nateglinide and Obesity

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

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

Topics: 1-Deoxynojirimycin; Acarbose; Aged; Blood Glucose; Carbamates; Contraindications; Cyclohexanes; Diabetes Mellitus, Type 2; Drug Therapy, Combination; Enzyme Inhibitors; Fasting; Follow-Up Studies; Germany; Glucosamine; Glyburide; Glycated Hemoglobin; Glycoside Hydrolase Inhibitors; Humans; Hypoglycemia; Hypoglycemic Agents; Imino Pyranoses; Insulin; Metformin; Middle Aged; Nateglinide; Obesity; Patient Compliance; Phenylalanine; Pioglitazone; Piperidines; Practice Guidelines as Topic; Risk Factors; Rosiglitazone; Sulfonylurea Compounds; Thiazolidinediones; Time Factors

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

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

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

Nateglinide is a novel rapid- and short-acting insulin secretagogue that ameliorates postprandial hyperglycemia by improving insulin secretory dynamics to a near normal level more effectively than sulfonylureas. Recent epidemiological studies have demonstrated that postprandial hyperglycemia can result in arteriosclerosis, and that advanced arteriosclerosis is present in the initial stage of impaired glucose tolerance. Since postprandial hyperglycemia could be well treated by nateglinide, we examined the background factors of type 2 diabetic patients to determine the optimal indication for nateglinide. Our results indicate that nateglinide is most effective in young and obese patients. Furthermore, fewer responders had microangiopathy or were previously on oral hypoglycemic agents or sulfonylureas compared with non-responders. Although nateglinide is generally indicated for patients with mild HbA1c level, the present findings indicate that the drug was effective in the aforementioned patients regardless of pretreatment HbA1c levels. In one obese patient, nateglinide improved late hyperinsulinemia to near normal secretory dynamics. Our findings suggest that nateglinide is a physiologically preferable and useful drug for early type 2 diabetes without microangiopathy.

Topics: Age Factors; Aged; Cyclohexanes; Diabetes Mellitus, Type 2; Female; Glycated Hemoglobin; Humans; Hypoglycemic Agents; Male; Middle Aged; Nateglinide; Obesity; Phenylalanine