The overall goal of this project is to identify and define changes in temporal patterns of insulin secretion and the interactions between insulin secretion and glucose in patients with NIDDM and impaired glucose tolerance. Alterations in the biochemical composition of serum insulin and proinsulin-like peptides will be characterized. The physiological factors involved in the in-vivo regulation of insulin secretion will be studied in healthy subjects. Pancreatic insulin secretion rates will be derived by deconvolution of peripheral C-peptide using individually derived C-peptide kinetic parameters and an open two-compartment model previously validated under the auspices of this grant. The experiments will focus on the mechanisms responsible for generating the ultradian oscillations of glucose and insulin secretion in normal volunteers and further defining the alterations in these oscillations in patients with early NIDDM and impaired glucose tolerance. We will attempt to determine if ultradian oscillations of secretion are an inherent feature of the insulin-glucose negative feedback loop or if they originate due to the activity of an intrapancreatic pacemaker. The temporal relationships between the oscillations in insulin secretion and glucose will be defined and we will determine if early NIDDM is associated with an impaired ability to entrain the secretory oscillations with exogenous glucose. The rapid, small amplitude oscillations in peripheral insulin which recur every 10-15 min will also be studied. Experimental, analytic and laboratory conditions which optimize our ability to detect these oscillations and distinguish them from random assay variation, will be defined. The physiological factors which regulate the amplitude and periodicity of these oscillations will be determined. The first phase insulin response to intravenous glucose is widely used as a test of beta cell function. We propose to establish the relationships between alterations in the first phase response and changes in ultradian oscillations of insulin secretion and the dynamic insulin secretory response to mixed meal ingestion in patients with early NIDDM and IGT, and recipients of functioning pancreas transplants. Concentrations of circulating proinsulin will be measured in a sensitive ELISA assay which does not cross react with insulin and C-peptide and intact proinsulin will be separated from circulating proinsulin conversion products by HPLC. This will allow the contribution of intact proinsulin and the various proinsulin conversion products to total insulin and proinsulin-like immunoreactivity to be defined and to ascertain if changes in each of the component peptides occurs in patients with NIDDM and IGT. It is anticipated that the proposed studies, by providing insight into the regulation and temporal patterns of oscillatory and meal induced insulin secretion, will define the experimental conditions which will allow investigators to identify early defects in insulin secretion even before the onset of overt hyperglycemia. These investigations will not only provide new insights into the pathophysiology of beta cell dysfunction in NIDDM but aid in the development of new methods of eliciting early abnormalities in beta cell secretory capacity.
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