocks the CR-induced inhibition of IGF-1 — and that the IGT largely coincided with the most OTHERWISE "CR-like" pattern of low  fasting glucose, T3, and testosterone (1,2).

However, a very puzzling dichotomy emerged within our group: everyone had good fasting glycemia, but several folks had impaired glucose tolerance. Surprisingly, the IGT folks were also found to have the same insulin sensitivity and initial insulin output on OGTT as those with normal or better glucose tolerance. And when they looked into the factors separating the 2 groups, one pattern that emerged pretty clearly was that folks who had good OGTT (most of us, myself included) ) had normal or high IGF-1, while most folks with good or excellent glucose has the full triad of low IGF-1, T3, and testosterone — exactly as you'd "want" to see on CR.

 

Unfortunately, of course, this implies that lowering your protein to bring down your IGF-1 will lead to this impaired glucose tolerance problem :( .

A few years ago now, evidence emerged to suggest that the CR-associated IGT might be the result of the reduction in GH/IGF-1 itself, rather than being an effect directly caused by the macronutrient shift, possibly due to the need for GH/IGF-1 in supporting beta-cell survival or function:
 

a novel mouse model of adult onset-isolated GH deficiency (AOiGHD) [so as to avoid the confounding effects of developmental GH deficiency on the adult body -- and thus making it more closely resemble adult-onset CR than most animals deficient in GH/IGF-1 -MR] was generated by ... [inserting a transgene that, when the animals were fed a drug, would selectively kill off the somatotropes (the cells of the pitutitary that produce growth hormone, and not other pituitary hormones), and then administering the drug so as to execute those cells when the animals were 10–12 weeks old -- a bit young, but after the main developmental process had run its course -MR summary] ... leading to a reduction in circulating GH and IGF-I levels. ...

AOiGHD improved whole body insulin sensitivity in both low-fat [LF] and high-fat [HF -- and thus high-Calorie] fed mice. ... In high-fat, but not low-fat fed AOiGHD mice, fat mass increased, hepatic lipids decreased and glucose clearance and insulin output were impaired. ...

To evaluate the interaction of AOiGHD and diet on glucose homeostasis, ITT [insulin tolerance test -- response of glucose to infused insulin, as a measure of insulin sensitivity] and GTT [ie, OGTT, as a measure of glucose tolerance] were performed at 5–6m [after knocking out the somatotropes] ... Fed and fasted glucose levels were increased in response to HF diet but were not altered by GH-status (Table-S2). The response to GTT did not differ between LF-fed, AOiGHD and control mice, while response to ITT was significantly improved... and this was associated with a significant reduction in fed and fasted insulin levels.

HF-feeding impaired insulin-mediated glucose clearance in both control and AOiGHD mice. However, in both HF- and LF-fed mice, glucose levels remained significantly lower in AOiGHD mice at the later time points following insulin injection [ie, GH deficiency improved insulin sensitivity in HF animals relative to HF but GH-producing controls].

Despite these differences in insulin sensitivity, the response to GTT deteriorated in HF-fed AOiGHD mice relative to controls. These differences may be attributed to the fact that the compensatory rise in insulin was blunted in HF-fed AOiGHD mice, resulting in a significant difference in insulin levels between AOiGHD and controls, under fasted and fed conditions :
 

2tQghvK.png

[Edit, 2016-08-09: This corrected Fig. 4 identified by and made postable by Dean]


These results suggest that GH/IGF-I may be important in maintaining ß cell function, which is supported by the observation that the level of whole pancreatic INS-2 mRNA, the primary transcript contributing to circulating insulin in mice, was significantly suppressed by AOiGHD ...

These observations strongly suggest GH/IGF-I is important in maintaining ß-cell function in the adult, a role only previously recognized in mouse models of developmental global and pancreatic GH insensitivity. A direct stimulatory effect of GH on ß-cell function is further supported by the observations that islets do express [growth hormone receptors], and GH stimulates ß–cell proliferation and insulin release in normal human islet cultures and protects against inflammatory cytokine-induced apoptosis in ß-cell lines ...

[Humans with congenital growth hormone deficiency] display impaired 1st phase insulin release [ie, the early spike in insulin in response to glucose entering the system] during a hyperglycemic clamp [45] and 30 months of low dose GH replacement improved insulin output in response to oral GTT 3-fold compared to the pre-GH response. Consistent with these observations, non-diabetic acromegalics [people with excessive GH production] were shown to have an exaggerated insulin response to glucose stimulation [47].

Admittedly, in clinical trials it is difficult to determine if GH-associated changes in insulin output are direct or due to GH-mediated changes in insulin sensitivity, however these observations coupled with our current findings showing AOiGHD have lower circulating insulin levels in both fed and fasted conditions and reduced pancreatic expression of INS-2, independent of diet, support a role for GH in maintaining adult ß-cell function.

It remains to be explored whether this effect is due to changes in ß-cell number and/or amount of insulin produced/cell and if the impact of AOiGHD is mediated by a direct or indirect mechanisms, perhaps via reduction in systemic or local production of IGF-I. ...

These results suggest the age-related decline in GH helps to preserve systemic insulin sensitivity, and in the context of moderate caloric intake, prevents the deterioration in metabolic function. However, in the context of excess caloric intake, low GH leads to impaired insulin output, and thereby could contribute to the development of diabetes.(3)

 


Now, of course, CR folk do not eat high-Calorie diets. But even the low-fat-fed GH-deficient mice had abnormally low fasting and postprandial insulin levels (see Fig 4B, above).

OTOH, while FASTING insulin is low in low-protein, low-IGF-1, impaired glucose tolerance folks just as it is in the rest of us, the insulin response to OGTT in the IGT folks was actually normal, not low, during most of the glucose tolerance curve -- and in fact, when it starts to fall in those with normal glucose tolerance, it keeps rising even higher in the IGT folks, presumably because the body is still pumping out more insulin to try to get the glucose down [Edit, 2016-08-09: this is a debatable interpretation of the data as Dean notes in a later post, which I should have emphasized and of which I'm actually now inclined to be a bit suspicious (see projected response to Dean): here are the relevant graphs, made postable by Dean]:
 

scEtKhe.png



So these animals do not offer a very compelling model for explaining the paradoxical glycemic response in low-protein, lower-IGF-1 CR folk. [Again, I now acknowledge, debatable].

Still, it's worrisome. Impaired beta-cell function or numbers might be irreversible, short beta-cell transplantation.


Reduced IGF-1 Signaling: Loss of Adiponectin-Releasing Metabolic Fat?
Ames dwarves are one of those mouse models of slow aging with reduced IGF-1 signaling: their Prop-1 mutation leads to failure of pituitary gonadotropes, somatotropes, & other pituitary cells to develop, resulting in deficient LH, FSH, GH, prolactin, and TSH. They hhave similar insulin sensitivity to CR animals on the same background, and CRing them increases it even further -- and CR robustly increases their LS. OTOH, GHR-KO mice (similar to human Laron syndrome) enjoy only very modest further increases in LS or insulin sensitivity when on CR, and what effect there is is more pronounced on BOTH fronts in males than felmales. Phosphorylation of the insulin receptor tyrosine in response to insulin is enhanced by CR in WT but not GHR-KO, with similar differences are seen in multiple insulin signal transducers. But, insulin and glucose levels are already as low or lower in AL-KO as in WT-CR, and are not FURTHER lowered by CR.

Suprisingly, GHR-KO mice are fat. In recent studies,(1) intact GHR-KO mice have similar insulin sensitivity and NS lower insulin than AL mice after visceral fat removal (VFR, which increases insulin sensitivity in AL WT animals, and partially normalized the LS in a study with short-lived controls); VFR leads to still-lower insulin levels in GHR-KO mice, but while glucose levels remain normal in AL, they climb in VFR mutants, associated with a reduction in both insulin and glucose tolerance (ie, when you shoot VFR GHR-KO mice up with glucose, they become hyperglycemic, and they FAIL to become hypoglycemic when shot up with insulin). The reason appears to be that GHR-KO mice have high levels of the insulin-sensitizing adipokine adiponectin, and VFR robs them of this advantage. (In humans, adiponectin is mostly produced in subcutaneous fat; in obesity, its release from subcu adipocytes is normal, but release from VF is low "and better predicts obesity-associated metabolic abnormalities" (pubmed/19219061), but/and people with more VF have disproportionately low adiponectin (pubmed/14747242); these animals seem to have lots of VF adiponectin). Similarly, GHR-KO mice have similar (low) levels of ectopic fat in skeletal muscle to VFR WT; AL WT *and* VFR GHR-KO mice have HIGHER levels than the aforementioned.

Interestingly, adiponectin-overexpressing TG mice have what IGF-1 investigator Bartke characterizes as a similar metaboic profile to that of Ames and GHR-KO mice (pubmed/17204560), altho' that seems to be only very fuzzily so to me; similarly, he notes several recent and older studies (PMID: 12543271, 21070591, 20398121, 20157552, 17228087, 16891987, 8967479, 21191145, 15582274) showing that centenarians (mostly drawing from cohorts with familial longevity) and offspring in longevous families show resistance to the "metabolic syndrome" (notably, lower fasting insulin levels & higher sensitivity and/or lower fasting glucose vs normals, and lower incidence of diabetes; PMID 15582274 was actually a genotype rather than phenotype study). I do note that PMID: 16891987 does specifically report that "In [general-population] centenarians we found that adiponectin concentrations were significantly increased, compared with young, early elderly and obese women. Insulin concentrations were lower than those in young and obese subjects. HOMA-IR [insulin resistance] was significantly lower than in obese women. Positive correlations were found between adiponectin and HDL, and negative correlations between adiponectin and HOMA-IR, total cholesterol, LDL, triglycerides, blood pressure and BMI." And, the Leiden Longevity Study and a couple of others found no effect on IGF-1 levels, tho' in other cohorts there are eg. changes in receptor polymorphism in and similar transduction pathways in some others.

Based on the discordant effects of CR, Ames mutation, and GHR-KO on insulin sensitivity & longevity, Bartke had already proposed (pubmed/19304940 ) that "Insulin sensitivity %5Bis%5D a key mediator of growth hormone actions on longevity"; I don't know if they already had the results of the unpublished & unmentioned VFR experiments to hand at the time, but in later papers he uncovered evidence that the lipokine adiponectin is a key mediator of all of this.

This might be an elegant, if somewhat disturbing, explanation for the about the curious intersection of impaired glucose tolerance with low IGF-1 and other putative mediators of CR in a subgroup of our human cohort (see discussioin in my post linked above, and the post linked inside of it in turn), except that BOTH subgroups of human practitioners seem to have high adiponectin levels and good insulin sensitivity!

In response to a separate question from me, re: the aforementioned (3) study showing impaired insulin release and associated glucose intolerance in inducible, adult-onset GH deficiency in mice, and about how it might intersect with the findings in our human cohort (recall that this doesn't quite match what SEEMS to be going on in the human subgroup, as first-phase insulin release SEEMS normal but just doesn't keep glucose down at the peak, leading to ongoing insulin release when it's returning to baseline in the other subgroup, despite ALL CR folk apparently having excellent insulin sensitivity per se: PMID 19904628) -- in response to my inquiry on this, and its relationship to the mutants he studies, Bartke referred to an earlier (1995) finding of his that "Islet volume ... decreased 2- to 5-fold in [Ames] dwarf mice. Analysis of the distributions of islet sizes revealed that almost all of the volume ... decreases in dwarf mice were accounted for by alterations in the numbers and sizes of large (diameter, > 150 microns) islets" - PMID: 7720649.

He also SAID, at a previous CR Society Conference, that he had found this for insulin secretory reserve. Moreover, digging, I see from an independent group that "Adult GHR(-/-) mice exhibited significant reductions in the levels of blood glucose and insulin, as well as insulin mRNA accumulation. Immunohistochemical analysis of pancreatic sections revealed normal distribution of the islets despite a significantly smaller size ... [ie,] only one-third of that in wild-type littermates. Total beta-cell mass was reduced 4.5-fold in GHR(-/-) mice, significantly more than their body size reduction. This reduction in pancreatic islet mass appears to be related to decreases in proliferation and cell growth. GHR(-/-) mice were different from the human Laron syndrome in serum insulin level, insulin responsiveness, and obesity"(5). This last statement (that THESE guys' GHR-KO mice are NOT obese) appears to be rather misleading, when you dig into the full text:
 

GHR–/– mice were not obviously obese up to 4 mo of age. The mean body mass index ... was not increased (Table 3). Blood biochemistry assays revealed normal lipid profiles ... Nevertheless, careful measurement of the relative weight (to total body wt) of 3 fat pads revealed a selective enlargement in subcutaneous fat mass. The relative weight of the subcutaneous, lateral abdominal fat increased 2.5-fold compared with wild-type littermates. Other visceral fat pads found in the abdomen and surrounding the kidney were virtually unchanged (Table 3). As expected, GHR–/– mice exhibited a significant 22% decrease in relative weight of their livers (to total body wt)".(5)


Reviewing the possible human translatability of impaired GH/IGF-1 signaling: again, several centenarian populations DO seem to have reduced signaling thru' the pathway (PMID 19489743, 18316725, 15771611), tho' it must be said that in the general population low IGF-1 levels put the elderly at incraesed risk of mortality (I think it's reasonable to suggest that this is reverse causation, or failure to compensate, rather than a lifelong effect on aging: CR animals notably have low IGF-1 in youth but higher IGF-1 than age-matched AL in late life). Untreated patients with lifelong isolated GH deficiency have no early athero deespite central obesity, elevated cholesterol, and BP (PMID 16522693); not cited by Bartke, I find that the same group "conducted a cross-sectional study of 20 IGHD individuals (seven males; age, 50.8 ± 14.6 yr) and 22 control subjects (eight males; age, 49.9 ± 11.5 yr) ... Adiponectin was higher [12.8 (7.1) vs. 9.7 (5) ng/ml; P = 0.041] ... whereas no difference was observed in leptin [7.3 (6.3) vs. 9.3 (18.7 ng/ml] and UAE [urinary albumin excretion, which they say is "a marker of endothelial disease"] [8.6 (13.8) vs. 8.5 (11.1) μg/min]. ... [H]igh adiponectin and normal leptin levels may delay vascular damage and lesions of the renal (and in this context, vascular? -MR] endothelium" - pubmed/20016047]

Similarly, "Obese adults with ... Classic Laron Syndrome ... a recessive disease of insulin-like growth factor I (IGF-I) deficiency and primary growth hormone insensitivity, clinically characterized by dwarfism and marked obesity ... have normal endothelial function" - pubmed/17320443 . "Patients with congenital deficiency of IGF-I seem protected from the development of malignancies: a preliminary report" (PMID: 17166755) -- NB, in a young cohort. And see also the recent PMID 21325617.

Observed CR-Associated IGT in Mice, Monkeys, and Men
Some have suggested that this might be a question of some people tested in Luigi's studies having higher BMI and/or adipose tissue and/or energy intake because of varying practices (Dean, tho' he was "CR proper" at the time; Paul McG) and/or the sheer statistical noise of the small size of our cohort. There are aspects of the data that wold seem consistent with that idea, but overall I think the evidence tends to rule out the former kind of explanation:

"BMI was significantly lower in the CR-IGT subgroup than in the CR-NGT subgroup (Table 4). Total energy intake was not different between the two CR subgroups [tho' it should be noted that in fact it was nonsignificantly higher in the IGT group, which if real would support your hypothesis], but fiber intake was significantly higher in the CR-IGT group."(1) The CR-IGT subgroup includes a lot of people with quite low Calorie intake; my own apparent transition into CR-IGT (see below) happened while I was lowering Calorie intake (I had been >1900 Cal/d then, and was <1800 Cal when I first observed it ); and perhaps most tellingly the CR-IGT subgroup has the MOST "CR-like" endocrinology: low IGF-1, testosterone, and active T3, suggesting that they are MORE CRed from a physiological/metabolic standpoint.

(As a reminder, when I was originally tested by Luigi on a relatively high-protein diet and with very high IGF-1 in 2006, my OGTT was the best he had ever seen (and I was tested after Saul, whose OGTT was the best out of the rest of the cohort by a significant margin). I haven't been in for an OGTT since my protein reduction, but my HbA1c has gone from ≤5 (normal) in all tests prior to lowering my protein intake to ~5.6 (high-normal to at-risk) afterward in a series of tests. Since it's not fasting glucose that's the problem, it's evidently postprandial).

(I also note, without intending to alarm him and with apologies for Fermat's Theorem risk, that Dean's recent bloodwork (Posted 01 July 2016) is no longer quite in line with this profile). [MR, 2016-08-09: Somehow miscalculated this. Dean's bloodwork is fully in line therewith].

Another counterargument to this being truly a CR phenomenon:
 

If there was one thing that seemed to distinguish CR'd animals from ad lib, it was that the CR'd ones never got diabetes - including the monkey studies so far. Of course, perhaps diabetes status or insulin resistance is not the right measure, or maybe humans are unique in their response to CR in this respect as compared to other animals



It is DEFINITELY not the right metric, since (first) the CR-IGT subgroup appears, based on HOMA-IR, to have *excellent* insulin sensitivity. You're right that the CR animals don't develop diabetes as measured by fasting glycemia, but our fasting glycemia is also excellent -- whereas there IS evidence, in mice(6) and nonhuman primates (7), of impaired glucose tolerance and in particular apparent impairment in insulin output.

Now, the abstract of (6) might actually seem to support a (very odd) too-many-Calories-on-CR hypothesis: "Glucose tolerance curves were unchanged by age in ad libitum fed or 50% restricted animals, but in 80% ad libitum [ie, 20% CR] groups, older animals showed evidence of decreased glucose tolerance with respect to young animals." In fact, however, it finds the opposite of what my interlocutor is proposing. As is plain from their Figure 2 (excerpt below), the young and old AL animals have similar "OGTT" to one another, rising from 100 mg/dL fasting to <150 under glucose challenge. The young 20%-CR mice have a similar curve to the young and old AL animals (perhaps even slightly better), but the "OGTT" worsens in the old 20% CR animals, going up to ~175 mg/dL, unlike the AL aged mice. And the kicker is the 50% CR animals, who have far worse OGTT at any age than any other group, spiking to ~210 mg/dL. Ie, more severe CR --> worse OGTT, and earlier in life.
 

gallery_727_15_34531.jpg


And, while it's hard to know for sure, it sure LOOKS like the reason is failure to secrete enough insulin in response to the glucose load.

Here is what Walford & colleagues say in their Discussion, further complicating the matter and reducing any comfort from mouse glycemia studies:
 

Both rats and mice undergo islet cell hypertrophy with advancing age, but may display contrasting patterns of glucose tolerance. In a study of glucose homeostasis in aging C57BL/6J mice, Leiter et al. [ref] found that old mice had *improved* glucose clearances (i.p. loading) and lower non-fasting glucose concentrations than mature younger mice, and this was associated with increased pancreatic islet size and increased stimulated insulin secretion capacity in the older mice. By contrast, rats have been reported to exhibit worsening glucose tolerance between 1 and 2, and 9 and 12 months of age due to insulin insensitivity [refs], and perhaps also a delay in first phase insulin release [ref].

In examining the effect of lifetime energy restriction on glucose handling in mice we found that severe [ie, 50%] restriction decreases glucose tolerance, and prevents the age-related decrement in glucose handling that occurs with some levels of energy restriction in our mouse strain. In Sprague-Dawley rats, 12 months of energy restriction improved glucose tolerance [citing PMID: 6337897], and prevented much of the 'normal' age-associated exocrine [sic -- I (MR) wonder if this was a typo? The EXOCRINE pancreas supplies digestive enzymes, rather than insulinergic beta-cells] cell mass enlargement in the pancreas, as well as age-associated insulin resistance [ref]. However, maximal stimulated insulin output per islet was *still* decreased with age under chronic energy restriction [ref].

Similarly, Koizumi et al. [ref] have reported that lifetime energy restriction decreases pancreatic islet cell mass in the mouse strain, diet, and lab conditions used in the present study, and others have reported that chronic energy restriction abolishes the normal exocrine [sic] hypertrophy noted with aging in another mouse strain [ref]. These findings, together with present results, suggest that severe restriction blunts maximum insulin secretion in young and old mice.(6)


[Edit: added 2016-08-23]: Somewhat similarly, though with a more optimistic ultimate finding, the "CR" primates appear to have lower beta-cell response to glucose (although in both cases there is ambiguity about their "CR" status). At NIA, "Several measures of the insulin response (baseline, maximum, and integrated areas under curve) increased with age and were lower in DR monkeys. ... {I]ntegrated insulin response was lowered in DR monkeys compared with controls .... [similar to a previous report on] DR in rats. Acute insulin response (first-phase) and second-phase insulin response, represented by areas under the curve for O-10 and 10-60 min, respectively, were also lowered in DR monkeys."(10) However, in the NIA primates, this was accompanied by a lower peak glucose concentration during OGTT, suggesting that beta-cell function was adequate, and was lower simply because it didn't need to be any higher, due to the animals' enhanced insulin sensitivity. "These findings confirm earlier reports (5) that age-related increases in insulin levels, which could develop into hyperinsulinemia and diabetes, are ameliorated by calorie restriction."(10)

There is a parallel at WUSTL, too, though the result is not actually the same, and we have to be particularly skeptical of the relevance of the result, as it is pretty clear that the WUSTL "CR" study was not a proper CR study, but a study of avoidance of obesity by controlled energy intake. Still, it's still notable (and in some senses even more striking) that even following mere obesity-avoidance amongst the nonhuman primates at WUSTL, (10) "[CR] monkeys had less body fat, lower basal β-cell sensitivity to glucose (Ø(b)), greater insulin sensitivity, and lower first-phase plasma insulin response. DR did not significantly affect first-phase and second-phase β-cell sensitivity to glucose."(11) This is not the contradiction it seems: basal sensitivity is the unchallenged sensitivity of the beta-cell to fasting glucose, and first-phase insulin sensitivity is the degree to which beta-cells are activated in response to rising glucose; first-phase insulin response reflects the level of plasma insulin that appears in circulation in response to incoming glucose from IVGTT. What they find, then, is that their "CR" animals' beta-cells do respond to incoming glucose by producing more insulin, but it is more rapidly cleared from the plasma:
 


C-peptide and insulin are released in equimolar amounts into the portal vein upon stimulation of the ß-cells by plasma glucose. C-peptide is cleared relatively slowly by the kidney and negligibly by the liver. By contrast, insulin exhibits a much shorter half-life in large part because of rapid extraction by the liver. ...

ß-cell sensitivity to glucose did not differ in either the first or second phase of secretion. During the first phase of secretion, only a marginal difference in the glucose stimulus and no difference between groups in plasma C-peptide concentration could be detected. At the same time, plasma insulin levels were different between groups, suggesting a difference in hepatic insulin extraction. ... Since C-peptide is cleared more slowly (long half-life of ∼30 min) than insulin (<15 min), it could be argued that plasma C-peptide levels measured within 10 minutes of the glucose bolus mainly reflect its secretion, not clearance, unlike later in the IVGTT. Because insulin but not C-peptide concentrations differed, insulin extraction in this early stage of the IVGTT may have been greater in the R group, lower in the C group, or both may have occurred to some degree. Although we have no evidence for a greater hepatic extraction among R, there is some evidence that additional body fat among C monkeys may have reduced hepatic extraction in that group. ... Indices of body fatness were highly predictive of the effect of DR on Ø(b), fasting insulin concentration and insulin responses to glucose. Enhanced peripheral insulin sensitivity among R monkeys was strongly correlated with lower Ø(b).
 
Abdominal obesity, exhibited by many of the C monkeys, has been associated in dogs with hepatic insulin resistance and elevated portal fatty acid levels (45); the latter have been shown to reduce hepatic insulin extraction in vitro and in vivo. In vitro studies with rat hepatocytes have also demonstrated that fatty acids reduce insulin binding, degradation, and function (48). Furthermore, in obese rats, hepatic triglyceride levels are inversely associated with extraction. ... Reduced insulin extraction would effectively expose peripheral tissues to excess insulin over time, increasing the risk for development of several metabolic disorders. Hyperinsulinemia has been proposed to be detrimental to healthy aging in general  and, specifically, it has been implicated in the increasing levels of oxidative stress with age. Thus, the flexibility in the liver's capacity to extract newly secreted insulin may be an important mechanism by which it regulates the amount of insulin to which peripheral tissues are exposed.(11)


All well and good, so long as insulin secretion and plasma levels are adequate to match postprandial glucose. The problem for CR-IGT is that whatever the underlying mechanism, the latter is not happening without additional steps to control it.[Here endeth edit of 2016-08/23]
 
mTOR and "Starvation Diabetes"
CR does inhibit the autophagy-repressing, protein-synthesis-enabling mTOR, which is the mechanism of action of rapamycin, the first (but, happily, no longer the sole) true anti-aging drug in rodents. And so a parallel phenomenon in rapamycin-treated mice, and related matters, as well as a potential mechanism for it involving the differing metabolic effects of inhibiting the two mTOR complexes (mTORC1 and mTORC2), are suggestive — and way around the effect in drug design is promising, if not clearly actionable (tho' Dean has hypothesized that it may be via cold exposure):

 

Calorie restriction (CR), which deactivates the nutrient-sensing mTOR pathway, slows down aging and prevents age-related diseases such as type II diabetes. Compared with CR, rapamycin more efficiently inhibits mTOR. Noteworthy, severe CR and starvation cause a reversible condition known as “starvation diabetes.” As was already discussed, chronic administration of rapamycin can cause a similar condition in some animal models. A recent paper published in Science [(9) below] reported that chronic treatment with rapamycin causes a diabetes-like condition in mice by indirectly inhibiting mTOR complex 2. Here I introduce the notion of benevolent diabetes and discuss whether starvation-like effects of chronic high dose treatment with rapamycin are an obstacle for its use as an anti-aging drug.(8)


Rapamycin, an inhibitor of mechanistic target of rapamycin complex 1 (mTORC1), extends the lifespans of yeast, flies, and mice. Calorie restriction, which increases lifespan and insulin sensitivity, is proposed to function by inhibition of mTORC1, yet paradoxically, chronic administration of rapamycin substantially impairs glucose tolerance and insulin action. [As we've seen, CR also impairs glucose tolerance, tho' at least in rodents it clearly sustains insulin action in aging, and I don't think this is likely the explanation for the human phenomenon -MR]. We demonstrate that rapamycin disrupted a second mTOR complex, mTORC2, in vivo and that mTORC2 was required for the insulin-mediated suppression of hepatic gluconeogenesis. Further, decreased mTORC1 signaling was sufficient to extend lifespan independently from changes in glucose homeostasis, as female mice heterozygous for both mTOR and mLST8 exhibited decreased mTORC1 activity and extended lifespan, but had normal glucose tolerance and insulin sensitivity. Thus, mTORC2 disruption is an important mediator of the effects of rapamycin in vivo.(9)

On the one hand, the recent finding of the predicted additive or synergistic effect of adding metformin to rapamycin — despite the lack of effect of metformin alone on lifespan in normal, healthy mice — is supportive of the models in (8,9). On the oher hand, a lot of papers have now been published showing divergent effects of CR and rapamycin, and it's not clear to me how this impacts the translatability (tho' I've not looked into this more than superficially).

Apologies for lack of elaboration ... More may possibly come later, but no promises ...

Health Implications
Of course, this is all on its face scary shit: both possible beta-cell loss, and postprandial hyperglycemia, and as discussed in recent threads like this and this, people exhibiting CR-IGT are prudently attempting to manage the hyperglycemia in particular. It must be said, tho', that however intuitively bad this all sounds, CR mice none the less retard the aging process and live dramatically longer than AL mice, despite exhibiting these same phenomena. This would seem to stand as a counterargument even in the face of uncertainty about the human translatability of CR, since this is exactly a translatable phenomenonboth the glucoregulatory pattern itself, and the associated endocrinology. And, as discussed here, the evidence on actual implications of all of this on health and aging are often surprising in their absence, in mouse and man.

I certainly still think it's prudent to work to bring down postpradial hyperglycemia, but there are clearly some things going on that my own little brain has not managed to capture and digest.

References
1: Luigi Fontana, Samuel Klein, John O. Holloszy. Effects of long-term calorie restriction and endurance exercise on glucose tolerance, insulin action, and adipokine production. Age (Dordr). 2010 Mar;32(1):97-108. Epub 2009 Nov 11. PMID: 19904628 [And see, when it's up:
http://www.crsociety.org/archive/read.php?2,197226,197244#msg-197244

2: Fontana L, Weiss EP, Villareal DT, Klein S, Holloszy JO. Long-term effects of calorie or protein restriction on serum IGF-1 and IGFBP-3 concentration in humans. Aging Cell. 2008 Oct;7(5):681-7. PubMed PMID: 18843793; PubMed Central PMCID: PMC2673798.

3. PLoS One. 2011 Jan 19;6(1):e15767.
Metabolic impact of adult-onset, isolated, growth hormone deficiency (AOiGHD) due to destruction of pituitary somatotropes.
Luque RM, Lin Q, Córdoba-Chacón J, Subbaiah PV, Buch T, Waisman A, Vankelecom H, Kineman RD.
PMID: 21283519
http://dx.plos.org/10.1371/journal.pone.0015767

4. Masternak MM, Bartke A, Wang F, Spong A, Gesing A, Fang Y, Salmon AB, Hughes
LF, Liberati T, Boparai R, Kopchick JJ, Westbrook R. Metabolic effects of
intra-abdominal fat in GHRKO mice. Aging Cell. 2011 Oct 31. doi:
10.1111/j.1474-9726.2011.00763.x. [Epub ahead of print] PubMed PMID: 22040032.
http://dx.doi.org/10.1111/j.1474-9726.2011.00763.x

5. Liu JL, Coschigano KT, Robertson K, Lipsett M, Guo Y, Kopchick JJ, Kumar U, Liu YL. Disruption of growth hormone receptor gene causes diminished pancreatic islet size and increased insulin sensitivity in mice. Am J Physiol Endocrinol Metab. 2004 Sep;287(3):E405-13. Epub 2004 May 11. PubMed PMID: 15138153.

6. Harris SB, Gunion MW, Rosenthal MJ, Walford RL. Serum glucose, glucose tolerance, corticosterone and free fatty acids during aging in energy restricted mice. Mech Ageing Dev. 1994 Mar;73(3):209-21. PubMed PMID: 8057691.

7. Gresl TA, Colman RJ, Havighurst TC, Allison DB, Schoeller DA, Kemnitz JW. Dietary restriction and beta-cell sensitivity to glucose in adult male rhesus monkeys. J Gerontol A Biol Sci Med Sci. 2003 Jul;58(7):598-610. PubMed PMID: 12865475.

8. Blagosklonny MV. Once again on rapamycin-induced insulin resistance and longevity: despite of or owing to. Aging (Albany NY). 2012 May;4(5):350-8. Review. PubMed PMID: 22683661; PubMed Central PMCID: PMC3384435.

9. Lamming DW, Ye L, Katajisto P, Goncalves MD, Saitoh M, Stevens DM, Davis JG, Salmon AB, Richardson A, Ahima RS, Guertin DA, Sabatini DM, Baur JA. Rapamycin-induced insulin resistance is mediated by mTORC2 loss and uncoupled from longevity. Science. 2012; 335: 1638-1643.

11: Lane MA, Ball SS, Ingram DK, Cutler RG, Engel J, Read V, Roth GS. Diet restriction in rhesus monkeys lowers fasting and glucose-stimulated glucoregulatory end points. Am J Physiol. 1995 May;268(5 Pt 1):E941-8. PubMed PMID: 7762649.

11: Gresl TA, Colman RJ, Havighurst TC, Allison DB, Schoeller DA, Kemnitz JW. Dietary restriction and beta-cell sensitivity to glucose in adult male rhesus monkeys. J Gerontol A Biol Sci Med Sci. 2003 Jul;58(7):598-610. PubMed PMID: 12865475.

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Thanks, Michael!

 

This was a very revealing post, very well presented.  As you noted in your post, my response to Luigi's OGTT was excellent, as was your own.  Since reducing protein intake, my latest test results for IGF1, this June 15, was 118 ng/mL -- according to Dean and Al Pater, this is similar to their "lowish" level -- in your opinion, is this on the low side?  (I'm not really sure what levels are common in our CR human cohort).

 

Perhaps more importantly, I don't know how I would respond now to a glucose tolerance test.  I'm toying with the idea of asking my CR-friendly nephrologist (who requests my bloodwork and urine work) to perhaps schedule a glucose tolerance test.

 

  --  Saul.

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Hi Dean and Tom!

 

What level of IGF1 is considered "too low" (for a CRONnie or any human), and what level is considered "CRONNie too high" (which presumably is lower than "Ad Lib too high")?  (Perhaps I'm asking questions not entirely resolved?)

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Saul,

 

You answered your own question about optimal IGF1 level:

 

Perhaps I'm asking questions not entirely resolved?

 

How the heck do you think we would know the answer to that question with any degree of certainty?

 

--Dean

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I've been reading the blog Dean recommended: Michael Lustgarten - by someone who feels that we should strive to reach optimal values for various biomarkers. In his favor, he does cite a number of studies - some of which I have not seen before - and that is always valuable as a data point. However, the greater problem strikes me that as this thread abundantly illustrates, once you are at the very extreme of a bell curve - and CRONies and CR-like folks often are at those extremes and sometimes beyond (and so are not captured in studies) - many of those biomarkers need to be assessed according to a different scale instead of seeing them in isolation and based upon the ad lib population. A fasting glucose number in a CRONie is not the same thing as a fasting glucose number in an ad-lib person. The IGF-1 number in a CRONie is not the same thing as an IGF-1 number in an ad-lib person. Failing to account for that can lead us into paradoxes like a CR'd person who has by conventional standards excellent levels of some glucose numbers, nonetheless developing diabetes or pre-diabetes or damaging their pancreas; and problems that the CRONies develop as a result will not be cured based upon interventions meant to adjust some biomarker or another that was developed with ad-lib people in mind. That has me rather sceptical about Michael Lustgarten's approach - we simply don't have enough data or understanding about folks like us, who are at the very extreme of the bell curves. Now, there have been studies done in our populations by some researchers like Fontana, but those are on the whole a tiny minority and not what Michael Lustgarten appears to base his approach on. This is yet another instance where the nagging voice in the back of my mind "but this study was done in ad-lib, and we are emphatically not ad-lib, we are CR!" grows particularly loud when reading his blog. It's bad enough when people make recommendations based on in vitro or animal studies, more and more I have to look somewhat askance at studies in ad-lib populations - how relevant are those for folks in our situation? 

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TomB,

 

I agree with you. Mike Lustgarten and I have had several long debates on the CR Society FaceBook page regarding his (over-)reliance on studies of "normal" people to estimate optimal levels for biomarkers. At least in some instances, they don't seem relevant for CR folks, or even people simply eating an impeccably healthy diet. 

 

Don't worry Michael - I'm working on a big post in response to your (amazing) post which started this thread. It will definitely bring us back on topic.

 

--Dean

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Hi Tom and Dean!

 

Perhaps Luigi's numbers (without names) is available, in a paper somewhere?  If so, there MAY be some data for CR people  --  admittedly, on much too small a sample -- but, if available, better than numbers for a study on  12 mice (which we often look at with interest).

 

:)xyz

 

  --  Saul

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Wow Michael,

 

Why does it always seem that reading your posts is like drinking from a firehose? Both practices tend to blast your head off, but at the end you remain less than quenched, thinking "if I were only a little smarter or tried a little harder to understand all that Michael was getting at, I might be a lot better off". 

 

I'm going to attempt to help clarify in my own mind what you wrote, perhaps help others to grasp it as well, and hopefully fill in some of the gaps if possible, with this follow-up post. Call it "Michael for Dummies" ☺.

 

First off, thanks for so clearly describing the tradeoff between the Scylla of high IGF1 on the one side and the Charybdis of impaired glucose tolerance (IGT) on the other. That is indeed the tradeoff that many serious CR practitioners have seemed to face, and at least in some respects it seems like jumping from the frying pan into the fire.

 

Regarding the mechanism. I'm sure you didn't realize it (nor apparently did Saul or TomB), but the linked image you referred to as "Figure 4B" from [3] was incorrect. Your link pointed to Figure 2. Here is the real Figure 4:

 

 

2tQghvK.png

 

What is shows is exactly what you indicated - namely that mice that are made growth hormone (and IGF1) deficient in adulthood produce dramatically less insulin, and as a result, have impaired glucose tolerance, especially on a diet replete with fat and calories (4A).

 

As you indicate, this seems to suggest that low GH/IGF1 may directly contribute to the impaired glucose tolerance that some CR folks exhibit. But what is really disconcerting is possible mechanism suggested in [3] which I'll synopsize with this small excerpt from your longer quote from [3] (my emphasis):

 

A direct stimulatory effect of GH on ß-cell function is further supported by the observations that islets do express [growth hormone receptors], and GH stimulates ß–cell proliferation and insulin release in normal human islet cultures and protects against inflammatory cytokine-induced apoptosis in ß-cell lines ...

 

In other words, it appears GH/IGF1 signalling not only stimulates insulin production in pancreatic β-cells, but may also stimulate β-cell proliferation and prevent the β-cells from being killed off via apoptosis. If true for humans too, that would be an unfortunate explanation for CR-induced IGT, to put it mildly. In short, our low levels of GH/IGF1 could be trashing our pancreases. Not good, particularly coupled with the report from Paul M. (discussed here) about two seriously calorie-restricted people he knew who were very skinny, had impaired glucose tolerance and died of pancreatic cancer, which is quite a rare form of cancer...

 

Quoting you again Michael:

...the insulin response to OGTT in the IGT folks was actually normal , not low, during most of the glucose tolerance curve -- and in fact, when it starts to fall in those with normal glucose tolerance, it keeps rising even higher in the IGT folks, presumably because the body is still pumping out more insulin to try to get the glucose down. So these animals do not offer a very compelling model for explaining the paradoxical glycemic response in low-protein, lower-IGF-1 CR folk.

 

You've actually got it only ½ right with these statements.

 

Below are the two relevant graphs from Luigi's paper [1] showing serum glucose (top) and insulin (bottom). The two graphs on the left shows glucose and insulin responses of "normal" controls (WD, BMI ~25), very fit exercisers (EX - BMI ~22) and us CR folks (CR - BMI ~19.5). The two graphs on the right (or bottom if it wraps for you) shows a comparison within the CR cohort of people with normal glucose tolerance (CR-NGT) vs. those of us who had impaired glucose tolerance (CR-IGT). 

 

hE2SHQy.png scEtKhe.png

 

I presume when you say "the insulin response to OGTT in the IGT folks was actually normal, not low, during most of the glucose tolerance curve" you are simply observing that the CR-IGT folks look similar to the CR-NGT folks in terms of insulin for most of the two hours (bottom graph on right above). While this is indeed true, the entire CR cohort had insulin levels far below the control folks (WD group) for the entire 2 hours (bottom graph on left above) and as a result had elevated glucose relative to controls (and especially exercisers!) by the end of the OGTT (top graph on the left above).

 

So in general, contrary to what you say, and line with the GH-knockout mice, it appears most CR folks (not just the CR-IGT folks) have blunted insulin release in response to a glucose challenge relative to normal people. It's just that the CR-IGT folks don't seem to clear glucose from the bloodstream as well as the CR-NGT folks (or the exercisers!) with a given (relatively small) amount of circulating insulin.

 

So if all CR folks have downregulated (or if you are pessimistic - atrophied or damaged...) pancreases, and therefore blunted insulin release, what explains the difference between the CR folks who are NGT vs. those who are IGT? Take a look at the highlighted lines of Table 4 from [1]:

 

t6hFLjO.png

 

As you (and Luigi) pointed out Michael, the IGT folks had a more classic CR hormonal profile (lower IGF1, T & T3 - bottom of the table). But in addition, they also were a lot thinner (BMI 18.6 vs. 20.0), had less muscle mass (lean mass 47.9 vs. 51.2 kg) and apparently were a lot more sedentary (VO2max 34.5 vs. 44.2).

 

So perhaps Tasbin is onto something. Perhaps it does have something to do with less muscle mass, and less glucose-consuming mitochondria in muscles (and I would add, ditto for brown/beige fat). Try this hypothesis on for size:

 

All CR folks, both NGT and IGT alike, produce less insulin for whatever reason. The same was true of the endurance exercisers in Luigi's study (EX group above). But all three groups (CR-NGT, CR-IGT and EX) also have increased insulin sensitivity to compensate. For the CR-NGT and EX groups, they have enough muscle (and/or brown/beige fat) mass and enough glucose-consuming mitochondria in those muscle/fat cells to slurp up and squirrel away the glucose during the OGTT.

 

In contrast, the very skinny and relatively sedentary CR-IGT folks don't have enough muscle (and/or brown/beige fat) mass to serve as sinks for the glucose. So despite the high insulin sensitivity of the CR-IGT folks and despite what would otherwise be sufficient insulin release, the glucose had nowhere to go and just kept (keeps) circulating, resulting in elevated postprandial glucose, and poor OGTT performance.

 

Luigi seems to think this is the explanation too. Quoting from [1] (my emphasis):

 

Therefore, our data suggest that severe chronic CR, in some individuals, may be associated with a relative peripheral insulin resistance mainly due to a low muscle mass with decreased capacity to take up glucose.

 

Needless to say, this syndrome in the CR-IGT group looks strikingly similar to what happens in the progression of type 2 diabetes. Namely, cells stop accepting additional glucose, leaving it circulating in the bloodstream, along with the insulin meant to shuttle the glucose into cells. This elevated circulating glucose and insulin wreaks all kinds of havoc, eventually snowballing into fully blown diabetes...

 

Back to Michael:

Still, it's worrisome. Impaired beta-cell function or numbers might be irreversible, short beta-cell transplantation.

 

That's an understatement I would say!. And IGT is worrisome whether or not it results from damage to the pancreas.

 

Michael next talks about:

Reduced IGF-1 Signaling: Loss of Adiponectin-Releasing Metabolic Fat?

 

Now you're singing my tune Michael. You go on to observe based on [4]:

 

Surprisingly, GHR-KO mice are fat [with copious visceral fat, which appears to paradoxically improve their insulin sensitivity - DP synopsis]. ​The reason appears to be that GHR-KO mice have high levels of the insulin-sensitizing adipokine adiponectin, and [visceral fat removal] robs them of this advantage.

 

You know what else makes long-lived GHR-KO mice unusual? They have a higher metabolic rate than wild-type mice at cool temperatures, but not at thermoneutral temperatures and this may be causal in their longevity (see here for discussion). It appears GHR-KO mice not only have metabolically active (i.e. heat-producing, beige-ish) visceral fat %5B4%5D, they also have more brown adipose tissue %5B5%5D%5B6%5D.  Both these forms of fat generate adioponectin and improve insulin sensitivity and glucose metabolism - according to this model. Know what else increases longevity-promoting adiponectin in humans? Yup - cold exposure. ☺ From the Cold Exposure Albatross post:

 

Adiponectin Production - Like CR [ref], cold exposure increases adiponectin levels. Two hours of cold exposure resulted in a 70% increase in circulating adiponectin in adult men [ref]. Study [ref] found centenarians and their offspring had genetic mutations that boost adiponectin, and had higher circulating adiponectin, suggesting to the authors "their [i.e. adiponectin-promoting gene mutations] may promote increased lifespan through the regulation of adiponectin production and/or secretion." Study [ref] found the same thing in a group of centenarian women - "As compared to BMI-matched [young, ~28 year-old] female controls, female centenarians had significantly higher plasma adiponectin concentrations. In addition, high concentrations of plasma adiponectin in centenarians was associated with favorable metabolic indicators, and with lower levels of C-reactive protein and E-selectin". For those of us who aren't lucky enough to have adiponectin-boosting genes, we can increase adiponectin levels via CR, cold exposure, or both. This video illustrates how two hours of cold exposure raises a cold-adapted person's adiponectin level by a whopping 62%.

 

Back to Michael, who wrote:

This [lack of adiponectin-generating, insulin-sensitizing, metabolically active fat - DP] might be an elegant, if somewhat disturbing, explanation for the about the curious intersection of impaired glucose tolerance with low IGF-1 and other putative mediators of CR in a subgroup of our human cohort... except that BOTH subgroups of human practitioners seem to have high adiponectin levels and good insulin sensitivity...

 

You're so close Michael...

 

Yes, even the skinny IGT CR folks have relatively high adiponectin and good insulin sensitivity. But, per my hypothesis above, only the CR-NGT and EX groups had enough metabolically active muscle and (brown/beige) fat tissue to provide a place for the glucose to be absorbed and burned. In short, all the insulin-sensitizing adiponectin in the world won't help clear your glucose if you don't have the muscle or (mitochondrial-rich brown/beige) fat cells to absorb and consume the glucose. Skinny CR folks don't have much of either - hence their IGT (such is my hypothesis).

 

Some have suggested that this might be a question of some people tested in Luigi's studies having higher BMI and/or adipose tissue and/or energy intake because of varying practices...

 

Yes - but in exactly the opposite way you seem to be suggesting. Specifically, it appears Michael you think others were suggesting that that higher BMI might be bad for glucose tolerance. Quite the opposite. At least I'm suggesting that higher BMI is better for glucose tolerance. This seems to be borne out in your n-of-1 experience with IGT (you had been lowering your calorie intake, and presumably dropping some weight, when your glucose tolerance went south), and moreover, as I pointed out above, and you mention as well, the CR-IGT folks in Luigi's study had significantly lower BMI, as well as lower lean mass, than the CR-NGT folks. It all adds up - you need some muscle/fat on your bones to absorb the glucose...

 

Next you say:

(I also note, without intending to alarm him and with apologies for Fermat's Theorem risk, that Dean's recent bloodwork (Posted 01 July 2016) is no longer quite in line with this profile).

 

Now that's really not fair. You need to elaborate on that forthwith. It's not even clear what "profile" you are referring to, to say nothing of what aspect of my bloodwork you think no longer conforms to it!

 

The three hormonal hallmarks of the CR-IGT group in Luigi's study were low testosterone, low IGF1, and low T3. My latest free testosterone is still 50% below the bottom of the reference range, my most recent IGF-1 is substantially lower than it was when Luigi tested it, and while I haven't recently had the same T3 test as Luigi performed, my most recent free T3 was near the bottom of the reference range (2.6 vs. 2.0-4.4). So by those metrics it seems I'd still qualify for the CR-IGT club - not that I'd want to...

 

What I don't have anymore is postprandial glucose intolerance, which I documented here earlier today. This is a welcome change which I attribute to boosting the volume and metabolic capacity of mitochondria both in my muscles (via copious exercise and sarcolipin-promoting cold exposure) and in my fat (via UCP1-promoting and mitochondria-proliferation-promoting cold exposure). I really should get my VO2Max tested again. Unlike other CR-IGT folks, my VO2Max wasn't bad in Luigi's study, but I'm certain it's much better now - given my current endurance and running capacity. So both my exercise-boosted muscles and my cold-exposure-boosted brown/beige fat are now able to absorb the glucose, so I'm no longer in the IGT club.

 

Back to Michael:

Now, the abstract of [7] might actually seem to support a (very odd) too-many-Calories-on-CR hypothesis: 

 

You're darn right it's very odd. In fact it's a silly and nonsensical strawman, as you point out yourself. In short, this hypothesis makes no sense and doesn't fit the data, even of [7], as you point out:

But the kicker is the 50% CR animals, who have FAR worse OGTT at any age than any other group, spiking to ~210 mg/dL. Ie, more severe CR --> WORSE OGTT, and earlier in life.

 

Exactly. And what's the difference between the severely CRed, glucose intolerant mice and those less severely CRed mice with better glucose metabolism? Not insulin sensitivity. The difference is that 50% CR mice have a lot less muscle and fat mass than the 20% CR mice. Once again we see a case where the skinnier CR group has no sink to absorb their glucose, leading to impaired glucose tolerance relative to the less severely CRed or ad lib groups.

 

Coming to the close you say:

Of course, this is all on its face scary shit: both possible beta-cell loss, and postprandial hyperglycemia, and as discussed in recent threads like this and this, people exhibiting CR-IGT are prudently attempting to manage the hyperglycemia in particular. It must be said, tho', that however intuitively bad this all sounds, CR mice none the less retard the aging process and live dramatically longer than AL mice, despite exhibiting these same phenomena. 

 

Yes - scary sh*t. And to me, your bolded observation (your emphasis) about severe CR extending mouse lifespan despite impairing glucose metabolic isn't much comfort. Why? Because the vast majority of mice die of cancer.  So in cancer-prone mice, the apparent protective effects of CR-induced low IGF-1 against cancer may more than compensate for the negative effects of CR on glucose metabolism. But most humans, and especially most diabetic humans, die of cardiovascular disease, not cancer. So the adverse effects of severe CR on glucose metabolism may be bad news for long-term human health and longevity.

 

I certainly still think it's prudent to work to bring down postprandial hyperglycemia, but there are clearly some things going on that my own little brain has not managed to capture and digest.

 

It looks pretty clear to me. The really skinny CR folks may have reduce insulin release, which may be caused by messed up β-cells in our pancreas. But the real culprit for impaired glucose metabolism in really skinny CR folks seems to me to be too little glucose-absorbing muscle and/or fat mass.

 

To me, all of this provides more compelling evidence that serious CR won't beat a healthy, obesity-avoiding diet and lifestyle...

 

--Dean

 

----------------

[1] Luigi Fontana, Samuel Klein, John O. Holloszy. Effects of long-term calorie restriction and endurance exercise on glucose tolerance, insulin action, and adipokine production. Age (Dordr). 2010 Mar;32(1):97-108. Epub 2009 Nov 11. PMID: 19904628 

 

 

[3] PLoS One. 2011 Jan 19;6(1):e15767.

Metabolic impact of adult-onset, isolated, growth hormone deficiency (AOiGHD) due to destruction of pituitary somatotropes.

Luque RM, Lin Q, Córdoba-Chacón J, Subbaiah PV, Buch T, Waisman A, Vankelecom H, Kineman RD.

PMID: 21283519

http://dx.plos.org/1...al.pone.0015767

 

[4] Masternak MM, Bartke A, Wang F, Spong A, Gesing A, Fang Y, Salmon AB, Hughes

LF, Liberati T, Boparai R, Kopchick JJ, Westbrook R. Metabolic effects of

intra-abdominal fat in GHRKO mice. Aging Cell. 2011 Oct 31. doi:

10.1111/j.1474-9726.2011.00763.x. [Epub ahead of print] PubMed PMID: 22040032.

http://dx.doi.org/10...26.2011.00763.x

 

[5] Egecioglu E, Bjursell M, Ljungberg A, et al. Growth hormone receptor deficiency results in blunted ghrelin feeding response, obesity, and hypolipidemia in mice. Am J Physiol Endocrinol Metab 2006;290:E317-E325.Abstract[/size]/[/size]FREE [/size]Full Text[/size]

 

[6] Li Y, Knapp JR, Kopchick JJ. Enlargement of interscapular brown adipose tissue in growth hormone antagonist transgenic and in growth hormone receptor gene-disrupted dwarf mice. Exp Biol Med (Maywood) 2003;228:207-215. [/size]Abstract[/size]/[/size]FREE [/size]Full Text[/size]

 

[7]. Harris SB, Gunion MW, Rosenthal MJ, Walford RL. Serum glucose, glucose tolerance, corticosterone and free fatty acids during aging in energy restricted mice. Mech Ageing Dev. 1994 Mar;73(3):209-21. PubMed PMID: 8057691.

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So when Michael started this thread and posted his massive text bomb at the top, I was in the middle of composing a long response to Tasbin for the Impaired Glucose Tolerance Now thread. Some of it was quotes from Michael from the old email archives which he and I covered in our exchange above. But some his copious musing on the topic of IGT he didn't cover (I know, hard to believe given the length of what he posted), and some of what I was putting together was new stuff on IGT that neither Michael nor I covered above.

 

So this post picks up where I left off above, before I got distracted this morning and went down an important (to me at least) rabbit hole of metaphysical musings. That discussion might also be interesting for anyone who has ever wondered about my motivation for obsessive/excessive posting around here...

 

But without further ado, here is a post that might be summarized as "Impaired glucose tolerance sucks, and maybe here is what we should do about it."

 

---------

Tasbin,

 

Thanks for the links to studies showing the correlation between low muscle mass and impaired glucose tolerance.. Coincidentally, I happen to be in the midst of an email conversation with a friend who eats a very healthy, mostly whole-food, plant-based diet who doesn't restrict calories (eats almost as much as I do!) and who is reasonably active (not nearly as active as I am) but nonetheless is very thin - substantially skinner than either of us. This person appears to exhibit the classic Fontana-esque impaired glucose tolerance (IGT) that several of us demonstrated, lending support to the idea that low muscle mass is a major contributor to the IGT exhibited by CR folks, independent of calorie intake.

 

Prompted by this thread, as well as my off-forum discussions on the topic of IGT, I've been digging into both the primary literature and old discussions on the CR email forums about this issue.. I'm going to quote Michael pretty extensively from the archives, since he's done a lot of thinking/research on the topic.. I hope he doesn't mind (I later verified with Michael it was ok).

 

First, Michael and all of us (including Paul McGlothin - as you saw in the video of Paul we discussed here) take the IGT many of us exhibited in Luigi's study quite seriously - although it is unclear whether or not Paul thinks it's a problem to have IGT on CR if one properly manages it.. To quote from one of Michael's posts to the email list (on 6/25/12), he summarized IGT in CR folks as:

 

This is a real bastard.

 

But interestingly, at least at that time he didn't attribute it to CR-induced low muscle mass.. Instead he thought it was a result of reduced protein intake and/or reduced IGF1.. Again quoting from Michael's 6/25/12 email post:

 

Someone (besides Michael) wrote:
 
I see no evidence CR causes IGT.  As [X] says,
it is likely rooted in genetic predispositions, and to damage from
eating a normal American diet before we started CR.
 
To which Michael responded (my emphasis):
 
Then you need to pay more attention ;) .. Most of the people with CR-associated IGT did not have it before going on CR; moreover, in at least some cases (my own included), we had EXCELLENT OGTTs practicing CR on *high-protein* diets, and with high-IGF-1.. When we switched to RDAish protein, our IGF-1 went down, and IGT appeared.. In fact, having IGT while on CR at Luigi's original test, or developing it following protein moderation, was associated with having the most overall "CR-like" endocrine profile: low IGF-1, IGF-1, T3, and testosterone. This is a CR-related phenomenon, with IGF-1 and protein intake being the key variables AMONGST CR folk.
 
This is a real bastard.
 
[My Discussion of Michael's silly straw man "Eating to Many Calories while Practicing CR" hypothesis deleted - since he and I addressed that above]
 
 
Michael points to this additional Blagosklonny paper [2] to support his hypothesis that lowish dietary protein + CR → low IGF1 → low mTORC1 activity → reduced pancreatic β-cell insulin production (perhaps due to cell death or reduced cell replacement / proliferation?) → impaired glucose tolerance.
 
But whether the cause of our IGT is low muscle mass, low IGF1 or low dietary protein, impaired glucose tolerance is bad news, especially if, but whether or not, it results from impairment or death of β-cells in our pancreas. 
 
In support of this perspective on the deleterious effects of IGT, here is a good paper [3] posted by Al Pater on 5/7/14, titled Survival of the fattest: unexpected findings about hyperglycaemia and obesity in a population based study of 75-year-olds. Troublingly, it found that among older individuals, the combination of a low BMI and impaired glucose tolerance resulted in an increase in mortality compared with chubbier people with IGT..Specifically, among older people with IGT, risk of death went up 10% for every 1 point drop in BMIThat's definitely bad news.
 
Several times over the years Michael has pointed to [4], a study of the association of mortality risk with glucose level after a glucose challenge among nondiabetic folks.. It basically found people without diabetes but who nevertheless had worse performance on an oral glucose tolerance test had a 20-30% higher risk of mortality than people with good post-challenge glucose control.
 
He also has pointed to [5], which Michael summarized (on 6/25/12) as follows:
 
Ie, a postprandial glucose anywhere higher than fasting levels at the 2 h mark was at elevated risk of CVD and total mortality -- and this is in a cohort where no one had a fasting level >109 mg/dL.
 
Or put even more succinctly - if your glucose hasn't returned to its fasting level (or below) by 2 hours after a meal, you're at elevated risk of dying from CVD or any cause, even if your fasting glucose is within the normal range.
 
Michael repeatedly goes to great pains in the email list archives to point out that just because IGT is induced by CR and/or low IGF1 and/or low weight, that does not mean it is benign.. In kindly reviewing this post before I posted it, Michael said he was of two minds on whether or not there is such a thing as "benign IGT". I'll leave him to tease apart for us the nuances of his perspective on this. But he did say (again on 6/25/12):
 
As has been posted several times in the past, there is plenty of evidence that elevated postprandial glucose levels -- even within the subdiabetic range, and even with normal fasting glucose -- is associated with negative health outcomes, most notably cardiovascular disease. 
 
And in more detail from another post that day, someone said:
 
How does a CR person like me know whether their glucose spikes are
benign "CR-associated" IGT or whether they have plain ordinary IGT which
needs to be controlled with diet and exercise?
 
To which Michael responded (my emphasis):
 
Elevated glycemia stoichiometrically increases the rate of nonenzymatic glycation crosslinks in structural proteins (and leads to aberrant intracellular metabolism in neurons, nephrons, and a few other cell types that don't use insulin to absorb glucose).. It may be WORSE when it's caused for reasons other than those that cause the CR-associated variety, because those causes IN THEMSELVES cause problems that CR per se does not, but having excessive sugar in your blood  causes increased chemical damage to your tissues thru' sheer chemistry, in the same way that having excessive alcohol or acetaldehyde does.
 
As Michael points out, it's not just our hemoglobin that gets glycated by elevated post-meal glucose. Glycated LDL is now thought to be a serious risk factor for CVD and CVD complications/mortality, in addition to, and perhaps (adversely) synergistic with the deleterious effects of oxidized LDL [6]-[9].. Quoting from [9]:
 
 Even in nondiabetic individuals, however, there is generally more circulating glycated
LDL than oxidatively modified LDL.. Probably, oxidation and glycation of LDL are
partially interdependent and indisputably coexist, and both prevent LDL
receptor-mediated uptake and promote macrophage scavenger receptor-mediated LDL
uptake. The recognition that LDL glycation is at least as important as oxidation 
in atherogenesis may lead to improvements in our understanding of its mechanism
and how to prevent it.
 
And from this informative page on LDL and CVD:
 
Glycation is another type of atherogenic modification of LDL that may contribute to atherosclerosis (ref)..Glycation is the result of bonding of a protein or lipid molecule with a sugar molecule, such as fructose or glucose, without the controlling action of an enzyme.. Small, dense LDL is more susceptible to glycation than more buoyant LDL (ref).
 
Glycation and oxidation of LDL appear to be intimately linked and glycated LDL is more likely to be oxidized than non-glycated LDL (ref).
 
 
In short, whether or not we're killing off our pancreatic β-cells via low-calorie, low-BMI, low-IGF1 calorie restriction, the evidence clearly shows we should take steps to manage our postprandial glucose spikes.
 
So what should we non-diabetic but somewhat glucose metabolism-impaired folks do about our IGT? 
 
On 5/6/14 Michael posted a bunch of studies [10]-[15] showing what many of us have found through self-experimentation - namely that post meal exercise greatly reduces the postprandial glucose spike and area-under-the-curve in healthy, non-diabetic people.. From watching him at the recent CR conference, Michael too appears to have taken this intervention to heart, despite being unable to engage in glucose testing himself (due to his alleged inability to bleed ☺)..
 
It was clear Michael didn't want to sit for too long, particularly after meals - getting up to walk around during conference sessions, presumably to help bring down glucose.. I even heard from a reliable source that on the drive to visit the Biosphere, Michael got out of the car when stopped at a stop light, jogged up to the car ahead and back, presumably to get a little additional exercise to bring glucose down..Michael, you're a man after my own heart, but feel free to affirm/deny/explain your thoughts and practices regarding post-meal activity for glucose control. [i should note that in an exchange with Michael after he reviewed this post he did not deny these observations about his post-meal glucose regulating practices].
 
As I've mentioned, Paul McGlothin structures much of his CR Way diet/lifestyle around optimizing glucose control, including both pre- and post-meal exercise, eating a very low GI / GL diet, pre-meal 'tease' foods, etc..And as you indicated Tasbin, Paul also recommends against reducing calories or weight too much.. I'm not sure about his latest recommendation, but as I recall he admonishes against dropping below a BMI in the 19-20 range.. I too have recently put on weight intentionally (BMI 17.3 → 18.6)  in part to to maintain muscle mass but also to built metabolically active, glucose-lowering brown/beige adipose tissue via cold exposure. 
 
Which brings me to the observation that I and several other folks (esp.. Gordo) have found - namely that deliberate and chronic cold exposure has dramatic beneficial effects on glucose control.. Not only is there a mountain of direct evidence in rodents and people (discussed in the cold exposure thread) about the benefits of cold exposure for glucose metabolism, there is also an interesting (although speculative) model of why this might be the case, both biochemically, which I discussed here, and evolutionarily, which I discuss here..
 
In a nutshell, biochemically, it appears cold exposure upregulates MTORC1, but not via the usual insulin/IGF1 pathway (but via PKA instead).. As a result of increased MTORC1 activity, you may get many of the anabolic benefits IGF1 including improved glucose metabolism, without many of the downsides.. In this way CR and CE could be synergistic. In fact, it's my hypothesis that CR won't work without CE - the evidence for which I discuss extensively in the cold exposure thread.
 
So from personal experience and the observations of others, there are many ways we can (and should) manage CR-related impaired glucose tolerance if one is unfortunate enough to suffer from it.
 
--Dean
 
--------
[1] Mech Ageing Dev.. 1994 Mar;73(3):209-21.
 
Serum glucose, glucose tolerance, corticosterone and free fatty acids during
aging in energy restricted mice.
 
Harris SB(1), Gunion MW, Rosenthal MJ, Walford RL.
 
Author information: 
(1)Department of Pathology, University of California at Los Angeles 90024.
 
Energy restriction, the only method known to increase maximum life span in
laboratory animals, was used as a tool to test hypotheses regarding possible
mechanisms of aging.. Serum glucose and corticosterone (CS) concentrations in mice

of a long-lived hybrid mouse strain, aged 7, 17, and 29 months, and on 50%, 80%, 

and 100% of ad libitum intake, were measured.. Serum glucose and CS concentrations

were also measured in response to intraperitoneal (i.p.) glucose challenge in

mice at ages 7 and 29 months.. Serum glucose and CS concentrations were also
measured at several time points over 36 h, to assess their diurnal variation.
There were no differences in single fasting glucose concentrations in 7- and
29-month-old mice at the same degree of energy restriction, but energy
restriction decreased glucose concentrations.. Serum CS concentrations were
generally increased restricted animals with respect to fully fed ones.. Average

serum glucose concentrations were found to be significantly decreased by dietary 

restriction.. Glucose tolerance curves were unchanged by age in ad libitum fed or 

50% restricted animals, but in 80% ad libitum groups, older animals showed

evidence of decreased glucose tolerance with respect to young animals.. For each
age, peak serum glucose concentrations after i.p.. glucose loading varied with

degree of energy restriction, with more severely restricted animals showing less 

glucose tolerance.. Average serum CS concentrations were elevated at 7 months by

restriction, especially at night and long after feeding, but we found no

differences with age or diet in average CS concentrations.. Our serum glucose

results support the hypothesis that nonenzymatic glycation is mechanistically

involved in normal aging.. Our serum CS results do not support the hypothesis that
CS contributes significantly to the pathophysiology of normal aging in mice.
 
PMID: 8057691
 
----------
[2] Aging (Albany NY).. 2012 May;4(5):350-8.
Once again on rapamycin-induced insulin resistance and longevity: despite of or owing to.
Blagosklonny MV.
 
Free full text
 
Abstract
 
Calorie restriction (CR), which deactivates the nutrient-sensing mTOR pathway, slows down aging and prevents age-related diseases such as type II diabetes.. Compared with CR, rapamycin more efficiently inhibits mTOR..Noteworthy, severe CR and starvation cause a reversible condition known as "starvation diabetes." As was already discussed, chronic administration of rapamycin can cause a similar condition in some animal models.. A recent paper published in Science reported that chronic treatment with rapamycin causes a diabetes-like condition in mice by indirectly inhibiting mTOR complex 2.. Here I introduce the notion of benevolent diabetes and discuss whether starvation-like effects of chronic high dose treatment with rapamycin are an obstacle for its use as an anti-aging drug.
 
PMID:22683661
 
----------
[3] BMJ Open.. 2011 Apr 10;1(1):e000012.. doi: 10.1136/bmjopen-2010-000012.
 
Survival of the fattest: unexpected findings about hyperglycaemia and obesity in a population based study of 75-year-olds.
 
Nilsson G, Hedberg P, Öhrvik J.
 
Free PMC Article:
 
Abstract
 
OBJECTIVE: To study the relationship between body mass index (BMI) and mortality among 75-year-olds with and without diabetes mellitus type 2 (DM) or impaired fasting glucose (IFG).
 
DESIGN: Prospective population-based cohort study with a 10-year follow-up.
 
PARTICIPANTS: A random sample of 618 of the 1100 inhabitants born in 1922 and living in the city of Västerås in 1997 were invited to participate in a cardiovascular health survey; 70% of those invited agreed to participate (432 individuals: 210 men, 222 women).
 
OUTCOME MEASURES: All-cause and cardiovascular mortality.
 
RESULTS: 163 of 432 (38%) participants died during the 10-year follow-up period.. The prevalence of DM or IFG was 41% (35% among survivors, 48% among non-survivors).. The prevalence of obesity/overweight/normal weight/underweight according to WHO definitions was 12/45/42/1% (14/43/42/1% among survivors, 9/47/42/2% among non-survivors).. The hazard rate for death decreased by 10% for every kg/m(2) increase in BMI in individuals with DM/IFG (HR 0.91, 95% CI 0.86 to 0.97; p=0.003).. After adjustment for sex, current smoking, diagnosed hypertension, diagnosed angina pectoris, previous myocardial infarction and previous stroke/transient ischaemic attack, the corresponding decrease in mortality was 9% (HR 0.92, 95% CI 0.86 to 0.99; p=0.017)..These findings remained after exclusion of individuals with BMI<20 or those who died within 2-year follow-up.. In individuals without DM/IFG, BMI had no effect on mortality (HR 1.01, 95% CI 0.95 to 1.07; p=0.811).. The HR for BMI differed significantly between individuals with and without DM/IFG (p interaction=0.025). The increased all-cause mortality in individuals with DM/IFG in combination with lower BMI was driven by cardiovascular death.
 
CONCLUSION: High all-cause and cardiovascular mortality was associated with lower BMI in 75-year-olds with DM/IFG but not in those without DM/IFG.. Further studies on the combined effect of obesity/overweight and DM/IFG are needed in order to assess the appropriateness of current guideline recommendations for weight reduction in older people with DM/IFG.
 
PMID:22021724
 
-------
[4] Arch Intern Med.. 2004 Oct 25;164(19):2147-55.

Is nondiabetic hyperglycemia a risk factor for cardiovascular disease? A
meta-analysis of prospective studies.

Levitan EB(1), Song Y, Ford ES, Liu S.

Author information:
(1)Division of Preventive Medicine, Harvard Medical School and Brigham and
Women's Hospital, Boston, MA 02215, USA.

BACKGROUND: Although hyperglycemia increases the risk of cardiovascular disease
(CVD) in diabetic patients, the risk associated with blood glucose levels in the
nondiabetic range remains unsettled.
METHODS: We identified 38 reports in which CVD incidence or mortality was an end
point, blood glucose levels were measured prospectively, and the relative risk
(RR) and information necessary to calculate the variance were reported comparing

groups of nondiabetic people.. These reports were prospective studies, published
in English-language journals.. First author, publication year, participant age and
sex, study duration, CVD end points, glucose assessment methods, control for
confounding, range of blood glucose levels, RR, and confidence intervals (CIs) or

P values were extracted.. Using a random effects model, we calculated pooled RRs
and 95% CIs.
RESULTS: The group with the highest postchallenge blood glucose level (midpoint
range, 150-194 mg/dL [8.3-10.8 mmol/L]) had a 27% greater risk for CVD compared
with the group with the lowest level (midpoint range, 69-107 mg/dL [3.8-5.9

mmol/L]) (RR, 1.27 [95% CI, 1.09-1.48]).. The results were similar when combining
studies regardless of type of blood glucose assessment (RR, 1.36 [95% CI,
1.23-1.52]) and when using strict criteria for exclusion of diabetic subjects

(RR, 1.26 [95% CI, 1.11-1.43]).. Adjustment for CVD risk factors attenuated but
did not abolish this relationship (RR, 1.19 [95% CI, 1.07-1.32]).. The RR was
greater in cohorts including women than in cohorts of men (RR, 1.56 vs 1.24 [P =
.03]).
CONCLUSION: Blood glucose level is a risk marker for CVD among apparently healthy
individuals without diabetes.

DOI: 10.1001/archinte.164.19.2147
PMID: 15505129

 

---------

[5] Arch Intern Med.. 2004 Oct 25;164(19):2147-55.

 
Is nondiabetic hyperglycemia a risk factor for cardiovascular disease? A
meta-analysis of prospective studies.
 
Levitan EB(1), Song Y, Ford ES, Liu S.
 
Author information: 
(1)Division of Preventive Medicine, Harvard Medical School and Brigham and
Women's Hospital, Boston, MA 02215, USA.
 
BACKGROUND: Although hyperglycemia increases the risk of cardiovascular disease
(CVD) in diabetic patients, the risk associated with blood glucose levels in the 
nondiabetic range remains unsettled.
METHODS: We identified 38 reports in which CVD incidence or mortality was an end 
point, blood glucose levels were measured prospectively, and the relative risk
(RR) and information necessary to calculate the variance were reported comparing 
groups of nondiabetic people.. These reports were prospective studies, published
in English-language journals.. First author, publication year, participant age and
sex, study duration, CVD end points, glucose assessment methods, control for
confounding, range of blood glucose levels, RR, and confidence intervals (CIs) or
P values were extracted.. Using a random effects model, we calculated pooled RRs
and 95% CIs.
RESULTS: The group with the highest postchallenge blood glucose level (midpoint
range, 150-194 mg/dL [8.3-10.8 mmol/L]) had a 27% greater risk for CVD compared
with the group with the lowest level (midpoint range, 69-107 mg/dL [3.8-5.9
mmol/L]) (RR, 1.27 [95% CI, 1.09-1.48]).. The results were similar when combining 
studies regardless of type of blood glucose assessment (RR, 1.36 [95% CI,
1.23-1.52]) and when using strict criteria for exclusion of diabetic subjects
(RR, 1.26 [95% CI, 1.11-1.43]).. Adjustment for CVD risk factors attenuated but
did not abolish this relationship (RR, 1.19 [95% CI, 1.07-1.32]).. The RR was
greater in cohorts including women than in cohorts of men (RR, 1.56 vs 1.24 [P = 
.03]).
CONCLUSION: Blood glucose level is a risk marker for CVD among apparently healthy
individuals without diabetes.
 
DOI: 10.1001/archinte.164.19.2147 
PMID: 15505129
 
--------
[6] Angiology.. 2005 Jul-Aug;56(4):431-8.
 
Hyperglycemia, lipoprotein glycation, and vascular disease.
 
Veiraiah A(1).
 
Author information: 
(1)Llandough Hospital, Penarth, Wales, UK.
 
Hyperlipidemia and its treatment are currently recognized as important modulators
of cardio-vascular mortality in the presence of disordered glucose control.. On

the other hand, the effects of hyperglycemia and its treatment on hyperlipidemia 

are not widely appreciated.. Hyperglycemia is commonly associated with an increase
in intestinal lipoproteins and a reduction in high-density lipoprotein (HDL).
This could be a consequence of hyperglycemia-induced glycation of lipoproteins,
which reduces the uptake and catabolism of the lipoproteins via the classical
low-density lipoprotein (LDL) receptor.. A high dietary carbohydrate load

increases the glycation of intestinal lipoproteins, prolongs their circulation,

and increases their plasma concentration.. Hyperglycemia also leads to inhibition 
of lipoprotein lipase, further aggravating hyperlipidemia.. Circulating advanced
glycation end-products (AGEs) also bind lipoproteins and delay their clearance, a
mechanism that has particularly been implicated in the dyslipidemia of diabetic
nephropathy.. As uptake via scavenger receptors is not inhibited, glycation
increases the proportion of lipoproteins that are taken up via inflammatory cells
and decreases the proportion taken up by hepatocytes via classical LDL receptors.
This promotes the formation of atheromatous plaques and stimulates inflammation. 
Hyperglycemia increases the formation of oxidized LDL and glycated LDL, which are
important modulators of atherosclerosis and cardiovascular death.. The risk of
cardiovascular death is increased by even short-term derangement of blood sugar
control, owing perhaps to the glycation of lipoproteins and other critical
proteins.. Glycated LDL could prove very useful in measuring the effect of
hyperglycemia on cardiovascular disease, its risk factors, and its complications.
Comparing different glucose-lowering and lipid-lowering drugs in respect to their
influence on glycated LDL could increase knowledge of the mechanism by which they
alter cardiovascular risk.
 
PMID: 16079928
 
------
[7] Cardiovasc Diabetol.. 2002 Apr 8;1:1.

How hyperglycemia promotes atherosclerosis: molecular mechanisms.

Aronson D(1), Rayfield EJ.

Author information:
(1)Cardiology Division, Rambam Medical Center, 31096 Haifa, Israel.
daronson@netvision.net.il

Both type I and type II diabetes are powerful and independent risk factors for
coronary artery disease (CAD), stroke, and peripheral arterial disease.
Atherosclerosis accounts for virtually 80% of all deaths among diabetic patients.
Prolonged exposure to hyperglycemia is now recognized a major factor in the

pathogenesis of atherosclerosis in diabetes.. Hyperglycemia induces a large number
of alterations at the cellular level of vascular tissue that potentially
accelerate the atherosclerotic process.. Animal and human studies have elucidated
three major mechanisms that encompass most of the pathological alterations
observed in the diabetic vasculature: 1) Nonenzymatic glycosylation of proteins
and lipids which can interfere with their normal function by disrupting molecular
conformation, alter enzymatic activity, reduce degradative capacity, and

interfere with receptor recognition.. In addition, glycosylated proteins interact
with a specific receptor present on all cells relevant to the atherosclerotic
process, including monocyte-derived macrophages, endothelial cells, and smooth

muscle cells.. The interaction of glycosylated proteins with their receptor
results in the induction of oxidative stress and proinflammatory responses 2)
oxidative stress 3) protein kinase C (PKC) activation with subsequent alteration

in growth factor expression.. Importantly, these mechanisms may be interrelated.
For example, hyperglycemia-induced oxidative stress promotes both the formation
of advanced glycosylation end products and PKC activation.

PMCID: PMC116615
PMID: 12119059

 

--------

[8] Mol Metab.. 2013 Dec 7;3(2):94-108.. doi: 10.1016/j.molmet.2013.11.006.. eCollection

2014.
 
Vascular effects of advanced glycation endproducts: Clinical effects and
molecular mechanisms.
 
Stirban A(1), Gawlowski T(2), Roden M(3).
 
Author information: 
(1)Profil Institut für Stoffwechselforschung GmbH, Hellersbergstrasse 9, 41460
Neuss, Germany.. (2)University of Paderborn, Warburger Str.. 100, 33098 Paderborn, 
Germany.. (3)Institute for Clinical Diabetology, German Diabetes Center, Leibniz
Institute for Diabetes Research at Heinrich Heine University, 40225 Düsseldorf,
Germany ; Division of Endocrinology and Diabetology, University Clinics
Düsseldorf, 40225 Düsseldorf, Germany.
 
The enhanced generation and accumulation of advanced glycation endproducts (AGEs)
have been linked to increased risk for macrovascular and microvascular
complications associated with diabetes mellitus.. AGEs result from the
nonenzymatic reaction of reducing sugars with proteins, lipids, and nucleic
acids, potentially altering their function by disrupting molecular conformation, 
promoting cross-linking, altering enzyme activity, reducing their clearance, and 
impairing receptor recognition.. AGEs may also activate specific receptors, like
the receptor for AGEs (RAGE), which is present on the surface of all cells
relevant to atherosclerotic processes, triggering oxidative stress, inflammation 
and apoptosis.. Understanding the pathogenic mechanisms of AGEs is paramount to
develop strategies against diabetic and cardiovascular complications.
 
DOI: 10.1016/j.molmet.2013.11.006 
PMCID: PMC3953708
PMID: 24634815
 
------
[9] Curr Opin Lipidol.. 2011 Aug;22(4):254-61.. doi: 10.1097/MOL.0b013e328348a43f.
 
Susceptibility of LDL and its subfractions to glycation.
 
Soran H(1), Durrington PN.
 
Author information: 
(1)Cardiovascular Research Group, School of Biomedicine, Core Technology
Facility, University of Manchester, Manchester, UK.
 
PURPOSE OF REVIEW: To highlight the potential importance of glycation as an
atherogenic modification of LDL, factors determining glycated apolipoprotein B in
vivo and susceptibility of LDL to glycation in vitro.. We also discuss the
distribution of glycated apolipoprotein B across different LDL subfractions in
healthy controls, patients with type 2 diabetes and metabolic syndrome.
RECENT FINDINGS: Small, dense LDL, which is known to be most closely associated
with atherogenesis, is more preferentially glycated in vivo and more susceptible 
to glycation in vitro than more buoyant LDL.. Glycation and oxidation of LDL
appear to be intimately linked.. In patients with type 2 diabetes, plasma glycated

apolipoprotein B correlated with small, dense LDL apolipoprotein B, but not with 

HbA1c.. Glycated apolipoprotein B is significantly lower in statin-treated type 2 
diabetes compared with those not on statins.
SUMMARY: Glycation of LDL occurs chiefly because of the nonenzymatic reaction of 
glucose and its metabolites with the free amino groups of lysine of which
apolipoprotein B is rich.. Higher concentrations of glycated LDL are present in
diabetes than in nondiabetic individuals and metabolic syndrome. Even in
nondiabetic individuals, however, there is generally more circulating glycated
LDL than oxidatively modified LDL.. Probably, oxidation and glycation of LDL are
partially interdependent and indisputably coexist, and both prevent LDL
receptor-mediated uptake and promote macrophage scavenger receptor-mediated LDL
uptake.. The recognition that LDL glycation is at least as important as oxidation 
in atherogenesis may lead to improvements in our understanding of its mechanism
and how to prevent it.
 
DOI: 10.1097/MOL.0b013e328348a43f 
PMID: 21734572
 
-----------
10: DiPietro L, Gribok A, Stevens MS, Hamm LF, Rumpler W.. Three 15-min bouts of
moderate postmeal walking significantly improves 24-h glycemic control in older
people at risk for impaired glucose tolerance.. Diabetes Care.. 2013
Oct;36(10):3262-8.. doi: 10.2337/dc13-0084.. Epub 2013 Jun 11.. PubMed PMID:
23761134; PubMed Central PMCID: PMC3781561.
 
11: Nygaard H, Tomten SE, Høstmark AT.. Slow postmeal walking reduces postprandial
glycemia in middle-aged women.. Appl Physiol Nutr Metab.. 2009 Dec;34(6):1087-92.
doi: 10.1139/H09-110.. PubMed PMID: 20029518.
 
12: Gaudet-Savard T, Ferland A, Broderick TL, Garneau C, Tremblay A, Nadeau A,
Poirier P.. Safety and magnitude of changes in blood glucose levels following
exercise performed in the fasted and the postprandial state in men with type 2
diabetes.. Eur J Cardiovasc Prev Rehabil.. 2007 Dec;14(6):831-6.. PubMed PMID:
18043307.
 
13: Derave W, Mertens A, Muls E, Pardaens K, Hespel P.. Effects of post-absorptive
and postprandial exercise on glucoregulation in metabolic syndrome.. Obesity
(Silver Spring).. 2007 Mar;15(3):704-11.. PubMed PMID: 17372321.
 
14: Høstmark AT, Ekeland GS, Beckstrøm AC, Meen HD.. Postprandial light physical
activity blunts the blood glucose increase.. Prev Med.. 2006 May;42(5):369-71.. Epub
2006 Mar 20.. PubMed PMID: 16549107.
 
15: Poirier P, Tremblay A, Catellier C, Tancrède G, Garneau C, Nadeau A.. Impact of
time interval from the last meal on glucose response to exercise in subjects with
type 2 diabetes.. J Clin Endocrinol Metab.. 2000 Aug;85(8):2860-4.. PubMed PMID:
10946894.

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All,

 

For more evidence for the likely reason why and how being too scrawny on a serious CR diet results in glucose intolerance, see this new post on the cold exposure thread.  In short, the combination of exercise and a high-fat/calorie-replete diet results in the creation of glucose-burning beige fat deposits inside skeletal muscle cells, improving insulin sensitivity and glucose clearance. Without much muscle, glucose has nowhere to go in skinny CR folks, so it just keeps circling round and round the bloodstream, looking for a home, as I speculated above.

 

--Dean

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Dear ALL,

 

I spoke with my Endocrinologist, Dr. Steven Wittlin, Head of the Division of Endocrinology at Strong Memorial Hospital (aka UR Medicine).  First, let me note that Dr. Wittlin is no "lightweight" (pun not intended).  He has conducted endocrinological studies, and is very knowledgeable on the subject of diabetes; and, in addition, he is "CR-friendly".

 

Dr. Wittlin pointed out that, with my numbers, I obviously didn't need a glucose tolerance test.  However, at my request, he did agree to send me a prescription for a glucose tolerance test.

 

However, he noted that the current guidelines for a GTT require the taker to consume 300 GRAMS OF CARBOHYDRATE per day, for THREE DAYS, prior to taking the test.  Dr. Wittlin noted that, this is necessary, especially for people like us -- otherwise we might get a false positive of being diabetic.

 

I noted (if I understand correctly) that Luigi thought it possible that protein-reduced CRONnies who failed a GTT might simply not have enough protein, resulting in loss of pancreatic beta cells.  Dr. Wittlin didn't agree -- he said that after the load of a GTT, without the bulidup of 300gm of glucose for the 3 consecutive days immediately preceding the test, that "no wonder" the beta cells would struggle to make adequate insulin --not that beta cells were "dying".

 

He asked me to pass this on to you.

 

One other thing:  I don't know if I'm personally willing to consume 300G OF CARBOHYDRATE FOR 3 CONSECUTIVE DAYS under any circumstances.  (Maybe I could "cheat" by eating 300 g of fiber?)

 

  -- Saul

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Saul,

 

I'm glad you were able to speak with Dr. Wittlin, and he gave you an OGTT prescription. I disagree with his (apparent?) suggestion that an OGTT wouldn't be worthwhile in your situation. Given your mildly elevated postprandial glucose in response to an apparently fiber-rich and not-excessive carb- or calorie-rich meal, and your apparent refusal to do glucose self-testing, an official OGTT seems like the right course of action for you to pursue.

 

But Dr. Wittlin is right about the pre-OGTT carb loading. As Michael has pointed out, low-carb folks, who live in a state of near-constant ketosis (just like you claim to...), often 'fail' an OGTT simply because their pancreas isn't accustomed to needing to pump out the required amount of insulin. I'm skeptical about your claim of personal ketosis, and I suspect that you do eat 300g (1200kcal) of digestible carbs per day, so your concern about needing to change your diet for 3-days prior to the OGTT may be moot. Have you ever actually tried tracking what you eat for a day or two to see how many carbs calories you consume!?

 

I noted (if I understand correctly) that Luigi thought it possible that protein-reduced CRONnies who failed a GTT might simply not have enough protein, resulting in loss of pancreatic beta cells.  

 

Yet again you haven't understood correctly, if by 'protein-reduced' you mean eating little dietary protein and not 'protein-reduced' in the sense of lacking lean muscle mass. Luigi blamed (and showed evidence) that high dietary protein put the kibosh on the IGF-1 lowering effects of CR in some of us CRed humans. As far as I know, Luigi has neither said nor found anything that relates dietary protein to impaired glucose tolerance. As discussed here, what Luigi did find relating to glucose was that CR folks with IGT were on average more severely CRed, and had lower muscle mass and poorer cardiovascular performance than the CR folks with normal glucose metabolism. So Dr. Wittin was right to doubt your (mis)understanding of Luigi's findings.

 

Hope that helps clarify and gives you some food for thought on how to proceed with your own situation.

 

Personally I'd do my own home glucose testing first, but if you balk at that, I'd then track my diet to see if I'm getting 300g of carbs/day, and if not, bite the bullet and eat that much for 3-days prior to getting the OGTT.

 

But hey, that's just me. Do whatever floats your boat.

 

--Dean

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...I suspect that you do eat 300g (1200kcal) of digestible carbs per day, so your concern about needing to change your diet for 3-days prior to the OGTT may be moot. Have you ever actually tried tracking what you eat for a day or two to see how many carbs calories you consume!?

 

Yes, thanks for pointing this out because when I read Saul's 300 grams of carbs comment I was like uh wonder what mine is (I track my diet on cronometer daily) and I was like oh eating a bunch of greens and beans and berries and grapefruit and nuts and olive oil everyday is like whoopsie sometimes creeping into the 200-300 g range of "carbs."

 

So my response is: "define carbs"

 

There are good carbs, there are less good carbs. Well, actually all food is detrimental (like breathing is killing us: thanks computer simulation god-programmer in the sky for killing us with the necessities of existence like the sun, the food, the breath...) so I should say there are bad carbs (SAD) and there are less bad carbs (WFPB).

 

Which do you eat, Saul?

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All:
 

 

I noted (if I understand correctly) that Luigi thought it possible that protein-reduced CRONnies who failed a GTT might simply not have enough protein, resulting in loss of pancreatic beta cells.

 
Yet again you haven't understood correctly, if by 'protein-reduced' you mean eating little dietary protein and not 'protein-reduced' in the sense of lacking lean muscle mass. Luigi blamed (and showed evidence) that high dietary protein put the kibosh on the IGF-1 lowering effects of CR in some of us CRed humans. As far as I know, Luigi has neither said nor found anything that relates dietary protein to impaired glucose tolerance. As discussed here, what Luigi did find relating to glucose was that CR folks with IGT were on average more severely CRed, and had lower muscle mass and poorer cardiovascular performance than the CR folks with normal glucose metabolism. So Dr. Wittin was right to doubt your (mis)understanding of Luigi's findings.

We-e-e-l, yes and no. Strictly, he didn't put the pieces together (either empirically or AFAIK as an integrated hypothesis). But he did, as you say, show that "high dietary protein put the kibosh on the IGF-1 lowering effects of CR in some of us CRed humans," and he did link CR-IGT to the endocrinological triad of low IGF-1, low T3, and low T. And low IGF-1 also seems a reasonable mediator (n addition to sheer energy availability) for low muscle mass in the group.

 

It's good to be precise in language, but in this case I think Saul largely has the gist. The only thing I would definitely not impute to Luigi is any speculation about beta-cells: that comes from me (above).

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Michael,

 

We-e-e-l, yes and no. Strictly, ...

 

Question-beggary and nitpickery at its finest.

 

How about helping Saul out with a little useful advice and insights? What would you do if you were in his position - which who knows, maybe you are, given your own issues with glucose self-testing...

 

--Dean

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All:
 

 

We-e-e-l, yes and no. Strictly, ...

 
Question-beggary and nitpickery at its finest.

But Dean, your original reply really wasn't a good summary, and could leave folks with a mistaken impression. The Protein-->CR Triad-->CR-IGT is from a practical POV a pretty important thing to understand, even if not yet definitively pinned down, and a reader of your response might get the impression that there's nothing at all to protein-->>CR-IGT.

 

If one is going to oversimplify, Saul's oversimplification is better than yours in this case ;) .

 

(By the way: on "begging the question:

 

7JaloAX.gif

 

(Wikipedia agrees).
 

How about helping Saul out with a little useful advice and insights? What would you do if you were in his position - which who knows, maybe you are, given your own issues with glucose self-testing...


I'd like to say I'd get the darned OGTT, tho' I sheepishly admit I've not done it myself yet ...

 

An important related thing: in an earlier post I'd suggested using Glycomark, which measures the sugar alcohol 1,5-anhydroglucitol (1,5-AG) and is apparently a pretty good marker of chronic postprandial glucose excursions (tho' this would get at one's day-to-day level of such excursions which might not represent  the underlying functional capacity of the organism as well as an OGTT if one is doing things to proactively manage such excursions). Unfortunately (tho' somewhat to my relief, after getting an alarming-looking result), it turns out that Glycomark has a few problems for many people like us: first, teh sugar in question is generally thought to be pretty widely distributed in plant foods, but is known to be esp. high in soybeans, so tofu-munchers might get false reassurance from the test which they might be especially inclined to believe if their critical thinking were impaired from all that soy. (And, actually, even if you don't eat soy, I wonder if (and I've yet to find any data on) whether it might also be high in other legumes).

 

Second, two trials have reported that weight loss on a Zonish diet artificially lowers Glycomark (1,2), which could give you a false positive for IGT.

 

References

1: Elin Chorell, Mats Ryberg, Christel Larsson, Susanne Sandberg, Caroline Mellberg, Bernt Lindahl, Henrik Antti, Tommy Olsson. Plasma metabolomic response to postmenopausal weight loss induced by different diets. Metabolomics (2016) 12: 85. doi:10.1007/s11306-016-1013-x

 

2: Khakimov B, Poulsen SK, Savorani F, Acar E, Gürdeniz G, Larsen TM, Astrup A, Dragsted LO, Engelsen SB. New Nordic Diet versus Average Danish Diet: A Randomized Controlled Trial Revealed Healthy Long-Term Effects of the New Nordic Diet by GC-MS Blood Plasma Metabolomics. J Proteome Res. 2016 Jun 3;15(6):1939-54. doi: 10.1021/acs.jproteome.6b00109. Epub 2016 May 20. PubMed PMID: 27146725.

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Michael,

But Dean, your original reply really wasn't a good summary, and could leave folks with a mistaken impression. The Protein-->CR Triad-->CR-IGT is from a practical POV a pretty important thing to understand, even if not yet definitively pinned down, and a reader of your response might get the impression that there's nothing at all to protein-->>CR-IGT.

Fair enough. There certainly could be the linkage you suggest. Just to be completely explicit, what you are suggesting is something like Low (RDA-ish) Mostly-Vegetal Dietary Protein → CR Triad → CR-IGT, right?

 

Even if demonstrated, it's far from clear that such a linkage has any relevance to salmon-munching Saul's case, although without more info on precisely what Saul is eating these days it's impossible to tell...

 

I'd like to say I'd get the darned OGTT, tho' I sheepishly admit I've not done it myself yet ...

Hey - we're on the same page on this too! Twice (or once and a half) in one day. Not bad. ☺

 

--Dean

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Well, I definitely will accept Dr. Wittlin's prescription, when he submits it, and have a standard GTT done by my medical providers (cost covered by my insurance).  What I HAVEN'T decided is whether or not to eat 300g of carbs for three days, or just take the   test, without the three days of 300g carbs -- in fact, I'll need clarification by Dr. Wittlin as to what "300mg carbs" means -- e.g., can just a CRNoMeter indication of "300 grams" be adequate?  (Even that would be forcing myself to eat things that I usually avoid).  Or, does it mean 300g of SIMPLE carbs, for three days in a row?  For example, can I "get away with" counting fiber as "carbs" -- e.g., 300g of soluble (and/or insoluble) fiber?

 

(BTW, in a more personal vein:  Luigi found my muscles to be small, but strong.  I ate much more protein then than I do now -- as now, my "carbs" came mostly from raw vegetables.  I, like Michael, passed the IGT that Luigi gave me.  (I don't recall being required to eat "300g carbs for three days" prior to the test.)

 

Now, when my dietary protein is much lower -- and similarly my IGF1 is lower -- I don't know what the result will be.

 

Diabetes ran in my family when I was a child -- both my older brother and father were insulin taking type 2 diabetics.  So I was given a GTT as a child -- again, I'm sure there was no "300g of carbs" component to the test.

 

My take:  As Dr. Wittlin explained, it's exactly to prevent such "false positives" people like us might get otherwise.  I'm guessing that the 3 days of 300g carbs might "train" the body to not be too surprised by the glucose bolus it will get" on IGT day.  So passing such a test is not the same as taking the IGT without three days of glucose ingestion.

 

Confusing:  Should I try to get away with 300g of fiber (e.g., cellulose); or should I show 300g of carbs in CronOMeter -- or should I skip doing this (which probably would be unethical)?

 

How do you compare these so-different IGT tests?

Edited by Saul

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Ask Dr. Wittlin what are the healthiest 300 grams of carbs he recommends. Then reevaluate his response by searching online.

 

"Dr. Wittlin's major clinical interest, apart from general endocrinology, is treatment of diabetes, especially new modalities of therapy with an emphasis on insulin pumps and continuous glucose monitoring...."

Edited by Sthira

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Saul,

 

I agree with you and Sthira - you need to clarify with Dr. Wittlin just what he means by '300g of carbs' for pre-loading. I suspect what he really wants to make sure is that you're not on a low-carb diet, and therefore not able to tolerate a large bolus of glucose due simply to a dormant pancreas and/or muscles used to running more on ketones than glucose, both of which will leave glucose circulating in your bloodstream for a long time during an OGTT. But one thing he sure doesn't mean is 300g of carbs as fiber -  eating 300g of fiber could really mess you up.

 

Here is where I patiently reiterate - none of us can help you Saul until/unless you tell us exactly the foods and macro-nutrient quantities you are eating these days. Track two days of your diet in friggin' CRON-O-Meter already... If you're eating close to 300g of carbs already (which would be a not-unreasonably diet consisting of 2000kcal / day with 60% carbs), even if they are "good" carbs, I'd say don't worry about any sort of pre-loading unless Dr. Wittlin tells you otherwise (i.e. he insists the carbs to be stuff like bagels and pasta). In fact it would be better if you don't, since as you suggest, preloading lots of carbs wouldn't reflect your normal metabolic state.

 

But whether or not you preload with good (or crappy) carbs, an OGTT is most likely still going to leave you wondering what to do. Here's why. Please read and think carefully about the following.

 

There is a 2x2 "payout" matrix associated with the OGTT you are planning to get. I'd draw the matrix as a 2D grid, but I'm not sure it would be worth the trouble. So I'll just enumerate the four combinations:

 

Scenario 1 - You don't pre-load carbs, and "pass" the OGTT

Scenario 2 - You don't pre-load carbs, and "fail" the OGTT

Scenario 3 - You do pre-load carbs, and "pass" the OGTT

Scenario 4 - You do pre-load carbs, and "fail" the OGTT

 

Note - if you're already eating (nearly) 300g of carbs, my advice is to consider pre-loading unnecessary and unwarranted, so the four scenarios collapse to just two - pass vs. fail the OGTT. In that case, the two (pass vs. fail) are equivalent in outcomes to scenarios 1 and 4 above, respectively.

 

Let's consider Scenario 1 first - you don't pre-load and you pass. That's a great outcome. Whether you are on a low-carb diet or not, your body is able to effectively and relatively rapidly clear a large bolus of pure glucose - which is presumably much more of a challenge than what you normally subject your body to day-to-day. So you're golden, and you get to gloat about your continued good metabolic health to the rest of us. Bully for you!

 

Now let's consider Scenario 2 - You don't pre-load and you fail. This one is completely ambiguous. Was your pancreas simply in a dormant mode, and so you'd have passed if you'd pre-loaded? Maybe. Was the large OGTT bolus of glucose just too big for your CR- and age-shrunken body (no offense) to handle? Maybe. Are you gumming up your arteries, organs and brain cells with advanced glycation end products every day eating your normal diet and spiking your post-meal glucose? Maybe. See, it tells you nothing that's useful. To see why this is the case. Consider what Dr. Wittlin is likely to say (assuming he just doesn't scold you for not pre-loading carbs). He's likely to say something like: 

 

"Saul. It looks like you've got a serious case of impaired glucose tolerance. Your fasting glucose is low, so you're not technically diabetic, so it wouldn't be right for me to prescribe insulin. But perhaps you should start taking Metformin or Glucophage." 

 

What would be your response? If you're rational and you trust Michael that it probably isn't wise for people who aren't diabetic to take Metformin, you'll be reluctant to pop the pills, not knowing if elevated postprandial glucose is a problem for you day-to-day. See?

 

Now let's consider Scenario 3 - You pre-load carbs and pass the OGTT. That's pretty good news. But you'll still be left wondering - did the carb pre-loading transiently help me to clear the glucose during the OGTT? Might my day-to-day diet still be spiking my post-meal glucose (as the single data point you shared suggests) and thereby be pickling my innards? Maybe...

 

Finally, let's consider Scenario 4 - You pre-load carbs and fail the OGTT. This one leaves you in almost exactly the same ambiguous boat as Scenario 2. Granted, you know (or think) that it probably wasn't a dormant pancreas, or keto-adapted muscles unaccustomed to burning much glucose, that made you fail. But that doesn't help your decision making. You're still left wondering if the big glucose load during the OGTT might simply have been too much for your system to handle and that maybe day-to-day you're alright, since you never eat much in the way of simple carbs anyway. Once again consider how you'd respond to Dr. Wittlin's suggestion in this scenario that you start popping metformin/glucophage pills for the rest of your life as a result of your failed OGTT...

 

If you've really thought through these scenarios carefully with me Saul, you'll realize why I've previously told you several times that post-meal glucose self-testing is really the best way to figure out what (if anything) you should do. Sure, you might get lucky in the OGTT and fall into scenario 1. But otherwise (and more likely IMO), you're left hanging in one of the ambiguous scenarios 2-4, and you'll end up wanting/needing to do your own post-meal glucose testing to figure out how to proceed anyway. Might as well bite the bullet right off the bat, and skip the middle man (OGTT).

 

Don't get me wrong - given the information you've shared with us, and your irrational refusal to do glucose self-testing, I still think an OGTT is your next best option, and might show you are in Scenario 1.  I sincerely hope you pass the OGTT with flying colors, and if you do I'll be the first to eat crow (but not literally ☺). And if you don't pass, that might be good outcome too - since it would presumably motivate you to track your diet more closely and engage in post-meal glucose testing, whether you decided to take the pills or not.

 

Given your age, your family history of diabetes, your shrunken lean muscle mass (again, no offense), your only modest and brief cold exposure practices (occasional cold showers), your apparently much lower dietary protein intake these days (despite your advancing age), your (incredibly irresponsible - IMO) decision to continue practicing CR without bothering to track nutrition to make sure you're meeting your dietary requirements despite apparently large 'dietary drift' over the years, the farm-raised salmon you've been eating ever since I've known you, and the troubling single post-meal glucose test you've told us about, I'd be quite surprised if you didn't exhibit impaired glucose tolerance either during a formal OGTT or during home glucose testing. 

 

As I said, I really hope I'm wrong, but from where I sit it seems you should just cut to the chase and test your postprandial glucose yourself. Since you're already willing to jab yourself with a much bigger needle  in order to inject your daily dose of Forteo, it clearly isn't squeamishness over needles or blood that's hold you back. So what is it? Doubts about the accuracy of glucometer readings is really quite overblown, as we've discussed elsewhere.

 

--Dean

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Hi ALL!

 

I should note that the last six tests of my HgA1C  are all between 5.1-5.4%.  According to Dr. Wittlin, this is outstanding, and implies that I don't need a GTT (but at my request, he will order a prescription for one).  When I receive Dr. Wittlin's prescription (or run into him in the gym :)xyz), I'll query him further about the "300g carbs" business.  However, when we spoke, he indicated that simply 300g carbs as shown by CronOMeter is exactly the sort of thing that he had in mind.

 

I should note that I'm one the ones who participated in CRONA.  My diet then was similar to now (although I ate 2 lbs celery in the morning; now I eat 2 pouds of Nappa cabbage in the morning -- same number of cals (15) according to CRON).  My typical calorie intake is about 1500 calories per day -- not 2000, which Dean seems to think is great.  In my group of 4 at CRONA, I had the lowest body fat in every single site -- including the ones where women usually have less fat.

 

My level of CR is fairly intense; my philosophy very different from Dean's (although I agree with him about most things -- also, my diet is no grain, very small amounts of fish, otherwise vegan).

 

;)xyz

 

  --  Saul

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Saul,

 

Those HBA1c numbers look good and match your low fasting glucose. Definitely a good sign, although HBA1c is not a very good metric for assessing glucose control in healthy folks.   I'm living proof that low HBA1c is no guarantee - my HBA1c was in the 4.x's when I failed Luigi's OGTT big-time. Having very little body fat and little in the way of muscle mass (even if strong), and eating only 1500 kcal/day is not much to brag about especially at your age, both for longevity in general, and glucose tolerance in particular. According to our data from WUSTL, those who are most severely CRed, with the least lean mass, has the most trouble with glucose metabolism.

 

My level of CR is fairly intense; my philosophy very different from Dean's (although I agree with him about most things -- also, my diet is no grain, very small amounts of fish, otherwise vegan).

 

Yes - our 'philosophies' differ quite a bit Saul.  At your age ( (late 70s?) I don't believe "fairly intense" CR is wise, especially without carefully tracking your nutrition, and with apparently very little protein, since you only eat a near-vegan diet with a "very small" amount of fish (whatever that means) and no grains.  Does this virtually vacuous statement about your diet mean you're not going to run your typical diet through CRON-O-Meter? Why does it seem like pulling teeth with you Saul? We're only trying to help...

 

One thing I'm glad to see (from your response to the CR Motivation survey) that you BMI isn't that low, at 20-22.5. 

 

--Dean

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Hi Dean!

BMI is a poor measurement of %body fat --.the shape of my body is such that my BMI is high. (BMI is useful when computed on a large cohort as a group -- but often misleading when dealing with individuals. A better metric is waist-to-hip ratio -- but, as you pointed out previously, that may be misleading as well.) .What.I think would be a useful.metric for a rough estimate of visceral fat is: waist divided.by.weight.

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