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

The aim of this study was to determine the ouabain receptor density, Na+,K(+)-ATPase function and contractile properties of cardiac muscle in insulin-dependent and non-insulin-dependent rat diabetes mellitus (IDDM and NIDDM, respectively) and the reversibility of the diabetes-induced changes by insulin or thyroxin substitution. IDDM and NIDDM were induced in Wistar rats by streptozotocin injection. Contractile parameters were measured in isolated left ventricular trabeculae. [3H]Ouabain binding to myocardium was measured in right and left ventricular strips obtained from diabetic animals and their age-matched controls. Both the maximum [3H]ouabain binding capacity (Bmax) and the Kd for [3H]ouabain binding, as well as maximum 86Rb+ uptake and rate of contraction, were decreased in IDDM myocardium compared with controls. Insulin or thyroxin substitution reversed the reduction in Bmax and contraction rate, but not the decrease in Kd. In young, but not old, control animals, both Bmax and maximum 86Rb+ uptake were higher in the right ventricular myocardium than in the left one. In contrast to changes observed in IDDM, both Bmax and Kd for [3H]oubain binding were increased in the left but not in the right ventricle of NIDDM animals. NIDDM caused no alterations in contractile properties. Prominent differences were observed in [3H]ouabain binding characteristics and myocardial contractility between young and old control animals. Bmax of [3H]ouabain binding and rate of contraction were inversely proportional in all preparations studied. It is concluded that IDDM and NIDDM induce different alterations in myocardial Na+,K(+)-ATPase, and these changes may influence the contractile properties of cardiac muscle.
 ...
PMID:Altered [3H]ouabain binding to cardiac muscle in insulin-dependent and non-insulin-dependent diabetic rats. 948 20

The primary physiological role of insulin is in glucose homeostasis. This is accomplished through the inhibition of gluconeogenesis in the liver and the stimulation of glucose uptake into insulin-sensitive tissues, such as adipose tissue, skeletal muscle and cardiac muscle. The ability of insulin to stimulate glucose uptake relies on a complex signaling cascade that leads to the translocation of glucose transporter protein 4 (GLUT4) from an intracellular compartment to the plasma membrane, which results in increased glucose uptake. Defects in the ability of insulin to regulate this key metabolic event can lead to insulin resistance and non-insulin-dependent type 2 diabetes mellitus (T2DM). To design effective treatments for diabetes, there have been major efforts to understand the insulin-regulated mechanisms that govern glucose uptake. These have involved defining the components of the insulin signaling network and identifying the molecular machinery that is used to translocate GLUT4.
 ...
PMID:GLUT4 and company: SNAREing roles in insulin-regulated glucose uptake. 1104 65

Insulin-resistant muscle tissue contains low proportions of arachidonic acid (AA), and increased proportions of muscle AA correlate with improved insulin sensitivity. Dehydroepiandrosterone (DHEA) and AA, like the thiazolidinedione drugs that decrease insulin resistance (IR), are peroxisome proliferators. Long-chain fatty acids (FA) have been named the "one true" endogenous ligand for activating the peroxisome proliferator-activator receptor (PPAR), and DHEA has been named a "good candidate" as a naturally occurring indirect activator of PPAR. This study was conducted to determine DHEA's effects on lipid profiles of skeletal and cardiac muscle in lean and obese Zucker rats (ZR), a model of IR, type 2 diabetes mellitus, and obesity. We hypothesize that DHEA may alter long-chain FA profiles in muscle tissue of obese rats such that they more closely resemble that of the lean. In our experiments, we employed a DHEA and a pair-fed (PF) group (n = 6) for 12 lean and 12 obese ZR. For 30 d, the diet of the two DHEA groups was supplemented with 0.6% DHEA; PF groups were given the average daily calories consumed by their corresponding treatment group. Hearts and gastrocnemius muscles were assayed for phospholipid (PL), free FA, and triglyceride (TG) FA profiles. The proportion of PL AA was significantly greater in both muscle types of lean compared to obese rats. Hearts from both DHEA groups had greater PL proportions of AA and less oleic (18:1) acid than their PF controls. Likewise, 18:1 proportions were significantly lower in the gastrocnemius; however, AA proportions were not significantly different. Similar phenotypic profile differences were observed in the TG fraction of both muscle types. There were no DHEA-related TG FA profile alterations.
 ...
PMID:Dehydroepiandrosterone alters phospholipid profiles in Zucker rat muscle tissue. 1183 92

Pharmacological modulation of ATP-sensitive K+ (K(ATP)) channels is used in the treatment of a number of clinical conditions, including type 2 diabetes and angina. The sulphonylureas and related drugs, which are used to treat type 2 diabetes, stimulate insulin secretion by closing K(ATP) channels in pancreatic beta-cells. Agents used to treat angina, by contrast, act by opening K(ATP) channels in vascular smooth and cardiac muscle. Both the therapeutic K(ATP) channel inhibitors and the K(ATP) channel openers target the sulphonylurea receptor (SUR) subunit of the K(ATP) channel, which exists in several isoforms expressed in different tissues (SUR1 in pancreatic beta-cells, SUR2A in cardiac muscle and SUR2B in vascular smooth muscle). The tissue-specific action of drugs that target the K(ATP) channel is attributed to the properties of these different SUR subtypes. In this review, we discuss the molecular basis of tissue-specific drug action, and its implications for clinical practice.
 ...
PMID:Pharmacological modulation of K(ATP) channels. 1202 75

Plasma free fatty acids (FFA) play important physiological roles in skeletal muscle, heart, liver and pancreas. However, chronically elevated plasma FFA appear to have pathophysiological consequences. Elevated FFA concentrations are linked with the onset of peripheral and hepatic insulin resistance and, while the precise action in the liver remains unclear, a model to explain the role of raised FFA in the development of skeletal muscle insulin resistance has recently been put forward. Over 30 years ago, Randle proposed that FFA compete with glucose as the major energy substrate in cardiac muscle, leading to decreased glucose oxidation when FFA are elevated. Recent data indicate that high plasma FFA also have a significant role in contributing to insulin resistance. Elevated FFA and intracellular lipid appear to inhibit insulin signalling, leading to a reduction in insulin-stimulated muscle glucose transport that may be mediated by a decrease in GLUT-4 translocation. The resulting suppression of muscle glucose transport leads to reduced muscle glycogen synthesis and glycolysis. In the liver, elevated FFA may contribute to hyperglycaemia by antagonizing the effects of insulin on endogenous glucose production. FFA also affect insulin secretion, although the nature of this relationship remains a subject for debate. Finally, evidence is discussed that FFA represent a crucial link between insulin resistance and beta-cell dysfunction and, as such, a reduction in elevated plasma FFA should be an important therapeutic target in obesity and type 2 diabetes.
 ...
PMID:Free fatty acids in obesity and type 2 diabetes: defining their role in the development of insulin resistance and beta-cell dysfunction. 1202 71

Clustering of classical cardiovascular risk factors is insufficient to account for the excess coronary artery disease (CAD) of patients with diabetes, and chronic hyperglycemia and insulin resistance (IR) are obvious culprits. Whole-body and skeletal muscle IR is characteristic of patients with type 2 diabetes, but whether it extends to the normally contracting cardiac muscle is controversial. We investigated whether type 2 diabetes is associated with myocardial IR independent of CAD in a case-control series (n = 55) of male nondiabetic and diabetic (type 2 and type 1) patients with or without angiographically documented CAD. Baseline blood flow ((15)O-water) and insulin-stimulated glucose uptake ((18)F-fluoro-deoxyglucose) during euglycemic (5.6 mmol/l), physiological hyperinsulinemia (40 mU x min(-1) x m(-2) insulin clamp) were measured by positron emission tomography in skeletal muscle and normally contracting myocardium. Skeletal muscle glucose uptake was reduced in association with both CAD and type 2 diabetes. In regions with normal baseline perfusion, insulin-mediated myocardial glucose uptake was reduced in non-CAD type 2 diabetic (0.36 +/- 0.14 micro mol x min(-1). g(-1)) and nondiabetic CAD patients (0.44 +/- 0.15 micro mol x min(- 1) x g(-1)) in comparison with healthy control subjects (0.61 +/- 0.08) or with non-CAD type 1 diabetic patients (0.80 +/- 0.13; P < 0.001 for both CAD and diabetes). Neither basal skeletal muscle nor basal myocardial blood flow differed across groups; both skeletal muscle and myocardial IR were directly related to whole-body IR. We conclude that type 2 diabetes is specifically associated with myocardial IR that is independent of and nonadditive with angiographic CAD and proportional to skeletal muscle and whole-body IR.
 ...
PMID:Independent association of type 2 diabetes and coronary artery disease with myocardial insulin resistance. 1235 42

The sulphonylurea receptor (SUR) subunits of K(ATP) channels are the targets for several classes of therapeutic drugs. Sulphonylureas close K(ATP) channels in pancreatic beta-cells and are used to stimulate insulin release in type 2 diabetes, whereas the K(ATP) channel opener nicorandil acts as an antianginal agent by opening K(ATP) channels in cardiac and vascular smooth muscle. The predominant type of SUR varies between tissues: SUR1 in beta-cells, SUR2A in cardiac muscle, and SUR2B in smooth muscle. Sulphonylureas and related drugs exhibit differences in tissue specificity, as the drugs interact to varying degrees with different types of SUR. Gliclazide and tolbutamide are beta-cell selective and reversible. Glimepiride, glibenclamide, and repaglinide, however, inhibit cardiac and smooth muscle K(ATP) channels in addition to those in beta-cells and are only slowly reversible. Similar properties have been observed by recording K(ATP) channel activity in intact cells and in Xenopus oocytes expressing cloned K(ATP) channel subunits. While K(ATP) channels in cardiac and smooth muscle are largely closed under physiological conditions (but open during ischaemia), they are activated by antianginal agents such as nicorandil. Under these conditions, they may be inhibited by sulphonylureas that block SUR2-type K(ATP) channels (e.g., glibenclamide). Care should, therefore, be taken when choosing a sulphonylurea if potential interactions with cardiac and smooth muscle K(ATP) channels are to be avoided.
 ...
PMID:Differential selectivity of insulin secretagogues: mechanisms, clinical implications, and drug interactions. 1262 63

Consumption of large amounts of coffee has been shown to decrease the incidence of type 2 diabetes. However, the specific compounds and mechanisms responsible for this effect are not known. The aim of this study was to determine the effects of a decaffeinated coffee extract and a synthetic quinide, representative of those found in roasted coffee, 3,4-diferuloyl-1,5-quinolactone, on insulin-stimulated glucose disposal and muscle glucose uptake. Experiments were performed on conscious rats during hyperinsulinemic, euglycemic clamps receiving gastric infusions of saline, a decaffeinated coffee extract (DECAF) (220 mg/kg), or 3,4-diferuloyl-1,5-quinide (DIFEQ) (110 mg/kg). Following treatment, rats received an intravenous bolus of deoxy-[2-3H] glucose to assess muscle glucose uptake (Rg, micromol x 100 g(-1) x min(-1)). Glucose infusions [mg/(kg x min)] required to maintain euglycemia during the tracer period were higher with DIFEQ (14.6 +/- 0.7) than with saline (10.8 +/- 0.7) and DECAF (11.5 +/- 1.1). Despite increased glucose requirements, Rg in skeletal (soleus, gastrocnemius, superficial vastus lateralis) and cardiac muscle were unchanged. DECAF or DIFEQ did not affect heart rate, blood pressure, plasma nonesterified fatty acids or liver aminotransferase activity. These results demonstrate that DIFEQ increases whole-body glucose disposal independently of skeletal muscle Rg.
 ...
PMID:Quinides of roasted coffee enhance insulin action in conscious rats. 1460 69

Hyperlipidemia (HL) impairs cardiac glucose homeostasis, but the molecular mechanisms involved are yet unclear. We examined HL-regulated GLUT4 and peroxisome proliferator-activated receptor (PPAR) gamma gene expression in human cardiac muscle. Compared with control patients, GLUT4 protein levels were 30% lower in human cardiac muscle biopsies from patients with HL and/or type 2 diabetes mellitus, whereas GLUT4 mRNA levels were unchanged. PPARgamma mRNA levels were 30-50% lower in patients with HL and/or diabetes mellitus type 2 than in controls. Reporter studies in H9C2 cardiomyotubes showed that HL in vitro, induced by high levels of arachidonic (AA) stearic, linoleic, and oleic acids (24 h, 200 mum) repressed transcription from the GLUT4 promoter; AA also repressed transcription from the PPARgamma1 and PPARgamma2 promoters. Co-expression of PPARgamma2 repressed GLUT4 promoter activity, and the addition of AA further enhanced this effect. 5'-Deletion analysis revealed three GLUT4 promoter regions that accounted for AA-mediated effects: two repression-mediating sequences at -443/-423 bp and -222/-197 bp, the deletion of either or both of which led to a partial derepression of promoter activity, and a third derepression-mediating sequence at -612/-587 bp that was required for sustaining this derepression effect. Electromobility shift assay further shows that AA enhanced binding to two of the three regions of cardiac nuclear protein(s), the nature of which is still unknown. We propose that HL, exhibited as a high free fatty acid level, modulates GLUT4 gene expression in cardiac muscle via a complex mechanism that includes: (a) binding of AA mediator proteins to three newly identified response elements on the GLUT4 promoter gene and (b) repression of GLUT4 and the PPARgamma genes by AA.
 ...
PMID:Free fatty acids repress the GLUT4 gene expression in cardiac muscle via novel response elements. 1609 83

The Zucker diabetic fatty (ZDF) rat is a commonly used animal model of type 2 diabetes yet complete descriptions of insulin resistance in this model are limited. We present a full characterisation of in vivo insulin resistance in obese (fa/fa) animals compared to lean (+/?) littermates. Anaesthetised, ten-week old, obese ZDF rats and their lean littermates underwent a hyperinsulinaemic euglycaemic glucose clamp. Compared with lean littermates, obese ZDF rats required an 89% lower glucose infusion rate to maintain euglycaemia and showed a 35% decrease in peripheral glucose disposal. Insulin-stimulated glucose uptake (R(g')) in obese animals was also significantly less in all skeletal muscles studied. R(g') in cardiac and white adipose tissue was not different between the two groups. Total glycogen content in skeletal and cardiac muscle was significantly less in obese animals, while total glycogen content in the liver was significantly greater than in lean littermates. Glycogen synthesis was also decreased in skeletal muscle of obese animals. Compared with lean animals, total triglyceride content was significantly greater in skeletal muscle, heart and liver of obese ZDF rats. Obese animals also showed significantly increased glucose incorporation into lipid in all of these tissues, indicating an increase in lipogenesis. Collectively, these results provide an integrated characterisation of in vivo insulin resistance in obese ZDF rats and a direct comparison with lean littermates.
 ...
PMID:Insulin resistance in the Zucker diabetic fatty rat: a metabolic characterisation of obese and lean phenotypes. 1638 3


1 2 3 4 Next >>