Effects of free fatty acid elevation on postabsorptive endogenous glucose production and gluconeogenesis in humans.

Roden, Michael; Stingl, Harald; Chandramouli, Visvanathan; Schumann, William C.; Hofer, Astrid; Landau, Bernard R.; Nowotny, Peter; Waldhäusl, W.; Shulman, Gerald I.

doi:10.2337/diabetes.49.5.701

Cited by 253 publications

(208 citation statements)

References 53 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%

“…Although there is no evidence that increased PEPCK activity is a mechanism for impaired suppression of endogenous glucose production in human diabetes, it has been shown that high fat availability stimulates gluconeogenesis [18,57,58]. Thus it is possible that fat can cause peripheral insulin resistance not only by direct effects on muscle and adipose tissue but secondarily by stimulation of gluconeogenesis.…”

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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supporting

confidence: 54%

Section: Discussionmentioning

confidence: 99%

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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“…Other studies also showed enhanced insulin secretion when plasma NEFA concentrations were increased for 20 min, 90 min or 5 h, by Intralipid and heparin in healthy volunteers [12,13,15]. A short-term (9-h) plasma NEFA increase induced insulin secretion in humans and this was sufficient to prevent an increase in plasma glucose concentrations [28]. However, no hyperinsulinaemic response has been reported when plasma NEFA concentrations were increased for 5 h to 10 h [29,30] and this turned into an inhibitory effect after a very long-term increase (>24 h) [13,15].…”

Section: Discussionmentioning

confidence: 84%

Interaction between specific fatty acids, GLP-1 and insulin secretion in humans

et al. 2002

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Aims/hypothesis. Fatty acids affect insulin secretion in vivo, but little is known about the effects of specific fatty acids. Our aim was to investigate differential effects of acutely increased plasma monounsaturated, polyunsaturated and saturated fatty acids on glucosestimulated insulin secretion in healthy humans. Methods. A new experimental protocol was used to increase plasma monounsaturated (MUFA test), polyunsaturated (PUFA test) or saturated (SFA test) nonesterified fatty acids for 2 h by repeated oral fat feeding and continuous intravenous heparin infusion. This was followed by a hyperglycaemic clamp (10 mmol/l) to test insulin secretion in response to a prior plasma NEFA increase. Results. Total plasma NEFA concentrations were increased during the fat tests compared to the control visit (1.7-fold increase for MUFA and SFA tests and 1.4-fold increase for PUFA test; p<0.001). Exaggerated responses in plasma insulin, C-peptide and proinsulin concentrations were seen during the hyperglycaemic clamp after increasing plasma NEFA concentrations compared with the control (p<0.01). The effects were greatest for the MUFA test followed by the PUFA test and SFA test (p<0.01). Plasma GLP-1 concentrations increased during fat feeding, with a higher response during the MUFA test compared to PUFA and SFA tests (p<0.01). Conclusion/interpretation. Increasing plasma NEFA concentrations by oral fat feeding with heparin infusion augments glucose-stimulated insulin secretion with the greatest effect for monounsaturated fatty acids and the lowest effect for saturated fatty acids. Monounsaturated fatty acids also increase GLP-1 more than saturated fatty acids. Therefore, the exaggerated insulin concentrations could be due to both NEFA and GLP-1. [Diabetologia (2002[Diabetologia ( ) 45:1533[Diabetologia ( -1541 Keywords Monounsaturated fatty acids, polyunsaturated fatty acids, saturated fatty acids, insulin secretion, GLP-1. High fat diets lead to obesity, which in turn is one of the main causes of the development of Type II (noninsulin-dependent) diabetes mellitus. Both obesity and Type II diabetes are characterized by increased plasma non-esterified fatty acid concentrations [1] and raised fasting plasma NEFA concentrations are a risk marker for the development of Type II diabetes in Caucasian subjects [2] and in Pima Indians [3]. Increased plasma NEFA concentrations can have adverse effects on various tissues. Excess plasma NEFA concentrations can lead to a reduced skeletal muscle glucose uptake and oxidation [4,5,6], increased hepatic glucose output [7] and a decrease in hepatic insulin clearance [8,9]. These mechanisms could lead to glucose intolerance and insulin resistance leading to Type II diabetes.Inappropriately high concentrations of plasma NEFA have also been shown to alter glucose-stimulat-

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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: 87%

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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Effects of free fatty acid elevation on postabsorptive endogenous glucose production and gluconeogenesis in humans.

Cited by 253 publications

References 53 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

Interaction between specific fatty acids, GLP-1 and insulin secretion in humans

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

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