Insulin resistance compensation: not just a matter of β-Cells?

The global epidemic of type 2 diabetes is largely secondary to insulin resistance induced by obesity and sedentary lifestyles. Most insulin-resistant subjects are able to increase b-cell secretion to meet the increased insulin demand and do not develop diabetes. However, when b-cell compensation fails, type 2 diabetes develops (1,2). Understanding the mechanisms of this compensatory response is of fundamental importance to elucidate the pathophysiology of type 2 diabetes and has implications for the treatment of the disease. The capacity of b-cell mass to increase in response to insulin resistance is well established in rodents, where it has been able to prevent diabetes even in extreme conditions (3). In humans, b-cell mass expansion has been shown in normal physiological growth (4) and in insulinresistant conditions such as pregnancy (5) and obesity (6–10). However, b-cell mass increment is more modest in obese humans than in rodents, has not been confirmed in all ethnic backgrounds (11), and shows a large variability among subjects (10,12). Current imaging techniques are not sensitive enough to accurately measure b-cell mass in vivo, and ethical considerations preclude obtaining pancreatic samples from living subjects. Thus, human b-cell mass has been determined in autopsied pancreata. The cross-sectional nature of the studies, the potential interference of preand postmortem processes, and the absence of concomitant or even previous assessment of insulin resistance and insulin secretion are significant limitations of the available morphological studies. In the current issue, Mezza et al. (13) present a detailed analysis of islet function, insulin resistance, and islet morphology in 18 nondiabetic patients requiring a pancreatoduodenectomy (;50% pancreatectomy) to treat a tumor of the ampulla of Vater. One week before surgery a hyperinsulinemic-euglycemic clamp, a hyperglycemic clamp followed by acute stimulation with L-arginine, and a mixed-meal test were performed. Based on the hyperinsulinemic-euglycemic clamp, patients were divided into more insulin-sensitive and more insulin-resistant. At surgery, a pancreatic sample was collected, and the full metabolic study was repeated ;40 days after surgery when 77% of the insulinresistant subjects but none of the insulin-sensitive subjects had developed diabetes. Mean islet size and fractional insulin, glucagon, and somatostatin areas were higher in insulin-resistant subjects. b-Cell replication, apoptosis, and individual b-cell size were similar in insulin-resistant and insulin-sensitive subjects, suggesting that these factors did not contribute to increase b-cell mass. In contrast, increased islet neogenesis was suggested in insulin-resistant subjects based on higher b-cell and islet densities and on indirect markers of neogenesis that are compatible with a ductal origin of new b-cells. Insulin-resistant subjects showed a dramatic increment of fractional a-cell area that correlated inversely with insulin sensitivity, a reduced b-/a-cell ratio, and an increased percentage of cells double-positive for insulin and glucagon. Glucagon-like peptide 1 (GLP-1) expression, colocalized with glucagon, was identified in the pancreas in both groups, and GLP-1 secretion correlated positively with the a-cell area and negatively with insulin sensitivity. The simultaneous and comprehensive functional study and morphological analysis of islets in pancreas from living subjects is a major strength of the study. The increased b-cell mass in insulin-resistant subjects is in line with current concepts about b-cell plasticity and compensation for insulin resistance. Among the several possible origins of the increased b-cell mass (Fig. 1), Mezza et al. support a role for islet neogenesis that some previous studies have also suggested (14). The increased