Incretin Effects on β-Cell Function, Replication, and Mass: The human perspective

ALAN J. GARBER PHD - T b-cell function in patients with type here is a progressive deterioration in 2 diabetes. At diagnosis, islet function may be reduced by up to 50% compared with healthy control subjects, and there is also likely to be a reduction in b-cell mass of up to 60%. The reduction in b-cell mass is due to accelerated apoptosis. Currently, few pharmacological therapies address this reduction in b-cell mass and function. This means that patients are generally subjected to an increasing polypharmacy to control their diabetes, with most eventually being treated by insulin. Incretin hormones, which are released from the gastrointestinal tract after a meal, enhance glucose-dependent insulin secretion from the pancreas, aiding the overall regulation of glucose homeostasis in healthy subjects. In addition, these hormones, especially glucagon-like peptide (GLP)-1, have a number of protective effects on the b-cells, including a reduction in apoptosis and enhancement of b-cell proliferation and neogenesis. These benefits are lost to a significant extent in patients with diabetes. The recently developed diabetes therapies, GLP-1 receptor agonists, such as exenatide and liraglutide, appear to have beneficial effects on b-cell function and hence offer promise for durable glycemic control as well as potentially reducing the micro- and macrovascular complications associated with type 2 diabetes. THE CLINICAL COURSE OF TYPE 2 DIABETESThe clinical course of type 2 diabetes is characterized by a progressive decline in b-cell mass and function. Although the elevated levels of fasting glucose and impairment of insulin action in peripheral tissues may predate the diagnosis of type 2 diabetes, chronic hyperglycemia only results after a prolonged period of b-cell degeneration, a process that may begin as much as 12 years before diagnosis, involving a progressive reduction in functionality and mass (1,2). In the UK Prospective Diabetes Study, it was estimated that, at diagnosis, type 2 diabetic patients may have already lost up to 50% of their b-cell function. Because most current therapeutic options address the impaired glucose action or stimulate insulin secretion rather than the declining b-cell function, the ongoing decline in b-cell function leads to eventual failure of most antidiabetic therapies (3,4). Indeed, some secretagogues may accelerate b-cell failure. In the UK Prospective Diabetes Study, which involved .5,000 patients newly diagnosed with type 2 diabetes treated with either intensive therapy involving insulin or conventional therapy (diet alone), progressively worsening glycemic control and decline in b-cell function was reported regardless of the therapy used (3). In the cohort who received the conventional therapy regimen, b-cell function declined from 53% of normal at year 1 to 28% at year 6 (3). Glycemic control mirrored the decline in b-cell function. In many patients, addressing declining glycemic control due to secondary treatment failure by progression to multiple classes of agents will eventually lead to the use of insulin. Moreover, several c c c c c c c c c c c c c c c c c c c c c c c c c c c c c c c c c c c c c c c c c c c c c c c c c THE b-CELL IN TYPE 2 DIABETESPhysiologically, b-cells secrete insulin at low levels between meals to control hepatic glucose output and at higher levels after meals to facilitate the uptake of glucose (6). Insulin secretion with meals occurs in two distinct phases: a first phase that reduces basal glucagon secretion, thereby decreasing hepatic glucose production, and a second phase, commencing 10 min or so after glucose exposure, that is sustained until normoglycemia (blood glucose levels of 7199 mg/dL) is restored (6). The firstphase insulin response is almost abolished or at least severely blunted in patients with type 2 diabetes (7), although levels of fasting insulin may be higher than normal (8). The loss in b-cell function appears to be accompanied by a reduction in b-cell mass (9). Maintenance of b-cell mass involves a dynamic balance between cell replication, neogenesis, and apoptosis. For patients with type 2 diabetes, there appears to be a shift toward an increase in apoptosis that outweighs cell renewal. b-Cell apoptosis is multifactorial; chronic exposure of the b-cells to elevated levels of glucose leads to glucotoxicity, a process where hyperglycemia causes cellular dysfunction and mortality (10). Lipotoxicity, associated with high concentrations of free fatty acids, commonly observed in people who are obese, are insulin-resistant, or have type 2 diabetes, has also been linked to increased metabolic stress of the b-cells (11). The reduction in b-cell mass in type 2 diabetes was demonstrated convincingly in a series of studies that compared b-cell mass in patients with type 2 diabetes with that in healthy control subjects (9). Using pancreatic autopsy tissue, Butler et al. (9) showed that obese patients with impaired fasting glucose or type 2 diabetes had a 40% (P , 0.05) and 63% (P , 0.01) reduction in b-cell mass compared with obese individuals without diabetes (9). Compared with lean nondiabetic subjects, lean patients with type 2 diabetes had a 41% deficit in relative b-cell mass (P , 0.05). Evidence suggests that a decrease in b-cell mass of $50% leads to the development of diabetes in primates (12). Butler et al. also demonstrated a significantly increased frequency of apoptotic events in patients with type 2 diabetes compared with nondiabetic case subjects. The implication for prevention of type 2 diabetes is that strategies that avoid the increased frequency of b-cell apoptosis may potentially be of clinical benefit. INCRETIN HORMONES, NOTABLY GLP-1The decline in b-cell function in type 2 diabetes has been linked with impaired action of the incretin hormones, glucose-dependent insulinotropic polypeptide (GIP) and GLP-1. These hormones are secreted from the intestine in response to energy intake and glucose and may potentiate as much as 70% of the meal-induced insulin response in healthy individuals (13). In patients with type 2 diabetes, the incretin response and subsequent insulin secretory response after oral glucose is typically reduced by 50% compared with healthy control subjects (14). These observations suggest that deficient incretin secretion may play a critical role in the pathogenesis of type 2 diabetes. Although in normal subjects both GIP and GLP-1 act as incretin hormones, diabetes is often associated with a blunted or absent response to GIP (15). Even when infused at pharmacological levels, GIP only marginally stimulates insulin secretion in type 2 diabetes; hence, GLP-1 has been investigated as a potential pharmacological agent to treat type 2 diabetes. In healthy subjects, infusion of physiological levels of GLP-1 resulted in an increase in insulin secretion. By contrast, in patients with type 2 diabetes, the insulin response to physiological levels of GLP-1 was substant (...truncated)