Mechanisms and Emerging Treatments of the Metabolic Complications of Chronic Pancreatitis

Abstract

Exocrine and endocrine abnormalities in chronic pancreatitis contribute to the morbidity and mortality risks of the disease. Complications of exocrine insufficiency include malabsorption, vitamin deficiency syndromes, and weight loss. Oral enzyme replacement therapy is usually effective if attention is paid to factors that affect the bioavailability of enzyme preparations. Complications of endocrine insufficiency can be more difficult to treat due in part to an incomplete knowledge of their etiology. This review focuses on the endocrine aspects of chronic pancreatitis and highlights the observations of our laboratory on the pathogenesis of the metabolic complications of the disease. In addition to decreased insulin secretory capacity, pancreatogenic (or apancreatic) diabetes is characterized by decreased or absent glucagon and pancreatic polypeptide (PP) secretion, a loss of hepatic insulin receptor (IR) expression/availability, and an impairment in hepatic IR function (phosphorylation and endocytosis). Diminished hepatic IR expression in chronic pancreatitis appears to be because of PP deficiency; laboratory animals and patients with PP deficiency demonstrate decreased hepatic IR availability that is reversed by prolonged (8-hour) PP administration. The impairment in hepatic IR function appears independent of PP deficiency but is reversed by prolonged (28-day) treatment with the insulinotropic/insulinomimetic hormone glucagon-like peptide 1. The endocytosis of hepatic IR is linked to the endocytosis of the glucose transporter 2 from the hepatocyte plasma membrane, and studies suggest that the 2 plasma membrane-bound proteins are complexed noncovalently to function and translocate as a unit after insulin binding to the hepatic IR. The process appears vigorous and sensitive enough to account for a significant reduction in hepatic glucose output and may represent a major mechanism for insulin regulation of hepatic glucose production. The regulatory mechanisms of PP-mediated hepatic IR expression and combined IR and GLUT2 endocytosis after insulin binding are defective in chronic pancreatitis and contribute to the apancreatic diabetes, which characterizes this disease.