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)

Non-insulin-dependent diabetic (NIDDM) patients show a high incidence of cardiovascular disease, with greater risk of recurrent myocardial infarction and a less favourable clinical outcome than non-diabetic patients. The majority of NIDDM patients are treated with sulphonylurea (SU) derivatives. In the 1970's the University Group Diabetes Program concluded that tolbutamide treatment caused increased cardiovascular mortality; the study, which led to curtailment of oral antidiabetic treatment in the USA, was received with scepticism in Europe. Later criticism of its methodology reduced the impact of the study; however, the question of the safety of SU in NIDDM patients with cardiovascular disease has been re-opened in the face of new experimental data. The heart and vascular tissues do have prerequisites for SU action, i.e. SU receptors and ATP-dependent K+ (K+ATP) channels. These channels play an important role in the protection of the myocardium against ischaemia-reperfusion damage, and their closure by SU could lead to amplified ischaemic damage. Here we review evidence from animal and human studies for deleterious SU effects on ischaemia-induced myocardial damage, either by direct action or through diminished cardioprotective preconditioning. Closure of K+ATP channels by SU can lead to reduction of post-infarct arrhythmias; the drug has also been claimed to improve various atherosclerosis risk factors. The evidence for these beneficial effects of SU is also reviewed. We look at the major difficulties that hamper transfer of information from experimental studies to clinical decision-making: a) The affinity of SU for heart K+ATP channels is orders of magnitude lower than for beta-cell channels; is it reasonable to expect in vivo cardiac effects with therapeutic 'pancreatic' SU doses? b) Most studies utilized high doses of acutely administered SU; are effects similar in the chronic steady-state of the SU-treated diabetic patient? c) Convincing SU effects have been demonstrated in acutely induced ischaemia by acutely administering the drug; do such effects persist in the clinical situation of gradually progressive ischaemia? d) Ischaemia and modification of K+ATP channel activity induce complex events, some with opposing effects; what is the net result of SU action, and do different SU derivatives lead to different outcomes? e) In the chronic (and hence clinically relevant) situation, how can direct (deleterious or beneficial) SU effects be separated from beneficial effects mediated by the metabolic action of the drug? Only large prospective clinical studies, making use of advanced technology for assessment of cardiovascular function, can answer these questions. Millions of NIDDM patients are treated with SU derivatives; many are in the age group where cardiovascular risks are extremely high. The question of whether SU derivatives are beneficial or deleterious for these patients must finally be settle unequivocally.
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PMID:Sulphonylurea treatment of NIDDM patients with cardiovascular disease: a mixed blessing? 873 9

Two novel oral hypoglycaemic agents, NN623 and A4166, have been developed and are now in phase II clinical trial. Both agents have several common characteristics from sulphonylureas. NN623 is a stereoisomer of derivatives of benzoic acid and A4166 is also a stereoisomer of phenylalanine derivative. The predominant mechanism of the action is thought to be like sulphonylureas. Both NN623 and A4166 occupy, at least partly, a common receptor site with glibenclamide and close the ATP-dependent K+ channel. They are rapidly absorbed from the intestine and are eliminated mainly into the bile. NN623 is about 10 times more potent in hypoglycaemic action than glibenclamide and 100 times more than A4166 in terms of dosage. When 1.0 mg NN623 or 60 mg A4166 was given orally in the post-absorptive state to healthy volunteers, both agents evoked hypoglycaemia by 40 min. The duration of hypoglycaemia after NN623 was longer than after A4166 by about 1 hour. The effect of food on their bioavailability is similar. Food has marked influence on the absorption of both drugs and on their efficacy. When 1 mg of NN623 or 60 mg of A4166 was administered just before the meal, Tmax of NN623 and A4166 was 34 +/- 18 min and 18 +/- 6 min, while T1/2 was 0.64 +/- 0.12 h and 0.98 +/- 0.06 h, respectively. The postprandial rise in plasma glucose was reduced at 45 min and thereafter over 4-h after 1.0 mg NN623 and at 30 min to 90 min after 60 mg A4166. Plasma insulin levels rose more than those after placebo from 30 to 90 min after NN623 and at 20 to 40 min after A4166. Both agents stimulated insulin release much more in the postprandial than in the fasting state. There was no difference in the bioavailability after 5 or 7 days of administration. However, when administered immediately after the meal, the absorption of both drugs was delayed and the rise in plasma absorption was not suppressed until 60 min after the meal. Both fasting and postprandial hyperglycaemia were reduced after 1 to 4 weeks of premeal treatment with 0.5 mg NN623 or 60 mg A4166 in subjects with NIDDM. Plasma glucose levels were decreased over 4 h after NN623 and over 1 h after A4166. The meal-induced insulin response was almost doubled by NN623 over 2 h and 1 h by A4166. There was no difference in the bioavailability after breakfast between the first and last administrations of both drugs. In conclusion, a rapid rise in plasma insulin levels is associated with the suppression of postprandial hyperglycaemia.
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PMID:Modulation of insulin secretion in non-insulin-dependent diabetes mellitus by two novel oral hypoglycaemic agents, NN623 and A4166. 889

The abnormalities of the membrane carrier proteins, mainly of glucose transporters were screened in NIDDM patients. Several polymorphisms that result in amino acid substitutions have been identified in GLUT2 and GLUT4 genes. However no significant associations have been found between NIDDM and these polymorphisms. Although the screening of ATP-sensitive potassium channel gene that has recently been isolated in pancreatic beta cells is now in progress, so far no abnormalities of the membrane carrier proteins have been reported to contribute in the causes of NIDDM.
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PMID:[Membrane carrier proteins and NIDDM]. 890 34

Sulfonylureas are widely used to treat non-insulin dependent diabetes mellitus. These drugs exert their hypoglycaemic effects by stimulating insulin secretion from the pancreatic beta-cell. Their primary mechanism of action is to close ATP-sensitive K-channels in the beta-cell plasma membrane, and so initiate a chain of events which results in insulin release. Recent studies have shown that the beta-cell ATP-sensitive K-channel is a complex of two proteins: a pore-forming subunit (Kir6.2) and a drug-binding subunit (SUR1) which functions as the receptor for sulfonylureas. This review summarizes recent advances in our understanding of the molecular mechanism of sulfonylurea action, focusing on the relationship between the sulfonylurea receptor and the K-ATP channel. Earlier studies are also re-examined in the light of new findings.
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PMID:Mechanisms of the glycaemic effects of sulfonylureas. 891 83

PACAP and GLP-1 depolarize pancreatic beta cells and stimulate insulin secretion in the presence of glucose. Depolarization occurs through at least two distinct mechanisms: (1) closure of ATP-sensitive K+ channels, and (2) activation of nonselective cation channels (NSCCs). Under physiological conditions the NSCCs carry a predominantly Na(+)-dependent current. The current may also have a Ca2+ component, but this remains to be determined. Acting together, these two signaling systems reinforce each other and serve to promote membrane depolarization, a rise of [Ca2+]i, and exocytosis of insulin-containing secretory granules. The NSCCs in beta cells are dually regulated by intracellular cAMP and [Ca2+]i. In view of this dual regulation, it appears likely that NSCC channel activation results from signaling events occurring not only at the plasma membrane (gating of channels by cAMP; protein kinase A-mediated phosphorylation of channels) but also at intracellular sites (mobilization of calcium stores by an as yet to be determined process). It is noteworthy that activation of NSCCs has also been reported following stimulation of beta-cells with maitotoxin, or after depletion of intracellular Ca2+ stores. Therefore, the possibility arises that PACAP, GLP-1, and maitotoxin all act on the same types of ion channels in these cells, and that these channels are sensitive to alterations in the content of intracellular calcium. FIGURE 6 summarizes our current knowledge concerning the properties of the PACAP and GLP-1 signaling systems as they pertain to the regulation of NSCCs and intracellular calcium homeostasis in the beta cell. Given that PACAP and GLP-1 are proven to be exceptionally potent insulin secretagogues, it is of considerable interest to determine their usefulness as blood glucose-lowering agents. Initial evaluations of the therapeutic effectiveness of GLP-1 indicate a role for this peptide in the treatment of NIDDM, and also possibly insulin-dependent diabetes mellitus (IDDM). A very attractive feature of such a strategy is the demonstrated lack of hypoglycemic side effects attendant to administration of GLP-1 to diabetic subjects. These observations reinforce the notion that peptides of the PACAP/glucagon/VIP family represent important pharmacological tools for use in experimental therapeutics.
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PMID:Signal transduction of PACAP and GLP-1 in pancreatic beta cells. 899 95

Signals derived from the metabolism of glucose in pancreatic beta-cells lead to insulin secretion via the closure of ATP-sensitive K+ channels (KATP). The cloning of the gene encoding the beta-cell inward rectifier Kir6.2 (Bir), a subunit of the beta-cell KATP channel, provided the opportunity to look for mutations in this gene that might contribute to the impaired insulin secretion of NIDDM. By single-strand conformational polymorphism (SSCP) analysis on 35 Northern-European Caucasian patients with NIDDM, six sequence variants were detected: Glu10gag-->Lys10aag (E1OK), Glu23gag-->Lys23aag (E23K), Leu270ctg-->Val270gtg (L270V), Ile337atc-->Val337gtc (I337V), and two silent mutations. Allelic frequencies for the missense variants were compared between the NIDDM group (n = 306) and nondiabetic control subjects (n = 175) and did not differ between the two groups. Pairwise allelic associations indicated significant linkage disequilibrium between the variants in Kir6.2 and between them and a nearby pancreatic beta-cell sulfonylurea receptor (SUR1) missense variant (S1370A), but these linkage disequilibria did not differ between the NIDDM and control groups. The results of these studies thus revealed that mutations in the coding region of Kir6.2 1) were not responsible for the previously noted association of the SUR1 variants with NIDDM (Inoue H et al., Diabetes 45:825-831, 1996) and 2) did not contribute to the impaired insulin secretion characteristic of NIDDM in Caucasian patients.
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PMID:Sequence variants in the pancreatic islet beta-cell inwardly rectifying K+ channel Kir6.2 (Bir) gene: identification and lack of role in Caucasian patients with NIDDM. 903 9

Kir6.2 is an inwardly rectifying potassium channel that is expressed in pancreatic beta-cells and cardiac and skeletal muscle. Expressed together with the high-affinity sulphonylurea receptor, it reconstitutes a sulphonylurea- and also ATP-sensitive potassium channel resembling the native beta-cell channel. The objective of this study was to search for mutations in the Kir6.2 gene that might be associated with NIDDM or related to altered insulin secretion, insulin action, or glucose metabolism in healthy subjects. Using polymerase chain reaction-single-strand conformation polymorphism analysis (PCR-SSCP) on genomic DNA from 69 Danish NIDDM patients and 66 matched control subjects, we report the finding of three missense polymorphisms in otherwise conserved codons and three silent polymorphisms in the gene encoding Kir6.2: codon 23 (GAG/AAG), Glu-->Lys; codon 190 (GCT/GCC), Ala-->Ala; codon 267 (CTC/CTG), Leu-->Leu; codon 270 (CTG/GTG), Leu-->Val; codon 337 (ATC/GTC), Ile-->Val; codon 381 (AAG/AAA), Lys-->Lys. The codon 23 and codon 337 amino acid polymorphisms were always coupled. The allelic frequencies of the polymorphisms were similar in NIDDM patients and control subjects. The amino acid polymorphisms were not associated with altered insulin secretion after intravenous glucose or tolbutamide injections or with altered glucose effectiveness in a phenotype study of 346 young healthy subjects. However, carriers of the maximal load of amino acid variants, the compound homozygous codon 23/337 and heterozygous codon 270, had on average a 62% higher insulin sensitivity index (P = 0.006), compared with noncarriers. We conclude that a combination of common Kir6.2 amino acid variants may contribute to the genetic background behind the large variation of the insulin sensitivity index in the general population.
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PMID:Amino acid polymorphisms in the ATP-regulatable inward rectifier Kir6.2 and their relationships to glucose- and tolbutamide-induced insulin secretion, the insulin sensitivity index, and NIDDM. 903 10

Na+/K(+)- and Ca(2+)-ATPase are the major ATP-dependent membrane-bound enzymes that regulate the cation transmembrane gradient which is altered both in red blood cell (RBC) senescence and in RBCs of diabetic patients. In an attempt to clarify the possible connection between diabetes mellitus and ageing, we investigated the relationship between RBC ATP content, Na+/K(+)-ATPase, Ca(2+)-ATPase activities and ageing in healthy, insulin-dependent (IDDM) and non-insulin-dependent (NIDDM) subjects. A significant correlation was found (r = -0.82; P < 0.001) between RBC ATP content and subject's age only in the control group. A significant reduction in Na+/K(+)-ATPase activity was observed in the older group (C2) of control subjects, in comparison with the younger (C1) one. In both IDDM and NIDDM subjects, the enzymatic activity was significantly decreased when compared with health subjects of similar age (P < 0.001). A significant negative correlation was found between age and enzymatic activity in healthy subjects (r = -0.60; P < 0.001). No difference was observed in the RBC membrane Ca(2+)-ATPase activity between younger (C1) and older (C2) healthy subjects. Ca(2+)-ATPase activity was significantly increased both in IDDM patients compared with C1 (P < 0.001) and in NIDDM patients compared with C2 (P < 0.001). The present data indicate that ageing causes a reduction in the erythrocyte ATP content in both healthy and diabetic subjects. In diabetic patients Na+/K(+)-ATPase activity decreases independently of age.
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PMID:Diabetes mellitus and subjects' ageing: a study on the ATP content and ATP-related enzyme activities in human erythrocytes. 913 82

In the genetic mutant mouse models ob/ob or db/db, leptin deficiency or resistance, respectively, results in severe obesity and the development of a syndrome resembling NIDDM. One of the earliest manifestations in these mutant mice is hyperinsulinemia, suggesting that leptin may normally directly suppress the secretion of insulin. Here, we show that pancreatic islets express a long (signal-transducing) form of leptin-receptor mRNA and that beta-cells bind a fluorescent derivative of leptin (Cy3-leptin). The expression of leptin receptors on insulin-secreting beta-cells was also visualized utilizing antisera generated against an extracellular epitope of the receptor. A functional role for the beta-cell leptin receptor is indicated by our observation that leptin (100 ng/ml) suppressed the secretion of insulin from islets isolated from ob/ob mice. Furthermore, leptin produced a marked lowering of [Ca2+]i in ob/ob beta-cells, which was accompanied by cellular hyperpolarization and increased membrane conductance. Cell-attached patch measurements of ob/ob beta-cells demonstrated that leptin activated ATP-sensitive potassium channels (K(ATP)) by increasing the open channel probability, while exerting no effect on mean open time. These effects were reversed by the sulfonylurea tolbutamide, a specific inhibitor of K(ATP). Taken together, these observations indicate an important physiological role for leptin as an inhibitor of insulin secretion and lead us to propose that the failure of leptin to inhibit insulin secretion from the beta-cells of ob/ob and db/db mice may explain, in part, the development of hyperinsulinemia, insulin resistance, and the progression to NIDDM.
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PMID:Leptin suppression of insulin secretion by the activation of ATP-sensitive K+ channels in pancreatic beta-cells. 916 85

Recent progress in experimental diabetes research is reviewed in this article. The application of the patch-clamp technique to the insulin-secreting pancreatic beta-cell has revolutionised our understanding of how an increase in the blood glucose concentration is linked to stimulation of insulin secretion. A major advance was the identification of an ATP-regulated K-channel (KATP-channel) as the glucose-sensitive membrane conductance of the beta-cell. Closure of these channels underlies the glucose-induced depolarisation of the beta-cell, which then triggers the opening of voltage-gated Ca(2+)-channels and the onset of Ca(2+)-dependent exocytosis. With the patch-clamp technique, it was also possible to demonstrate that the KATP-channel represents the molecular target of the hypoglycaemic sulphonylureas, compounds which are used clinically in the treatment of type 2 diabetes.
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PMID:[Electrophysiological studies of insulin secretion, physiology and pathophysiology]. 927 7


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