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)

The pharmacokinetics of the sulfonylurea, glimepiride, in risk groups of NIDDM patients are reviewed with regard to pharmacokinetic-effect relationships. A variety of factors, such as regulatory processes, glucose absorption, insulin sensitivity, might prevent the definition of a clear concentration-effect relationship for sulfonylureas. However, when these processes are minimized, as with the glucose clamp technique, such relationships can be defined. This is true for glibenclamide or glimepiride, for which saturation of effect is apparent in the upper therapeutic dose range in healthy subjects. However, pharmacokinetic-pharmacodynamic relationships are less readily defined during long-term treatment of NIDDM patients. In kidney or liver disease, the hypoglycemic effect of sulfonylureas can be increased and prolonged, mainly due to a decrease in insulin metabolism or of hepatic glucose output; the risk of hypoglycemia is increased. The pharmacokinetics of most sulfonylureas have not been well characterised in patients with kidney or liver disease. Generally, sulfonylureas are eliminated by renal excretion of metabolites, some of which have similar pharmacological activity to the parent drug e.g. glibenclamide, chlorpropamide, tolbutamide. In renal disease, elimination of these metabolites can be impaired. In 31 NIDDM patients with kidney disease, elimination of unchanged glimepiride was greater in patients with more severe renal disease, probably due to a decrease in the plasma protein-bound fraction. Elimination of the renally excreted metabolites was also impaired in the same group of patients. 12 of 16 NIDDM patients with kidney disease who continued glimepiride treatment for three months maintained fasting blood glucose levels of less than 9.99 mmol/l at a daily dose of 1-6 mg, the typical dose range for patients with normal renal function. Pharmacokinetic data on sulfonylureas are generally inconsistent in cirrhotic patients. In 11 patients with liver disease, the pharmacokinetics of glimepiride were similar to those of healthy volunteers. In conclusion, pharmacokinetics, pharmacodynamics and their relationships can be defined for glimepiride under controlled conditions. Such information is lacking for many commonly used sulfonylureas in risk group NIDDM patients. Studies described here show that the pharmacokinetics of glimepiride are altered in renal disease but may not be seriously affected in patients with liver disease.
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PMID:Pharmacokinetic basis for the safety of glimepiride in risk groups of NIDDM patients. 891 79

Sulfonylurea (SU) derivatives exert their hypoglycemic effect by blockade of adenosine-5'-triphosphate-sensitive potassium (KATP) channels in the beta-cell of the pancreas. Interestingly, KATP channels also occur in the cardiovascular system, where they are thought to play an important role in cardioprotective mechanisms against ischemia. We have recently shown that the classical second generation SU-derivative glibenclamide is able to block vascular KATP channels in man, whereas the newly developed second generation derivative glimepiride was devoid of this property. The aim of this study was to determine whether the first generation SU derivative tolbutamide has KATP channel blocking properties in humans. In a group of 12 healthy male non-smoking volunteers, we investigated whether therapeutic concentrations of tolbutamide were able to inhibit the forearm vasodilation in response to the infusion of the KATP channel opening drug diazoxide into the brachial artery. Changes in forearm blood flow were recorded by venous occlusion mercury-in-silastic strain-gauge plethysmography. Diazoxide alone increased the forearm blood flow ratio dose-dependently by ultimately 691 +/- 198%. A second diazoxide infusion in the presence of tolbutamide revealed a comparable vasodilator response with a percentage increase in forearm blood flow ratio of ultimately 542 +/- 111%. This response did not differ from the vasodilator response to diazoxide alone. The present study shows that therapeutic concentrations of tolbutamide are not able to attenuate the vasodilation caused by the KATP channel opener diazoxide in man. When compared with published data on second generation SU derivatives, tolbutamide shows an intermediate position between glibenclamide (with significant blockade of vascular KATP channels) versus glimepiride (with no blockade at all). It remains to be determined whether these acute effects of SU derivatives on pharmacological opening of forearm vascular KATP channels can be extrapolated to the chronic effects of these drugs on ischemia-mediated opening of myocardial KATP channels during treatment of NIDDM patients.
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PMID:Effects of tolbutamide on vascular ATP-sensitive potassium channels in humans. Comparison with literature data on glibenclamide and glimepiride. 891 89

Phosphatidylinositol 3-kinase (PI3-K) may regulate the basal plasma membrane glucose transporter recycling and the organization of the transporter intracellular pool in addition to being an insulin signal for translocation of glucose transporters to the plasma membrane. The objectives of the present study were to examine for genetic variability in the human regulatory p85alpha subunit of PI3-K, to look for an association between gene variants and NIDDM in a case-control study, and to relate identified variability to potential changes in whole-body insulin sensitivity and glucose turnover in a phenotype study. Single-strand conformational polymorphism and heteroduplex analysis of the coding region of the regulatory p85alpha subunit in cDNA isolated from human muscle tissue from 70 insulin-resistant NIDDM patients and 12 control subjects revealed three silent polymorphisms and a missense mutation at nucleotide position 1020 (G-->A), changing a Met to Ile at codon 326. Using allele-specific oligohybridization, we found a similar allelic frequency of the codon 326Met-->Ile variant in 404 NIDDM patients (0.15 [95% CI 0.13-0.17]) and 224 matched glucose tolerant control subjects (0.16 [0.13-0.19]). In a random sample of 380 unrelated healthy young Caucasians aged 18-32 years, in whom we have performed a tolbutamide modified intravenous glucose tolerance test, we identified 263 wildtype subjects, 109 heterozygous subjects, and 8 subjects homozygous for the codon 326 variant (allelic frequency = 0.16 [0.13-0.19]). No difference in glucose disappearance constant (KG), insulin sensitivity index (SI), and glucose effectiveness (SG) was observed between wildtype and heterozygous subjects. However, compared with the combined values for wildtype and heterozygous carriers, KG was reduced by 40% (P = 0.004) and SG by 23% (P = 0.03) in homozygous carriers of the p85alpha variant. Moreover, in homozygous carriers, a 32% reduction was found in SI (P = 0.08). In conclusion, a codon 326Met-->Ile variant in the gene encoding the PI3-K p85alpha regulatory subunit is found in 31% of a random sample of young healthy Caucasians. About 2% of the subjects in this population carry the gene variant in its homozygous form, and these carriers are characterized by significant reductions in whole-body glucose effectiveness and intravenous glucose disappearance constant. In itself, the gene variant does not confer an increased risk of diabetes.
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PMID:Identification of a common amino acid polymorphism in the p85alpha regulatory subunit of phosphatidylinositol 3-kinase: effects on glucose disappearance constant, glucose effectiveness, and the insulin sensitivity index. 903 8

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

Both type 1 and type 2 diabetes mellitus are associated with reduced pancreatic size. This could be caused by insulinopenia with loss of a trophic insulin effect and/or other factors associated with a diabetic state. To investigate the role of long-term moderate insulinemia per se, we compared the pancreatic size in healthy subjects with documented low (n = 5) and high (n = 5) insulin secretion. Insulin responses to a glucose clamp (11 mM) procedure were threefold higher in the high insulin responders (HIR) than low insulin responders (LIR). Age, body mass index (BMI), and blood glucose were similar between groups. Computed tomography showed no difference in total pancreatic size (total pancreas volume 84.8 +/- 29.4 ml in LIR, 79.8 +/- 8.4 ml in HIR; NS) nor in the size of various parts (caput, corpus, or cauda). We conclude that moderate hypoinsulinemia of long duration does not affect the pancreatic size.
Acta Diabetol 1996 Dec
PMID:Pancreas size and insulin secretion: lack of association in non-diabetic subjects. 903 67

Correct classification of diabetic patients in adulthood at the time of diagnosis is often difficult. Some may be initially diagnosed as having non-insulin-dependent diabetes mellitus and be treated with diet and/or oral hypoglycaemic agents (OHA) but later require insulin treatment. Islet cell antibodies and antibodies to GAD 65 have been associated with the development of insulin deficiency in this group of patients. In the present study, 150 patients with the initial diagnosis of type 2 diabetes mellitus in adulthood (30-60 years) were seen regularly over a period of 5 years in our diabetes outpatient clinic. Though treatment was started with diet or diet plus OHA, insulin therapy had to be introduced in a subset of patients. In all cases, serum obtained at the time of the initial diagnosis was analysed for islet cell antibodies and GAD 65 antibodies, as well as for thyroid and adrenal autoantibodies as possible markers for polyendocrine involvement. Islet cell antibody status, body mass index and the presence of thyroid and adrenal autoantibodies showed no significant correlation to subsequent insulin requirement (< 2 years after diagnosis). In contrast, GAD 65 antibodies were significantly associated with the occurrence of clinical insulin dependency less than 2 years after the initial diagnosis (P < 0.01), thus identifying a substantial proportion of patients requiring insulin therapy within the first 2 years after the diagnosis of type 2 diabetes. Determination of GAD 65 antibodies in patients with late-onset diabetes may contribute to their correct classification and adequate treatment.
Acta Diabetol 1996 Dec
PMID:GAD 65 antibody but not ICA positivity in adult-onset diabetic patients is associated with early progression to clinical insulin dependency. 903 70

One form of maturity-onset diabetes of the young (MODY3) results from mutations in the hepatocyte nuclear factor (HNF)-1alpha gene, located on chromosome 12q24.2. The primary objective of the present study was to search for genetic variation in the HNF-1alpha gene in nine nonrelated Danish Caucasian subjects with MODY. Direct sequencing of the coding region and intron-exon boundaries of the HNF-1alpha gene revealed 2 novel and 1 previously reported missense mutations and 2 novel frameshift mutations in five of nine MODY subjects. These five mutations were found in neither 84 NIDDM patients nor 84 control subjects. One glucose-tolerant lean male with a P447L missense mutation, which in his relatives caused MODY, underwent an oral glucose tolerance test (OGTT), a tolbutamide modified frequently sampled intravenous glucose tolerance test, and a glucagon test to examine for a possible early beta-cell abnormality. He had a low insulin secretion rate during an OGTT, but a twofold increase in pancreatic beta-cell response after intravenous glucose and a 2.5- to 4-fold increase in beta-cell response after either intravenous tolbutamide or intravenous glucagon loads. In conclusion, 1) mutations in the HNF-1alpha gene are common in Danish Caucasian MODY patients, and 2) early stages in the pathogenesis of MODY3 caused by the P447L mutation may be characterized by a hyperexcitability of beta-cells to intravenous secretagogues.
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PMID:Novel MODY3 mutations in the hepatocyte nuclear factor-1alpha gene: evidence for a hyperexcitability of pancreatic beta-cells to intravenous secretagogues in a glucose-tolerant carrier of a P447L mutation. 907 19

Anti-single-stranded(ss)DNA antibodies were searched for by enzyme-linked immunosorbent assay (ELISA) in the serum of 202 outpatients with non-insulin-dependent diabetes mellitus and 135 healthy subjects to investigate their prevalence in the serum of patients with type 2 diabetes and their relationship with the presence of vascular complications. Of the 202 patients 128 had vascular complications. Anti-ssDNA antibodies were observed to be significantly more frequent in the serum of patients with vascular complications (33.6%) and in particular in patients with overt nephropathy (50%) than in patients without complications (6.7%) or controls (6.7%). Anti-ssDNA antibodies have been previously described in patients with type 1 diabetes before clinical evidence of vascular disease and their cross-reactivity with a variety of anionic biological molecules or cells, i.e. platelets and endothelial cells, assessed. It seems not unreasonable that these auto-antibodies detected in patients with type 2 diabetes could be of importance in the pathogenesis or progression of angiopathy.
Acta Diabetol 1997 Mar
PMID:Anti-single-stranded DNA antibody in the sera of patients with type 2 diabetes mellitus. Relation to vascular complications. 913 56

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

Well-characterized defects in insulin secretion, most notably a loss of glucose-induced insulin secretion, are found in virtually all forms of NIDDM, as well as in early IDDM. Similar abnormalities have been found in all animal models of diabetes in which they have been studied. A novel hypothesis is being proposed to explain the mechanisms responsible for these alterations. Many abnormalities in the various steps of glucose-induced insulin secretion have been identified in rodent models of diabetes, but none by itself seems sufficient to explain the defects. These include a loss of GLUT2, glycogen accumulation, glucose recycling, abnormal glucokinase or hexokinase, altered mitochondrial glycerol phosphate dehydrogenase (mGPDH) activity, abnormal ion channel function and beta cell degranulation. We propose that optimal secretory function is dependent upon the unique differentiation of beta cells that is maintained by a set of transcription factors and that this control is disrupted by the diabetic state. Therefore, we propose that key transcription factors are affected even when beta cells are stressed by insulin resistance in very earliest stages of diabetes and that the abnormality becomes more severe as full-blown diabetes develops, which leads to loss of beta cell differentiation and a resultant derangement of insulin secretion.
Acta Diabetol 1997 Oct
PMID:Transcription factor abnormalities as a cause of beta cell dysfunction in diabetes: a hypothesis. 940 38


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