ao-128 and Obesity

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: Acarbose; Animals; Diabetes Mellitus, Type 2; Enzyme Inhibitors; Glycoside Hydrolase Inhibitors; Humans; Hyperglycemia; Hyperinsulinism; Hyperlipidemias; Hypoglycemic Agents; Inositol; Obesity; Postprandial Period

To compare the effects of miglitol [an alpha-glucosidase inhibitor (AGI) absorbed in the intestine] and voglibose (an AGI not absorbed) on plasma glucagon-like peptide-1 (GLP-1) and gastric inhibitory polypeptide (GIP) levels, 26 and 24 Japanese type 2 diabetic patients were randomly assigned to receive miglitol or voglibose, respectively. After 12-week administration of both drugs, during 2-h meal tolerance test, plasma glucose, serum insulin and total GIP were significantly decreased and active GLP-1 was significantly increased. Miglitol group showed a significantly lower total GIP level than voglibose group. Miglitol, but not voglibose, significantly reduced body weight (BW). In all participants, the relative change in BW was positively correlated with that of insulin significantly and of GIP with a weak tendency, but not of GLP-1. In conclusion, both drugs can enhance postprandial GLP-1 responses and reduce GIP responses. The significant BW reduction by miglitol might be attributable to its strong GIP-reducing efficacy.

Topics: 1-Deoxynojirimycin; Asian People; Diabetes Mellitus, Type 2; Drug Administration Schedule; Female; Gastric Inhibitory Polypeptide; Glucagon-Like Peptide 1; Humans; Hypoglycemic Agents; Incretins; Inositol; Male; Middle Aged; Obesity; Postprandial Period

Type 2 diabetes mellitus (T2DM) associated with metabolic syndrome (MetS) represents a high risk of cardiovascular disease. We compared the effect of early intervention with pioglitazone versus voglibose on physical and metabolic profiles and serum adiponectin level in patients with T2DM associated with MetS. Sixty patients who were diagnosed for the first time as T2DM associated with MetS were analyzed for insulin sensitivity, lipid profile, serum adiponectin and systemic inflammation. Those patients were randomly assigned to oral pioglitazone group (n = 30) or voglibose group (n = 30) in addition to conventional diet and exercise training. Body mass index and waist circumference did not change in the pioglitazone group, whereas these physical parameters significantly decreased in the voglibose group during a 6-month follow-up period. However, glycosylated hemoglobin, fasting plasma glucose, and HOMA-IR more significantly decreased in the pioglitazone group. The level of serum adiponectin especially high-molecular weight adiponectin markedly increased in the pioglitazone group. Moreover, high sensitive CRP significantly decreased only in the pioglitazone group. These results suggest that voglibose is superior in improving obesity, while pioglitazone is superior in ameliorating insulin sensitivity and increasing serum adiponectin in patients with an early stage of T2DM associated with MetS.

Topics: Adiponectin; Diabetes Mellitus, Type 2; Glycoside Hydrolase Inhibitors; Humans; Hypoglycemic Agents; Inositol; Insulin Resistance; Metabolic Syndrome; Metabolome; Obesity; Pioglitazone; Thiazolidinediones

Postprandial hyperglycemia and hyperlipidemia are considered risk factors for cardiovascular disease. This study was designed to elucidate whether improving the postprandial state by voglibose, an alpha-glucosidase inhibitor, leads to the reduction of oxidative stress markers and soluble adhesion molecules in obese type 2 diabetic patients. A total of 30 Japanese obese type 2 diabetic patients were randomly assigned and treated for 3 weeks with either diet alone (the control group) or diet plus voglibose (0.9 mg daily) (the voglibose group) (n=15 each). Analysis of the diurnal metabolic profiles revealed a significant reduction of postprandial hyperglycemia and hyperlipidemia in the voglibose group relative to the control group (P<.05), despite the similar improvement in body mass index and hemoglobin A(1c) in both groups. Voglibose also decreased significantly the plasma levels of soluble intercellular adhesion molecule 1 and urinary excretion of 8-iso-prostaglandin F(2)alpha and 8-hydroxydeoxyguanosine (P<.01) and C-reactive protein (P<.05) relative to the control group. In conclusion, this study represents the first demonstration that voglibose reduces oxidative stress generation and soluble intercellular adhesion molecule 1 in parallel with the reduction of postprandial hyperglycemia and hyperlipidemia in obese type 2 diabetic patients.

Topics: Adult; Biomarkers; Diabetes Mellitus, Type 2; Female; Glycoside Hydrolase Inhibitors; Humans; Hyperglycemia; Hyperlipidemias; Hypoglycemic Agents; Inositol; Intercellular Adhesion Molecule-1; Japan; Male; Middle Aged; Obesity; Oxidative Stress; Single-Blind Method; Solubility

Topics: Animals; Antioxidants; Azoxymethane; Biomarkers; Biopsy; Cell Proliferation; Colonic Neoplasms; Cytokines; Diabetes Mellitus, Type 2; Disease Models, Animal; Glycoside Hydrolase Inhibitors; Humans; Inflammation Mediators; Inositol; Intestinal Mucosa; Mice; NF-kappa B; Obesity; Oxidative Stress; Precancerous Conditions

Soft-drink diabetic ketosis, characterized by acute onset ketosis induced by excessive ingestion of sugar-containing drinks, is often seen in obese, young patients, even with undiagnosed type 2 diabetes. We herein report a 15-year-old obese patient with the apolipoprotein E4/2 phenotype, in whom eruptive xanthomas lead to a diagnosis of soft-drink diabetic ketosis. He developed multiple asymptomatic yellowish papules on the auricles, back, buttocks and the extensor surfaces of the elbows and knees. He initially visited a dermatology clinic and his blood triglyceride and HbA1c levels were found to be 6,490 mg/dL and 16.5%, respectively. He was referred to our hospital for treatment of hyperglycemia and hypertyriglyceridemia. On admission, he had ketonuria and increased blood levels of 3-hydroxybutylate and acetoacetate. He habitually drank 1-3 litters of sweet beverages daily to quench his thirst. Therefore, "soft-drink diabetic ketosis" was diagnosed. Severe hypertriglyceridemia was considered to have been a consequence of impaired insulin action and his apolipoprotein E4/2 phenotype. We treated the diabetic ketosis and hypertriglyceridemia with intensive insulin therapy and a fat-restricted diet. At discharge, he no longer required insulin therapy and his blood glucose levels were controlled with metformin and voglibose. Along with amelioration of the hyperglycemia, triglyceride levels decreased to 247 mg/dL without administration of anti-hyperlipidemia agents. The eruptive xanthoma lesions gradually diminished in size and number and eventually disappeared by 12 months. This case provides an instructive example of eruptive xanthomas serving as a sign of severe dysregulation, not only of lipid, but also glucose, metabolism.

Topics: 3-Hydroxybutyric Acid; Acetoacetates; Adolescent; Apolipoprotein E2; Apolipoprotein E4; Carbonated Beverages; Diabetes Mellitus, Type 2; Diabetic Ketoacidosis; Diet, Fat-Restricted; Glycated Hemoglobin; Humans; Hypertriglyceridemia; Hypoglycemic Agents; Inositol; Insulin; Ketosis; Male; Metformin; Obesity; Xanthomatosis

Administration of an alpha-glucosidase inhibitor, voglibose, increases the secretion of glucagon-like peptide (GLP)-1, a key modulator of pancreatic islet hormone secretion and glucose homeostasis. In the present study, novel mechanisms by which voglibose increases active GLP-1 circulation were evaluated. Voglibose (0.001 and 0.005%) was administered in the diet to ob/ob mice for 1 day or 3 to 4 weeks to determine effects on incretin profiles and plasma activity of dipeptidyl peptidase-4 (DPP-4), an enzyme responsible for GLP-1 degradation. Voglibose showed no direct inhibitory effect against DPP-4 in vitro (DPP-4 inhibitor alogliptin, IC(50) < 10 nM). Likewise, 1-day treatment with voglibose did not change plasma DPP-4 activity; however, it increased plasma active GLP-1 by 1.6- to 3.4-fold. After chronic treatment, voglibose stimulated GLP-1 secretion, as evidenced by the 1.3- to 1.5-fold increase in plasma active plus inactive amidated GLP-1 levels. Plasma DPP-4 activity was decreased unexpectedly by 40 to 51%, resulting from reduced plasma DPP-4 concentrations in voglibose-treated mice. Voglibose increased GLP-1 content by 1.5- to 1.6-fold and 1.4- to 1.6-fold in the lower intestine and colon, respectively. The increased GLP-1 content in the colon was associated with elevated expression of gut glucagon gene. Chronic treatment with voglibose resulted in 1.9- to 4.1-fold increase in active GLP-1 circulation, which was higher than 1-day treatment. A similar treatment with pioglitazone (0.03%), an insulin sensitizer, did not affect plasma DPP-4 activity or GLP-1 levels. These results suggest that increased GLP-1 secretion, decreased DPP-4 activity, and increased gut GLP-1 content may have contributed to increased active GLP-1 circulation after chronic treatment with voglibose in a glucose control-independent manner in ob/ob mice.

Topics: Animals; Blood Glucose; Diabetes Mellitus, Experimental; Dipeptidyl Peptidase 4; Dipeptidyl-Peptidase IV Inhibitors; Dose-Response Relationship, Drug; Gene Expression; Glucagon; Glucagon-Like Peptide 1; Glycoside Hydrolase Inhibitors; Hypoglycemic Agents; Inositol; Intestinal Mucosa; Male; Mice; Mice, Inbred C57BL; Mice, Obese; Obesity; Time Factors

The age-related changes in acute insulin response after glucose loading and the influence of suppression of body weight gain were investigated by using blood samples from portal and peripheral veins. We placed indwelling catheters in the portal vein of 12- and 24- wk-old Otsuka Long-Evans Tokushima fatty (OLETF) rats (n = 8, 12), and age-matched control Long-Evans Tokushima Otsuka (LETO) rats (n = 8, 6). To suppress the body weight gain, 6 out of 12 OLETF rats were fed chow containing 50 ppm voglibose (VOG) from 8 until 24 wk of age. After fasting for 17 h, rats underwent 1 g/kg oral glucose tolerance test (OGTT). Peripheral glucose levels after glucose loading were significantly higher in 12- and 24-wk-old OLETF rats than in the age-matched LETO rats. Values for delta insulin 15 min/delta glucose 15 min (delta I15 min/delta G15 min) in portal blood were 0.029 +/- 0.011 and 0.009 +/- 0.009 (12 wk of age) and 0.03 +/- 0.03 and -0.01 +/- 0.01 (24 wk of age) in the LETO rats and OLETF rats. At the age of 24 wk, the body weights in VOG-treated OLETF rats were significantly lower than those in the OLETF rats. And there was significantly greater acute insulin response to glucose in VOG-treated OLETF rats than in the OLETF rats. Acute insulin response to glucose decreased with advancing age and the suppression of body weight gain preserved the response in spontaneously type 2 diabetic rats with visceral fat obesity.

Topics: Animals; Blood Glucose; Diabetes Mellitus, Type 2; Fatty Acids, Nonesterified; Glucose; Glucose Tolerance Test; Hypoglycemic Agents; Immunohistochemistry; Inositol; Insulin; Islets of Langerhans; Obesity; Portal Vein; Prediabetic State; Rats; Rats, Inbred OLETF; Weight Gain

Alpha-glucosidase inhibitor can suppress postprandial hyperglycemia by delaying the absorption of carbohydrates in the intestine, and may be useful in obese patients with non-insulin-dependent diabetes mellitus (NIDDM) and preserved insulin secretion. We encountered an obese elderly patient with NIDDM in whom gait disturbance had developed after cerebral hemorrhage and who suffered from ileus after treatment with voglibose. The patient had received voglibose which is reported to cause fewer abdominal symptoms than acarbose, for 15 days. The patient, a 63-year-old woman, was given a diagnosis of NIDDM in February 1995, and was treated with a sulfonylurea agent. However, her glycemic control remained poor and she was admitted to our hospital in April 1995. Her body mass index was 30.5 kg/m2 and laboratory investigation revealed a fasting plasma glucose level of 211 mg/dl, a postprandial (2 h) plasma glucose level of 288 mg/dl, HbAlc of 9.9%, a fasting insulin level of 9 microU/ml, urinary C-peptide excretion of 95.7 micrograms/ day, and an coefficient of variation of R-R value of 2.1%. Fifteen days after glibenclamide was replaced by to voglibose, abdominal pain, nausea, constipation, and ausculatory sounds of gurgling developed, and niveau were noted on an abdominal roentgenogram which indicated that simple ileus had developed. Voglibose was discontinued and the patient was treated with an enema and hot air. She recovered from simple ileus on the next day. This patient had had two abdominal surgeries and a cerebral hemorrhage, and her daily physical activities were limited, which might have contributed to ileus. In elderly patients with NIDDM, a history of abdominal surgery and the amount of daily exercise must be considered when deciding whether or not to give alpha-glucosidase inhibitors.

Topics: Cerebral Hemorrhage; Cyclohexanols; Diabetes Mellitus; Diabetes Mellitus, Type 2; Enzyme Inhibitors; Female; Gait; Glycoside Hydrolase Inhibitors; Humans; Intestinal Obstruction; Middle Aged; Obesity

Antiobesity and antidiabetic actions of the alpha-glucosidase inhibitor AO-128 were examined using genetically obese-diabetic rats, Wistar fatty. Ten-week-old, male fatty rats were kept on CE-2 diet containing 10 or 25 ppm of AO-128 for 4 weeks. The average drug intake was calculated to be 0.74 or 1.78 mg/kg/day from the average food intake, respectively. The intestinal maltase and sucrase activities were decreased by AO-128 in a dose-related fashion. Food intake of fatty rats treated with AO-128 was decreased throughout the experiment. This decrease in food intake could hardly be explained only by diarrhea which occurred for the first 5 days of the administration of AO-128. AO-128 normalized hyperglycemia and markedly reduced hypertriglyceridemia and hyperinsulinemia in fatty rats. In addition, AO-128 decreased body weight gain, food efficiency, epididymal adipose tissue weight, carcass weight, and body fat deposition. These findings indicate that AO-128 may be useful for treating human obesity and diabetes.

Topics: Animals; Body Weight; Cyclohexanols; Diabetes Mellitus; Eating; Enzyme Inhibitors; Glycoside Hydrolase Inhibitors; Male; Obesity; Rats; Rats, Wistar

AO-128 is a potent and structurally novel inhibitor of the intestinal disaccharidases, such as maltase and sucrase. Genetically obese-diabetic mice, KKA(y), were used to examine the acute or long-term effectiveness of this compound. AO-128 decreased a postprandial rise in blood glucose after sucrose solution loading dose-dependently; the ED50 to reduce a delta increment of blood glucose by 50% was 0.22 mg/kg. The intestinal sucrase and maltase activities were suppressed to 7 and 48% of the control levels, respectively, at a dose of 0.21 mg/kg. Four-week-old female KKA(y) mice were kept on a laboratory diet containing 10 or 50 ppm of AO-128 for 12 weeks. The high dose of AO-128 reduced food intake and body weight gain throughout the experimental period. On the other hand, the low dose reduced body weight gain for the first 4 weeks without any effect on food intake. Development of the hyperglycemia and hyperinsulinemia characteristic of KKA(y) mice was moderately prevented by the low dose, and completely by the high dose. Hypertriglyceridemia tended to be suppressed by the AO-128 treatment. The high dose decreased the hemoglobin A1 level and parametrial adipose tissue weight. Hepatomegaly and fatty liver were ameliorated by AO-128 dose-dependently. Nephropathy was ameliorated by the high dose. These findings indicate that AO-128 may be useful for treating human obesity and diabetes.

Topics: Animals; Blood Glucose; Cyclohexanols; Diabetes Mellitus, Experimental; Female; Glycoside Hydrolase Inhibitors; Intestine, Small; Kidney; Liver; Mice; Mice, Inbred Strains; Obesity; Sucrase

A new disaccharidase inhibitor, AO-128, showed 190-3900-fold more potent inhibition of purified rat small intestine sucrase-isomaltase (S-1) complex and 23-33-fold more potent inhibition of semipurified porcine small intestine disaccharidases than acarbose. AO-128 suppressed elevation of the blood glucose concentration after oral sucrose, maltose, and starch, but not after oral glucose, fructose, and lactose. The chronic addition of AO-128 to the diet produced antiobesity and antidiabetic actions in obese and/or diabetic animals. Undesirable side effects, such as diarrhea and soft feces, were observed only for the first 5-7 d and suppression of intestinal disaccharidase activities was observed even at the end of the experiment, suggesting that the suppressive or delaying effect of AO-128 on elevation of the postprandial blood glucose concentrations is involved in reduction in body weight gain and prevention and/or amelioration of the diabetic state. Thus, AO-128 is useful as an adjunct to the dietary management of obesity and diabetes.

Topics: Acarbose; Animals; Cyclohexanols; Diabetes Mellitus, Experimental; Disaccharidases; Glycoside Hydrolase Inhibitors; Intestines; Male; Obesity; Oligo-1,6-Glucosidase; Rats; Rats, Inbred Strains; Rats, Zucker; Sucrase; Trisaccharides

Topics: 1-Deoxynojirimycin; Adipose Tissue; Animals; Cyclohexanols; Diet, Reducing; Disaccharides; Exercise Therapy; Glycoside Hydrolase Inhibitors; Humans; Obesity; Skin; Sucrase; Viscera

The relationship between mesenteric fat accumulation and metabolic disorder was studied in genetically obese Zucker fatty rats. These animals had high levels of plasma glucose, triglyceride and total cholesterol as well as increased liver triglyceride in comparison with lean rats. In addition, portal free fatty acid (FFA) levels were also higher in fatty rats than in lean rats. Direct measurement of fat weight revealed a substantial increase of mesenteric as well as subcutaneous fat. The volume of mesenteric fat cells was greater than that of subcutaneous fat cells in Zucker fatty rats (1.67 +/- 0.49 nl versus 1.00 +/- 0.31 nl), although the mesenteric fat cell volume was less than half of the subcutaneous fat cell volume (0.05 +/- 0.02 nl versus 0.14 +/- 0.07 nl) in lean rats. An increase in mesenteric fat cell volume was thus more predominant than that of subcutaneous fat cells in the fatty rats. Administration of AO-128 (50 p.p.m./day), a new alpha-glucosidase inhibitor, caused a substantial reduction of mesenteric fat weight accompanied by a marked decrease in fat cell volume in Zucker fatty rats. The drug also caused a significant reduction of FFA levels in the portal vein in parallel with a marked reduction of triglyceride content in the liver. These observations indicate that the fat accumulation in the markedly enlarged mesenteric fat cells is related to the elevated levels of FFA in the portal vein, which in turn may cause metabolic disorders in the liver. A new alpha-glucosidase inhibitor improves these disorders, at least in part, by preventing an enlargement of mesenteric fat cells.

Topics: Adipose Tissue; Animals; Cyclohexanols; Fatty Acids, Nonesterified; Female; Glycoside Hydrolase Inhibitors; Obesity; Rats; Rats, Zucker; Viscera

Topics: Administration, Oral; Animals; Cyclohexanols; Fatty Liver; Glycoside Hydrolase Inhibitors; Lipid Metabolism; Liver; Obesity; Rats; Rats, Zucker