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)

Two substituted ureas of beta-D-glucose, N-acetyl-N'-beta-D-glucopyranosyl urea (Acurea) and N-benzoyl-N'-beta-D-glucopyranosyl urea (Bzurea), have been identified as inhibitors of glycogen phosphorylase, a potential target for therapeutic intervention in type 2 diabetes. To elucidate the structural basis of inhibition, we determined the structure of muscle glycogen phosphorylase b (GPb) complexed with the two compounds at 2.0 A and 1.8 A resolution, respectively. The structure of the GPb-Acurea complex reveals that the inhibitor can be accommodated in the catalytic site of T-state GPb with very little change in the tertiary structure. The glucopyranose moiety makes the standard hydrogen bonds and van der Waals contacts as observed in the GPb-glucose complex, while the acetyl urea moiety is in a favourable electrostatic environment and makes additional polar contacts with the protein. The structure of the GPb-Bzurea complex shows that Bzurea binds tightly at the catalytic site and induces substantial conformational changes in the vicinity of the catalytic site. In particular, the loop of the polypeptide chain containing residues 282-287 shifts 1.3-3.7 A (Calpha atoms) to accommodate Bzurea. Bzurea can also occupy the new allosteric site, some 33 A from the catalytic site, which is currently the target for the design of antidiabetic drugs.
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PMID:Binding of N-acetyl-N '-beta-D-glucopyranosyl urea and N-benzoyl-N '-beta-D-glucopyranosyl urea to glycogen phosphorylase b: kinetic and crystallographic studies. 1189 39

The prevalence of nephropathy in black patients with type 2 diabetes mellitus is poorly defined. We performed a cross-sectional analysis of 98 unrelated and unselected black type 2 diabetic patients treated in indigent care internal medicine clinics to determine the prevalence of proteinuria and nephropathy. Serum creatinine, blood urea nitrogen, urine albumin and urine creatinine concentrations were measured. A Spearman's rank correlation was computed to test for a relationship between diabetes duration and continuous outcomes. For binary outcomes, an odds ratio and 95% confidence interval were computed for a change of 10 years diabetes duration based on logistic regression. Cases were 61% female, and had mean (+/- SD) age 59.9 +/- 12.5 years, diabetes duration 12.6 +/- 9.4 years, body mass index 32.4 +/- 9.3 kg/m(2), hemoglobin A1C (HbA1C) 9.2 +/- 2.3%, and serum creatinine concentration 1.60 +/- 1.1 mg/dl. For continuous variables, diabetes duration was positively associated with albuminuria (r = 0.31; p = 0.0017), serum creatinine (r = 0.36; p = 0.0003) and blood urea nitrogen concentration (r = 0.36; p = 0.0003). For binary variables, cases with longer diabetes duration were at increased risk for urinary albumin:creatinine >300 microg/mg (p = 0.006), elevated serum creatinine concentration (> or = 1.4 mg/dl in women or > or = 1.6 mg/dl in men; p = 0.045), elevated blood urea nitrogen concentration (> or = 20 mg/dl; p = 0.026), and clinical cerebrovascular disease (p = 0.028). HbA1C, body mass index, and blood pressure did not correlate with diabetes duration in this population. Among the cases, 33.7% had elevated serum creatinine concentration and 71.5% had abnormal levels of albuminuria (27.6% > 300 microg albumin/mg Cr and 43.9% 30-300 microg albumin/mg Cr). Abnormal proteinuria was seen in the majority of black patients with poorly controlled type 2 diabetes mellitus treated in indigent care clinics. This prevalence may be conservative, due to the widespread use of angiotensin-converting enzyme inhibitor therapy and exclusion of cases treated only by nephrologists. Approximately 70% of black patients with type 2 diabetes cared for in indigent care clinics have abnormal proteinuria and are at heightened risk for ESRD and death.
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PMID:Prevalence of nephropathy in black patients with type 2 diabetes mellitus. 1191 1

We report tamoxifen-induced hypertriglyceridemia and asymptomatic acute pancreatitis in a 51 year-old women with type 2 diabetes mellitus and stage III-b infiltrative ductal carcinoma, admitted to the hospital with weakness, oliguria and glucose dysregulation. On admission, there was no fever, abdominal or back pain, rebound tenderness, nausea, or vomiting. Following 1 year of tamoxifen treatment, triglycerides increased from 400 to 1344 mg/dl (blood urea nitrogen 52 mg/dl, creatinine 2.0 mg/dl, glucose 341 mg/dl). Hypertriglyceridemia was considered to be due to either diabetic dyslipidemia and/or tamoxifen. On computerized tomography, pancreatic enlargement, heterogenity, hypodensity and a pancreatic pseudocyst (5 x 7.5 cm diameter) were found. Acute pancreatitis was suspected, and serum amylase level was found to be increased (273 IU/L). Tamoxifen was discontinued and gemfibrozil was started. Triglycerides decreased to 301 mg/dl and amylase decreased to 66 IU/L a week later and remained normal thereafter. This case indicates that tamoxifen-induced hypertriglyceridemia may cause acute pancreatitis without classical symptoms which might be due to autonomic neuropathy in diabetic patients. Effects on lipid metabolism should be considered and triglycerides should be closely followed in patients on tamoxifen.
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PMID:Asymptomatic acute pancreatitis due to tamoxifen-induced severe hypertriglyceridemia in a patient with diabetes mellitus and breast cancer. 1212 Aug 88

Helicobacter pylori (Hp) infection in diabetic patients has been related to impaired gastric clearance of bacteria due to autonomic neuropathy. Gastrointestinal dysfunction has been described in primary autonomic failure (AF). The aim of the study was to evaluate, for the first time, the presence of Hp infection and gastric function in patients with primary AF Twelve patients with primary AF (aged 58-78), 31 healthy controls (aged 48-75) and 31 patients affected by type 2 diabetes (aged 46-75) were studied. A 13C-urea breath test was performed to assess the presence of Hp infection. To evaluate gastric function, AF patients underwent two non-invasive tests: 1) 13C-octanoic acid breath test (OBT) to evaluate gastric emptying, and 2) electrogastrogram (EGG) to evaluate gastric electrical activity. Hp infection was found in 100% of AF patients, in 48% of controls and in 71% of diabetic patients (p = 0.02 between groups). Electrical or mechanical gastric function was altered in 50% of AF patients. In particular, 1) after OBT, half-time gastric emptying was delayed in 6 out of 12 patients, and 2) EGG showed the presence of gastric dysrhythmias in 6 out of 12 patients. In conclusion, Hp infection was detected in all AF patients studied; as previously demonstrated in diabetes, such a finding might be related to autonomic neuropathy causing mechanical or electrical gastric dysfunction. Hp detection might be important for the gastrointestinal and extradigestive complications of such infection.
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PMID:Helicobacter pylori infection and gastric function in primary autonomic neuropathy. 1226 53

Type 2 diabetes mellitus is a complex metabolic disorder with adverse cardiovascular risk. The role of micronutrients has not yet been well clarified in this condition, especially in India.THE OBJECTIVES OF THIS STUDY WERE TO: (1) evaluate chromium status in Indian subjects with type 2 diabetes mellitus, (2) assess the effect of chromium picolinate (200 &mgr;g trivalent chromium twice daily) administration on glycaemic control and lipid profile in these subjects and (3) comment on the possible mechanism of any beneficial effect noted above.Fifty subjects were studied in a double blind, placebo-controlled, crossover fashion, with each treatment arm (chromium/placebo) lasting 12 weeks and 4 weeks' wash-off period in between. 50 healthy age- and sex-matched volunteers served as controls. Serum chromium level appeared to be higher in the general population in our country compared to western countries (36.5-59.5 nmol/L as compared to 2.3-40.3 nmol/L) However, the local diabetics were found to have a lower serum chromium level than the healthy controls (32.3 nmol/L against 44.7 nmol/L; p < 0.0001) and a mean increase of 3.5 nmol/L was noted after 12 weeks of chromium supplementation that was, expectedly, not seen in the placebo phase (p < 0.0001).Significant improvement in glycaemic control was noted in the chromium-treated group (DeltaFasting serum glucose = 0.44 mmol/L, p < 0.001; DeltaPost-prandial serum glucose = 1.97 mmol/L, p < 0.001; Deltaglycated hemoglobin = 0.01; p = 0.04, in comparison to placebo) This was accompanied by a significant greater fall in fasting serum insulin in the chromium-treated group, p < 0.05.The change in lipid parameters (total serum cholesterol, high density lipoprotein cholesterol, low density lipoprotein cholesterol and triglycerides) did not show significant difference between the chromium and placebo groups.Clinically significant hematological, renal or hepatic toxicity were excluded by routine hemogram, serum urea, creatinine, alanine amino transferase (ALT) and alkaline phosphatase estimations.In conclusion, chromium supplementation seems to improve glycaemic control in type 2 diabetic patients, which appears to be due to an increase in insulin action rather than stimulation of insulin secretion.
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PMID:Role of chromium supplementation in Indians with type 2 diabetes mellitus. 1255 67

Diabetes is among the largest contributors to global mortality through its long term complications. The worldwide epidemic of type 2 diabetes has been stimulating the quest for new concepts and targets for the treatment of this incurable disease. A new target is glycogen phosphorylase (GP), the main regulatory enzyme in the liver responsible for the control of blood glucose levels. One of several approaches to influence the action of GP is the use of glucose derivatives as active site inhibitors. This field of research commenced 10-15 years ago and, due to joint efforts in computer aided molecular design, organic synthesis, protein crystallography, and biological assays, resulted in glucopyranosylidene-spiro-hydantoin 16 (K(i) = 3-4 micro M) as the most efficient glucose analog inhibitor of GP of that time. The present paper surveys the recent developments of this field achieved mainly in the last five years: the synthesis and evaluation of glucopyranosylidene-spiro-thiohydantoin 18 (K(i) = 5 micro M) which has proven equipotent with 16, and is available in gram amounts; furanosylidene- and xylopyranosylidene-spiro-(thio)hydantoins whose ineffectiveness (K(i) > 10 mM) confirmed the high specificity of the catalytic site of GP towards the D-glucopyranosyl unit; "open" hydantoins like methyl N-(1-carboxamido-D-glucopyranosyl)carbamate 37 (K(i) = 16 micro M) and N-acyl-N'-(beta-D-glucopyranosyl)ureas among them the to date best glucose analog inhibitor N-(2-naphthoyl)-N'-(beta-D-glucopyranosyl)urea (35, K(i) = 0.4 micro M) which can also bind to the so-called new allosteric site of GP; C-(beta-D-glucopyranosyl)heterocycles (tetrazole, 1,3,4-oxadiazoles, benzimidazole (K(i) = 11 micro M), and benzothiazole). Iminosugars like isofagomine (45, IC(50) = 0.7 micro M), noeuromycin (53, IC(50) = 4 micro M), and azafagomine (54, IC(50) = 13.5 micro M) also bind strongly to the active site of GP, however, substitution on the nitrogens makes the binding weaker. The natural product five-membered iminosugar DAB (56) exhibited IC(50) approximately 0.4-0.5 micro M. Azoloperhydropyridines which can be regarded iminosugar-annelated heterocycles show moderate inhibition of GP: nojiritetrazole 12 (K(i) = 53 micro M) is the best inhibitor and fewer nitrogens in the five-membered ring weakens the binding. Physiological investigations have been carried out with N-acetyl-beta-D-glucopyranosylamine 6, spiro-thiohydantoin 18, isofagomine 45, and DAB 56 to underline the potential use of these compounds in the treatment of type 2 diabetes. Computational methods suggest to synthesize further anomerically bifunctional glucose derivatives which may be good inhibitors of GP.
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PMID:Glucose analog inhibitors of glycogen phosphorylases as potential antidiabetic agents: recent developments. 1276 45

To determine the effect of a low-dose angiotensin receptor blocker, candesartan, on early kidney damage associated with diabetes. Fifty-two patients with type 2 diabetes with normo- and microalbuminuria participated in this study. Nineteen patients with high-normal and mildly high blood pressure received low-dose candesartan cilexetil at 4 mg daily (candesartan group), and 33 patients did not receive candesartan (control group). Blood pressure, urinary excretion of albumin, transferrin, and type IV collagen (expressed as urinary creatinine index) and plasma parameters were determined at baseline and at 2, 6, 12 and 18 months after the start of candesartan therapy. Baseline urinary albumin, transferrin, and type IV collagen excretions was similar in the control and candesartan groups. The higher baseline systolic blood pressure was decreased by candesartan treatment to a level similar to that in the control group, such that blood pressure was comparable between the control and candesartan groups during the run-in period. In the control group, urinary albumin excretion was significantly increased at 18 months when compared with baseline, while urinary albumin excretion did not increase in the candesartan group throughout the study. Urinary transferrin excretion was significantly increased at 6, 12, and 18 months when compared with baseline in the control group, while it did not increase in the candesartan group during the study. In both groups, urinary type IV collagen excretion did not change significantly during the study. Hemoglobin A1c, serum urea nitrogen, creatinine, albumin, and lipids were comparable between the two groups throughout the study. In conclusion, low-dose candesartan can prevent early kidney damage in type 2 diabetic patients with mildly higher blood pressure independently of its hypotensive action.
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PMID:Low-dose candesartan cilexetil prevents early kidney damage in type 2 diabetic patients with mildly elevated blood pressure. 1286 1

In a randomized, crossover 5-wk study design, we recently reported that a weight-maintaining diet in which the percentage of total food energy as protein was increased from 15-30% resulted in a decrease in postprandial glucose and glycohemoglobin in people with untreated type 2 diabetes without a significant change in insulin. Protein was substituted for carbohydrate in the diet. The fat content remained unchanged. In this publication, we present data on other hormones and metabolites that were considered to potentially be affected by substitution of protein for carbohydrate in the diet. The mean fasting plasma GH and total IGF-I concentrations were elevated on the 30% protein diet. The urinary free cortisol also was increased. However, the urinary aldosterone was unchanged. Although urinary pH was decreased, calcium excretion was not significantly increased. The plasma postprandial alpha-amino nitrogen concentrations were increased, but the 24-h integrated concentration was unchanged, indicating an accelerated amino acid removal rate. The plasma urea nitrogen was increased as expected. The urea production rate also was increased such that a new steady-state fasting value was present. The calculated urea production rate accounted for 97% of the protein ingested on the 15% protein diet, but only 80% on the 30% protein diet, suggesting net nitrogen retention on the high-protein diet. In conclusion, an increase in dietary protein results in a number of metabolic adaptations in addition to reducing the circulating glucose concentration. Serum TSH, total T(3), free T(4), B(12), folate, homocysteine, uric acid, and creatinine concentrations were unchanged.
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PMID:The metabolic response of subjects with type 2 diabetes to a high-protein, weight-maintenance diet. 1291 39

Data concerning the prevalence of Helicobacter pylori (H. pylori) in diabetic patients are scanty and controversial. The aim of this study was to evaluate the prevalence of H. pylori infection in patients with diabetes mellitus (DM), and to assess whether the presence of bacterium was associated with severity of dyspeptic symptoms and endoscopic findings in such patients. The study involved 42 patients (19 men, 23 women; mean age 55 years, range 34-75 years) with DM and dyspeptic symptoms. Sixteen patients (38%) were classified as having type 1 diabetes and 26 (62%) patients as having type 2 diabetes. All patients had chronic dyspepsia, and each patient has completed a self-report questionnaire to obtain information concerning the presence and severity of upper gastrointestinal tract symptoms. H. pylori status was confirmed by 13C-urea breath test (13C-UBT), and diabetic patients underwent upper gastrointestinal endoscopy. Twenty-six (61.9%) of patients with DM were positive for 13C-UBT. There were no statistically significant differences in the infection rate between patients with type 1 and type 2 diabetes, and the prevalence of H. pylori infection was not associated with the known duration of diabetes. There was no significant difference in the symptoms score between H. pylori-positive and H. pylori-negative diabetic patients, and endoscopic findings in patients with DM were in the same range with those found in dyspeptic subjects from the same region. In conclusion, H. pylori infection is not associated with DM, duration of diabetes, or severity of dyspeptic symptoms in patients with DM.
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PMID:Helicobacter pylori infection in patients with diabetes mellitus. 1475 71

Polycystic ovary syndrome is a very common disease affecting 6.5% of women. It is frequently associated with obesity with the link between the two disorders being insulin resistance. From morbidly obese women submitted to surgical treatment of obesity, we obtain intra-abdominal adipose tissue samples in order to compare protein patterns between women with and without polycystic ovary syndrome by two-dimensional gel electrophoresis (2-DE) analysis. Adipose tissue is a complex material extremely rich in lipids. To improve protein solubilization a lysis buffer containing 8.4 M urea, 2.4 M thiourea, 5% 3-((3-cholamidoproyl)dimethyl-amino)-1-propanesulfonate and 50 mM dithiothreitol was used and samples were centrifuged to remove fat. Hydroxyethyl disulfide was added to increase resolution in the alkaline region (Olsson, I., Larsson, K., Palmgren, R., Bjellqvist, B., Proteomics 2002, 2, 1630-1632) and it also improved resolution in a wide pH range (3-10). Our work shows for the first time 2-DE maps of human adipose tissue and identifies some of the proteins by mass spectrometry. This information will aid studies on metabolic diseases such as polycystic ovary syndrome, obesity, hypertension and type 2 diabetes.
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PMID:Improved resolution of the human adipose tissue proteome at alkaline and wide range pH by the addition of hydroxyethyl disulfide. 1476 Jul 14


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