The Greater Contribution of Gluconeogenesis to Glucose Production in Obesity Is Related to Increased Whole-Body Protein Catabolism

Abstract

Obesity is associated with an increase in the fractional contribution of gluconeogenesis (GNG) to glucose production. We tested if this was related to the altered protein metabolism in obesity. GNG PEP (via phosphoenol pyruvate [PEP]) was measured after a 17-h fast using the deuterated water method and 2 H nuclear magnetic resonance spectroscopy of plasma glucose. Whole-body 13 C-leucine and 3 Hglucose kinetics were measured in the postabsorptive state and during a hyperinsulinemic-euglycemic-isoaminoacidemic clamp in 19 (10 men and 9 women) lean and 16 (7 men and 9 women) obese nondiabetic subjects. Endogenous glucose production was not different between groups. Postabsorptive %GNG PEP and GNG PEP flux were higher in obese subjects, and glycogenolysis contributed less to glucose production than in lean subjects. GNG PEP flux correlated with all indexes of adiposity and with postabsorptive leucine rate of appearance (R a ) (protein catabolism). GNG PEP was negatively related to the clamp glucose rate of disposal (R d ) and to the protein anabolic response to hyperinsulinemia. In conclusion, the increased contribution of GNG to glucose production in obesity is linked to increased postabsorptive protein catabolism and insulin resistance of both glucose and protein metabolism. Due to increased protein turnover rates, greater supply of gluconeogenic amino acids to the liver may trigger their preferential use over glycogen for glucose production. Diabetes 55:675-681, 2006 T he increased fractional contribution of gluconeogenesis (GNG) to postaborptive endogenous glucose production (EGP) in type 2 diabetes is well established (1), but its role in obesity is less clear. Elevated GNG has also been reported in obesity but is associated with a smaller contribution of glycogenolysis (GLY), and hence with no increase in EGP, and therefore euglycemia (2-4). Thus, since hepatic autoregulation (5) is apparently intact in obese subjects, it is not immediately clear what mechanism is responsible for increased GNG. Such autoregulation does not appear to be intact in type 2 diabetes (2,3,6), but it remains uncertain whether it causes increased EGP as hyperglycemia increases (1)(2)(3)7,8). Insulin resistance is a hallmark of both type 2 diabetes and obesity, affecting not only glucose and lipid metabolism (9) but protein as well. We have shown that whole-body protein catabolism is increased in hyperglycemic type 2 diabetic people but improves when normoglycemia is achieved with insulin and oral antihyperglycemic agents and with hypoenergetic feeding (10,11). Recently, we reported that postabsorptive rates of endogenous leucine rate of appearance (R a ) (index of protein catabolism) are increased in obese compared with lean women (12). Further, it is well known that when the portal vein glucagon/insulin relationship favors GNG, its rate can be controlled by the supply of substrate from the periphery (9,13). Taken together, these data led us to hypothesize that elevated protein catabolism in obesity contributes to higher GNG via incr...

Whole-Body Proteolysis Rate Is Elevated in HIV-Associated Insulin Resistance

“…Blunted insulinmediated suppression of glucose R a is likely due to increased proteolysis and amino acid availability rather than HIV infection or its treatment. This notion is supported by a recent report that elevated whole-body proteolytic rates are related to elevated rates of gluconeogenesis in obese HIV-negative subjects (33). The relationship between whole-body proteolysis and glucose production may be explained by increased hepatic and renal conversion of alanine and glutamine to glucose (34) in HIVϩIGT subjects.…”

Increasing Dietary Leucine Intake Reduces Diet-Induced Obesity and Improves Glucose and Cholesterol Metabolism in Mice via Multimechanisms

“…Two important players in the regulation of hepatic glucose production, plasma glucagon concentrations and hepatic G6P expression levels, were both lower in HFD-Leu mice. Additionally, plasma concentrations of glycogenic amino acids, which provide substrates for hepatic gluconeogenesis in the postabsorptive state (42), were also lower in HFD-Leu mice. Taken together, these results suggest that hepatic glucose production may be decreased in HFD-Leu mice, which could contribute to the improved glycemic control.…”

Stressing diabetes? The hidden links between insulinotropic peptides and the HPA axis

“…glucagon, catecholamines and growth hormone), which culminates in the release of glucose by hepatocytes (van Raalte et al 2009). In this regard, GCs promote the expression rate of limiting enzymes of gluconeogenesis in rats, including phosphoenolpyruvate carboxykinase (PEPCK) and glucose-6-phosphatase (G6Pase: Sasaki et al 1984, Chevalier et al 2006, van Raalte et al 2009). In the muscle, GCs inhibit glucose uptake and glycogen synthesis, cellular processes regulated by the insulin/IGF-1 signalling pathway (Heszele & Price 2004, Vegiopoulos & Herzig 2007.…”