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Antibiotic Use Linked to Higher Diabetes Risk


Note: I'm starting a new generic thread about diabetes prevention with a rather narrowly focused post about diabetes and antibiotics, because I thought the study was interesting and suggested a link I hadn't heard about before. Over time I hope we'll build up posts on this thread dealing with other means of avoiding this important cause of morbidity and mortality.


With that background, I thought this recent observational study [1] of a possible link between antibiotic use and subsequent development of type 2 diabetes was quite interesting and potentially relevant for CR Practitioners.


It found quite a clear and dramatic dose-response relationship between the number of antibiotic prescriptions a person fills, and their subsequent risk of developing type 2 diabetes, among 5.6 million Danish people tracked for 12 years. Here is the kicker graph from the full text of the paper:




As you can see from the graph, 2-4 courses of an antibiotic raised one's risk of developing diabetes by about 20%, and 5-8 courses raised it by about 40%.


The authors suggest (warn) that there are two possible ways to interpret this association:


There are two competing interpretations of our findings: 1) patients with type 2 diabetes are more prone to develop infections many years before they become diagnosed with type 2 diabetes and therefore have increased demand for antibiotics and 2) antibiotics increase the risk of type 2 diabetes.


They suggest it may be a combination of both, but that there is definitely evidence that messing up one's gut microbiome via antibiotics can lead to weight gain, glucose intolerance, etc. So a causal link that goes as follows: antibiotics -> gut dysbiosis -> metabolic syndrome -> Type 2 diabetes seems quite plausible.


I'm personally thankful that I haven't needed antibiotics in many, many years, and would be reluctant to take them  now unless there was a significant danger of serious health consequences from not doing so.





[1] J Clin Endocrinol Metab. 2015 Oct;100(10):3633-40. doi: 10.1210/jc.2015-2696.

Epub 2015 Aug 27.

Use of Antibiotics and Risk of Type 2 Diabetes: A Population-Based Case-Control

Mikkelsen KH(1), Knop FK(1), Frost M(1), Hallas J(1), Pottegård A(1).

CONTEXT AND OBJECTIVE: Evidence that bacteria in the human gut may influence
nutrient metabolism is accumulating. We investigated whether use of antibiotics
influences the risk of developing type 2 diabetes and whether the effect can be
attributed to specific types of antibiotics.
METHODS: We conducted a population-based case-control study of incident type 2
diabetes cases in Denmark (population 5.6 million) between January 1, 2000, and
December 31, 2012. Data from the Danish National Registry of Patients, the Danish
National Prescription Registry, and the Danish Person Registry were combined.
RESULTS: The odds ratio (OR) associating type 2 diabetes with exposure to
antibiotics of any type was 1.53 (95% confidence interval 1.50-1.55) with
redemption of more than or equal to 5 versus 0-1 prescriptions. Although no
individual group of antibiotics was specifically associated with type 2 diabetes
risk, slightly higher ORs for type 2 diabetes were seen with narrow-spectrum and
bactericidal antibiotics (OR 1.55 and 1.48) compared to broad-spectrum and
bacteriostatic types of antibiotics (OR 1.31 and 1.39), respectively. A clear
dose-response effect was seen with increasing cumulative load of antibiotics. The
increased use of antibiotics in patients with type 2 diabetes was found up to 15
years before diagnosis of type 2 diabetes as well as after the diagnosis.
CONCLUSIONS: Our results could support the possibility that antibiotics exposure
increases type 2 diabetes risk. However, the findings may also represent an
increased demand for antibiotics from increased risk of infections in patients
with yet-undiagnosed diabetes.

PMCID: PMC4596043
PMID: 26312581

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Metaformin's Benefits for Treating Diabetes Mediated by Gut Bacteria?


Earlier I reported what I considered to be Useful Insights into Gut Bacteria and Health, suggesting that bacteria that produce the short-chain fatty acid butyrate may be beneficial for keeping systemic inflammation at bay.


This new study [1], shared by Al Pater on the CR mailing list (thanks Al!) jibes nicely with this hypothesis, and connects it with the drug metaformin and diabetes, the disease that metaformin was developed to treat. So it makes it relevant for this thread in general (diabetes prevention) and the first post in this thread about the connection between disturbances in the gut microbiome (via antibiotics) and diabetes.


In [1], the researchers analyzed previous studies of the benefits of metformin on diabetes progression, looking at microbiome analysis of diabetics both with and without metaformin treatment. They found that in general diabetics have depleted levels of fiber-loving, butyrate-producing bacteria in their gut, which is consistent with my previous post that the butyrate bacteria are health promoting. They found that treatment with metaformin reverses this dearth of butyrate bacteria, and may explain at least in part why & how metaformin is beneficial for the treatment of diabetes.


If this is true, then eating a high fiber diet, like many of us do, may provide some of the same benefits as metaformin by promoting the health and wellness of butyrate-producing bacteria in our gut. This is particularly interesting not just for avoiding diabetes, but also because metaformin is also one of the few drugs that are thought to be potential longevity promoting (as a CR mimetic), as the recent news about a USDA-approved anti-aging human trial of metaformin attests.


So feed your gut bacteria the fiber it wants and perhaps you'll avoid diabetes and live longer to boot!





[1] Nature. 2015 Dec 2. doi: 10.1038/nature15766. [Epub ahead of print]

Disentangling type 2 diabetes and metformin treatment signatures in the human gut

Forslund K(1), Hildebrand F(1,)(2,)(3), Nielsen T(4), Falony G(2,)(5), Le
Chatelier E(6,)(7), Sunagawa S(1), Prifti E(6,)(7,)(8), Vieira-Silva S(2,)(5),
Gudmundsdottir V(9), Krogh Pedersen H(9), Arumugam M(4), Kristiansen K(10),
Yvonne Voigt A(1,)(11,)(12), Vestergaard H(4), Hercog R(1), Igor Costea P(1),
Roat Kultima J(1), Li J(13), Jørgensen T(14,)(15,)(16), Levenez F(6,)(7), Dore
J(6,)(7); MetaHIT consortium, Bjørn Nielsen H(9), Brunak S(9,)(17), Raes
J(2,)(3,)(5), Hansen T(4,)(18), Wang J(10,)(13,)(19,)(20,)(21), Dusko Ehrlich
S(6,)(7,)(22), Bork P(1,)(12,)(23,)(24), Pedersen O(4).

In recent years, several associations between common chronic human disorders and
altered gut microbiome composition and function have been reported. In most of
these reports, treatment regimens were not controlled for and conclusions could
thus be confounded by the effects of various drugs on the microbiota, which may
obscure microbial causes, protective factors or diagnostically relevant signals.
Our study addresses disease and drug signatures in the human gut microbiome of
type 2 diabetes mellitus (T2D). Two previous quantitative gut metagenomics
studies of T2D patients that were unstratified for treatment yielded divergent
conclusions regarding its associated gut microbial dysbiosis. Here we show, using
784 available human gut metagenomes, how antidiabetic medication confounds these
results, and analyse in detail the effects of the most widely used antidiabetic
drug metformin. We provide support for microbial mediation of the therapeutic
effects of metformin through short-chain fatty acid production, as well as for
potential microbiota-mediated mechanisms behind known intestinal adverse effects
in the form of a relative increase in abundance of Escherichia species.
Controlling for metformin treatment, we report a unified signature of gut
microbiome shifts in T2D with a depletion of butyrate-producing taxa. These in
turn cause functional microbiome shifts, in part alleviated by metformin-induced
changes. Overall, the present study emphasizes the need to disentangle gut
microbiota signatures of specific human diseases from those of medication.

PMID: 26633628

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Plant Protein Better than Animal Protein for Glycemic Control


This new meta-analysis [1] of randomized control trials comparing animal vs. plant protein for glycemic control in diabetics found (not surprisingly perhaps) that plant protein is much better than animal protein.


On average, replacing 35% of animal protein with plant protein resulted in a 15% improvement in HbA1c, the standard measure of medium term glycemic control. Similar improvements were seen for fasting glucose and fasting insulin levels. 


From the free full text, here is the forest plot for the HbA1c data across the multiple studies included in the meta-analysis, to give a feel for the variation and magnitude of the effect:




So at least for the control of type 2 diabetes, and likely glycemic control more generally, it looks like a diet of predominantly plant protein is the way to go.





[1] Nutrients. 2015 Dec 1;7(12):9804-24. doi: 10.3390/nu7125509.

Effect of Replacing Animal Protein with Plant Protein on Glycemic Control in
Diabetes: A Systematic Review and Meta-Analysis of Randomized Controlled Trials.

Viguiliouk E(1,)(2), Stewart SE(3,)(4), Jayalath VH(5,)(6,)(7), Ng AP(8),
Mirrahimi A(9,)(10), de Souza RJ(11,)(12,)(13), Hanley AJ(14,)(15,)(16,)(17),
Bazinet RP(18), Blanco Mejia S(19,)(20), Leiter LA(21,)(22,)(23,)(24,)(25), Josse
RG(26,)(27,)(28,)(29,)(30), Kendall CW(31,)(32,)(33), Jenkins
DJ(34,)(35,)(36,)(37,)(38), Sievenpiper JL(39,)(40,)(41,)(42).


Free full text: http://www.mdpi.com/2072-6643/7/12/5509/htm

Previous research on the effect of replacing sources of animal protein with plant
protein on glycemic control has been inconsistent. We therefore conducted a
systematic review and meta-analysis of randomized controlled trials (RCTs) to
assess the effect of this replacement on glycemic control in individuals with
diabetes. We searched MEDLINE, EMBASE, and Cochrane databases through 26 August
2015. We included RCTs ≥ 3-weeks comparing the effect of replacing animal with
plant protein on HbA1c, fasting glucose (FG), and fasting insulin (FI). Two
independent reviewers extracted relevant data, assessed study quality and risk of
bias. Data were pooled by the generic inverse variance method and expressed as
mean differences (MD) with 95% confidence intervals (CIs). Heterogeneity was
assessed (Cochran Q-statistic) and quantified (I²-statistic). Thirteen RCTs (n =
280) met the eligibility criteria. Diets emphasizing a replacement of animal with
plant protein at a median level of ~35% of total protein per day significantly
lowered HbA1c (MD = -0.15%; 95%-CI: -0.26, -0.05%), FG (MD = -0.53 mmol/L;
95%-CI: -0.92, -0.13 mmol/L) and FI (MD = -10.09 pmol/L; 95%-CI: -17.31, -2.86
pmol/L) compared with control arms. Overall, the results indicate that replacing
sources of animal with plant protein leads to modest improvements in glycemic
control in individuals with diabetes. Owing to uncertainties in our analyses
there is a need for larger, longer, higher quality trials.TRIAL REGISTRATION:
ClinicalTrials.gov registration number: NCT02037321.

PMID: 26633472 [PubMed - in process]

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