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)

Cholecystokinin (CCK) act as hormones and neuropeptides on central and peripheral CCK receptors. The application of modern molecular biological techniques has identified two CCK receptors, CCK-A receptor (CCKAR) and CCK-B/gastrin receptor (CCKBR). The genes of CCKAR and CCKBR consist of five exons interrupted by four introns. We have reported that OLETF rats, which have been established as an animal model of NIDDM, revealed no expression of CCKAR gene (a naturally occurring CCKAR gene knockout rat). Pancreatic exocrine functions in OLETF rats are regulated by all neural and peptidergic agents except CCK. Therefore, we have proposed that OLETF rats may be a useful experimental model for examining the biological functions of the CCKAR.
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PMID:[Cholecystokinin and cholecystokinin receptor]. 892 Jun 81

The hemodynamic changes occurring early in the course of non-insulin-dependent diabetes mellitus (Type II, NIDDM) are not well understood. We applied the radioactive microspheres technique at an early stage of diabetes in Psammomys abesus (sand rat), an established animal model of spontaneous NIDDM. Ten diabetic and 7 control male animals were studied. Plasma glucose and insulin levels in the diabetic group were significantly higher than in the control group (21.3 +/- 2.1 vs. 6.2 +/- 1.1 mmol/l, and 2,650 +/- 480 vs. 770 +/- 120 pmol/l, respectively). Mean arterial blood pressure, heart rate, cardiac output, splanchnic blood flow, muscular blood flow, and total peripheral resistance were not statistically different between the two groups. Renal blood flow was significantly lower in the diabetic group (7.45 +/- 0.32 vs. 10.48 +/- 0.99 ml/min) and renal arterial resistance was higher (11.65 +/- 0.93 vs. 8.33 +/- 0.76 mm Hg.min/ml) compared with the control group. These results suggest that increased renal resistance and decreased renal blood flow may be the initial hemodynamic alterations in NIDDM. The combination of this animal model with the radioactive microspheres technique provides a new tool for studying the physiopathology, the natural history of hemodynamic changes, and possible therapeutic interventions of Type II diabetes.
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PMID:Hemodynamic characterization of the diabetic Psammomys obesus--an animal model of type II diabetes mellitus. 896 75

Recently it has been postulated that membrane fatty acid composition may be involved in the pathogenesis of insulin resistance and non-insulin dependent diabetes mellitus (NIDDM). The aim of this study was to determine whether alterations in tissue phospholipid (PL) fatty acids are present in hyperglycemic and hyperinsulinemic Psammomys obesus. On a native diet of salt bush, P. obesus (Israeli sand rat) remains lean and free of diabetes; however, when placed on a normal laboratory chow, a significant proportion of these animals develops a number of metabolic disorders associated with NIDDM, providing an ideal animal model of obesity and NIDDM. Four groups of mature P. obesus were studied: group A: normoglycemic and normoinsulinemic; group B: normoglycemic and hyperinsulinemic; group C: hyperglycemic and hyperinsulinemic; and group D: hyperglycemic and hypoinsulinemic. In liver and red gastrocnemius muscle, there were no significant differences between groups A, B, and C in fatty acid composition of PL. Minor differences in individual fatty acids were demonstrated in group D animals (increased liver 20:4n-6 and increased muscle 22:5n-3); however, the unsaturation indices in liver and muscle were not significantly different between any of the groups. In considering that the minor changes in group D animals were not demonstrated in hyperinsulinemic group B animals or hyperglycemic, hyperinsulinemic group C animals, it is likely that the differences in group D animals were secondary to the more severe disturbances in glucose homeostasis and hypoinsulinemia present in these animals. The results of this study suggest that in this rodent diabetic model significant disturbances in glucose homeostasis and hyperinsulinemia may develop independently of changes in tissue fatty acid composition.
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PMID:Non-insulin dependent diabetes mellitus in Psammomys obesus is independent of changes in tissue fatty acid composition. 907 69

Animal species with genetic or nutritionally induced insulin resistance, diabetes and obesity (diabesity) may be divided into two broad groups: those with resilient pancreatic beta-cells, e.g. ob/ob mice and fa/fa rats, capable of long-lasting compensatory insulin over-secretion, and those with labile beta-cells in which the secretion pressure leads to irreversible beta-cell degranulation, e.g. db/db mice, Macaca mulatta primates, ZDF diabetic rats. Prominent in this group is the Israeli desert gerbil Psammomys obesus (sand rat), which features low insulin receptor density in liver and muscle. On a diet of relatively high energy, the capacity of insulin to activate the receptor tyrosine kinase (TK) is reduced, in the face of hyperinsulinemia. With the following hyperglycemia, the rising insulin resistance imposes a vicious cycle of insulinemia and glycemia, accentuating the TK activation failure and the beta-cell failure. Among various factors affecting the insulin signaling pathway, multisite phosphorylation, including serine and threonine on the receptor beta-subunit, due to overexpression of certain protein kinase C isoforms, seems to be responsible for the inhibition of the critical step of TK phosphorylation activity. The compromised TK activation is reversible by diet restriction which restores to normal the glycemia and insulinemia. The beta-cell response to long-lasting stimulation and the receptor malfunction in diabesity have implications for a similar etiology in human insulin resistance syndrome and type 2 diabetes, particularly in populations emerging from a food scarce environment into nutritional affluence, inappropriate to the human metabolic capacity. It is suggested that the "thrifty gene" is characterized by a low threshold for insulin secretion and low capacity for insulin clearance. Thus, nutritionally-induced hyperinsulinemia is potentiated and becomes the primary phenotypic expression of the thrifty gene, linked to the insulin receptor signaling pathway malfunction.
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PMID:Cellular mechanism of nutritionally induced insulin resistance: the desert rodent Psammomys obesus and other animals in which insulin resistance leads to detrimental outcome. 1021 43

Type 2 diabetes mellitus features an asymptomatic insulin resistance phase preceding the onset of diabetes. Hyperglycemia occurs when a relative insulin deficiency appears, meaning that beta cell secretory dysfunction is a key element in type 2 diabetes pathophysiology. So far, insulin secretion deficiency is explained by pancreatic beta cell "exhaustion" phenomena. Recent data suggest that apoptotic mechanisms could explain insulin deficiency through a reduction in the absolute pancreatic beta cell number. Psammomys obesus (sand rat) is an animal model for type 2 diabetes mellitus, initially characterized by hyperinsulinism followed by insulin deficiency linked with a reduction in the number of pancreatic beta cells. Transition to diabetes can be observed following changes in usual lifestyle of the sand rat. In the desert, caloric intake is low and physical expenditure is heavy. In the laboratory, animals turn diabetic as early as 4 days following a high calorie diet. At a later stage, diabetes is irreversible and animals die from diabetic ketoacidosis. beta cell apoptosis rate is low in non diabetic animals and increases 14-fold by 20 days after diabetes onset. At this stage, cells undergoing apoptosis can be observed, coexisting with necrotic cells without any insulitis. Similar results were obtained in vitro in isolated pancreatic islets that were exposed to increasing glucose concentrations, suggesting that chronic hyperglycemia plays a role in the onset or the deterioration of the process. However, precise mechanisms of apoptosis in this case remain poorly understood. Aminoguanidin does not prevent beta cell apoptosis in vitro, suggesting that advanced glycation products or NO production are not involved in this beta cell destruction process. Similar mechanisms secondary to hyperglycemia could play a role in the diabetes process in man and explain the marked insulin secretory deficiency that is sometimes observed in these patients. In addition to its preventing role on diabetes complication, the obtention of normoglycemia could help maintaining beta cell function.
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PMID:[Type 2 diabetes and beta cell apoptosis]. 1094 45

To investigate the long-term effects of normal pancreatic islet transplantation on progression of obese type 2 diabetes mellitus (DM), 1500 normal islets (per rat) from Wistar King A rats at 8 weeks of age were transplanted into the liver through the portal vein of Otsuka Long Evans Tokushima Fatty (OLETF) rats, an animal model of obese type 2 DM, at 12 weeks of age. Body weight in the transplanted OLETF (IT) rats 8 and 28 weeks after islet transplantation did not differ from that in the corresponding sham-operated (SO) rats, but was greater than that in lean littermates (LETO rats; P < 0.05 for each group). In the early phase, 8 weeks after transplantation, rats in both IT and SO groups were normoglycemic, but hyperinsulinemic (P < 0.05 for each compared with LETO rats), probably resulting from increased body weight. In the late phase, 28 weeks after transplantation, hyperglycemia in the IT group was greatly attenuated compared with the SO group (P < 0.05), but hyperinsulinemia remained in both the IT and the SO groups compared with that in the LETO group (P < 0.05 for each). Immunohistochemical studies demonstrated that hypertrophic and fibrotic changes in pancreatic islets, together with mesangial proliferation of the glomerular matrix, an indicator for diabetic nephropathy, were attenuated predominantly in the IT group at the late phase after transplantation compared with those in the corresponding phase of the SO group. Islet transplantation into the liver of OLETF rats thus prevented further progression of obese type 2 DM. A possible mechanism is that islet transplantation may prevent development of hyperglycemia by improving abnormal hepatic glucose metabolism and consequently insulin resistance, which may lead to blockade of a vicious cycle between advancing damage to pancreatic islet cells and increased demand for insulin secretion, thus sparing original pancreatic cells from exhaustion induced by increased demand for insulin secretion.
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PMID:Transplantation of normal islets into the portal vein of Otsuka Long Evans Tokushima Fatty rats prevents diabetic progression. 1144 4

Psammomys obesus (sand rat) is an appropriate model to highlight the development of hyperinsulinemia, insulin resistance, obesity, and diabetes. This animal species, with genetically predetermined diabetes, acquires non-insulin dependent diabetes mellitus when exposed to energy-rich diets. In the present study, we explored the possibility that glycation of LDL may occur in diabetes-prone P. obesus and affect platelet and macrophage functions. The glycation of LDL, isolated from diabetic animals, was significantly (P < 0.05) higher (40%) than that of control animals. The incubation of platelets with glycated LDL enhanced the reactivity of platelets by 32-44% depending on the aggregating agents (thrombin, collagen, ADP). Furthermore, LDL derived from diabetic rats were chemotactic for normal monocytes and stimulated the incorporation of [14C]oleate into cellular cholesteryl esters. The enhancement of platelet aggregation and cholesterol esterification in monocytes may contribute toward the accelerated development of atherosclerotic cardiovascular disease in diabetic P. obesus animals. This study also illustrates the relevance of studying atherosclerosis in the P. obesus animal model, as it shows an increased tendency to develop diet-induced diabetes, which is associated with cardiovascular disorders.
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PMID:Impact of in vivo glycation of LDL on platelet aggregation and monocyte chemotaxis in diabetic psammomys obesus. 1505 39

The islet in type 2 diabetes is characterized by a deficit in beta-cell mass, increased beta-cell apoptosis, and impaired insulin secretion. Also, islets in type 2 diabetes often contain deposits of islet amyloid derived from islet amyloid polypeptide (IAPP), a 37-amino acid protein cosecreted with insulin by beta-cells. Several lines of evidence suggest that proteins with a capacity to develop amyloid fibrils may also form small toxic oligomers that can initiate apoptosis. The amino acid sequence of IAPP in rats and mice is identical and differs from that in humans by substitution of proline residues in the amyloidogenic sequence so that the protein no longer forms amyloid fibrils or is cytotoxic. In the present study, we report a novel rat model for type 2 diabetes: rats transgenic for human IAPP (the HIP rat). HIP rats develop diabetes between 5 and 10 months of age, characterized by an approximately 60% deficit in beta-cell mass that is due to an increased frequency of beta-cell apoptosis. HIP rats develop islet amyloid, but the extent of amyloid was not related to the frequency of beta-cell apoptosis (r = 0.10, P = 0.65), whereas the fasting blood glucose was (r = 0.77, P < 0.001). The frequency of beta-cell apoptosis was related to the frequency of beta-cell replication (r = 0.97, P < 0.001) in support of the hypothesis that replicating cells are more vulnerable to apoptosis than nondividing cells. The HIP rat provides additional evidence in support of the potential role of IAPP oligomer formation toward the increased frequency of apoptosis in type 2 diabetes, a process that appears to be compounded by glucose toxicity when hyperglycemia supervenes.
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PMID:Diabetes due to a progressive defect in beta-cell mass in rats transgenic for human islet amyloid polypeptide (HIP Rat): a new model for type 2 diabetes. 1516 55

Herein we describe a series of potent and selective PPARgamma agonists with moderate PPARalpha affinity and little to no affinity for other nuclear receptors. In vivo studies in a NIDDM animal model (ZDF rat) showed that these compounds are efficacious at low doses in glucose normalization and plasma triglyceride reduction. Compound 1b (LY519818) was selected from our SAR studies to be advanced to clinical evaluation for the treatment of type II diabetes.
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PMID:2-Alkoxydihydrocinnamates as PPAR agonists. Activity modulation by the incorporation of phenoxy substituents. 1558 9

Many 3-aryl-4-(1,2,3,4-tetrahydro[1,4]diazepino[6,7,1-hi]indol-7-yl)maleimides exhibit potent GSK3 inhibitory activity (<100 nM IC(50)), although few show significant selectivity (>100x) versus CDK2, CDK4, or PKCbetaII. However, combining 3-(imidazo[1,2-a]pyridin-3-yl), 3-(pyrazolo[1,5-a]pyridin-3-yl) or aza-analogs with a 4-(2-acyl-(1,2,3,4-tetrahydro[1,4]diazepino[6,7,1-hi]indol-7-yl)) group on the maleimide resulted in very potent inhibitors of GSK3 (</=5 nM) with >160 to >10,000-fold selectivity versus CDK2/4 and PKCbetaII. These compounds also inhibited tau phosphorylation in cells and were effective in lowering plasma glucose in a rat model of type 2 diabetes (ZDF rat).
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PMID:The development of potent and selective bisarylmaleimide GSK3 inhibitors. 1568 83


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