Insulin resistance in growth hormone-deficient adults: defects in glucose utilization and glycogen synthase activity

Abstract

Fourteen GH-deficient (GHD) adults were compared with 12 age-, sex-, and body mass index-matched control subjects using a baseline tritiated glucose equilibration period and euglycemic-hyperinsulinemic (approximately 55 mU/L) clamp in conjunction with paired muscle biopsies for measurement of glycogen synthase fractional velocity (FV0.1). Despite similar basal rates of total glucose disposal (Rd), there was a 64% reduction in the insulin-stimulated rise (delta) in Rd in the GHD adults compared to that in controls [16.6 +/- 2.8 vs. 44.7 +/- 6.0 mumol/kg fat free mass (FFM)/min; P < 0.001], which was mainly due to a decreased glucose storage (GS) rate (delta GS, 12.6 +/- 2.9 vs. 39.5 +/- 7.5 mumol/kg FFM/min; P < 0.01). Furthermore, the insulin sensitivity indexes of Rd (0.39 +/- 0.07 vs. 0.85 +/- 0.11; P < 0.05) and GS (0.25 +/- 0.07 vs. 0.72 +/- 0.13 mumol/kg FFM/min per mU/L; P < 0.02) were reduced in GHD adults compared to the control values. The insulin sensitivity of the glycolytic pathway was also reduced by approximately 50% in GHD adults (P = 0.07 vs. controls). Insulin-stimulated FV0.1 was decreased in GHD adults (0.31 +/- 0.02 vs. 0.47 +/- 0.03; P < 0.005) despite similar basal FV0.1. Using multiple and stepwise regression analysis, duration of GH deficiency, fasting triglycerides and fasting insulin accounted for 67% of the variance in the insulin sensitivity index of Rd. In conclusion, the severe insulin resistance in GHD adults is mainly due to the inhibition of the GS pathway and glycogen synthase activity in peripheral tissues, which is related to the duration of GH deficiency, fasting triglycerides, and fasting insulin.

Prevalence of diabetes mellitus in 6050 hypopituitary patients with adult-onset GH deficiency before GH replacement: a KIMS analysis

“…The fact that isolated GHD and GHD in combination with multiple pituitary deficiencies are both equally associated with the development of diabetes adds an indirect argument to the concept that GHD in adult-onset hypopituitarism by itself plays a not unimportant role in the development of the characteristic adverse metabolic profile, and therefore GH replacement may be regarded essential (28). The duration of GHD had no influence on the presence of diabetes, despite this determinant having previously been demonstrated to be the single most important predictor of insulin resistance in a study using the hyperinsulinemic normoglycemic clamp technique in a small group of patients (10). The advantages and drawbacks of large pharmacoepidemiological databases are now well recognized (13).…”

“…Moreover, the first clinical studies pointed toward an impaired carbohydrate metabolism, because an increased prevalence of impaired glucose tolerance was found in 14 out of 40 adult GHD patients (8). Furthermore, using the hyperinsulinemic normoglycemic clamp technique, a significant impairment of insulin sensitivity was observed (9,10). An increase in free fatty acids related to the tendency toward obesity and to the increase in visceral fat has been implicated in the insulin resistance, because reduction of the free fatty acids by the niacin derivative acipimox ameliorates GH secretion in obesity and in GHD (11).…”

Insulin Sensitivity in Adults with Growth Hormone Deficiency and Effect of Growth Hormone Treatment

“…In one of the most comprehensive studies of the metabolic consequences of GHD, Hew et al [9] showed that fat mass was clearly higher (31.1 vs. 25.5%) and insulin-stimulated glucose uptake severely impaired (30 vs. 55 µmol/kg·FFM·min) in 14 patients with GHD matched for age and body mass index (BMI) with 12 healthy controls. Similarly, when we compared 10 patients with GHD with 300 controls matched for BMI (27 kg/m 2 ), the patients with GHD again appeared to have 20% more fat (30.4 vs. 25%) than the controls (M. Bramnert, unpublished data).…”

Overall and cause-specific mortality in GH-deficient adults on GH replacement

“…During the past two decades, evidence has emerged linking hypopituitarism with cardiovascular risk factors, including hyperlipidaemia (11,12,13,14), visceral adiposity (15,16), insulin resistance (17) and vascular endothelial dysfunction (18,19,20).…”