Pharmacological Antilipolysis Restores Insulin Sensitivity During Growth Hormone Exposure

Nielsen, Strange; Møller, Niels; Christiansen, Jens Sandahl; Jørgensen, Jens Otto Lunde

doi:10.2337/diabetes.50.10.2301

Cited by 123 publications

(102 citation statements)

References 41 publications

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“…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%

“…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%

“…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: 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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“…Elevation of plasma GH levels also results in increased plasma insulin levels and insulin resistance (6). The increased insulin secretion can be explained by a direct effect of GH on the pancreatic ␤-cells (33,40), whereas the insulin resistance may be explained by increased fatty acid oxidation in some (34), but not all, situations (18,37).…”

mentioning

confidence: 99%

Effects of gender and GH secretory pattern on sterol regulatory element-binding protein-1c and its target genes in rat liver

Améen¹,

Lindén²,

Larsson³

et al. 2004

American Journal of Physiology-Endocrinology and Metabolism

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. Effects of gender and GH secretory pattern on sterol regulatory element-binding protein-1c and its target genes in rat liver. Am J Physiol Endocrinol Metab 287: E1039 -E1048, 2004. First published July 27, 2004 doi:10.1152/ ajpendo.00059.2004.-We investigated whether the sexually dimorphic secretory pattern of growth hormone (GH) in the rat regulates hepatic gene expression of sterol regulatory element-binding protein-1c (SREBP-1c) and its target genes. SREBP-1c, fatty acid synthase (FAS), and glycerol-3-phosphate acyltransferase (GPAT) mRNA were more abundant in female than in male livers, whereas acetyl-CoA carboxylase-1 (ACC1) and stearoyl-CoA desaturase-1 (SCD-1) were similarly expressed in both sexes. Hypophysectomized female rats were given GH as a continuous infusion or as two daily injections for 7 days to mimic the female-and male-specific GH secretory patterns, respectively. The female pattern of GH administration increased the expression of SREBP-1c, ACC1, FAS, SCD-1, and GPAT mRNA, whereas the male pattern of GH administration increased only SCD-1 mRNA. FAS and SCD-1 protein levels were regulated in a similar manner by GH. Incubation of primary rat hepatocytes with GH increased SCD-1 mRNA levels and decreased FAS and GPAT mRNA levels but had no effect on SREBP-1c mRNA. GH decreased hepatic liver X receptor-␣ (LXR␣) mRNA levels both in vivo and in vitro. Feminization of the GH plasma pattern in male rats by administration of GH as a continuous infusion decreased insulin sensitivity and increased expression of FAS and GPAT mRNA but had no effect on SREBP-1c, ACC1, SCD-1, or LXR␣ mRNA. In conclusion, FAS and GPAT are specifically upregulated by the female secretory pattern of GH. This regulation is not a direct effect of GH on hepatocytes and does not involve changed expression of SREBP-1c or LXR␣ mRNA but is associated with decreased insulin sensitivity. growth hormone; hypophysectomy; acetyl-CoA carboxylase; fatty acid synthase; stearoyl-CoA desaturase; glycerol-3-phosphate acyltransferase; liver X receptor-␣; insulin sensitivity GROWTH HORMONE (GH) plays an important role in the regulation of lipid metabolism. GH has lipolytic and antilipogenic effects in adipose tissue (6) that contribute to the decreased body fat mass observed after GH treatment (2, 42). Elevation of plasma GH levels also results in increased plasma insulin levels and insulin resistance (6). The increased insulin secretion can be explained by a direct effect of GH on the pancreatic ␤-cells (33, 40), whereas the insulin resistance may be explained by increased fatty acid oxidation in some (34), but not all, situations (18, 37).GH secretion from the pituitary is sexually differentiated in all mammals, but the difference is particularly pronounced in rodents (8,17,21). In female rats, the GH secretion is frequent and nearly continuous with high basal levels, whereas GH is secreted as regular, high-amplitude pulses with low or undetectable levels between peaks in males (8, 46). Several hepatic functions that are sex differentiated a...

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“…2001), which may in part be mediated by an increase in adipose lipolysis and circulating FFAs (Nielsen et al. 2001). Initial studies with ghrelin in humans attempted to control for ghrelin's secondary GH release, using either infusion of somatostatin to inhibit GH release, or GH‐deficient participants (Gauna et al.…”

Section: Discussionmentioning

confidence: 99%

Acylated and unacylated ghrelin do not directly stimulate glucose transport in isolated rodent skeletal muscle

Cervone

Dyck

2017

Physiol Rep

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Emerging evidence implicates ghrelin, a gut‐derived, orexigenic hormone, as a potential mediator of insulin‐responsive peripheral tissue metabolism. However, in vitro and in vivo studies assessing ghrelin's direct influence on metabolism have been controversial, particularly due to confounding factors such as the secondary rise in growth hormone (GH) after ghrelin injection. Skeletal muscle is important in the insulin‐stimulated clearance of glucose, and ghrelin's exponential rise prior to a meal could potentially facilitate this. This study was aimed at elucidating any direct stimulatory action that ghrelin may have on glucose transport and insulin signaling in isolated rat skeletal muscle, in the absence of confounding secondary factors. Oxidative soleus and glycolytic extensor digitorum longus skeletal muscles were isolated from male Sprague Dawley rats in the fed state and incubated with various concentrations of acylated and unacylated ghrelin in the presence or absence of insulin. Ghrelin did not stimulate glucose transport in either muscle type, with or without insulin. Moreover, GH had no acute, direct stimulatory effect on either basal or insulin‐stimulated muscle glucose transport. In agreement with the lack of observed effect on glucose transport, ghrelin and GH also had no stimulatory effect on Ser473 AKT or Thr172 AMPK phosphorylation, two key signaling proteins involved in glucose transport. Furthermore, to our knowledge, we are among the first to show that ghrelin can act independent of its receptor and cause an increase in calmodulin‐dependent protein kinase 2 (CaMKII) phosphorylation in glycolytic muscle, although this was not associated with an increase in glucose transport. We conclude that both acylated and unacylated ghrelin have no direct, acute influence on skeletal muscle glucose transport. Furthermore, the immediate rise in GH in response to ghrelin also does not appear to directly stimulate glucose transport in muscle.

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Pharmacological Antilipolysis Restores Insulin Sensitivity During Growth Hormone Exposure

Cited by 123 publications

References 41 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

Effects of gender and GH secretory pattern on sterol regulatory element-binding protein-1c and its target genes in rat liver

Acylated and unacylated ghrelin do not directly stimulate glucose transport in isolated rodent skeletal muscle

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