Hepatic Gluconeogenesis and the Activity of PDH in Individual Tissues of GTG‐Obese Mice Following Adrenalectomy

Abstract

1996;4:367-375. Adrenalectomy (ADX) lowers circulating glucose levels in animal models of non-insulin dependent diabetes (NIDDM) and obesity. To investigate the role of hepatic glucose production (HGP) and tissue glucose oxidation in the improvement in glucose tolerance, hepatocyte gluconeogenesis and the activity of pyruvate dehydrogenase (pDH) were examined in different tissues of gold thioglucose (GTG) obese mice 2 weeks after ADX or sham ADX. GTG-obese mice which had undergone ADX weighed significantly less than their adrenal intact counterparts (GTG ADX: .37.5 ± 0.7g; GTG: 44.1 ± 0.4g; p<0.05), and demonstrated lower serum glucose (GTG ADX: 22.5 ± 1.6 mmollL; GTG: 29.4 ± 1.9 mmollL; p<0.05) and serum insulin levels (GTG ADX: 76 ± 10JlU/mL; GTG: 470 ± 63JlU/mL; p<0.05). Lactate conversion to glucose by hepatocytes isolated from ADX GTG mice was significantly reduced compared with that of hepatocytes from GTG mice (GTG ADX: 125 ± 10 nmol glucosell0 6 cells; GTG: 403 ± 65 nmol glucosell0 6 cells; p<0.05). ADX also significantly JlIDol/liver; GTG: 614 ± 60 umol/llver; p<0.05) and fatty acid content (GTG ADX: 101 ± 9 mg fatty acidlg liver; GTG: 404 ± 40 mg fatty acidlg liver; p<0.05) of the liver of GTG-obese mice. ADX of GTG-obese mice reduced PDH activity by varying degrees in all tissues, except quadriceps muscle. These observations are consistent with an ADX induced decrease in hepatic lipid stores removing fatty acid-induced increases in gluconeogenesis and increased peripheral availability of fatty acids inhibiting PDH activity via the glucose/fatty acid cycle. It is also evident that the improvement in glucose tolerance which accompanies ADX of GTGobese mice is not due to increased PDH activity resulting in enhanced peripheral glucose oxidation. Instead, it is more likely that reduced blood glucose levels after ADX of GTG-obese mice are the result of decreased gluconeogenesis in the liver.