Islet amyloid polypeptide : Perspectives on the storage and plasma concentration of islet amyloid polypeptide (IAPP) in rodent models of obesity and non-insulin-dependent diabetes mellitus and aspects of amyloidogenesis andelimination of IAPP

Sammanfattning: The present study was aimed to investigate plasma concentrations and pancreatic storage of IAPP in relation to that of insulin in four different animal models with hyperglycemia, hyperinsulinemia, obesity and/or NIDDM. The NMRI mice fed a high-fat diet for six months, the Psammomys on high-energy (HE) diet and the genetically obese (ob/ob) mice studied for one year all revealed significantly elevated plasma IAPP concentrations, while the IAPP levels were unchanged in the spontaneously diabetic GK rats during a glucose tolerance test.In the NMRI mice the fasting plasma glucose and insulin concentrations had also increased, suggesting a possible development of insulin resistance. The increase in plasma IAPP concentrations was even greater than that of insulin, which was reflected in an increased plasma IAPP/insulin molar ratio.The Psammomys developed obesity, hyperinsulinemia and hyperglycemia in response to the HE diet. The plasma IAPP concentration was also elevated, but changed in parallel with that of insulin. After vanadyl sulphate treatment the glucose and insulin concentrations were normalized, while IAPP remained elevated.The OK rats showed significantly decreased plasma concentrations of IAPP and insulin during the glucose tolerance test. The insulin response to the glucose load was even lower than that of IAPP, resulting in a modest elevation of the plasma IAPP/insulin ratio. The elevated IAPP/insulin ratios in these three animal models might reflect a negative feedback effect of IAPP on insulin release.In the ob/ob mice the plasma glucose concentration was initially greatly elevated, but had by the end of study returned to almost normal, presumbly due to the tremendous increase in hyperinsulinemia. The plasma IAPP concentration reached extremely high levels, which however was relatively low to that of insulin, resulting in a sudden significant decrease in the plasma IAPP/insulin ratio at 21 weeks of age, possibly indicating a deficiency in the negative feedback effect of IAPP on insulin secretion.IAPP-immunoreactivity was detected in the morning urine of healthy human volunteers and was by reverse phase HPLC-analysis confirmed to be identical to full-length IAPP. This finding gives strong support to the previous suggestions that IAPP is eliminated by the kidneys, why slight disturbances in plasma TAPP/insulin ratios in dynamic situations (as e.g. in the GK rat) should be carefully interpreted.