The pathogenesis of NIDDM remains unknown although it is clear that genetic and environmental factors are involved, and that progressive defects in insulin secretion and insulin action are present. Impaired first phase insulin secretion has been considered the most sensitive measurement of the B cell defect although it now appears that loss of pulsatility of insulin secretion is also an early marker of defective insulin secretion in NIDDM. However, it is unknown what, if any, physiologic significance either first phase or pulsatile insulin secretion have in regulation of carbohydrate metabolism. The following studies have been designed to address the regulatory role of insulin pulsatility in healthy humans, to consider the potential contribution of impaired insulin pulsatility towards insulin resistance in NIDDM, and to explore the relationship between first phase and pulsatile insulin secretion. Therefore, the specific aim of these studies is to answer the following three questions: I. Does insulin pulsatility regulate insulin sensitivity in healthy humans? II. Does impaired insulin pulsatility contribute in insulin resistance in patients with NIDDM? III. Does insulin pulsatility (and first phase insulin secretion) depend on the presence of a rapidly releasable insulin pool which is lost when insulin secretory demand per B cell is increased? To determine the regulatory role of pulsatile insulin secretion, pulsatile versus continuous insulin infusions overnight will be followed by in vivo measurement of hepatic versus extrahepatic insulin sensitivity in diabetic and nondiabetic humans. The mechanism of any effect will be addressed by simultaneous in vitro techniques. To address the relationship between first phase insulin secretion versus insulin pulsatility insulin pulses and first phase insulin secretion will be measured when B cell insulin synthesis/demand ratio is perturbed, acutely after intravenous glucose and chronically by obesity (before and after weight loss) and partial pancreatectomy. If insulin pulsatility enhances insulin action in these short term studies, longer term studies will be required to address the clinical benefits of pulsatile insulin delivery.
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