Ethnic Differences in Insulin Granule Exocytosis

Abstract

Type 2 diabetes (T2D) is diagnosed based on high fasting plasma glucose (FPG) or high glucose at the two-hour time point of an oral glucose tolerance test (OGTT). However, clinical data show that this may not be appropriate for all ethnic groups. For example, Koreans often have high glucose one hour into the OGTT but normal FPG and two-hour glucose. We have developed a comprehensive model of the pathogenesis of T2D, based on the model of Topp et al (J. Theor Biol. 2000), modified to include a subsystem for exocytosis, and have applied it to simulate OGTTs. The model suggests that the Korean OGTT pattern results a defect in early (first-phase) insulin secretion and a delay in late (second phase) secretion. This may contribute to the high prevalence of T2D in Korea and points to the danger of under-diagnosis using the standard criteria. In contrast, African Americans typically exhibit strong first-phase insulin secretion relative to Whites and second phase insulin secretion similar to that of Whites. This group therefore also has normal FPG and two-hour glucose during OGTT, which again can result in under-diagnosis of their high risk for T2D. The simulations for this case suggest that the strong first phase results from a large readily releasable pool of insulin granules but that the diabetes risk results from trafficking of reserve vesicles to the plasma membrane that is more susceptible to deterioration under the stress of insulin resistance. We conclude that a detailed analysis of insulin secretion dynamics is necessary to properly interpret OGTT results for ethnically diverse populations.