Effects of hyperglycemia on hepatic gluconeogenic flux during glycogen phosphorylase inhibition in the conscious dog

Edgerton, Dale S.; Cardin, Sylvain; Neal, Doss; Farmer, Ben; Lautz, Margaret; Pan, Catherine; Cherrington, Alan D.

doi:10.1152/ajpendo.00211.2003

Cited by 13 publications

(18 citation statements)

References 48 publications

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“…It was assumed that all of the gluconeogenic precursors taken up by the liver were completely converted into glucose 6-phosphate (G6P) (17,18). Gluconeogenic flux to G6P was estimated by summing net hepatic gluconeogenic precursor uptake and dividing by two (to convert the data into glucose equivalents).…”

Section: Methodsmentioning

confidence: 99%

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Effects of 11β-hydroxysteroid dehydrogenase-1 inhibition on hepatic glycogenolysis and gluconeogenesis

Winnick

Ramnanan

Saraswathi

et al. 2013

American Journal of Physiology-Endocrinology and Metabolism

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The aim of this study was to determine the effect of prolonged 11␤-hydroxysteroid dehydrogenase-1 (11␤-HSD1) inhibition on basal and hormone-stimulated glucose metabolism in fasted conscious dogs. For 7 days prior to study, either an 11␤-HSD1 inhibitor (HSD1-I; n ϭ 6) or placebo (PBO; n ϭ 6) was administered. After the basal period, a 4-h metabolic challenge followed, where glucagon (3ϫ-basal), epinephrine (5ϫ-basal), and insulin (2ϫ-basal) concentrations were increased. Hepatic glucose fluxes did not differ between groups during the basal period. In response to the metabolic challenge, hepatic glucose production was stimulated in PBO, resulting in hyperglycemia such that exogenous glucose was required in HSD-I (P Ͻ 0.05) to match the glycemia between groups. Net hepatic glucose output and endogenous glucose production were decreased by 11␤-HSD1 inhibition (P Ͻ 0.05) due to a reduction in net hepatic glycogenolysis (P Ͻ 0.05), with no effect on gluconeogenic flux compared with PBO. In addition, glucose utilization (P Ͻ 0.05) and the suppression of lipolysis were increased (P Ͻ 0.05) in HSD-I compared with PBO. These data suggest that inhibition of 11␤-HSD1 may be of therapeutic value in the treatment of diseases characterized by insulin resistance and excessive hepatic glucose production.11␤-hydroxysteroid dehydrogenase-1; cortisol; hepatic glucose production; glycogenolysis; gluconeogenesis CORTISOL IS A STEROID HORMONE with many physiological effects, including the regulation of carbohydrate, protein, and fat metabolism. At pathological concentrations, cortisol produces metabolic abnormalities similar to the metabolic syndrome, including obesity, insulin resistance, fasting hyperglycemia, hypertension, and dyslipidemia (2,42,56,58). In vivo cortisol action can be modified by 11␤-hydroxysteroid dehydrogenase-1 (11␤-HSD1), an enzyme that converts intracellular cortisone into active cortisol without necessarily modifying plasma cortisol concentrations (4, 6, 59). Liver (55, 57) and adipose (30, 33) 11␤-HSD1 activity has been shown to be elevated in obese humans with type 2 diabetes mellitus and the metabolic syndrome, and an intracellular Cushings-like state may contribute to these abnormalities (28, 32). In mice, hepatic 11␤-HSD1 overexpression can increase hepatic lipid flux, thereby causing dyslipidemia and insulin resistance (46), whereas overexpression in adipose tissue causes obesity, impaired glucose tolerance, and hypertension (35, 36). Conversely, when the enzyme is knocked out or acutely inhibited, mouse models of diabetes are protected against the manifestations of the metabolic syndrome (1, 31, 43). Together, these data demonstrate an overarching ability of dysregulated cortisol metabolism to generate a phenotype similar to that of type 2 diabetes and illustrate the potential therapeutic value of 11␤-HSD1 inhibition in the treatment of insulin resistance.Cortisol has potent effects on the glucoregulatory actions of hormones that regulate hepatic glucose production (HGP). For example, cortisol has been...

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Section: Methodsmentioning

confidence: 99%

“…Net hepatic glycogenolysis was determined by subtracting net hepatic gluconeogenic flux from net hepatic glucose output (18).…”

Section: Methodsmentioning

confidence: 99%

Effects of 11β-hydroxysteroid dehydrogenase-1 inhibition on hepatic glycogenolysis and gluconeogenesis

Winnick

Ramnanan

Saraswathi

et al. 2013

American Journal of Physiology-Endocrinology and Metabolism

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“…The data shown were calculated using transonic flows, since no assumptions regarding the distribution of flow in the portal vein and hepatic artery were then required. Plasma glucose values were converted to blood glucose values using previously established correction factors (38). Net hepatic balance was determined as previously described (36).…”

Section: Figurementioning

confidence: 99%

“…Data calculation was carried out using the 2-compartment model described by Mari (39) and canine parameters reported by Dobbins (40). The approximate plasma insulin and glucagon concentrations in the hepatic sinusoidal bed were calculated as previously described (38).…”

Section: Figurementioning

confidence: 99%

“…Therefore, there is a distinction between gluconeogenic flux to glucose-6-phosphate, which is the conversion of precursors to glucose-6-phosphate, and gluconeogenesis per se, which is the release of glucose derived from gluconeogenic flux into the blood. In the present study, we estimated NHGNG flux relative to glucose-6-phosphate and NHGLY flux as described previously (38).…”

Section: Nhgng Flux and Nhgly Flux Calculationsmentioning

confidence: 99%

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Insulin-induced hypoglycemia increases hepatic sensitivity to glucagon in dogs

Rivera¹,

Ramnanan²,

An³

et al. 2010

J. Clin. Invest.

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In individuals with type 1 diabetes, hypoglycemia is a common consequence of overinsulinization. Under conditions of insulin-induced hypoglycemia, glucagon is the most important stimulus for hepatic glucose production. In contrast, during euglycemia, insulin potently inhibits glucagon's effect on the liver. The first aim of the present study was to determine whether low blood sugar augments glucagon's ability to increase glucose production. Using a conscious catheterized dog model, we found that hypoglycemia increased glucagon's ability to overcome the inhibitory effect of insulin on hepatic glucose production by almost 3-fold, an effect exclusively attributable to marked enhancement of the effect of glucagon on net glycogen breakdown. To investigate the molecular mechanism by which this effect comes about, we analyzed hepatic biopsies from the same animals, and found that hypoglycemia resulted in a decrease in insulin signaling. Furthermore, hypoglycemia and glucagon had an additive effect on the activation of AMPK, which was associated with altered activity of the enzymes of glycogen metabolism. IntroductionIn individuals with type 1 diabetes, hypoglycemia is a common consequence of overinsulinization. The incidence of hypoglycemia is less frequent in individuals with type 2 diabetes, but as the disease progresses and patients begin to use insulin, it once again becomes a limiting factor in glycemic control (1). The counterregulatory response to hypoglycemia in the normal individual involves the release of glucagon, epinephrine, norepinephrine, cortisol, and growth hormone, which together increase glucose production and limit glucose utilization (2). Glucagon has been shown to provide the primary stimulus for the counterregulatory increase in glucose production in response to insulin-induced hypoglycemia in the normal individual (2). Furthermore, abnormalities in the response of the α cell to hypoglycemia make individuals with diabetes more prone to low blood sugar (1, 2).We have previously examined the interaction between insulin and glucagon in controlling glucose production in the conscious dog (3). Intraportal replacement of basal amounts of insulin and glucagon in the presence of somatostatin infusion was associated with sustained basal glucose production. A selective 4-fold rise in glucagon resulted in an increment in glucose production of approximately 4.5 mg/kg/min at 30 minutes. In contrast, a selective 4-fold rise in insulin resulted in a decrement in glucose production of approximately 1.3 mg/kg/min at 30 minutes. When both hormones were simultaneously increased 4-fold, the decrement in glucose production at 30 minutes was only approximately 0.6 mg/kg/min. Therefore, glucagon's effect was 4.5 mg/kg/min in the presence of basal insulin -despite the accompanying hyperglycemia - and only 0.7 mg/kg/min in the presence of high insulin and euglycemia, a reduction of almost 85%. These data indicate that, in the absence of hypoglycemia, insulin dominates glucagon's action on the liver even when equimolar in...

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Exercise-induced improvements in glucose effectiveness are blunted by a high glycemic diet in adults with prediabetes

et al. 2019

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Background: Glucose effectiveness (GE) refers to the ability of glucose to influence its own metabolism through insulin-independent mechanisms. Exercise training improves GE, however; little is known about how dietary interventions such as manipulating the glycemic index of diets, interact with exercise-induced improvements in GE in at-risk populations. Objective: To determine the effect of glycemic index of the diet on exercise-induced enhancement of GE in people with obesity and insulin resistance. Design: A randomized, controlled, parallel-group, repeated-measures study. Participants: 33 adults with obesity and pre-diabetes (17 males, 65.7±4.3 yrs, 34.9±4.2 kg/m 2) Interventions: Participants were recruited into a 12-week exercise training program (1 hr/d, 5 d/wk at ~85% of maximum heart rate) while being randomized to concurrently receive either a low (EX-LOG: 40±0.3 au) or high (EX-HIG: 80±0.6 au) glycemic diet. A 75-g oral-glucosetolerance test (OGTT) was performed before and after the intervention and GE was calculated using the Nagasaka equation. Results: Both EX-LOG and EX-HIG groups had similar improvements in weight (8.6±5.1 Kg, P<0.001), VO 2max (6±3.5 ml. kg −1 .min −1 , P<0.001) and clamp-measured peripheral insulin resistance (1.7±0.9 mg.kg −1 .min −1 , P<0.001

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Effects of hyperglycemia on hepatic gluconeogenic flux during glycogen phosphorylase inhibition in the conscious dog

Cited by 13 publications

References 48 publications

Effects of 11β-hydroxysteroid dehydrogenase-1 inhibition on hepatic glycogenolysis and gluconeogenesis

Effects of 11β-hydroxysteroid dehydrogenase-1 inhibition on hepatic glycogenolysis and gluconeogenesis

Insulin-induced hypoglycemia increases hepatic sensitivity to glucagon in dogs

Exercise-induced improvements in glucose effectiveness are blunted by a high glycemic diet in adults with prediabetes

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