GLUCOSE HOMEOSTASIS AND THE SURGICALLY ALTERED PANCREAS

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Regulation of insulin secretion and the resultant glucoregulatory processes are not completely understood. Considerable research has been done in the intact organism and in models which mimic pathologic states such as diabetes. Less research has been completed which deals with the effect that surgical intervention might have on glucose homeostasis. Such studies are valuable not only in predicting what alterations might occur because of the surgery itself, but also in clarifying these processes in the intact organism. Surgical alterations of the pancreas with clinical relevance include resection, systemic drainage and autotransplantation. Our initial studies in dogs with 80% pancreatectomy (and intact portal drainage) demonstrate peripheral hypoinsulinemia and altered glucose disposal. Animals with the same pancreatectomy but with systemic diversion of venous effluent have "normalized" insulin levels and glucose disposal. Therefore "de-insulinization" of the portal vein appears to result in a correction of the altered glucose homeostasis shown by the animals with portal drainage. Animals with total pancreatectomy and autotransplantation of this same reduced beta cell mass (PAT) likewise have "normalized" values. Further studies in PAT animals show that they dispose of glucose in a fashion identical to that of a normal animal whose insulin secretion has been abolished by the suppressor peptide, somatostatin. In addition, studies of the autotransplanted animals show severe deficiencies of GIP and pancreatic polypeptide (PP). We propose to test four separate hypotheses from these surgically altered models concerning glucose homeostasis in normal and postoperative animals. First, in the pancreas resection animals, the liver extracts a mandatory amount of insulin which overrides all other glucoregulatory processes and results in altered glucose disposal. Second, hepatic glucose output plays a key role in "normalization" of glucose homeostasis when the portal vein is "de-insulinized". Third, insulin-independent glucose disposal plays an important part in the "normalized" glucose disposal when insulin is drained systemically. Fourth, the peptide deficiency state likewise contributes to the altered glucoregulatory processes after pancreatic resection and these can be corrected by supplementation with these peptides. We believe that by use of our already established animal models and provocative test methodologies, we will be able to evaluate the effect of surgical alteration of the pancreas in a unique fashion.