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 aim of the present study is to explore whether the renal and cardiovascular response to clonidine in type II diabetic patients is different from that in control subjects, and to clarify the role of central alpha 2-receptor in the regulation of cardiovascular response and sodium handling in type II diabetes mellitus (DM). Thirty-five diabetic inpatients aged 30-71 years (54.1 +/- 9.7) and ten control subjects (N) were enrolled in this study after their fasting plasma glucose had been improved. To evaluate the peripheral sympathetic nerve activity, 24-hour urinary catecholamine was measured, and pulse rate (PR) responses to a 30-second standing test was determined. On another day, blood pressure (BP), PR, plasma norepinephrine (PNE), cyclic AMP (p-cAMP), renin activity (PRA), aldosterone (PAC) and growth hormone (p-GH) were measured at 0, 30, 60, 90, 120, 150, 180 minutes following the oral administration of clonidine (150 micrograms). Type II DM were classified as DM with hyper-response (DM-HR, n = 12) when their PR decreased after clonidine more than that of N, and if not, they were classified as DM with normal response (DM-NR, n = 23). Urinary catecholamine excretions in type II DM were within the normal range. BP, PNE and p-cAMP were markedly decreased with clonidine in similar fashion in DM-NR, DM-HR and N. The percent changes of PNE were correlated positively with the changes of p-cAMP in both N and DM-NR (r = 0.660 and 0.449, respectively), but not in DM-HR. No significant difference in the changes of p-GH (delta p-GH) and integral of GH (the area under the curve) following clonidine administration was observed in the three groups. The decrease in PR was correlated with neither delta p-GH (N: r = 0.082, DM-NR: r = -0.400, DM-HR: r = 0.242) or integral of GH (N: r = 0.191, DM-NR: r = 0.382, DM-HR: r = 0.162). The fractional excretion of sodium (FENa) decreased in N (p < 0.01), increased in DM-NR (p < 0.05) and did not change in DM-HR. The changes of FENa were not correlated with those of PRA and PAC.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:[Altered responses of heart rate, renal sodium handling and plasma growth hormone to clonidine in type II diabetic patients]. 133 89

Four overlapping DNA fragments spanning 32 kb containing the human GLUT4 facilitative glucose-transporter gene were isolated and characterized. The sequence of the GLUT4 gene (approximately 6.3 kb) and 2.0 kb of the promoter region was determined. The sequence of the promoter revealed potential binding sites for transcription factors known to regulate gene expression in muscle cells and adipocytes. However, transfection of constructs including 2 kb of the GLUT4 promoter fused to the bacterial CAT gene into 3T3-L1 adipocytes displayed only weak promoter activity. Because insulin resistance plays a prominent role in the development of NIDDM, genetic variation in the sequence of GLUT4 also was evaluated. Oligonucleotide primer pairs were selected that allowed the protein-coding region of the human GLUT4 gene to be amplified by PCR. The sequence of the protein-coding region of the GLUT4 gene and all intron-exon junctions was determined for a single diabetic Pima Indian and was identical to that of the cloned gene and cDNA. SSCP analysis was used to screen patients with diabetes mellitus and normal, healthy nondiabetic individuals for mutations at the GLUT4 locus. In addition to the silent substitution in the codon for Asn130 (AAC or AAT) and a Val383 (GTC)-->Ile(ATC) replacement described previously, two new variants were identified. One was a T-->A substitution in intron 1 that was found in 1 of 36 NIDDM patients who were typed for this variant. The second was a Ile385(ATT)-->Thr(ACT) replacement that occurred in 1 normal individual and was not found in any of 676 other normal and diabetic subjects. A large and racially diverse group of normal and diabetic individuals also was screened for the Ile383 polymorphism. It occurred in both diabetic and nondiabetic subjects. There is no indication from our data that these polymorphisms are associated with NIDDM.
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PMID:Human GLUT4/muscle-fat glucose-transporter gene. Characterization and genetic variation. 139 19

In order to investigate whether there was any association between autoimmunity to pancreatic antigens with FCPD as well as IDDM, cell-mediated immune response to pancreatic antigens was studied by lymphoproliferation assay in 7 FCPD, 17 IDDM, 33 NIDDM patients and 102 normal controls. Optimal pancreatic antigen concentrations used were 100, 150 and 200 micrograms/ml. Positive results were considered for each concentration of antigens tested, at stimulation index (SI) > (mean +/- 2 SD) SI obtained from normal age-matched controls with the use of the corresponding concentration of antigen. The one who gave positive result with any of these optimal antigen concentrations was considered to be the responder to pancreatic antigens. With this criterion, the responders were found to be 3/7 (42.9%) FCPD, 6/17 (35.3%) IDDM and 6/33 (18.2%) NIDDM patients; while there were 11 of all 102 (10.8%) normal controls.
Asian Pac J Allergy Immunol 1996 Dec
PMID:A study of cell-mediated immune response to pancreatic antigens in patients with fibrocalculous pancreatic diabetes. 917 22

Non-insulin-dependent diabetes mellitus (NIDDM), or type II diabetes is rapidly becoming one of the most common chronic disease in the United States and worldwide, with more than 7% of the adult population affected. NIDDM is even more common in the elderly and in minority population including Hispanic Americans, African Americans, Asian and Pacific Island Americans, and Native Americans. In these populations, NIDDM may be present in 10% to as much as 50% of the adult population. However diagnosed NIDDM is only the tip of the iceberg of an epidemic of glucose intolerance. Impaired glucose intolerance (IGT) is even more prevalent that NIDDM; and in addition to be a major risk factor for the development of NIDDM, IGT is associated with an increased risk of macrovascular disease. Recent advances in research into the etiology and natural history of diabetes have increased the knowledge to such an extent that primary prevention of NIDDM is becoming a reality. This primary prevention can be implemented a) through a population strategy, i.e. changing the lifestyle and environmental determinants that are known to be risk factors for diabetes, and b) through high-risk strategy, i.e. targeting preventive measures only at those specific individuals or groups that are at high risk for the future development of NIDDM. The latter is the strategy of the Diabetes Prevention Program (DDP), a clinical study sponsored by the National Institute of Diabetes and Digestive and Kidney Disease in USA. Twenty five centers were selected to participate in this program. The purpose of DPP is prevent or delay the development of NIDDM in those persons who are at high risk because they have IGT. DPP will also evaluate if the interventions selected to prevent the development of NIDDM can decrease the frequency of cardiovascular events and the occurrence and magnitude of the cardiovascular risk factors that accompany NIDDM and IGT. Four thousand volunteers will be recruited from populations known to be at particular high risk fo IGT and NIDDM including the following: elderly, overweight individuals, persons with family history of NIDDM, women with history of gestational diabetes, and minority populations. In order to be eligible, persons who are older than 25 years will have to demonstrate IGT with plasma glucose levels 100-139 mg/dl fasting and 140-199 mg/dL two hours after a 75 g OGTT. Three study intervention were selected based on their potential efficacy in ameliorating abnormal glucose metabolism in IGT and on their safety and tolerable profile of side-effects. The interventions include: intensive lifestyle intervention which focuses on a healthy diet to achieve and maintain at least a 7% loss of body weight and an increase in caloric expenditure of at least 700 kcal per week. The drug therapy interventions include the biguanide metformin and the thiazolidinedione troglizatone. Standard life-style recommendations, which include conventional instructions regarding diet and exercise, will be provided to all participants, including a placebo treated group which will serve as the control group for the study. After randomization, participants will have quarterly evaluations and have, in addition, a fasting plasma glucose at semi-annual visits and a 75 g OGTT at annual visits. All participants will be followed for three years after the study-wide closing date for recruitment, resulting in 3 to 6 years of participant follow-up. The primary outcome is the development of NIDDM according to WHO criteria (fasting plasma glucose level 140 mg/dL or 2-hour plasma glucose 200 mg/dL after a 75 g OGTT). Secondary outcome will focus en cardiovascular disease and its risk factors and change of glycemia, insulin secretion and sensitivity, obesity, physical activity and nutrient intake, quality of life, and the occurrence of adverse events.
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PMID:[Steps toward the primary prevention of type II diabetes mellitus. Various epidemiological considerations]. 923 72

Proglucagon contains the sequence of two glucagon-like peptides, GLP-1 and GLP-2, secreted from enteroendocrine cells of the small and large intestine. GLP-1 lowers blood glucose in both NIDDM and IDDM patients and may be therapeutically useful for treatment of patients with diabetes. GLP-1 regulates blood glucose via stimulation of glucose-dependent insulin secretion, inhibition of gastric emptying, and inhibition of glucagon secretion. GLP-1 may also regulate glycogen synthesis in adipose tissue and muscle; however, the mechanism for these peripheral effects remains unclear. GLP-1 is produced in the brain, and intracerebroventricular GLP-1 in rodents is a potent inhibitor of food and water intake. The short duration of action of GLP-1 may be accounted for in part by the enzyme dipeptidyl peptidase 4 (DPP-IV), which cleaves GLP-1 at the NH2-terminus; hence GLP-1 analogs or the lizard peptide exendin-4 that are resistant to DPP-IV cleavage may be more potent GLP-1 molecules in vivo. GLP-2 has recently been shown to display intestinal growth factor activity in rodents, raising the possibility that GLP-2 may be therapeutically useful for enhancement of mucosal regeneration in patients with intestinal disease. This review discusses recent advances in our understanding of the biological activity of the glucagon-like peptides.
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PMID:Glucagon-like peptides. 951 8

The insulinotropic hormone, glucagon-like peptide 1 (GLP-1), which has been proposed as a new treatment for type 2 diabetes, is metabolized extremely rapidly by the ubiquitous enzyme, dipeptidyl peptidase IV (DPP-IV), resulting in the formation of a metabolite, which may act as an antagonist at the GLP-1 receptor. Because of this, the effects of single injections of GLP-1 are short-lasting, and for full demonstration of its antidiabetogenic effects, continuous intravenous infusion is required. To exploit the therapeutic potential of GLP-1 clinically, we here propose the use of specific inhibitors of DPP-IV. We have demonstrated that the administration of such inhibitors may completely protect exogenous GLP-1 from DPP-IV-mediated degradation, thereby greatly enhancing its insulinotropic effect, and provided evidence that endogenous GLP-1 may be equally protected. Preliminary studies by others in glucose-intolerant experimental animals have shown that DPP-IV inhibition greatly ameliorates the condition. GLP-1 has multifaceted actions, which include stimulation of insulin gene expression, trophic effects on the beta-cells, inhibition of glucagon secretion, promotion of satiety, inhibition of food intake, and slowing of gastric emptying, all of which contribute to normalizing elevated glucose levels. Because of this, we predict that inhibition of DPP-IV, which will elevate the levels of active GLP-1 and reduce the levels of the antagonistic metabolite, may be useful to treat impaired glucose tolerance and perhaps prevent transition to type 2 diabetes. The actions of DPP-IV, other than degradation of GLP-1, particularly in the immune system are discussed, but it is concluded that side effects of inhibition therapy are likely to be mild. Thus, DPP-IV inhibition may be an effective supplement to diet and exercise treatment in attempts to prevent the deterioration of glucose metabolism associated with the Western lifestyle.
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PMID:Inhibition of the activity of dipeptidyl-peptidase IV as a treatment for type 2 diabetes. 979 33

Inhibition of dipeptidyl peptidase IV (DPP-IV) has been proposed recently as a therapeutic approach to the treatment of type 2 diabetes. N-Substituted-glycyl-2-cyanopyrrolidide compounds, typified by NVP-DPP728 (1-[[[2-[(5-cyanopyridin-2-yl)amino]ethyl]amino]acetyl]-2-cyano-(S )-p yrrolidine), inhibit degradation of glucagon-like peptide-1 (GLP-1) and thereby potentiate insulin release in response to glucose-containing meals. In the present study NVP-DPP728 was found to inhibit human DPP-IV amidolytic activity with a K(i) of 11 nM, a k(on) value of 1.3 x 10(5) M(-)(1) s(-)(1), and a k(off) of 1.3 x 10(-)(3) s(-)(1). Purified bovine kidney DPP-IV bound 1 mol/mol [(14)C]-NVP-DPP728 with high affinity (12 nM K(d)). The dissociation constant, k(off), was 1.0 x 10(-)(3) and 1.6 x 10(-)(3) s(-)(1) in the presence of 0 and 200 microM H-Gly-Pro-AMC, respectively (dissociation t(1/2) approximately 10 min). Through kinetic evaluation of DPP-IV inhibition by the D-antipode, des-cyano, and amide analogues of NVP-DPP728, it was determined that the nitrile functionality at the 2-pyrrolidine position is required, in the L-configuration, for maximal activity (K(i) of 11 nM vs K(i) values of 5.6 to >300 microM for the other analogues tested). Surprisingly, it was found that the D-antipode, despite being approximately 500-fold less potent than NVP-DPP728, displayed identical dissociation kinetics (k(off) of 1.5 x 10(-)(3) s(-)(1)). NVP-DPP728 inhibited DPP-IV in a manner consistent with a two-step inhibition mechanism. Taken together, these data suggest that NVP-DPP728 inhibits DPP-IV through formation of a novel, reversible, nitrile-dependent complex with transition state characteristics.
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PMID:NVP-DPP728 (1-[[[2-[(5-cyanopyridin-2-yl)amino]ethyl]amino]acetyl]-2-cyano-(S)- pyrrolidine), a slow-binding inhibitor of dipeptidyl peptidase IV. 1051 14

Although the synergetic effects of multiple marker loci regarding quantitative traits such as blood glucose level have attracted interest, previous conclusions have been based on assumptions that each marker locus behaves independently of the other, leading to approximation. To cope with this problem, this paper focuses on the effects of multiple genetic factors and tries to find significant marker combinations by using conjunctive rules regarding genotypes at multiple marker loci. Application of the proposed method on the OLETF model rat of non-insulin dependent diabetes mellitus (NIDDM) has found significant combinations of marker loci with respect to oral glucose tolerance (OGT).
Pac Symp Biocomput 2000
PMID:Mining the quantitative trait loci associated with oral glucose tolerance in the OLETF rat. 1090 85

The search for intestinal factors regulating the endocrine secretion of the pancreas started soon after the discovery of secretin, i.e. nearly 100 years ago. Insulinotropic factors of the gut released by nutrients and stimulating insulin secretion in physiological concentrations in the presence of elevated blood glucose levels have been named incretins. Of the known gut hormones only gastric inhibitory polypeptide (GIP) and glucagon-like polypeptide-1 (GLP-1 [7-36] amide) fulfill this definition.--The incretin effect (i.e. the ratio between the integrated insulin response to an oral glucose load and an isoglycaemic intravenous glucose infusion) is markedly diminished in patients with type 2 diabetes mellitus, while the plasma levels of GIP and GLP-1 and their responses to nutrients are in the normal range. Therefore, a reduced responsiveness of the islet B-cells to incretins has been postulated. This insensitivity of the diabetic B-cells towards incretins can be overcome by supraphysiological (pharmacological) concentrations of GLP-1 [7-36], however not of GIP. Accordingly, fasting and postprandial glucose levels can be normalized in patients with type 2 diabetes by infusions of GLP-1 [7-36]. Further studies revealed that this is partially due to the fact that GLP-1 [7-36]--in addition to its insulinotropic effect--also inhibits glucagon secretion and delays gastric emptying. These three antidiabetic effects qualify GLP-1 [7-36] as an interesting therapeutic tool, mainly for type 2 diabetes. However, because of its short plasma half life time natural GLP-1 [7-36] is not suitable for subcutaneous application. At present methods are being developed to improve the pharmacokinetics of GLP-1 by inhibition of the cleaving enzyme dipeptidyl peptidase IV (DPP-IV) or by synthesis of DPP-IV resistant GLP-1 analogues. Also naturally occurring GLP-1 analogues (for instance exendin-4) with a much longer half life time than GLP-1 [7-36] are being tested.--Thus, after 100 years of speculations and experimentations, incretins and their analogues are emerging as new antidiabetic drugs.
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PMID:The entero-insular axis in type 2 diabetes--incretins as therapeutic agents. 1146 May 78

In order to investigate whether there would be any association between abnormalities of either reg1 alpha or reg1 beta gene and diabetes mellitus in man, these two genes were analyzed in 42 patients with type 1 diabetes mellitus, 12 with fibrocalculous pancreatopathy, 37 with type 2 diabetes mellitus, and 22 normal controls, by PCR-SSCP analysis and nucleotide sequencing technique. Polymorphism in the reg1 alpha gene resulted in three mobility patterns in the PCR-SSCP analysis, due to nucleotide constituents at position -10 before exon 1 being either C/C, T/C or T/T. These three mobility patterns were observed in every group of subjects. The analysis of reg1 beta gene showed nucleotide substitutions in exon 4 in one patient, exon 5 in another patient with type 1 diabetes, and in exon 4 and intron 5 in one patient with fibrocalculous pancreatopathy. The nucleotide substitutions in exon 4 in the patient with type 1 diabetes and that with fibrocalculous pancreatopathy occurred at codons 103 and 84 while that in exon 5 in the patient with type 1 diabetes occurred at codon 141, changing the codons from CAT to CAC, GTG to GCG, and ACT to AAT and resulting in H103H silent, V84A and T141N missense mutations, respectively. In conclusion, using PCR-SSCP and nucleotide sequence analyses, we did not find any association between abnormalities of either reg1 alpha or reg1 beta gene with any type of diabetes studied.
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PMID:No abnormalities of reg1 alpha and reg1 beta gene associated with diabetes mellitus. 1179 76


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