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Insulin resistance is frequently associated with hypertension and type 2 diabetes. The cytochrome P450 (CYP) arachidonic acid epoxygenases (CYP2C, CYP2J) and their epoxyeicosatrienoic acid (EET) products lower blood pressure and may also improve glucose homeostasis. However, the direct contribution of endogenous EET production on insulin sensitivity has not been previously investigated. In this study, we tested the hypothesis that endogenous CYP2C-derived EETs alter insulin sensitivity by analysing mice lacking CYP2C44, a major EET producing enzyme, and by testing the association of plasma EETs with insulin sensitivity in humans. We assessed insulin sensitivity in wild-type (WT) and Cyp2c44 −/− mice using hyperinsulinaemic–euglycaemic clamps and isolated skeletal muscle. Insulin secretory function was assessed using hyperglycaemic clamps and isolated islets. Vascular function was tested in isolated perfused mesenteric vessels. Insulin sensitivity and secretion were assessed in humans using frequently sampled intravenous glucose tolerance tests and plasma EETs were measured by mass spectrometry. Cyp2c44 −/− mice showed decreased glucose tolerance (639 ± 39.5 vs 808 ± 37.7 mmol/l × min for glucose tolerance tests, p = 0.004) and insulin sensitivity compared with WT controls (hyperinsulinaemic clamp glucose infusion rate average during terminal 30 min 0.22 ± 0.02 vs 0.33 ± 0.01 mmol kg−1 min−1 in WT and Cyp2c44 −/− mice respectively, p = 0.003). Although glucose uptake was diminished in Cyp2c44 −/− mice in vivo (gastrocnemius Rg 16.4 ± 2.0 vs 6.2 ± 1.7 μmol 100 g−1 min−1, p

Aims/hypothesis Obesity and type 2 diabetes are among the most serious health pathologies worldwide. Stress has been proposed as a factor contributing to the development of these health risk factors; however, the underlying mechanisms that link stress to obesity and diabetes need to be further clarified. Here, we study in mice how chronic stress affects dietary consumption and how that relationship contributes to obesity and diabetes. Methods C57BL/6J mice were subjected to chronic variable stress (CVS) for 15 days and subsequently fed with a standard chow or high-fat diet. Food intake, body weight, respiratory quotient, energy expenditure and spontaneous physical activity were measured with a customised calorimetric system and body composition was measured with nuclear magnetic resonance. A glucose tolerance test was also applied and blood glucose levels were measured with a glucometer. Plasma levels of adiponectin and resistin were measured using Lincoplex kits. Results Mice under CVS and fed with a high-fat diet showed impaired glucose tolerance associated with low plasma adiponectin:resistin ratios. Conclusions/interpretation This study demonstrates, in a novel mouse model, how post-traumatic stress disorder enhances vulnerability for impaired glucose metabolism in an energy-rich environment and proposes a potential adipokine-based mechanism.

We have investigated the association of a family history of diabetes with glucose tolerance in a population of Swedish men. All men 35-54 years of age in 1992 and living in four different local municipalities of the outer Stockholm area were screened by questionnaire. From 10236 completed questionnaires 1622 men, selected for presence of such a history but without known diabetes, as well as 1507 men without a family history underwent an oral glucose tolerance test. Diabetes (2 h-plasma glucose levels11.0 mmol/l) was detected in 55 and impaired glucose tolerance (plasma glucose levels 7.8-11.0 mmol/l) in 172 subjects. The odds ratio of diabetes, associated with a family history, was 4.1, confidence interval 2.1-8.3 and for impaired glucose tolerance 1.6, confidence interval 1.2-2.3. Influence of a family history was measurable also within the range of normal 2-h glucose concentrations: compared to 2-h glucose levels3.8 mmol/l; the odds ratio associated with a family history was 1.4, confidence interval 1.1-1.7 and 1.3, confidence interval 1.1-1.6 for concentrations 4.8-5.7 mmol/l and 5.8-7.7 mmol/l respectively. The odds ratio of diabetes and impaired glucose tolerance among men with a family history increased with number and closeness of relatives with diabetes but was not affected by the gender of the family member. Overweight (BMI25.0 kg/m2) increased the odds ratio of diabetes in subjects with a family history, the odds ratio being 24, confidence interval 3-177, when both conditions were present. In subjects with Type II (non-insulin-dependent) diabetes mellitus discovered during the investigation, the presence of a family history of diabetes was associated with decreased insulin secretion rather than insulin resistance as assessed by fasting insulin, homeostasis model assessment, and the 2-h insulin response to the oral glucose tolerance test. We conclude that a family history of diabetes strongly but independently of gender associates with decreased glucose tolerance. Furthermore, the results are compatible with a major role for low insulin secretion in the diabetogenic influence of a family history of diabetes in middle-aged Swedish men. Lastly, the very high risk for diabetes in middle-aged men with both a family history of diabetes and obesity indicates that such people should, for the purpose of therapeutic intervention, be identified in the general population.

The inner ear of spontaneously diabetic WBN/Kob rats was functionally and morphologically examined in order to elucidate the relationship between diabetes mellitus and hearing impairment. At 3 months of age, WBN/Kob rats were non-diabetic, and their hearing function was normal. At 6–7 months of age, they showed decreased glucose tolerance and an increasing tendency toward urinary excretion of glucose without high plasma concentration of glucose, and were therefore judged to be pre-diabetic. They also displayed a significant elevation of hearing threshold in the auditory brainstem response, but showed little morphological and histochemical changes in the inner ear. At 12–13 months of age, they were spontaneously diabetic and showed a more apparent elevation of hearing threshold in auditory brainstem response than that in pre-diabetic animals. In addition, they displayed a marked decrease in the number of spiral ganglion cells and oedematous changes in the stria vascularis. The stria vascularis also showed a decrease in the intensity of staining with some lectins, i. e., wheat germ agglutinin, succinylated wheat germ agglutinin, Soranum tuberosum lectin, and concanavalin A. In conclusion, hearing impairment is induced by diabetes in the WBN/ Kob rats first as an elevation of hearing threshold along with glucose intolerance; secondly, as a decrease in the number of spiral ganglion cells; and thirdly, as oedematous change of the stria vascularis with decreased intensity of lectin staining.

4 years after controlled clinical treatment with a 1000 calorie mixed diet, 24 patients were reinvestigated to assess (1) whether the improved metabolism, as observed during therapy, is merely the result of starvation and (2) to what extent this improvement continues beyond the time of dietary treatment. — The following tests were carried out: Oral G.T.T. (100 g), immunoreactive insulin, free fatty acids, free glycerol, triglycerides, cholesterol, acetoacetate and beta-hydroxybutyrate. — 12 patients had been able to maintain their weight or reduce further. They showed a slightly improved glucose tolerance and a more normal secretion kinetic for insulin release. However, 12 individuals who were found to have a 35% weight gain (Broca), returning almost to their initial weight, showed a decreased glucose tolerance compared with previous examination, while insulin levels were slightly elevated, with a typically delayed secretion. Both groups showed a weight-independent elevation of cholesterol and triglyceride levels and a marked decline of plasma FFA, free glycerol and ketone bodies. The parameters of lipid metabolism may possibly be influenced by the composition of the diet, while a change of weight after reduction primarily affects blood sugar levels and, to a lesser extent, insulin levels.

A decreased glucose tolerance as compared with that of healthy young rats was found in male aged rats (52 weeks) of the Sprague-Dawley strain whose pancreatic islet morphology was normal. This abnormal pattern of tolerance was further exaggerated in rats with a spontaneous islet change (fibrosis and enlargement) described by us previously. These observations suggest that in aged rats a discrepancy between insulin demand and availability preceded the morphological changes of the pancreatic islets. Thus, the islet fibrosis and enlargement may be regarded as an expression of a failing compensatory adjustment.

In a colony of Mongolian gerbils maintained on a standard laboratory diet, occasional obese animals were found. Obesity developed in animals of both sexes and was either transitory or permanent. The mean fasting blood glucose level in non-obese and obese gerbils was 83 and 105mg/100 ml, respectively. Glucosuria and hyperglycemia were found only in a few obese animals, whereas the glucose tolerance was decreased in most obese gerbils. — The endocrine pancreas of the obese animals was morphologically either normal or more often hyperplastic, sometimes with the appearance of adenomatous islets. Theβ-cells possessed prominent Golgi complex and endoplasmic reticulum, and sparse granulation. Large, granule-poor, cells and mitotic figures were seen in the islets. Degenerative changes occurred in theβ-cells of diabetic animals. — It is suggested that the maintenance of the gerbils under laboratory conditions with free access to laboratory diet plays a major role in the development of obesity and that the endocrine pancreas of these animals has a good capacity for hyperplasia that often is sufficient to maintain normo-glycemia in obese animals, although the glucose tolerance is decreased.