The roles of insulin and glucagon in the regulation of hepatic glycogen synthesis and turnover in humans.

Roden, Michael; Perseghin, Gianluca; Petersen, Kitt Falk; Hwang, Jonghee; Cline, Gary W.; Gerow, Karynn; Rothman, Douglas L.; Shulman, Gerald I.

doi:10.1172/jci118460

Cited by 141 publications

(149 citation statements)

References 51 publications

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“…This view is supported by the fact that in type 1 diabetic patients with long-term near-normoglycaemia (HbA 1 c <7% for 1 year), hepatic glycogen synthesis was normalised after ingestion of a mixed meal in association with restoration of the glucagon/estimated hepatic insulin ratio [29]. Insulin and glucagon are considered to be of pivotal importance in the regulation of hepatic glycogen synthesis and turnover in humans [30]. We would expect a similar behaviour for the IHF content, and we are in the process of testing this hypothesis by measuring the long-term effects of intrahepatic pancreatic islet transplantation on the IHF content in individuals with type 1 diabetes.…”

Section: Discussionmentioning

confidence: 95%

Reduced intrahepatic fat content is associated with increased whole-body lipid oxidation in patients with type 1 diabetes

Perseghin

Lattuada²,

Cobelli

et al. 2005

Diabetologia

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Aims/hypothesis: Insulin resistance may be associated with ectopic fat accumulation potentially determined by reduced lipid oxidation. In patients with type 1 diabetes peripheral insulin resistance is associated with higher intramyocellular lipid content. We assessed whether these patients are also characterised by intrahepatic fat accumulation and abnormal fat oxidation. Methods: Nineteen patients with type 1 diabetes (6 women, 13 men, age 35±7 years, BMI 23±3 kg/m 2 , HbA 1 c 8.7±1.4%) and 19 healthy matched individuals were studied by (1) euglycaemic−hyperinsulinaemic clamp combined with [6, H 2 ]glucose infusion to assess whole-body glucose metabolism; (2) indirect calorimetry to assess glucose and lipid oxidation; and (3) localised 1 H-magnetic resonance spectroscopy of the liver to assess intrahepatic fat content. Results: Patients with type 1 diabetes showed a reduced insulin-stimulated metabolic clearance rate of glucose (4.3±1.3 ml kg -1 min -1 ) in comparison with normal subjects (6.0±1.6 ml kg -1 min -1 ; p<0.001). Endogenous glucose production was higher in diabetic patients (p=0.001) and its suppression was impaired during insulin administration (66±30 vs 92±8%; p=0.047) in comparison with normal subjects. Plasma glucagon concentrations were not different between groups. The estimated hepatic insulin concentration was lower in diabetic patients than in normal subjects (p<0.05), as was the intrahepatic fat content (1.5±0.7% and 2.2±1.0% respectively; p<0.03), the latter in association with a reduced respiratory quotient (0.74±0.05 vs 0.84±0.06; p=0.01) and increased fasting lipid oxidation (1.5±0.5 vs 0.8±0.4 mg kg -1 min -1 ; p<0.01). Conclusions/interpretation: In patients with type 1 diabetes, insulin resistance was not associated with increased intrahepatic fat accumulation. In fact, diabetic patients had reduced intrahepatic fat content, which was associated with increased fasting lipid oxidation. The unbalanced hepatic glucagon and insulin concentrations affecting patients with type 1 diabetes may be involved in this abnormality of intrahepatic lipid metabolism.

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Section: Discussionmentioning

confidence: 95%

Reduced intrahepatic fat content is associated with increased whole-body lipid oxidation in patients with type 1 diabetes

Perseghin

Lattuada²,

Cobelli

et al. 2005

Diabetologia

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“…Either the factors determining flux through the cycle changed or the glycosyl units released were increasingly labelled. The increase in portal insulin relative to glucagon activities [44,45] would favour an increase in glycogen synthesis and a decrease in the activity of phosphorylase, hence the breakdown of glycogen [46][47][48]. The glycosyl units deposited are assumed not to be those released [1].…”

Section: Discussionmentioning

confidence: 99%

Changes in hepatic glycogen cycling during a glucose load in healthy humans

et al. 2005

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Aims/hypothesis: Glycogen cycling, i.e. simultaneous glycogen synthesis and glycogenolysis, affects estimates of glucose fluxes using tracer techniques and may contribute to hyperglycaemia in diabetic conditions. This study presents a new method for quantifying hepatic glycogen cycling in the fed state. Glycogen is synthesised from glucose by the direct and indirect (gluconeogenic) pathways. Since glycogen is also synthesised from glycogen, i.e. glycogen→glucose 1-phosphate→glycogen, that synthesised through the direct and indirect pathways does not account for 100% of glycogen synthesis. The percentage contribution of glycogen cycling to glycogen synthesis then equals the difference between the sum of the percentage contributions of the direct and indirect pathways and 100. Materials and methods: The indirect and direct pathways were measured independently in nine healthy volunteers who had fasted overnight. They ingested 2 H 2 O (5 ml/kg body water) and were infused with [5-3 H] glucose and acetaminophen (paracetamol; 1 g) during hyperglycaemic clamps (7.8 mmol/l) lasting 8 h. The percentage contribution of the indirect pathway was calculated from the ratio of 2 H enrichments at carbon 5 to that at carbon 2, and the contribution of the direct pathway was determined from the 3 H-specific activity, relative to plasma glucose, of the urinary glucuronide excreted between 2 and 4, 4 and 6, and 6 and 8 h. Results: Glucose infusion rates increased (p<0.01) to ∼50 μmol kg −1 min −1 . Plasma insulin and the insulin : glucagon ratio rose ∼3.6-and ∼8.3-fold (p<0.001), respectively. From the difference between 100% and the sum of the direct (2-4 h, 54±6%; 4-6 h, 59±5%; 6-8 h, 63±4%) and indirect (32±3, 38±4, 36±3%) pathways, glycogen cycling was seen to be decreased (p<0.05) from 14±4% (2-4 h) to 4±3% (4-6 h) and 1±3% (6-8 h). Conclusions/interpretation: This method allows measurement of hepatic glycogen cycling in the fed state and demonstrates that glycogen cycling occurs most in the early hours after glucose loading subsequent to a fast.

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“…There are also reports that amino acid metabolism was abnormal in diabetes (Wijekoon et al, 2004;Noguchi et al, 2006). Excess amino acids in the liver can act as substrates for gluconeogenesis (Felig,1975), interfere with the inhibitory effect of insulin on glucose production (Boden and Tappy, 1990), and change the insulin/glucagon ratio (Roden et al, 1996), all of which may increase the output of hepatic glucose. Moreover, abnormal amino acid metabolism in the liver may change levels of amino acids throughout the whole body.…”

Section: Discussionmentioning

confidence: 99%

Quantitative proteomic analysis of S-nitrosated proteins in diabetic mouse liver with ICAT switch method

et al. 2010

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In this study we developed a quantitative proteomic method named ICAT switch by introducing isotope-coded affinity tag (ICAT) reagents into the biotin-switch method, and used it to investigate S-nitrosation in the liver of normal control C57BL/6J mice and type 2 diabetic KK-Ay mice. We got fifty-eight S-nitrosated peptides with quantitative information in our research, among which thirty-seven had changed S-nitrosation levels in diabetic mouse liver. The S-nitrosated peptides belonged to fortyeight proteins (twenty-eight were new S-nitrosated proteins), some of which were new targets of S-nitrosation and known to be related with diabetes. S-nitrosation patterns were different between diabetic and normal mice. Gene ontology enrichment results suggested that S-nitrosated proteins are more abundant in amino acid metabolic processes. The network constructed for Snitrosated proteins by text-mining technology provided clues about the relationship between S-nitrosation and type 2 diabetes. Our work provides a new approach for quantifying S-nitrosated proteins and suggests that the integrative functions of S-nitrosation may take part in pathophysiological processes of type 2 diabetes.

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The roles of insulin and glucagon in the regulation of hepatic glycogen synthesis and turnover in humans.

Cited by 141 publications

References 51 publications

Reduced intrahepatic fat content is associated with increased whole-body lipid oxidation in patients with type 1 diabetes

Reduced intrahepatic fat content is associated with increased whole-body lipid oxidation in patients with type 1 diabetes

Changes in hepatic glycogen cycling during a glucose load in healthy humans

Quantitative proteomic analysis of S-nitrosated proteins in diabetic mouse liver with ICAT switch method

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