A comparison of the effects of selective increases in peripheral or portal insulin on hepatic glucose production in the conscious dog

Sindelar, D. K.; Balcom, J. H.; Chu, C. A.; Neal, Doss W.; Cherrington, Alan D.

doi:10.2337/diabetes.45.11.1594

Cited by 66 publications

(106 citation statements)

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“…In normal human subjects, Gastaldelli and co-workers showed that, after an overnight fast, GNG decreased significantly in the presence of insulin [16]. However, in fasted conscious dogs, there was a non-significant decrease in GNG during a 3 h portal-venous infusion of insulin [17]. Insulin influences hepatic GNG by powerfully regulating the transcription of important gluconeogenic enzymes [18,19], but the effect of enzyme expression on glucose production may not be immediate, since the mRNA half-life of many gluconeogenic enzymes is close to 1 h [20] and the enzyme itself takes several hours to degrade [21].…”

Section: Introductionmentioning

confidence: 99%

Effects of insulin and cytosolic redox state on glucose production pathways in the isolated perfused mouse liver measured by integrated 2H and 13C NMR

Hausler

Browning

Merritt

et al. 2006

Biochemical Journal

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A great deal is known about hepatic glucose production and its response to a variety of factors such as redox state, substrate supply and hormonal control, but the effects of these parameters on the flux through biochemical pathways which integrate to control glucose production are less clear. A combination of 13 C and [ 2 H]water tracers and NMR isotopomer analysis were used to investigate metabolic fluxes in response to altered cytosolic redox state and insulin. In livers isolated from fed mice and perfused with a mixture of substrates including lactate/pyruvate (10:1, w/w), hepatic glucose production had substantial contributions from glycogen, PEP (phosphoenolpyruvate) and glycerol. Inversion of the lactate/pyruvate ratio (1:10, w/w) resulted in a surprising decrease in the contribution from glycogen and an increase in that from PEP to glucose production. A change in the lactate/pyruvate ratio from 10:1 to 1:10 also stimulated flux through the tricarboxylic acid cycle (2-fold), while leaving oxygen consumption and overall glucose output unchanged. When lactate and pyruvate were eliminated from the perfusion medium, both gluconeogenesis and tricarboxylic-acid-cycle flux were dramatically lower. Insulin lowered glucose production by inhibiting glycogenolysis at both low and high doses, but only at high levels of insulin did gluconeogenesis or tricarboxylic-acid-cycle flux tend towards lower values (P < 0.1). Our data demonstrate that, in the isolated mouse liver, substrate availability and cellular redox state have a dramatic impact on liver metabolism in both the tricarboxylic acid cycle and gluconeogenesis. The tight correlation of these two pathways under multiple conditions suggest that interventions which increase or decrease hepatic tricarboxylic-acid-cycle flux will have a concomitant effect on gluconeogenesis and vice versa.

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Section: Introductionmentioning

confidence: 99%

Effects of insulin and cytosolic redox state on glucose production pathways in the isolated perfused mouse liver measured by integrated 2H and 13C NMR

Hausler

Browning

Merritt

et al. 2006

Biochemical Journal

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“…A large body of evidence concerning hepatic glucose metabolism during exercise in diabetes has been derived from animal experiments [18][19][20][21][22] but there is a lack of in vivo human data. Human studies using magnetic resonance spectroscopy (MRS) have reported defects in mobilisation of hepatic glycogen stores in patients with type 1 diabetes [23,24].…”

Section: Introductionmentioning

confidence: 99%

Hyperinsulinaemia during exercise does not suppress hepatic glycogen concentrations in patients with type 1 diabetes: a magnetic resonance spectroscopy study

et al. 2007

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Aims/hypothesis We compared in vivo changes in liver glycogen concentration during exercise between patients with type 1 diabetes and healthy volunteers. MethodsWe studied seven men with type 1 diabetes (mean ± SEM diabetes duration 10±2 years, age 33±3 years, BMI 24±1 kg/m 2 , HbA 1c 8.1±0.2% and VO 2 peak 43±2 ml [kg lean body mass] −1 min −1 ) and five non-diabetic controls (mean ± SEM age 30±3 years, BMI 22±1 kg/m 2 , HbA 1c 5.4±0.1% and VO 2 peak 52±4 ml [kg lean body mass] −1 min −1 , before and after a standardised breakfast and after three bouts (EX1, EX2, EX3) of 40 min of cycling at 60% VO 2 peak. 13 C Magnetic resonance spectroscopy of liver glycogen was acquired in a 3.0 T magnet using a surface coil. Whole-body substrate oxidation was determined using indirect calorimetry.Results Blood glucose and serum insulin concentrations were significantly higher (p<0.05) in the fasting state, during the postprandial period and during EX1 and EX2 in subjects with type 1 diabetes compared with controls. Serum insulin concentration was still different between groups during EX3 (p<0.05), but blood glucose concentration was similar. There was no difference between groups in liver glycogen concentration before or after the three bouts of exercise, despite the relative hyperinsulinaemia in type 1 diabetes. There were also no differences in substrate oxidation rates between groups. Conclusions/interpretation In patients with type 1 diabetes, hyperinsulinaemic and hyperglycaemic conditions during moderate exercise did not suppress hepatic glycogen concentrations. These findings do not support the hypothesis that exercise-induced hypoglycaemia in patients with type 1 diabetes is due to suppression of hepatic glycogen mobilisation.

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“…Acute effects of insulin on HGP are mediated by both direct and indirect mechanisms (5)(6)(7)(8)(9). Multiple mechanisms have been proposed to account for insulin's indirect effects on HGP, including glucagon (10,11), gluconeogenic substrates released from muscle (12) and fat (13), and hypothalamic signals (9,14). In addition, adipocytokines have been shown to either increase (e.g., resistin) or decrease (e.g., adiponectin) glucose production (15,16).…”

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confidence: 99%

Adiponectin Resistance Exacerbates Insulin Resistance in Insulin Receptor Transgenic/Knockout Mice

et al. 2007

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OBJECTIVE-Adiponectin increases insulin sensitivity and contributes to insulin's indirect effects on hepatic glucose production.RESEARCH DESIGN AND METHODS-To examine adiponectin's contribution to insulin action, we analyzed adiponectin levels and activation of AMP-activated protein kinase (AMPK) in insulin receptor transgenic/knockout mice (L1), a genetic model of resistance to insulin's indirect effects on hepatic glucose production.RESULTS-In euglycemic, insulin-resistant L1 mice, we detected hyperadiponectinemia with normal levels of adiponectin receptor-1 and -2. Moreover, adiponectin administration is unable to lower glucose levels or induce activation of AMPK, consistent with a state of adiponectin resistance. In a subset of hyperglycemic L1 mice, we observed decreased mRNA expression of AdipoR2 in liver and muscle, as well as decreased peroxisome proliferator-activated receptor (PPAR)␣ target gene expression in liver, raising the possibility that deterioration of adiponectin/AdipoR2 signaling via PPAR␣ activation contributes to the progression from compensated insulin resistance to diabetes. In contrast, we failed to detect changes in other markers of the systemic or local inflammatory response.CONCLUSIONS-These data provide evidence for a mechanism of adiponectin resistance and corroborate the notion that adiponectin potentiates hepatic insulin sensitivity. Diabetes

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A comparison of the effects of selective increases in peripheral or portal insulin on hepatic glucose production in the conscious dog

Cited by 66 publications

References 0 publications

Effects of insulin and cytosolic redox state on glucose production pathways in the isolated perfused mouse liver measured by integrated 2H and 13C NMR

Effects of insulin and cytosolic redox state on glucose production pathways in the isolated perfused mouse liver measured by integrated 2H and 13C NMR

Hyperinsulinaemia during exercise does not suppress hepatic glycogen concentrations in patients with type 1 diabetes: a magnetic resonance spectroscopy study

Adiponectin Resistance Exacerbates Insulin Resistance in Insulin Receptor Transgenic/Knockout Mice

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