Abstract
Type 1 diabetes (T1D) is a chronic autoimmune disease and is increasing by approximately 2-3% per year. One characteristic feature of T1D is the increased production of ketone bodies. However, the role of ketone bodies and/or ketogenesis in the pathogenesis of T1D remains unknown. We generated mice with conditional ketogenic insufficiency by knocking out the ketogenic enzyme 3-hydroxy methylglutaryl CoA synthase 2 (Hmgcs2) in the liver. Six to eight-week-old Hmgcs2ΔLiv and Hmgcs2F/F(littermates that do not express Alb-Cre) were injected with tamoxifen @200 mg/kg body weight. One week later, Hmgcs2ΔLiv and Hmgcs2F/F mice were injected with strep tozotocin (STZ; 50mg/kg B.W for 5 consecutive days) to induce hyperglycemia. We found that Hmgcs2ΔLiv mice had significantly lower blood glucose than their littermate controls. The improvement in glycemia is not due to a change in food intake or body weight. Moreover, no difference in serum insulin levels and Akt phosphorylation in the liver suggested that ketogenic insufficiency does not improve glycemia in T1D via the insulin signaling pathway. When we assessed glucose production by pyruvate tolerance test, Hmgcs2ΔLiv mice showed lower glucose levels. Further, the mRNA and protein levels of gluconeogenic genes such as G6PCand PCK1 were significantly decreased in the livers of Hmgcs2ΔLivmice. We also observed a significant reduction in PGC-1α, the transcriptional regulator of gluconeogenesis, suggesting that ketogenic insufficiency in T1D reduces hepatic gluconeogenesis. The metabolism of ketone bodies in peripheral tissues impairs their ability to utilize glucose. Our indirect calorimetry analysis showed a trend toward increased respiratory exchange ratio (RER) in STZ-treated Hmgcs2ΔLiv mice, suggesting that ketogenic insufficiency increases carbohydrate metabolism in T1D. Our data show that ketogenesis may contribute to hyperglycemia in T1D by regulating hepatic glucose production and peripheral glucose utilization. Disclosure R.Mooli: None. S.Ramakrishnan: None. Funding National Institute of Diabetes and Digestive and Kidney Diseases (DK110537)
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