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S Patterson, P R Flatt, L Brennan, P Newsholme and N H McClenaghan

homocysteine has recently been reported in obese subjects with defective insulin secretion and insulin resistance compared with normoinsulinaemic obese subjects ( Sanchez-Margalet et al. 2002 ). An increased prevalence of hyperhomocysteinaemia in patients

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K Alexander H Iwen, Oezge Senyaman, Arne Schwartz, Maren Drenckhan, Britta Meier, Dirk Hadaschik and Johannes Klein

reported to ameliorate insulin resistance in vivo , and their expression is reduced in subjects with insulin resistance ( Fasshauer & Paschke 2003 , Hug & Lodish 2005 , Klein et al . 2006 ). Our study provides evidence for an acute decrease in the

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Srividya Vasu, Mary K McGahon, R Charlotte Moffett, Tim M Curtis, J Michael Conlon, Yasser H A Abdel-Wahab and Peter R Flatt

of type 2 diabetes, which is treated clinically by strategies that target pancreatic beta cell dysfunction and/or insulin resistance ( Bailey 2009 , Irwin & Flatt 2015 ). Recently, peptide therapeutics for diabetes using stable mimetics of GLP-1 have

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Claudia E Robert-Cooperman, Grace C Dougan, Shari L Moak, Mark G Athanason, Melanie N Kuehl, Harris Bell-Temin, Stanley M Stevens Jr and Brant R Burkhardt

. 2 A. The difference in fasting glycemia was diminished over time due to WT group (6 months of age) having increased glucose levels potentially attributed to age-dependent insulin resistance ( Fig. 2 A). Significantly higher ( P <0.001) glycemic

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Johannes Klein, Sören Westphal, Daniel Kraus, Britta Meier, Nina Perwitz, Volker Ott, Mathias Fasshauer and H Harald Klein

function could have important implications for therapeutic strategies of the insulin resistance syndrome. Figure 1 Metformin acutely activates p44/p42 MAP kinase. Fully differentiated brown adipocytes were stimulated with metformin for the times (1

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Keld Fosgerau, Kirsten Raun, Cecilia Nilsson, Kirsten Dahl and Birgitte S Wulff

effective weight lowering drugs remains very relevant as complement to existing therapies ( Nguyen et al . 2012 ). Insulin-resistance plays a significant role in both obesity and prediabetes ( Reaven 1988 , Ferrannini 1993 ) and the reversal of the insulin

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Gary J Remington, Celine Teo, Virginia Wilson, Araba Chintoh, Melanie Guenette, Zohra Ahsan, Adria Giacca and Margaret K Hahn

Insulin resistance and decreased glucose-stimulated insulin secretion after acute olanzapine administration . Journal of Clinical Psychopharmacology 28 494 – 499 . ( doi:10.1097/JCP.0b013e318184b4c5 ) Chintoh AF Mann SW Lam L Giacca A Fletcher

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Jessica C Hogan and Jacqueline M Stephens

). Interestingly, there is recent evidence that SOCS3 is a regulator of insulin signaling and may cause insulin resistance in adipocytes through its effects on IRS protein expression ( Shi et al. 2004 ). Although we did not observe any significant effects on

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J Shao, H Yamashita, L Qiao and JE Friedman

Recent studies suggest that the serine/threonine kinase protein kinase B (PKB or Akt) is involved in the pathway for insulin-stimulated glucose transporter 4 (GLUT4) translocation and glucose uptake. In this study we examined the components of the Akt signaling pathway in skeletal muscle and adipose tissue in vivo from C57BL/KsJ-Lepr(db/db) mice (db/db), a model of obesity, insulin resistance, and type II diabetes. There were no changes in the protein levels of GLUT4, p85alpha, or Akt in tissues from db/db mice compared with non-diabetic littermate controls (+/+). In response to acute insulin administration, GLUT4 recruitment to the plasma membrane increased twofold in muscle and adipose tissue from +/+ mice, but was significantly reduced by 42-43% (P<0.05) in both tissues from db/db mice. Insulin increased Akt-Ser(473) phosphorylation by two- to fivefold in muscle and adipose tissue from all mice. However, in db/db mice, maximal Akt-Ser(473) phosphorylation was decreased by 32% (P<0.05) and 69% (P<0.05) in muscle and adipose tissue respectively. This decreased phosphorylation in db/db mice corresponded with a significant decrease in maximal Akt kinase activity using a glycogen synthase kinase-3 fusion protein as a substrate (P<0.05). The level of insulin-stimulated tyrosine phosphorylation of p85alpha from phosphatidylinositol 3 (PI 3)-kinase, which is upstream of Akt, was also reduced in muscle and adipose tissue from db/db mice (P<0.05); however, there was no change in extracellular signal-regulated kinase-1 or -2 phosphorylation. These data implicate decreased insulin-stimulated Akt kinase activity as an important component underlying impaired GLUT4 translocation and insulin resistance in tissues from db/db mice. However, impaired insulin signal transduction appears to be specific for the PI 3-kinase pathway of insulin signaling, while the MAP kinase pathway remained intact.

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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.