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Query: UNIPROT:P06889 (Mol)
 630,302 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Studies ex vivo have shown that phosphoinositide 3-kinase (PI3K) activity is necessary but not sufficient for insulin-stimulated glucose uptake. Unexpectedly, mice lacking either of the PI3K regulatory subunits p85alpha or p85beta exhibit increased insulin sensitivity. The insulin hypersensitivity is particularly unexpected in p85alpha-/- p55alpha-/- p50alpha-/- mice, where a decrease in p110alpha and p110beta catalytic subunits was observed in insulin-sensitive tissues. These results raised the possibility that decreasing total PI3K available for stimulation by insulin might circumvent negative feedback loops that ultimately shut off insulin-dependent glucose uptake in vivo. Here we present results arguing against this explanation. We show that p110alpha+/- p110beta+/- mice exhibit mild glucose intolerance and hyperinsulinemia in the fasted state. Unexpectedly, p110alpha+/- p110beta+/- mice showed a approximately 50% decrease in p85 expression in liver and muscle. Consistent with this in vivo observation, knockdown of p110 by RNA interference in mammalian cells resulted in loss of p85 proteins due to decreased protein stability. We propose that insulin sensitivity is regulated by a delicate balance between p85 and p110 subunits and that p85 subunits mediate a negative role in insulin signaling independent of their role as mediators of PI3K activation.
Mol Cell Biol 2005 Mar
PMID:Phosphoinositide 3-kinase catalytic subunit deletion and regulatory subunit deletion have opposite effects on insulin sensitivity in mice. 1571 20

Glucose intolerance is often observed after pancreatic islet cell transplantation. The administration of immunosuppressive agents (ISD), necessary to avoid tissue rejection, is in part responsible for hyperglycemia. To investigate whether mouse insulinoma (MIN6) cells transfected with the glucagon like peptide-1 (GLP-1) fragment of the proglucagon gene (RIP/GLP-1 MIN6 cells) are resistant to the toxicity derived from the administration of ISD. RIP/GLP-1 MIN6 cells, as well as parental MIN6 cells, were exposed to a cocktail of ISD. The secretion of insulin and the expression of apoptosis-related proteins were investigated by RIA and western blot analysis. Cell apoptosis was quantified by FACS analysis. Finally, to study whether the antiapoptotic action of GLP-1 was a function of its effect on insulin secretion, or rather it was a direct effect of GLP-1, cells were cultured with or without diazoxide or exendin-9. GLP-1 improved the functional activity and the viability of cells exposed to ISD. The insulin secretion of RIP/GLP-1 MIN6 cells after exposure to ISD was preserved. The expression of GLP-1 by beta-cells reduced the number of apoptotic cells and increased the expression of the antiapoptotic protein Bcl-2. GLP-1 also decreased the abundance of the proapoptotic markers PARP-p85 and Smac/Diablo. Treatment of cells with the diazoxide did not abolish the protective advantage that cells transfected with GLP-1 had; conversely the exposure of cells to exendin-9 was associated with a restored susceptibility to apoptosis. This report demonstrates that GLP-1 is capable of preserving beta-cell function and protecting cells from apoptotic cell death.
J Mol Endocrinol 2005 Apr
PMID:Pancreatic beta-cells expressing GLP-1 are resistant to the toxic effects of immunosuppressive drugs. 1582 Nov 4

Regulation of adult beta-cell mass in pancreatic islets is essential to preserve sufficient insulin secretion in order to appropriately regulate glucose homeostasis. In many tissues mitogens influence development by stimulating D-type cyclins (D1, D2, or D3) and activating cyclin-dependent kinases (CDK4 or CDK6), which results in progression through the G(1) phase of the cell cycle. Here we show that cyclins D2 and D1 are essential for normal postnatal islet growth. In adult murine islets basal cyclin D2 mRNA expression was easily detected, while cyclin D1 was expressed at lower levels and cyclin D3 was nearly undetectable. Prenatal islet development occurred normally in cyclin D2(-/-) or cyclin D1(+/-) D2(-/-) mice. However, beta-cell proliferation, adult mass, and glucose tolerance were decreased in adult cyclin D2(-/-) mice, causing glucose intolerance that progressed to diabetes by 12 months of age. Although cyclin D1(+/-) mice never developed diabetes, life-threatening diabetes developed in 3-month-old cyclin D1(-/+) D2(-/-) mice as beta-cell mass decreased after birth. Thus, cyclins D2 and D1 were essential for beta-cell expansion in adult mice. Strategies to tightly regulate D-type cyclin activity in beta cells could prevent or cure diabetes.
Mol Cell Biol 2005 May
PMID:Cyclins D2 and D1 are essential for postnatal pancreatic beta-cell growth. 1583 79

The common forms of abnormal glucose regulation including type 2 diabetes and impaired glucose tolerance with pathological implications on vascular biology have a complex aetiology involving multiple cross-talks between genetic influences and important environmental modifying factors. Due to complexity of the genetics and the clinical heterogeneity of these disorders it has proven difficult to apply the same methodological approaches that have recently given insights into the molecular genetics of several single-gene disorders of glucose metabolism. This review gives some reflections on the challenges posed by the current hypotheses about the genetics of the widespread forms of abnormal glucose regulation as well as on the strengths and limitations of the methodological approaches applied to unravel the genetic components of common disorders. Also, we review recent progress in relation to a model for the pathogenesis of the various stages of abnormal glucose regulation based on the concepts of thrifty genes of metabolism and pro-inflammation and genes responsible for the appearance of impaired pancreatic beta-cell function and insulin signalling under the pressure of a westernized environment.
Curr Mol Med 2005 May
PMID:Genetics of common forms of glycaemia with pathological impact on vascular biology: are we on the right track? 1589 46

Changes in the human environment and in human behavior and lifestyle, in conjunction with genetic susceptibility, have resulted in a dramatic increase in the incidence and prevalence of diabetes in the world. The rapid escalation of the number of people with type 2 diabetes (T2DM) and diabetes-related cardiovascular disease demands urgent action on prevention. The Finnish Diabetes Prevention Study and The Diabetes Prevention Program showed that the prevention (or delaying) of T2DM is feasible and effective. Both of these trials led to a reduction of 58% in the conversion to diabetes in subjects with impaired glucose tolerance. Compared to lifestyle changes, drug treatment in the prevention of diabetes in people at high risk for T2DM has been less beneficial. Metformin (31%) or acarbose (25%) treatment obtained only about a half of the reduction in the conversion to diabetes compared to lifestyle changes. These drugs require monitoring, and have significant side-effects. Also the effect of orlistat (37%) did not reach the effect of lifestyle modification. Results of the Troglitazone in Prevention of Diabetes study are suggestive for the prevention, but the trial was too small, and included only one ethnic group (Hispanic) and one gender (women). On the basis of the evidence available, we do not have a definite proof that T2DM is prevented in any of these trials. However, we can safely conclude that the current evidence strongly favors the notion that lifestyle changes are the primary means to tackle the epidemic of T2DM.
Curr Mol Med 2005 May
PMID:Prevention of type 2 diabetes. 1589 55

The transcription factor Stat3 is activated by multiple cytokines, including leptin and those signaling through the gp130 receptor. In two independent studies, mice in which the Stat3 gene was inactivated using a RIP-Cre transgene led to glucose intolerance, defects in early-phase insulin secretion, and mild obesity [S. Gorogawa, Y. Fujitani, H. Kaneto, Y. Hazama, H. Watada, Y. Miyamoto, K. Takeda, S. Akira, M. Magnuson, Y. Yamasaki, Y. Kajimoto, M. Hori, Insulin secretory defects and impaired islet architecture in pancreatic beta-cell-specific STAT3 knockout mice, Biochem. Biophys. Res. Commun. 319 (2004) 1159; Y. Cui, L. Huang, F. Elefteriou, G. Yang, J. Shelton, J. Giles, O. Oz, T. Pourbahrami, C. Lu, J. Richardson, G. Karsenty, C. Li, Essential role of STAT3 in body weight and glucose homeostasis, Mol. Cell. Biol. 24 (2004) 258]. However, since the RIP-Cre transgene is also expressed in the hypothalamus, and thereby Stat3 was deleted from neurons expressing the leptin receptor, it was not clear as to which of the metabolic defects were due to the loss of Stat3 from beta-cells or the hypothalamus. We have addressed this issue through the inactivation of Stat3 from pancreatic beta-cells using a Pdx1-Cre transgene. Complete loss of Stat3 was observed in islets from mice, which carry two floxed Stat3 alleles and the Pdx1-Cre transgene. However, these mice did not develop glucose intolerance or obesity over a period of 6 months, demonstrating that Stat3 is dispensable for the generation and physiology of beta-cells. Similarly, mice that express only the Pdx1-Cre transgene display a normal physiology. In contrast, mice that expressed only the RIP-Cre transgene developed glucose intolerance as early as 6 weeks of age. The finding that RIP-Cre transgenic mice in a C57B/6 dominated background develop glucose intolerance is important as this line has been used in several studies.
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PMID:The transcription factor Stat3 is dispensable for pancreatic beta-cell development and function. 1602 57

Nebivolol is a vasodilator that combines beta-adrenergic blocking activity with a relaxant effect on vascular smooth muscle cells (VSMC) mediated by the endothelial nitric oxide (NO) pathway. FFR provide a model of dietary-induced insulin-resistance syndrome, which has been used to study the pathophysiological mechanisms associated with this syndrome. Our main objective was to examine the effect of long-term administration of nebivolol on metabolic and cardiovascular variables in fructose-fed rats (FFR), a model in which an altered bioavailability of NO has been already described. Male Wistar rats were randomly assigned to 4 groups (n = 8 each): I. Control (C); II. Control + nebivolol (C+N): 1 mg/kg(-1) x day(-1) in drinking water during the last 4 weeks. III. FFR: rats receiving fructose in drinking water as a 10% (w/v) solution during 8 weeks, and IV. FFR+N: idem II plus III. During the 8 weeks experimental period, variations in systolic blood pressure (SBP), glucose tolerance test (GTT) and plasma thiobarbituric acid-reactive substances (TBARS) were assessed. At the end of this experimental period, rats were killed and heart and kidneys were excised for calculation of relative heart weight (RHW) and histological evaluation of lumen to media ratio (L/M) in renal arteries. Rats from FFR group increased their SBP and RHW, showed glucose intolerance and an increment in lipid peroxidation. Moreover, FFR showed vascular remodeling in renal arteries evidenced by changes in L/M. Although the metabolic changes were not reverted by the administration of nebivolol, this drug successfully decreased SBP, TBARS levels and reverted structural changes such as cardiac hypertrophy and renal arterial remodeling. Data demonstrate that nebivolol administration could participate in the reversion of cardiovascular structural changes associated with the insulin-resistance syndrome.
Cell Mol Biol (Noisy-le-grand) 2005 Nov 08
PMID:Effect of nebivolol on cardiovascular changes associated with a rat model of insulin-resistance. 1630 77

There is strong evidence that excess dietary salt (NaCl) is a major factor contributing to the development of hypertension. Salt sensitive humans and rats develop hypertension even on a normal salt diet. Salt sensitivity is associated with glucose intolerance and insulin resistance in both humans and animal models, including Dahl salt sensitive (DSS) rats. In insulin resistance, impaired glucose metabolism leads to elevated endogenous aldehydes. These aldehydes bind sulfhydryl groups of membrane proteins, altering calcium channels, increasing cytosolic free calcium ([Ca2+]i) and blood pressure. Treatment with lipoic acid, an endogenous sulfur-containing fatty acid, normalizes insulin resistance and lowers tissue aldehyde conjugates, cytosolic [Ca2+]i, and blood pressure in spontaneously hypertensive rats (SHR). The objective of this study was to investigate the effects of a normal salt diet on tissue aldehyde conjugates, cytosolic [Ca2+]i and blood pressure in DSS rats and to determine whether lipoic acid supplementation prevents the increase in blood pressure and biochemical changes. Starting at 7 weeks of age, DSS rats were divided into three groups of six animals each and treated for 6 weeks with diets as follows: DSS-low salt, 0.4% NaCl; DSS-normal salt, 0.7% NaCl, and; DSS-normal salt + lipoic acid, 0.7% NaCl + lipoic acid 500 mg/kg feed. At completion, animals in the normal salt group had elevated systolic blood pressure, cytosolic [Ca2+]i and tissue aldehyde conjugates as compared to the low salt group. They also showed smooth muscle cell hyperplasia in small arteries and arterioles of the kidney. Dietary lipoic acid supplementation attenuated the increase in systolic blood pressure and associated biochemical and histopathological changes.
Mol Cell Biochem 2005 Jul
PMID:Dietary lipoic acid supplementation attenuates hypertension in Dahl salt sensitive rats. 1633 93

Prohormone convertase 1 (PC1) mutations lead to obesity in humans. However, Pc1 knockout mice do not become obese; in fact, they are runted due to a defect in growth-hormone releasing hormone processing, leading to the speculation that PC1 subserves different functions between mouse and human. Here, we report a novel allele of mouse Pc1 (N222D) that leads to obesity, abnormal proinsulin processing and multiple endocrinological defects. Increased energy intake and a more efficient metabolism contribute to the obesity in Pc1(N222D/N222D) mice. Defective proinsulin processing leads to glucose intolerance, but neither insulin resistance nor diabetes develop despite obesity. The obesity is associated with impaired autocatalytic activation of mature PC1 and reduced hypothalamic alpha-MSH. This is the first characterization of Pc1 mutation in a model organism that mimics human PC1 deficiency.
Hum Mol Genet 2006 Jun 01
PMID:Obesity, hyperphagia and increased metabolic efficiency in Pc1 mutant mice. 1664 67

Stress-associated endoplasmic reticulum (ER) protein 1 (SERP1), also known as ribosome-associated membrane protein 4 (RAMP4), is a Sec61-associated polypeptide that is induced by ER stress. SERP1-/- mice, made by targeted gene disruption, demonstrated growth retardation, increased mortality, and impaired glucose tolerance. Consistent with high levels of SERP1 expression in pancreas, pancreatic islets from SERP1-/- mice failed to rapidly synthesize proinsulin in response to a glucose load. In addition, reduced size and enhanced ER stress were observed in the anterior pituitary of SERP1-/- mice, and growth hormone production was slowed in SERP1-/- pituitary after insulin stimulation. Experiments using pancreatic microsomes revealed aberrant association of ribosomes and the Sec61 complex and enhanced ER stress in SERP1-/- pancreas. In basal conditions, the Sec61 complex in SERP1-/- microsomes was more cofractionated with ribosomes, compared with SERP1+/+ counterparts, in high-salt conditions. In contrast, after glucose stimulation, the complex showed less cofractionation at an early phase (45 min) but more at a later phase (120 min). Although intracellular insulin/proinsulin levels were not significantly changed in both genotypes, these results suggest that subtle changes in translocation efficiency play an important role in the regulation of ER stress and rapid polypeptide synthesis.
Mol Cell Biol 2006 Jun
PMID:Deletion of SERP1/RAMP4, a component of the endoplasmic reticulum (ER) translocation sites, leads to ER stress. 1670 75


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