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Growth Hormone Replacement Therapy Induces Insulin Resistance by Activating the Glucose-Fatty Acid Cycle

Department of Endocrinology (M.B., M.S., E.L., P.M., L.G.), University Hospital, S-205 02 Malmö, Sweden; and Copenhagen Muscle Research Centre (J.R.D.), Department of Human Physiology, DK-2100 Copenhagen, Denmark

Address all correspondence and requests for reprints to: Margareta Bramnert, Department of Endocrinology, University Hospital MAS, S-205 +2 Malmö, Sweden. E-mail: margareta.bramnert{at}skane.se.

The effects of GH replacement therapy on energy metabolism are still uncertain, and long-term benefits of increased muscle mass are thought to outweigh short-term negative metabolic effects. This study was designed to address this issue by examining both short-term (1 wk) and long-term (6 months) effects of a low-dose (9.6 µg/kg body weight·d) GH replacement therapy or placebo on whole-body glucose and lipid metabolism (oral glucose tolerance test and euglycemic hyperinsulinemic clamp combined with indirect calorimetry and infusion of 3-[³H]glucose) and on muscle composition and muscle enzymes/metabolites, as determined from biopsies obtained at the end of the clamp in 19 GH-deficient adult subjects.

GH therapy resulted in impaired insulin-stimulated glucose uptake at 1 wk (-52%; P = 0.008) and 6 months (-39%; P = 0.008), which correlated with deterioration of glucose tolerance (r = -0.481; P = 0.003). The decrease in glucose uptake was associated with an increase in lipid oxidation at 1 wk (60%; P = 0.008) and 6 months (60%; P = 0.008) and a concomitant decrease in glucose oxidation. The deterioration of glucose metabolism during GH therapy also correlated with the enhanced rate of lipid oxidation (r = -0.508; P = 0.0002). In addition, there was a shift toward more glycolytic type II fibers during GH therapy.

In conclusion, replacement therapy with a low-dose GH in GH-deficient adult subjects is associated with a sustained deterioration of glucose metabolism as a consequence of the lipolytic effect of GH, resulting in enhanced oxidation of lipid substrates. Also, a shift toward more insulin-resistant type II X fibers is seen in muscle. Glucose metabolism should be carefully monitored during long-term GH replacement therapy.

This work was supported by the Nordisk Insulin Foundation, Albert Påhlsson's Foundation, and Pharmacia \|[amp ]\| Upjohn, Inc. (Stockholm, Sweden).

Abbreviations: AUC, Area under the curve; B, blood; BIA, bioelectrical impedance; BMI, body mass index; BW, body weight; CV, coefficient(s) of variation; FFA, free fatty acid; FV, fractional velocity of GS activity; G-6-P, glucose-6-phosphate; GHD, GH-deficient or GH deficiency; GS, glycogen synthase; HGP, hepatic glucose production; NADH, nicotinamide adenine dinucleotide phosphate; OGTT, oral glucose tolerance test; S, serum; TBW, total body water; UDP, uridine diphosphate.

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