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Gerald I Shulman - One of the best experts on this subject based on the ideXlab platform.
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fgf19 as a postprandial insulin independent activator of hepatic protein and Glycogen Synthesis
Science, 2011Co-Authors: Sara A Beddow, Kelly Suinopowell, Eric H Xu, Steven A. Kliewer, Varman T Samuel, Gerald I Shulman, Paul Miller, Stephen F Previs, David J. MangelsdorfAbstract:Fibroblast growth factor (FGF) 19 is an enterokine synthesized and released when bile acids are taken up into the ileum. We show that FGF19 stimulates hepatic protein and Glycogen Synthesis but does not induce lipogenesis. The effects of FGF19 are independent of the activity of either insulin or the protein kinase Akt and, instead, are mediated through a mitogen-activated protein kinase signaling pathway that activates components of the protein translation machinery and stimulates Glycogen synthase activity. Mice lacking FGF15 (the mouse FGF19 ortholog) fail to properly maintain blood concentrations of glucose and normal postprandial amounts of liver Glycogen. FGF19 treatment restored the loss of Glycogen in diabetic animals lacking insulin. Thus, FGF19 activates a physiologically important, insulin-independent endocrine pathway that regulates hepatic protein and Glycogen metabolism.
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stimulating effects of low dose fructose on insulin stimulated hepatic Glycogen Synthesis in humans
Diabetes, 2001Co-Authors: Kitt Falk Petersen, Didier Laurent, Gary W Cline, Gerald I ShulmanAbstract:Fructose has been shown to have a catalytic effect on glucokinase activity in vitro; however, its effects on hepatic Glycogen metabolism in humans is unknown. To address this question, we used 13 C nuclear magnetic resonance (NMR) spectroscopy to noninvasively assess rates of hepatic Glycogen Synthesis and Glycogenolysis under euglycemic (∼5 mmol/l) hyperinsulinemic conditions (∼400 pmol/l) with and without a low-dose infusion of fructose (∼3.5 μmol · kg –1 · min –1 ). Six healthy overnight-fasted subjects were infused for 4 h with somatostatin (0.1 μg · kg –1 · min –1 ) and insulin (240 pmol · m –2 · min –1 ). During the initial 120 min, [1- 13 C]glucose was infused to assess Glycogen synthase flux followed by an ∼120-min infusion of unlabeled glucose to assess rates of Glycogen phosphorylase flux. Acetaminophen was given to assess the percent contribution of the direct and indirect (gluconeogenic) pathways of Glycogen Synthesis by the 13 C enrichment of plasma UDP-glucuronide and C-1 of glucose. In the control studies, the flux through Glycogen synthase and Glycogen phosphorylase was 0.31 ± 0.06 and 0.17 ± 0.04 mmol/l per min, respectively, and the rate of net hepatic Glycogen Synthesis was 0.14 ± 0.05 mmol/l per min. In the fructose studies, the Glycogen synthase flux increased 2.5-fold to 0.79 ± 0.16 mmol/l per min ( P = 0.018 vs. control), whereas Glycogen phosphorylase flux remained unchanged (0.24 ± 0.06; P = 0.16 vs. control). The infusion of fructose resulted in a threefold increase in rates of net hepatic Glycogen Synthesis (0.54 ± 0.12 mmol/l per min; P = 0.008 vs. control) without affecting the pathways of hepatic Glycogen Synthesis (direct pathway ∼60% in both groups). We conclude that during euglycemic hyperinsulinemia, a low-dose fructose infusion causes a threefold increase in net hepatic Glycogen Synthesis exclusively through stimulation of Glycogen synthase flux. Because net hepatic Glycogen Synthesis has been shown to be diminished in patients with poorly controlled type 1 and type 2 diabetes, stimulation of hepatic Glycogen Synthesis by this mechanism may be of potential therapeutic value.
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impaired glucose transport as a cause of decreased insulin stimulated muscle Glycogen Synthesis in type 2 diabetes
The New England Journal of Medicine, 1999Co-Authors: Gary W Cline, Douglas L. Rothman, Kitt Falk Petersen, Martin Krssak, Jun Shen, Ripudaman S Hundal, Zlatko Trajanoski, Silvio E Inzucchi, Alan Dresner, Gerald I ShulmanAbstract:Background Insulin resistance, a major factor in the pathogenesis of type 2 diabetes mellitus, is due mostly to decreased stimulation of Glycogen Synthesis in muscle by insulin. The primary rate-controlling step responsible for the decrease in muscle Glycogen Synthesis is not known, although hexokinase activity and glucose transport have been implicated. Methods We used a novel nuclear magnetic resonance approach with carbon-13 and phosphorus-31 to measure intramuscular glucose, glucose-6-phosphate, and Glycogen concentrations under hyperglycemic conditions (plasma glucose concentration, approximately 180 mg per deciliter [10 mmol per liter]) and hyperinsulinemic conditions in six patients with type 2 diabetes and seven normal subjects. In vivo microdialysis of muscle tissue was used to determine the gradient between plasma and interstitial-fluid glucose concentrations, and open-flow microperfusion was used to determine the concentrations of insulin in interstitial fluid. Results The time course and conce...
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increased glucose transport phosphorylation and muscle Glycogen Synthesis after exercise training in insulin resistant subjects
The New England Journal of Medicine, 1996Co-Authors: Gianluca Perseghin, Douglas L. Rothman, Kitt Falk Petersen, Gary W Cline, Michael Roden, Karynn Gerow, Thomas B Price, Gerald I ShulmanAbstract:Background Insulin resistance in the offspring of parents with non-insulin-dependent diabetes mellitus (NIDDM) is the best predictor of development of the disease and probably plays an important part in its pathogenesis. We studied the mechanism and degree to which exercise training improves insulin sensitivity in these subjects. Methods Ten adult children of parents with NIDDM and eight normal subjects were studied before starting an aerobic exercise-training program, after one session of exercise, and after six weeks of exercise. Insulin sensitivity was measured by the hyperglycemic–hyperinsulinemic clamp technique combined with indirect calorimetry, and the rate of Glycogen Synthesis in muscle and the intramuscular glucose-6-phosphate concentration were measured by carbon-13 and phosphorus-31 nuclear magnetic resonance spectroscopy, respectively. Results During the base-line study, the mean (±SE) rate of muscle Glycogen Synthesis was 63±9 percent lower in the offspring of diabetic parents than in the n...
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impaired hepatic Glycogen Synthesis in glucokinase deficient mody 2 subjects
Journal of Clinical Investigation, 1996Co-Authors: Gilberto Velho, Douglas L. Rothman, Kitt Falk Petersen, Gary W Cline, Gianluca Perseghin, Jonghee Hwang, Maria E Pueyo, Philippe Froguel, Gerald I ShulmanAbstract:All glucokinase gene mutations identified to date have been localized to exons that are common to the pancreatic and hepatic isoforms of the enzyme. While impaired insulin secretion has been observed in glucokinase-deficient subjects the consequences of this mutation on hepatic glucose metabolism remain unknown. To examine this question hepatic Glycogen concentration was measured in seven glucokinase-deficient subjects with normal glycosylated hemoglobin and 12 control subjects using 13C nuclear magnetic spectroscopy during a day in which three isocaloric mixed meals were ingested. The relative fluxes of the direct and indirect pathways of hepatic Glycogen Synthesis were also assessed using [1-13C]glucose in combination with acetaminophen to noninvasively sample the hepatic UDP-glucose pool. Average fasting hepatic Glycogen content was similar in glucokinase-deficient and control subjects (279+/-20 vs 284+/-14 mM; mean+/-SEM), and increased in both groups after the meals with a continuous pattern throughout the day. However, the net increment in hepatic Glycogen content after each meal was 30-60% lower in glucokinase-deficient than in the control subjects (breakfast, 46% lower, P < 0.02; lunch, 62% lower, P = 0.002; dinner; 30% lower, P = 0.04). The net increment over basal values 4 h after dinner was 105 +/-18 mM in glucokinase-deficient and 148+/-11 mM in control subjects (P = 0.04). In the 4 h after breakfast, flux through the gluconeogenic pathway relative to the direct pathway of hepatic Glycogen Synthesis was higher in glucokinase-deficient than in control subjects (50+/-2% vs 34+/-5%; P = 0.038). In conclusion glucokinase-deficient subjects have decreased net accumulation of hepatic Glycogen and relatively augmented hepatic gluconeogenesis after meals. These results suggest that in addition to the altered beta cell function, abnormalities in liver Glycogen metabolism play an important role in the pathogenesis of hyperglycemia in patients with glucokinase-deficient maturity onset diabetes of young.
Gary W Cline - One of the best experts on this subject based on the ideXlab platform.
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pepck1 antisense oligonucleotide prevents adiposity and impairs hepatic Glycogen Synthesis in high fat male fed rats
Endocrinology, 2019Co-Authors: Sara A Beddow, Daniel F Vatner, Arijeet K Gattu, Lauren Paolella, Abdulelah Alqarzaee, Nedda Tashkandi, Violeta B Popov, Christopher D Church, Matthew S Rodeheffer, Gary W ClineAbstract:The increased hepatic gluconeogenesis in type 2 diabetes mellitus has often been ascribed to increased transcription of phosphoenolpyruvate carboxykinase 1, cystolic form (PEPCK1), although recent evidence has questioned this attribution. To assess the metabolic role of PEPCK1, we treated regular chow fed and high-fat fed (HFF) male Sprague-Dawley rats with a 2'-O-methoxyethyl chimeric antisense oligonucleotide (ASO) against PEPCK1 and compared them with control ASO-treated rats. PEPCK1 ASO effectively decreased PEPCK1 expression in the liver and white adipose tissue. In chow fed rats, PEPCK1 ASO did not alter adiposity, plasma glucose, or insulin. In contrast, PEPCK1 ASO decreased the white adipose tissue mass in HFF rats but without altering basal rates of lipolysis, de novo lipogenesis, or glyceroneogenesis in vivo. Despite the protection from adiposity, hepatic insulin sensitivity was impaired in HFF PEPCK1 ASO-treated rats. PEPCK1 ASO worsened hepatic steatosis, although without additional impairments in hepatic insulin signaling or activation of inflammatory signals in the liver. Instead, the development of hepatic insulin resistance and the decrease in hepatic Glycogen Synthesis during a hyperglycemic clamp was attributed to a decrease in hepatic glucokinase (GCK) expression and decreased Synthesis of Glycogen via the direct pathway. The decrease in GCK expression was associated with increased expression of activating transcription factor 3, a negative regulator of GCK transcription. These studies have demonstrated that PEPCK1 is integral to coordinating cellular metabolism in the liver and adipose tissue, although it does not directly effect hepatic glucose production or adipose glyceroneogenesis.
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stimulating effects of low dose fructose on insulin stimulated hepatic Glycogen Synthesis in humans
Diabetes, 2001Co-Authors: Kitt Falk Petersen, Didier Laurent, Gary W Cline, Gerald I ShulmanAbstract:Fructose has been shown to have a catalytic effect on glucokinase activity in vitro; however, its effects on hepatic Glycogen metabolism in humans is unknown. To address this question, we used 13 C nuclear magnetic resonance (NMR) spectroscopy to noninvasively assess rates of hepatic Glycogen Synthesis and Glycogenolysis under euglycemic (∼5 mmol/l) hyperinsulinemic conditions (∼400 pmol/l) with and without a low-dose infusion of fructose (∼3.5 μmol · kg –1 · min –1 ). Six healthy overnight-fasted subjects were infused for 4 h with somatostatin (0.1 μg · kg –1 · min –1 ) and insulin (240 pmol · m –2 · min –1 ). During the initial 120 min, [1- 13 C]glucose was infused to assess Glycogen synthase flux followed by an ∼120-min infusion of unlabeled glucose to assess rates of Glycogen phosphorylase flux. Acetaminophen was given to assess the percent contribution of the direct and indirect (gluconeogenic) pathways of Glycogen Synthesis by the 13 C enrichment of plasma UDP-glucuronide and C-1 of glucose. In the control studies, the flux through Glycogen synthase and Glycogen phosphorylase was 0.31 ± 0.06 and 0.17 ± 0.04 mmol/l per min, respectively, and the rate of net hepatic Glycogen Synthesis was 0.14 ± 0.05 mmol/l per min. In the fructose studies, the Glycogen synthase flux increased 2.5-fold to 0.79 ± 0.16 mmol/l per min ( P = 0.018 vs. control), whereas Glycogen phosphorylase flux remained unchanged (0.24 ± 0.06; P = 0.16 vs. control). The infusion of fructose resulted in a threefold increase in rates of net hepatic Glycogen Synthesis (0.54 ± 0.12 mmol/l per min; P = 0.008 vs. control) without affecting the pathways of hepatic Glycogen Synthesis (direct pathway ∼60% in both groups). We conclude that during euglycemic hyperinsulinemia, a low-dose fructose infusion causes a threefold increase in net hepatic Glycogen Synthesis exclusively through stimulation of Glycogen synthase flux. Because net hepatic Glycogen Synthesis has been shown to be diminished in patients with poorly controlled type 1 and type 2 diabetes, stimulation of hepatic Glycogen Synthesis by this mechanism may be of potential therapeutic value.
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impaired glucose transport as a cause of decreased insulin stimulated muscle Glycogen Synthesis in type 2 diabetes
The New England Journal of Medicine, 1999Co-Authors: Gary W Cline, Douglas L. Rothman, Kitt Falk Petersen, Martin Krssak, Jun Shen, Ripudaman S Hundal, Zlatko Trajanoski, Silvio E Inzucchi, Alan Dresner, Gerald I ShulmanAbstract:Background Insulin resistance, a major factor in the pathogenesis of type 2 diabetes mellitus, is due mostly to decreased stimulation of Glycogen Synthesis in muscle by insulin. The primary rate-controlling step responsible for the decrease in muscle Glycogen Synthesis is not known, although hexokinase activity and glucose transport have been implicated. Methods We used a novel nuclear magnetic resonance approach with carbon-13 and phosphorus-31 to measure intramuscular glucose, glucose-6-phosphate, and Glycogen concentrations under hyperglycemic conditions (plasma glucose concentration, approximately 180 mg per deciliter [10 mmol per liter]) and hyperinsulinemic conditions in six patients with type 2 diabetes and seven normal subjects. In vivo microdialysis of muscle tissue was used to determine the gradient between plasma and interstitial-fluid glucose concentrations, and open-flow microperfusion was used to determine the concentrations of insulin in interstitial fluid. Results The time course and conce...
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increased glucose transport phosphorylation and muscle Glycogen Synthesis after exercise training in insulin resistant subjects
The New England Journal of Medicine, 1996Co-Authors: Gianluca Perseghin, Douglas L. Rothman, Kitt Falk Petersen, Gary W Cline, Michael Roden, Karynn Gerow, Thomas B Price, Gerald I ShulmanAbstract:Background Insulin resistance in the offspring of parents with non-insulin-dependent diabetes mellitus (NIDDM) is the best predictor of development of the disease and probably plays an important part in its pathogenesis. We studied the mechanism and degree to which exercise training improves insulin sensitivity in these subjects. Methods Ten adult children of parents with NIDDM and eight normal subjects were studied before starting an aerobic exercise-training program, after one session of exercise, and after six weeks of exercise. Insulin sensitivity was measured by the hyperglycemic–hyperinsulinemic clamp technique combined with indirect calorimetry, and the rate of Glycogen Synthesis in muscle and the intramuscular glucose-6-phosphate concentration were measured by carbon-13 and phosphorus-31 nuclear magnetic resonance spectroscopy, respectively. Results During the base-line study, the mean (±SE) rate of muscle Glycogen Synthesis was 63±9 percent lower in the offspring of diabetic parents than in the n...
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impaired hepatic Glycogen Synthesis in glucokinase deficient mody 2 subjects
Journal of Clinical Investigation, 1996Co-Authors: Gilberto Velho, Douglas L. Rothman, Kitt Falk Petersen, Gary W Cline, Gianluca Perseghin, Jonghee Hwang, Maria E Pueyo, Philippe Froguel, Gerald I ShulmanAbstract:All glucokinase gene mutations identified to date have been localized to exons that are common to the pancreatic and hepatic isoforms of the enzyme. While impaired insulin secretion has been observed in glucokinase-deficient subjects the consequences of this mutation on hepatic glucose metabolism remain unknown. To examine this question hepatic Glycogen concentration was measured in seven glucokinase-deficient subjects with normal glycosylated hemoglobin and 12 control subjects using 13C nuclear magnetic spectroscopy during a day in which three isocaloric mixed meals were ingested. The relative fluxes of the direct and indirect pathways of hepatic Glycogen Synthesis were also assessed using [1-13C]glucose in combination with acetaminophen to noninvasively sample the hepatic UDP-glucose pool. Average fasting hepatic Glycogen content was similar in glucokinase-deficient and control subjects (279+/-20 vs 284+/-14 mM; mean+/-SEM), and increased in both groups after the meals with a continuous pattern throughout the day. However, the net increment in hepatic Glycogen content after each meal was 30-60% lower in glucokinase-deficient than in the control subjects (breakfast, 46% lower, P < 0.02; lunch, 62% lower, P = 0.002; dinner; 30% lower, P = 0.04). The net increment over basal values 4 h after dinner was 105 +/-18 mM in glucokinase-deficient and 148+/-11 mM in control subjects (P = 0.04). In the 4 h after breakfast, flux through the gluconeogenic pathway relative to the direct pathway of hepatic Glycogen Synthesis was higher in glucokinase-deficient than in control subjects (50+/-2% vs 34+/-5%; P = 0.038). In conclusion glucokinase-deficient subjects have decreased net accumulation of hepatic Glycogen and relatively augmented hepatic gluconeogenesis after meals. These results suggest that in addition to the altered beta cell function, abnormalities in liver Glycogen metabolism play an important role in the pathogenesis of hyperglycemia in patients with glucokinase-deficient maturity onset diabetes of young.
Douglas L. Rothman - One of the best experts on this subject based on the ideXlab platform.
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impaired glucose transport as a cause of decreased insulin stimulated muscle Glycogen Synthesis in type 2 diabetes
The New England Journal of Medicine, 1999Co-Authors: Gary W Cline, Douglas L. Rothman, Kitt Falk Petersen, Martin Krssak, Jun Shen, Ripudaman S Hundal, Zlatko Trajanoski, Silvio E Inzucchi, Alan Dresner, Gerald I ShulmanAbstract:Background Insulin resistance, a major factor in the pathogenesis of type 2 diabetes mellitus, is due mostly to decreased stimulation of Glycogen Synthesis in muscle by insulin. The primary rate-controlling step responsible for the decrease in muscle Glycogen Synthesis is not known, although hexokinase activity and glucose transport have been implicated. Methods We used a novel nuclear magnetic resonance approach with carbon-13 and phosphorus-31 to measure intramuscular glucose, glucose-6-phosphate, and Glycogen concentrations under hyperglycemic conditions (plasma glucose concentration, approximately 180 mg per deciliter [10 mmol per liter]) and hyperinsulinemic conditions in six patients with type 2 diabetes and seven normal subjects. In vivo microdialysis of muscle tissue was used to determine the gradient between plasma and interstitial-fluid glucose concentrations, and open-flow microperfusion was used to determine the concentrations of insulin in interstitial fluid. Results The time course and conce...
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increased glucose transport phosphorylation and muscle Glycogen Synthesis after exercise training in insulin resistant subjects
The New England Journal of Medicine, 1996Co-Authors: Gianluca Perseghin, Douglas L. Rothman, Kitt Falk Petersen, Gary W Cline, Michael Roden, Karynn Gerow, Thomas B Price, Gerald I ShulmanAbstract:Background Insulin resistance in the offspring of parents with non-insulin-dependent diabetes mellitus (NIDDM) is the best predictor of development of the disease and probably plays an important part in its pathogenesis. We studied the mechanism and degree to which exercise training improves insulin sensitivity in these subjects. Methods Ten adult children of parents with NIDDM and eight normal subjects were studied before starting an aerobic exercise-training program, after one session of exercise, and after six weeks of exercise. Insulin sensitivity was measured by the hyperglycemic–hyperinsulinemic clamp technique combined with indirect calorimetry, and the rate of Glycogen Synthesis in muscle and the intramuscular glucose-6-phosphate concentration were measured by carbon-13 and phosphorus-31 nuclear magnetic resonance spectroscopy, respectively. Results During the base-line study, the mean (±SE) rate of muscle Glycogen Synthesis was 63±9 percent lower in the offspring of diabetic parents than in the n...
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impaired hepatic Glycogen Synthesis in glucokinase deficient mody 2 subjects
Journal of Clinical Investigation, 1996Co-Authors: Gilberto Velho, Douglas L. Rothman, Kitt Falk Petersen, Gary W Cline, Gianluca Perseghin, Jonghee Hwang, Maria E Pueyo, Philippe Froguel, Gerald I ShulmanAbstract:All glucokinase gene mutations identified to date have been localized to exons that are common to the pancreatic and hepatic isoforms of the enzyme. While impaired insulin secretion has been observed in glucokinase-deficient subjects the consequences of this mutation on hepatic glucose metabolism remain unknown. To examine this question hepatic Glycogen concentration was measured in seven glucokinase-deficient subjects with normal glycosylated hemoglobin and 12 control subjects using 13C nuclear magnetic spectroscopy during a day in which three isocaloric mixed meals were ingested. The relative fluxes of the direct and indirect pathways of hepatic Glycogen Synthesis were also assessed using [1-13C]glucose in combination with acetaminophen to noninvasively sample the hepatic UDP-glucose pool. Average fasting hepatic Glycogen content was similar in glucokinase-deficient and control subjects (279+/-20 vs 284+/-14 mM; mean+/-SEM), and increased in both groups after the meals with a continuous pattern throughout the day. However, the net increment in hepatic Glycogen content after each meal was 30-60% lower in glucokinase-deficient than in the control subjects (breakfast, 46% lower, P < 0.02; lunch, 62% lower, P = 0.002; dinner; 30% lower, P = 0.04). The net increment over basal values 4 h after dinner was 105 +/-18 mM in glucokinase-deficient and 148+/-11 mM in control subjects (P = 0.04). In the 4 h after breakfast, flux through the gluconeogenic pathway relative to the direct pathway of hepatic Glycogen Synthesis was higher in glucokinase-deficient than in control subjects (50+/-2% vs 34+/-5%; P = 0.038). In conclusion glucokinase-deficient subjects have decreased net accumulation of hepatic Glycogen and relatively augmented hepatic gluconeogenesis after meals. These results suggest that in addition to the altered beta cell function, abnormalities in liver Glycogen metabolism play an important role in the pathogenesis of hyperglycemia in patients with glucokinase-deficient maturity onset diabetes of young.
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the roles of insulin and glucagon in the regulation of hepatic Glycogen Synthesis and turnover in humans
Journal of Clinical Investigation, 1996Co-Authors: Michael Roden, Douglas L. Rothman, Kitt Falk Petersen, Gary W Cline, Gianluca Perseghin, Jonghee Hwang, Karynn Gerow, Gerald I ShulmanAbstract:To determine the respective roles of insulin and glucagon for hepatic Glycogen Synthesis and turnover, hyperglycemic clamps were performed with somatostatin [0.1 micrograms/(kg.min)] in healthy young men under conditions of: (I) basal fasting) portal vein insulinemia-hypoglucagonemia, (II) basal portal vein insulinemia-basal glucagonemia, and (III) basal peripheral insulinemia-hypoglucagonemia. Synthetic rates, pathway (direct versus indirect) contributions, and percent turnover of hepatic Glycogen were assessed by in vivo 13C nuclear magnetic resonance spectroscopy during [1-13C]glucose infusion followed by a natural abundance glucose chase in conjunction with acetaminophen to noninvasively sample the hepatic UDP-glucose pool. In the presence of hyperglycemia (10.4 +/- 0.1 mM) and basal portal vein insulinemia (192 +/- 6 pM), suppression of glucagon secretion (plasma glucagon, I:31 +/- 4, II: 63 +/- 8 pg/ml) doubled the hepatic accumulation of Glycogen (Vsyn) compared with conditions of basal glucagonemia [I: 0.40 +/- 0.06, II: 0.19 +/- 0.03 mumol/(liter.min): P < 0.0025]. Glycogen turnover was markedly reduced (I: 19 +/- 7%, II: 69 +/- 12%; P < 0.005), so that net rate of Glycogen Synthesis increased approximately fivefold (P < 0.001) by inhibition of glucagon secretion. The relative contribution of gluconeogenesis (indirect pathway) to Glycogen Synthesis was lower during hypoglucagonemia (42 +/- 6%) than during basal glucagonemia (54 +/- 5%; P < 0.005). Under conditions of basal peripheral insulinemia (54 +/- 2 pM) and hypoglucagonemia (III) there was negligible hepatic Glycogen Synthesis and turnover. In conclusion, small changes in portal vein concentrations of insulin and glucagon independently affect hepatic Glycogen Synthesis and turnover. Inhibition of glucagon secretion under conditions of hyperglycemia and basal concentrations of insulin results in: (a) twofold increase in rate of hepatic Glycogen Synthesis, (b) reduction of Glycogen turnover by approximately 73%, and (c) augmented percent contribution of the direct pathway to Glycogen Synthesis compared with conditions of basal glucagonemia.
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In vivo regulation of muscle Glycogen synthase and the control of Glycogen Synthesis
Proceedings of the National Academy of Sciences of the United States of America, 1995Co-Authors: Robert G. Shulman, G Bloch, Douglas L. RothmanAbstract:The activity of Glycogen synthase (GSase; EC 2.4.1.11) is regulated by covalent phosphorylation. Because of this regulation, GSase has generally been considered to control the rate of Glycogen Synthesis. This hypothesis is examined in light of recent in vivo NMR experiments on rat and human muscle and is found to be quantitatively inconsistent with the data under conditions of Glycogen Synthesis. Our first experiments showed that muscle Glycogen Synthesis was slower in non-insulin-dependent diabetics compared to normals and that their defect was in the glucose transporter/hexokinase (GT/HK) part of the pathway. From these and other in vivo NMR results a quantitative model is proposed in which the GT/HK steps control the rate of Glycogen Synthesis in normal humans and rat muscle. The flux through GSase is regulated to match the proximal steps by "feed forward" to glucose 6-phosphate, which is a positive allosteric effector of all forms of GSase. Recent in vivo NMR experiments specifically designed to test the model are analyzed by metabolic control theory and it is shown quantitatively that the GT/HK step controls the rate of Glycogen Synthesis. Preliminary evidence favors the transporter step. Several conclusions are significant: (i) glucose transport/hexokinase controls the Glycogen Synthesis flux; (ii) the role of covalent phosphorylation of GSase is to adapt the activity of the enzyme to the flux and to control the metabolite levels not the flux; (iii) the quantitative data needed for inferring and testing the present model of flux control depended upon advances of in vivo NMR methods that accurately measured the concentration of glucose 6-phosphate and the rate of Glycogen Synthesis.
Kitt Falk Petersen - One of the best experts on this subject based on the ideXlab platform.
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stimulating effects of low dose fructose on insulin stimulated hepatic Glycogen Synthesis in humans
Diabetes, 2001Co-Authors: Kitt Falk Petersen, Didier Laurent, Gary W Cline, Gerald I ShulmanAbstract:Fructose has been shown to have a catalytic effect on glucokinase activity in vitro; however, its effects on hepatic Glycogen metabolism in humans is unknown. To address this question, we used 13 C nuclear magnetic resonance (NMR) spectroscopy to noninvasively assess rates of hepatic Glycogen Synthesis and Glycogenolysis under euglycemic (∼5 mmol/l) hyperinsulinemic conditions (∼400 pmol/l) with and without a low-dose infusion of fructose (∼3.5 μmol · kg –1 · min –1 ). Six healthy overnight-fasted subjects were infused for 4 h with somatostatin (0.1 μg · kg –1 · min –1 ) and insulin (240 pmol · m –2 · min –1 ). During the initial 120 min, [1- 13 C]glucose was infused to assess Glycogen synthase flux followed by an ∼120-min infusion of unlabeled glucose to assess rates of Glycogen phosphorylase flux. Acetaminophen was given to assess the percent contribution of the direct and indirect (gluconeogenic) pathways of Glycogen Synthesis by the 13 C enrichment of plasma UDP-glucuronide and C-1 of glucose. In the control studies, the flux through Glycogen synthase and Glycogen phosphorylase was 0.31 ± 0.06 and 0.17 ± 0.04 mmol/l per min, respectively, and the rate of net hepatic Glycogen Synthesis was 0.14 ± 0.05 mmol/l per min. In the fructose studies, the Glycogen synthase flux increased 2.5-fold to 0.79 ± 0.16 mmol/l per min ( P = 0.018 vs. control), whereas Glycogen phosphorylase flux remained unchanged (0.24 ± 0.06; P = 0.16 vs. control). The infusion of fructose resulted in a threefold increase in rates of net hepatic Glycogen Synthesis (0.54 ± 0.12 mmol/l per min; P = 0.008 vs. control) without affecting the pathways of hepatic Glycogen Synthesis (direct pathway ∼60% in both groups). We conclude that during euglycemic hyperinsulinemia, a low-dose fructose infusion causes a threefold increase in net hepatic Glycogen Synthesis exclusively through stimulation of Glycogen synthase flux. Because net hepatic Glycogen Synthesis has been shown to be diminished in patients with poorly controlled type 1 and type 2 diabetes, stimulation of hepatic Glycogen Synthesis by this mechanism may be of potential therapeutic value.
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impaired glucose transport as a cause of decreased insulin stimulated muscle Glycogen Synthesis in type 2 diabetes
The New England Journal of Medicine, 1999Co-Authors: Gary W Cline, Douglas L. Rothman, Kitt Falk Petersen, Martin Krssak, Jun Shen, Ripudaman S Hundal, Zlatko Trajanoski, Silvio E Inzucchi, Alan Dresner, Gerald I ShulmanAbstract:Background Insulin resistance, a major factor in the pathogenesis of type 2 diabetes mellitus, is due mostly to decreased stimulation of Glycogen Synthesis in muscle by insulin. The primary rate-controlling step responsible for the decrease in muscle Glycogen Synthesis is not known, although hexokinase activity and glucose transport have been implicated. Methods We used a novel nuclear magnetic resonance approach with carbon-13 and phosphorus-31 to measure intramuscular glucose, glucose-6-phosphate, and Glycogen concentrations under hyperglycemic conditions (plasma glucose concentration, approximately 180 mg per deciliter [10 mmol per liter]) and hyperinsulinemic conditions in six patients with type 2 diabetes and seven normal subjects. In vivo microdialysis of muscle tissue was used to determine the gradient between plasma and interstitial-fluid glucose concentrations, and open-flow microperfusion was used to determine the concentrations of insulin in interstitial fluid. Results The time course and conce...
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increased glucose transport phosphorylation and muscle Glycogen Synthesis after exercise training in insulin resistant subjects
The New England Journal of Medicine, 1996Co-Authors: Gianluca Perseghin, Douglas L. Rothman, Kitt Falk Petersen, Gary W Cline, Michael Roden, Karynn Gerow, Thomas B Price, Gerald I ShulmanAbstract:Background Insulin resistance in the offspring of parents with non-insulin-dependent diabetes mellitus (NIDDM) is the best predictor of development of the disease and probably plays an important part in its pathogenesis. We studied the mechanism and degree to which exercise training improves insulin sensitivity in these subjects. Methods Ten adult children of parents with NIDDM and eight normal subjects were studied before starting an aerobic exercise-training program, after one session of exercise, and after six weeks of exercise. Insulin sensitivity was measured by the hyperglycemic–hyperinsulinemic clamp technique combined with indirect calorimetry, and the rate of Glycogen Synthesis in muscle and the intramuscular glucose-6-phosphate concentration were measured by carbon-13 and phosphorus-31 nuclear magnetic resonance spectroscopy, respectively. Results During the base-line study, the mean (±SE) rate of muscle Glycogen Synthesis was 63±9 percent lower in the offspring of diabetic parents than in the n...
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impaired hepatic Glycogen Synthesis in glucokinase deficient mody 2 subjects
Journal of Clinical Investigation, 1996Co-Authors: Gilberto Velho, Douglas L. Rothman, Kitt Falk Petersen, Gary W Cline, Gianluca Perseghin, Jonghee Hwang, Maria E Pueyo, Philippe Froguel, Gerald I ShulmanAbstract:All glucokinase gene mutations identified to date have been localized to exons that are common to the pancreatic and hepatic isoforms of the enzyme. While impaired insulin secretion has been observed in glucokinase-deficient subjects the consequences of this mutation on hepatic glucose metabolism remain unknown. To examine this question hepatic Glycogen concentration was measured in seven glucokinase-deficient subjects with normal glycosylated hemoglobin and 12 control subjects using 13C nuclear magnetic spectroscopy during a day in which three isocaloric mixed meals were ingested. The relative fluxes of the direct and indirect pathways of hepatic Glycogen Synthesis were also assessed using [1-13C]glucose in combination with acetaminophen to noninvasively sample the hepatic UDP-glucose pool. Average fasting hepatic Glycogen content was similar in glucokinase-deficient and control subjects (279+/-20 vs 284+/-14 mM; mean+/-SEM), and increased in both groups after the meals with a continuous pattern throughout the day. However, the net increment in hepatic Glycogen content after each meal was 30-60% lower in glucokinase-deficient than in the control subjects (breakfast, 46% lower, P < 0.02; lunch, 62% lower, P = 0.002; dinner; 30% lower, P = 0.04). The net increment over basal values 4 h after dinner was 105 +/-18 mM in glucokinase-deficient and 148+/-11 mM in control subjects (P = 0.04). In the 4 h after breakfast, flux through the gluconeogenic pathway relative to the direct pathway of hepatic Glycogen Synthesis was higher in glucokinase-deficient than in control subjects (50+/-2% vs 34+/-5%; P = 0.038). In conclusion glucokinase-deficient subjects have decreased net accumulation of hepatic Glycogen and relatively augmented hepatic gluconeogenesis after meals. These results suggest that in addition to the altered beta cell function, abnormalities in liver Glycogen metabolism play an important role in the pathogenesis of hyperglycemia in patients with glucokinase-deficient maturity onset diabetes of young.
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the roles of insulin and glucagon in the regulation of hepatic Glycogen Synthesis and turnover in humans
Journal of Clinical Investigation, 1996Co-Authors: Michael Roden, Douglas L. Rothman, Kitt Falk Petersen, Gary W Cline, Gianluca Perseghin, Jonghee Hwang, Karynn Gerow, Gerald I ShulmanAbstract:To determine the respective roles of insulin and glucagon for hepatic Glycogen Synthesis and turnover, hyperglycemic clamps were performed with somatostatin [0.1 micrograms/(kg.min)] in healthy young men under conditions of: (I) basal fasting) portal vein insulinemia-hypoglucagonemia, (II) basal portal vein insulinemia-basal glucagonemia, and (III) basal peripheral insulinemia-hypoglucagonemia. Synthetic rates, pathway (direct versus indirect) contributions, and percent turnover of hepatic Glycogen were assessed by in vivo 13C nuclear magnetic resonance spectroscopy during [1-13C]glucose infusion followed by a natural abundance glucose chase in conjunction with acetaminophen to noninvasively sample the hepatic UDP-glucose pool. In the presence of hyperglycemia (10.4 +/- 0.1 mM) and basal portal vein insulinemia (192 +/- 6 pM), suppression of glucagon secretion (plasma glucagon, I:31 +/- 4, II: 63 +/- 8 pg/ml) doubled the hepatic accumulation of Glycogen (Vsyn) compared with conditions of basal glucagonemia [I: 0.40 +/- 0.06, II: 0.19 +/- 0.03 mumol/(liter.min): P < 0.0025]. Glycogen turnover was markedly reduced (I: 19 +/- 7%, II: 69 +/- 12%; P < 0.005), so that net rate of Glycogen Synthesis increased approximately fivefold (P < 0.001) by inhibition of glucagon secretion. The relative contribution of gluconeogenesis (indirect pathway) to Glycogen Synthesis was lower during hypoglucagonemia (42 +/- 6%) than during basal glucagonemia (54 +/- 5%; P < 0.005). Under conditions of basal peripheral insulinemia (54 +/- 2 pM) and hypoglucagonemia (III) there was negligible hepatic Glycogen Synthesis and turnover. In conclusion, small changes in portal vein concentrations of insulin and glucagon independently affect hepatic Glycogen Synthesis and turnover. Inhibition of glucagon secretion under conditions of hyperglycemia and basal concentrations of insulin results in: (a) twofold increase in rate of hepatic Glycogen Synthesis, (b) reduction of Glycogen turnover by approximately 73%, and (c) augmented percent contribution of the direct pathway to Glycogen Synthesis compared with conditions of basal glucagonemia.
Asker E. Jeukendrup - One of the best experts on this subject based on the ideXlab platform.
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fructose and galactose enhance postexercise human liver Glycogen Synthesis
Medicine and Science in Sports and Exercise, 2011Co-Authors: Jacques Decombaz, Roy Jentjens, Asker E. Jeukendrup, Michael Ith, Eva Scheurer, Tania Buehler, Chris BoeschAbstract:Both liver and muscle Glycogen stores play a fundamental role in exercise and fatigue, but the effect of different CHO sources on liver Glycogen Synthesis in humans is unclear. The aim was to compare the effect of maltodextrin (MD) drinks containing galactose, fructose, or glucose on postexercise liver Glycogen Synthesis.
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Determinants of Post-Exercise Glycogen Synthesis During Short-Term Recovery
Sports Medicine, 2003Co-Authors: Roy Jentjens, Asker E. JeukendrupAbstract:The pattern of muscle Glycogen Synthesis following Glycogen-depleting exercise occurs in two phases. Initially, there is a period of rapid Synthesis of muscle Glycogen that does not require the presence of insulin and lasts about 30–60 minutes. This rapid phase of muscle Glycogen Synthesis is characterised by an exercise-induced translocation of glucose transporter carrier protein-4 to the cell surface, leading to an increased permeability of the muscle membrane to glucose. Following this rapid phase of Glycogen Synthesis, muscle Glycogen Synthesis occurs at a much slower rate and this phase can last for several hours. Both muscle contraction and insulin have been shown to increase the activity of Glycogen synthase, the rate-limiting enzyme in Glycogen Synthesis. Furthermore, it has been shown that muscle Glycogen concentration is a potent regulator of Glycogen synthase. Low muscle Glycogen concentrations following exercise are associated with an increased rate of glucose transport and an increased capacity to convert glucose into Glycogen. The highest muscle Glycogen Synthesis rates have been reported when large amounts of carbohydrate (1.0–1.85 g/kg/h) are consumed immediately post-exercise and at 15.60 minute intervals thereafter, for up to 5 hours post-exercise. When carbohydrate ingestion is delayed by several hours, this may lead to ∼50% lower rates of muscle Glycogen Synthesis. The addition of certain amino acids and/ or proteins to a carbohydrate supplement can increase muscle Glycogen Synthesis rates, most probably because of an enhanced insulin response. However, when carbohydrate intake is high (≥1.2 g/kg/h) and provided at regular intervals, a further increase in insulin concentrations by additional supplementation of protein and/or amino acids does not further increase the rate of muscle Glycogen Synthesis. Thus, when carbohydrate intake is insufficient (1 g/min) of glucose are ingested following exercise.
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determinants of post exercise Glycogen Synthesis during short term recovery
Sports Medicine, 2003Co-Authors: Roy Jentjens, Asker E. JeukendrupAbstract:The pattern of muscle Glycogen Synthesis following Glycogen-depleting exercise occurs in two phases. Initially, there is a period of rapid Synthesis of muscle Glycogen that does not require the presence of insulin and lasts about 30–60 minutes. This rapid phase of muscle Glycogen Synthesis is characterised by an exercise-induced translocation of glucose transporter carrier protein-4 to the cell surface, leading to an increased permeability of the muscle membrane to glucose. Following this rapid phase of Glycogen Synthesis, muscle Glycogen Synthesis occurs at a much slower rate and this phase can last for several hours. Both muscle contraction and insulin have been shown to increase the activity of Glycogen synthase, the rate-limiting enzyme in Glycogen Synthesis. Furthermore, it has been shown that muscle Glycogen concentration is a potent regulator of Glycogen synthase. Low muscle Glycogen concentrations following exercise are associated with an increased rate of glucose transport and an increased capacity to convert glucose into Glycogen.
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addition of protein and amino acids to carbohydrates does not enhance postexercise muscle Glycogen Synthesis
Journal of Applied Physiology, 2001Co-Authors: Roy Jentjens, Luc J C Van Loon, Christopher H Mann, Anton J M Wagenmakers, Asker E. JeukendrupAbstract:Ingestion of a protein-amino acid mixture (Pro; wheat protein hydrolysate, leucine, and phenylalanine) in combination with carbohydrate (CHO; 0.8 g x kg(-1) x h(-1)) has been shown to increase muscle Glycogen Synthesis after exercise compared with the same amount of CHO without Pro. The aim of this study was to investigate whether coingestion of Pro also increases muscle Glycogen Synthesis when 1.2 g CHO. kg(-1). h(-1) is ingested. Eight male cyclists performed two experimental trials separated by 1 wk. After Glycogen-depleting exercise, subjects received either CHO (1.2 g x kg(-1) x h(-1)) or CHO+Pro (1.2 g CHO x kg(-1) x h(-1) + 0.4 g Pro x kg(-1) x h(-1)) during a 3-h recovery period. Muscle biopsies were obtained immediately, 1 h, and 3 h after exercise. Blood samples were collected immediately after the exercise bout and every 30 min thereafter. Plasma insulin was significantly higher in the CHO+Pro trial compared with the CHO trial (P < 0.05). No difference was found in plasma glucose or in rate of muscle Glycogen Synthesis between the CHO and the CHO+Pro trials. Although coingestion of a protein amino acid mixture in combination with a large CHO intake (1.2 g x kg(-1) x h(-1)) increases insulin levels, this does not result in increased muscle Glycogen Synthesis.