The Role of Pulsatile Insulin Secretion (A Study Investigating the Effects of Partial Pacreatectomy on Glucose Metabolism)

Overview

The purpose of this study is to examine changes in sugar metabolism that may occur in subjects who have previously had part of their pancreas removed due to a benign lesion.

Beta cells of the pancreas are the insulin producing cells. People with impaired fasting glucose have a beta cell mass \~50% of that of normal glucose tolerant subjects. A 2006 canine study by Dr. Peter Butler's group at UCLA demonstrated that glucose stimulated insulin secretion was deficient after 50% decrease in beta cell mass after distal pancreatectomy compared to those dogs who had sham surgery. The pancreatectomized dogs had impaired fasting glucose with impaired insulin secretion and insulin resistance. The decreased insulin secretion was a result of decreased insulin secretory pulses or bursts with no change seen in pulse frequency, the same pattern seen in humans with Type 2 diabetes. Conclusions derived from this study include the following: 1. When beta cell mass declines to \~50% the capacity for the remaining beta cells to secrete insulin in appropriate secretory bursts is compromised, leading to a deficit in insulin secretion most obvious on glucose stimulation. 2. The decreased insulin burst mass results in an additional component of insulin resistance, and this together with the compromised capacity for insulin secretion leads to decompensation of glucose regulation and diabetes onset. How does this translate in humans who have had partial pancreatectomy? In 1990, Kendall and colleagues published a study looking at the effects of hemipancreatectomy in healthy human subjects on insulin secretion and glucose tolerance. These subjects were donors for pancreatic transplantation. They showed that fasting insulin and c-peptide levels were lower one year after hemipancreatectomy. Seven of the 28 donors had abnormal glucose tolerance one year after hemipancreatectomy, but all 28 had normal fasting plasma glucose levels. This study and others like it confirm the development of impaired glucose tolerance after partial pancreatectomy, but pulsatile insulin secretion and hepatic insulin clearance were not measured. As stated above, the main objective of this pilot study is to establish and quantify the impact of a deficit in beta cell mass, due to partial pancreatectomy for benign tumors, on glucose tolerance. Results of this study may be used to develop a future metabolic study that uses glucose isotopes to establish the effects of partial pancreatectomy on glucose tolerance, basal and stimulated insulin secretion as well as hepatic and extrahepatic insulin sensitivity under conditions of usual physiology. This will enable us to further understand the relationship between loss of beta cells, decreased insulin secretion and increased insulin resistance in humans.

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