Diazoxide Suppression Test P&F Study

Hyperinsulinemia, Insulin Resistance, Obesity

Insulin resistance, Hyperinsulinemia, Type 2 diabetes, Obesity

The goal of this study is to learn about how the hormone insulin controls blood sugar. The main question it aims to answer is about how much insulin the body actually needs to maintain a normal blood sugar level. People with obesity and high insulin levels will receive eight doses of diazoxide, a drug that suppresses the pancreas's production of insulin, and will have their fasting blood sugar and insulin levels checked daily while taking the drug.

The investigators are interested in determining to what extent the hyperinsulinemia commonly associated with insulin resistance (IR) in those at risk for type 2 diabetes (T2D) is a primary phenomenon, rather than merely a secondary, compensatory response to IR. The study hypothesis is that some people with obesity and hyperinsulinemia exhibit a primary, non-compensatory hyperinsulinemia that may foment IR and its dysmetabolic sequelae. If this were the case, lowering insulin levels should not result in a proportional rise in blood glucose as might be expected if the hyperinsulinemia truly were purely compensatory. This hypothesis has been difficult to prove, however, because of the tight feedback mechanism between blood glucose and insulin secretion; under normal circumstances insulin secretion declines only alongside blood glucose. As such, an attempt to lower insulin levels independently of blood glucose will raise blood glucose and trigger further insulin secretion, negating the purpose of the experiment. In order to circumvent this feedback regulation of glucose-stimulated insulin secretion, the study team has developed a modification of the insulin suppression test (IST) called the "graded IST" (GIST) that suppresses endogenous insulin secretion with octreotide and then measures steady-state plasma glucose (SSPG) at both replacement euinsulinemia and hyperinsulinemia. It is expected that some people with high insulin levels at baseline will not demonstrate a prominent rise in SSPG even when their insulin levels are lowered. However, the GIST is a cumbersome procedure that is difficult to scale for larger study populations. As such, the investigators are also working to develop an outpatient diazoxide suppression test (DzST) that suppresses endogenous insulin secretion with the oral insulin anti-secretagogue diazoxide rather than octreotide, and will validate it against the incipient "gold-standard" GIST. GIST participants found to have evidence of primary hyperinsulinemia (i.e., euinsulinemic euglycemia or near-euglycemia despite baseline hyperinsulinemia) will, several weeks later, take diazoxide 3 mg/kg per dose, twice daily, for four days. The investigators will check fasting glucose and insulin levels daily at baseline and then after each of the four days of diazoxide administration. The investigators expect that suppression of insulin secretion with diazoxide will, in accordance with the GIST, lead to no significant rise in blood glucose in people who have true primary hyperinsulinemia.

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United States