Role of glutamine in human carbohydrate metabolism in kidney and other tissues.
(1/1508)
Glutamine is the most abundant amino acid in the human body and is involved in more metabolic processes than any other amino acid. Until recently, the understanding of many aspects of glutamine metabolism was based on animal and in vitro data. However, recent studies using isotopic and balance techniques have greatly advanced the understanding of glutamine metabolism in humans and its role in glucose metabolism in the kidney and other tissues. There is now evidence that in postabsorptive humans, glutamine is an important glucose precursor and makes a significant contribution to the addition of new carbon to the glucose carbon pool. The importance of alanine for gluconeogenesis, viewed in terms of the addition of new carbons, is less than previously assumed. It appears that glutamine is predominantly a renal gluconeogenic substrate, whereas alanine gluconeogenesis is essentially confined to the liver. As shown recently, renal gluconeogenesis contributes 20 to 25% to whole-body glucose production. Moreover, glutamine has been shown not only to stimulate net muscle glycogen storage but also to stimulate gluconeogenesis in normal humans. Finally, in humans with type II diabetes, conversion of glutamine to glucose is increased (more so than that of alanine). The available evidence on the hormonal regulation of glutamine gluconeogenesis in kidney and liver and its alterations under pathological conditions are discussed. (+info)
Inactivation of the winged helix transcription factor HNF3alpha affects glucose homeostasis and islet glucagon gene expression in vivo.
(2/1508)
Mice homozygous for a null mutation in the winged helix transcription factor HNF3alpha showed severe postnatal growth retardation followed by death between P2 and P12. Homozygous mutant mice were hypoglycemic despite unchanged expression of HNF3 target genes involved in hepatic gluconeogenesis. Whereas insulin and corticosteroid levels were altered as expected, plasma glucagon was reduced markedly in the mutant animals despite the hypoglycemia that should be expected to increase glucagon levels. This correlated with a 70% reduction in pancreatic proglucagon gene expression. We also showed that HNF3alpha could bind to and transactivate the proglucagon gene promoter. These observations invoke a central role for HNF3alpha in the regulatory control of islet genes essential for glucose homeostasis in vivo. (+info)
Contributions of net hepatic glycogenolysis and gluconeogenesis to glucose production in cirrhosis.
(3/1508)
Net hepatic glycogenolysis and gluconeogenesis were examined in normal (n = 4) and cirrhotic (n = 8) subjects using two independent methods [13C nuclear magnetic resonance spectroscopy (NMR) and a 2H2O method]. Rates of net hepatic glycogenolysis were calculated by the change in hepatic glycogen content before ( approximately 11:00 PM) and after ( approximately 7:00 AM) an overnight fast using 13C NMR and magnetic resonance imaging. Gluconeogenesis was calculated as the difference between the rates of glucose production determined with an infusion of [6,6-2H2]glucose and net hepatic glycogenolysis. In addition, the contribution of gluconeogenesis to glucose production was determined by the 2H enrichment in C-5/C-2 of blood glucose after intake of 2H2O (5 ml/kg body water). Plasma levels of total and free insulin-like growth factor I (IGF-I) and IGF-I binding proteins-1 and -3 were significantly decreased in the cirrhotic subjects (P < 0.01 vs. controls). Postprandial hepatic glycogen concentrations were 34% lower in the cirrhotic subjects (P = 0.007). Rates of glucose production were similar between the cirrhotic and healthy subjects [9.0 +/- 0.9 and 10.0 +/- 0.8 micromol. kg body wt-1. min-1, respectively]. Net hepatic glycogenolysis was 3.5-fold lower in the cirrhotic subjects (P = 0.01) and accounted for only 13 +/- 6% of glucose production compared with 40 +/- 10% (P = 0.03) in the control subjects. Gluconeogenesis was markedly increased in the cirrhotic subjects and accounted for 87 +/- 6% of glucose production vs. controls: 60 +/- 10% (P = 0.03). Gluconeogenesis in the cirrhotic subjects, as determined from the 2H enrichment in glucose C-5/C-2, was also increased and accounted for 68 +/- 3% of glucose production compared with 54 +/- 2% (P = 0.02) in the control subjects. In conclusion, cirrhotic subjects have increased rates of gluconeogenesis and decreased rates of net hepatic glycogenolysis compared with control subjects. These alterations are likely important contributing factors to their altered carbohydrate metabolism. (+info)
Enhanced gluconeogenesis and hepatic insulin resistance in insulin-like growth factor binding protein-1 transgenic mice.
(4/1508)
Fasting hyperglycemia is observed in transgenic mice which overexpress insulin-like growth factor binding protein-1. In an attempt to understand the mechanisms underlying this observation we have examined glycogenolysis and gluconeogenesis in isolated hepatocytes from wild-type and transgenic mice. Glucose production from pyruvate was significantly less responsive to inhibition by insulin in hepatocytes from transgenic mice compared to hepatocytes from wild-type mice. Serum from transgenic mice resulted in more glucose production by hepatocytes than serum from wild-type mice. Serum alanine was increased while serum lactate was significantly reduced in transgenic mice compared to wild-type mice. Serum free fatty acids and beta-hydroxybutyrate were similar in both groups of mice. These data suggest that fasting hyperglycemia is due to enhanced gluconeogenesis, hepatic insulin resistance and increased serum gluconeogenic substrate in transgenic mice. (+info)
Resistance to insulin's acute direct hepatic effect in suppressing steady-state glucose production in individuals with type 2 diabetes.
(5/1508)
We and others have shown that insulin acutely suppresses glucose production in fasting nondiabetic humans and dogs, by both a direct hepatic effect and an indirect (extrahepatic) effect, and in diabetic dogs by an indirect effect alone. In type 2 diabetes, there is resistance to insulin's ability to suppress hepatic glucose production, but it has not previously been determined whether the resistance is primarily at the level of the hepatocyte or the peripheral tissues. To determine whether the diabetic state reduces the direct effect of insulin in humans, we studied nine patients with untreated type 2 diabetes who underwent three studies each, 4-6 weeks apart. 1) Portal study (POR): intravenous tolbutamide was infused for 3 h with calculation of pancreatic insulin secretion from peripheral plasma C-peptide. 2) Peripheral study (PER): equidose insulin was infused by peripheral vein. 3) Half-dose peripheral insulin study (1/2 PER): matched peripheral insulin levels with study 1. In all studies, glucose was clamped at euglycemia, glucose turnover was measured with the constant specific activity method, and 3-[3H]glucose was purified by high-performance liquid chromatography. Peripheral insulin was lower in POR versus PER but slightly higher in POR versus 1/2 PER, although most of the difference could be accounted for by higher proinsulin levels in POR (stimulated by tolbutamide). Calculated portal insulin was approximately 1.3-fold higher in POR versus PER and approximately 2.2-fold higher in POR versus 1/2 PER. In the final 30 min of the clamp, glucose production reached a lower steady-state level in PER than in POR (4.0 +/- 0.4 vs. 5.3 +/- 0.5 pmol(-1) x kg(-1) x min(-1), P < 0.05), despite the higher hepatic insulin level in POR. In contrast with our studies in nondiabetic individuals, glucose production was not more suppressed at steady state in POR versus 1/2 PER (5.3 +/- 0.4 micromol x kg(-1) x min(-1)), despite much higher hepatic insulin levels in POR. In conclusion, this is the first study in patients with type 2 diabetes to characterize insulin resistance to the acute direct suppressive effect of insulin on hepatic glucose production. (+info)
Gluconeogenesis in very low birth weight infants receiving total parenteral nutrition.
(6/1508)
Very low birth weight (VLBW) infants are dependent on total parenteral nutrition (TPN) to prevent hypoglycemia and provide a sufficient energy intake. However, diminished tolerance for parenteral glucose delivered at high rates frequently provokes hyperglycemia. We hypothesized that when their glucose supply is reduced to prevent hyperglycemia, VLBW infants can maintain normoglycemia via gluconeogenesis from glycerol and amino acids. Twenty infants born at 27 +/- 0.2 (mean +/- SE) gestational weeks and having a birth weight of 996 +/- 28 g, received lipids (1.6 +/- 0.1 mg x kg(-1) x min(-1)), protein (2.2 +/- 0.1 mg x kg(-1) x min(-1)), and glucose (3.1 +/- 0.1 mg x kg(-1) x min(-1) [17.1 +/- 0.2 micromol x kg(-1) x min(-1)]) parenterally over a period of 8-12 h on day 5.0 +/- 0.2 of life. Gluconeogenesis was estimated using [U-13C]glucose (n = 8) or [2-(13)C] glycerol (n = 6) and mass isotopomer distribution analysis (MIDA), or 2H2O (n = 6) and the rate of deuterium incorporation in carbon 6 of glucose. Blood glucose averaged 3.0 +/- 0.1 mmol/l; plasma glucose appearance rate (glucose Ra), 28.8 +/- 1.1 micromol x kg(-1) x min(-1); and glucose production rate (GPR), 10.7 +/- 1.0 micromol x kg(-1) x min(-1). The [U-13C]glucose and [2-(13)C]glycerol tracers provided similar estimates of gluconeogenesis, averaging 28 +/- 2 and 26 +/- 2% of glucose Ra and 72 +/- 5 and 73 +/- 9% of GPR, respectively. Glycerol contributed 64 +/- 5% of total gluconeogenesis. Gluconeogenesis measured by 2H2O, which does not include the contribution from glycerol, was comparable to the nonglycerol fraction of gluconeogenesis derived by the [2-(13)C]glycerol MIDA. We conclude that in VLBW infants receiving TPN, normoglycemia was maintained during reduced glucose infusion by glucose production primarily derived from gluconeogenesis, and that glycerol was the principal gluconeogenic substrate. (+info)
Acn9 is a novel protein of gluconeogenesis that is located in the mitochondrial intermembrane space.
(7/1508)
Previous studies have indicated that the Acn9 protein is involved in gluconeogenesis. Yeast mutants defective in the ACN9 gene display phenotypes identical with mutants defective in metabolic enzymes required for carbon assimilation. These phenotypes include the inability to utilize acetate as a carbon and energy source, elevated levels of enzymes of the glyoxylate cycle, gluconeogenesis and acetyl-CoA mobilization, and a deficiency in de novo synthesis of glucose from ethanol. The ACN9 gene was isolated by functional complementation of the acetate growth defect of an acn9 mutant. The open reading frame corresponds to YDR511w, and encodes a protein of unknown function. Homologs have been identified in human, mouse, and nematode databases. Two mutant alleles were sequenced. The mutations altered amino acid residues that are conserved among members of the new gene family. ACN9 gene expression was slightly repressed by glucose, and the level of the transcript was approximately 100-fold lower than that of glyoxylate or tricarboxylic acid cycle enzymes. A functional epitope-tagged form of Acn9 was expressed to study expression and the subcellular localization of the protein. The tagged protein was localized to the mitochondrial intermembrane space. (+info)
Effects of a high-fat diet and voluntary wheel running on gluconeogenesis and lipolysis in rats.
(8/1508)
The purpose of the present study was to determine the effects of diet composition and exercise on glycerol and glucose appearance rate (Ra) and on nonglycerol gluconeogenesis (Gneo) in vivo. Male Wistar rats were fed a high-starch diet (St, 68% of energy as cornstarch, 12% corn oil) for a 2-wk baseline period and then were randomly assigned to one of four experimental groups: St (n = 7), high-fat (HF; 35% cornstarch, 45% corn oil; n = 8), St with free access to exercise wheels (StEx; n = 7), and HF with free access to exercise wheels (HFEx; n = 7). After 8 wk, glucose Ra when using [3-3H]glucose, glycerol Ra when using [2H5]glycerol (estimate of whole body lipolysis), and [3-13C]alanine incorporation into glucose (estimate of alanine Gneo) were determined. Body weight and fat pad mass were significantly (P < 0.05) decreased in exercise vs. sedentary animals only. The average amount of exercise was not significantly different between StEx (3,212 +/- 659 m/day) and HFEx (3,581 +/- 765 m/day). The ratio of glucose to alanine enrichment and absolute glycerol Ra (micromol/min) were higher (P < 0.05) in HF and HFEx compared with St and StEx rats. In separate experiments, the ratio of 3H in C-2 to C-6 of glucose from 3H2O (estimate of Gneo from pyruvate) was also higher (P < 0.05) in HF (n = 5) and HFEx (n = 5), compared with St (n = 5) and StEx (n = 5) rats. Voluntary wheel running did not significantly increase estimated alanine or pyruvate Gneo or absolute glycerol Ra. Voluntary wheel running increased (P < 0.05) glycerol Ra when normalized to fat pad mass. These data suggest that a high-fat diet can increase in vivo Gneo from precursors that pass through pyruvate. They also suggest that changes in the absolute rate of glycerol Ra may contribute to the high-fat diet-induced increase in Gneo. (+info)