Insulin and leptin action: roles in diabetes and obesity.

Obesity is a major risk factor for insulin resistance and therefore type 2 diabetes. However, the precise mechanisms whereby obesity causes insulin resistance are complex and not completely understood. The adipocyte derived hormone leptin and the pancreatic derived hormone insulin act as satiety factors to the central nervous system, regulating long-term energy homeostasis. In addition both hormones have been shown to act in the central nervous system (CNS) to acutely regulate peripheral glucose homeostasis. Leptin and insulin have also been shown to regulate pancreatic islet function. A growing amount of evidence suggests there is considerable overlap in the pathways by which these hormones act to mediate their physiological effects. The insulin receptor substrate-2 (IRS-2) protein is a critical mediator of cellular responses to insulin, especially those associated with somatic growth and carbohydrate metabolism. It has been suggested that IRS-2 signalling pathways act as a potential point of convergence for insulin and leptin signalling. Much of our current understanding of both the cellular and molecular effects of leptin and insulin has been derived from studies of murine models of obesity and diabetes. In this thesis I have exploited three such models to generate mice with defective 1) IRS-2 function (IRS-2 KO) and leptin production (ob/ob) and 2) IRS-2 function and leptin receptor (db/db) function. I have also produced mice which lack IRS-2 and STAT-3 specifically in their P-cells and hypothalamus. As insulin resistance and leptin resistance coexist in obese subjects, it was hoped that such murine models would give some insights into the contribution of these processes to the obesity phenotype and its associated insulin resistance and type 2 diabetes. In particular it was hoped to address the hypothesis that a linear relationship exists between IRS-2 and STAT-3 in mediating the effects of insulin and leptin action, with IRS-2 being upstream of the events that lead to the phosphorylation of STAT-3. Considering either systemic or tissue-specific approaches, it was evident that insults to leptin signalling in combination with lrs-2 deletion results in additive effects upon growth, adiposity, glucose homeostasis and islet function. These additive effects would indicate that IRS-2 and STAT-3 mediate these effects by acting in separate signalling pathways, as opposed to converging upon a linear pathway. However cross talk between these parallel pathways is likely to be critical for the maintenance of insulin and leptin sensitivity in target tissues

The role of insulin receptor substrate 2 in hypothalamic and β cell function

Insulin receptor substrate 2 (Irs2) plays complex roles in energy homeostasis. We generated mice lacking Irs2 in β cells and a population of hypothalamic neurons (RIPCreIrs2KO), in all neurons (NesCreIrs2KO), and in proopiomelanocortin neurons (POMCCreIrs2KO) to determine the role of Irs2 in the CNS and β cell. RIPCreIrs2KO mice displayed impaired glucose tolerance and reduced β cell mass. Overt diabetes did not ensue, because β cells escaping Cre-mediated recombination progressively populated islets. RIPCreIrs2KO and NesCreIrs2KO mice displayed hyperphagia, obesity, and increased body length, which suggests altered melanocortin action. POMCCreIrs2KO mice did not display this phenotype. RIPCreIrs2KO and NesCreIrs2KO mice retained leptin sensitivity, which suggests that CNS Irs2 pathways are not required for leptin action. NesCreIrs2KO and POMCCreIrs2KO mice did not display reduced β cell mass, but NesCreIrs2KO mice displayed mild abnormalities of glucose homeostasis. RIPCre neurons did not express POMC or neuropeptide Y. Insulin and a melanocortin agonist depolarized RIPCre neurons, whereas leptin was ineffective. Insulin hyperpolarized and leptin depolarized POMC neurons. Our findings demonstrate a critical role for IRS2 in β cell and hypothalamic function and provide insights into the role of RIPCre neurons, a distinct hypothalamic neuronal population, in growth and energy homeostasis

Phenomenology of the Lense-Thirring effect in the Solar System

Recent years have seen increasing efforts to directly measure some aspects of the general relativistic gravitomagnetic interaction in several astronomical scenarios in the solar system. After briefly overviewing the concept of gravitomagnetism from a theoretical point of view, we review the performed or proposed attempts to detect the Lense-Thirring effect affecting the orbital motions of natural and artificial bodies in the gravitational fields of the Sun, Earth, Mars and Jupiter. In particular, we will focus on the evaluation of the impact of several sources of systematic uncertainties of dynamical origin to realistically elucidate the present and future perspectives in directly measuring such an elusive relativistic effect.Comment: LaTex, 51 pages, 14 figures, 22 tables. Invited review, to appear in Astrophysics and Space Science (ApSS). Some uncited references in the text now correctly quoted. One reference added. A footnote adde

A history of previous gestational diabetes mellitus is associated with adverse changes in insulin secretion and VLDL metabolism independently of increased intrahepatocellular lipid

<p>Aims/hypothesis: We have previously reported a high prevalence of non-alcoholic fatty liver disease (NAFLD) among women with previous gestational diabetes mellitus (pGDM). We wanted to confirm that intrahepatocellular lipid (IHCL) is associated with pGDM independently of adiposity and determine: (1) if VLDL metabolism is dysregulated; and (2) the extent to which NAFLD and IHCL account for the dysmetabolic phenotype in pGDM.</p> <p>Methods We analysed data from a cohort of 234 women (114 with pGDM) and identified effects of pGDM on lipid and glucoregulation that were independent of ultrasound-diagnosed NAFLD. We then measured IHCL by MR spectroscopy in a representative subgroup (n = 36) and conducted detailed metabolic studies (IVGTT, VLDL apolipoprotein B [apoB] kinetics and palmitate turnover) and measurement of regional body fat by MRI to demonstrate effects of IHCL that were independent of a history of pGDM.</p> <p>Results pGDM was associated with increased IHCL (p = 0.04) after adjustment for adiposity. Independently of IHCL, pGDM was associated with a lower IVGTT disposition index (p = 0.02) and acute insulin response to glucose (pGDM+/NAFLD−, 50% lower; pGDM+/NAFLD+, 36% lower; effect of pGDM, p = 0.03), increased VLDL apoB pool size (pGDM+/NAFLD−, 3.1-fold higher; pGDM+/NAFLD+, 1.2-fold higher; effect of pGDM, p = 0.02) and, at borderline significance (p = 0.05), increased rate of VLDL apoB synthesis.</p> <p>Conclusions/interpretation pGDM is associated with increased IHCL independently of adiposity. The increased liver fat contributes to the phenotype, but pGDM status is independently associated with diminished insulin secretion and (shown for the first time) augmented VLDL metabolism. IHCL with pGDM may compound a dysmetabolic phenotype.</p&gt

Wind energy R and D in the United Kingdom 5 biennial wind energy conference and workshop

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