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

Prostaglandins of the E series are implicated as regulators of glucose homeostasis because of their effects on glucose production and secretion of insulin and glucagon. PGE is postulated to play a role in the pathophysiology of insulin secretion in adult-onset (Type II) diabetes mellitus. Evidence supporting this hypothesis includes the demonstration that PGE inhibits glucose-induced acute insulin responses in normal humans. Moreover, drugs that inhibit synthesis of PGE improve abnormal insulin secretion in human subjects with Type II diabetes mellitus.
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PMID:Prostaglandins, glucose homeostasis, and diabetes mellitus. 634 49

1. A fructose (Fru)-enriched diet induces a mild increase in blood pressure associated with hyperglycaemia, hypertriglyceridaemia, and insulin resistance, resembling the human 'syndrome X', being an useful model to study hypertension and type 2 diabetes. 2. A sustained elevation of blood pressure is associated with cardiovascular structural modifications such as left ventricular hypertrophy and increased wall thickness:lumen diameter ratio in blood vessels. 3. Prostanoids (PR), metabolites of arachidonic acid through the cyclooxygenase pathway, include vasoactive substances synthesized and released by the vessel walls. 4. The aim of the present study was to analyse, in Fru-treated rats: (i) the morphology of mesenteric vessels and; (ii) the PR production in aorta and mesenteric vessels, in order to assess whether these parameters are related with the haemodynamic alterations observed in this experimental model. 5. Blood pressure, glycaemia and triglyceridaemia, were significantly elevated in both (4 and 22 weeks) Fru-treated groups. Meanwhile body and heart weight as well as insulinaemia were similar between experimental animals and controls. 6. The mesenteric vessels of Fru-treated rats (22 weeks) showed an increased thickness and area of the media when compared with the controls; meanwhile, the lumen diameter was similar in both groups. 7. The Fru treatment for 4 weeks did not modify PR production in aorta, whereas in the mesenteric bed it diminished prostaglandin (PG) E(2) release significantly compared with the controls. However, in the group treated for 22 weeks, Fru reduced PGI(2) production in the aorta, as assessed by 6-keto-PGF(1)alpha measurements. Meanwhile, in the mesenteric bed, the chronic Fru treatment decreased PGE(2) release but, rather surprisingly, increased the output of PGI(2) when compared with its corresponding controls. 8. In conclusion, the present study shows the existence of an alteration in the morphology of mesenteric vessels in Fru-treated rats, which could be related to an increase in peripheral resistance and the consequent mild hypertension observed in this model. However, a diminished release of vasodilator PRs, such as PGE(2) in mesenteric vessels at 4 and 22 weeks and PGI(2) in aorta at 22 weeks could further impair the vessel response. The increase in PGI(2) observed in the chronic group in mesenteric vessels could be attributed to a compensatory mechanism.
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PMID:Fructose overload modifies vascular morphology and prostaglandin production in rats. 1545 41

Childhood obesity is prevalent and linked to the development of Type 2 diabetes mellitus (DM) and poor bone health. Some PUFA enhance bone mass and thus may improve bone health in obese children. The study objective was to determine the effects of dietary (n-6) compared with (n-3) essential PUFA and long-chain PUFA (LCPUFA) on bone in an obese and insulin-resistant state. Male fa/fa (n = 48) and lean Zucker rats (n = 48) were fed diets containing safflower oil [SO, high (n-6) PUFA], flaxseed oil [FXO, high (n-3) PUFA], or menhaden oil [MO, high (n-3) LCPUFA] for 9 wk. Measurements included the following: femur bone area (BA), mineral content (BMC), density (BMD), morphometry and ex vivo release of prostaglandin E(2) (PGE(2)); plasma osteocalcin and C-terminal telopeptides of type I collagen. Differences among groups were detected using 2-way ANOVA. Genotype effects in the fa/fa rats included lower femoral weight, length, BA, and BMC, as well as femoral head and proximal epiphysis widths compared with the lean rats, but BMD was not affected. Femur BA, BMC, and BMD did not differ among the dietary groups, but diaphysis width was elevated in the MO group and PGE(2) release was reduced by the FXO and MO diets. No genotype x diet interactions were observed. These data indicate that the fa/fa Zucker rat is at risk for low bone mass and that dietary (n-3) FA effectively reduce PGE(2) release. Whether reduced PGE(2) will support optimal peak bone mass during childhood and conserve bone mass with aging warrants investigation.
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PMID:(n-3) fatty acids reduce the release of prostaglandin E2 from bone but do not affect bone mass in obese (fa/fa) and lean Zucker rats. 1573 84

The leaf of Psidium guajava Linn. (family, Myrtaceae) is used traditionally in African folk medicine to manage, control, and/or treat a plethora of human ailments, including diabetes mellitus and hypertension. In order to scientifically appraise some of the anecdotal, folkloric, ethnomedical uses of P. guajava Linn., the present study was undertaken to investigate the hypoglycemic and hypotensive effects of P. guajava leaf aqueous extract (PGE, 50-800 mg/kg) in rat experimental paradigms. The hypoglycemic effect of the plant's extract was examined in normal and diabetic rats, using streptozotocin (STZ)-induced diabetes mellitus model. Hypertensive Dahl salt-sensitive rats were used to investigate the hypotensive (antihypertensive) effect of the plant's extract. Chlorpropamide (CPP; 250 mg/kg, p.o.) was used as the reference hypoglycemic agent for comparison. Acute oral administrations of the plant's extract (PGE; 50-800 mg/kg, p.o.) caused dose-related, significant (p < 0.05-0.001) hypoglycemia in normal (normoglycemic) and STZ-treated, diabetic rats. Moreover, acute intravenous administrations of the plant's extract (PGE, 50-800 mg/kg i.v.) produced dose-dependent, significant reductions (p < 0.05-0.001) in systemic arterial blood pressures and heart rates of hypertensive, Dahl salt-sensitive rats. Although the exact mechanisms of action of the plant's extract still remain speculative at present, it is unlikely that the extract causes hypotension in the mammalian experimental animal model used via cholinergic mechanisms, since its cardiodepressant effects are resistant to atropine pretreatment. The numerous tannins, polyphenolic compounds, flavonoids, pentacyclic triterpenoids, guiajaverin, quercetin, and other chemical compounds present in the plant are speculated to account for the observed hypoglycemic and hypotensive effects of the plant's leaf extract. However, the results of this experimental animal study indicate that the leaf aqueous extract of P. guajava possesses hypoglycemic and hypotensive properties, and thus lend pharmacological credence to the suggested folkloric, ethnomedical uses of the plant in the management or control of adult-onset, type 2 diabetes mellitus and hypertension in some rural African communities.
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PMID:Hypoglycemic and hypotensive effects of Psidium guajava Linn. (Myrtaceae) leaf aqueous extract. 1639 18

Type 2 diabetes mellitus is characterized by insulin resistance of peripheral tissues and dysfunction of pancreatic beta-cells. Furthermore, the number of pancreatic beta-cells decreases as a secondary effect of advanced type 2 diabetes, although the molecular mechanism has not been elucidated. Recently, it has been shown that hyperglycemic conditions induce the expression of cyclooxygenase-2 in pancreatic islets and increase the downstream product prostaglandin E(2) (PGE(2)). To investigate whether high glucose-induced PGE(2) has an adverse effect on pancreatic beta-cells, we generated transgenic mice (RIP-C2mE) that express cyclooxygenase-2 and microsomal prostaglandin E synthase-1 in their beta-cells using the rat insulin-2 gene promoter (RIP). The homozygous RIP-C2mE (Tg/Tg) mice showed severe hyperglycemia from six weeks of age. Although the heterozygous RIP-C2mE (Tg/-) mice showed normal blood glucose levels throughout their lifetime, this level increased significantly compared with that of wild-type mice when glucose was loaded. The relative number of beta-cells to the total islet cell number was reduced to 54 and 14% in the RIP-C2mE (Tg/-) and (Tg/Tg) mice, respectively, whereas that in the wild-type mice was 84%. Importantly, the proliferation rate in the islets of the RIP-C2mE (Tg/Tg) mice at four weeks of age decreased significantly in comparison to that in the wild-type mice. Because beta-cells replicate not only during the postnatal period but also in the adult pancreas at a basal level, it is possible that increased PGE(2) signaling thus contributes to the reduction of the pancreatic beta-cell mass through inhibition of proliferation, thereby aggravating diabetes further.
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PMID:Destruction of pancreatic beta-cells by transgenic induction of prostaglandin E2 in the islets. 1687 78

The white adipose tissue, especially of humans, is now recognized as the central player in the mild inflammatory state that is characteristic of obesity. The question is how the increased accumulation of lipid seen in obesity causes an inflammatory state and how this is linked to the hypertension and type 2 diabetes that accompanies obesity. Once it was thought that adipose tissue was primarily a reservoir for excess calories that were stored in the adipocytes as triacylglycerols. In times of caloric deprivation these stored lipids were mobilized as free fatty acids and the insulin resistance of obesity was attributed to free fatty acids. It is now clear that in humans the expansion of adipose tissue seen in obesity results in more blood vessels, more connective tissue fibroblasts, and especially more macrophages. There is an enhanced secretion of some interleukins and inflammatory cytokines in adipose tissue of the obese as well as increased circulating levels of many cytokines. The central theme of this chapter is that human adipose tissue is a potent source of inflammatory interleukins plus other cytokines and that the majority of this release is due to the nonfat cells in the adipose tissue except for leptin and adiponectin that are primarily secreted by adipocytes. Human adipocytes secrete at least as much plasminogen activator inhibitor-1 (PAI-1), MCP-1, interleukin-8 (IL-8), and IL-6 in vitro as they do leptin but the nonfat cells of adipose tissue secrete even more of these proteins. The secretion of leptin, on the other hand, by the nonfat cells is negligible. The amount of serum amyloid A proteins 1 & 2 (SAA 1 & 2), haptoglobin, nerve growth factor (NGF), macrophage migration inhibitory factor (MIF), and PAI-1 secreted by the adipocytes derived from a gram of adipose tissue is 144%, 75%, 72%, 37%, and 23%, respectively, of that by the nonfat cells derived from the same amount of human adipose tissue. However, the release of IL-8, MCP-1, vascular endothelial growth factor (VEGF), TGF-beta1, IL-6, PGE(2), TNF-alpha, cathepsin S, hepatocyte growth factor (HGF), IL-1beta, IL-10, resistin, C-reactive protein (CRP), and interleukin-1 receptor antagonist (IL-1Ra) by adipocytes is less than 12% of that by the nonfat cells present in human adipose tissue. Obesity markedly elevates the total release of TNF-alpha, IL-6, and IL-8 by adipose tissue but only that of TNF-alpha is enhanced in adipocytes. However, on a quantitative basis the vast majority of the TNF-alpha comes from the nonfat cells. Visceral adipose tissue also releases more VEGF, resistin, IL-6, PAI-1, TGF-beta1, IL-8, and IL-10 per gram of tissue than does abdominal subcutaneous adipose tissue. In conclusion, there is an increasing recognition that adipose tissue is an endocrine organ that secretes leptin and adiponectin along with a host of other paracrine and endocrine factors in addition to free fatty acids.
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PMID:Release of interleukins and other inflammatory cytokines by human adipose tissue is enhanced in obesity and primarily due to the nonfat cells. 1702 26

It has been shown that enhancement of vasoconstrictor prostanoids plays an important role in the development of cardiovascular diseases. The aim of the present study was to examine the effects of pyrrolidine dithiocarbamate (PDTC), a low-molecular-weight thiol antioxidant and a potent inhibitor of nuclear factor-kappaB (NF-kappaB), on both the response to and production of prostanoids in arterial vessels isolated from rats at the chronic stage of type 2 diabetes. Using aortas from type 2 diabetic Otsuka Long-Evans Tokushima Fatty (OLETF) rats, control Long-Evans Tokushima Otsuka (LETO) rats, and LETO and OLETF rats treated with PDTC (30 mg/kg, s.c., daily, for 1 week), we measured the production of prostanoids and NF-kappaB activity. The arachidonic acid-induced contraction and the acetylcholine-induced endothelium-derived contracting factor (EDCF)-mediated contraction in mesenteric arteries were also compared among these groups. OLETF rats exhibited (vs. age-matched LETO rats) the following: increased responses to both arachidonic acid and EDCF and greater productions of PGE(2) and TXA(2). Treatment with PDTC resulted in the following: 1) reduced arachidonic acid- and EDCF-mediated contractions, 2) suppressed the production of prostanoids, and 3) normalized NF-kappaB activity. These results suggest that PDTC has beneficial effects against the abnormal vasoconstrictor prostanoid signaling present in rats at the chronic stage of type 2 diabetes.
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PMID:Pyrrolidine dithiocarbamate reduces vascular prostanoid-induced responses in aged type 2 diabetic rat model. 1957 60

Delayed gastric emptying in patients with both type 1 and type 2 diabetes mellitus (DM) occurs in approximately 50% of these patients. However, the role and the action mechanism of insulin on gastrointestinal (GI) motility are still unclear. The purpose of the present study was to investigate the involvement of cyclooxygenase-2 (COX-2) and prostaglandin E(2) in the effects of insulin on gastric emptying in male rats. The normal and streptozotocin (STZ)-pretreated rats were injected intraperitoneally with or without insulin, atropine and specific muscarinic receptor antagonists before examination of measurement of gastric emptying, spontaneous contractile activity of smooth muscle strips, plasma cholecystokinin (CCK), and prostaglandin E(2) (PGE(2)) analysis. Protein expression of COX-2 and insulin receptors (IRs) were analyzed by the technique of western blot. Acute different doses of insulin accelerated gastric emptying. Atropine interrupted the insulin effect on gastric emptying, and muscarnic M1/M3 receptor antagonists interrupted the insulin-reversed gastric emptying in normal and DM rats. Besides, we observed the expression of (IRs) in GI and found that IR was changed under the insulin and DM treatment, and was also different between STZ-pretreated rats and hyperglycemic rats. Expression of COX-2 in stomach was decreased in DM rats but restored by insulin. The COX inhibitor, indomethacin, decreased the gastric emptying which was induced or reversed by insulin in normal and DM rats, respectively. PGE(2) production in stomach corresponded to the COX-2 expression. The contraction of GI smooth muscle stimulated by PGE(2) was increased in insulin-pretreated normal and DM rats. We conclude that insulin changed the expression of IRs in stomach in DM rats. The delayed GI motility in diabetes was at least in part due to the COX-2 and PGE(2) pathway which associated with decreasing COX-2 and diminishing PGE(2) production in stomach. The attenuation of PGE(2) production was employed for the index of the reduction of smooth muscle contraction in stomach in diabetes. Insulin stimulated the smooth muscle contraction through the IRs and COX-2 expression plus PGE(2) production in rat stomach as well as reversed the delayed gastric emptying via the nervous actions of muscarinic M1 and M3 receptors in DM rats.
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PMID:Involvement of cyclooxygenase 2 and prostagladin E(2) in the effects of insulin on gastric emptying in male rats. 1982 89

Prostaglandin E(2) (PGE(2)) is a well-known mediator of beta-cell dysfunction in both type 1 and type 2 diabetes. We recently reported that down-regulation of the Akt pathway activity is implicated in PGE(2)-induced pancreatic beta-cell dysfunction. The aim of this study was to further dissect the signaling pathway of this process in pancreatic beta-cell line HIT-T15 cells and primary mouse islets. We found that PGE(2) time-dependently increased the c-Jun N-terminal kinase (JNK) pathway activity. JNK inhibition by the JNK-specific inhibitor SP600125 reversed PGE(2)-inhibited glucose-stimulated insulin secretion (GSIS). PGE(2) induced dephosphorylation of Akt and FOXO1, leading to nuclear localization and transactivation of FOXO1. Activation of FOXO1 induced nuclear exclusion but had no obvious effect on the whole-cell protein level of pancreatic and duodenal homeobox 1 (PDX1). However, these effects were all attenuated by JNK inhibition. Furthermore, adenovirus-mediated overexpression of dominant-negative (DN)-FOXO1 abolished whereas constitutively active (CA)-FOXO1 mimicked the effects of PGE(2) on GSIS in isolated mouse islets. In addition, we demonstrated that DN-JNK1 but not DN-JNK2 or CA-Akt abolished the PGE(2)-induced AP-1 luciferase reporter activity, whereas DN-JNK1 and CA-Akt but not DN-JNK2 reversed the effect of PGE(2) on FOXO1 transcriptional activity, and overexpression of DN-JNK1 rescued PGE(2)-impaired GSIS in mouse islets. Our results revealed that activation of the JNK is involved in PGE(2)-induced beta-cell dysfunction. PGE(2)-mediated JNK1 activation, through dephosphorylation of Akt and FOXO1, leads to nuclear accumulation of FOXO1 and nucleocytoplasmic shuttling of PDX1, finally resulting in defective GSIS in pancreatic beta-cells.
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PMID:Forkhead box O1/pancreatic and duodenal homeobox 1 intracellular translocation is regulated by c-Jun N-terminal kinase and involved in prostaglandin E2-induced pancreatic beta-cell dysfunction. 1983 72

It is well known that type 2 diabetes mellitus is frequently associated with vascular dysfunction and an elevated systemic blood pressure, yet the underlying mechanisms are not completely understood. We previously reported that in mesenteric arteries from established type 2 diabetic Otsuka Long-Evans Tokushima fatty (OLETF) rats, which exhibit endothelial dysfunction, there is an imbalance between endothelium-derived vasodilators [namely, nitric oxide (NO) and hyperpolarizing factor (EDHF)] and vasoconstrictors [contracting factors (EDCFs) such as cyclooxygenase (COX)-derived prostanoids]. Here, we investigated whether the angiotensin II receptor antagonist losartan might improve endothelial dysfunction in OLETF rats at the established stage of diabetes. In mesenteric arteries isolated from OLETF rats [vs. those from age-matched control Long-Evans Tokushima Otsuka (LETO) rats]: (1) the acetylcholine (ACh)-induced relaxation was impaired, (2) the NO- and EDHF-mediated relaxations were reduced, (3) the ACh-induced EDCF-mediated contraction and the production of prostanoids were increased, and (4) superoxide generation was increased. After such OLETF rats had received losartan (25 mg/kg/day p.o. for 4 weeks), their isolated mesenteric arteries exhibited: (1) improvements in ACh-induced NO- and EDHF-mediated relaxations, (2) reduced EDCF- and arachidonic acid-induced contractions, (3) suppressed production of prostanoids, (4) reduced PGE(2)-mediated contraction, and (5) reduced superoxide generation. Within the timescale studied here, losartan did not change the protein expressions of endothelial NO synthase, COX1, or COX2 in mesenteric arteries from either OLETF or LETO rats. Losartan thus normalizes vascular dysfunction in this type 2 diabetic model, and the above effects may contribute to the reduction of adverse cardiovascular events seen in diabetic patients treated with angiotensin II receptor blockers.
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PMID:Mechanisms underlying the losartan treatment-induced improvement in the endothelial dysfunction seen in mesenteric arteries from type 2 diabetic rats. 2030 70


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