Leahy *et al.*[^1^](#b1){ref-type="ref"} recently issued a consensus statement that recommends targeting β‐cell function for therapy in type 2 diabetes. The consensus is based on recent studies showing that declining β‐cell function, a pathogenesis of type 2 diabetes, begins early in the disease's natural history, accelerates markedly after reaching a compensatory threshold, drives the progression of the disease and is potentially reversible, particularly in the early stages. They concluded that continued multidisciplinary effort to realign treatment of type 2 diabetes to preserve β‐cell function by early intervention is both necessary and important.

In a longitudinal study of obese Pima Indians by Weyer *et al.*[^2^](#b2){ref-type="ref"}, failure to augment β‐cell function to compensate for increased insulin demand as a result of decreased insulin sensitivity, due to weight gain for example, was found to be involved in deterioration of glucose homeostasis in type 2 diabetes. It is important to determine whether or not this pathogenesis is also applicable to lean type 2 diabetes in Asia. Sato *et al.*[^3^](#b3){ref-type="ref"} showed, by a cross‐sectional study using the oral glucose tolerance test, that β‐cells begin to deteriorate during normoglycemia with a minimal elevation of fasting plasma glucose in Japanese subjects. In our previous cross‐sectional study, endogenous insulin secretion shown by indices of serum C‐peptide immunoreactivity (CPR) levels was negatively correlated with years from diagnosis, suggesting progressive deterioration of β‐cell function over several decades of diabetes exposure in Japanese type 2 diabetes[^4^](#b4){ref-type="ref"}. Interestingly, body mass index (BMI) was positively correlated with indices of CPR, suggesting that increased insulin resistance positively affects endogenous insulin secretion, even in lean type 2 diabetes. However, the positive effect of BMI on endogenous insulin secretion is weaker in patients with longer duration of diabetes than in those with shorter duration, suggesting a decrease in the capacity to compensate insulin secretion against insulin resistance by disease duration and that early intervention might be necessary, even in lean type 2 diabetes.

A previous study using streptozotocin‐treated mini‐pigs showed that β‐cell function *in vivo* is closely related to β‐cell mass, even when only slightly reduced[^5^](#b5){ref-type="ref"}. A decrease in β‐cell mass in type 2 diabetes compared with that in normal subjects is shown by cross‐sectional studies using specimens of autopsies or surgical operations, but longitudinal studies are absent. In a cross‐sectional study using specimens derived from autopsies, β‐cell mass in individuals showed extreme variability and markedly overlapped in normal subjects and patients with type 2 diabetes, despite the significant average decrease in β‐cell mass in type 2 diabetes[^6^](#b6){ref-type="ref"}. These results show that measurement of β‐cell mass at one time point in an individual cannot predict progression to type 2 diabetes and that longitudinal observation is necessary. Trials to find useful probes to visualize β‐cell mass *in vivo* continue[^7^](#b7){ref-type="ref"}. Such non‐invasive methods, if realized, will be valuable to clarify the relationship between function and mass of β‐cells during the natural course of type 2 diabetes in longitudinal studies and to evaluate the effects of early intervention.

In the consensus statement, Leahy *et al.* stressed the importance of basic research to elucidate the nature and mechanisms of β‐cell failure in type 2 diabetes. Understanding the molecular basis of β‐cell proliferation and apoptosis is required to realize clinical application of early intervention to preserve β‐cell mass. Unlike in rodents, a 50% pancreatectomy does not prompt β‐cell regeneration in adult humans[^8^](#b8){ref-type="ref"}; the difference between the mechanisms of β‐cell replication in human and rodents has been shown[^9^](#b9){ref-type="ref"}. Many beneficial effects of incretin on the preservation of rodent β‐cells have been proposed, but thorough evaluation of the effects in human β‐cells is required. Furthermore, extreme variability of β‐cell mass in humans shows that the pathogenesis of type 2 diabetes is derived from functional impairment of insulin secretion, as well as from reduction of β‐cell mass ([Figure 1](#f1){ref-type="fig"}). Indeed, glucose‐specific impairment of insulin secretion is characteristic in type 2 diabetes; the insulin response to intravenous administration of arginine is preserved, whereas the insulin response to intravenous administration of glucose is severely impaired in patients with type 2 diabetes[^10^](#b10){ref-type="ref"}. Results from diabetic rodent and human islets show that decreased glucose‐stimulated insulin secretion in diabetes is derived, at least in part, from impaired metabolism--secretion coupling in β‐cells; impaired glucose metabolism and adenosine triphosphate (ATP) production in β‐cells causes a decrease in glucose‐stimulated insulin secretion. We propose that ATP production in β‐cells is impaired by endogenous overproduction of reactive oxygen species (ROS) and by diminished hyperpolarization of mitochondrial membrane potential as a result of overexpression of uncoupling protein and a nuclear factor[^11,12^](#b11 b12){ref-type="ref"}. Interestingly, an increase in the intracellular cAMP level by GLP‐1 receptor agonist ameliorates impaired ATP production by suppressing endogenous ROS generation in diabetic β‐cells, which suggests that incretin therapy might have an important role in recovering impaired metabolism‐secretion coupling[^11^](#b11){ref-type="ref"}. Studies to elucidate the mechanism of β‐cell dysfunction, including mass reduction and functional impairment, will contribute to establishing novel strategies to preserve β‐cell function in treatment of type 2 diabetes.

![ Pathogenesis of type 2 diabetes mellitus.](jdi-2-178-g1){#f1}
