Short-term administration of pegvisomant improves hepatic insulin sensitivity and reduces soleus muscle intramyocellular lipid content in young adults with type 1 diabetes.

CONTEXT: Data on the metabolic effects of GH derived from studies using GH suppression by pharmacological agents may not reflect selective actions. OBJECTIVE: The purpose of this study was to evaluate the effects of GH antagonism on glucose and lipid metabolism using pegvisomant, a selective GH receptor antagonist in patients with type 1 diabetes (T1D). DESIGN AND PARTICIPANTS: In a randomized, placebo-controlled, crossover study, 10 young adults with T1D were evaluated at baseline and after 4 weeks of treatment with either 10 mg of pegvisomant or placebo. The assessments included an overnight euglycemic steady state followed by a hyperinsulinemic euglycemic clamp and used glucose and glycerol cold stable isotopes. OUTCOME MEASURES: Hepatic and peripheral insulin sensitivity (IS), lipid turnover, and intramyocellular lipid (IMCL) were measured. RESULTS: Compared with placebo, pegvisomant treatment resulted in lower IGF-I levels (P < .001). During the overnight steady state, insulin requirements for euglycemia (P = .019), insulin levels (P = .008), and glucose production rates (Ra) (P = .033) were reduced. During the clamp study, glucose infusion rates (P = .031) increased and glucose Ra (P = .015) decreased whereas glucose disposal rates were unchanged. Free fatty acid levels were similar during the steady state but were lower during the clamp (P = .040) after pegvisomant. Soleus muscle IMCL decreased after treatment (P = .024); however, no change in tibialis anterior muscle was observed. CONCLUSIONS: The study demonstrates that GH antagonism in T1D results in improved hepatic insulin sensitivity. Lack of consistent changes in free fatty acid levels may suggest a direct effect of GH on IS. Unchanged peripheral IS despite reductions in IMCL indicate that GH-induced alterations in IMCL may not be causally linked to glucose metabolism.

Prevention and treatment of microvascular disease in childhood type 1 diabetes.

INTRODUCTION: The incidence of type 1 diabetes (T1D) is increasing worldwide, particularly in children, and is associated with a significant burden, mainly related to the development of vascular complications. The prevention and treatment of microvascular complications, which include nephropathy, retinopathy and neuropathy, are of paramount importance to decrease the associated mortality and morbidity. SOURCES OF DATA: A literature search was performed on Medline and articles on microvascular complications, with particular emphasis on the increasing incidence of childhood T1D and its implications on prevention and treatment of complications, were selected. AREAS OF AGREEMENT: The incidence of childhood T1D is increasing. Early identification of subjects at risk for long-term complications and early implementation of preventive and therapeutic strategies are fundamental in order to reduce the burden associated with microvascular complications of diabetes. Improving glycaemic control is the principle way of preventing and treating T1D complications. AREAS OF CONTROVERSY: In adults with T1D and microvascular complications, treatment with anti-hypertensive drugs and statins is increasingly common, whereas there are no definitive indications for treatment with these drugs in children and adolescents with early signs of complications. GROWING POINTS: There is growing interest in the development of new preventive and therapeutic strategies targeting specific pathways implicated in the pathogenesis of microvascular complications. AREAS TIMELY FOR DEVELOPING RESEARCH: Investigations to clarify genetic and environmental factors implicated in the pathogenesis of microvascular complications could lead to the identification of biochemical markers with high predictive values, to be used as a guide for screening and intervention programmes.