Inhibition of the Rise in FFA by Acipimox Partially Prevents GH-Induced Insulin Resistance in GH-Deficient Adults

Segerlantz, Mikael; Bramnert, Margareta; Manhem, Per; Laurila, Esa; Groop, Leif

doi:10.1210/jcem.86.12.8096

Cited by 47 publications

(26 citation statements)

References 23 publications

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“…We also assessed EGP by the radiolabeled glucose method to avoid problems from negative values of EGP (17). In keeping with results during chronic therapy, the acute injection of GH had no significant effect on EGP in these subjects and suppression of EGP during the clamp could not be completely restored by prior administration of acipimox during GH treatment (9). In contrast and in keeping with some earlier findings (30), only when FFA levels were suppressed in due time before the clamp with acipimox alone suppression of EGP was enhanced.…”

Section: Discussionsupporting

confidence: 87%

“…There is ample evidence that chronic GH replacement therapy in GHD patients induces insulin resistance by concomitant activation of lipolysis and that this untoward effect on glucose metabolism can be prevented by prior inhibition of lipolysis by acipimox (9,10). To dissect the effects of GH on lipolysis and glucose metabolism from other secondary effects we studied the metabolic effects of GH in previously GH-untreated patients.…”

Section: Discussionmentioning

confidence: 99%

“…Some (11,28) but not all (9,10,27) studies have shown that GH might have a direct effect on EGP. 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).…”

Section: Discussionmentioning

confidence: 99%

“…GH is a lipolytic hormone and has been reported to increase free fatty acid (FFA) (7,8). The negative effects of GH on glucose metabolism during chronic GH replacement therapy have been ascribed to its lipolytic effect and thus by an activated fatty-acid glucose cycle (9,10). Previous studies evaluating the lipolytic effect of GH have in general been performed in subjects on chronic GH replacement therapy (9 -11).…”

Section: Introductionmentioning

confidence: 99%

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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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Section: Discussionsupporting

confidence: 87%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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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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“…GH therapy is often associated with impaired insulin sensitivity. Prevention of lipolysis by coadministration of GH with FFA regulators can partially prevent the deterioration of insulin sensitivity, indicating that insulin resistance is a consequence of enhanced GH-induced lipolysis (99). In addition, the GH plus FFA regulator combination treatment significantly enhances linear body growth in SGA and control rats.…”

Section: Glucose Homeostasismentioning

confidence: 99%

Genetic disorders in the GH–IGF-I axis in mouse and man

Walenkamp

Wit²

2007

eur j endocrinol

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Animal knockout experiments have offered the opportunity to study genes that play a role in growth and development. In the last few years, reports of patients with genetic defects in GH-IGF-I axis have greatly increased our knowledge of genetically determined causes of short stature. We will present the animal data and human reports of genetic disorders in the GH-IGF-I axis in order to describe the role of the GH-IGF-I axis in intrauterine and postnatal growth. In addition, the effects of the GH-IGF-I axis on the development and function of different organ systems such as brain, inner ear, eye, skeleton, glucose homeostasis, gonadal function, and immune system will be discussed. The number of patients with genetic defects in the GH-IGF-I axis is small, and a systematic diagnostic approach and selective genetic analysis in a patient with short stature are essential to identify more patients. Finally, the implications of a genetic defect in the GH-IGF-I axis for the patient and the therapeutic options will be discussed.European Journal of Endocrinology 157 S15-S26

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Free fatty acid flux in African‐American and caucasian adults—effect of sex and race

Nielsén

Sumner

Miller

et al. 2013

Obesity

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ObjectiveObesity, insulin resistance and diabetes disproportionately affect African American (AA) women. Abnormal adipose tissue free fatty acid (FFA) release is associated with these conditions. Resting energy expenditure (REE) and sex predict FFA release in Caucasians, but whether this is true in AA is unknown. We sought to understand the sex-specific relationships between FFA release, REE and race.Design and Methods100 adults (47% AA, 50% male, age 32±8y (mean ± SD)) from 3 different centers underwent duplicate measures of FFA release ([U-13C] palmitate) and REE (indirect calorimetry). Body composition was determined by DXA and abdominal imaging.ResultsAA participants had lower REE, but similar FFA concentrations and flux compared with Caucasian participants. The significant predictors of palmitate release were REE, sex, and race. REE and FFA flux were correlated in both sexes and both races. In a multiple-linear regression analysis with palmitate flux as the dependent variable and REE, sex, race, total fat mass, fat free mass, and insulin as independent variables, REE was the only independent predictor of FFA release in men. Both REE and race predicted palmitate flux in women.ConclusionsFFA flux is related to REE, but the relationship differs in AA and Caucasian women.

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Inhibition of the Rise in FFA by Acipimox Partially Prevents GH-Induced Insulin Resistance in GH-Deficient Adults

Cited by 47 publications

References 23 publications

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

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

Genetic disorders in the GH–IGF-I axis in mouse and man

Free fatty acid flux in African‐American and caucasian adults—effect of sex and race

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