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FP Dominici, G Arostegui Diaz, A Bartke, JJ Kopchick, and D Turyn

Growth hormone (GH) deficiency is associated with increased sensitivity to insulin, but the molecular mechanisms involved in this association are poorly understood. In the current work, we have examined the consequences of the absence of the biological effects of GH on the first steps of the insulin signaling system in vivo in liver of mice with targeted disruption of the GH receptor/GH binding protein gene (GHR-KO mice). In these animals, circulating insulin concentrations are less than 4 microIU/ml, and glucose concentrations are low, concordant with a state of insulin hypersensitivity. The abundance and tyrosine phosphorylation state of the insulin receptor (IR), the IR substrate-1 (IRS-1), and Shc, the association between IRS-1 and the p85 subunit of phosphatidylinositol (PI) 3-kinase, the IRS-1- and the phosphotyrosine-associated PI 3-kinase in liver were examined. We found that, in liver of GHR-KO mice, the lack of GHR and GH eff! ects is associated with: (1) increased IR abundance, (2) increased insulin-stimulated IR tyrosine phosphorylation, (3) normal efficiency of IRS-1 and Shc tyrosine phosphorylation and (4) normal activation of PI 3-kinase by insulin. These alterations could represent an adaptation to the low insulin concentrations displayed by these animals, and may account for their increased insulin sensitivity.

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MC Sugden and MJ Holness

Insulin secretion and glucose tolerance were studied in 20-week-old male and female offspring of rat dams maintained on an isocaloric 20% or 8% protein diet during pregnancy and lactation after transfer to the same diet at weaning. Protein-restricted male and female offspring were also weaned onto a 20% protein diet. In males, post-absorptive insulin concentrations were suppressed by protein restriction from conception to adulthood (by 41%; P<0.001); however, basal insulin levels were 2.6-fold higher (P<0.001) if protein restriction was limited to gestation and lactation. Post-absorptive insulinaemia in females was unaffected by early or sustained protein restriction, but was lower than for males in the control group and the group exposed to protein restriction during early life alone (by 40% (P<0.001) and 52% (P<0.001) respectively). Plasma insulin/blood glucose ratios were higher in males compared with females in both control and early protein-restricted groups (1.6-fold (P<0.05) and 2.3-fold (P<0.001) respectively). A positive linear relationship existed between mean ambient insulin and glucose concentrations in males (r=1.0) and females (r=0.9), but the gradient was 12.4-fold greater (P<0.01) in males. beta-Cell function was evaluated after intravenous glucose challenge. In males, the acute insulin response and the suprabasal 30-min area under the insulin curve were dramatically higher in rats exposed to protein restriction during gestation and lactation alone (2.6- and 2.8-fold respectively; P<0.001). In contrast, these parameters were lowered by extending the exposure to protein restriction to adulthood in males, and by either early or prolonged exposure to protein restriction in females. The insulin resistance index was increased (2.5-fold; P<0.001) in male, but not female, rats exposed to protein restriction during gestation and lactation alone, and was not increased by extending the period of protein restriction to adulthood in either sex. Thus the data have demonstrated gender-specific lowering of insulin sensitivity due to protein restriction during early life only. The insulinogenic index (insulin response in relation to prevailing glycaemia) was increased in male, but not female, rats exposed to protein restriction during gestation and lactation alone (3.0-fold; P<0.001). A modest decline in insulin secretion in the female groups exposed to protein restriction until either the end of lactation or adulthood was compensated by increased insulin sensitivity, as demonstrated by significant decreases in the insulin resistance index in both groups (by 48% and 52% respectively; P<0.05). Glucose disappearance rates did not differ between the male and female control or early protein-restricted groups but were higher in both male (31%; P<0.05) and female groups (46%; P<0.001) exposed to protein restriction from conception to adulthood. Marked gender differences in glucose-stimulated insulin secretion were not associated with gender differences with respect to glucose tolerance. Our data therefore demonstrated that exposure to protein restriction during early life alone leads to relative insulin resistance and hyperinsulinaemia in adulthood, but this relationship is gender specific, observed only in males, and glucose tolerance is maintained.

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S Matthaei, B Trost, A Hamann, C Kausch, H Benecke, H Greten, W Höppner, and H H Klein

Abstract

To examine the effect of thyroid hormone status on insulin action in isolated rat adipocytes, age- and weight-matched Sprague–Dawley rats were rendered hypothyroid (h) by i.p. injection of 2 mCi [131I]/kg. Another group of rats was made hyperthyroid (H) by i.p. injection of 500 μg l-thyroxine/kg/day for 7 days. The T4 levels in experimental groups were: controls, 33·5±0·95; h, 12·3±1·59: H, 133·2±8·8 μg/l. Adipocytes were isolated and 3-O-methylglucose transport (GT), insulin binding (IB) and insulin receptor kinase activity (IRKA) were determined. Subcellular membrane fractions (low-density microsomes, plasma membranes) were prepared and GLUT1 and GLUT4 glucose transporter immunodetected.

Hyperthyroidism caused no significant effect on either IB or IRKA but increased insulin-stimulated GT by 43·6%. This increase of GT was associated with an increase of primarily GLUT4 glucose transporters. Hypothyroidism was associated with both increased insulin receptor affinity and enhanced IRKA. Despite a marked reduction of primarily GLUT4 glucose transporters, basal and insulinstimulated GT was not reduced when compared with control.

These results suggest that (1) in hyperthyroidism, increased insulin-stimulated glucose transport is associated with an increase of primarily GLUT4 glucose transporters, which may be responsible for the increment of peripheral glucose utilization in hyperthyroidism, and (2) the effect of hypothyroidism on insulin action in adipocytes is characterized by a state of increased insulin sensitivity, as indicated by the increase in insulin receptor affinity and tyrosine kinase activity. Despite the marked reduction of primarily GLUT4 glucose transporters, insulin-stimulated glucose transport is not diminished, which may suggest that functional activity of plasma membrane glucose transporters is enhanced in hypothyroidism.

Journal of Endocrinology (1995) 144, 347–357

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Y Khalfallah, G Sassolas, F Borson-Chazot, N Vega, and H Vidal

Our aim was to investigate the effects of one year recombinant human growth hormone (rhGH) therapy on the regulation by insulin of gene expression in muscle and adipose tissue in adults with secondary GH deficiency (GHD). Six GHD subjects without upper-body obesity were submitted to a 3-h euglycemic hyperinsulinemic clamp before and after one year of rhGH therapy. Muscle and abdominal subcutaneous adipose tissue biopsies were taken before and at the end of each clamp. The mRNA levels of insulin receptor, p85 alpha-phosphatidylinositol-3 kinase (p85 alpha PI-3K), insulin dependent glucose transporter (Glut4), hexokinase II, glycogen synthase, lipoprotein lipase (LPL) in muscle and in adipose tissue, hormone sensitive lipase and peroxisome proliferator-activated receptor gamma (PPAR gamma) in adipose tissue were quantified by RT-competitive PCR. One year treatment with rhGH (1.25 IU/day) increased plasma IGF-I concentrations (54+/-7 vs 154+/-11 ng/ml, P<0.01) but did not affect insulin-stimulated glucose disposal rate measured during the hyperinsulinemic clamp (74+/-9 vs 85+/-5 micromol/kg free fat mass/min). Insulin significantly increased p85 alpha PI-3K, hexokinase II and Glut4 mRNA levels in muscle both before and after rhGH treatment. One year of GH therapy increased LPL mRNA levels in muscle (38+/-2 vs 70+/-7 amol/microg total RNA, P<0.05) and in adipose tissue (2490+/-260 vs 4860+/-880 amol/microg total RNA, P<0.05), but did not change the expression of the other mRNAs. We conclude from this study that GH therapy did not alter whole body insulin sensitivity and the response of gene expression to insulin in skeletal muscle of adult GHD patients, but it did increase LPL expression in muscle and adipose tissue. This result could be related to the documented beneficial effect of GH therapy on lipid metabolism.

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TY Tai, JY Lu, CL Chen, MY Lai, PJ Chen, JH Kao, CZ Lee, HS Lee, LM Chuang, and YM Jeng

This study aimed at elucidating the effects of interferon (IFN)-alpha on glucose metabolism in patients with chronic hepatitis B and C infections. Twenty-eight biopsy-proven patients with chronic hepatitis B (ten cases) and hepatitis C (18 cases) were given IFN-alpha for a total of 24 weeks. The patients received a 75 g oral glucose tolerance test (OGTT), glucagon stimulation test, tests for type 1 diabetes-related autoantibodies and an insulin suppression test before and after IFN-alpha therapy. Ten of the 28 patients responded to IFN-alpha therapy. Steady-state plasma glucose of the insulin suppression test decreased significantly in responders (13.32+/-1.48 (S.E.M.) vs 11.33+/-1.19 mmol/l, P=0.0501) but not in non-responders (12.29+/-1.24 vs 11.11+/-0.99 mmol/l, P=0.2110) immediately after completion of IFN-alpha treatment. In the oral glucose tolerance test, no significant difference was observed in plasma glucose in either responders (10.17+/-0.23 vs 10.03+/-0.22 mmol/l) or non-responders (10.11+/-0.22 vs 9.97+/-0.21 mmol/l) 3 Months after completion of IFN-alpha treatment. However, significant differences were noted in C-peptide in both responders (2.90+/-0.13 vs 2.20+/-0.09 nmol/l, P=0.0040) and non-responders (2.45+/-0.11 vs 2.22+/-0.08 nmol/l, P=0.0287) before vs after treatment. The changes of C-peptide in an OGTT between responders and non-responders were also significantly different (P=0.0028), with responders reporting a greater reduction in C-peptide. No case developed autoantibodies during the treatment. In patients who were successfully treated with IFN-alpha, insulin sensitivity improved and their plasma glucose stayed at the same level without secreting as much insulin from islet beta-cells.

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D. J. Millward, J. G. Brown, and J. van Bueren

ABSTRACT

To examine whether the low plasma levels of triiodothyronine (T3) in fasted rats might limit the recovery of muscle protein synthesis on refeeding, rats were fasted for either 3 or 4 days and refed with or without pretreatment with thyroid hormones. Fasting suppressed T3 levels, plasma insulin and the rate of the translational phase of muscle protein synthesis (K RNA; the rate per unit RNA), especially after the 4-day fast. On refeeding, plasma T3 levels remained low for more than 3 h after the 3-day fast and for more than 8 h after the 4-day fast. Insulin concentrations increased within the first hour of refeeding, eventually achieving supranormal concentrations after the 3-day fast. The K RNA increased within the first hour of refeeding, achieving well-fed control values by 3 h after the 3-day fast or 24 h after the 4-day fast. The increases in K RNA were significantly correlated with the increases in insulin at low insulin concentrations, achieving a plateau value at 150 pmol/l, so that further increases in insulin were not associated with any further increases in protein synthesis. Pretreatment with thyroid hormone induced increased T3 levels which were maintained for up to 8 h of refeeding. This had no effect on the responses of either insulin or protein synthesis to refeeding after the 3-day fast, but did result in an acceleration of the recovery in the K RNA and plasma insulin levels in the rats fasted for 4 days. Analysis of the insulin–K RNA relationship showed no evidence for any increase in the insulin sensitivity of muscle protein synthesis with thyroid pretreatment, the initial stimulation of protein synthesis on refeeding the rats fasted for 4 days reflecting increased insulin secretion. Since in the untreated animals, insulin secretion on refeeding was also correlated with T3 levels, these results are consistent with the previously reported thyroidal dependence of insulin secretion.

J. Endocr. (1988) 118, 417–422

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R Romero, B Casanova, N Pulido, AI Suarez, E Rodriguez, and A Rovira

In 3T3-L1 adipocytes we have examined the effect of tri-iodothyronine (T(3)) on glucose transport, total protein content and subcellular distribution of GLUT1 and GLUT4 glucose transporters. Cells incubated in T(3)-depleted serum were used as controls. Cells treated with T(3) (50 nM) for three days had a 3.6-fold increase in glucose uptake (P<0.05), and also presented a higher insulin sensitivity, without changes in insulin binding. The two glucose carriers, GLUT1 and GLUT4, increased by 87% (P<0.05) and 90% (P<0. 05), respectively, in cells treated with T(3). Under non-insulin-stimulated conditions, plasma membrane fractions obtained from cells exposed to T(3) were enriched with both GLUT1 (3. 29+/-0.69 vs 1.20+/-0.29 arbitrary units (A.U.)/5 microg protein, P<0.05) and GLUT4 (3.50+/-1.16 vs 0.82+/-0.28 A.U./5 microg protein, P<0.03). The incubation of cells with insulin produced the translocation of both glucose transporters to plasma membranes, and again cells treated with T(3) presented a higher amount of GLUT1 and GLUT4 in the plasma membrane fractions (P<0.05 and P<0.03 respectively). These data indicate that T(3) has a direct stimulatory effect on glucose transport in 3T3-L1 adipocytes due to an increase in GLUT1 and GLUT4, and by favouring their partitioning to plasma membranes. The effect of T(3) on glucose uptake induced by insulin can also be explained by the high expression of both glucose transporters.

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Tanja Jene, Inigo Ruiz de Azua, Annika Hasch, Jennifer Klüpfel, Julia Deuster, Mirjam Maas, Cora H Nijboer, Beat Lutz, Marianne B Müller, and Michael van der Kooij

Stress has a major impact on the modulation of metabolism, as previously evidenced by hyperglycemia following chronic social defeat (CSD) stress in mice. Although CSD-triggered metabolic dysregulation might predispose to pre-diabetic conditions, insulin sensitivity remained intact, and obesity did not develop, when animals were fed with a standard diet (SD). Here, we investigated whether a nutritional challenge, a high fat diet (HFD), aggravates the metabolic phenotype, and whether there are particularly sensitive time windows for the negative consequences of HFD exposure. Chronically stressed male mice and controls (CTRL) were kept under (i) SD-conditions, (ii) with HFD commencing post-CSD, or (iii) provided with HFD lasting throughout, and after CSD. Under SD conditions, stress increased glucose levels early post-CSD. Both HFD regimens increased glucose levels in non-stressed mice, but not in stressed mice. Nonetheless, when HFD was provided after CSD, stressed mice did not differ from controls in long-term body weight gain, fat tissue mass and plasma insulin, and leptin levels. In contrast, when HFD was continuously available, stressed mice displayed reduced body weight gain, lowered plasma levels of insulin, and leptin, and reduced white adipose tissue weights as compared to their HFD-treated non-stressed controls. Interestingly, stress-induced adrenal hyperplasia and hypercortisolemia were observed in mice treated with SD and with HFD after CSD, but not in stressed mice exposed to a continuous HFD treatment. The present work demonstrates that CSD can reduce HFD-induced metabolic dysregulation. Hence, HFD during stress may act beneficially, as comfort food, by decreasing stress-induced metabolic demands.

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M Fasshauer, J Klein, S Krahlisch, U Lossner, M Klier, M Bluher, and R Paschke

Tumor necrosis factor (TNF) alpha-induced adipose-related protein (TIARP) has recently been cloned as a TNFalpha-stimulated protein expressed in adipocytes. Its expression is differentiation-dependent and potentially involved in mediating TNFalpha-induced insulin resistance. To further characterize regulation of TIARP gene expression, 3T3-L1 adipocytes were treated with key hormones modulating insulin sensitivity and influencing adipocyte metabolism, and TIARP gene expression was determined by quantitative real-time RT-PCR. Interestingly, TIARP mRNA expression was stimulated almost 9-fold after 500 ng/ml GH were added for 16 h whereas addition of 10 microM isoproterenol, 100 nM insulin and 100 nM dexamethasone for 16 h significantly decreased TIARP gene expression to between 35 and 50% of control levels. In contrast, angiotensin 2 (10 microM) and triiodothyronine (1 microM) did not have any effect. The stimulatory effect of GH was time- and dose-dependent with stimulation occurring as early as 1 h after effector addition and at concentrations as low as 5 ng/ml GH. Moreover, pharmacological inhibition of Janus kinase 2 and p42/44 mitogen-activated protein kinase reversed the stimulatory effect of GH, suggesting that both signaling molecules are involved in activation of TIARP gene expression by GH. Furthermore, an increase of TIARP mRNA could be completely reversed to control levels by withdrawal of GH for 24 h. Taken together, these results show that TIARP is not only responsive to TNFalpha but also to important other hormones influencing glucose homeostasis and adipocyte metabolism. Thus, this factor may play an integrative role in the pathogenesis of insulin resistance and its link to obesity.

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AR Assali, A Ganor, Y Beigel, Z Shafer, T Hershcovici, and M Fainaru

Weight reduction is recommended for the treatment of subjects with insulin resistance (IR) syndrome; however, the relative importance of the decrease in body fat or the negative energy balance achieved during a hypo-energetic diet in the improvement of this metabolic syndrome is still debated. Therefore, we undertook to study their relative impact on amelioration of the metabolic abnormalities associated with IR in obese subjects. Twelve obese subjects (six males and six females, mean+/-s.d. body mass index 36.1+/-4.7 kg/m(2)) aged 38-57 years were investigated. During the first phase they were fed a hypo-energetic diet for 6 weeks (week 0-6). During the second phase, lasting 4 weeks (week 6-10) they consumed an iso-energetic diet. During the third phase (week 10-16) the subjects were put again on a hypo-energetic diet. Insulin sensitivity (SI) was assessed by an insulin-enhanced, frequently sampled i.v. glucose tolerance test with minimal model analysis. All subjects reduced weight during both hypo-energetic periods: 5.49+/-0.75 and 2.32+/-0.37%, means+/-s.e.m., P<0.005, week 0-6 and 10-16 respectively. One-third of this loss was achieved within the first week of each period. SI increased by 353+/-121 and 147+/-38% (P<0.005), means+/-s.e.m., at the end of both hypo-energetic periods (week 6 vs 0 and 16 vs 10 respectively). Two-thirds of this improvement were observed within the first week of each period (week 1 vs 0 and 11 vs 10 respectively). During the iso-energetic weight-maintaining period (week 10 vs 6), SI decreased by 43.5+/-7.9% (P<0.002). Serum levels of leptin and triglyceride followed a similar pattern, but to a lesser extent. It may be concluded that negative energy balance is more effective when compared with maintaining a stable lower weight in achieving an improvement in the metabolic parameters of the IR syndrome.