Treatment with recombinant human insulin-like growth factor (rhIGF)-I/rhIGF binding protein-3 complex improves metabolic control in subjects with severe insulin resistance.

OBJECTIVE: Diabetes in the context of severe insulin resistance (SIR) presents a major therapeutic challenge because conventional therapies including insulin and insulin sensitizers often fail to achieve adequate metabolic control. Adjunctive therapy with recombinant human IGF-I (rhIGF-I)/recombinant human IGF binding protein-3 (rhIGFBP-3) has been shown to improve insulin sensitivity in both type 1 and type 2 diabetes and may have a role in the treatment of SIR. We report clinical and physiological outcomes after adjunctive therapy with rhIGF-I/rhIGFBP-3 in five subjects with SIR. RESEARCH DESIGN AND METHODS: Five females (median age, 17 yr; range, 5-37) with SIR (two with pathogenic insulin receptor mutations) were treated with 0.5-2.0 mg/kg rhIGF-I/rhIGFBP-3 using a 16-wk dose escalation protocol. Glycosylated hemoglobin was recorded monthly. At baseline and end of treatment all patients were evaluated using continuous glucose monitoring sensing and admitted for overnight GH profiling and insulin-modified stable-label iv glucose tolerance test. Changes in body composition were assessed using dual-energy x-ray absorptiometry and magnetic resonance imaging. RESULTS: Treatment with rhIGF-I/rhIGFBP-3 was well tolerated, and all subjects reported clinical improvements with reduction in acanthosis nigricans. Glycosylated hemoglobin was reduced (8.5% pretreatment to 7.1%; P < 0.03) with a trend toward reduction in mean continuous glucose monitoring sensing glucose (10.7 vs. 8.5 mmol/liter; P = 0.08). Effects of treatment on other biochemical measures were variable, but there was a trend toward improved C-peptide responses during the iv glucose tolerance test. CONCLUSIONS: rhIGF-I/rhIGFBP-3 is well tolerated and clinically effective in subjects with SIR.

IGF-I treatment of insulin resistance.

Severe insulin resistance resulting from known or putative genetic defects affecting the insulin receptor or post-insulin receptor signalling represents a clinical spectrum ranging from Donohue's and Rabson-Mendenhall syndrome, where the genetic defect is identified, through to the milder phenotype of type A insulin resistance, where a genetic defect can only be detected in around 10% of cases. Paradoxically, subjects with these conditions may present with hypoglycaemia due to mismatch of post-prandial glucose excursion and compensatory hyperinsulinaemia. Ultimately, treatment with insulin and insulin sensitisers will be unsuccessful and subjects may succumb to diabetes or its complications. Recombinant human IGF-I alone or combined with its binding protein (IGFBP-3) provides an alternative therapy as IGF-I receptor shares structural and functional homology with the insulin receptor and recombinant human insulin-like growth factor I (rhIGF-I) therapy could improve glucose disposal by signalling through the IGF-I receptor, whilst reducing the adverse effects of high insulin concentrations. There are also data which indicate that IGF-I signalling through the IGF-I receptor on the pancreatic beta-cell may be important in maintaining insulin secretion. Pilot studies confirmed that rhIGF-I could reduce glucose and insulin levels in subjects with type A insulin resistance and those with Rabson-Mendenhall syndrome with sustained beneficial effects on HbA1c. Continued study has confirmed efficacy of rhIGF-I when combined with IGFBP-3 in the treatment of Donohue's and type A insulin resistance subjects. Observations that IGF-I treatment can improve C-peptide levels in these subjects may indicate that it might be more valuable as a first line intervention to preserve beta-cell function, rather than its current use as a medication of last resort in subjects where all other therapies have failed.

The impact of early nutrition in premature infants on later childhood insulin sensitivity and growth.

OBJECTIVES: Children born prematurely have decreased insulin sensitivity. The etiology of this insulin resistance is unknown. The aim of this study was to evaluate infant nutrition and its influence on insulin sensitivity and postnatal growth in children born < or = 32 weeks' gestation. METHODS: A total of 56 healthy, developmentally normal, prepubertal children, aged 4 to 10 years were recruited. Thirty-seven were born < or = 32 weeks' gestation, and 19 were control subjects born at term with a birth weight > 10th percentile. Insulin sensitivity (10(-4) min(-1) microU/mL) was calculated from a 90-minute frequently sampled intravenous glucose tolerance test. Perinatal, nutritional, and growth data were obtained retrospectively from both neonatal and early infancy records in the premature cohort. RESULTS: Children born prematurely had decreased insulin sensitivity when compared with those born at term (13.8 vs 30.6). Neonatal nutrition was not correlated with insulin sensitivity; however, all of the infants had inadequate protein in the first month followed by excessive fat intake thereafter. Premature children with greater weight gain had lower insulin sensitivity. Higher carbohydrate intake in the first month of life was associated with greater weight gain from birth. No relationship was seen between weight gain and either protein or lipid intake. CONCLUSIONS: Prematurely born children are insulin resistant and have suboptimal neonatal nutrition. Greater childhood weight gain magnifies this reduction in insulin sensitivity and seems to be associated with early nutrition. We speculate that a high carbohydrate neonatal diet may lead to greater weight gain and a greater reduction in insulin sensitivity in this group.

Childhood and adolescent diabetes.

Circulating levels of insulin-like growth factor-I (IGF-I) and its principal binding protein IGFBP-3 are reduced, whereas those of the inhibitory binding protein, IGFBP-1, tend to be high in children and adolescents with type 1 diabetes mellitus (T1DM). These abnormalities are thought to arise because of relative portal hypoinsulinaemia and partial resistance at the hepatic growth hormone (GH) receptor. During adolescence, reductions in IGF-I and IGF bioactivity lead to feedback for GH hypersecretion and the elevated GH and low IGF-I levels lead to an increase of the normal insulin resistance encountered during puberty. Low IGF-I levels, but in particular elevated GH levels, have been implicated in the pathogenesis of diabetic microangiopathic complications, in particular, renal hypertrophy, glomerular hyperfiltration and the development of microalbuminuria. Early study of IGF-I replacement with recombinant human IGF-I (rhIGF-I) demonstrated, in the short term, reductions in GH hypersecretion with improved insulin sensitivity and, in the longer term, reductions in insulin requirements and improvements in HbA1c levels. However, larger doses of rhIGF-I were associated with retinopathy either due to rapid improvements in glycaemic control or direct effects of high levels of 'free' IGF-I. More recently, pilot studies using the combination of rhIGF-I/rhIGFBP-3 have confirmed the physiological efficacy of IGF-I replacement in T1DM. The combined treatment is better tolerated and may result in reduced tissue exposure to high levels of 'free' IGF-I. Longer term clinical studies with this IGF-I/IGFBP-3 combination are needed.