Adaptative secretory changes to a fructose-induced insulin resistance state: Role of glucokinase and glucose metabolism in the islets

MAIZTEGUI B; BORELLI MI; GAGLIARDINO JJ

Roma, Italia

Congreso; 44th EASD (European Association for the Study of Diabetes) Annual Meeting; 2008

European Association for the Study of Diabetes (EASD)

Background and Aims: The role of glucokinase (GK) in the compensatory increased secretion of insulin observed in rats with normoglycemia and dietary-induced insulin resistance (IR) was studied. Materials and Methods: Normal male Wistar rats received a standard commercial diet and tap water without (control, C) or with (FRD) 10% fructose for 3 weeks. Blood glucose (strips), triglyceride (commercial kit) and insulin (radioimmunoassay) levels were measured at the time of sacrifice. Islets were isolated by collagenase digestion to study glucose-induced insulin release, glucose metabolism (14CO2 and 3H2O production from labeled glucose), hexokinase (HK) and GK transcription (RT-PCR), protein expression (Western blot), compartmentalization (cytosol and particulate fractions) and activity (bioassay). Results: C and FRD rats had similar body weights. FRD rats presented normoglycemia, hypertriglyceridemia, hyperinsulinemia and increased HOMA-R index. FRD islets released significantly more insulin and produced higher amounts of 14CO2 and 3H2O in response to high glucose. While no differences were found in HK transcription, protein expression and activity between groups, GK total and cytosolic fraction activity and protein expression were significantly higher in FRD rat islets. FRD did not induce significant changes in GK transcription rate. Conclusions: Our results demonstrate that in rats with sustained induced IR and normoglycemia, GK activity increased due to a combination of posttranslational mechanisms of increased GK protein amount and compartmentalization, which resulted in increased glucose metabolism and insulin secretion. These data demonstrate that GK plays a pivotal role in functional islet adaptation to maintain normal glucose homeostasis. Supported by: grants from FONCyT and CONICET