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Effects of Growth Hormone and Free Fatty Acids on Insulin Sensitivity in Patients with Type 1 Diabetes

University Department of Paediatrics (B.S., M.L.M., R.M.W., C.L.A., D.B.D.), University of Cambridge, Cambridge CB2 0QQ, United Kingdom; Medical Research Council-Human Nutrition Research (S.J.J., L.J.B.), Cambridge CB1 9NL, United Kingdom; and Oxford Centre for Diabetes, Endocrinology, and Metabolism (S.M.H.), University of Oxford, Oxford OX1 3QX, United Kingdom

Address all correspondence and requests for reprints to: Dr. Burak Salgin, University Department of Pediatrics, Addenbrooke’s Hospital, Level 8, Box 116, Cambridge CB2 0QQ, United Kingdom. E-mail: burak{at}cantab.net.

Context: Because GH stimulates lipolysis, an increase in circulating free fatty acid levels, as opposed to a direct effect of high GH levels, could underlie the development of insulin resistance in type 1 diabetes (T1D). Our aim was to explore the relative contributions of GH and free fatty acids to the development of insulin resistance in patients with T1D.

Patients: Seven (four females, three males) nonobese patients with T1D aged 21–30 yr were studied on four occasions in random order. On each visit, overnight endogenous GH production was suppressed by octreotide. Three 1-h pulses of recombinant human GH (rhGH) or placebo were administered on two visits each. Acipimox, an antilipolytic drug, or a placebo were ingested every 4 h on two visits each. Stable glucose and glycerol isotopes were used to assess glucose and glycerol turnover. The overnight protocol was concluded by a two-step hyperinsulinemic euglycemic clamp on each visit.

Main Outcome: rhGH administration led to increases in the insulin infusion rate required to maintain euglycemia overnight (P = 0.008), elevated basal endogenous glucose production (P = 0.007), decreased basal peripheral glucose uptake (P = 0.03), and reduced glucose uptake during step 1 of the clamp (P < 0.0001). Coadministration of rhGH and acipimox reversed these effects and suppression of lipolysis in the absence of GH replacement led to further increases in insulin sensitivity.

Results: GH pulses were associated with an increase in endogenous glucose production and decreased rates of peripheral glucose uptake, which was entirely reversed by acipimox. Therefore, GH-driven decreases in insulin sensitivity are mainly determined by the effect of GH on lipolysis.