Genetic Predisposition

The fact that type 2 diabetes is a genetic disease was confirmed more than 2 decades ago by a famous study of identical twins in the U.K. that found essentially a 100% concordance rate (9). However, this kind of study provides no insight into the underlying genetic defect (s) either directly impairing the glucose homeostasis system or causing insulin resistance or another defect that exceeds the capacity of a normal glucose homeostasis system. With the advent of molecular biology, the basis is now known for many monogenic forms of diabetes, such as mitochondrial genome defects and their association with diabetes and deafness (10), Wolfram's syndrome (11), several syndromes of extreme insulin resistance (12), and most of the MODY syndromes (13). Still, these account for only a small proportion of diabetes cases.

In contrast, genetic insight into type 2 diabetes has been frustratingly slow. One identified gene is calpain 10, a member of a ubiquitously expressed family of cysteine proteases. In the mid 1990s, linkage analysis identified a locus on chromosome 2 that was calculated to account for about 30% of type 2 diabetes in Mexican-Americans (14). The specific gene was later shown to be calpain 10 (15). However, the role of calpain 10 in glucose homeostasis remains unclear, with a current focus on a regulatory role in insulin exocytosis (16).

A recent study of isolated islets from humans with type 2 diabetes reported a 90% reduced mRNA expression of aryl hydrocarbon receptor nuclear translocator (ARNT), a transcription factor previously unknown to the diabetes field (17). Mice were created with a B-cell specific knockout of the ARNT gene. These animals developed glucose intolerance and impaired glucose-induced insulin secretion, along with a B-cell mRNA expression profile that closely matches the human type 2 diabetes islets. Considerable interest was generated by these findings, and a role for ARNT in type 2 diabetes is under investigation.

Other chromosomal "hot spots" have been identified in various populations, and looking for the specific genes is now much faster because of the human genome project. Also, many research groups have focused on various gene polymorphisms. To date, all have lacked a strong association with type 2 diabetes after rigorous study. An example is Insulin Receptor Substrate-1 (IRS-1), the first downstream intermediate from the insulin receptor in the insulin action cascade. A common IRS-1 polymorphism was proposed to influence the kinetics of insulin secretion (18), but a large study failed to show a link with type 2 diabetes (19). Current polymorphisms of interest are the transcription factors TCF7L2 (20) and KLF11 (21), and the Kir6.2 subunit of the B-cell K+TP channel (22,23).

Finally the breakthrough occurred in 2007 with the advent of genome-wide association screens for common diseases including type 2 diabetes. Unlike prior genetic studies that often tested for genes that seemed plausible as causing a predisposition for type 2 diabetes (so-called candidate gene approach, but in reality guesses), this kind of study uses small nucleotide sequences that are spaced throughout the whole genome to search for patterns that track with a disease such as type 2 diabetes, and thus identify regions in which to look for a predisposition gene. And they have been amazingly successful. In less than a year, 6 genome-wide association studies that examined 7,200 cases of type 2 diabetes and 12,000 controls in several population groups have identified 11 predisposition genes (reviewed in 163). Plus the results are fascinating. Only one, PPARy, was ever proposed as a candidate gene, with most having no known physiologic role in glucose homeostasis. Still, its easy to envision how they might act as several of the factors likely influence beta-cell development, insulin secretion, or proinsulin biosynthesis. And thats the second interesting finding, in that most of the identified genes seem to be involved in beta-cell biology as opposed to the insulin signaling or glucose transport systems. Finally, the greatest impact of any of these genes is quite modest - a 20% to 30% increase in diabetes risk - so we still have lots to learn about how these different genes interact to produce the profound diabetes susceptibility in certain families and ethnic groups. And one guesses more susceptibility genes will be found. So we have finally entered the genetic era, and its likely to be a very exciting time that finally may answer some of the tough questions in type 2 diabetes.

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