Stimulation of gluconeogenesis by palmitic acid in rat hepatocytes: Evidence that this effect can be dissociated from the provision of reducing equivalents

Blumenthal, Stanley A.

doi:10.1016/0026-0495(83)90137-3

Cited by 64 publications

(19 citation statements)

References 20 publications

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“…This has been associated with a NEFA-induced increase in gluconeogenesis [15,16,17,18]. Recently, we have confirmed that the dietary fat-induced increase in gluconeogenesis is associated with increased levels of fructose-1,6-bisphosphatase, a regulatory enzyme in the glucose synthesising pathway [15,19].…”

supporting

confidence: 54%

“…Furthermore, it has been suggested that the defect in the suppression of EGP by insulin precedes the defect in insulin action in peripheral tissues [13]. While a high-fat diet might cause peripheral insulin resistance by direct effects on muscle and adipose tissue, the effect of high fat to stimulate gluconeogenesis [15,16,17,18] could have more consequences than simply impaired suppression of endogenous glucose output, as chronic impaired suppression of glucose production leads to obesity and peripheral insulin resistance.…”

Section: Discussionmentioning

confidence: 99%

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Peripheral insulin resistance develops in transgenic rats overexpressing phosphoenolpyruvate carboxykinase in the kidney

et al. 2003

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Aims/hypothesis. To study the secondary consequences of impaired suppression of endogenous glucose production (EGP) we have created a transgenic rat overexpressing the gluconeogenic enzyme phosphoenolpyruvate carboxykinase (PEPCK) in the kidney. The aim of this study was to determine whether peripheral insulin resistance develops in these transgenic rats. Methods. Whole body rate of glucose disappearance (R d ) and endogenous glucose production were measured basally and during a euglycaemic/hyperinsulinaemic clamp in phosphoenolpyruvate carboxykinase transgenic and control rats using [6-3 H]-glucose. Glucose uptake into individual tissues was measured in vivo using 2-[1-14 C]-deoxyglucose. Results. Phosphoenolpyruvate carboxykinase transgenic rats were heavier and had increased gonadal and infrarenal fat pad weights. Under basal conditions, endogenous glucose production was similar in phosphoenolpyruvate carboxykinase transgenic and control rats (37.4±1.1 vs 34.6±2.6 µmol/kg/min). Moderate hyperinsulinaemia (810 pmol/l) completely suppressed EGP in control rats (−0.6±5.5 µmol/kg/min, p<0.05) while there was no suppression in phosphoenolpyruvate carboxykinase rats (45.2±7.9 µmol/kg/min). Basal R d was comparable between PEPCK transgenic and control rats (37.4±1.1 vs 34.6±2.6 µmol/kg/min) but under insulin-stimulated conditions the increase in R d was greater in control compared to phosphoenolpyruvate carboxykinase transgenic rats indicative of insulin resistance (73.4±11.2 vs 112.0±8.0 µmol/kg/min, p<0.05). Basal glucose uptake was reduced in white and brown adipose tissue, heart and soleus while insulin-stimulated transport was reduced in white and brown adipose tissue, white quadriceps, white gastrocnemius and soleus in phosphoenolpyruvate carboxykinase transgenic compared to control rats. The impairment in both white and brown adipose tissue glucose uptake in phosphoenolpyruvate carboxykinase transgenic rats was associated with a decrease in GLUT4 protein content. In contrast, muscle GLUT4 protein, triglyceride and long-chain acylCoA levels were comparable between PEPCK transgenic and control rats. Conclusions/interpretation. A primary defect in suppression of EGP caused adipose tissue and muscle insulin resistance. [Diabetologia (2003[Diabetologia ( ) 46:1338[Diabetologia ( -1347

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confidence: 54%

Section: Discussionmentioning

confidence: 99%

Peripheral insulin resistance develops in transgenic rats overexpressing phosphoenolpyruvate carboxykinase in the kidney

et al. 2003

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“…In turn, FPG was strongly correlated with EGPR (r = 0.90). FFA and fat oxidation have been reported to stimulate gluconeogenesis and glucose production in other studies (28)(29)(30) in animals and man. Increased plasma concentrations of three carbon substrates are also known to stimulate gluconeogenesis and have previously been reported to be increased in subjects with NIDDM (31).…”

Section: Discussionmentioning

confidence: 74%

Relationships between insulin secretion, insulin action, and fasting plasma glucose concentration in nondiabetic and noninsulin-dependent diabetic subjects.

Bogardus¹,

Lillioja²,

Howard³

et al. 1984

J. Clin. Invest.

409

220

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Abstract. The relationships between insulin secretion, insulin action, and fasting plasma glucose concentration (FPG) were examined in 34 southwest American Indians (19 nondiabetics, 15 noninsulin-dependent diabetics) who had a broad range of FPG (88-310 mg/100 ml). Fasting, glucose-stimulated, and mealstimulated plasma insulin concentrations were negatively correlated with FPG in diabetics but not in nondiabetics. In contrast, fasting and glucose-stimulated plasma Cpeptide concentrations did not decrease with increasing FPG in either group and 24-h urinary C-peptide excretion during a diet of mixed composition was positively correlated with FPG for all subjects (r = 0.36, P < 0.05). Fasting free fatty acid (FFA) was correlated with FPG in nondiabetics (r = 0.49, P < 0.05) and diabetics (r = 0.77, P < 0.001). Fasting FFA was also correlated with the isotopically determined endogenous glucose production rate in the diabetics (r = 0.54, P < 0.05). Endogenous glucose production was strongly correlated with FPG in the diabetics (r = 0.90, P < 0.0001), but not in the nondiabetics. Indirect calorimetry showed that FPG was also negatively correlated with basal glucose oxidation rates (r = -0.61, P < 0.001), but positively with lipid oxidation (r = 0.74, P < 0.001) in the diabetics. Insulin action was measured as total insulinmediated glucose disposal, glucose oxidation, and storage rates, using the euglycemic clamp with simultaneous indirect calorimetry at plasma insulin concentrations of 135±5 and 1738±59 ,uU/ml. These parameters of insulin Address reprint requests to Dr. Bogardus.Receivedfor publication 10 April 1984 and in revisedform 21 June 1984.The Journal of Clinical Investigation, Inc. Volume 74, October 1984October , 1238October -1246 action were significantly, negatively correlated with FPG in the nondiabetics at both insulin concentrations, but not in the diabetics although all the diabetics had markedly decreased insulin action. We conclude that decreased insulin action is present in the noninsulindependent diabetics in this population and marked hyperglycemia occurs with the addition of decreased peripheral insulin availability. Decreased peripheral insulin availability leads to increased FFA concentrations and lipid oxidation rates (and probably also increased concentrations of gluconeogenic precursors) that together stimulate gluconeogenesis, hepatic glucose production, and progressive hyperglycemia.

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“…Most in vitro studies have found that FFA augment gluconeogenesis (6)(7)(8)(9)(10)(11)(12)(13). However, in vivo studies have yielded conflicting results concerning the effects of FFA on overall hepatic glucose output (14)(15)(16)(17)(18)(19)(20)(21)(22)(23)(24)(25)(26)(27).…”

Section: Introductionmentioning

confidence: 99%

Demonstration of a critical role for free fatty acids in mediating counterregulatory stimulation of gluconeogenesis and suppression of glucose utilization in humans.

Fanelli¹,

Calderone²,

Epifano³

et al. 1993

J. Clin. Invest.

150

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In vitro studies indicate that FFA compete with glucose as an oxidative fuel in muscle and, in ,gM in control experiments, P < 0.001. Concomitantly, overall glucose production was reduced by 40% (5.5±11 vs. 9.3±0.7,gmol/kg per min, P < 0.001), and gluconeogenesis from alanine was reduced by nearly 70% (0.32±0.09 vs. 1. 00±0.18 Aumol/kg per min, P < 0.001), while glucose utilization increased by 15% (10.8±1.4 vs. 9.3±0.7 Amol/kg per min). We conclude that FFA play a critical role in mediating changes in glucose metabolism during counterregulation, and that under these conditions, FFA exert a much more profound effect on hepatic glucose production than on glucose utilization. (J. Clin.

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Stimulation of gluconeogenesis by palmitic acid in rat hepatocytes: Evidence that this effect can be dissociated from the provision of reducing equivalents

Cited by 64 publications

References 20 publications

Peripheral insulin resistance develops in transgenic rats overexpressing phosphoenolpyruvate carboxykinase in the kidney

Peripheral insulin resistance develops in transgenic rats overexpressing phosphoenolpyruvate carboxykinase in the kidney

Relationships between insulin secretion, insulin action, and fasting plasma glucose concentration in nondiabetic and noninsulin-dependent diabetic subjects.

Demonstration of a critical role for free fatty acids in mediating counterregulatory stimulation of gluconeogenesis and suppression of glucose utilization in humans.

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