nateglinide and Insulin-Resistance

The recent Nateglinide and Valsartan in Impaired Glucose Tolerance Outcomes Research (NAVIGATOR) trial reported that nateglinide, a non-sulfonylurea insulin secretagogue, failed to prevent progression from impaired glucose tolerance to diabetes. In order to determine the beneficial effect of insulin secretagogues as a class in diabetes prevention, we performed a literature search for randomized controlled studies and review articles on diabetes prevention and use of sulfonylureas, nateglinide, and meglitinide in PubMed and Ovid Medline since 1950. Three studies were identified with none of them reporting success in preventing diabetes, indicating that insulin secretagogues should not be recommended for diabetes prevention.

Topics: Benzamides; Blood Glucose; Cyclohexanes; Diabetes Mellitus, Type 2; Disease Progression; Evidence-Based Medicine; Humans; Hypoglycemic Agents; Insulin; Insulin Resistance; Nateglinide; Phenylalanine; Preventive Health Services; Sulfonylurea Compounds; Treatment Outcome

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

Several epidemiological studies have shown an association between postprandial hyperglycemia and mortality from cardiovascular disease. Postprandial hyperglycemia is frequently associated with visceral obesity which plays a key role in metabolic abnormalities such as dyslipidemia and hypertension. Inhibitors of alpha-glucosidase and nateglinide have beneficial effects on the metabolic syndrome associated with visceral obesity. Voglibose in combination with diet therapy reduces visceral fat deposition and ameliorates insulin resistance. Acarbose slightly reduces blood pressure of hypertensive diabetic patients. Nateglinide, a rapidly acting insulin secretagogue, lowers postprandial glucose levels without significant body weight gain. These drugs may protect pancreatic beta-cells from postprandial glucose toxicity and prevent the progression of diabetes.

Topics: Acarbose; Cyclohexanes; Diabetes Complications; Diabetes Mellitus; Diabetes Mellitus, Type 2; Enzyme Inhibitors; Glycoside Hydrolase Inhibitors; Humans; Hyperglycemia; Hypertension; Hypoglycemic Agents; Inositol; Insulin Resistance; Nateglinide; Obesity; Phenylalanine; Postprandial Period

Patients with type 2 diabetes mellitus are associated with insulin resistance and/or impaired insulin secretion. Previous observations indicate that Japanese patients with type 2 diabetes tend to have impaired insulin response after glycemic load more often than Caucasian counterparts. Recently it has been reported that hyperglycemia after glucose load is itself a risk factor for the development of cardiovascular complications in the absence of elevated fasting plasma glucose. Recent observations on the association of post-challenge or post-prandial hyperglycemia with cardiovascular events suggest that lowering post-prandial plasma glucose may protect patients from developing cardiovascular diseases. Results of STOP-NIDDM trial suggest that nateglinide, which attenuates post-prandial glycemic surge in type 2 diabetes, may also be helpful for the protection against cardiovascular events. Nateglinide exerts its effects shortly after its administration and the effects continue for only about 3 hours. The patients receiving this agent rarely gain weight and develop hypoglycemia. This agent exerts hypoglycemic effects additively with alpha-gulucosidase inhibitors or metformin.

Topics: Cardiovascular Diseases; Cyclohexanes; Diabetes Mellitus, Type 2; Drug Therapy, Combination; Humans; Hyperglycemia; Hypoglycemic Agents; Indoles; Insulin; Insulin Resistance; Insulin Secretion; Isoindoles; Metformin; Nateglinide; Phenylalanine; Postprandial Period; Stimulation, Chemical

Topics: Acarbose; Administration, Oral; Biguanides; Cyclohexanes; Drug Interactions; Glycoside Hydrolase Inhibitors; Humans; Hypoglycemic Agents; Insulin; Insulin Resistance; Insulin Secretion; Nateglinide; Phenylalanine; Pioglitazone; Sulfonylurea Compounds; Thiazoles; Thiazolidinediones

Topics: Carbamates; Chromans; Cyclohexanes; Diabetes Mellitus, Type 2; Humans; Hypoglycemic Agents; Insulin Resistance; Metformin; Nateglinide; Phenylalanine; Piperidines; Thiazoles; Thiazolidinediones; Troglitazone

Studies have shown that repeated post-prandial hyperglycemia may play an important role in the development of atherosclerosis by suppressing endothelial function. α-Glucosidase inhibitors (α-GIs), which reduce post-prandial hyperglycemia without stimulating insulin secretion, significantly reduce the risk of coronary artery disease (CAD), whereas glinides, which improve post-prandial hyperglycemia through post-prandial insulin secretion, do not appear to affect CAD.. A total of 104 diabetic patients with CAD were randomly divided into 2 groups: those treated with miglitol (M-group; n=52) and those treated with nateglinide (N-group; n=52). After 4 months' treatment, although hemoglobin A1c and 1,5-anhydroglucitol were significantly improved in both groups, only the M-group had significant reductions in insulin resistance index and triglyceride/high-density lipoprotein cholesterol (TG/HDL-C; a beneficial index for assessing the presence of small dense low-density lipoprotein, and a marker of atherogenic dyslipidemia). Furthermore, only the M-group had improvement in percentage flow-mediated dilatation (%FMD) and reactive oxygen metabolites. In the M-group, multiple regression analysis showed that improvement in TG/HDL-C, in addition to 1,5-anhydroglucitol, was an independent predictor of improvement in %FMD.. The ameliorating effect of α-GI on post-prandial hyperglycemia without stimulating insulin secretion may improve atherogenic dyslipidemia by reducing insulin resistance. These effects are associated with its beneficial impact on oxidative stress, consequently leading to an improvement in endothelial dysfunction.

Topics: 1-Deoxynojirimycin; Aged; Aged, 80 and over; Coronary Artery Disease; Cyclohexanes; Diabetic Angiopathies; Dyslipidemias; Endothelium, Vascular; Enzyme Inhibitors; Female; Glycoside Hydrolase Inhibitors; Humans; Hyperglycemia; Hypoglycemic Agents; Insulin Resistance; Lipids; Male; Middle Aged; Nateglinide; Phenylalanine

Thiazoledinediones decrease blood glucose by their insulin-sensitizing properties. Here, we examined whether pioglitazone plus nateglinide (PIO) interferes with hepatocellular lipid (HCL) content and/or improves insulin sensitivity in well-controlled non-obese patients with type 2 diabetes mellitus (T2DM).. Sixteen patients [body mass index (BMI): 28 ± 1 kg/m(2) ; HbA1c: 7.1 ± 0.6%] were studied in a randomized, double-blind, 12-week parallel group trial, whereas matched healthy humans [non-diabetic control subjects (CON), BMI: 26 ± 1 kg/m(2)] were studied once. Treatment with pioglitazone (30 mg/day) plus nateglinide (PIO arm) to control for glimepiride-induced insulin secretion was compared to treatment with glimepiride (2 mg/day) plus placebo (GLI arm). Multinuclei magnetic resonance spectroscopy (MRS) was combined with pancreatic normoglycaemic-two-step-insulin clamps and stable isotopes to assess glucose turnover, glucose transport/phosphorylation, HCL and intramyocellular lipid (IMCL) contents, non-esterified fatty acids (NEFA) and adipokines.. At baseline, HCL was approximately 5.6-fold higher in T2DM (p < 0.05 vs. CON). This was paralleled by approximately doubled leptin : adiponectin ratios (p < 0.05). HCL decreased by approximately 39% (p < 0.05) after PIO and only tended to decrease after GLI (p = 0.12). Treatment with PIO did not affect leptin : adiponectin ratios, but slightly improved (p < 0.05) insulin-mediated NEFA suppression, which related to lower HCL. PIO further prevented the insulin-induced increase in IMCL content of soleus and tibialis anterior muscles. Peripheral and hepatic insulin sensitivity, glucose transport and glycaemic control did not change in both groups.. Short-term, low-dose thiazolidendione treatment improves insulin sensitivity of lipolysis and HCL, without affecting muscle and liver insulin sensitivity. It appears that metabolic PIO action in T2DM is primarily mediated via a decline in HCL associated with greater sensitivity of lipolysis to insulin.

Topics: Adiponectin; Blood Glucose; Body Mass Index; C-Reactive Protein; Cyclohexanes; Diabetes Mellitus, Type 2; Double-Blind Method; Female; Glycated Hemoglobin; Hepatocytes; Humans; Hypoglycemic Agents; Insulin; Insulin Resistance; Lipid Metabolism; Lipolysis; Male; Middle Aged; Nateglinide; Phenylalanine; Pioglitazone; Sulfonylurea Compounds; Thiazolidinediones; Treatment Outcome

To compare the efficacy and tolerability of nateglinide with those of acarbose in Chinese type 2 diabetes mellitus (T2DM) patients.. This multi-center, randomized, double-blind, parallel-arm study compared the efficacy and tolerability of nateglinide (120 mg, 3/d, n = 119) and those of acarbose (100 mg, 3/d, n = 118) during a 12-week treatment in T2DM patients uncontrolled by diet with glycosylated haemoglobin (HbA1c) 6.5% - 11.0%.. Monotherapy with nateglinide (120 mg, 3/d) or acarbose (100 mg, 3/d) decreased HbA1c to a similar extent during 12-week treatment. The mean change from baseline to end-point in HbA1c was (-0.90 +/- 0.98)% and (-0.83 +/- 0.81)% in patients receiving nateglinide and acarbose, respectively, with no significant difference between the two groups (P > 0.05). The decrease in fasting plasma glucose (FPG) was similar between nateglinide and acarbose (P > 0.05). The mean change in 2-hour postprandial plasma glucose (PG2h) was (-1.45 +/- 2.74) mmol/L and (-2.20 +/- 2.21) mmol/L in patients receiving nateglinide and acarbose (P = 0.0017). Body weight was significantly decreased in both groups at the end-point (P < 0.05), although the decrease was more with acarbose than nateglinide [(-0.66 +/- 1.79) kg vs (-2.06 +/- 2.00) kg, P = 0.0000]. And the proportion of patients experiencing any presumed drug related adverse events was not significantly different between the two groups.. Nateglinide (120 mg, 3/d) is effective and well tolerated in T2DM patients uncontrolled by diet, demonstrating similar HbA1c reductions as compared with acarbose (100 mg, 3/d).

Topics: Acarbose; Adult; Cyclohexanes; Diabetes Mellitus, Type 2; Double-Blind Method; Female; Follow-Up Studies; Humans; Insulin Resistance; Male; Middle Aged; Nateglinide; Phenylalanine

The aim of the study is to determine if attenuation of postprandial hyperglycemia, by acutely and chronically enhancing postprandial insulin secretion in insulin-resistant individuals, improves the endothelial dysfunction. We assessed postoral glucose-load endothelial function in 56 insulin-resistant subjects with the Flow-Mediated-Dilation (FMD) technique. We randomized subjects to intervention/control group, and examined the acute and chronic effect of nateglinide, an oral antidiabetic drug of rapid action. In the intervention group, postoral glucose-load (post-OGL) FMD delta values deteriorated when compared to pre-OGL values, most significantly at 3 h post-OGL, on the following days: on the first study day termed "Baseline day" (p=0.04); on both days after 3 months of nateglinide treatment [with nateglinide administered on study-day "acute+chronic" (p=0.01); and without nateglinide on study-day "Closing day", p=0.001]. Post-OGL changes in the control group were nonsignificant both at Baseline and on Closing day. After a single dose of nateglinide "Acute day", post-OGL FMD deterioration was abolished. There was an increment in post-OGL FMD delta values most significant at 2 h post-OGL (p=0.02). Insulin concentrations increased while glucose concentrations decreased on study-days with nateglinide when compared to study-days without (p=<0.001 for both insulin and glucose). Comparisons for insulin and glucose concentrations between days with nateglinide, and likewise between days without, showed no significant difference. Postglucose load endothelial dysfunction can be prevented by administration of nateglinide, however, after 3 months of nateglinide treatment, this effect is abolished. Chronically increased insulin secretion could counteract the initial beneficial effect of reduced glucose excursions. We found no relationship between postprandial hyperglycemia and post-OGL FMD.

Topics: Blood Glucose; Case-Control Studies; Cyclohexanes; Endothelium; Female; Glucose; Humans; Hyperglycemia; Insulin; Insulin Resistance; Insulin Secretion; Male; Middle Aged; Nateglinide; Phenylalanine; Postprandial Period; Risk Factors; Vasodilation

Nateglinide, a rapid insulin secretagogue, is known to facilitate the early phase of insulin secretion and has been used for the treatment of type 2 diabetic patients with postprandial hyperglycemia. The aim of this study is to evaluate the effect of nateglinide on insulin resistance as well as insulin secretory defects in type 2 diabetic patients. Insulin secretion ability was evaluated by the hyperglycemic clamp test, and insulin sensitivity was evaluated by the euglycemic hyperinsulinemic clamp test, using an artificial pancreas. The hyperglycemic clamp test showed that a 7-day treatment with nateglinide significantly increased insulin secretion in response to high glucose. Interestingly, although nateglinide is known to facilitate insulin secretion, daily urinary C-peptide excretion was decreased after nateglinide treatment. Moreover, in the euglycemic hyperinsulinemic clamp test, glucose infusion rate was significantly increased by nateglinide treatment, indicating that nateglinide functions to decrease insulin resistance. Nateglinide ameliorates insulin resistance as well as insulin secretory defects in type 2 diabetic patients.

Topics: Blood Glucose; Body Mass Index; Cyclohexanes; Diabetes Mellitus, Type 2; Glycated Hemoglobin; Humans; Hyperglycemia; Hypoglycemic Agents; Insulin; Insulin Resistance; Insulin Secretion; Middle Aged; Nateglinide; Phenylalanine; Postprandial Period

An endothelial barrier for the insulin transport from the circulation to the target tissues of insulin has previously been suggested to contribute to insulin resistance. The interstitial insulin concentration (I-insulin) and insulin kinetics following a mixed meal have, however, previously not been characterized in human adipose tissue.. Eight nondiabetic first-degree relatives (FDR) of type 2 diabetes patients were recruited. Their I-insulin was measured by microdialysis after a test meal with or without oral administration of the insulin secretagogue nateglinide (120 mg). In parallel, adipose tissue blood flow and lipolysis were measured by xenon-clearance and microdialysis, respectively.. The I-insulin increased after the test meal, and this response was more prominent on the day the subjects received the nateglinide tablet when compared with the day the subjects received the placebo tablet [I-insulin incremental area under the curve (IAUC) nateglinide 7612 +/- 3032 vs. Plac 4682 +/- 2613 pmol L(-1) min; P < 0.05, mean +/- SE]. However, the postprandial I-insulin(max)/P-insulin(max) ratio was similar on the two test days (nateglinide: 213 +/- 62 vs. 501 +/- 92 pmol L(-1), I/P-ratio: 0.38 +/- 0.06 and placebo: 159 +/- 39 vs. 410 +/- 74 pmol L(-1), I/P-ratio: 0.36 +/- 0.05). There was no difference in time of onset of insulin action in situ, or responsiveness, when comparing placebo and nateglinide.. Microdialysis can now be used to measure the I-insulin in human adipose tissue following a mixed meal. The data also showed that the transendothelial delivery of insulin occurs rapidly, supporting the concept that transcapillary insulin transfer is a nonsaturable process in nondiabetic first-degree relatives of type 2 diabetes patients.

Topics: Adipose Tissue; Adult; Anthropometry; Biological Transport; Cyclohexanes; Diabetes Mellitus, Type 2; Double-Blind Method; Female; Humans; Hypoglycemic Agents; Insulin; Insulin Resistance; Insulin Secretion; Lipolysis; Male; Microdialysis; Middle Aged; Nateglinide; Phenylalanine; Postprandial Period; Regional Blood Flow

The respiratory quotient (RQ) is useful for evaluating glucose and lipid metabolism in vivo. We previously reported that the RQ value, even after fasting, was high in diabetics being treated with sulphonylurea (SU), which might explain the accumulation of fat, leading to weight gain in such individuals. In the present study, we measured the RQ in type II diabetic patients who were being treated with a rapid-onset/short-duration insulinotropic agent, nateglinide, and compared it with those being treated with SU.. A glucose tolerance test was performed in 20 patients with type II diabetes mellitus treated with nateglinide and in 14 patients treated with SU, and the RQ was simultaneously measured.. The RQ values in the patients treated with nateglinide, were similar to those in healthy adults, but was lower than in those treated with SU. No weight gain was observed in patients treated with nateglinide.. A significant weight gain was reported in subjects treated with SU, accompanied by an increase in RQ. However, weight gain was less frequent in diabetics treated with nateglinide.

Topics: Aged; Blood Glucose; Body Weight; Cyclohexanes; Diabetes Mellitus, Type 2; Female; Glyburide; Humans; Hypoglycemic Agents; Insulin Resistance; Lipid Metabolism; Lipids; Male; Middle Aged; Nateglinide; Phenylalanine; Weight Gain

We studied the effects of the oral insulin secretagogue nateglinide on insulin secretion using a modeling approach to obtain beta-cell function parameters from a meal test and examined the impact of the beta-cell improvement on glucose tolerance.. Mild type 2 diabetic men and women (n = 108; fasting glucose 7.0-8.3 mmol/l) on diet treatment alone randomly received 30, 60, or 120 mg nateglinide or placebo for 24 weeks. Beta-cell function parameters were derived by modeling (based on C-peptide deconvolution) from a standardized meal test at baseline and after 24 weeks of treatment.. The baseline demographic and metabolic characteristics of the four groups were similar. Nateglinide treatment resulted in dose-dependent reductions in the mean postprandial glucose response and at the 120-mg dose in fasting glucose. Fasting or total insulin secretion during the meal were not different. In contrast, we found differences in the model parameters. Rate sensitivity (expressing early insulin secretion when glucose is rising) was significantly enhanced at 24 weeks with the lowest nateglinide dose, with no further stimulation at higher doses. Early potentiation (expressing an initial insulin secretion enhancement), glucose sensitivity (the slope of the glucose-insulin secretion relationship), and insulin secretion at a fixed- reference 7-mmol/l glucose concentration all showed a trend toward increasing, with increasing nateglinide dose, and were significantly greater than placebo at the 120-mg dose. In multiple regression analyses, changes in rate sensitivity, glucose sensitivity, and potentiation all contributed to the observed glucose changes.. The model-derived parameters are sensitive measures of beta-cell function, showing improvements after nateglinide treatment and predicting changes in glucose tolerance.

Topics: Aged; Blood Glucose; Cyclohexanes; Diabetes Mellitus, Type 2; Female; Humans; Hypoglycemic Agents; Insulin Resistance; Islets of Langerhans; Male; Middle Aged; Models, Biological; Nateglinide; Phenylalanine; Placebos; Severity of Illness Index

The insulin secretory pattern as a phenotype of type 2 diabetes is an impairment in the rapid, pulsatile secretion of insulin in response to a rise in blood glucose after meal-intake. The restoration of endogenous rapid insulin secretion after oral glucose load was established for the first time by using nateglinide, which is a newly developed insulin secretagogue, in obese patients with type 2 diabetes mellitus. It was clearly demonstrated that with nateglinide, serum insulin levels were quickly raised, and glycemic response curves were almost normalized with the same amount of insulin secretion during 180 min. Therefore, the lack of rapid, pulsatile secretion of insulin in response to glycemic rise after oral glucose load, rather than insulin resistance, is responsible for postprandial glycemic response in obese type 2 diabetes patients.

Topics: Adult; Cyclohexanes; Diabetes Mellitus, Type 2; Female; Glucose; Humans; Hyperglycemia; Hypoglycemic Agents; Insulin; Insulin Resistance; Insulin Secretion; Male; Middle Aged; Nateglinide; Obesity; Phenylalanine; Postprandial Period

Topics: Animals; Diabetes Mellitus, Experimental; Glycogen Synthase Kinase 3 beta; Humans; Insulin; Insulin Resistance; Mice; Microgels; Nateglinide; Phenylalanine

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

Advanced glycation end products (AGEs) and their receptor (RAGE) have been shown to play a role in insulin resistance. We have previously shown that combination therapy with nateglinide (NAT) and telmisartan (TEL) improves postprandial metabolic derangements in Zucker fatty (ZF) rats, an animal model of insulin resistance with obesity. However, effects of combination therapy on insulin resistance remain unknown. We investigated here whether combination therapy with TEL and NAT could ameliorate insulin resistance in ZF rats by suppressing AGE-RAGE axis. NAT and/or TEL inhibited insulin receptor substrate-1 (IRS-1) serine phosphorylations at 307 and 636/639 residues in the liver of ZF rats. Further, combination therapy with NAT and TEL, but not each monotherapy alone, significantly restored the decrease in hepatic IRS-1 tyrosine phosphorylation in these animals. In addition, serum levels of AGEs, RAGE expression levels in the liver and hepatic AGE-RAGE index were decreased in NAT plus TEL-treated ZF rats. The present study suggests that combination therapy with NAT and TEL could ameliorate insulin resistance in ZF rats by suppressing the AGE-RAGE axis in the liver.

Topics: Animals; Benzimidazoles; Benzoates; Cyclohexanes; Disease Models, Animal; Down-Regulation; Drug Therapy, Combination; Glycation End Products, Advanced; Humans; Insulin Resistance; Liver; Male; Nateglinide; Phenylalanine; Rats; Rats, Zucker; Receptor for Advanced Glycation End Products; Receptors, Immunologic; Telmisartan

Insulin resistance prevails not only among diabetic patients but also among hypertensive and obese patients. The relationship between insulin resistance and cardiovascular diseases was investigated in hemodialysis (HD) patients. Eighty-one maintenance HD patients were enrolled. The homeostasis model assessment of insulin resistance (HOMA-IR) method was used to assess insulin resistance. The relationship of HOMA-IR with cardiovascular and all-cause events was assessed. Compared with nondiabetic patients (n = 55), diabetic patients (n = 26) showed higher HOMA-IR (2.5 +/- 0.3 vs 1.4 +/- 0.2, P < .05), lower ankle-brachial pressure index (ABI, 0.85 +/- 0.09 vs 1.12 +/- 0.02, P < .01), and shorter HD duration (3 +/- 1 vs 9 +/- 1 years, P < .01), although their body mass index was similar (22.3 +/- 0.5 vs 21.5 +/- 0.4 kg/m(2)). Nondiabetic patients taking angiotensin-converting enzyme inhibitors or angiotensin receptor blockers (n = 36) had lower HOMA-IR (1.2 +/- 0.2 vs 1.8 +/- 0.4, P < .05) and higher ABI (1.18 +/- 0.02 vs 1.02 +/- 0.05, P < .01) than those without (n = 17). Cardiovascular events were less common in HD patients with normal HOMA-IR (P < .05) or ABI (P < .01). Our data indicate that 69% of diabetic and 27% of nondiabetic patients have HOMA-IR greater than 1.6, implying reduced insulin sensitivity in HD patients. The present results provide evidence that angiotensin inhibition improves insulin resistance, possibly preventing vascular injury in HD patients. Finally, our findings suggest that insulin resistance is prognostic of cardiovascular events in HD patients.

Topics: Aged; Blood Pressure; Carnitine; Cyclohexanes; Diabetic Nephropathies; Female; Homeostasis; Humans; Hypoglycemic Agents; Insulin Resistance; Lipoprotein Lipase; Lipoproteins, LDL; Male; Middle Aged; Nateglinide; Phenylalanine; Regression Analysis; Renal Dialysis; Vascular Diseases

The aim of this study was to investigate the influence of changes in insulin resistance and early insulin secretion on the insulin secretagogic effects of nateglinide.. Oral glucose tolerance testing (OGTT, 75 g) was performed in obese patients before and after weight loss on 2 consecutive days (first day OGTT without nateglinide, second day OGTT with nateglinide), to compare any weight loss associated changes in the nateglinide-induced insulin response to glucose loading.. Reductions in visceral fat, liver fat, skeletal muscle fat and homeostasis model assessment (HOMA)-R due to weight loss were associated with increased Delta insulin 30 min/Delta glucose 30 min (DeltaI30/DeltaG30), and reduced area under the curve (AUC) for plasma glucose as seen in OGTT results. Results from OGTT showed that nateglinide administration was associated with reductions in plasma glucose AUC, both before and after weight loss. Before weight loss, although there was a significant elevation of DeltaI30/DeltaG30 associated with nateglinide treatment, no major change in the insulin-secreting dynamics after glucose loading was observed. After weight loss, nateglinide administration produced a significant increase in DeltaI30/DeltaG30, with insulin secretion peaking more quickly.. Insulin response to nateglinide after glucose loading varied greatly in conjunction with weight loss. This may be accounted for not only by the enhancement of early insulin response to nateglinide associated with the improvement of early insulin response with weight loss but also by the reduced visceral fat, which in turn led to reduced levels of free fatty acids in portal blood and hepatic triglycerides, as well as increased hepatic insulin clearance.

Topics: Adipose Tissue; Administration, Oral; Blood Glucose; C-Peptide; Cyclohexanes; Fatty Acids, Nonesterified; Female; Glucose Tolerance Test; Homeostasis; Humans; Hypoglycemic Agents; Insulin; Insulin Resistance; Insulin Secretion; Liver; Male; Middle Aged; Muscle, Skeletal; Nateglinide; Obesity; Phenylalanine; Weight Loss

Topics: Administration, Oral; Cardiovascular Diseases; Cyclohexanes; Diabetes Complications; Diabetes Mellitus; Drug Therapy, Combination; Glycoside Hydrolase Inhibitors; Humans; Hypoglycemia; Hypoglycemic Agents; Indoles; Inositol; Insulin; Insulin Resistance; Insulin Secretion; Isoindoles; Nateglinide; Phenylalanine; Risk Factors; Stimulation, Chemical; Sulfonylurea Compounds; Thiazolidinediones

Type 2 diabetes is a heterogeneous disorder characterized by defects in the early phase of insulin secretion after meals and in insulin resistance at its early stage. A new insulin secretagogue, nateglinide, has been shown to elicit an acute insulin release and to reduce postprandial hyperglycemia. We have treated 30 patients with type 2 diabetes using nateglinide and performed a standard meal test at breakfast, both before and after the treatment. Insulin resistance and beta-cell function was assessed by the HOMA model. Nateglinide, at 1 and 2 h after the test meal, significantly stimulated postprandial insulin secretion by 62.0 and 41.0% and improved blood glucose values by 17.3 and 21.9%, respectively, after the treatment. Fasting blood glucose (FBG) and glycohemoglobin was significantly reduced by 9.8 and 10.3%, respectively. The reduction was significantly larger in postprandial glucose than in FBG (P<0.0005). A significant correlation was found in the HOMA-insulin resistant (IR) index and in the changes of fasting IRI. When the patients were divided into three groups, forming a markedly insulin resistant (MIR) group, an IR group and a non-insulin resistant (NIR) group, HOMA-IR levels improved significantly, from 7.0 +/- 4.3 to 4.5 +/- 2.8 (P=0.026) in the MIR group and showed a tendency toward improvement in the IR group, from 2.9 +/- 0.7 to 2.3 +/- 1.1 (P=0.062), but failed to exhibit such a positive response in the NIR group, changing from 1.2 +/- 0.2 to 1.9 +/- 0.9 (P=0.21). HOMA-beta, on the other hand, improved significantly in the NIR group only, from 16.4 +/- 7.8 to 26.9 +/- 9.9 (P=0.017), but not in the IR nor MIR groups (M +/- S.D.). In conclusion, nateglinide improved the excessive excursion of postprandial glucose by the augmentation of early insulin secretion after a meal and differentially affected fasting insulin levels and HOMA-IR indexes, depending on the degree of insulin resistance.

Topics: Aged; Blood Glucose; Body Mass Index; Cyclohexanes; Glycated Hemoglobin; Homeostasis; Humans; Hypoglycemic Agents; Insulin; Insulin Resistance; Insulin Secretion; Kinetics; Middle Aged; Models, Biological; Nateglinide; Phenylalanine; Regression Analysis

Topics: Cyclohexanes; Diabetes Mellitus, Type 2; Diabetic Angiopathies; Drug Therapy, Combination; Humans; Hyperglycemia; Hypoglycemic Agents; Insulin Resistance; Metformin; Nateglinide; Phenylalanine; Postprandial Period

Topics: Arteriosclerosis; Blood Glucose; Cyclohexanes; Diabetic Angiopathies; Drug Therapy, Combination; Humans; Hypoglycemic Agents; Insulin; Insulin Resistance; Islets of Langerhans; Metformin; Nateglinide; Phenylalanine; Postprandial Period; Risk

Topics: Blood Glucose; Cardiovascular Diseases; Cyclohexanes; Diabetes Mellitus, Type 2; Drug Therapy, Combination; Fasting; Glucose Tolerance Test; Humans; Hypoglycemic Agents; Insulin Resistance; Metformin; Nateglinide; Patient Selection; Phenylalanine; Postprandial Period; Practice Guidelines as Topic; Predictive Value of Tests

Islet dysfunction, characterized by the loss of an acute insulin secretory response (AIR) to glucose is a well-established pathology of type 2 diabetes mellitus. Using oral insulin secreting agents with very different pharmacodynamic profiles, the present study was undertaken to test the hypothesis that, within the setting of an underlying insulin resistance, changes in the insulin response profile can differentially affect glycaemic control.. The mildly insulin resistant high-fat fed Sprague Dawley (HF) rat and the very insulin resistant Zucker fatty (fa/fa) rat, chronically fitted with indwelling jugular cannula were subjected to an oral glucose load. Compounds were administered 5 min before the oral glucose load. Nateglinide (Nateg) was administered to elicit only an early insulin secretory response and glipizide (Glip) to elicit a later but greater insulin secretory response. Acetaminophen was used as a marker to assess for potential effects of these compounds on gastric emptying rates.. Nateg rapidly increased early insulin release (from -5 to 0) while the effects on total insulin release were similar to those in the controls and glucose excursions were eliminated in both diabetic models with no evidence of sustained hypoglycaemia. Conversely, Glip did not affect early insulin release but increased total insulin release (- 15 to 120 min), but only after the oral glucose load. Glip partially curbed glucose excursions in the mildly insulin resistant HF rodent and was totally ineffective in the very insulin resistant Zucker rat. The differential effects could not be attributed to effects on gastric emptying rates.. These data support the importance of early insulin release in type 2 diabetes mellitus and indicate that, independent of the level of insulin resistance, stimulating insulin release early and briefly provides for more effective and tighter glycaemic control than increasing insulin exposure to a greater magnitude later.

Topics: Animals; Blood Glucose; Cyclohexanes; Diabetes Mellitus, Type 2; Dietary Fats; Gastric Emptying; Glipizide; Glucose Tolerance Test; Hypoglycemic Agents; Insulin; Insulin Resistance; Insulin Secretion; Islets of Langerhans; Kinetics; Male; Nateglinide; Phenylalanine; Rats; Rats, Sprague-Dawley; Rats, Zucker

To test the effects of novel oral hypoglycemic agent A-4166 on lipolysis and lipogenesis in adipocytes from normal rats and non-obese, hypertriglyceridemic, insulin resistant and hypertensive rats (HTG) fed basal or high fat diet.. Adult male Wistar rats and hereditary HTG rats (from our own colony) were used. They were fed either basal or high fat diet for three weeks. On the day of observation the active substance A-4166 was administered intragastrically by gavage 30 minutes before decapitation. Blood was collected for the determination of insulin, glycemia, non esterified fatty acids (NEFA) by using commercial kits. The isolated adipocytes were prepared from epididymal fat pads and lipolysis (by measurement of glycerol release) and lipogenesis (by estimation of labeled glucose incorporation into lipids) were determined.. The administration of A-4166 results in increased serum insulin and decreased serum glucose level in all rats irrespective of the diet. A significant diminution of serum NEFA levels was observed in A-4166 administered Wistar and HTG rats fed high fat diet. In both groups of rats fed basal diet the lipolysis was not affected by A-4166. However, a decrease of lipolysis was found after A-4166 in Wistar rats fed high fat diet. The stimulation of lipolysis by norepinephrine was not influenced by A-4166. A lowered basal lipolysis was found in HTG rats fed high fat diet. The stimulation of lipolysis by norepinephrine was diminished in HTG rats as compared to Wistar animals. Administration of A-4166 did not affect the stimulation of lipolysis by norepinephrine in HTG rats. A decrease of stimulatory action of insulin on lipogenesis was found in Wistar rats fed high fat diet and in all groups of HTG rats. The administration of A-4166 did not change the basal lipogenesis and also the effect of insulin on lipogenesis.. Besides the hyperinsulinemic and hypoglycemic effect of A-4166 also an influence on nonesterified fatty acid serum levels was observed in rats fed high fat diet. This can be partially explained by an antilipolytic action of hyperinsulinemia after A-4166. The studies of lipogenesis showed that Wistar rats fed high fat diet and HTG animals are resistant to the stimulatory action of insulin on lipogenesis and that administration of A-4166 did not affect this response to insulin.

Topics: Adipocytes; Animals; Blood Glucose; Cyclohexanes; Fatty Acids, Nonesterified; Hypertension; Hypoglycemic Agents; Insulin; Insulin Resistance; Lipids; Lipolysis; Male; Nateglinide; Norepinephrine; Phenylalanine; Rats; Rats, Wistar

A-4166, a phenylalanine derivative, is a hypoglycemic agent, which has been shown to improve blood glucose levels mainly due to the rapid and short term stimulation of insulin release. Nevertheless, a possible extrapancreatic action of A-4166 has not yet been investigated. Therefore, insulin action (euglycemic hyperinsulinemic 6.4 mU.kg-1.min-1 clamp plus 3H-2-deoxyglucose tracer administration) was studied after 3 weeks on either standard (BD) or high fat (HF) diet in normal control (C) or in hereditary insulin resistant (hHTg) rats which were given a single dose of A-4166 (10 mg per kg BW, i.v.) 60 min after clamp commencement. HF feeding reduced the glucose infusion rate (GIR) required to maintain euglycemia to about 50% of C (p < 0.001). In hHTg rats, HF did not further pronounce the pre-existing decrease of GIR of hHTg animals fed BD. A-4166 changed GIR neither in C, nor in the hHTg group. The estimated glucose disposal (Rd) (C-BD: 32.3 +/- 1.9 vs C-HF: 25.5 +/- 1.9 mg.kg-1.min-1, p < 0.001) and glucose metabolic index (Rg') in skeletal muscles (Q. femoris: C-BD: 25.6 +/- 1.5 vs C-HF: 12.3 +/- 1.1 mmol.100 g-1.min-1, p < 0.001) were reduced by HF in control rats but were not restored by a concomitant bolus of A-4166. Nevertheless, in hHTg rats fed the HF diet a single dose of A-4166 brought back their Rd (hHTg-HF: 23.5 +/- 1.3 vs hHTg-HF plus A-4166: 31.0 +/- 3.5 p < 0.03) and Rg' (Soleus muscle: hHTg-HF: 29.2 +/- 3.2 vs hHTg-HF plus A-4166: 41.3 +/- 4.0) to values of the control group on BD. In summary, a) a single bolus administration of A-4166 to the control or to the insulin resistant hHTg rats, fed either the BD or HF diets, did not abolish the reduction of GIR required to maintain euglycemia during hyperinsulinemic clamps; b) nevertheless, A-4166 caused a significant increase of the estimated plasma glucose disposal (Rd) and skeletal muscle glucose metabolic index (Rg') of hHTG rats fed the HF diet; c) we suggest that A-4166 may have an extrapancreatic action but this needs to be proven using a long-term administration plan of A-4166.

Topics: Animals; Body Weight; Cyclohexanes; Deoxyglucose; Dietary Fats; Glucose; Glucose Clamp Technique; Hypoglycemic Agents; Insulin Resistance; Male; Nateglinide; Phenylalanine; Phosphorylation; Rats; Rats, Wistar