Diabetes mellitus, fasting blood glucose concentration, and risk of vascular disease: a collaborative meta-analysis of 102 prospective studies.

BACKGROUND: Uncertainties persist about the magnitude of associations of diabetes mellitus and fasting glucose concentration with risk of coronary heart disease and major stroke subtypes. We aimed to quantify these associations for a wide range of circumstances. METHODS: We undertook a meta-analysis of individual records of diabetes, fasting blood glucose concentration, and other risk factors in people without initial vascular disease from studies in the Emerging Risk Factors Collaboration. We combined within-study regressions that were adjusted for age, sex, smoking, systolic blood pressure, and body-mass index to calculate hazard ratios (HRs) for vascular disease. FINDINGS: Analyses included data for 698 782 people (52 765 non-fatal or fatal vascular outcomes; 8.49 million person-years at risk) from 102 prospective studies. Adjusted HRs with diabetes were: 2.00 (95% CI 1.83-2.19) for coronary heart disease; 2.27 (1.95-2.65) for ischaemic stroke; 1.56 (1.19-2.05) for haemorrhagic stroke; 1.84 (1.59-2.13) for unclassified stroke; and 1.73 (1.51-1.98) for the aggregate of other vascular deaths. HRs did not change appreciably after further adjustment for lipid, inflammatory, or renal markers. HRs for coronary heart disease were higher in women than in men, at 40-59 years than at 70 years and older, and with fatal than with non-fatal disease. At an adult population-wide prevalence of 10%, diabetes was estimated to account for 11% (10-12%) of vascular deaths. Fasting blood glucose concentration was non-linearly related to vascular risk, with no significant associations between 3.90 mmol/L and 5.59 mmol/L. Compared with fasting blood glucose concentrations of 3.90-5.59 mmol/L, HRs for coronary heart disease were: 1.07 (0.97-1.18) for lower than 3.90 mmol/L; 1.11 (1.04-1.18) for 5.60-6.09 mmol/L; and 1.17 (1.08-1.26) for 6.10-6.99 mmol/L. In people without a history of diabetes, information about fasting blood glucose concentration or impaired fasting glucose status did not significantly improve metrics of vascular disease prediction when added to information about several conventional risk factors. INTERPRETATION: Diabetes confers about a two-fold excess risk for a wide range of vascular diseases, independently from other conventional risk factors. In people without diabetes, fasting blood glucose concentration is modestly and non-linearly associated with risk of vascular disease. FUNDING: British Heart Foundation, UK Medical Research Council, and Pfizer.

Relationship between serum and urinary insulin-like growth factor-I through childhood and adolescence: their use in the assessment of disordered growth.

OBJECTIVE: Serum insulin-like growth factor-I (sIGF-I) measurement as an index of growth hormone status has become a common test in the investigation of disordered growth. IGF-I may also be measured in the urine. The aims of this study were to investigate the correlation between serum and urinary IGF-I in normal children and compare their use in the evaluation of growth disorders. DESIGN: Normal ranges for serum and urinary IGF-I were devised from a cross-sectional study of normal schoolchildren. These were then used to assess the sensitivity and specificity of serum and urinary IGF-I in the diagnosis of childhood GH deficiency. PATIENTS: A cohort of 333 (M = 156, F = 177) healthy schoolchildren aged 5-19 years were recruited and data previously collected from 22 growth hormone deficient (GHD) and 47 short normal (SN) children were compared with those of the normal children. MEASUREMENTS: Height, weight and pubertal status were assessed in all children. Serum IGF-I (sIGF-I) (n = 305) and total amount of urinary IGF-I excreted overnight (TuIGF-I) (n = 205) were measured by RIA using excess IGF-II to block the interference of IGFBPs. RESULTS: Serum IGF-I was loge transformed and overall levels (geometric mean +/- 1 tolerance factor) were higher in females than males (F: 569 (329, 985) micrograms/l; M: 398 (227, 696) micrograms/l). LogeIGF-I correlated with age (F: r = +0.76, P < 0.001, M: r = +0.71, P < 0.001) and was significantly affected by both sex and Tanner stage of puberty (TS) (both P < 0.001). The distribution of TuIGF-I was normalized by performing a square root transformation (square root of TuIGF-I). square root of TuIGF-I was correlated with age (F: r = +0.36, P < 0.001; M: r = +0.5, P < 0.001) and was significantly affected by TS (P < 0.001). In both sexes there was a highly significant correlation between logeIGF-I and square root of TuIGF-I (F: r = +0.39, P < 0.001; M: r = +0.41, P < 0.001). Using the third centile of our normal ranges as a cut off to identify GHD, sIGF-I had a sensitivity of 82% and specificity of 62%, whereas TuIGF-I had a sensitivity of 18% and specificity of 79%. CONCLUSIONS: This study demonstrates that although urinary IGF-I has no place in the diagnosis of growth disorders, in normal children there is a highly significant relationship between serum and urinary IGF-I with levels of each changing in a similar manner through childhood and adolescence. Thus, TuIGF-I could be used as a valid surrogate for sIGF-I in the physiological assessment of the relationship between IGF-I status and the normal growth process.

Insulin-like growth factor I, IGF binding protein 3, and IGFBP protease activity: relation to anthropometric indices in solid tumours or leukaemia.

OBJECTIVES: To measure the serum concentrations of insulin-like growth factor I (IGF-I) and IGF binding protein 3 (IGFBP-3), and the level of IGFBP-3 protease activity in 38 children presenting with malignancies, and to assess their relation with auxological parameters and nutritional status. METHODS: Height, weight, skinfold thickness, and mid-upper arm circumference (MUAC) were recorded using standard techniques. IGF-I and IGFBP-3 were measured using specific radioimmunoassays. Serum IGFBPs were also visualised on western ligand blot. IGFBP-3 protease activity was assessed by the extent of fragmentation of recombinant [125I]-IGFBP-3, compared with that induced by pregnancy serum. Anthropometric and radioimmunoassay data were expressed as standard deviation scores (SDS). RESULTS: The median (range) IGF-I SDS was significantly reduced in all patients (-1.1 (-5.1 to 1.2)) and lower in children who were malnourished (-2.5 (-3.9 to 0.1)). IGFBP-3 SDS was within the normal range for 31 of 38 patients but IGFBP-3 protease activity was raised in all patients. Neither IGFBP-3 concentration nor protease activity was affected by nutritional status. IGF-I correlated with MUAC (r = 0.41) and subscapular skinfold thickness SDS (r = 0.38), but not with weight, height, weight for height, or triceps skinfold thickness. CONCLUSIONS: IGF-I is low in children with malignancies, and even lower in those who are malnourished. IGFBP-3 concentrations were normal in most patients but interpretation is complicated by the presence of raised IGFBP-3 protease activity, which could lead to overestimating concentrations of intact peptide. IGF-I appears to relate to arm anthropometry as an index of nutritional status but not height, weight, or weight for height, as would be expected in normal children.

Modification of plasma insulin-like growth factors and binding proteins during oral contraceptive use and the normal menstrual cycle.

OBJECTIVE: Sex steroid regulation of the insulin-like growth factor axis is a subject of contention. We examined the effect of combined oral contraceptives and investigated the cyclic variations in the insulin-like growth factor axis. STUDY DESIGN: Fasting blood samples were taken from 9 women receiving oral contraceptives, 10 women receiving no medication, and 10 male subjects. RESULTS: In women receiving oral contraceptives, insulin-like growth factor binding protein 1 remained highly phosphorylated and levels were acutely increased by sex steroid treatment (305 +/- 110 microg/L on day 14 of the cycle [medication phase] vs 118 +/- 70 microg/L during the medication-free period, P <.03). In women receiving no medication, insulin-like growth factor binding protein 1 levels were significantly lower (69 +/- 50 microg/L on day 14 of the menstrual cycle, P <.001) and varied cyclically, with a rise in the late-secretory phase that coincided with the appearance of nonphosphorylated and less phosphorylated insulin-like growth factor binding protein 1 isoforms. Compared with those in untreated women and in men, insulin-like growth factor I levels were decreased in women receiving oral contraceptives (405 +/- 104 ng/mL in untreated women and 330 +/- 28 ng/mL in men vs 287 +/- 73 ng/mL in women receiving oral contraceptives, P <.004). Oral contraceptive use had no effect on insulin-like growth factor II levels, and neither insulin-like growth factor I nor insulin-like growth factor II showed cyclic variation. CONCLUSION: The bioavailability of insulin-like growth factor I is reduced in users of oral contraceptives. This may contribute to the metabolic changes observed in such subjects.

Serum insulin-like growth factor-I, IGF binding protein-3 and IGFBP-3 protease activity after cranial irradiation.

The relationship between peak growth hormone (GH), insulin-like growth factor I (IGF-I), IGF-I binding protein 3 (IGFBP-3) and IGFBP-3 protease activity was studied in 28 children and adolescents undergoing investigation of pituitary function 0.4-14.2 years after cranial or craniospinal irradiation for the treatment of CNS tumours distant from the hypothalamic-pituitary axis (n = 16) or prophylaxis against CNS leukaemia (n = 12). Seven out of 15 patients with GH deficiency (GHD) (defined as a peak GH concentration <7.5 ng/ml in a stimulation test) had IGF-I <-2 standard deviation score (SDS). None of the 28 patients had serum IGFBP-3 concentrations measured by radioimmunoassay (RIA) <-1.5 SDS with no difference between those with and without GHD. IGFBP-3 concentrations measured by RIA were strongly correlated to IGFBP-3 band density on Western ligand blot (WLB) (r = 0.71; p < 0.0001). IGFBP-3 protease activity was negatively correlated to IGFBP-3 by RIA (r = -0.55; p < 0.01) and to IGFBP-3 by WLB (r = -0.51; p < 0.01). Twenty-two patients had normal IGFBP-3 protease activity (<30% of the activity in pregnancy serum) indicating that serum IGFBP-3 protease activity does not account for the normal levels of IGFBP-3 in RIA. Low serum IGF-I but normal IGFBP-3 concentrations and in the majority normal IGFBP-3 protease activity was found in patients in the years after CNS irradiation. Neither serum IGF-I nor IGFBP-3 can be used as a reliable index of the development of radiation-induced GHD.