Increasing urine albumin excretion is associated with growth hormone hypersecretion and reduced clearance of insulin in adolescents and young adults with type 1 diabetes: the Oxford Regional Prospective Study.

We previously described lower insulin-like growth factor I (IGF-I) levels in association with increased microalbuminuria (MA) risk in type 1 diabetic subjects followed from diabetes diagnosis through puberty into adulthood. By inference lower IGF-I levels may be associated with higher GH levels and changes in insulin sensitivity. To test this hypothesis, microalbuminuric subjects (MA+, n = 14) from the same cohort had overnight GH levels measured during euglycaemia (5 mmol/l, 01:00-07:30 h) maintained by a variable rate insulin infusion followed by a 2-step hyperinsulinaemic, euglycaemic clamp study using [6.6 2H2] glucose, and were compared to MA- controls (MA-, n = 14), matched for age (median 19.3 years, range 15.8-30.5), sex, duration of diabetes (11.1 years, range 5.1-16.4). In MA+ cases GH levels, measured by the Pulsar programme, were higher (baseline; 1.8 +/- 1.4 vs. 0.7 +/- 0.5 ng/ml, P = 0.02, mean; 3.8 +/- 1.3 vs. 2.6 +/- 1.6 ng/ml, P = 0.03, maximum; 16.7 +/- 7.0 vs. 12.3 +/- 5.4, P = 0.02), despite similar HbA1(c) levels (9.8%vs. 9.6%, P = 0.6) and body or truncal fat mass. Fourier transform revealed increased GH pulse amplitude at all periodicities and overnight insulin clearance was reduced (11.7 +/- 6.9 vs. 20.1 +/- 6.5 ml/kg/min, P < 0.02). In multiple regression analysis, urine albumin excretion was associated with higher GH levels and reduced insulin clearance, independent of HbA1(c) and body composition. In female cases (n = 9), dextrose requirements were reduced during the first step of the euglycaemic clamp (1.7 +/- 0.8 vs. 2.7 +/- 1.4, P < 0.05) but no such differences existed in males or in the rate of glucose production or disposal. The development of MA during puberty and young adulthood is associated with higher GH levels and abnormalities in insulin metabolism, particularly in females. These data extend support for our previous findings indicating a role for the GH/IGF-I axis in the pathogenesis of MA.

Amin R ，Williams RM ，Frystyk J ，Umpleby M ，Matthews D ，Orskov H ，Dalton RN ，Dunger DB ... -  《CLINICAL ENDOCRINOLOGY》

Short-term suppression of elevated growth hormone concentrations following insulin-like growth factor 1 administration in young adults with type 1 diabetes does not alter glomerular filtration or albumin excretion rates.

Young adults with type 1 diabetes mellitus (T1DM) have increased glomerular filtration rate (GFR), which may mediate progressive renal disease and microalbuminuria. This may be secondary to low concentrations of insulin-like growth factor (IGF)-I and GH hypersecretion. We tested the hypothesis that restoration of circulating IGF-I concentrations in young adults with T1DM might suppress GH secretion, GFR and urinary albumin excretion. In a randomized double blind crossover study six young adults with T1DM (three men, 19-24 years) received 7 days treatment with rhIGF-I/insulin-like growth factor binding protein (IGFBP)-3 complex (SomatoKine) 0.4 mg/kg/day and placebo. Subjects underwent overnight insulin infusion for euglycaemia, followed by determination of GFR and albumin excretion rate. Following IGF-I/IGFBP-3 complex, overnight insulin requirements (0.15 vs placebo 0.21 mU/kg/min, P < 0.04), plasma insulin (77 vs placebo 152 pmol/l, P < 0.01) and mean overnight GH (2.6 vs placebo 4.8 mU/l, P < 0.04) fell. IGF-I (492 vs placebo 218 ng/ml, P < 0.01) and IGFBP-3 (4.5 vs placebo 3.9 microg/ml, P < 0.05) increased. GFR did not change (145.5 (23.9) ml/min/1.73 m(2) post-IGF-I/IGFBP-3 complex vs 152.2 (19.8) post placebo). Albumin excretion rate did not change 9.5 (5.5-16.6)mg/24 h pre- vs 11.5 (9.9-20.2) post-IGF-I/IGFBP-3 complex and 10.7 (8.1-21.2) pre- vs 11.5 (8.7-29.9) post placebo. Plasma creatinine levels were lower following IGF-I/IGFBP-3 complex (mean +/- SD, 56.2 +/- 16.8 micromol/l) vs placebo (61.5, 45.0, P < 0.02). Seven days treatment with IGF-I/IGFBP-3 complex enhanced overnight insulin sensitivity and reduced GH levels, but there was no effect on glomerular hyperfiltration or albumin excretion rates.

Williams RM ，Yuen K ，White D ，Mallard B ，Dalton RN ，Acerini CL ，Dunger DB ... -  《CLINICAL ENDOCRINOLOGY》

Improvement in insulin sensitivity without concomitant changes in body composition and cardiovascular risk markers following fixed administration of a very low growth hormone (GH) dose in adults with severe GH deficiency.

Untreated GH-deficient adults are predisposed to insulin resistance and excess cardiovascular mortality. We showed previously that short-term treatment with a very low GH dose (LGH) enhanced insulin sensitivity in young healthy adults. The present study was therefore designed to explore the hypothesis that LGH, in contrast to the standard GH dose titrated to normalize serum IGF-I levels (SGH), may have differing effects on insulin sensitivity, body composition, and cardiovascular risk markers [lipid profile, C-reactive protein (CRP), interleukin-6 (IL-6), tumour necrosis factor-alpha (TNF-alpha) and adiponectin] in adults with severe GH deficiency. In this 12-month open, prospective study, 25 GH-deficient adults were randomized to receive either a fixed LGH (0.10 mg/day, n = 13) or SGH (mean dose 0.48 mg/day, n = 12), and eight age- and body mass index (BMI)-matched GH-deficient adults acted as untreated controls. Fasting blood samples were collected at baseline and at months 1, 3, 6, 9 and 12. Assessments of insulin sensitivity, using the hyperinsulinaemic euglycaemic clamp technique, and body composition, using dual-energy X-ray absorptiometry, were performed at baseline and at month 12. The LGH decreased fasting glucose levels (P < 0.01) and enhanced insulin sensitivity (P < 0.02), but body composition, nonesterified fatty acid (NEFA) levels and cardiovascular risk markers were unchanged. The SGH did not modify insulin sensitivity, decreased truncal fat mass (P < 0.05), CRP (P < 0.05) and IL-6 (P < 0.05) levels, and increased NEFA levels (P < 0.05). No changes were observed with the untreated controls. Our data indicate that, in contrast to the SGH, fixed administration of the LGH enhances insulin sensitivity with no apparent effects on body composition, lipolysis and other surrogate cardiovascular risk markers in adults with severe GH deficiency. Thus, the LGH may potentially be a beneficial replacement dose in reducing type 2 diabetes risk in adults with severe GH deficiency.

Yuen KC ，Frystyk J ，White DK ，Twickler TB ，Koppeschaar HP ，Harris PE ，Fryklund L ，Murgatroyd PR ，Dunger DB ... -  《CLINICAL ENDOCRINOLOGY》

Growth hormone, IGF-I and its binding proteins (IGFBP-1 and -3) in adult uraemic patients undergoing peritoneal dialysis and haemodialysis.

The GH/IGF axis is altered in chronic renal failure (CRF). CRF patients usually show normal or high serum concentrations of GH and IGF-I, whereas all IGF binding proteins (IGFBP-1 to -6), except IGFBP-5, considerably increase with declining renal function. The aims of the present study were to quantify serum concentrations of GH, IGF-I, IGFBP-1 and IGFBP-3 in a group of patients with CRF, and determine whether there were differences according to the type of dialysis, that is, peritoneal dialysis (PD) and haemodialysis (HD). A cross-sectional study in the setting of a dialysis unit of a general hospital. We studied 108 dialysis patients treated by PD (n = 54, 32 males and 22 females, mean age 61.0 +/- 1.4 years) or HD (n = 54, 31 males and 23 females, age 62.6 +/- 1.5 years). A group of 42 healthy subjects of similar age, sex and body mass index (BMI) served as the control group. Baseline serum concentrations of GH, insulin, IGF-I, IGFBP-1 and IGFBP-3 were measured in all patients and control subjects. Fasting serum concentrations of IGF-I and its binding proteins (IGFBP-1 and IGFBP-3) were significantly higher in dialysis patients than in subjects with normal renal function. IGF-I (248.9 +/- 23.4 vs. 205.5 +/- 15.5 micro g/l, NS), IGFBP-3 (5.6 +/- 0.4 vs. 5.5 +/- 0.2 mg/l, NS) and IGFBP-1 (36.1 +/- 5.9 vs. 44.1 +/- 6.5 micro g/l, NS) concentrations were similar in both groups of dialysis (PD vs. HD) patients. However, GH (2.3 +/- 0.3 vs. 1.1 +/- 0.1 micro g/l, P < 0.001) and insulin (40.4 +/- 4.5 vs. 30.1 +/- 3.1 micro U/ml, P < 0.05) levels were significantly higher in the PD group than in the HD group. Both groups of dialysis patients showed significantly higher levels of insulin than healthy subjects (14.7 +/- 1.9 micro U/ml, P < 0.0001 and P < 0.01 for PD and HD, respectively). In both groups of dialysis patients, IGF-I correlated inversely with IGFBP-1 (PD group r = -0.46, P = 0.0006; HD group r = -0.57, P = 0.0001) and directly with IGFBP-3 (PD group r = 0.44, P = 0.001; HD group r = 0.73, P = 0.001). No correlation between insulin and IGFBP-1 was found in any of the groups studied. These findings demonstrate that adult dialysis patients have elevated IGF-I, IGFBP-1 and IGFBP-3 serum concentrations compared with subjects with normal renal function. Only GH and insulin show statistically significant differences in relation to type of dialysis. Finally, the negative correlation between IGF-I and IGFBP-1 and the positive correlation between IGF-I and IGFBP-3 are maintained in both groups of adult dialysis patients.

Iglesias P ，Díez JJ ，Fernández-Reyes MJ ，Méndez J ，Bajo MA ，Aguilera A ，Selgas R ... -  《CLINICAL ENDOCRINOLOGY》

Serum insulin-like growth factor II levels in normal adolescents and those with insulin dependent diabetes mellitus.

Unlike IGF-I and its principal binding proteins, data regarding IGF-II levels have not been well defined in normal subjects and those with insulin-dependent diabetes mellitus (IDDM). We have therefore measured IGF-II, as well as IGF-I, and IGFBP-3, levels in a large cohort of subjects with IDDM and in age/sex matched controls. One hundred and fourteen patients with IDDM (57 males, 57 females) and 89 control subjects (49 males, 40 females). Random blood samples were obtained from each subject for the measurement of IGF-II, IGF-I and IGFBP-3 levels. Mean values of IGF-II (+/- SEM) were 630 (+/- 27.8) micrograms/l and 646 (+/- 32.3) micrograms/l in female and male controls, compared to 569 (+/- 23.3) micrograms/l and 623.3 (+/- 28.1) micrograms/l in female and male diabetics respectively. IGF-II levels did not differ significantly between the sexes or show any change with transition through puberty in either control or diabetic groups. In contrast, IGF-I levels increased through puberty peaking at stages 3-5 in controls (P < 0.001) and G4-5 (P = 0.002) in diabetic males but not females. IGF-I levels in all diabetics were generally lower than in controls, differences reaching significance at G4-5 in males (P = 0.002) and B5 in females (P = 0.002). IGFBP-3 levels did not show any variation with puberty stage in diabetics, in contrast to controls where levels increased, peaking at G4-5 in males (P = 0.001) and B3 in females. IGFBP-3 levels were lower in diabetics of both sexes and at all stages compared to controls (P range 0.047 to < 0.001). Multiple regression analysis revealed significant correlations between IGF-II and IGFBP-3 (F = 20.1, P = < 0.001) and reaffirmed previously observed associations for IGF-I and IGFBP-3. The sum of IGF-I and IGF-II (expressed as nmol/l) correlated with IGFBP-3; r = 0.47 in controls and 0.60 in diabetics. Insulin-dependent diabetes mellitus is not associated with any significant changes in IGF-II levels during puberty. The binding of IGFBP-3 for both IGF-I and IGF-II is unaltered by insulin-dependent diabetes mellitus.

Acerini CL ，Clayton KL ，Hintz R ，Baker B ，Watts A ，Holly JM ，Dunger DB ... -  《CLINICAL ENDOCRINOLOGY》