Graded Insulin Suppression Test P&F

The goal of this study is to learn about how the hormone insulin controls blood sugar in a variety of people. The main question it aims to answer is about how much insulin the body actually needs to maintain a normal blood sugar level. Participants will be asked to come in for a one-day study visit in which they will undergo a "graded insulin suppression test" ("GIST"). The GIST involves intravenous (into the vein) infusions of octreotide, a medication that turns off the body's own production of insulin, as well as replacement of insulin at two different levels (low and high), with or without replacement of glucagon, and glucose (sugar). The study investigators will check blood sugar levels every few minutes during the procedure to determine the effect of the two different insulin levels. This study will evaluate the GIST in both healthy volunteers and those at higher risk for type 2 diabetes.

This study aims to determine 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 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, this study will adapt the existing insulin suppression test (IST) technique, which employs the somatostatin receptor ligand octreotide to suppress endogenous insulin secretion and then replaces insulin and dextrose exogenously as a measure of insulin action. In addition to employing the current standard hyperinsulinemic IST protocol to assess insulin sensitivity, this study will introduce a preceding, euinsulinemic step, in which insulin is lowered toward a healthy fasting serum insulin while assessing the resultant steady-state glucose, potentially with replacement of basal glucagon. The primary endpoints in this study are the steady-state plasma glucose and serum insulin levels during low- and high-dose insulin infusions meant to induce euinsulinemia and hyperinsulinemia, respectively. The study investigators will carefully monitor plasma glucose levels every 5-15 min, drawing from an indwelling peripheral IV catheter and performing the analysis using a dedicated bedside glucose analyzer. These glucose values will be used to detect and arrest any trends toward hypo or hyperglycemia and will also serve as the readout of the primary outcome - the euinsulinemic steady-state glucose (E-SSG) and hyperinsulinemic steady-state glucose (H-SSG). Serum insulin, C-peptide, growth hormone, and glucagon levels will be measured periodically during the procedure, but these results will not be available until several days later.