Type 2 Diabetes: Hypoinsulinism, Hyperinsulinism, or Both?

T ype 2 diabetes is a very common metabolic disease and its incidence is increasing rapidly worldwide [1]. Despite fi ve to six decades of extensive investigation, the basic physiologic defect responsible for type 2 diabetes mellitus (T2DM) is still not known. It is now well accepted that T2DM develops when the beta-cell is unable to supply the amount of insulin needed to maintain normal glucose levels [2]. But is the primary problem in the beta-cell itself? Or is the problem resistance to insulin action, which puts an abnormally high load on the beta-cell, causing it to eventually fail? Epidemiologic studies have shown that genetic variation plays a very important part in determining the risk of developing diabetes. Currently available data suggest that for the vast majority of patients with T2DM, the genetic risk is determined by a variable combination of an unknown number of common genetic variants. Any of these variants alone is neither suffi cient nor necessary for diabetes to occur. Genetic analysis of T2DM has yielded only a few such genetic variants that are consistently associated with risk of disease. The study of monogenic disorders of glucose metabolism may shed light on potential mechanisms for the common form of T2DM. To date, mutations in more than ten genes have been associated with different forms of monogenic diabetes. Maturity-onset diabetes of the young (MODY), an autosomal dominant disease with onset of diabetes typically before the age of 25 years, can be caused by mutations in more than six genes [3]. Neonatal diabetes, either transient or permanent, can be caused by mutations in at least four different genes as well as an imprinting disorder on chromosome 6, the precise genetic mechanism of which has yet to be defi ned [4]. Common polymorphisms in some of these genes have been associated with increased risk of developing the more common form of polygenic T2DM. Most of the diabetes-related genes thus far identifi ed are expressed in beta-cells and the diabetes-associated mutations are thought to result in decreased beta-cell function and inadequate insulin secretion. In an article published in PLoS Medicine, Pearson et al. report the birth weight of patients carrying a mutation in either of two closely related genes associated with the MODY syndrome, HNF4A and HNF1A, testing the hypothesis that the primary defect caused by these genes results in decreased insulin secretion [5]. Birth weight is largely determined by fetal …