nateglinide and Glucose-Intolerance

Topics: Acarbose; Cyclohexanes; Diet, Carbohydrate-Restricted; Dietary Fiber; Dumping Syndrome; Enzyme Inhibitors; Gastrectomy; Glucose Intolerance; Glucose Tolerance Test; Glycoside Hydrolase Inhibitors; Humans; Hypoglycemia; Hypoglycemic Agents; Insulin; Insulin Secretion; Nateglinide; Phenylalanine; Weight Loss

Diabetic macroangiopathy has already developed before diagnosis of diabetes mellitus. Postprandial hyperglycemia has been known as a risk factor for diabetic macroangiopathy and may be more powerful than fasting hyperglycemia. To intervene in hyperglycemia, insulin secretagogues, glinides which selectively stimulate early meal-induced insulin secretion and improve postprandial hyperglycemia, and sulfonylureas which enhance total daily insulin secretion and improve fasting hyperglycemia, have been prescribed as major oral antidiabetic agents. Few evidences that amelioration of glycemic control with insulin secretagogues lower the risk of cardiovascular diseases have been reported. But current studies have shown that intervention in postprandial hyperglycemia with drugs including glinides decreased thickness of carotid IMT as a surrogate marker of atherosclerosis. Results from on-going large scale intervention study with glinides may clarify whether amelioration of hyperglycemia lower the risk of atherosclerotic events.

Topics: Arteriosclerosis; Cardiovascular Diseases; Cyclohexanes; Diabetic Angiopathies; Glucose Intolerance; Hyperglycemia; Hypoglycemic Agents; Indoles; Insulin; Insulin Secretion; Isoindoles; Nateglinide; Phenylalanine; Postprandial Period; Risk Factors; Sulfonylurea Compounds

Topics: Acarbose; Cyclohexanes; Fasting; Glucose Intolerance; Glycation End Products, Advanced; Humans; Hyperglycemia; Hypoglycemic Agents; Insulin Resistance; Life Style; Myocardial Ischemia; Nateglinide; Phenylalanine; Pioglitazone; Postprandial Period; Protein Kinase C; Thiazolidinediones

Topics: Cardiovascular Diseases; Clinical Trials as Topic; Cyclohexanes; Diabetes Mellitus, Type 2; Glucose Intolerance; Humans; Hyperglycemia; Hypoglycemic Agents; Insulin; Insulin Resistance; Insulin Secretion; Nateglinide; Obesity; Phenylalanine; Postprandial Period; Risk Factors

Topics: Cardiovascular Diseases; Cyclohexanes; Diabetes Mellitus, Type 2; Endpoint Determination; Glucose Intolerance; Humans; Hypoglycemic Agents; Insulin; Insulin Resistance; Insulin Secretion; Life Style; Nateglinide; Phenylalanine; Primary Prevention; Randomized Controlled Trials as Topic; Risk

Topics: Acarbose; Cyclohexanes; Diabetes Mellitus, Type 2; Diet Therapy; Enzyme Inhibitors; Exercise Therapy; Glucose; Glucose Intolerance; Glycogen; Glycoside Hydrolase Inhibitors; Humans; Hypoglycemic Agents; Insulin; Insulin Resistance; Insulin Secretion; Metformin; Nateglinide; Phenylalanine; Sulfonylurea Compounds; Thiazolidinediones

To elucidate the long-term cardiovascular benefit of lowering postprandial hyperglycemia (PPG) in early-stage T2DM patients.. This 10-year post-trial follow-up study included 243 patients from the DIANA (DIAbetes and diffuse coronary Narrowing) study, a multi-center randomized controlled trial which compared the efficacy of one-year life-style and pharmacological (voglibose/nateglinide) intervention lowering PPG on coronary atherosclerosis in 302 early-stage T2DM subjects [impaired glucose tolerance (IGT) or newly-diagnosed T2DM] (UMIN-CTRID#0000107). MACE (all-cause death, non-fatal MI or unplanned coronary revascularization) were compared in (1) three assigned therapies (life-style intervention/vogliose/nateglinide) and (2) patients with and without improvement of PPG (reversion from IGT to NGT or from DM to IGT/NGT on 75 g oral glucose tolerance test).. During the 10-year post-trial observational period, voglibose (HR = 1.07, 95%CI: 0.69-1.66, p = 0.74) or nateglinide (HR = 0.99, 95%CI: 0.64-1.55, p = 0.99) did not reduce MACE. Similarly, achieving the improvement of PPG was not associated with a reduction of MACE (HR = 0.78, 95%CI: 0.51-1.18, p = 0.25). However, in IGT subjects (n = 143), this glycemic management significantly reduced the occurrence of MACE (HR = 0.44, 95%CI: 0.23-0.86, p = 0.01), especially unplanned coronary revascularization (HR = 0.46, 95%CI: 0.22-0.94, p = 0.03).. The early improvement of PPG significantly reduced MACE and unplanned coronary revascularization in IGT subjects during the post-trial 10-year period.

Topics: Blood Glucose; Coronary Artery Disease; Diabetes Mellitus, Type 2; Follow-Up Studies; Glucose Intolerance; Humans; Nateglinide

Contemporary studies suggest an association between venous thromboembolism and a higher incidence of major cardiovascular events, mostly attributed to arterial atherothrombosis. Using data from the Nateglinide and Valsartan in Impaired Glucose Tolerance Outcomes Research (NAVIGATOR) trial, we assessed the association of venous thromboembolism with major cardiovascular events.. In NAVIGATOR, patients with impaired glucose tolerance were randomly allocated to receive valsartan or placebo and nateglinide or placebo in addition to lifestyle modification. Baseline characteristics and prior history of venous thromboembolism were assessed. After adjusting for important baseline covariates, Cox proportional hazards regression models were used to assess the association between venous thromboembolism and major cardiovascular outcomes.. Of the 9306 patients enrolled, 129 (1.4%) had a history of venous thromboembolism. Patients with venous thromboembolism were older, more frequently white and female, and had a higher body mass index. Patients with venous thromboembolism had higher 5-year event rates for the composite of death, myocardial infarction, and stroke, as compared with patients without venous thromboembolism (10.7% vs 5.9%; P < .001; adjusted hazard ratio 2.12; 95% confidence interval, 1.36-3.31; P = .001).. In patients with impaired glucose tolerance at high risk for cardiovascular events, the prevalence of venous thromboembolism was rare but associated with worse long-term cardiovascular outcomes, including arterial events. Venous thromboembolism is a marker of risk, and attention should be paid to this high-risk group of patients.

Topics: Aged; Angiotensin II Type 1 Receptor Blockers; Cardiovascular Diseases; Confidence Intervals; Cyclohexanes; Female; Glucose Intolerance; Glycated Hemoglobin; Humans; Hypoglycemic Agents; Male; Middle Aged; Nateglinide; Outcome Assessment, Health Care; Phenylalanine; Prevalence; Proportional Hazards Models; Risk Assessment; Risk Factors; Tetrazoles; Time Factors; Valine; Valsartan; Venous Thromboembolism

While bidirectional relationships exist between body weight and physical activity, direction of causality remains uncertain and previous studies have been limited by self-reported activity or weight and small sample size. We investigated the prospective relationships between weight and physical activity.. Observational analysis of data from the Nateglinide And Valsartan in Impaired Glucose Tolerance Outcomes Research (NAVIGATOR) study, a double-blinded randomised clinical trial of nateglinide and valsartan, respectively.. Multinational study of 9306 participants.. Participants with biochemically confirmed impaired glucose tolerance had annual measurements of both weight and step count using research grade pedometers, worn for 7 days consecutively. Along with randomisation to valsartan or placebo plus nateglinide or placebo, participants took part in a lifestyle modification programme.. Longitudinal regression using weight as response value and physical activity as predictor value was conducted, adjusted for baseline covariates. Analysis was then repeated with physical activity as response value and weight as predictor value. Only participants with a response value preceded by at least three annual response values were included.. Adequate data were available for 2811 (30%) of NAVIGATOR participants. Previous weight (χ(2)=16.8; p<0.0001), but not change in weight (χ(2)=0.1; p=0.71) was inversely associated with subsequent step count, indicating lower subsequent levels of physical activity in heavier individuals. Change in step count (χ(2)=5.9; p=0.02) but not previous step count (χ(2)=0.9; p=0.34) was inversely associated with subsequent weight. However, in the context of trajectories already established for weight (χ(2) for previous weight measurements 747.3; p<0.0001) and physical activity (χ(2) for previous step count 432.6; p<0.0001), these effects were of limited clinical importance.. While a prospective bidirectional relationship was observed between weight and physical activity, the magnitude of any effect was very small in the context of natural trajectories already established for these variables.. NCT00097786.

Topics: Body Weight; Cyclohexanes; Double-Blind Method; Glucose Intolerance; Humans; Hypoglycemic Agents; Life Style; Motor Activity; Nateglinide; Phenylalanine; Prospective Studies; Valsartan

Low and low-normal serum potassium is associated with an increased risk of diabetes. We hypothesized that the protective effect of valsartan on diabetes risk could be mediated by its effect of raising serum potassium.. We analyzed data from the Nateglinide and Valsartan in Impaired Glucose Tolerance Outcomes Research (NAVIGATOR) trial, which randomized participants at risk for diabetes to either valsartan (up to 160mg daily) or no valsartan. Using Cox models, we evaluated the effect of valsartan on diabetes risk over a median of 4 years of follow-up and calculated the mediation effect of serum potassium as the difference in treatment hazard ratios from models excluding and including 1-year change in serum potassium. The 95% confidence interval (CI) for the difference in log hazard ratios was computed by bootstrapping.. The hazard ratio for developing diabetes among those on valsartan vs. no valsartan was 0.866 (95% CI = 0.795-0.943) vs. 0.868 (95% CI = 0.797-0.945), after controlling for 1-year change in potassium. The bootstrap 95% CI for a difference in these log hazard ratios was not statistically significant (-0.003 to 0.009).. Serum potassium does not appear to significantly mediate the protective effect of valsartan on diabetes risk.

Topics: Antihypertensive Agents; Biomarkers; Cyclohexanes; Diabetes Mellitus; Female; Follow-Up Studies; Glucose Intolerance; Humans; Hypoglycemic Agents; Male; Middle Aged; Nateglinide; Phenylalanine; Potassium; Tetrazoles; Time Factors; Treatment Outcome; Valine; Valsartan

The role of dysglycemia as an additional risk factor for atrial fibrillation (AF) is controversial. Therefore, it was of interest to assess risk factors for incident AF in a large, representative population of patients with cardiovascular risk factors and impaired glucose tolerance but not overt diabetes in NAVIGATOR.. Predictors of incident AF were analyzed in 8,943 patients without AF at baseline by Cox proportional hazards regression. Study treatments (valsartan vs no valsartan and nateglinide vs no nateglinide) and the time-dependent covariate for progression to type 2 diabetes mellitus were added separately to the model.. The median age of the 8,943 patients included in the present analysis of the NAVIGATOR trial was 63 years. Half of those patients were men, 6,922 (77.4%) had a history of hypertension, and 255 (2.9%) had heart failure. The median glycated hemoglobin was 6%. During the study, 613 of the 8,943 patients without AF at baseline presented with at least 1 episode of AF (6.9% 5-year incidence). Besides established predictors of incident AF, a 1 mmol/L increment of baseline fasting glucose, but not progression to diabetes, was found to be associated with a 33% increased risk of incident AF. Neither valsartan nor nateglinide affected AF incidence.. In a trial population with impaired glucose tolerance, fasting plasma glucose and well-known risk factors (age, hypertension, and elevated body weight), but not progression to diabetes, predict risk of AF.

Topics: Aged; Atrial Fibrillation; Blood Glucose; Cyclohexanes; Diabetes Mellitus, Type 2; Double-Blind Method; Female; Glucose Intolerance; Humans; Hypoglycemic Agents; Incidence; Male; Middle Aged; Nateglinide; Outcome Assessment, Health Care; Phenylalanine; Proportional Hazards Models; Risk Assessment; Risk Factors; Tetrazoles; Valine; Valsartan

The Nateglinide and Valsartan Impaired Glucose Tolerance Outcomes Research (NAVIGATOR) trial is exploring two pharmacological strategies (nateglinide and valsartan, both alone and in combination) in the prevention of overt diabetes mellitus (DM) and the reduction of cardiovascular disease (CVD) in subjects at high risk for these events. In this analysis, we provide baseline characteristics of the randomized NAVIGATOR study population and contrast them with those from other trials of DM prevention. Key eligibility criteria include impaired glucose tolerance (IGT) and impaired fasting glucose (IFG), a history of CVD (in patients aged > or =50 years), and > or =1 cardiovascular risk factor (in patients aged > or =55 years). Baseline demographic characteristics, laboratory findings, cardiovascular risk factors, CVD history, and medication use are described and compared with other trials of DM prevention. The full analysis set of subjects (N = 9306) showed a clustering of risk factors consistent with the metabolic syndrome: high rates of hypertension (77.5%), dyslipidemia (44.7%), increased waist circumference (101.0 cm), and high body mass index (BMI) (47.5% with BMI > or =30 kg/m(2)). A minority of patients had a history of CVD (24.3%); of these, 11.7% had a history of myocardial infarction and most of the remainder had evidence of coronary artery disease. Subjects also had elevated blood pressure (BP) (predominantly systolic) (139.7/82.6 mm Hg), increased serum low-density lipoproteins cholesterol levels (3.27 mmol/L), and borderline elevation of triglyceride levels (1.97 mmol/L). Demographic data, BP, and lipid profiles in NAVIGATOR were similar to those of previous DM prevention trials, which were also based largely on meeting criteria for IGT. Medication use at baseline among NAVIGATOR subjects, which frequently included aspirin, beta-blockers, calcium channel blockers, diuretics, and lipid-lowering agents, reflects enhanced CVD risk. However, little prescribing of renin-angiotensin-aldosterone system blockers was observed, likely due to protocol exclusion criteria. In conclusion, the NAVIGATOR study comprises prediabetic subjects who typically have concurrent BP and metabolic disturbances and an enhanced risk of CVD, and are thus at higher risk for cardiovascular events than subjects in previous DM prevention trials.

Topics: Aged; Angiotensin II Type 1 Receptor Blockers; Blood Glucose; Blood Pressure; Cardiovascular Diseases; Cyclohexanes; Diabetes Mellitus; Female; Glucose Intolerance; Humans; Hypoglycemic Agents; Male; Middle Aged; Nateglinide; Patient Selection; Phenylalanine; Prediabetic State; Research Design; Risk Assessment; Risk Factors; Tetrazoles; Valine; Valsartan

The ability of short-acting insulin secretagogues to reduce the risk of diabetes or cardiovascular events in people with impaired glucose tolerance is unknown.. In a double-blind, randomized clinical trial, we assigned 9306 participants with impaired glucose tolerance and either cardiovascular disease or cardiovascular risk factors to receive nateglinide (up to 60 mg three times daily) or placebo, in a 2-by-2 factorial design with valsartan or placebo, in addition to participation in a lifestyle modification program. We followed the participants for a median of 5.0 years for incident diabetes (and a median of 6.5 years for vital status). We evaluated the effect of nateglinide on the occurrence of three coprimary outcomes: the development of diabetes; a core cardiovascular outcome that was a composite of death from cardiovascular causes, nonfatal myocardial infarction, nonfatal stroke, or hospitalization for heart failure; and an extended cardiovascular outcome that was a composite of the individual components of the core composite cardiovascular outcome, hospitalization for unstable angina, or arterial revascularization.. After adjustment for multiple testing, nateglinide, as compared with placebo, did not significantly reduce the cumulative incidence of diabetes (36% and 34%, respectively; hazard ratio, 1.07; 95% confidence interval [CI], 1.00 to 1.15; P=0.05), the core composite cardiovascular outcome (7.9% and 8.3%, respectively; hazard ratio, 0.94, 95% CI, 0.82 to 1.09; P=0.43), or the extended composite cardiovascular outcome (14.2% and 15.2%, respectively; hazard ratio, 0.93, 95% CI, 0.83 to 1.03; P=0.16). Nateglinide did, however, increase the risk of hypoglycemia.. Among persons with impaired glucose tolerance and established cardiovascular disease or cardiovascular risk factors, assignment to nateglinide for 5 years did not reduce the incidence of diabetes or the coprimary composite cardiovascular outcomes. (ClinicalTrials.gov number, NCT00097786.)

Topics: Angiotensin II Type 1 Receptor Blockers; Blood Glucose; Body Weight; Cardiovascular Diseases; Cyclohexanes; Diabetes Mellitus, Type 2; Double-Blind Method; Drug Therapy, Combination; Exercise; Female; Follow-Up Studies; Glucose Intolerance; Humans; Hypoglycemic Agents; Incidence; Kaplan-Meier Estimate; Male; Middle Aged; Nateglinide; Phenylalanine; Proportional Hazards Models; Risk Factors; Tetrazoles; Treatment Failure; Valine; Valsartan

It is not known whether drugs that block the renin-angiotensin system reduce the risk of diabetes and cardiovascular events in patients with impaired glucose tolerance.. In this double-blind, randomized clinical trial with a 2-by-2 factorial design, we assigned 9306 patients with impaired glucose tolerance and established cardiovascular disease or cardiovascular risk factors to receive valsartan (up to 160 mg daily) or placebo (and nateglinide or placebo) in addition to lifestyle modification. We then followed the patients for a median of 5.0 years for the development of diabetes (6.5 years for vital status). We studied the effects of valsartan on the occurrence of three coprimary outcomes: the development of diabetes; an extended composite outcome of death from cardiovascular causes, nonfatal myocardial infarction, nonfatal stroke, hospitalization for heart failure, arterial revascularization, or hospitalization for unstable angina; and a core composite outcome that excluded unstable angina and revascularization.. The cumulative incidence of diabetes was 33.1% in the valsartan group, as compared with 36.8% in the placebo group (hazard ratio in the valsartan group, 0.86; 95% confidence interval [CI], 0.80 to 0.92; P<0.001). Valsartan, as compared with placebo, did not significantly reduce the incidence of either the extended cardiovascular outcome (14.5% vs. 14.8%; hazard ratio, 0.96; 95% CI, 0.86 to 1.07; P=0.43) or the core cardiovascular outcome (8.1% vs. 8.1%; hazard ratio, 0.99; 95% CI, 0.86 to 1.14; P=0.85).. Among patients with impaired glucose tolerance and cardiovascular disease or risk factors, the use of valsartan for 5 years, along with lifestyle modification, led to a relative reduction of 14% in the incidence of diabetes but did not reduce the rate of cardiovascular events. (ClinicalTrials.gov number, NCT00097786.)

Topics: Angiotensin II Type 1 Receptor Blockers; Blood Glucose; Blood Pressure; Body Weight; Cardiovascular Diseases; Cyclohexanes; Diabetes Mellitus, Type 2; Double-Blind Method; Drug Therapy, Combination; Exercise; Female; Follow-Up Studies; Glucose Intolerance; Humans; Hypoglycemic Agents; Incidence; Male; Middle Aged; Nateglinide; Phenylalanine; Proportional Hazards Models; Risk Factors; Tetrazoles; Valine; Valsartan

Patients with impaired glucose tolerance (IGT) have increased risk for developing type 2 diabetes mellitus (T2DM) and cardiovascular disease (CVD). Lifestyle modification and medication can prevent or delay progression to diabetes (PD), but whether such interventions also reduce the risk of CVD has not been rigorously tested. The Nateglinide And Valsartan in Impaired Glucose Tolerance Outcomes Research (NAVIGATOR) trial is a multinational, randomized, double-blind, 2 x 2 factorial trial in subjects with IGT (on a screening oral glucose tolerance test [OGTT]) aged > or = 50 years with known CVD or aged > or = 55 years with > or = 1 CVD risk factor. Enrollment began in January 2002 and was completed January 2004, with 9,518 patients randomized to receive 1 of 4 possible treatment combinations as follows: nateglinide with valsartan, nateglinide with valsartan-placebo, nateglinide-placebo with valsartan, or nateglinide-placebo with valsartan-placebo. All subjects are participating in a clinic-based and telephone-based lifestyle intervention aimed at reducing weight and dietary fat and increasing physical activity. The 3 coprimary end points are new onset of T2DM, a "core" composite of major cardiovascular events (death, myocardial infarction, stroke, or hospitalization for heart failure), and an "extended" composite including the components of the core composite plus coronary revascularization and hospitalization for unstable angina. The study was designed to evaluate whether reducing postprandial hyperglycemia, blockade of the renin-angiotensin-aldosterone system, or both interventions reduce the risk of T2DM or cardiovascular events in patients with IGT.

Topics: Angiotensin II Type 1 Receptor Blockers; Angiotensin-Converting Enzyme Inhibitors; Cyclohexanes; Diabetic Angiopathies; Disease Progression; Double-Blind Method; Glucose Intolerance; Humans; Hypoglycemic Agents; Life Style; Nateglinide; Outcome Assessment, Health Care; Phenylalanine; Research Design; Tetrazoles; Valine; Valsartan

Regional differences in risk of diabetes mellitus and cardiovascular outcomes in people with impaired glucose tolerance are poorly characterized. Our objective was to evaluate regional variation in risk of new-onset diabetes mellitus, cardiovascular outcomes, and treatment effects in participants from the NAVIGATOR (Nateglinide and Valsartan in Impaired Glucose Tolerance Outcomes Research) trial.. NAVIGATOR randomized people with impaired glucose tolerance and cardiovascular risk factors or with established cardiovascular disease to valsartan (or placebo) and to nateglinide (or placebo) with a median 5-year follow-up. Data from the 9306 participants were categorized by 5 regions: Asia (n=552); Europe (n=4909); Latin America (n=1406); North America (n=2146); and Australia, New Zealand, and South Africa (n=293). Analyzed outcomes included new-onset diabetes mellitus; cardiovascular death; a composite cardiovascular outcome of cardiovascular death, nonfatal myocardial infarction, or nonfatal stroke; and treatment effects of valsartan and nateglinide. Respective unadjusted 5-year risks for new-onset diabetes mellitus, cardiovascular death, and the composite cardiovascular outcome were 33%, 0.4%, and 4% for Asia; 34%, 2%, and 6% for Europe; 37%, 4%, and 8% for Latin America; 38%, 2%, and 6% for North America; and 32%, 4%, and 8% for Australia, New Zealand, and South Africa. After adjustment, compared with North America, European participants had a lower risk of new-onset diabetes mellitus (hazard ratio 0.86, 95% CI 0.78-0.94; P=0.001), whereas Latin American participants had a higher risk of cardiovascular death (hazard ratio 2.68, 95% CI 1.82-3.96; P<0.0001) and the composite cardiovascular outcome (hazard ratio 1.48, 95% CI 1.15-1.92; P=0.003). No differential interactions between treatment and geographic location were identified.. Major regional differences regarding the risk of new-onset diabetes mellitus and cardiovascular outcomes in NAVIGATOR participants were identified. These differences should be taken into account when planning global trials.. URL: http://www.ClinicalTrials.gov. Unique identifier: NCT00097786.

Topics: Aged; Angiotensin II Type 1 Receptor Blockers; Asia; Australia; Cardiovascular Diseases; Cyclohexanes; Diabetes Mellitus, Type 2; Europe; Female; Glucose Intolerance; Humans; Hypoglycemic Agents; Incidence; Latin America; Male; Middle Aged; Multivariate Analysis; Myocardial Infarction; Nateglinide; New Zealand; North America; Outcome Assessment, Health Care; Phenylalanine; Proportional Hazards Models; Randomized Controlled Trials as Topic; Risk Factors; South Africa; Stroke; Valsartan

To investigate whether previous physical activity levels are associated with blood glucose levels in individuals with impaired glucose tolerance in the context of an international pharmaceutical trial.. Data were analysed from the NAVIGATOR trial, which involved 9306 individuals with impaired glucose tolerance and high cardiovascular risk from 40 different countries, recruited in the period 2002-2004. Fasting glucose, 2-h post-challenge glucose and physical activity (pedometer) were assessed annually. A longitudinal regression analysis was used to determine whether physical activity levels 2 years (t-2 ) and 1 year (t-1 ) previously were associated with levels of glucose, after adjusting for previous glucose levels and other patient characteristics. Those participants with four consecutive annual measures of glucose and two consecutive measures of physical activity were included in the analysis.. The analysis included 3964 individuals. Change in physical activity from t-2 to t-1 and activity levels at t-2 were both associated with 2-h glucose levels after adjustment for previous glucose levels and baseline characteristics; however, the associations were weak: a 100% increase in physical activity was associated with a 0.9% reduction in 2-h glucose levels. In addition, previous physical activity only explained an additional 0.05% of the variance in 2-h glucose over the variance explained by the history of 2-h glucose alone (R(2)  = 0.3473 vs. 0.3468). There was no association with fasting glucose.. In the context of a large international clinical trial, previous physical activity levels did not meaningfully influence glucose levels in those with a high risk of chronic disease, after taking into account participants' previous trajectory of glucose control.

Topics: Accelerometry; Actigraphy; Aged; Angiotensin II Type 1 Receptor Blockers; Blood Glucose; Cardiovascular Diseases; Cohort Studies; Cyclohexanes; Fasting; Female; Glucose Intolerance; Glucose Tolerance Test; Humans; Hypoglycemic Agents; Longitudinal Studies; Male; Middle Aged; Motor Activity; Nateglinide; Phenylalanine; Prospective Studies; Regression Analysis; Risk Factors; Risk Reduction Behavior; Valsartan

We have previously isolated spontaneous insulin-resistant mice (ddY-H) and non-insulin-resistant mice (ddY-L) from ddY mice. In the present study, age-dependent onset of insulin resistance in obese ddY-H mice was investigated by comparing with lean ddY-L mice. In ddY-H mice fed a standard diet, an increase in elevation of glucose-stimulated plasma insulin level, glucose intolerance in an intraperitoneal glucose tolerance test, and a reduction of hypoglycemic action of insulin were found at 9 weeks of age, but not at 6 weeks of age. When ddY-H mice were administered nateglinide, a greater elevation of plasma insulin level and a less decrease of serum glucose level were observed at 9 weeks of age. These changes developed progressively with age. These findings suggest that insulin resistance is induced at 9 weeks of age. The age-related change in insulin resistance was correlated with reductions in mRNA expression and protein content of the insulin receptor (InsR), and insulin receptor substrate (IRS)-1 and IRS-2 in the epididymal adipose tissue. On the other hand, in the liver, mRNA expression of InsR and IRS-1 did not change at any age, although that of the IRS-2 was reduced. Thus, in ddY-H mice, insulin resistance and glucose-stimulated hyper-secretion of insulin are induced at 9 weeks of age and are reciprocally affected, resulting in progression to a more severe state at an older age. Insulin resistance may be attributed, at least in part, to the decreases in the mRNA expressions and proteins of InsR, IRS-1 and IRS-2 in adipose tissue.

Topics: Adipose Tissue; Age Factors; Animals; Blood Glucose; Cyclohexanes; Glucose; Glucose Intolerance; Hypoglycemic Agents; Insulin; Insulin Receptor Substrate Proteins; Insulin Resistance; Male; Mice, Inbred Strains; Nateglinide; Obesity; Phenylalanine; Receptor, Insulin; RNA, Messenger

Risk factors for stroke are well-established in general populations but sparsely studied in individuals with impaired glucose tolerance.. We identified predictors of stroke among participants with impaired glucose tolerance in the Nateglinide and Valsartan in Impaired Glucose Tolerance Outcomes Research (NAVIGATOR) trial. Cox proportional-hazard regression models were constructed using baseline variables, including the 2 medications studied, valsartan and nateglinide.. Among 9306 participants, 237 experienced a stroke over 6.4 years. Predictors of stroke included classical risk factors such as existing cerebrovascular and coronary heart disease, higher pulse pressure, higher low-density lipoprotein cholesterol, older age, and atrial fibrillation. Other factors, including previous venous thromboembolism, higher waist circumference, lower estimated glomerular filtration rate, lower heart rate, and lower body mass index, provided additional important predictive information, yielding a C-index of 0.72. Glycemic measures were not predictive of stroke. Variables associated with stroke were similar in participants with no prior history of cerebrovascular disease at baseline.. The most powerful predictors of stroke in patients with impaired glucose tolerance included a combination of established risk factors and novel variables, such as previous venous thromboembolism and elevated waist circumference, allowing moderately effective identification of high-risk individuals.

Topics: Aged; Antihypertensive Agents; Comorbidity; Controlled Clinical Trials as Topic; Cyclohexanes; Drug Therapy, Combination; Female; Glucose Intolerance; Humans; Hypoglycemic Agents; Male; Middle Aged; Nateglinide; Outcome Assessment, Health Care; Phenylalanine; Predictive Value of Tests; Risk Factors; Stroke; Tetrazoles; Valine; Valsartan

To examine the degree to which use of β blockers, statins, and diuretics in patients with impaired glucose tolerance and other cardiovascular risk factors is associated with new onset diabetes.. Reanalysis of data from the Nateglinide and Valsartan in Impaired Glucose Tolerance Outcomes Research (NAVIGATOR) trial.. NAVIGATOR trial.. Patients who at baseline (enrolment) were treatment naïve to β blockers (n=5640), diuretics (n=6346), statins (n=6146), and calcium channel blockers (n=6294). Use of calcium channel blocker was used as a metabolically neutral control.. Development of new onset diabetes diagnosed by standard plasma glucose level in all participants and confirmed with glucose tolerance testing within 12 weeks after the increased glucose value was recorded. The relation between each treatment and new onset diabetes was evaluated using marginal structural models for causal inference, to account for time dependent confounding in treatment assignment.. During the median five years of follow-up, β blockers were started in 915 (16.2%) patients, diuretics in 1316 (20.7%), statins in 1353 (22.0%), and calcium channel blockers in 1171 (18.6%). After adjusting for baseline characteristics and time varying confounders, diuretics and statins were both associated with an increased risk of new onset diabetes (hazard ratio 1.23, 95% confidence interval 1.06 to 1.44, and 1.32, 1.14 to 1.48, respectively), whereas β blockers and calcium channel blockers were not associated with new onset diabetes (1.10, 0.92 to 1.31, and 0.95, 0.79 to 1.13, respectively).. Among people with impaired glucose tolerance and other cardiovascular risk factors and with serial glucose measurements, diuretics and statins were associated with an increased risk of new onset diabetes, whereas the effect of β blockers was non-significant.. ClinicalTrials.gov NCT00097786.

Topics: Adrenergic beta-Antagonists; Aged; Calcium Channel Blockers; Cardiovascular Diseases; Cyclohexanes; Diabetes Mellitus, Type 2; Diuretics; Double-Blind Method; Female; Follow-Up Studies; Glucose Intolerance; Glucose Tolerance Test; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Incidence; Male; Middle Aged; Models, Statistical; Nateglinide; Phenylalanine; Risk Factors; Tetrazoles; Treatment Outcome; Valine; Valsartan

As part of a program to identify potent GPR40 agonists with drug-like properties suitable for clinical development, the incorporation of polar substituents was explored with the intention of decreasing the lipophilicity of our recently disclosed phenylpropanoic acid derivative 1. This incorporation would allow us to mitigate the cytotoxicity issues observed with compound 1 and enable us to move away from the multifunctional free fatty acid-like structure. Substitutions on the 2',6'-dimethylbiphenyl ring were initially undertaken, which revealed the feasibility of introducing polar functionalities at the biphenyl 4'-position. Further optimization of this position and the linker led to the discovery of several 4'-alkoxybiphenyl derivatives, which showed potent GPR40 agonist activities with the best balance in terms of improved cytotoxicity profiles and favorable pharmacokinetic properties. Among them, 3-{2-fluoro-4-[({4'-[(4-hydroxy-1,1-dioxidotetrahydro-2H-thiopyran-4-yl)methoxy]-2',6'-dimethylbiphenyl-3-yl}methyl)amino]phenyl}propanoic acid (35) exhibited a robust plasma glucose-lowering effect and insulinotropic action during an oral glucose tolerance test in rats with impaired glucose tolerance.

Topics: Animals; Calcium; Caspases; Cell Survival; CHO Cells; Cricetinae; Cyclic S-Oxides; Diabetes Mellitus, Type 2; Female; Glucose Intolerance; Hep G2 Cells; Humans; Hypoglycemic Agents; Inhibitory Concentration 50; Male; Phenylpropionates; Rats; Receptors, G-Protein-Coupled; Structure-Activity Relationship

Topics: Angiotensin II Type 1 Receptor Blockers; Blood Glucose; Cardiovascular Diseases; Cyclohexanes; Diabetes Mellitus, Type 2; Drug Therapy, Combination; Glucose Intolerance; Humans; Hypoglycemic Agents; Nateglinide; Phenylalanine; Tetrazoles; Valine; Valsartan

Nateglinide is a new, fast-onset, short-acting hypoglycemic agent, which increases early phase insulin secretion and the total amount of insulin secreted. However, it is not clear which of these effects contribute more to the decrease in postprandial plasma glucose (PG). To further clarify the pharmacologic actions of nateglinide, we investigated the changes in PG and insulin levels during meal tolerance tests with and without nateglinide. Subjects were 10 newly diagnosed and untreated inpatients with type 2 diabetes. After diet and exercise therapy for 1 week, nateglinide at 270 mg divided 3 times a day, was started. Meal tolerance tests were performed before (baseline) and after a single nateglinide administration (day 1), after 7 days of repeated administration (day 7), and after cessation of nateglinide on day 8. Mean fasting PG was 146 +/- 6 mg/dl (mean +/- SEM) at baseline and 130 +/- 6 mg/dL on day 7 (P =.0004). The 2-hour postprandial PG level was 226 +/- 10 mg/dL at baseline, 145 +/- 11 mg/dL on day 1 (P =.0008), and 190 +/- 15 mg/dL on day 8 (P =.08, baseline; P =.01, day 7). The mean fasting insulin level was 5.4 +/- 1.0 microU/mL at baseline and did not change significantly during the study. The 30-minute postprandial insulin level was 14.4 +/- 1.9 microU/mL at baseline, 39.5 +/- 4.5 microU/mL on day 1 (P =.0004), and 23.6 +/- 3.6 microU/mL on day 8 (P =.045, baseline; P =.010, day 7). The total insulin amount, in terms of area under the curve (AUC. IRI), was 3.99 +/- 0.7 x 10(3) microU/mL. min at baseline, 5.47 +/- 0.8 microU/mL. min on day 1 (P =.029), and 6.01 +/- 1.9 microU/mL. min on day 8 (P =.047 v baseline). The early phase of insulin secretion, based on the ratio of delta IRI to delta PG from fasting to 30 minutes after a meal was 0.15 +/- 0.13 at baseline, 1.44 +/- 0.26 on day 1 (P =.0009) and 0.26 +/- 0.06 on day 8 (P =.05 v day 1). After cessation of nateglinide, the postprandial PG level increased immediately. Although early phase insulin secretion returned nearly to the baseline level, total insulin secretion remained at a high level. These results suggested that early phase insulin secretion contributes more than total insulin secretion to the improvement of postprandial hyperglycemia in type 2 diabetes.

Topics: Adult; Aged; Blood Glucose; Cyclohexanes; Female; Glucose Intolerance; Humans; Hypoglycemic Agents; Insulin; Insulin Secretion; Male; Middle Aged; Nateglinide; Phenylalanine; Postprandial Period; Time Factors