Abnormal renal and hepatic glucose metabolism in type 2 diabetes mellitus.

Abstract

Release of glucose by liver and kidney are both increased in diabetic animals. Although the overall release of glucose into the circulation is increased in humans with diabetes, excessive release of glucose by either their liver or kidney has not as yet been demonstrated. The present experiments were therefore undertaken to assess the relative contributions of hepatic and renal glucose release to the excessive glucose release found in type 2 diabetes. Using a combination of isotopic and balance techniques to determine total systemic glucose release and renal glucose release in postabsorptive type 2 diabetic subjects and age-weight-matched nondiabetic volunteers, their hepatic glucose release was then calculated as the difference between total systemic glucose release and renal glucose release. Renal glucose release was increased nearly 300% in diabetic subjects (321 Ϯ 36 vs. 125 Ϯ 15 mol/min, P Ͻ 0.001). Hepatic glucose release was increased ‫ف‬ 30% ( P ϭ 0.03), but increments in hepatic and renal glucose release were comparable (2.60 Ϯ 0.70 vs. 2.21 Ϯ 0.32, mol и kg Ϫ 1 и min Ϫ 1 , respectively, P ϭ 0.26). Renal glucose uptake was markedly increased in diabetic subjects (353 Ϯ 48 vs. 103 Ϯ 10 mol/min, P Ͻ 0.001), resulting in net renal glucose uptake in the diabetic subjects (92 Ϯ 50 mol/ min) versus a net output in the nondiabetic subjects (21 Ϯ 14 mol/min, P ϭ 0.043). Renal glucose uptake was inversely correlated with renal FFA uptake ( r ϭ Ϫ 0.51, P Ͻ 0.01), which was reduced by ‫ف‬ 60% in diabetic subjects (10.9 Ϯ 2.7 vs. 27.0 Ϯ 3.3 mol/min, P Ͻ 0.002). We conclude that in type 2 diabetes, both liver and kidney contribute to glucose overproduction and that renal glucose uptake is markedly increased. The latter may suppress renal FFA uptake via a glucose-fatty acid cycle and explain the accumulation of glycogen commonly found in the diabetic kidney. ( J. Clin. Invest. 1998. 102:619-624.)

Renal amino acid, fat and glucose metabolism in type 1 diabetic and non-diabetic humans: effects of acute insulin withdrawal

“…The renal contribution to endogenous glucose production has been a matter of much controversy [4][5][6][7][8][9][10][11][12]28]. Much of the confusion in all likelihood has arisen from the fact that measurements across the renal bed, because of the high renal blood flow of around 1 l/min, are highly susceptible to methodological imprecision as regards analysis of differences in arteriovenous glucose concentrations and dilution of tracers.…”

“…This renewed interest in the metabolic role of the kidney was fuelled by a study by Cersosimo et al [5] who used arteriovenous balance and isotopic dilution techniques to report that in postabsorptive dogs renal glucose utilisation and production each accounted for close to 30% of total glucose turnover in the presence of net balances close to zero. More recent studies in humans have reported that the renal contribution to postabsorptive whole-body glucose production may amount to between 15 and 30%, that glutamine appears to be an important precursor for renal gluconeogenesis and that renal glucose production increases in response to epinephrine and hypoglycaemia and decreases during insulin exposure [6][7][8][9][10][11]. Other investigators, however, have failed to show any significant renal contribution to overall endogenous glucose production [12].…”

Peripheral insulin resistance develops in transgenic rats overexpressing phosphoenolpyruvate carboxykinase in the kidney

“…Furthermore experimental diabetes in animals results in increased renal gluconeogenesis and glucose production in vitro [43,44]. Recently increased renal glucose production has been described in patients with Type 2 diabetes which could contribute to the ensuing hyperglycaemic state [45].…”

Insulin Resistance in CKD

“…Thus, it is hypothesized that kidney dysfunction would lead to complex disturbances of glucose appearance in the circulation, resulting in insulin resistance. Metabolic studies in patients with type 2 diabetes mellitus have revealed that renal gluconeogenesissimilarly to hepatic gluconeogenesis-is not suppressed by insulin to a similar extent as in healthy individuals (14). This observation points to the presence of insulin resistance on the level of renal glucose metabolism.…”