Mary, Mary, Quite Contrary, How Do Your β-Cells Fail?

The dogma regarding the pathogenesis of type 2 diabetes has evolved over the last decade to view the islet -cell as the final determinant of whether glucose tolerance is normal or abnormal (1). While obesity and insulin resistance have reached epidemic proportions around the world, the presence of an appropriate compensation of insulin secretion (“healthy -cells”) allows daylong glycemia to be indistinguishable from metabolically normal individuals (2). In turn, pre-diabetes and type 2 diabetes result from progressive -cell dysfunction (3). As such, an army of researchers worldwide is searching for the pathogenic basis of this -cell dysfunction, along with strategies of when, and how, to intervene. What has resulted is a reasonably good mapping of the natural history of the -cell dysfunction, plus a lengthy list of potential mechanisms. Most are based on animal studies; therefore, homing in on the operative mechanisms in humans remains a challenge. Still, there is high confidence within the -cell research arena that we are on the right track to identifying the molecular details of -cell compensation and failure. Figure 1 shows the proposed stages of -cell dysfunction. It begins early, perhaps at birth, with -cells that are programmed to be at risk to fail (“susceptible -cells”). Indeed, the recent genome-wide scans have identified many susceptibility genes for type 2 diabetes that likely impact the development and ongoing homeostasis of the mass of -cells, as well as insulin secretion and synthesis (4). Although direct evidence is lacking, many are betting that a lowered mass of normally functional -cells, from genetics or environmentally based imprinting during fetal or early life, will end up being a common cause of susceptible -cells, based on animal (5,6) and human (Kumar et al. [7]) studies posthemipancreatectomy showing a predilection for diabetes. Eventually, -cell dysfunction (actually failed -cell compensation) occurs when the subject is still normally glucose tolerant, resulting in a slow rise in glycemia (8). Whether this reflects dysfunctional -cells, a loss of -cells, or both is unknown. By the onset of pre-diabetes, defective -cell function (glucose unresponsivesness and impaired insulin pulsatility) and a lowered -cell mass are both found and worsen with time (1). Many mechanisms for the -cell dysfunction and death are being studied, such as glucotoxicity, glucolipotoxicity, oxidative or endoplasmic reticulum stress, amyloid infiltration, inflammation, and so on. However, there is one stage of this sequence called “transition” (i.e., the time when insulin secretion switches from successful to failed compensation) that has gone relatively unstudied. In this issue of Diabetes, the article by Chakravarthy et al. (9) may provide important insight into this event, although that was not the original intent. They intensively studied a mouse model of intrauterine growth retardation (IUGR) due to haploinsufficiency for fatty acid synthase (FAS), noting modest hyperglycemia on a standard diet at 12 months of age and even worse hyperglycemia after fat feeding compared with the wildtype mice. The reason was defective insulin secretion and a falling -cell mass. Importantly, this propensity to diabetes came without the postnatal catch-up in body weight and insulin resistance that characterize most other models of IUGR, which allowed the authors to conclude that -cells were programmed for failure by events related to the IUGR. The story became even more interesting when they looked earlier (at 3 months) and found an opposite phenotype.TheFASheterozygousmicewerehypoglycemic/ hyperinsulinemic on a standard diet, with a larger -cell mass and insulin secretion that was hyperresponsive to glucose, when they were more insulin sensitive than age-matched wild-type mice. Furthermore, the FAS haploinsufficient mice compensated better to fat feeding than did wild-type mice in terms of a greater increase in -cell mass and insulin secretion; plus, there were lower-thannormal glucose values during a glucose challenge. So, early on there was super -cell compensation, and later there was failed compensation. The authors concluded that they had discovered a body weight–sensing mechanism during fetal development that regulates -cell mass. As such, growth retardation feeds back to enhance -cell mass and insulin secretion to augment whole-body fat and protein deposition. They supported this conclusion with a second mouse model of IUGR, also with enhanced insulin sensitivity (musclespecific uncoupling protein-1 transgenic mice), that showed the same early increases in -cell mass and From the Division of Endocrinology, Diabetes, and Metabolism, Department of Medicine, University of Vermont, Burlington, Vermont. Corresponding author: Jack L. Leahy, [email protected]. Received and accepted 30 June 2008. DOI: 10.2337/db08-0869 © 2008 by the American Diabetes Association. Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered. See http://creativecommons.org/licenses/by -nc-nd/3.0/ for details. See accompanying original article, p. 2698. Environment Promoting Insulin Resistance