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Query: UMLS:C0011860 (type 2 diabetes)
 57,723 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Evidence-based medicine (EBM) has come to be regarded as essential in all fields of medical sciences and practical medicine. In the field of diabetes and exercise, among the epidemiological studies of physical exercise, recent mega-trials such as the Diabetes Prevention Program (DPP) in the U.S. have shown that lifestyle intervention programs involving diet and/or exercise reduce the progression of impaired glucose tolerance (IGT) to type 2 diabetes. In studies examining the endocrinological and metabolic effects of exercise, it has been demonstrated that physical exercise promotes the utilization of blood glucose and free fatty acids in muscles and lowers blood glucose levels in well-controlled diabetic patients. Long-term, mild, regular jogging increases the action of insulin in both carbohydrate and lipid metabolism without influencing body mass index or maximal oxygen uptake. A significant correlation has been observed between delta MCR (Deltainsulin sensitivity) and the average number of steps performed in a day. Our recent data suggested that the improved effectiveness of insulin that occurs as a result of physical exercise is attributable, at least in part, to increases in GLUT4 protein, IRS1 and PI3-kinase protein in skeletal muscle. As a prescription for exercise, aerobic exercise of mild to moderate intensity, including walking and jogging, 10-30 min a day, 3-5 days a week, is recommended. Resistance training of mild intensity with the use of light dumbbells and stretch cords should be combined in elderly individuals who have decreased muscle strength. An active lifestyle is essential in the management of diabetes, which is one of typical lifestyle-related diseases.
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PMID:Clinical aspects of physical exercise for diabetes/metabolic syndrome. 1749 34

Insulin controls carbohydrate and lipid metabolism. Among other things, it stimulates glucose storage as glycogen and lipid storage as triglycerides. Insulin acts through a membrane receptor which is a tyrosine kinase. When activated by insulin binding, the tyrosine kinase will recruit and phosphorylate intracellular substrates called IRS (insulin receptor substrate). Phosphorylated IRS will be used as docking sites for proteins which will transmit the insulin signal through several systems (e.g. PI3-kinase). The insulin resistance which is concomitant with type 2 diabetes and obesity is linked to an increased intracellular availability of fatty acids which are precursors of lipid mediators inducing a decreased efficiency of insulin signal transmission. Therapies aimed at improving insulin sensitivity could then target proteins involved in the regulation of intacellular fatty acid availibility.
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PMID:[Insulin signaling and insulin resistance]. 1798 53

Essential hypertension is an insulin resistant state. Early insulin signaling steps are impaired in essential hypertension and a large body of data suggests that there is a crosstalk at multiple levels between the signal transduction pathways that mediate insulin and angiotensin II actions. At the extracellular level the angiotensin converting enzyme (ACE) regulates the synthesis of angiotensin II and bradykinin that is a powerful vasodilator. At early intracellular level angiotensin II acts on JAK-2/IRS1-IRS2/PI3-kinase, JNK and ERK to phosphorylate serine residues of key elements of insulin signaling pathway therefore inhibiting signaling by the insulin receptor. On another level angiotensin II inhibits the insulin signaling inducing the regulatory protein SOCS 3. Angiotensin II acting through the AT1 receptor can inhibit insulin-induced nitric oxide (NO) production by activating ERK 1/2 and JNK and enhances the activity of NADPH oxidase that leads to an increased reactive oxygen species generation. From the clinical standpoint, the inhibition of the renin angiotensin system improves insulin sensitivity and decreases the incidence of Type 2 Diabetes Mellitus (T2DM). This might represent an alternative approach to prevent type 2 diabetes in patients with hypertension and metabolic syndrome, (i.e. insulin resistant patients). This review will discuss: a) the molecular mechanisms of the crosstalk between the insulin and angiotensin II signaling systems b) the results of clinical studies employing drugs targeting the renin-angiotensin II-aldosterone systems and their role in glucose metabolism and diabetes prevention.
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PMID:The crosstalk between insulin and renin-angiotensin-aldosterone signaling systems and its effect on glucose metabolism and diabetes prevention. 1885 18

We recently reported that rs361072, a promoter C/T variant of p110beta, the catalytic subunit of PI3-kinase, was associated with a protection from insulin resistance (IR) in Caucasian adolescents in proportion of their body mass. We tested if this cis-regulatory QTL is associated with IR and type 2 diabetes in 7885 middle-aged obese and non-obese adults of European ancestry. We genotyped rs361072 in 1139 non-diabetic obese (NDO) European adults, in whom IR was estimated by the HOMA-IR index. We also studied 427 type 2 diabetic obese adults (DO) and 424 diabetic non-obese (DNO) adults to test whether their disease status was associated with a decreased prevalence of the protective variant. The prevalence of rs361072 and association with IR was also examined in 5895 non-obese non-diabetic adults (NDNO). rs361072 was associated with HOMA-IR (p=4.10(-4)) in NDO, so that C/C patients had a 17% decrease of this index (p=0.002). A statistical trend (p=1.1.10(-2)) for the same genotypic differences was also observed in NDNO adults, but of insignificant magnitude (4.2%). The distribution of rs361072 genotype was comparable in NDO, DO, DNO and NDNO individuals. Allele C of rs361072 is associated with a protection from IR in obese and non-obese adults, but has no significant effect, however, on diabetes risk in obese or non-obese Europeans.
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PMID:In obese and non-obese adults, the cis-regulatory rs361072 promoter variant of PIK3CB is associated with insulin resistance not with type 2 diabetes. 1909 21

Glimepiride is a third-generation sulfonylurea agent and is widely used in the treatment of type 2 diabetes mellitus. In addition to the stimulatory effects on pancreatic insulin secretion, glimepiride has also been reported to have extrapancreatic functions including activation of PI3 kinase (PI3K) and Akt in rat adipocytes and skeletal muscle. PI3-kinase and Akt are important signaling molecules in the regulation of proliferation and differentiation in various cells. This study investigated the actions of glimepiride in rat osteoblasts and the role of PI3K/Akt pathway. Cell proliferation was determined by measuring absorbance at 550 nm. Supernatant assay was used for measuring alkaline phosphatase activity. Western blot analysis was used for determining collagen I, insulin receptor substrate-1/2, PI3K/Akt, and endothelial nitric oxide synthase expression. We found that glimepiride significantly enhanced proliferation and differentiation of osteoblasts and led to activation of several key signaling molecules including insulin receptor substrate-1/2, PI3K/Akt, and endothelial nitric oxide synthase. Furthermore, a specific inhibitor of PI3K abolished the stimulatory effects of glimepiride on proliferation and differentiation. Taken together, these observations provide concrete evidence that glimepiride activates the PI3K/Akt pathway; and this activation is likely required for glimepiride to stimulate proliferation and differentiation of rat osteoblasts.
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PMID:Glimepiride induces proliferation and differentiation of rat osteoblasts via the PI3-kinase/Akt pathway. 1980 Jun 38

It is well known that systemic insulin resistance is closely associated with the metabolic syndrome including type 2 diabetes and hypertension. However, it remains unclear whether vascular insulin resistance acts as an early etiologic factor for the development of hypertension. Male spontaneously hypertensive rats (SHRs) aged 5 weeks (young) and 15 weeks (adult) were studied and vascular insulin resistance was assessed as the function of isolated aortic vasodilatory response to insulin in vitro. Compared with Wistar-Kyoto (WKY) rats, adult SHRs exhibited significant hypertension with significantly decreased aortic vasodilatation to insulin, whereas young SHRs had normal blood pressure but exhibited similar vascular insulin resistance. Both young and adult SHRs showed significant downregulated expression of PI3-kinase and decreased insulin-stimulated phosphorylations of Akt and eNOS in vascular tissues. Treatment with rosiglitazone (RSG), an insulin sensitizer, for 2 weeks increased vascular PPARgamma expression and restored PI3-kinase/Akt/eNOS-mediated signaling pathway only in young SHRs. More importantly, this treatment improved aortic vasodilatory response to insulin in young but not in adult SHRs. In summary, vascular insulin resistance, characterized by the impairment of PI3-kinase/Akt/eNOS-mediated signaling in vascular endothelium, may play important roles in endothelial dysfunction and subsequent development of hypertension in normotensive young SHRs.
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PMID:Vascular insulin resistance in prehypertensive rats: role of PI3-kinase/Akt/eNOS signaling. 1994 77

Chronic hyperglycemia and inflammatory cytokines disrupt and/or attenuate signal transduction pathways that promote normal beta-cell survival, leading to the destruction of endocrine pancreas in type 2 diabetes. There is convincing evidence that autocrine insulin signalling exerts protective anti-apoptotic effects on beta cells. Suppressors of cytokine signalling (SOCS) were induced by several cytokines and inhibit insulin-initiated signal transduction. The aim of this study was to investigate whether high glucose can influence endogenous interleukin-1beta (IL-1beta) and SOCS expression thus affecting insulin signalling and survival in insulin-producing mouse pancreatic beta cells (betaTC-6). Results showed that prolonged exposure of betaTC-6 cells to increased glucose concentrations resulted in significant inhibition of insulin-induced tyrosine phosphorylation of the insulin receptor (IR), and insulin receptor substrate-2 (IRS-2) as well as PI3-kinase activation. These changes were accompanied by impaired activation of the anti-apoptotic signalling protein Akt and annulment of Akt-mediated suppression of the Forkhead family of transcription factors (FoxO) activation. Glucose-induced attenuation of IRS-2/Akt-mediated signalling was associated with increased IL-1beta expression. Enhanced endogenous IL-1beta specifically induced mRNA and protein expression of SOCS-1 in betaTC-6 cells. Inhibition of SOCS-1 expression by SOCS-1-specific small interfering RNA restored IRS-2/PI3K-mediated Akt phosphorylation suppressed by high glucose. The upregulation of endogenous cytokine signalling and FoxO activation were accompanied by enhanced caspase-3 activation and increased susceptibility of cells to apoptosis. These results indicated that glucose-induced endogenous IL-1beta expression increased betaTC-6 cells apoptosis by inhibiting, at least in part, IRS-2/Akt-mediated signalling through SOCS-1 upregulation.
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PMID:High glucose induces suppression of insulin signalling and apoptosis via upregulation of endogenous IL-1beta and suppressor of cytokine signalling-1 in mouse pancreatic beta cells. 2006 33

Increased Very Low Density Lipoprotein (VLDL) production is a major feature of diabetic dyslipidemia with consequences on the metabolism of other lipoproteins such as Low Density Lipoproteins (LDL) and High Density Lipoproteins (HDL). More precisely, we observe, in patients with type 2 diabetes, an increased production of VLDL(1) particles that is potentially detrimental by generating atherogenic remnants, small dense LDL particles and triglyceride-rich HDL particles. Several pathophysiological factors are responsible for increased VLDL production, in type 2 diabetes. Among those, insulin resistance plays an important role. Indeed, defective activation of PI3-kinase, secondary to insulin resistance, is associated with a reduction of apoB degradation in the hepatocytes, a rise in MTP expression (by increasing nuclear transcription factors Fox01 and Foxa2) and an increased activity of phospholipase D1 and ARF-1, which are involved in VLDL(1) formation. Moreover, peripheral insulin resistance is responsible for increased lipolysis of adipose tissue leading to augmented portal flux of FFA to the liver and, as a consequence, activation of VLDL production. In addition, increased de novo lipogenesis is observed in type 2 diabetes. This is secondary to increased activation of SREBP-1c (Sterol Regulatory Element-Binding Protein-1c), mainly by Endoplasmic Reticulum stress, and of ChREBP (Carbohydrate Responsive Element Binding Protein), mainly by hyperglycemia. Furthermore, decreased plasma adiponectin observed in type 2 diabetes, may also play a role in increased VLDL production by decreasing liver AMP-kinase activation and by increasing plasma FFA levels as a consequence of reduced muscle FFA oxidation.
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PMID:Abnormal hepatic apolipoprotein B metabolism in type 2 diabetes. 2018 75

R-spondin-1 (Rspo1) is an intestinal growth factor known to exert its effects through activation of the canonical Wnt (cWnt) signaling pathway and subsequent expression of cWnt target genes. We have detected Rspo1 mRNA in murine islets and the murine MIN6 and betaTC beta-cell lines, and Rspo1 protein in MIN6 beta-cells. Rspo1 activated cWnt signaling in MIN6 beta-cells by increasing nuclear beta-catenin and c-myc, a cWnt target gene. Rspo1 also induced insulin mRNA expression in MIN6 cells. Analysis of MIN6 and mouse beta-cell proliferation by [(3)H]thymidine and BrdU incorporation, respectively, revealed that Rspo1 stimulated cell growth. Incubation of MIN6 and mouse beta-cells with cytokines (IL1beta/TNFalpha/interferon-gamma) significantly increased cellular apoptosis; this increase was abolished by pretreatment with Rspo1. Rspo1 also stimulated insulin secretion in a glucose-independent fashion. We further demonstrated that the glucagon-like peptide-1 receptor agonist, exendin4 (EX4), stimulated Rspo1 mRNA transcript levels in MIN6 cells in a glucose-, time-, dose-, and PI3-kinase-dependent fashion. This effect was not limited to this beta-cell line, as similar time-dependent increases in Rspo1 were also observed in the betaTC beta-cell line and mouse islets in response to EX4 treatment. Together, these studies demonstrate that Rspo1 is a novel beta-cell growth factor and insulin secretagogue that is regulated by EX4. These findings suggest that Rspo1 and the cWnt signaling pathway may serve as a novel target to enhance beta-cell growth and function in patients with type 2 diabetes.
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PMID:R-spondin-1 is a novel beta-cell growth factor and insulin secretagogue. 2044 4

Hyperglycemia in patients with type 2 diabetes causes multiple neuronal complications, e.g., diabetic polyneuropathy, cognitive decline, and embryonic neural crest defects due to increased apoptosis. Possible mechanisms of neuronal response to increased glucose burden are still a matter of debate. Insulin and insulin-like growth factor-1 (IGF-1) receptor signaling inhibits glucose-induced caspase-3 activation and apoptotic cell death. The insulin receptor substrates (IRS) are intracellular adapter proteins mediating insulin's and IGF-1's intracellular effects. Even though all IRS proteins have similar function and structure, recent data suggest different actions of IRS-1 and IRS-2 in mediating their anti-apoptotic effects in glucose neurotoxicity. We therefore investigated the role of IRS-1/-2 in glucose-induced caspase-3 activation using human neuroblastoma cells. Overexpression of IRS-1 or IRS-2 caused complete resistance to glucose-induced caspase-3 cleavage. Inhibition of PI3-kinase reversed this protective effect of IRS-1 or IRS-2. However, MAP-kinases inhibition had only minor impact. IRS overexpression increased MnSOD abundance as well as BAD phosphorylation while Bim and BAX levels remained unchanged. Since Akt promotes cell survival at least partially via phosphorylation and inhibition of downstream forkhead box-O (FoxO) transcription factors, we generated neuroblastoma cells stably overexpressing a dominant negative mutant of FoxO1 mimicking activation of the insulin/IGF-1 pathway on FoxO-mediated transcription. Using these cells we showed that FoxO1 is not involved in neuronal protection mediated by increased IRS-1/-2 expression. Thus, overexpression of both IRS-1 and IRS-2 induces complete resistance to glucose-induced caspase-3 activation via PI3-kinase mediated BAD phosphorylation and MnSOD expression independent of FoxO1.
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PMID:Insulin receptor substrate-1 and -2 mediate resistance to glucose-induced caspase-3 activation in human neuroblastoma cells. 2135 6


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