Probiotics Have Adjunctive Role in Diabetes Care

BifidobacteriumNearly a decade ago, microbiome researchers began publishing reports suggesting that bacteria in the intestines play a role in glucose metabolism.  Recent studies support that thesis, and provide a basis for use of probiotics as adjunctive treatments for people with type 2 diabetes.

The notion that microflora can affect insulin sensitivity has its roots in a landmark study by Nadja Larsen and colleagues at the University of Copenhagen. The Danish team showed that people with T2D have striking compositional changes in their intestinal flora compared to non-diabetic subjects.

Moreover, they found that the ratio of Bacteroidetes (“bad” bacteria) to Firmicutes (“good” bacteria) significantly correlated with reduced glucose tolerance (Larsen N, et al. PLoS One. 2010 Feb 5;5(2):e9085).

Since then, many groups have explored the use of probiotic supplements to alter the microbial ecosystem to improve insulin sensitivity and glucose metabolism. A number of these studies are turning up positive findings.

Small, Meaningful Changes

In a study published in late 2016, 46 patients with type 2 diabetes who were already on insulin therapy were randomly assigned to receive low-dose or high-dose Lactobacillus reuteri DSM 17938 supplements, or a placebo for 12 weeks.  The low-dose probiotic regimen provided 108 colony-forming units (CFU) per day; the high-dose preparation contained 1010 CFU. The patients took the probiotics in addition to standard insulin treatments.

At the end of the study, those on the highest dose of L.reuteri had increases in insulin sensitivity index (ISI) scores, as well as higher serum levels of deoxycholic acid (DCA)—a secondary bile acid--compared with baseline measures. No such changes were seen in the patients on the placebo or the low-dose probiotic.

Though there was a measurable improvement in insulin sensitivity, the investigators did not observe any significant change in glycated hemoglobin (HbA1c) measurements. The author acknowledged a small size of cohort as a limitation to the study (Mobini, R. et al. Diabetes Obes Metab. 2016. doi:10.1111/dom.12861).

In a similar double-blind, randomized trial design, Danish researchers looked at the effects of Lactobacillus acidophilus NCFM on insulin sensitivity and inflammatory responses in a mixed cohort of human subjects that included healthy individuals as well as those with impaired insulin sensitivity, and those with T2D.

The 45 subjects were randomized to a 4-week course of either L. acidophilus NCFM or a placebo.

The probiotic supplementation did not increase insulin sensitivity during the treatment period, though the treatment group showing preserved insulin sensitivity, while the placebo-treated group showed a decline.

When the investigators evaluated the patients with and without T2D, they found the same trend: those taking the probiotic had better insulin sensitivity compared to those on placebo, regardless of whether or not they’d been diagnosed with diabetes (Andreasen AS, et al. Br J Nutrition. 2010; 104(1831-1838).

Given the well-documented connections between chronic systemic inflammation and T2D, some researchers have proposed that the gut flora modulates insulin sensitivity via inflammation-mediated mechanisms.

Andreasen and colleagues actually measured inflammatory markers in their cohort and found no differences in inflammatory responses between the people on probiotics versus those on placebo. This does not rule out the possibility that inflammatory factors play a role—as has been shown in other studies. The data suggest that there may be inflammation-independent mechanisms in play as well.

Lowering Oxidative Stress

Several years ago, Iranian researchers showed that probiotic supplementation could reduce oxidative stress as well as other cardiovascular risk factors—a finding that implies potential benefit for diabetic patients.

In a single-blind trial, 40 adult patients with type 2 diabetes and baseline fasting blood glucose measures of >126mg/dl received 1,500 mg of a multi-strain lactobacillus probiotic (L. acidophilus, L. bulgaricus, L. bifidum, and L. Casei), or placebo twice daily for six weeks.

By the end of the trial period, there were no major reductions in fasting blood sugar or fasting plasma insulin levels in the patients taking probiotics. However, their lipid profiles and markers of oxidative stress and inflammation were different from those of their placebo-treated peers.

The probiotic-treated group showed a decrease in mean triglyceride levels, from 182 mg/dl to 173 mg/dl, while those in the placebo group showed a net increase from 179 to 191 mg/dl. They also showed measurable decreases in malonaldehyde (a marker of oxidative stress), and interleukin-6 (Mazloom Z, Yousefinejad A, Dabaghmanaesh MH. Iran J Med Sci. 2013; 38(1): 38-43).

While there are a number of positive studies showing potential benefits from probiotic supplementation in people with T2D, there have also been negative or inconclusive trials.

In an effort to provide better evidence-based guidance on the effect of probiotics on glycemic control, researchers in China published a systematic review and metanalysis in 2015, looking at the effect of probiotic in attenuating T2D.

They drew on all studies related to probiotics and diabetes published in Pubmed, The Cochrane Library, EMBASE, and the Clinicaltrial.gov databases until October 2014. Specifically, they were looking to aggregate and analyze the data about the impact of probiotics on fasting glucose, fasting insulin, and scores on homeostasis model assessment of insulin resistance (HOMA-IR).  

Seventeen parallel RCTs with similar baseline characteristics involving 1,105 participants were included in their analysis. In some studies the subjects were taking conventional anti-diabetes drugs, in others they were not. These trials tested a wide range of probiotic strains, including L. acidophilus, L. rhamnosus, L. bulgaricus, L. reuteri, L. plantarum, Bifidobacterium longum, B. animalis, B. infantis, and others.

Here’s what the metanalysis showed:

Fasting blood glucose (FBG):Based on the meta-analysis of the 17 trials, probiotic supplementation produced a significant reduction of FBG of 0.31 Mmol/L (95% CL: 0.56, 0.06; p = 0.02) compared with control treatments.  Beneficial effects in reducing FBG tend to occur after 8 weeks of supplementation, and occurred with all probiotic formulations used in these trials (Ruan, et al. Plos One 2015; 10(7):1-15).

Fasting Plasma Insulin:Overall, probiotics produced significant reductions in the range of -0.36 to -3.8 uU/ml in fasting plasma insulin. Multispecies probiotics and capsule formulations (compared to drinks or yogurts) resulted in the most significant insulin reduction.

HOMA-IR Scores: The studies also showed a significant reduction of HOMA-IR after consuming probiotics, with a mean difference of -0.41 to -1.60. The pooled mean difference in studies showing HOMA reductions was -0.48 (95 % CL -0.83, -0.31; p = 0.007).

The reviewers described the net impact as, “a modest effect of probiotics on glycemic control; however, even small glucose reductions may provide health benefits.”

Although the mechanism of action by which probiotics improve insulin sensitivity is not yet clear, the evidence does suggest they have a potential role in helping to mitigate the detrimental impact of insulin resistance and elevated glucose.

END

Lucy Karanja, PharmD, is a Clinical Intern at Maryland University of Integrative Health (MUIH). She received her post-masters degree in Nutrition in June 2016 from the same institution. She received her doctorate of Pharmacy from the University of Maryland, Baltimore. She is a clinical pharmacist licensed in Maryland and Pennsylvania.  Her goal is to practice integrative patient care by merging her training and experience in conventional medicine with holistic care approach through food, herbs and supplements.