Comparison of the effects of recombinant human insulin-like growth factor-I and insulin on glucose and leucine kinetics in humans.

Laager, R.; Ninnis, Ronald; Keller, Ulrich

doi:10.1172/jci116783

Cited by 91 publications

(66 citation statements)

References 39 publications

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“…It is possible that many of the anabolic effects of rhGH on body tissues observed in chronic studies are mediated via the stimulation of endogenous IGF-I synthesis, which may exert its effects via endocrine and/or paracrine mechanisms. In humans, IGF-I, like insulin, promotes whole body anabolism by inhibiting protein degradation (37), though an increase in protein synthesis has also been observed (38). When infused intraarterially into healthy volunteers, IGF-I has been shown to exert both GH-like effects, (increase in protein synthesis), and insulin-like effects, (inhibition of protein degradation), in forearm muscle (39).…”

Section: Discussionmentioning

confidence: 99%

Effects of recombinant human growth hormone on muscle protein turnover in malnourished hemodialysis patients.

Garibotto¹,

Barreca²,

Russo³

et al. 1997

J. Clin. Invest.

106

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To assess the effect of recombinant human growth hormone (rhGH) on muscle protein metabolism in uremic patients with malnutrition, forearm [ 3 H]phenylalanine kinetics were evaluated in six chronically wasted (body weight 79% of ideal weight) hemodialysis (HD) patients in a self-controlled, crossover study. Forearm protein dynamics were evaluated before, after a 6-wk course of rhGH (5 mg thrice weekly) and after a 6-wk washout period. After rhGH: ( a ) forearm phenylalanine net balance-the difference between phenylalanine incorporation into and phenylalanine release from muscle proteins-decreased by 46% ( Ϫ 8 Ϯ 2 vs. Ϫ 15 Ϯ 2 nmol/min·100 ml at the baseline and Ϫ 11 Ϯ 2 after washout,

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Section: Discussionmentioning

confidence: 99%

Effects of recombinant human growth hormone on muscle protein turnover in malnourished hemodialysis patients.

Garibotto¹,

Barreca²,

Russo³

et al. 1997

J. Clin. Invest.

106

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“…High doses of IGF-I have been shown to suppress FFA levels, oxidation and turnover (Guler et al 1987, Laager et al 1993, Boulware et al 1994, Usala et al 1994. Given the reduced expression of IGF-I receptors on the adipocyte (Zapf et al 1981, Sinha et al 1989, it was speculated that IGF-I suppresses lipolysis via its crossreactivity with the insulin receptor, thus requiring high IGF-I levels to mediate effects on the adipocyte.…”

Section: Discussionmentioning

confidence: 99%

“…Given the reduced expression of IGF-I receptors on the adipocyte (Zapf et al 1981, Sinha et al 1989, it was speculated that IGF-I suppresses lipolysis via its crossreactivity with the insulin receptor, thus requiring high IGF-I levels to mediate effects on the adipocyte. Thus, it was somewhat expected when low-dose IGF-I administration was found to have no effect on FFA metabolism (Mauras et al 1992, Elahi et al 1993, Laager et al 1993). In the current study, it was surprising to note that low-dose IGF-I induced suppression of FFA levels by 50% and glycerol by 30%.…”

Section: Discussionmentioning

confidence: 99%

“…Unfortunately, the acute metabolic responses to these low doses of IGF-I have been less well characterized. Many of the differential effects of IGF-I vs insulin in acutely stimulating glucose metabolism observed at higher doses (above 100 µg/kg) are not observed at lower doses (Laager et al 1993, Boulware et al 1994. Studies comparing metabolic responses to high-and low-dose IGF-I infusion have found that glucose kinetics may not respond in a dose-dependent fashion (Shojaee-Moradie et al 1995), which may be related to the effects of circulating IGF-binding proteins or variable suppression of endogenous insulin and/or glucagon.…”

Section: Introductionmentioning

confidence: 96%

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Low-dose IGF-I has no selective advantage over insulin in regulating glucose metabolism in hyperglycemic depancreatized dogs

Fisher¹,

Shi²,

Lickley³

et al. 2001

Journal of Endocrinology

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At supraphysiological levels, IGF-I bypasses some forms of insulin resistance and has been proposed as a therapeutic agent in the treatment of diabetes. Unfortunately, side effects of high-dose IGF-I (100-250 µg/kg) have precluded its clinical use. Low-dose IGF-I (40-80 µg/kg), however, shows minimal side effects but has not been systematically evaluated. In our previous study under conditions of declining glucose, low-dose IGF-I infusion was more effective in stimulating glucose utilization, but less effective in suppressing glucose production and lipolysis than low-dose insulin. However, under conditions of hyperglycemia, we could not observe any differential effects between high-dose infusions of IGF-I and insulin. To determine whether the differential effects of IGF-I and insulin are dose-related or related to the prevailing glucose level, 3 h glucose clamps were performed in the same animal model as in the previous studies, i.e. the moderately hyperglycemic (175 mg/dl) insulin-infused depancreatized dog, with additional infusions of low-dose IGF-I (67·8 µg/kg, i.e. 29·1 µg/kg bolus plus 0·215 µg/kg per min infusion; n=5) or insulin 49·5 mU/kg (9 mU/kg bolus plus 0·45 mU/kg per min; n=7). As in the previous study under conditions of declining glucose, low-dose IGF-I had significant metabolic effects in vivo, in our model of complete absence of endogenous insulin secretion. Glucose production was similarly suppressed with both IGF-I and insulin, by 54 3 and 56 2% .. (P=NS) respectively. Glucose utilization was stimulated to the same extent (IGF-I 5·2 0·2, insulin 5·5 0·3 mg/kg per min, P=NS). Glucagon, free fatty acid, glycerol, alanine and betahydroxybutyrate, were suppressed, while lactate and pyruvate levels were raised, similarly with IGF-I and insulin. We conclude that: (i) differential effects of IGF-I and insulin may be masked under hyperglycemic conditions, independent of the hormone dose; (ii) low-dose IGF-I has no selective advantage over additional insulin in suppressing glucose production and lipolysis, nor in stimulating glucose utilization during hyperglycemia and subbasal insulin infusion when insulin secretion is absent, as in type 1 diabetes mellitus.

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“…Previous studies investigating the effects of IGF-I administration on NEFA metabolism have produced conflicting results, with decreased (19,20,41,42), increased, and unaltered (2,35) plasma NEFA levels reported by various investigators. It is likely that decreased GH-mediated lipolysis and simultaneously enhanced insulin sensitivity resulted in the lower circulating NEFA levels during the IGF-I administration.…”

mentioning

confidence: 99%

IGF-I treatment in adults with type 1 diabetes: effects on glucose and protein metabolism in the fasting state and during a hyperinsulinemic-euglycemic amino acid clamp.

et al. 2000

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Type 1 diabetes is associated with abnormalities of the growth hormone (GH)-IGF-I axis. Such abnormalities include decreased circulating levels of IGF-I. We studied the effects of IGF-I therapy (40 µg · kg -1 · day -1 ) on protein and glucose metabolism in adults with type 1 diabetes in a randomized placebo-controlled trial. A total of 12 subjects participated, and each subject was studied at baseline and after 7 days of treatment, both in the fasting state and during a hyperinsulinemiceuglycemic amino acid clamp. Protein and glucose metabolism were assessed using infusions of [1- 13C]leucine and [6-6-2 H 2 ]glucose. IGF-I administration resulted in a 51% rise in circulating IGF-I levels (P < 0.005) and a 56% decrease in the mean overnight GH concentration (P < 0.05). After IGF-I treatment, a decrease in the overnight insulin requirement (0.26 ± 0.07 vs. 0.17 ± 0.06 U/kg, P < 0.05) and an increase in the glucose infusion requirement were observed during the hyperinsulinemic clamp (~67%, P < 0.05). Basal glucose kinetics were unchanged, but an increase in insulin-stimulated peripheral glucose disposal was observed after IGF-I therapy (37 ± 6 vs. 52 ± 10 µmol · kg -1 · min -1 , P < 0.05). IGF-I administration increased the basal metabolic clearance rate for leucine (~28%, P < 0.05) and resulted in a net increase in leucine balance, both in the basal state and during the hyperinsulinemic amino acid clamp (-0.17 ± 0.03 vs. -0.10 ± 0.02, P < 0.01, and 0.25 ± 0.08 vs. 0.40 ± 0.06, P < 0.05, respectively). No changes in these variables were recorded in the subjects after administration of placebo. These findings demonstrated that IGF-I replacement resulted in significant alterations in glucose and protein metabolism in the basal and insulinstimulated states. These effects were associated with increased insulin sensitivity, and they underline the major role of IGF-I in protein and glucose metabolism in type 1 diabetes. Diabetes 49:789-796, 2000 I GF-I shares a 40% sequence homology with human proinsulin and exhibits both insulin-like and anabolic effects (1,2). The availability of recombinant human IGF-I (rhIGF-I) has led to interest in the potential of this peptide in the treatment of a variety of disease states (3-7). Type 1 diabetes has received particular attention, because the relative portal insulin deficiency of this condition is thought to be responsible for the reduced circulating levels of IGF-I (8), which in turn, through decreased negative feedback, leads to increased secretion of growth hormone (GH) (9).Recent studies have demonstrated improved glycemic control in patients with types 1 and 2 diabetes after IGF-I treatment (10,11). IGF-I administration has also been shown to reduce the GH hypersecretion of adolescents and adults with type 1 diabetes (12,13). In those studies, the reductions in GH secretion were associated with decreased insulin requirements, without alteration in glycemic control, which indicates an increase in insulin sensitivity.In addition to disordered glucose metabolism, patients with t...

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Comparison of the effects of recombinant human insulin-like growth factor-I and insulin on glucose and leucine kinetics in humans.

Cited by 91 publications

References 39 publications

Effects of recombinant human growth hormone on muscle protein turnover in malnourished hemodialysis patients.

Effects of recombinant human growth hormone on muscle protein turnover in malnourished hemodialysis patients.

Low-dose IGF-I has no selective advantage over insulin in regulating glucose metabolism in hyperglycemic depancreatized dogs

IGF-I treatment in adults with type 1 diabetes: effects on glucose and protein metabolism in the fasting state and during a hyperinsulinemic-euglycemic amino acid clamp.

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