Apolipoprotein A-IV Stabilizes Glucose Metabolism in Diabetic Mouse Model

Apolipoprotein A-IV (apoA-IV), a protein manufactured by the small intestine during the digestive process, has been found to improve the ability of diabetic mice to control their glucose levels.

Investigators at the University of Cincinnati (OH, USA) worked with cultures of isolated pancreatic cells, with mice that had been genetically engineered to lack the gene for apoA-IV, and with KKAy diabetic mice.

They reported in the May 22, 2012, online edition of the journal Proceedings of the National Academy of Sciences of the USA that apoA-IV-treated isolated pancreatic islets had enhanced insulin secretion under conditions of high glucose but not of low glucose, suggesting a direct effect of apoA-IV to enhance glucose-stimulated insulin release. This enhancement involved cAMP (3'-5'-cyclic adenosine monophosphate) at a location distant from the point entry of calcium ions into insulin-producing beta cells.

Genetically engineered “knockout” of apoA-IV resulted in compromised insulin secretion and impaired glucose tolerance compared with wild type mice. Challenging mice lacking apoAI-V with a high-fat diet led to fasting hyperglycemia and more severe glucose intolerance associated with defective insulin secretion than occurred in wild type mice. Administration of exogenous apoA-IV to the “knockout” mice improved glucose tolerance by enhancing insulin secretion in mice fed either chow or a high-fat diet.

Injection of exogenous apoA-IV decreased blood glucose levels and stimulated a transient increase in insulin secretion in KKAy diabetic mice.

Senior author Dr. Patrick Tso, professor of pathology and laboratory medicine at the University of Cincinnati, said, “ApoA-IV behaves similar to an incretin - a gastrointestinal hormone causing an increased release of insulin after eating to combat the onset of elevated blood glucose. Two well-known incretins that have been used in the development of existing diabetes medications include gastric inhibitory peptide (GIP) and glucagon-like peptide-1 (GLP-1).”

"The problem with both of these incretins is that they are short-lived - lasting only for minutes - and are quickly inactivated by an enzyme,” said Dr. Tso. “They have also been linked to hypoglycemia, or low blood sugar, when administered when the body has a low glucose concentration. The challenge is to find something safer with a longer half-life.”

With its long (seven to eight hour) half-life apoA-IV may be a suitable therapeutic target for the regulation of glucose-stimulated insulin secretion and treatment of diabetes.

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