Growth hormone (GH) plays a pivotal role in growth and metabolism, with growth promotion mostly attributed to generation of insulin-like growth factor I (IGF-I) in liver or at local sites of GH action, whereas the metabolic effects of GH are considered to be intrinsic to GH itself. To distinguish the effects of GH from those of IGF-I, we developed a Cre-lox-mediated model of tissue-specific deletion of the growth hormone receptor (GHR). Near total deletion of the GHR in liver (GHRLD) had no effect on total body or bone linear growth despite a >90% suppression of circulating IGF-I; however, total bone density was significantly reduced. Circulating GH was increased 4-fold, and GHRLD displayed insulin resistance, glucose intolerance, and increased circulating free fatty acids. Livers displayed marked steatosis, the result of increased triglyceride synthesis and decreased efflux; reconstitution of hepatic GHR signaling via adenoviral expression of GHR restored triglyceride output to normal, whereas IGF-I infusion did not correct steatosis despite restoration of circulating GH to normal. Thus, with near total absence of circulating IGF-I, GH action at the growth plate, directly and via locally generated IGF-I, can regulate bone growth, but at the expense of diabetogenic, lipolytic, and hepatosteatotic consequences. Our results indicate that IGF-I is essential for bone mineral density, whereas hepatic GH signaling is essential to regulate intrahepatic lipid metabolism. We propose that circulating IGF-I serves to amplify the growth-promoting effects of GH, while simultaneously dampening the catabolic effects of GH.

The modified minimal model (MMM), a recently introduced method that assesses insulin sensitivity (SI) by a computed mathematical analysis of the relation between the change in insulin and glucose clearance after a bolus of iv glucose, followed 20 min later by a bolus of tolbutamide, has been standardized in adults, but this method has not been validated in children. We performed an abbreviated 90-min MMM test in 50 children who were siblings of patients with insulin-dependent diabetes mellitus and 7 healthy adult volunteers and compared the results to the standard 180-min MMM test in 11 of these subjects. The cohort consisted of 29 prepubertal children [16 males and 13 females; 8.7 +/- 2.0 (mean +/- SEM) yr old]; 16 pubertal children defined as less than 17 yr of age and Tanner stage 2-5 (8 males and 8 females; 13.4 +/- 1.8 yr old), and 12 postpubertal subjects (7 males and 5 females; 18.2 +/- 0.9 yr old), with no significant difference in the weight for length index (WLI) among the 3 groups and with sera of all subjects negative for islet cell antibodies and insulin autoantibodies. The test procedure consisted of 3 baseline blood samples over 30 min, followed at zero time by 0.3 g/kg 25% dextrose infused iv over 1 min and an iv injection of tolbutamide (5 mg/kg) 20 min later; sequential blood samples for glucose and insulin measurements were withdrawn from zero time until completion 90 or 180 min later. In the 11 subjects who underwent both the standard and the abbreviated tests, there was no significant difference between the SI estimated by the 2 methods provided that glucose and insulin values were interpolated at 180 min during the computer calculations of the abbreviated test. Using the 90-min abbreviated test, the SI of the pubertal subjects (2.92 +/- 0.45) was markedly less than that of the prepubertal subjects (6.57 +/- 0.45; P = 0.0001). While the postpubertal group value of 4.63 +/- 0.86 was significantly higher than that of the pubertal group (P = 0.0001), the pre- and postpubertal groups remained significantly different (P = 0.0001). The 10 obese subjects with WLI greater than 120% had a lower SI (3.5 +/- 0.53) than the 47 nonobese subjects with WLI less than 120% (SI = 5.48 +/- 0.42; P less than 0.04), and there was a negative correlation between SI and WLI. None of the study subjects experienced symptomatic hypoglycemia during the test.(ABSTRACT TRUNCATED AT 400 WORDS)

Growth hormone (GH) participates in the postnatal regulation of skeletal muscle growth, although the mechanism of action is unclear. Here we show that the mass of skeletal muscles lacking GH receptors is reduced because of a decrease in myofiber size with normal myofiber number. GH signaling controls the size of the differentiated myotubes in a cell-autonomous manner while having no effect on size, proliferation, and differentiation of the myoblast precursor cells. The GH hypertrophic action leads to an increased myonuclear number, indicating that GH facilitates fusion of myoblasts with nascent myotubes. NFATc2, a transcription factor regulating this phase of fusion, is required for GH action because GH is unable to induce hypertrophy of NFATc2؊͞؊ myotubes. Finally, we provide three lines of evidence suggesting that GH facilitates cell fusion independent of insulin-like growth factor 1 (IGF-1) up-regulation. First, GH does not regulate IGF-1 expression in myotubes; second, GH action is not mediated by a secreted factor in conditioned medium; third, GH and IGF-1 hypertrophic effects are additive and rely on different signaling pathways. Taken together, these data unravel a specific function of GH in the control of cell fusion, an essential process for muscle growth.

Cytokines may cause an acquired growth hormone (GH) resistance in patients with inflammatory diseases. Anabolic effects of GH are mediated through activation of STAT5 transcription factors. We have reported that TNF-alpha suppresses hepatic GH receptor (GHR) gene expression, whereas the cytokine-inducible SH2-containing protein 1 (Cis)/suppressors of cytokine signaling (Socs) genes are upregulated by TNF-alpha and IL-6 and inhibit GH activation of STAT5. However, the relative importance of these mechanisms in inflammatory GH resistance was not known. We hypothesized that IL-6 would prevent GH activation of STAT5 and that this would involve Cis/Socs protein upregulation. GH +/- LPS was administered to TNF receptor 1 (TNFR1) or IL-6 null mice and wild-type (WT) controls. STAT5, STAT3, GHR, Socs 1-3, and Cis phosphorylation and abundance were assessed by using immunoblots, EMSA, and/or real time RT-PCR. TNF-alpha and IL-6 abundance were assessed by using ELISA. GH activated STAT5 in WT and TNFR1 or IL-6 null mice. LPS pretreatment prevented STAT5 activation in WT and TNFR1 null mice; however, STAT5 activation was preserved in IL-6 null mice. GHR abundance did not change with LPS administration. Inhibition of STAT5 activation by LPS was temporally associated with phosphorylation of STAT3 and upregulation of Cis and Socs-3 protein in WT and TNFR1 null mice; STAT3, Cis, and Socs-3 were not induced in IL-6 null mice. IL-6 inhibits hepatic GH signaling by upregulating Cis and Socs-3, which may involve activation of STAT3. Therapies that block IL-6 may enhance GH signaling in inflammatory diseases.

The essential function of the kidney is to ensure formation of a relatively protein-free ultra-filtrate, urine. The rate of filtration and composition of the primary renal filtrate is determined by the transport of fluid and solutes across the glomerular filtration barrier consisting of endothelial cells, the glomerular basement membrane, and podocyte foot processes. In diabetes mellitus (DM), components of the kidney that enable renal filtration get structurally altered and functionally compromised resulting in proteinuria that often progresses to end-stage renal disease. Histological alterations in DM include early hypertrophy of glomerular and tubular components, subsequent thickening of basement membrane in glomeruli and tubules, progressive accumulation of extracellular matrix proteins in the glomerular mesangium and loss of podocytes, together constituting a clinical condition referred to as diabetic nephropathy (DN). The glomerulus has become the focus of research investigating the mechanism of proteinuria. In particular, the progressive dysfunction and/or loss of podocytes that is contemporaneous with proteinuria in DN have attracted intense scientific attention. The absolute number of podocytes predicts glomerular function and podocyte injury is a hallmark of various glomerular diseases. This review discusses the importance of podocytes in normal renal filtration and details the molecular and cellular events that lead to podocyte dysfunction and decreased podocyte count in DN.

Understanding the cellular and molecular basis for changes in podocyte structure and function in diabetes mellitus may lead to novel diagnostic tools and treatment strategies for diabetic nephropathy.

No abstract

Epidemiological studies have demonstrated an association between intrauterine growth retardation and an increased risk of adult diseases that include essential hypertension, noninsulin-dependent diabetes mellitus, and ischemic heart disease. A common feature of these diseases is insulin resistance. To investigate whether abnormal insulin sensitivity was a characteristic of subjects with intrauterine growth retardation (IUGR), we compared two groups of short prepubertal children: a group with IUGR (birth weight less than the tenth percentile; n = 15) and a normal birth weight group (n = 12). Subjects underwent a modified frequently sampled iv glucose tolerance test that permitted calculation of the acute insulin response, insulin sensitivity index, and glucose effectiveness. A marked difference in the insulin sensitivity index was noted between groups, with the IUGR group being less insulin sensitive [6.9 vs. 16.9 10(-4)min-1.(microU/mL); P = 0.0048]. The acute insulin response was also significantly different between groups, with IUGR subjects having higher insulin levels (445 vs. 174 microU/mL; P = 0.005). There was no difference in glucose effectiveness between groups. Short prepubertal IUGR children have a specific impairment in insulin sensitivity compared to their normal birth weight peers. In short IUGR children, impaired insulin sensitivity is a potential marker for the early identification and intervention in the development of late adult-onset noninsulin-dependent diabetes mellitus.