Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0011860 (type 2 diabetes)
 57,723 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Under normal physiological conditions, euglycaemia is maintained principally by the homeostatic balance of insulin and glucagon which are secreted from the pancreas. In both type 1 and type 2 diabetes mellitus there is a substantial and chronic increase in the circulating glucose concentration. This elevation in glucose levels is accompanied by a plethora of other biochemical disturbances, including disruption of carbohydrate, fat and protein metabolism. Clinical manifestations of diabetes, which arise from the metabolic disturbances vary between individuals but are often a serious threat to quality and length of life. Pancreas transplantation (Tx) and islet modifications are methods used to restore endogenous insulin secretion in insulin-dependent diabetic patients. In order for this to be achieved successfully, however, some of the problems such as hyperglycemia states (> 150 mg/dl), which may harm pancreatic graft beta cells, immunorejection, the effects of immunosuppression, for example, must be overcome. Considering these problems, therefore, it seems logical that the replacement of the islet tissue itself, either by transplanting a vascularised pancreatic allograft or by transplanting modified pancreatic islet cells, provides a better alternative therapeutic approach than simply replacing insulin that has been lost. This review will show the recent development in the use of pancreatic islets and their modification in a quest to halt the aberrations seen in diabetes mellitus.
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PMID:Future alternative therapies in a quest to halt aberrations in diabetes mellitus. 1593 70

Pancreas transplantation (PTx) has evolved as a clinical therapy to achieve sustained euglycemia. However, it remains unclear if naive diseased islets of the pancreas benefit from the avoidance of glucose toxicity by PTx. In the present study, using an animal model of type 2 diabetes, the Spontaneously Diabetic Torii (SDT; RT1a) rat, we syngeneically transplanted nondiabetic 10-week-old pancreaticduodenal grafts into diabetic 25-week-old recipients. In the control SDT rats that received no treatment, hyperglycemia developed with a mean onset time of 25 +/- 3.9 weeks of age. Few normal islet cells were found from 25 weeks and none at 40 weeks. However, in the PTx rats, the onset age (graft age) of diabetes was significantly prolonged (47 +/- 18.2 weeks). Moreover, we found that the beta-cell mass was significantly increased in the naive pancreases of 40-week-old PTx recipients (PTx40-naive). Interestingly, islet-like cell clusters of varying size were found close to ductal structures of PTx40-naive pancreases, suggesting that these cells are derived from ductal cells. Furthermore, pancreatic and duodenal homeobox factor-1 (PDX-1) was more clearly expressed in the nuclei of PTx40-naive pancreatic islet-like cell clusters. Our results demonstrate the development of duct-derived beta cells in the pancreas of type 2 diabetic recipients after PTx.
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PMID:Development of islet-like cell clusters after pancreas transplantation in the spontaneously diabetic Torri rat. 1616 83

Pancreas or pancreatic islet transplantation in humans is limited by organ availability, and success of the latter is negatively impacted upon by tissue loss post-transplantation and limited potential for expansion of beta cells. A way to overcome the supply and expansion problems is to xenotransplant embryonic tissue. Previously, we have shown that beta cells originating from embryonic day (E) 28 (E28) pig pancreatic primordia transplanted into the mesentery of streptozotocin-diabetic (type 1) Lewis rats engraft without the need for host immune-suppression and normalize glucose tolerance. Here we show long-term engraftment of pig beta cells within liver, pancreas and mesenteric lymph nodes post-transplantation of E28 pig pancreatic primordia into diabetic ZDF rats, a model for type 2 diabetes. Porcine insulin is present in circulation after an oral glucose load. Glucose tolerance is normalized in transplanted ZDF hosts and insulin sensitivity restored in formerly diabetic ZDF males. Release of porcine insulin in vitro from tissue originating in transplanted rats occurs within 1 min of glucose stimulation characteristic of first-phase secretion from beta cells. Of potential importance for application of this transplantation technology to treatment of type 2 diabetes in humans and confirmatory of our previous findings in Lewis rats, no host immunosuppression is required for engraftment of E28 pig pancreatic primordia.
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PMID:Glucose tolerance normalization following transplantation of pig pancreatic primordia into non-immunosuppressed diabetic ZDF rats. 1713 51

The increasing prevalence of diabetes worldwide is cause for concern both in terms of associated morbidity and increasing health costs. This review aims to focus on new and emerging treatments for type 1 and type 2 diabetes. There has been recent focus on diabetes prevention both for type 1 and type 2 diabetes. Prevention programme including lifestyle measures and oral hypoglycaemic agents have shown up to 61% reduction in the development of type 2 diabetes in patients with impaired glucose tolerance or impaired fasting glucose. Little progress has been made to date on type 1 diabetes prevention although current work is focusing on T-cell immunomodulation therapy and beta cell regeneration. Management of type 2 diabetes has been improved by the recent introduction of the peroxisome proliferator-activated receptor-gamma agonists and more recently by the incretins including glucagons like peptide analogues and dipeptidyl peptidase-4 inhibitors. This article focuses on the benefits and restrictions of these new agents. The new insulin analogues glargine and detemir have made significant improvements in the management of type 1 diabetes both in terms of improvement in glycaemic control and in reducing hypoglycaemia rates. Inhaled insulin also shows promise for needle-free treatment of diabetes and these insulins are currently undergoing phase 3 trials. Insulin infusion pumps are becoming more sophisticated and increasingly popular in the management of type 1 diabetes. Many studies have shown benefits for improved glycaemic control and reduced rates of hypoglycaemia with pump treatment compared with multiple daily injections. Pancreas and islet cell transplantation are the subject of ongoing research, but currently require immunosuppressive treatment regimes. The main limitation is lack of availability of donor pancreases. There is much hope that new treatments outlined in this review will result in improved outcomes in the treatment of diabetes.
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PMID:Diabetes: advances in treatment. 1753 82

Adenosine influences metabolism and the adenosine receptor antagonist caffeine decreases the risk of type 2 diabetes. In this study the metabolic role of one adenosine receptor subtype, the adenosine A(1)R, was evaluated in mice lacking this receptor [A(1)R (-/-)]. The HbA1c levels and body weight were not significantly different between wild type [A(1)R (+/+)] and A(1)R (-/-) mice (3-4 months) fed normal lab chow. At rest, plasma levels of glucose, insulin and glucagon were similar in both genotypes. Following glucose injection, glucose tolerance was not appreciably altered in A(1)R (-/-) mice. Glucose injection induced sustained increases in plasma insulin and glucagon levels in A(1)R (-/-) mice, whereas A(1)R (+/+) control mice reacted with the expected transient increase in insulin and decrease in glucagon levels. Pancreas perfusion experiments showed that A(1)R (-/-) mice had a slightly higher basal insulin secretion than A(1)R (+/+) mice. The first phase insulin secretion (initiated with 16.7 mM glucose) was of the same magnitude in both genotypes, but the second phase was significantly enhanced in the A(1)R (-/-) pancreata compared with A(1)R (+/+). Insulin- and contraction-mediated glucose uptake in skeletal muscle were not significantly different between in A(1)R (-/-) and A(1)R (+/+) mice. All adenosine receptors were expressed at mRNA level in skeletal muscle in A(1)R (+/+) mice and the mRNA A(2A)R, A(2B)R and A(3)R levels were similar in A(1)R (-/-) and A(1)R (+/+) mice. In conclusion, the A(1)R minimally affects muscle glucose uptake, but is important in regulating pancreatic islet function.
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PMID:A1 receptor deficiency causes increased insulin and glucagon secretion in mice. 1786 24

Several studies have recently reported strong association between type 2 diabetes and variation in the transcription factor 7-like 2 (TCF7L2) gene, which has been confirmed by several other genome-wide studies. However, the physiological implications of this transcription factor on the pathogenesis of type 2 diabetes is not yet known. The aim of this study was to investigate the alteration in TCF7L2 gene expression in human pancreatic cell line in response to various factors in vitro. MIA Paca-2 cell line (Human Pancreas cell line) was cultured in the presence of curcumin, lipopolysaccaride and glucose (low and high concentration). TCF7L2 gene expression was determined using quantitative real-time RT-PCR. Treatment with curcumin significantly increased TCF7L2 gene expression to 3.24 fold (1.7-log fold) (P = 0.003) compared to the controls while treatment with LPS decreased TCF7L2 gene expression to 0.88-fold (-0.18-log). On the other hand, glucose increased TCF7L2 gene expression in pancreatic cell line. Our data suggest a role for TCF7L2 in glucose homeostasis. The contrary effect of curcumin and LPS on expression of TCF7L2 in pancreatic cells supports a role for TCF7L2 in their survival and function in inflammatory conditions.
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PMID:In vitro modulation of TCF7L2 gene expression in human pancreatic cells. 1915 36

GPR39 is a G protein-coupled receptor expressed in liver, gastrointestinal tract, adipose tissue, and pancreas. We have recently shown that young GPR39(-/-) mice have normal body weight, food intake, and fasting glucose and insulin levels. In this study, we examined the role of GPR39 in aging and diet-induced obese mice. Body weight and food intake were similar in wild-type and GPR39(-/-) mice as they aged from 12 to 52 wk or when fed a low-fat/high-sucrose or high-fat/high-sucrose diet. Fifty-two-week-old GPR39(-/-) mice showed a trend toward decreased insulin levels after oral glucose challenge. When fed either a low-fat/high-sucrose or high-fat/high-sucrose diet, GPR39(-/-) mice had increased fed glucose levels and showed decreased serum insulin levels during an oral glucose tolerance test in the face of unchanged insulin tolerance. Pancreas morphology and glucose-stimulated insulin secretion in isolated islets from wild-type and GPR39(-/-) mice were comparable, suggesting that GPR39 is not required for pancreas development or ex vivo insulin secretion. Small interfering RNA-mediated knockdown of GPR39 in clonal NIT-1 beta-cells revealed that GPR39 regulates the expression of insulin receptor substrate-2 and pancreatic and duodenal homeobox-1 in a cell-autonomous manner; insulin receptor substrate-2 mRNA was also significantly decreased in the pancreas of GPR39(-/-) mice. Taken together, our data indicate that GPR39 is required for the increased insulin secretion in vivo under conditions of increased demand, i.e. on development of age-dependent and diet-induced insulin resistance. Thus, GPR39 agonists may have potential for the treatment of type 2 diabetes.
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PMID:Disruption of G protein-coupled receptor 39 impairs insulin secretion in vivo. 1921 41

We report about our experience with combined en-bloc liver-pancreas transplantation in 14 patients with liver cirrhosis and insulin dependent type 2 diabetes mellitus. Exocrine drainage was achieved by duodeno-duodenostomy. Median posttransplant follow-up is currently 92.5 months. All patients were rendered independent from insulin therapy shortly after transplantation. Levels of glycosylated hemoglobin normalized in all recipients. Mean fasting C-peptide values increased from pretransplant 7.0+/-1.7 ng/mL to 10.5+/-2.9 ng/mL 3 months posttransplantation (P<0.001). One recipient (7.1%) developed recurrent exogenous insulin dependence 7 years after transplantation. Pancreas allograft rejection was confirmed by endoscopic biopsy of donor duodenum mucosa in two patients (14.3%). Calculated 5- and 7-year survival is currently at 64.3% and 64.3%, respectively. Our results indicate that combined en-bloc liver-pancreas transplantation using duodeno-duodenostomy is technically feasible and leads to excellent long-term control of glucose metabolism in patients with liver cirrhosis and insulin-dependent type 2 diabetes.
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PMID:Combined en-bloc liver-pancreas transplantation in patients with liver cirrhosis and insulin-dependent type 2 diabetes mellitus. 1930 91

From December 16, 1966 to December 31, 2008 more than 30,000 pancreas transplants have been reported to the International Pancreas Transplant Registry (IPTR), including > 22,000 from the United States and > 8,000 from outside the US. This report focused on the most recent outcomes for pancreas transplants performed in the US, since we had reliable follow-up information available for US cases only at this time. Between 2004 and 2008 the most common pancreas transplant category was a combined pancreas/kidney transplant (SPK) (73%). Nineteen percent of diabetic patients had already received a kidney transplant before undergoing a pancreas transplant (PAK). In those cases, 76% of all kidneys came from a living donor. Pancreas transplants alone (PTA) accounted for 9% of all pancreas transplants in diabetic patients. The number of pancreas transplants for diabetic patients decreased over the last 5 years, and the decrease was highest in PAK, followed by PTA and SPK. During this time period, the patient age at transplant increased due to an increased number of patients with type 2 diabetes reported as reason for transplantation. The decrease in the number of pancreas transplants provided the opportunity for better selection of deceased donors. We noticed a significant decrease in the age of the deceased donor. Only 6-8% of all reported donors were 45 years of age or older, and the majority of donors were between 15 and 30 years old. In all three pancreas transplant categories (SPK, PAK, and PTA), the majority of patients received antibody therapy for induction and a maintenance protocol of Tacrolimus in combination with MMF. In a growing number of patients, the maintenance protocol was Sirolimus based. In all protocols a strong trend of steroids avoidance could be seen and accounted for one third of all transplants. The overall outcome of pancreas transplantation improved significantly. Patient survival at one year is now better than 95% and reached 90% at 3 years post-transplantation. Pancreas graft function also improved and is still significantly better in SPK than in PAK or PTA. One year graft survival reached 85% in SPK compared to 79% in solitary pancreas transplants. While the overall rate of technical problems decreased, immunological graft loss is still a problem in solitary transplants. While the immunological pancreas graft loss rate at one year was 2% in SPK, it was 6% for PAK and PTA. The use of young donors with short preservation time showed a significant decrease for the risk of graft failure in all 3 categories. This was especially important since the failure of a graft was the factor with the highest impact on patient survival. In summary, with modern immunosuppression regimens and careful donor selection, patient survival and pancreas transplant graft function can be further improved in all three pancreas transplant categories.
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PMID:Pancreas transplant outcomes for United States (US) cases as reported to the United Network for Organ Sharing (UNOS) and the International Pancreas Transplant Registry (IPTR). 1970 45

The islet in type 2 diabetes (T2DM) and the brain in neurodegenerative diseases share progressive cell dysfunction, increased apoptosis, and accumulation of locally expressed amyloidogenic proteins (islet amyloid polypeptide (IAPP) in T2DM). Excessive activation of the Ca(2+)-sensitive protease calpain-2 has been implicated as a mediator of oligomer-induced cell death and dysfunction in neurodegenerative diseases. To establish if human IAPP toxicity is mediated by a comparable mechanism, we overexpressed human IAPP in rat insulinoma cells and freshly isolated human islets. Pancreas was also obtained at autopsy from humans with T2DM and nondiabetic controls. We report that overexpression of human IAPP leads to the formation of toxic oligomers and increases beta cell apoptosis mediated by increased cytosolic Ca(2+) and hyperactivation of calpain-2. Cleavage of alpha-spectrin, a marker of calpain hyperactivation, is increased in beta cells in T2DM. We conclude that overactivation of Ca(2+)-calpain pathways contributes to beta cell dysfunction and apoptosis in T2DM.
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PMID:Calcium-activated calpain-2 is a mediator of beta cell dysfunction and apoptosis in type 2 diabetes. 1986 18


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