SURGERY OF THE PANCREAS--EFFECTS ON GLUCOSE METABOLISM

Project: Research project

Description

Pancreatic disease, injury, or surgical removal, frequently results in disordered glucose metabolism. Pancreatogenic diabetes differs from other forms of diabetes in its clinical characteristics, in part due to unique abnormalities in the levels, secretory regulation, and action of multiple islet cell products. Recent animal and clinical studies of chronic pancreatitis-induced diabetes suggest that hepatic insulin receptor function and hepatic glucose transporter content are altered in this disease. Studies are therefore proposed to examine the mechanisms by which pancreatic disease or removal alters insulin action and glucose transport in extra-pancreatic tissues. Through the use of animal models of chronic pancreatitis and pancreatic resection, the role of peptide mediators, such as pancreatic polypeptide (PP), on the availability, affinity, and internalization of hepatocyte insulin receptors will be assessed, as will the role of these peptides on the action and cellular localization of glucose transporter proteins such as GLUT-2. The role of neural mediation of the availability and action of hepatic insulin receptor and glucose transporter proteins will be examined as well, to determine whether altered hepatic glucose metabolism is a direct or indirect result of changes in the levels of peptide mediators of cholinergic neurotransmitter release. The possible direct hepatic effects of peptide mediators such as PP will be assessed by specific measurement of hepatic PP-binding proteins in models of pancreatic disease or removal, so that changes in hepatocyte receptor expression, function, and cellular localization can be related to specific changes in hepatic glucose metabolism. Methods will include isolated rat liver perfusion so that changes in the function and location of receptor and transporter proteins can be correlated with functional changes in hepatic glucose production. Because alterations in the cellular localization of receptor and transporter proteins have been suggested by initial studies, the role of low molecular weight GTP-binding proteins in hepatocytes isolated from animal models of pancreatic dysfunction will be studied, to determine whether disordered endo- and exocytosis account for the alterations seen in hepatic glucoregulatory protein localization. Specific GTP-binding proteins such as Rab3a and Rab4 will be quantified by immunoblots and two-dimensional gel chromatograms to determine whether the regulation of internalization of endosomes, or alternatively, the recycling of receptor to the plasma membrane, is altered in these models. Morphologic studies are also planned to determine whether insulin binding proteins and glucose transporter proteins are co-localized to sites of insulin receptor internalization on the hepatocyte plasma membrane. With the observation that abnormal hepatic glucose metabolism is a consistent feature of both clinical and laboratory models of pancreatogenic diabetes, these studies are designed to elucidate the cellular basis for altered hepatocyte glucose metabolism in these common disease states.
StatusFinished
Effective start/end date5/1/8912/31/99

Funding

  • National Institutes of Health: $196,598.00
  • National Institutes of Health: $177,956.00
  • National Institutes of Health
  • National Institutes of Health: $219,432.00
  • National Institutes of Health: $172,023.00
  • National Institutes of Health
  • National Institutes of Health
  • National Institutes of Health
  • National Institutes of Health

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Pancreas
Glucose
Liver
Pancreatic Polypeptide
Hormones
Pancreatic Diseases
Facilitative Glucose Transport Proteins
Insulin Receptor
Hepatocytes
Chronic Pancreatitis
Insulin
Peptides
Neurotransmitter Agents
Proteins
Pancreas Transplantation
Glucose Clamp Technique
Autologous Transplantation
GTP-Binding Proteins
Denervation
Glucagon

ASJC

  • Medicine(all)