Lipid-dependent control of hepatic glycogen stores in healthy humans

Stingl, Harald; Krššák, Martin; Krebs, Michael; Bischof, Martin; Nowotny, Peter; Fürnsinn, Clemens; Shulman, Gerald I.; Waldhäusl, W.; Roden, Michael

doi:10.1007/s001250051579

Cited by 73 publications

(75 citation statements)

References 26 publications

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“…Increased levels of serum free fatty acids have been implicated as a causative factor in excess HGP in type 2 diabetes (43)(44)(45)(46). IUGR animals used in the present study did not yet exhibit increased serum NEFA levels, suggesting that an alternate mechanism other than one involving fatty acids is responsible for increased glucose production by the liver.…”

Section: Discussionmentioning

confidence: 50%

Hepatic Insulin Resistance Precedes the Development of Diabetes in a Model of Intrauterine Growth Retardation

et al. 2004

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Intrauterine growth retardation (IUGR) has been linked to the development of type 2 diabetes in adulthood. We developed an IUGR model in rats whereby at age 3-6 months the animals develop a diabetes that is associated with insulin resistance. Hyperinsulinemiceuglycemic clamp studies were performed at age 8 weeks, before the onset of obesity and diabetes. Basal hepatic glucose production (HGP) was significantly higher in IUGR than in control rats (14.6 ؎ 0.4 vs. 12.3 ؎ 0.3 mg ⅐ kg ؊1 ⅐ min ؊1 ; P < 0.05). Insulin suppression of HGP was blunted in IUGR versus control rats (10.4 ؎ 0.6 vs. 6.5 ؎ 1.0 mg ⅐ kg ؊1 ⅐ min ؊1 ; P < 0.01); however, rates of glucose uptake and glycogenolysis were similar between the two groups. Insulin-stimulated insulin receptor substrate 2 and Akt-2 phosphorylation were significantly blunted in IUGR rats. PEPCK and glucose-6-phosphatase mRNA levels were increased at least threefold in liver of IUGR compared with control rats. These studies suggest that an aberrant intrauterine milieu permanently impairs insulin signaling in the liver so that gluconeogenesis is augmented in the IUGR rat. These processes occur early in life, before the onset of hyperglycemia, and indicate that uteroplacental insufficiency causes a primary defect in gene expression and hepatic metabolism that leads to the eventual development of overt hyperglycemia. Diabetes 53:2617-2622, 2004 U teroplacental insufficiency limits the availability of substrates to the fetus and retards growth during gestation (1,2). We have previously shown that this abnormal metabolic intrauterine milieu affects the development of the fetus by modifying the gene expression and function of susceptible cells in the pancreas, muscle, and liver (3-5). The end result is the development of type 2 diabetes in adulthood (4). The unique feature of our animal model of intrauterine growth retardation (IUGR) is its ability to induce diabetes in adult rats with the salient features of most forms of type 2 diabetes in humans, that is, defects in insulin action and insulin secretion. IUGR animals exhibit insulin resistance early in life (before the onset of hyperglycemia) that is characterized by blunted whole-body glucose disposal in response to insulin (4).The liver plays an important role in maintaining blood glucose homeostasis by controlling hepatic glucose production (HGP) (6,7). In type 2 diabetes, the high levels of HGP and the inability of insulin to adequately suppress hepatic glucose output are major contributors to both fasting hyperglycemia and exaggerated postprandial hyperglycemia (8 -14).Insulin resistance is associated with a postreceptor defect(s) in the intracellular insulin-signaling cascade, leading to the failure of insulin to suppress HGP (15). Insulin binds to its receptor, which leads to activation of the insulin receptor, insulin receptor substrates (IRSs) such as IRS-1 and -2, phosphatidylinositol 3-kinase, and Akt. Akt activation leads to decreased transcription of PEPCK and glucose-6-phosphatase (G6Pase) (16), thus reducing gluc...

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Section: Discussionmentioning

confidence: 50%

Hepatic Insulin Resistance Precedes the Development of Diabetes in a Model of Intrauterine Growth Retardation

et al. 2004

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“…In healthy individuals, increased plasma NEFAs have been shown to not only stimulate GNG, but cause compensatory inhibition of glycogenolysis during euglycaemia [32]. Indeed, we and others have previously demonstrated that isolated changes in NEFA levels do not change the rates of EGP during euglycaemia [9,33].…”

Section: Discussionmentioning

confidence: 69%

Elevated NEFA levels impair glucose effectiveness by increasing net hepatic glycogenolysis

et al. 2012

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Aims/hypothesis Acute hyperglycaemia rapidly suppresses endogenous glucose production (EGP) in non-diabetic individuals, mainly by inhibiting glycogenolysis. Loss of this 'glucose effectiveness' contributes to fasting hyperglycaemia in type 2 diabetes. Elevated NEFA levels characteristic of type 2 diabetes impair glucose effectiveness, although the mechanism is not fully understood. Therefore we examined the impact of increasing NEFA levels on the ability of hyperglycaemia to regulate pathways of EGP. Methods We performed 4 h 'pancreatic clamp' studies (somatostatin; basal glucagon/growth hormone/insulin) in seven non-diabetic individuals. Glucose fluxes (D-[6,6-2 H 2 ] glucose) and hepatic glycogen concentrations ( 13 C magnetic resonance spectroscopy) were quantified under three conditions: euglycaemia, hyperglycaemia and hyperglycaemia with elevated NEFA (HY-NEFA). Results EGP was suppressed by hyperglycaemia, but not by HY-NEFA. Hepatic glycogen concentration decreased ∼14% with prolonged fasting during euglycaemia and increased by ∼12% with hyperglycaemia. In contrast, raising NEFA levels in HY-NEFA caused a substantial ∼23% reduction in hepatic glycogen concentration. Moreover, rates of gluconeogenesis were decreased with hyperglycaemia, but increased with HY-NEFA. Conclusions/interpretation Increased NEFA appear to profoundly blunt the ability of hyperglycaemia to inhibit net glycogenolysis under basal hormonal conditions.

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“…during a glucose load or in type 2 diabetes [4]. Interestingly, the 2 H 2 O and MRS methods yield similar results in healthy humans during fasting [15][16][17] but different results in patients with liver cirrhosis [18] and type 2 diabetes [4], and during NEFA elevation [16,17,19], supporting the idea that glycogen cycling operates differently in diabetes mellitus and certain nutritive conditions.…”

Section: Introductionmentioning

confidence: 90%

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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Lipid-dependent control of hepatic glycogen stores in healthy humans

Cited by 73 publications

References 26 publications

Hepatic Insulin Resistance Precedes the Development of Diabetes in a Model of Intrauterine Growth Retardation

Hepatic Insulin Resistance Precedes the Development of Diabetes in a Model of Intrauterine Growth Retardation

Elevated NEFA levels impair glucose effectiveness by increasing net hepatic glycogenolysis

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

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