The effects of growth hormone treatment of adults with adult-onset pituitary insufficiency on lipoproteins and apolipoproteins were investigated. Nine patients, one women and eight men (age range, 34-58 years), who had been treated for pituitary tumors were studied. They had complete pituitary insufficiency with a duration of at least 1 year. All patients received replacement therapy with thyroid hormones, glucocorticoids, and gonadal steroids. The study had a double-blind, placebo-controlled, crossover design for active treatment with recombinant human growth hormone (0.25-0.5 units/kg per week s.c given each evening) for 6 months. Fasting serum levels of cholesterol; triglycerides; high density lipoprotein and low density lipoprotein cholesterol; apolipoproteins A-I, B, and E; and lipoprotein (a) were measured before and after 6 and 26 weeks of treatment Lipoprotein (a) concentrations increased markedly during treatment and were about twice as high compared with pretreatment levels. Serum cholesterol and low density lipoprotein cholesterol concentrations were decreased after 6 weeks of treatment, but levels had returned to pretreatment levels after 26 weeks. High density lipoprotein cholesterol concentrations increased during treatment and were significantly higher than pretreatment levels after 26 weeks of treatment Serum trigiyceride concentrations did not change significantly, but in two patients with marked hypertriglyceridemia, growth hormone treatment resulted in a marked decrease. Serum concentrations of apolipoproteins A-I, B, and E did not change significantly, but changes in apolipoprotein A-I and B concentrations were in parallel to those observed for high density lipoprotein cholesterol and low density lipoprotein cholesterol, respectively. These results suggest that growth hormone is a major regulator of lipoprotein metabolism and also demonstrate that lipoprotein (a) concentrations are regulated by growth hormone. (Arteriosclerosis and Thrombosis 1993;13:296-301) KEY WORDS • lipoproteins • growth hormone • hypopituitarism F ew human studies have been performed on the effects of growth hormone (GH) on the different lipoprotein fractions and apolipoprotein levels. Moreover, studies on the effects of GH on the regulation of serum lipid levels have given conflicting results. However, both GH excess, as in acromegaly, 1 and deficiency 2 result in an increased risk of death due to cardiovascular disorders, which might indicate a role for GH in the control of lipoprotein metabolism in humans.Several recent publications have reviewed the genetics, biochemistry, and possible role in arteriosclerosis and thrombogenesis of lipoprotein (a) (Lp[a]). 3~6 The plasma concentration of Lp(a) is mainly genetically From the Department of Physiology (S.E., J.O.), the

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Adiponectin, one of the most abundant gene transcript proteins in human fat cells, has been shown to improve insulin action and is also suggested to exert antiatherogenic effects. We measured circulating adiponectin levels and risk factors for atherosclerosis in 45 healthy first-degree relatives of type 2 diabetic subjects (FDR) as well as 40 healthy control subjects (CON) without a known family history of diabetes. Insulin sensitivity (S i ) was studied with the minimal model, and measurements of adiponectin, metabolic variables, inflammatory markers, and endothelial injury markers, as well as lipoprotein concentrations, were performed. FDR were insulin resistant (3.3 ؎ 2.4 vs. 4.5 ؎ 2.6 ؋ 10 ؊4 ؋ min ؊1per U/ml [mean ؎ SD], P < 0.01), and their circulating plasma adiponectin levels (6.6 ؎ 1.8 vs. 8.1 ؎ 3.0 g/ml, P < 0.03) were decreased. After adjustments for age in FDR, adiponectin levels were negatively correlated with fasting proinsulin (r ؊0.64, P < 0.001), plasminogen activator inhibitor (PAI)-1 activity (r ؊0.56, P < 0.001), fasting insulin (r ؊0.55, P < 0.001), and acute insulin response (r ؊0.40, P < 0.05); they were positively related to HDL cholesterol (r 0.48, P < 0.01) and S i (r 0.41, P < 0.01). Furthermore, when adjusted for age, waist, and S i , adiponectin was associated with HDL cholesterol and proinsulin, which explained 51% of the variation in adiponectin in multiple regression analyses in that group. In conclusion, circulating plasma adiponectin levels were decreased in nonobese but insulinresistant FDR and, in addition, related to several facets of the insulin resistance syndrome (IRS). Thus, hypoadiponectinemia may be an important component of the association between cardiovascular disease and IRS.

The epidemic increase in type 2 diabetes can be prevented only if markers of risk can be identified and used for early intervention. We examined the clinical phenotype of individuals characterized by normal or low IRS-1 protein expression in fat cells as well as the potential molecular mechanisms related to the adipose tissue. Twenty-five non-obese individuals with low or normal IRS-1 expression in subcutaneous abdominal fat cells were extensively characterized and the results compared with 71 carefully matched subjects with or without a known genetic predisposition for type 2 diabetes. In contrast to the commonly used risk marker, known heredity for diabetes, low cellular IRS-1 identified individuals who were markedly insulin resistant, had high proinsulin and insulin levels, and exhibited evidence of early atherosclerosis measured as increased intima media thickness in the carotid artery bulb. Circulating levels of adiponectin were also significantly reduced. Gene analyses of fat cells in a parallel study showed attenuated expression of several genes related to fat cell differentiation (adiponectin, aP2, PPARgamma, and lipoprotein lipase) in the group of individuals characterized by a low IRS-1 expression and insulin resistance. A low IRS-1 expression in fat cells is a marker of insulin resistance and risk for type 2 diabetes and is associated with evidence of early vascular complications. Impaired adipocyte differentiation, including low gene expression and circulating levels of adiponectin, can provide a link between the cellular marker and the in vivo phenotype.

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