Here we show that p38 mitogen activated protein kinase (p38 MAPK) phosphorylates spliced form of X-Box Binding Protein 1 (XBP1s) on Thr48 and Ser61 residues and greatly enhances nuclear migration of XBP1s. Mutation of Thr48 and Ser61 to alanine dramatically reduces nuclear translocation of XBP1s and activity. We also demonstrate that p38 MAPK activity is markedly reduced in the livers of obese mice and that activation of p38 MAPK by expression of constitutively active MAP Kinase Kinase 6 (MKK6Glu) greatly enhances nuclear translocation of XBP1s, reduces ER stress and establishes euglycemia in the severely obese and diabetic mice. Hence, our results define a crucial role for Thr48 and Ser61 phosphorylations of XBP1s in maintenance of glucose homeostasis in obesity and indicate that p38 MAPK activation in the livers of obese mice may provide a novel therapeutic approach for treatment of type 2 diabetes.

TNF-alpha, IL-6 and hs-CRP levels were positively, adiponectin negatively correlated with adipocyte size. Therefore, adiposity may be an inflammatory condition.

Abstract. The ssociation between coronary heart disease and subclinical hypothyroidism (SCH) is unclear. We aimed to determine hs-CRP concentrations in patients with SCH. Seventy-seven patients (age 34.6 ± 13.7 yr) with SCH (TSH >4.2 mIU/ml and serum free thyroxine level between 0.932-1.71 ng/dL), and 80 control subjects (age 33.9 ± 13.3 yr) were studied. Thyroid hormones, C-reactive protein, insulin, glucose, total, HDL, LDL and VLDL-cholesterol levels and HOMA-IR index were also determined. TSH levels of SCH group were higher than control (7.4 ± 2.9 and 1.55 ± 0.78 mIU/ml, respectively, p = 0.0001). However, FT4 levels were lower than control subjects (1.18 ± 0.22 ng/dL and 1.38 ± 0.26, respectively, p = 0.001). Serum hs-CRP levels of subjects with SCH were higher than control subjects (4.2 ± 0.8 mg/l and 1.05 ± 0.3 mg/l respectively, p = 0.0001). Insulin levels of SCH group were higher than control (8.5 ± 4.3 mU/ml and 7.1 ± 3.1 mU/ml respectively, p<0.02) but, Homa-IR levels of the two groups were not different. Mean total and LDL-cholesterol levels of SCH group were higher than control (p = 0.01 and p<0.02). We also found a positive correlation between hs-CRP levels and insulin (r = 0.362, p = 0.002 in men, r = 0.358, p = 0.0001 in women), TSH (r = 0.611, p = 0.0001 in men, r = 0.411 p = 0.0001 in women), and prolactin (r = 0.340, p = 0.01 in men r = 0.553, p = 0.0001 in women). Conclusions: Patients with SCH, irrespective of gender, have higher serum hs-CRP, insulin, total and LDL-cholesterol levels than healthy subjects. 2-High hs-CRP level, and thereby low grade inflammation may be associated with fasting hyperinsulinemia before insulin resistance becomes evident in patients with SCH.

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These mutations in patients with early-onset obesity represent a novel molecular mechanism of human POMC deficiency whereby naturally occurring mutations in its N-terminal sequence impair the ability of POMC to enter the trafficking pathway in which serial propeptide processing normally occurs.

The background and aim of the study is to evaluate insulin sensitivity in hyperprolactinemic subjects via euglycemic hyperinsulinemic clamp technique. Sixteen hyperprolactinemic subjects and 12 healthy subjects were included in the study. HOMA-B and HOMA-IR values of groups were calculated. Euglycemic hyperinsulinemic clamp technique was performed in both groups, and the M value of the groups was defined. Mann-Whitney U and chi-square tests were used in statistical analysis. Basal insulin level of hyperprolactinemic patients were higher than the control group (6.85 +/- 4.68; 3.66 +/- 0.88 microU/ml respectively; P < 0.05). Mean HOMA-IR and HOMA-B values of patients were higher than control group (1.49 +/- 1.30; 0.78 +/- 0.27 respectively; P = 0.02 and 136.28 +/- 72.53; 64.77 +/- 23.31, respectively, P < 0.001). M values of the patients were statistically lower than the control group (5.64 +/- 2.36; 7.05 +/- 1.62 kg/mg/min respectively; P < 0.05). (1) Hyperprolactinemic patients were more insulin resistant than control subjects. (2) Insulin resistance in hyperprolactinemic patients is not associated with obesity or anthropometric parameters such as fat content, waist circumference and BMI.

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