FFA cause hepatic insulin resistance by inhibiting insulin suppression of glycogenolysis

Boden, Guenther; Cheung, Peter; Stein, T. P.; Kresge, Karen; Mozzoli, Maria

doi:10.1152/ajpendo.00429.2001

Cited by 199 publications

(141 citation statements)

References 37 publications

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“…Since 2 H 2 O and C2 glucose enrichments are equal at steady state, many investigators have used the plasma C5 glucose-to-2 H 2 O ratio to calculate gluconeogenesis after an overnight fast (4 -7,9 -12,18). The C5 glucose-to-2 H 2 O ratio has also been used to measure gluconeogenesis during glucose clamps (4,6,7,11,12,18). However, the validity of this approach is uncertain.…”

Section: Results-plasma C2 Glucose and Plasmamentioning

confidence: 99%

“…We have reported that the rate of gluconeogenesis measured during the final hour of a 3-h hyperinsulinemic-euglycemic clamp in lean nondiabetic subjects using the C5-to-C2 glucose ratio correlated with that measured in the same subjects using the C5 glucose-to-2 H 2 O ratio (7). However, in those as well as other glucose clamp experiments (4,6,7,11,12,18), gluconeogenesis calculated using the C5 glucose-to-2 H 2 O ratio commonly exceeded total endogenous glucose production. Since endogenous glucose production equals the sum of glucose derived via gluconeogenesis and glycogenolysis, this result was biologically implausible.…”

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confidence: 90%

“…The deuterated water method is widely used for this purpose (1)(2)(3)(4)(5)(6)(7)(8)(9)(10)(11)(12)(13)(14)(15)(16)(17). This method relies on the fact that the fifth carbon of glucose is labeled during gluconeogenesis, whereas the second carbon of glucose is labeled with deuterium during equilibration of glucose-6-phosphate and fructose-6-phoshate (1,2).…”

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Plasma C5 Glucose–to–2H2O Ratio Does Not Provide an Accurate Assessment of Gluconeogenesis During Hyperinsulinemic-Euglycemic Clamps in Either Nondiabetic or Diabetic Humans

et al. 2008

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OBJECTIVE-Measurement of plasma C2 glucose enrichment is cumbersome. Therefore, the plasma C5 glucose-to-2 H 2 O rather than the plasma C5-to-C2 glucose ratio commonly has been used to measure gluconeogenesis and glycogenolysis during hyperinsulinemic-euglycemic clamps. The validity of this approach is unknown. RESEARCH DESIGN AND METHODS-Ten nondiabetic and 10 diabetic subjects ingested2 H 2 O the evening before study. The following morning, insulin was infused at a rate of 0.6 mU ⅐ kg Ϫ1⅐ min Ϫ1 and glucose was clamped at ϳ5.3 mmol/l for 5 h. Plasma C5 glucose, C2 glucose, and 2 H 2 O enrichments were measured hourly from 2 h onward. RESULTS-Plasma C2 glucose and plasma2 H 2 O enrichment were equal in both groups before the clamp, resulting in equivalent estimates of gluconeogenesis and glycogenolysis. In contrast, plasma C2 glucose and plasma C5 glucose enrichments fell throughout the clamp, whereas plasma 2 H 2 O enrichment remained unchanged. Since the C5 glucose concentration and, hence, the C5 glucose-to-2 H 2 O ratio is influenced by both gluconeogenesis and glucose clearance, whereas the C5-to-C2 glucose ratio is only influenced by gluconeogenesis, the C5 glucose-to-2 H 2 O ratio overestimated (P Ͻ 0.01) gluconeogenesis during the clamp. This resulted in biologically implausible negative (i.e., calculated rates of gluconeogenesis exceeding total endogenous glucose production) rates of glycogenolysis in both the nondiabetic and diabetic subjects.CONCLUSIONS-Plasma C5 glucose-to-2 H 2 O ratio does not provide an accurate assessment of gluconeogenesis in nondiabetic or diabetic subjects during a traditional (i.e., 2-3 h) hyperinsulinemic-euglycemic clamp. The conclusions of studies that have used this approach need to be reevaluated. Diabetes 57:1800-1804, 2008 M easurement of gluconeogenesis in humans is difficult. The deuterated water method is widely used for this purpose (1-17). This method relies on the fact that the fifth carbon of glucose is labeled during gluconeogenesis, whereas the second carbon of glucose is labeled with deuterium during equilibration of glucose-6-phosphate and fructose-6-phoshate (1,2). Therefore, at steady state, the ratio of plasma glucose with deuterium on the fifth carbon (C5 glucose) to plasma glucose labeled on the second carbon (C2 glucose) equals the percentage of plasma glucose derived from gluconeogenesis (1,2). Measurement of C2 glucose enrichment is cumbersome. Since 2 H 2 O and C2 glucose enrichments are equal at steady state, many investigators have used the plasma C5 glucose-to-2 H 2 O ratio to calculate gluconeogenesis after an overnight fast (4 -7,9 -12,18). The C5 glucose-to-2 H 2 O ratio has also been used to measure gluconeogenesis during glucose clamps (4,6,7,11,12,18). However, the validity of this approach is uncertain. We have reported that the rate of gluconeogenesis measured during the final hour of a 3-h hyperinsulinemic-euglycemic clamp in lean nondiabetic subjects using the C5-to-C2 glucose ratio correlated with that measured in the same subjects us...

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Section: Results-plasma C2 Glucose and Plasmamentioning

confidence: 99%

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confidence: 90%

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Plasma C5 Glucose–to–2H2O Ratio Does Not Provide an Accurate Assessment of Gluconeogenesis During Hyperinsulinemic-Euglycemic Clamps in Either Nondiabetic or Diabetic Humans

et al. 2008

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“…It is well established that elevation of plasma FFA concentrations by Intralipid can stimulate EGP (29,31,32) and it has been suggested that the inhibitory effect of FFA on suppression of EGP by insulin is more due to its effect on glycogenolysis than on gluconeogenesis (32). However, the effect of FFA on EGP is complex and requires a finely tuned balance between enhanced b-oxidation of lipids and inhibition of glycolysis and the Krebs cycle (33).…”

Section: Discussionmentioning

confidence: 99%

Inhibition of lipolysis during acute GH exposure increases insulin sensitivity in previously untreated GH-deficient adults

Segerlantz¹,

Bramnert²,

Manhem³

et al. 2003

European Journal of Endocrinology

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Objective: Previous studies evaluating the lipolytic effect of GH have in general been performed in subjects on chronic GH therapy. In this study we assessed the lipolytic effect of GH in previously untreated patients and examined whether the negative effect of enhanced lipolysis on glucose metabolism could be counteracted by acute antilipolysis achieved with acipimox. Methods: Ten GH-deficient (GHD) adults participated in four experiments each, during which they received in a double-blind manner: placebo (A); GH (0.88^0.13 mg) (B); GH þ acipimox 250 mg b.i.d. (C); and acipimox b.i.d. (no GH) (D), where GH was given the night before a 2 h euglycemic, hyperinsulinemic clamp combined with infusion of [3-3 H]glucose and indirect calorimetry. Results: GH increased basal free fatty acid (FFA) levels by 74% (P ¼ 0.0051) and insulin levels by 93% (P ¼ 0.0051). This resulted in a non-significant decrease in insulin-stimulated glucose uptakes (16.61^8.03 vs 12.74^5.50 mmol/kg per min (S.D.), P ¼ 0.07 for A vs B). The rates of insulin-stimulated glucose uptake correlated negatively with the FFA concentrations (r ¼ 2 0.638, P , 0.0001). However, acipimox caused a significant improvement in insulin-stimulated glucose uptake in the GH-treated patients (17.35^5.65 vs 12.74^5.50 mmol/kg per min, P ¼ 0.012 for C vs B). The acipimox-induced enhancement of insulin-stimulated glucose uptake was mainly due to an enhanced rate of glucose oxidation (8.32^3.00 vs 5.88^2.39 mmol/kg per min, P ¼ 0.07 for C vs B). The enhanced rates of glucose oxidation induced by acipimox correlated negatively with the rate of lipid oxidation in GH-treated subjects both in basal (r ¼ 2 0.867, P ¼ 0.0093) and during insulinstimulated (r ¼ 2 0.927, P ¼ 0.0054) conditions. GH did not significantly impair non-oxidative glucose metabolism (6.86^5.22 vs 8.67^6.65 mmol/kg per min, P ¼ NS for B vs A). The fasting rate of endogenous glucose production was unaffected by GH and acipimox administration (10.99^1.98 vs 11.73^2.38 mmol/kg per min, P ¼ NS for B vs A and 11.55^2.7 vs 10.99^1.98 mmol/kg per min, P ¼ NS for C vs B). On the other hand, acipimox alone improved glucose uptake in the untreated GHD patients (24.14^8.74 vs 16.61^8.03 mmol/kg per min, P ¼ 0.0077 for D vs A) and this was again due to enhanced fasting (7.90^2.68 vs 5.16^2.28 mmol/kg per min, P ¼ 0.01 for D vs A) and insulin-stimulated (9.78^3.68 vs 7.95^2.64 mmol/kg per min, P ¼ 0.07 for D vs A) glucose oxidation. Conclusion: The study of acute administration of GH to previously untreated GHD patients provides compelling evidence that (i) GH-induced insulin resistance is mainly due to induction of lipolysis by GH; and (ii) inhibition of lipolysis can prevent the deterioration of insulin sensitivity. The question remains whether GH replacement therapy should, at least at the beginning of therapy, be combined with means to prevent an excessive stimulation of lipolysis by GH.

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“…A role has been suggested for NEFA as they are commonly increased in states associated with insulin resistance [14,15,16] and induce insulin resistance in vivo and in vitro [15,16]. The lipolytically more active intra-abdominal fat [17] is an important source of NEFA in the portal circulation, draining them directly to the liver and thereby altering hepatic glucose and lipid metabolism [18,19,20]. Recently, it has been shown in mice fed a high fat, high sucrose diet that administration of the recently characterized adipocyte secreted protein adiponectin increases fat oxidation, thereby reducing NEFA concentrations and body weight [21].…”

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Relationship of adiponectin to body fat distribution, insulin sensitivity and plasma lipoproteins: evidence for independent roles of age and sex

et al. 2003

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Aims/hypothesis. Increased intra-abdominal fat is associated with insulin resistance and an atherogenic lipoprotein profile. Circulating concentrations of adiponectin, an adipocyte-derived protein, are decreased with insulin resistance. We investigated the relationships between adiponectin and leptin, body fat distribution, insulin sensitivity and lipoproteins. Methods. We measured plasma adiponectin, leptin and lipid concentrations, intra-abdominal and subcutaneous fat areas by CT scan, and insulin sensitivity index (S I ) in 182 subjects (76 M/106F). Results. Adiponectin concentrations were higher in women than in men (7.4±2.9 vs 5.4±2.3 µg/ml, p<0.0001) as were leptin concentrations (19.1±13.7 vs 6.9±5.1 ng/ml, p<0.0001). Women were more insulin sensitive (S I : 6.8±3.9 vs 5.9±4.4×10 −5 min −1 /(pmol/l), p<0.01) and had more subcutaneous (240±133 vs 187±90 cm 2 , p<0.01), but less intra-abdominal fat (82±57 vs 124±68 cm 2 , p<0.0001). By simple regression, adiponectin was positively correlated with age (r=0.227, p<0.01) and S I (r=0.375, p<0.0001), and negatively correlated with BMI (r=−0.333, p<0.0001), subcutaneous (r=−0.168, p<0.05) and intra-abdominal fat (r=−0.35, p<0.0001). Adiponectin was negatively correlated with triglycerides (r=−0.281, p<0.001) and positively correlated with HDL cholesterol (r=0.605, p<0.0001) and Rf, a measure of LDL particle buoyancy (r=0.474, p<0.0001). By multiple regression analysis, adiponectin was related to age (p<0.0001), sex (p<0.005) and intra-abdominal fat (p<0.01). S I was related to intraabdominal fat (p<0.0001) and adiponectin (p<0.0005). Both intra-abdominal fat and adiponectin contributed independently to triglycerides, HDL cholesterol and Rf. Conclusion/interpretation. These data suggest that adiponectin concentrations are determined by intra-abdominal fat mass, with additional independent effects of age and sex. Adiponectin could link intra-abdominal fat with insulin resistance and an atherogenic lipoprotein profile. [Diabetologia (2003) 46:459-469] Keywords Adiponectin, Acrp30, adipoQ, central obesity, subcutaneous fat, intra-abdominal fat, insulin sensitivity, lipids, hepatic lipase, cardiovascular disease, leptin. It is well recognized that obesity and insulin resistance are closely related [1,2,3,4]. Android body fat distribution is associated with insulin resistance more than is a gynoid body fat distribution [5], with the site of abdominal fat distribution being an additional determinant of insulin sensitivity [6,7,8,9,10,11]. We found in both lean and obese subjects that the intraabdominal fat (IAF) depot is a stronger determinant of insulin sensitivity than the subcutaneous fat (SCF) depot [11], while SCF is the main determinant of the plasma concentration of leptin [11], an adipocyte-derived hormone regulating energy metabolism [12,13].

show abstract

FFA cause hepatic insulin resistance by inhibiting insulin suppression of glycogenolysis

Cited by 199 publications

References 37 publications

Plasma C5 Glucose–to–2H2O Ratio Does Not Provide an Accurate Assessment of Gluconeogenesis During Hyperinsulinemic-Euglycemic Clamps in Either Nondiabetic or Diabetic Humans

Plasma C5 Glucose–to–2H2O Ratio Does Not Provide an Accurate Assessment of Gluconeogenesis During Hyperinsulinemic-Euglycemic Clamps in Either Nondiabetic or Diabetic Humans

Inhibition of lipolysis during acute GH exposure increases insulin sensitivity in previously untreated GH-deficient adults

Relationship of adiponectin to body fat distribution, insulin sensitivity and plasma lipoproteins: evidence for independent roles of age and sex

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