Things changed in 2007 with the advent of genome wide association scans (GWAS)–using the human genome map to probe patient and control populations with many hundreds of thousands of small nucleotide sequences (SNIPS) that span complete genomes to find polymorphism patterns that track with the disease. Then work backwards and see if that gene, or another one close by, accounts for the diabetes predisposition. Within the short time frame from then until now, many GWAS studies from multiple ethnic populations have been published. And the winner is…not what we expected! Many more predisposition genes have been found than ever anticipated, and new ones appear on a regular basis. In a review of the pathogenesis of type 2 diabetes that I finished about a month ago, I stated there were 24 identified mutations and counting; last week I was at a scientific meeting with experts in the field who said more than 40 and counting. Also all of these genes are associated with modest, almost trivial, diabetes risk.

 

So as yet we have no gene or genes, that excite in terms of clear potential to reshape future screening or therapy. Moreover, geneticists are warning that the results to date are based on early generation technology that is evolving rapidly–moving towards probing not just nucleotide sequences but epigenetic regulators of gene expression or function–so there are presumably many more genes and dysfunctional regulatory systems to be found. I can envision that a subfield in genetics will spring up specifically to exclude identified polymorphisms based on carefully defined relevance and biological criteria. There are many recent reviews on the genetics of type 2 diabetes. One of the best for general audiences is by Mark McCarthy in the New England Journal of Medicine.[1]

 

 

So what have we learned? Or more correctly, what have I learned from the results to date?

 

The report card – have the genetic loci identified to date for type 2 diabetes:

Clarified the cellular pathogenesis.   No.

Identified new screening or treatment targets.   Not definitively.

Revolutionized our thinking.   Somewhat.

Promised a different future.   Not sure, maybe.

Means that we have to keep waiting, maybe for a long time.   Absolutely.

 

Most interesting to me is virtually all of the identified loci seem to impact the islet ß-cell at some level–development, proliferation, survival, or insulin secretory function. Stated another way, almost none track with obesity or other parameters of tissue insulin action. Initially I viewed that as ultimate proof of the dominance of ß-cell dysfunction over insulin resistance in this disease. However, the insulin resistance-oriented thinkers have regrouped and pointed out, correctly I believe, that the deck is stacked. The control groups in these studies are ordinary folks with commonly found obesity and related metabolic issues that are matched to the type 2 diabetes population except for lack of type 2 diabetes or a family history. So variances in metabolic genes aren’t really tested for, ergo haven’t been found. They argue, with validity I believe, that a modest genetic predisposition for obesity and metabolic illness combined with others for defective ß-cells will instill a more powerful risk for diabetes than the ß-cell defects alone. Presumably that’s where our thinking will end up.    

 

The focus on the ß-cell location of the predisposition genes has morphed for me and many others to ask what do the identified genes do? What do they teach us about mechanisms of ß-cell failure and dysfunction? Unfortunately, that has proven to be more complex, and slowly answered, than originally thought. GWAS studies take an agnostic approach to finding diabetes predisposition genes by probing for nucleotide sequences within the genome that track with type 2 diabetes. Nothing in that technology requires knowing what the related gene does, where it is expressed, what it regulates or is regulated by, or the ability to pick only genes we’re interested in. And that’s the rub, since many of the identified polymorphisms/loci are without known functions for control of blood glucose. So, effectively, we are having to go back and rediscover the biology of the glucose homeostasis system. Slow and painful, but absolutely necessary if we want to truly understand normal biology and how it is altered to cause type 2 diabetes. A good example is transcription factor 7-like 2 (TCF7L2) that is the gene with the strongest type 2 diabetes risk. When first identified, it was unknown to diabetes researchers, but since then has been found to be an important regulator of the canonical Wnt signaling pathway of ß-cell development and function,[2] incretin-related insulin secretion by modulating ß-cell GIP and GLP-1 receptor expression,[3] and insulin granule fusion.[4] Another is the SLC30A8 marker of the islet zinc transporter ZnT8. Zinc was known to be part of the insulin crystal complex in ß-cell granules, but zinc transport or cellular content had never been considered an important aspect of ß-cell biology. That’s changed. Specific details are under investigation, with an early issue whether this might be a new pharmaceutical target.

 

 

One part of this that has become apparent, and I think is really interesting, is many of the discovered genes seem to act on some aspect of the incretin regulatory system. An excellent review on that topic is by Müssig et al. in a recent Diabetologia.[5] Also high-profile recent papers found the GIP receptor is a diabetes predisposition gene,[6] and the already mentioned discovery of TCF7L2 regulation of GIP and GLP-1 receptor expression.[7] Potentially this will end up being one of the keys that unlocks the true pathogenesis of type 2 diabetes. Also, I’ve met generalists and occasional diabetes specialists who are highly skeptical about diabetes researchers’ interest in (some would say obsession with) probing the wide-ranging details of incretin physiology, believing it’s pharma driven to bolster interest in incretin-based therapy. We’ll see. Based on the evolving gene-based findings, I’m a believer that defects within the incretin system will prove to be an (maybe the) important mode of risk for type 2 diabetes.

 

I recently wrote this sentence in a review on type 2 diabetes pathogenesis: “So it’s anyone’s guess where genetics will take us, how many susceptibility genes will be found, whether the number and diversity of identified genes will confuse rather than clarify the disease pathogenesis, and if the hope for new gene-defined drug targets revolutionizing therapy will be realized.” I stand by it.

 

References:

---