Effective diabetes treatment gets a nutraceutical pitch!

Type 2 Diabetes is a lifestyle disorder of an epic proportion. It is widely speculated that US, India and China are or are going to be the worst affected by this problem.

Current therapies focus on various strategies to control blood sugar but there is no cure at this stage. The older sulponylureas and metformins to the newer TZDs (thiazolidinediones), GLP-1 analogues and even SGLT2 inhibitors are vying to capture the diabetes market. The whole exercise is to promote medication that can control the HbA1c to controllable levels. 

Dietary extracts containing polyphenols, L-arginine etc. have been shown to have anti-diabetic potential. In a recent publication in the journal Endocrinology(Endocrinology August 19, 2013 en.2013-1529), it has been shown that dietery L-arginine can regulate glucose metabolism indirectly by inducing GLP-1 release in mice. Although the exact mechanism has not been dissected in the paper yet the authors suggest that G protein coupled receptor pathways might be involved. 

Since current strategies involve targeting the GLP-1 system by either inhibiting its rapid clearance by dipeptidyl-peptidase IV or using dipeptidyl-peptidase IV-resistant GLP-1 mimetics, it would be interesting to see development of novel approaches like dietary supplement with L-arginine and or L-arginine based therapies to enhance GLP-1 secretion from intestinal L cells. In essence, this study raises the possibility that nutritional-based strategies aiming to improve endogenous GLP-1 release may provide an alternative therapeutic approach to treat patients with metabolic disorder

Bug Therapy to treat Diabetes and obesity in future?

The long held notion of ‘junk DNA’ has been found to be incorrect (ENCODE project), similarly, characterizing the gut microbiota as bystanders in the intestinal tract is now being widely challenged (Osborn O, Olefsky JM (2012), Nature Med 18(3):363-374).

A recent paper in Proceedings of National Academy of Sciences (PNAS) adds muscle to the fact that a single species of bacteria (Akkermansia muciniphila) can modulate diet induced obesity in mice. A. muciniphila is a Gram-negative bacteria that constitutes 3–5% of the gut microbial community. The paper also highlights the various mechanisms by which this bacterium might exert its effect (Everard A et al. (2013), PNAS)

The study shows dramatic decrease in gut A.muciniphila in diet induced obese mice. On restoring the abundance of this strain in obese and diabetic mice it was found that viable A. muciniphila controls gut barrier function, fat mass storage, and glucose homeostasis via several mechanisms. This study identified an association of obesity with a decrease in mucus thickness that is characteristic of obesity and associated disorders. Interestingly, the authors found that A. muciniphila restored this mucus layer. Strikingly, viable A. muciniphila induces these effects, whereas heat-killed A. muciniphila did not protect the mice from diet-induced obesity and associated disorders. One of the other key findings was that treatment with this bacteria led to increase in acylglycerol levels more specifically 2-OG and 2-AG. Incidentally, 2-OG is known to stimulate intestinal L cells which lead to secretion of GLP-1 (Hansen KB, et al. (2011), J Clin Endocrinol Metab 96(9):E1409–E1417). GLP-1 is known to increase insulin secretion. Also, A. muciniphila treatment completely reversed diet-induced fasting hyperglycemia via a mechanism that was associated with a 40% reduction in hepatic glucose-6-phosphatase expression thereby suggesting a reduction in gluconeogenesis. Hence this association might point to how A. muciniphila exerts its effects on glucose homeostasis. 

Many bacteria (Lactobacilus spp, Bifidobacterium spp etc.) have been shown to have effect on fat mass development during diet induced obesity (Fåk F, Bäckhed F (2012), PLoS ONE 7(10):e46837). However, in this study the emphasis was to study the bacterial strain that is affected during obesity and type 2 diabetes in humans and rodents. It would be interesting to see how this development would enthuse the world of gut microbiome research and interest the pharmaceutical/biotech companies to invest in this field which would then pave the way for not only treatment but prevention of inflammatory, lifestyle and even mental diseases in the near future.

Inflammasome – Gut microflora link to Metabolic syndrome; A case for metagenomics

Metabolic syndrome so far is attributed to the deregulation of the metabolic processes leading to increase triglycerides, fat, insulin resistance etc. and thereby leading to diabetes mellitus, coronary heart disease and hypertension. Inflammation is also one of the key factors that can cause an onset of metabolic syndrome.

Recently, a new article in Cell Research (a Nature publication) puts a new perspective on the role of gut micro biota as a causative effect in the process of inflammatory response in the liver (http://www.nature.com/cr/journal/vaop/ncurrent/full/cr201255a.html)

The article highlights certain interesting points and hypothesizes that defective inflammasome signaling in the gastro-intestinal tract allows colitogenic microbes to prosper in the colon, and subsequently trigger harmful inflammatory signaling pathways in systemic organs when the gastro-intestinal barrier is breached. The fact that defective inflammasome signalling can skew the gut micro biota towards colitogenic species of the Prevotellaceae family and the candidate phylum TM7 is not only interesting but opens a new dimension on the role of intestinal “niche” environment in regulating the microbiota species and thereby controlling different aspects of well being of humans (though the research highlighted above is in mice).

Role of gut microbes in maintaining robust immune system or even mental health have been reported earlier. In this era of genomics, it is therefore imperative that we use metagenomics to study gut microflora to understand the intestinal “niche” microenvironment. This would help in designing better targeted antibiotics for therapeutical intervention and thereby possible prevention of many of today’s lifestyle diseases!

Diabetes cure - a fresh approach is the need of the hour

We are in the 21^st century. A new millennium and a hope that new discoveries, innovations would help us thwart diseases like cancer, diabetes, schizophrenia etc. Actually, if we leave the mental illness aside for a minute as the science studying mind/brain is pretty nascent; then one would ponder why we are still years if not decades away from finding a credible cure for diseases like cancer, diabetes and HIV! Right now we only treat diseases like diabetes not cure them………………….

Let’s talk about diabetes, type 2 to be precise for a moment. The best medicine for decades to treat (not cure, mind it!) has been metformin. This humble drug has shown tremendous resilience in terms of safety and efficacy and is and probably would be the first line of therapy for years to come!

 The current or upcoming therapies for diabetes mostly revolve around two aspects – a) increasing insulin secretion (sulphonylureas take the cake here) or b) increasing insulin sensitivity (PPARs/metformin etc). Even the new ones like the GLP-1s or DPP-IV inhibitors ultimately increase insulin secretion though independent of glucose concentration (better than sulphonylureas!). But to me these are just like “cosmetic” drugs treating the symptom not the cause and I feel that we have still not properly understood this disease. In this context, I would like to share a new discovery that can change the perception of how we look at type 2 diabetes.  New research has suggested that the development of insulin resistance and type 2 diabetes may be linked to an immune system reaction gone awry. Till now, we have been looking at type 2 diabetes as a metabolic disease and immune system malaise is mostly associated with the other cousin of diabetes , the type 1 diabetes. Now, if the above said observation is indeed found to be credible in subsequent research then it would mean a tremendous paradigm shift in type 2 diabetes research. I guess, this kind of observation/research is the step in the right direction to understand the cause of the disease.

Probably, joining the pieces of the diabetes puzzle through innovative and fresh thinking is the right approach to finding a “cure” for this scourge rather than trying to better the current therapies to “treat” the disease.