Reduction of islet pyruvate carboxylase activity might be related to the development of type 2 diabetes mellitus in Agouti-K mice.
Pyruvate carboxylase (PC) activity is enhanced in the islets of obese rats, but it is reduced in the islets of type 2 diabetic rats, suggesting the importance of PC in beta-cell adaptation to insulin resistance as well as the possibility that PC reduction might lead to hyperglycemia. However, the causality is currently unknown. We used obese Agouti mice (AyL) as a model to show enhanced beta-cell adaptation, and type 2 diabetic db/db mice as a model to show severe beta-cell failure. After comparison of the two models, a less severe type 2 diabetic Agouti-K (AyK) mouse model was used to show the changes in islet PC activity during the development of type 2 diabetes mellitus (T2DM). AyK mice were separated into two groups: mildly (AyK-M, blood glucose <250 mg/dl) and severely (AyK-S, blood glucose >250 mg/dl) hyperglycemic. Islet PC activity, but not protein level, was increased 1.7-fold in AyK-M mice; in AyK-S mice, islet PC activity and protein level were reduced. All other changes including insulin secretion and islet morphology in AyK-M mice were similar to those observed in AyL mice, but they were worse in AyK-S mice where these parameters closely matched those in db/db mice. In 2-day treated islets, PC activity was inhibited by high glucose but not by palmitate. Our findings suggest that islet PC might play a role in the development of T2DM where reduction of PC activity might be a consequence of mild hyperglycemia and a cause for severe hyperglycemia.
Han
J
J
The Research Institute for Children, Children's Hospital at New Orleans, New Orleans, Louisiana 70118, USA.
Liu
Y Q
YQ
D000375:Aging / Q000378:metabolism; D000818:Animals; D001786:Blood Glucose / Q000378:metabolism; D003924:Diabetes Mellitus, Type 2 / Q000201:enzymology* / Q000209:etiology; D005227:Fatty Acids / Q000378:metabolism; D005951:Glucose Tolerance Test; D006943:Hyperglycemia / Q000378:metabolism*; D007328:Insulin / Q000097:blood / Q000378:metabolism; D000078790:Insulin Secretion; D007515:Islets of Langerhans / Q000201:enzymology*; D008297:Male; D051379:Mice; D008820:Mice, Obese; D019308:Palmitic Acid / Q000378:metabolism; D011766:Pyruvate Carboxylase / Q000378:metabolism*; D011768:Pyruvate Dehydrogenase Complex / Q000378:metabolism
D001786:Blood Glucose; D005227:Fatty Acids; D007328:Insulin; D011768:Pyruvate Dehydrogenase Complex; D019308:Palmitic Acid; D011766:Pyruvate Carboxylase