The worldwide epidemic of obesity has developed alongside, and is causally linked to, the epidemic of insulin resistance and type 2 diabetes mellitus (T2DM). Plasma insulin concentrations are typically elevated in people with insulin resistance attributable to an increase in insulin secretion rate by pancreatic β-cells; however, in people with T2DM, β-cells eventually fail to 'keep up' and there is a crossover from insulin hypersecretion to undersecretion.
In the β-cell, KATP channels serve as the link between rising glucose and insulin secretion. Unlike other cells in the body, the uptake of glucose by the β-cell is directly proportional to the amount of glucose in the blood, so increasing blood glucose results in increased metabolism and production of ATP. This ATP closes the KATP channel, depolarizing the cell and driving an increase in intracellular Ca2+, which stimulates the secretion of insulin. The critical role of KATP channels in control of insulin secretion is clearly demonstrated by Gain-of-function (GOF) mutations that increase channel activity, preventing glucose mediated depolarization and secretion of insulin. Such mutations underlie neonatal diabetes mellitus (NDM) in humans and severe diabetes in experimental NDM mice that express transgenic GOF mutant KATP channels. While this paradigm implies that loss of KATP should cause the opposite effect, i.e. hypersecretion of insulin, mice with complete knockout (KO) of KATP show little evidence of hyperinsulinism, instead developing reduced secretion and impaired glucose tolerance from a very early age. Intriguingly, loss of function (LOF) mutations in mice have been shown to result increased insulin secretion, but these "crossover" to the under secreting KO phenotype when challenged with a high fat diet, mirroring the progression of T2DM from hypersecretion to undersecretion. In humans, LOF mutations have been associated with congenital hyperinsulinism, characterized by hypersecretion of insulin and hypoglycemia from a young age. However, despite this early hyperinsulinism, children from with CHI generally remit, losing insulin secretion and even progressing to diabetes with time. Counter to the simple model directly coupling KATP inhibition to insulin secretion, these observations from humans and mouse models suggest a more complex regulation wherein acute depolarization induces insulin secretion but when prolonged, secretion begins to fail.
Electrical measurements from β-cells of isolated islets have demonstrated that incubation in high glucose results in a reduction in KATP activity, and mouse models of obesity and diabetes show increased electrical activity and a loss of KATP in proportion to their loss of glycemic control. These observations have led us to develop the hypothesis that β-cells subjected to chronic stimulation due to increased insulin resistance will progressively lose KATP, eventually causing the "crossover" to undersecretion that is observed in T2DM. In this study our goal is to test this hypothesis, administering a single dose of the KATP antagonist glipizide (10 mg) and using the resulting insulin secretion to indirectly assess KATP channel activity in the islets of volunteers from the following four cohorts, lean and normoglycemic (Lean NGT), obese with normoglycemia (Obesity NGT), obese with impaired fasting glucose (Obesity IFG) and obese type 2 diabetes (Obesity T2DM).
