ao-128 and Hyperglycemia

Topics: 1-Deoxynojirimycin; Acarbose; Aged; Blood Glucose; Cardiovascular Diseases; Diabetes Mellitus, Type 2; Glycoside Hydrolase Inhibitors; Humans; Hyperglycemia; Hypoglycemic Agents; Inositol; Metformin; Prediabetic State

Alpha-glucosidase inhibitors have been available for clinical use for about 20 years. They have shown reasonably good efficacy comparable to other oral blood glucose lowering drugs and in some parts of the world are the most commonly prescribed oral diabetes medication, especially in Asian countries. Unlike as has been observed with some other blood glucose lowering agents, however, no adverse signals of potential cardiovascular harm have emerged in relation to their use. On the contrary, significant beneficial cardiovascular outcome results have been observed in the post-hoc analyses of randomised placebo-controlled trials with the alpha-glucosidase inhibitor acarbose. Targeting mainly postprandial hyperglycaemia, alpha-glucosidase inhibitors favourably affect several cardiovascular risk factors, such as obesity, hypertension and high glycaemic variability with little to no risk for hypoglycaemia. Furthermore, acarbose favourably affects endothelial dysfunction and carotid intima media thickening in humans and, in animal models, improves cardiac interstitial fibrosis and hypertrophy of cardiomyocytes. The ultimate determination of the cardiovascular effects of alpha-glucosidase inhibitors in terms of clinical outcomes awaits the results of ongoing long-term, randomised, placebo-controlled trials.

Topics: 1-Deoxynojirimycin; Acarbose; Cardiovascular Diseases; Diabetes Complications; Glycoside Hydrolase Inhibitors; Humans; Hyperglycemia; Hypoglycemic Agents; Inositol

Topics: Animals; Carbohydrate Metabolism; Diabetes Mellitus, Type 2; Enzyme Inhibitors; Glucose Intolerance; Glycoside Hydrolase Inhibitors; Humans; Hyperglycemia; Hypoglycemic Agents; Inositol; Insulin; Insulin Secretion; Intestinal Absorption; Male; Middle Aged; Randomized Controlled Trials as Topic

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

Topics: Acarbose; Clinical Trials as Topic; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Drug Therapy, Combination; Glycoside Hydrolase Inhibitors; Humans; Hyperglycemia; Hypoglycemic Agents; Inositol; Insulin; Postprandial Period

It is widely accepted that the most challenging goal in the management of patients with diabetes mellitus is to achieve blood glucose levels as close to normal as possible. In general, normalising postprandial blood glucose levels is more difficult than normalising fasting hyperglycaemia. In addition, some epidemiological studies suggest that postprandial hyperglycaemia (PPHG) or hyperinsulinaemia are independent risk factors for the development of macrovascular complications of diabetes mellitus. Recently, several drugs with differing pharmacodynamic profiles have been developed which target PPHG. These include insulin lispro, amylin analogues, alpha-glucosidase inhibitors and meglitinide analogues. Insulin lispro has a more rapid onset of action and shorter duration of efficacy compared with regular human insulin. In clinical trials, the use of insulin lispro was associated with improved control of PPHG and a reduced incidence of hypoglycaemic episodes. Repaglinide, a meglitinide analogue, is a short-acting insulinotropic agent which. when given before meals, stimulates endogenous insulin secretions and lowers postprandial hyperglycaemic excursions. Both insulin lispro and repaglinide are associated with postprandial hyperinsulinaemia. In contrast, amylin analogues reduce PPHG by slowing gastric emptying and delivery of nutrients to the absorbing surface of the gut. Alpha-Glucosidase inhibitors such as acarbose, miglitol and voglibose also reduce PPHG primarily by interfering with the carbohydrate-digesting enzymes and delaying glucose absorption. With the availability of agents which preferentially reduce postprandial blood glucose excursions, it is now possible to achieve glycaemic goals in a larger proportion of individuals with diabetes mellitus.

Topics: 1-Deoxynojirimycin; Acarbose; Amyloid; Carbamates; Diabetes Mellitus; Enzyme Inhibitors; Glucosamine; Glyburide; Humans; Hyperglycemia; Hypoglycemic Agents; Imino Pyranoses; Inositol; Insulin; Insulin Lispro; Islet Amyloid Polypeptide; Piperidines; Postprandial Period; Trisaccharides

Topics: Acarbose; Diabetes Mellitus, Type 2; Diet, Diabetic; Exercise Therapy; Humans; Hyperglycemia; Hypoglycemic Agents; Inositol; Insulin; Insulin Resistance; Postprandial Period; Sulfonylurea Compounds; Trisaccharides

We assessed the efficacy and safety of sitagliptin compared with α-glucosidase inhibitor (αGI) in 120 of Japanese patients with type 2 diabetes mellitus (T2DM) inadequately controlled on stable ≤2 mg/day glimepiride alone [mean hemoglobin A1c (HbA1c) 7.7%] by the randomized, active-controlled, non-inferiority trial. Patients were randomly assigned to receive additional sitagliptin or αGI for 24 weeks. The primary endpoint was change in HbA1c from baseline to week 12. After 12 weeks, sitagliptin reduced HbA1c by -0.44% (p < 0.001) relative to αGI. At 24 weeks, the reduction was almost identical between the groups (-0.091%, p = 0.47). Gastrointestinal disorders were more common with αGI than with sitagliptin, but only minor hypoglycaemia occurred in both groups at similar frequency. These data suggested that sitagliptin was not inferior to αGI for reduction of HbA1c in Japanese T2DM patients receiving glimepiride alone, and well tolerated with minimum risk of gastrointestinal symptoms and hypoglycaemia.

Topics: 1-Deoxynojirimycin; Aged; alpha-Glucosidases; Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV Inhibitors; Drug Therapy, Combination; Female; Gastrointestinal Agents; Glycated Hemoglobin; Glycoside Hydrolase Inhibitors; Humans; Hyperglycemia; Hypoglycemia; Hypoglycemic Agents; Inositol; Japan; Male; Middle Aged; Pyrazines; Sitagliptin Phosphate; Sulfonylurea Compounds; Triazoles

Postprandial hyperglycemia and blood glucose fluctuations increase the risk of macroangiopathy in patients with type 2 diabetes mellitus (T2DM). However, few studies have examined the effects of oral hypoglycemic drugs on blood glucose fluctuations in daily life.. Twenty-nine T2DM patients treated with acarbose were randomized to receive either sitagliptin (14 patients) or mitiglinide (15 patients) together with acarbose for 4 weeks. Patients were then switched to a combination of 10 mg mitiglinide and 0.2 mg voglibose for 4 weeks. All patients wore a continuous glucose monitoring (CGM) device for 5 - 7 days in week 3 of each treatment period.. The percentage of blood glucose levels in the hyperglycemic range, blood glucose indices derived from 24-h CGM profiles and the glycemic parameters (HbA1c, glycated albumin and fasting plasma glucose) were significantly improved by adding sitagliptin or mitiglinide to ongoing acarbose therapy. These parameters also tended to improve in the mitiglinide/voglibose combination period.. Daily blood glucose fluctuations were significantly improved by adding sitagliptin or mitiglinide to acarbose, and improved after switching to the mitiglinide/voglibose combination. Larger controlled studies are needed to verify the effects of adding sitagliptin or mitiglinide to acarbose on glucose fluctuations.

Topics: Acarbose; Aged; Asian People; Blood Glucose; Diabetes Mellitus, Type 2; Drug Substitution; Drug Therapy, Combination; Female; Glycated Serum Albumin; Glycation End Products, Advanced; Humans; Hyperglycemia; Hypoglycemic Agents; Inositol; Isoindoles; Male; Middle Aged; Prospective Studies; Pyrazines; Serum Albumin; Sitagliptin Phosphate; Triazoles

The effects of the mitiglinide/voglibose fixed-dose combination on postprandial glycemic/metabolic responses in patients with type 2 diabetes mellitus (T2DM) treated with dipeptidyl peptidase-4 (DPP-4) inhibitors are unknown.. Twelve T2DM patients treated with a DPP-4 inhibitor underwent identical meal tolerance tests (MTTs) at breakfast, lunch and dinner, before and 2 - 3 weeks after treatment with a fixed-dose combination of mitiglinide 10 mg and voglibose 0.2 mg (combination). Patients were randomized in a cross-over fashion to administer the combination either three-times-daily before each meal or twice-daily before breakfast and dinner. Glycemic/metabolic responses were evaluated at 0, 30, 60 and 120 min in each MTT.. Three-times-daily administration of the combination significantly suppressed postprandial hyperglycemia after each meal, particularly after lunch and dinner. Active glucagon-like peptide-1 levels increased significantly after each meal, as did early-phase insulin secretion without excessive insulin secretion. Postprandial hyperglycemia after lunch was significantly greater after twice-daily than three-times-daily administration, but there were no clinically relevant differences in other metabolic responses.. This study revealed that adding the mitiglinide/voglibose combination to a DPP-4 inhibitor elicited additive improvements in postprandial glycemic/metabolic responses assessed using MTTs at breakfast, lunch and dinner with identical meal compositions.

Topics: Aged; Blood Glucose; Breakfast; Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV Inhibitors; Drug Combinations; Drug Therapy, Combination; Female; Glucagon-Like Peptide 1; Humans; Hyperglycemia; Hypoglycemic Agents; Inositol; Insulin; Insulin Secretion; Isoindoles; Lunch; Male; Meals; Middle Aged; Postprandial Period

We examined the effects of a fixed-dose combination of 10 mg mitiglinide and 0.2 mg voglibose on postprandial glycemic excursions in Japanese type 2 diabetes mellitus (T2DM) patients.. After a 2-week baseline period, 11 T2DM patients were treated with mitiglinide alone for 2 weeks and with the mitiglinide/voglibose combination for 6 weeks.. Self-monitoring of blood glucose (SMBG) at home before and after unified meals, metabolic parameters during meal tolerance tests, and overall glycemic control parameters.. Postprandial glycemic excursions after all three meals, as assessed by SMBG, were significantly lower in the combination period than in the baseline period, and after lunch and dinner in the combination period than in the mitiglinide period. The meal tolerance test confirmed that the magnitude of postprandial hyperglycemia was significantly lower, with significantly greater early-phase serum insulin secretion and sustained GLP-1 production, in the combination period compared with the baseline period. Overall glycemic control parameters also improved significantly in the combination period compared with the baseline period. These profiles suggest the combination is superior to mitiglinide alone, and may spare insulin secretion.. The mitiglinide/voglibose combination significantly reduced postprandial glycemic excursions in Japanese T2DM patients. This trial was registered with the University Hospital Medical Information Network clinical trials database (no. UMIN000007202).

Topics: Blood Glucose; Diabetes Mellitus, Type 2; Drug Administration Schedule; Drug Combinations; Female; Humans; Hyperglycemia; Hypoglycemic Agents; Inositol; Isoindoles; Japan; Lipids; Male; Middle Aged; Postprandial Period; Treatment Outcome

The objective of this study was to compare the effects of mitiglinide, voglibose and its combination on metabolic responses after a test meal in Japanese patients with type 2 diabetes mellitus (T2DM).. This randomized crossover study consisted of four periods between August and November 2011. In the first period, all patients (n = 12) received water alone (control period). In the next three periods, the patients received 10 mg mitiglinide, 0.2 mg voglibose or a combination in a random order.. Postprandial metabolite/hormone levels were then measured.. Plasma glucose and serum insulin reached peak levels by 60 - 90 and 90 min, respectively, after the test meal in the control group. The combination reduced postprandial glucose levels compared with mitiglinide or voglibose alone, particularly at 30 - 90 min, which significantly exceeded the effects of mitiglinide (p < 0.05). Mitiglinide and the combination restored early insulin response, whereas the combination provided an insulin-sparing effect compared with mitiglinide alone. The combination improved postprandial lipid profiles, combining the effects of both drugs.. This study revealed marked differences in the postprandial metabolic effects of mitiglinide, voglibose and its combination in patients with T2DM. The combination therapy should enable tighter control of postprandial hyperglycemia compared with the individual drugs.

Topics: Aged; Asian People; Blood Glucose; Cross-Over Studies; Diabetes Mellitus, Type 2; Drug Combinations; Female; Glucagon; Humans; Hyperglycemia; Hypoglycemic Agents; Inositol; Insulin; Isoindoles; Male; Middle Aged

Mitiglinide, a rapid- and short-acting insulinotropic sulfonylurea receptor ligand, exhibits hypoglycemic action unlike other sulfonylureas. The efficacy of the combination of mitiglinide and alpha-glucosidase inhibitors for diabetic patients on hemodialysis (HD) has not been prospectively evaluated; therefore, we evaluated the efficacy and safety of mitiglinide in these patients.. We performed an open-label randomized study with 36 type 2 diabetics with poor glycemic control on HD and receiving daily doses of voglibose (0.9 mg). The patients were randomly assigned to two groups: a combination-therapy group (mitiglinide group), mitiglinide initial dose 7.5 - 15 mg titrated to 30 mg daily and constant daily dose 0.9 mg of voglibose, and a monotherapy group (control group), constant daily dose 0.9 mg of voglibose alone. The efficacy of the treatment was determined by monitoring plasma glucose, hemoglobin A1c (Hb(A1c)), and glycated albumin (GA) levels and using homeostasis model assessment of insulin resistance (HOMA-IR). Safety and tolerance were determined by monitoring clinical and laboratory parameters.. The final dose of mitiglinide was 22.9 +/- 8.9 (mean +/- s.d.) mg (0.41 mg/kg) daily. Mitiglinide reduced fasting plasma glucose and GA levels after 4 weeks and Hb(A1c) levels after 8 weeks. Triglyceride levels and HOMA-IR values also decreased significantly after mitiglinide treatment. No significant changes in blood pressure levels or serious adverse effects such as hypoglycemia or liver impairment were observed.. This study suggests a combination therapy of mitiglinide and voglibose may have potential for the treatment of diabetics on HD. Due to the small sample size used, further studies should be performed, particularly to assess the safety of mitiglinide treatment.

Topics: Aged; Diabetes Mellitus, Type 2; Female; Glycated Hemoglobin; Humans; Hyperglycemia; Hypoglycemia; Hypoglycemic Agents; Inositol; Isoindoles; Male; Renal Dialysis; Treatment Outcome

Good compliance with hypoglycemic therapy is important for diabetes treatment, since positive relationship between medication compliance and glycemic control has been reported. To improve medication compliance, the oral disintegrating tablet technology that facilitates drug administration without water has been employed in various drugs, including voglibose, an alpha glucosidase inhibitor. In the present survey, we investigated safety profile of voglibose oral disintegrating tablet (VODT), and whether treatment with VODT results in improvement of medication compliance and glycemic control. Patients with diabetes received VODT 0.6 or 0.9 mg/day for 12 weeks. Among 2,930 eligible patients, adverse drug reactions were observed in 3.6%, with the most common being abdominal distension, flatulence, diarrhea, and increased alanine aminotransferase levels. In 1,067 patients who received conventional voglibose tablet (CVT) prior to VODT, 53.1% reported that taking VODT was easier than taking CVT. Medication compliance was improved after switching to VODT in 28.4% of patients who missed taking tablets more than one time a week during CVT treatment. A significant decrease in HbA(1C) levels was observed in patients whose medication compliance was improved after switching to VODT (P = 0.033), but there was no significant reduction in HbA(1C) levels in patients whose medication compliance did not change. In conclusion, the present survey suggests that the safety profile of VODT is comparable with that of CVT, and switching from CVT to VODT has positive impact on medication compliance which may lead to an improvement in glycemic control.

Topics: Administration, Oral; Aged; Female; Glycated Hemoglobin; Humans; Hyperglycemia; Hypoglycemic Agents; Inositol; Male; Medication Adherence; Middle Aged; Tablets

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

The present study was designed to determine the possible significance of a therapeutic dose (0.2 mg) of AO-128 on carbohydrate absorption by measuring the breath hydrogen concentration, which is an index of the amount of unabsorbed carbohydrate in the large intestine. Post-prandial hyperglycemia is common among diabetic patients. AO-128, a potent alpha-glucosidase inhibitor, suppressed post-prandial hyperglycemia and hyperinsulinemia in healthy volunteers at a dose of 0.2 mg with each meal. These volunteers increased the breath hydrogen concentration in response to ingestion of non-absorbable lactulose, but decreased only slightly its concentration from the basal level after sucrose ingestion, indicating complete absorption. When AO-128 (0.2 mg) was given with sucrose, hydrogen production increased only slightly compared with placebo, suggesting that the inhibitory effect of AO-128 on sucrose absorption was minimal. Only 5 g of the 100 g of sucrose was not absorbed and this 5% reduction is too small to explain the observed inhibitory effect on the post-prandial rise in plasma glucose. Sucrose loading in rats (about 443 mg) sharply increased blood glucose and was accompanied by the rapid disappearance of sucrose from the upper small intestine. AO-128 (0.03 or 0.1 mg/kg) lessened the elevation of blood glucose after sucrose ingestion. The lower dose (0.03 mg/kg) retarded small intestinal absorption, but did not induce an influx of sucrose into the cecum and large intestine, while the higher dose (0.1 mg/kg) caused an increased influx of sucrose into the large bowel. These results indicated that AO-128 retards the absorption of carbohydrate and reduces post-prandial hyperglycemia.

Topics: Adolescent; Adult; Animals; Blood Glucose; Cross-Over Studies; Cyclohexanols; Dietary Carbohydrates; Eating; Enzyme Inhibitors; Glycoside Hydrolase Inhibitors; Humans; Hydrogen; Hyperglycemia; Hyperinsulinism; Intestinal Absorption; Male; Rats; Rats, Sprague-Dawley; Respiration; Single-Blind Method; Sucrose

Topics: Animals; Hyperglycemia; Inflammation; Inositol; Male; Polymers; Rats

Postprandial hyperglycemia considered to be a major risk factor for cerebrovascular complications.. The current study was designed to elucidate the beneficial role of voglibose via in-silico in vitro to in-vivo studies in improving the postprandial glycaemic state by protection against strokeprone type 2 diabetes.. In-Silico molecular docking and virtual screening were carried out with the help of iGEMDOCK+ Pymol+docking software and Protein Drug Bank database (PDB). Based on the results of docking studies, in-vivo investigation was carried out for possible neuroprotective action. T2DM was induced by a single injection of streptozotocin (90mg/kg, i.v.) to neonates. Six weeks after induction, voglibose was administered at the dose of 10mg/kg p.o. for two weeks. After eight weeks, diabetic rats were subjected to middle cerebral artery occlusion, and after 72 hours of surgery, neurological deficits were determined. The blood was collected for the determination of serum glucose, CK-MB, LDH and lipid levels. Brains were excised for determination of brain infarct volume, brain hemisphere weight difference, Na+-K+ ATPase activity, ROS parameters, NO levels, and aldose reductase activity.. In-silico docking studies showed good docking binding score for stroke associated proteins, which possibly hypotheses neuroprotective action of voglibose in stroke. In the present in-vivo study, pre-treatment with voglibose showed a significant decrease (p<0.05) in serum glucose and lipid levels. Voglibose has shown significant (p<0.05) reduction in neurological score, brain infarct volume, the difference in brain hemisphere weight. On biochemical evaluation, treatment with voglibose produced significant (p<0.05) decrease in CK-MB, LDH, and NO levels in blood and reduction in Na+-K+ ATPase, oxidative stress, and aldose reductase activity in brain homogenate.. In-silico molecular docking and virtual screening studies and in-vivo studies in MCAo induced stroke, animal model outcomes support the strong anti-stroke signature for possible neuroprotective therapeutics.

Topics: Animals; Cerebrovascular Disorders; Computer Simulation; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 2; Disease Models, Animal; Drug Evaluation, Preclinical; Humans; Hyperglycemia; Infarction, Middle Cerebral Artery; Inositol; Lipids; Molecular Docking Simulation; Neuroprotective Agents; Nitric Oxide; Rats; Risk Factors; Sodium-Potassium-Exchanging ATPase; Software; Stroke; User-Computer Interface

Insulin injection, especially with insulin analogs, occasionally induces the production of insulin antibodies with high binding capacity and low affinity, similar to the insulin autoantibodies characteristic of insulin autoimmune syndrome (IAS). Production of these "IAS-like" insulin antibodies causes marked glycemic fluctuations with postprandial hyperglycemia and fasting hypoglycemia.. A 66-year-old man with a 27-year history of diabetes was admitted because of marked glycemic fluctuations. Human insulin treatment had been initiated at age 56, followed by multiple daily injections of insulin analogs 5 years later. After the initial year of insulin analog treatment, the patient began to experience frequent morning hypoglycemic attacks and day-time hyperglycemia. Marked hyperinsulinemia (4500 μU/mL) and high titers of insulin antibodies (80.4%) with high binding capacity and low affinity indicated that IAS-like insulin antibodies were causing severe glucose fluctuations. Altering insulin formulations (insulin aspart → regular human insulin→ insulin lispro) proved to be ineffective. After several therapeutic trials, cessation of exogenous insulin and addition of mitiglinide to liraglutide with voglibose finally attenuated glycemic fluctuations with increased postprandial insulin secretion. Continuous glucose monitoring revealed improvement of morning hypoglycemia and postprandial hyperglycemia with smaller mean amplitude of glycemic excursion. Therefore, compared to exogenously injected insulin, endogenously secreted insulin directly and rapidly acts on hepatocytes and suppresses postprandial glucose output.. Proper enhancement of postprandial endogenous insulin aimed at suppressing postprandial glucose output without stimulating excessive glucose uptake in the periphery is potentially useful for treating diabetes with insulin antibody-induced glycemic instability.

Topics: Aged; Blood Glucose; Diabetes Mellitus, Type 2; Diabetic Angiopathies; Drug Therapy, Combination; Glycated Hemoglobin; Humans; Hyperglycemia; Hypoglycemia; Hypoglycemic Agents; Inositol; Insulin; Insulin Antibodies; Insulin Secretion; Isoindoles; Liraglutide; Male; Postprandial Period; Treatment Outcome

Sucrose is a major sweetener added to various foods and beverages. Excessive intake of sucrose leads to increases in blood glucose levels, which can result in the development and exacerbation of lifestyle-related diseases such as obesity and diabetes. In this study, we established an in vivo evaluation system using silkworms to explore substances that suppress the increase in blood glucose levels caused by dietary intake of sucrose. Silkworm hemolymph glucose levels rapidly increased after intake of a sucrose-containing diet. Addition of acarbose or voglibose, α-glycosidase inhibitors clinically used for diabetic patients, suppressed the dietary sucrose-induced increase in the silkworm hemolymph glucose levels. Screening performed using the sucrose-induced postprandial hyperglycemic silkworm model allowed us to identify some lactic acid bacteria that inhibit the increase in silkworm hemolymph glucose levels caused by dietary intake of sucrose. The inhibitory effects of the Lactococcus lactis #Ll-1 bacterial strain were significantly greater than those of different strains of lactic acid bacteria. No effect of the Lactococcus lactis #Ll-1 strain was observed in silkworms fed a glucose diet. These results suggest that the sucrose diet-induced postprandial hyperglycemic silkworm is a useful model for evaluating chemicals and lactic acid bacteria that suppress increases in blood glucose levels.

Topics: Acarbose; Animals; Bombyx; Dietary Sucrose; Disease Models, Animal; Glucose; Glycoside Hydrolase Inhibitors; Hemolymph; Humans; Hyperglycemia; Inositol; Lactobacillales; Phylogeny; Postprandial Period

Meal tolerance tests (MTTs) are usually conducted at breakfast after overnight fasting in type 2 diabetes mellitus (T2DM) patients, but differences in postprandial glycemic responses between meals have been reported.. We conducted MTTs at breakfast, lunch, and dinner to examine the effects of a fixed combination of 10 mg mitiglinide/0.2 mg voglibose (the combination) on glycemic/metabolic responses to meals during the day in T2DM patients. MTTs with unified meals were conducted in 11 T2DM patients before and after 4 weeks of treatment with the combination administered thrice daily before meals. Glycemic/metabolic profiles measured before and at 30, 60, and 120 min after each meal were compared between each meal and between the baseline and treatment periods.. The combination significantly reduced postprandial hyperglycemia after each meal. Postprandial AUC0 - 120 min for insulin significantly decreased after lunch and dinner compared with after breakfast, while insulin levels significantly increased at only 30 min after breakfast and dinner. The combination also significantly increased postprandial C-peptide and active glucagon-like peptide-1 levels, and reduced free fatty acid and triglyceride levels, but did not significantly affect glucagon levels compared with baseline, confirming that treatment with the combination improves postprandial responses in Japanese T2DM patients.

Topics: Aged; Blood Glucose; Breakfast; C-Reactive Protein; Diabetes Mellitus, Type 2; Drug Combinations; Fatty Acids, Nonesterified; Female; Glucagon; Glucagon-Like Peptide 1; Humans; Hyperglycemia; Hypoglycemic Agents; Inositol; Insulin; Isoindoles; Lunch; Male; Meals; Middle Aged; Postprandial Period; Triglycerides

This study compared glycemic variability in patients with type 2 diabetes given sitagliptin or voglibose.. Seventeen type 2 diabetes patients were given sitagliptin 50 mg/day or voglibose 0.9 mg/day for 2 months and were hospitalized for a 4-day evaluation by continuous glucose monitoring (CGM). On discharge, they were crossed over to the other regimen for 2 months of treatment/4 days of evaluation. The CGM data were used to compare each parameter for glycemic variability.. The average glucose levels with sitagliptin and voglibose were significantly different at 138.6 and 152.6 mg/dL for 24 h (P=0.014) and 147.2 and 160.9 mg/dL for during daytime (P=0.050), respectively. The patients' glucose levels with sitagliptin and voglibose were significantly different at 125.3 and 139.7 mg/dL before breakfast (P=0.015) and 112.7 and 131.4 mg/dL before lunch (P=0.049), respectively. The time from before meal to postprandial peak glucose levels was significantly longer after dinner with voglibose than with sitagliptin (91.5 and 122.3 min, respectively; P=0.012). All of the slopes of glucose elevation were significantly lower with voglibose after each meal, with that after breakfast, lunch, and dinner being 1.16 and 0.86 mg/dL/min (P=0.031), 0.70 and 0.45 mg/dL/min (P=0.048), and 1.06 and 0.73 mg/dL/min (P=0.028), respectively.. This CGM-based pilot study revealed that sitagliptin significantly lowered 24-h and daytime mean glucose levels and glucose levels before breakfast and lunch compared with voglibose, whereas the time from before dinner to peak postprandial glucose levels was significantly longer, and the slope of postprandial elevation of glucose level was significantly lower after each meal, with voglibose compared with sitagliptin.

Topics: Aged; Asian People; Blood Glucose; Body Mass Index; Diabetes Mellitus, Type 2; Drug Combinations; Female; Humans; Hyperglycemia; Hypoglycemic Agents; Inositol; Japan; Male; Middle Aged; Monitoring, Physiologic; Pilot Projects; Postprandial Period; Pyrazines; Sitagliptin Phosphate; Triazoles

We report on the synthesis and the biological evaluation of a series of α-1-C-alkylated 1,4-dideoxy-1,4-imino-l-arabinitol (LAB) derivatives. The asymmetric synthesis of the derivatives was achieved by asymmetric allylic alkylation, ring-closing metathesis, and Negishi cross-coupling as key reactions. α-1-C-Butyl-LAB is a potent inhibitor of intestinal maltase, isomaltase, and sucrase, with IC50 values of 0.13, 4.7, and 0.032 μM, respectively. Matrix-assisted laser desorption ionization time-of-flight mass spectrometric analysis revealed that this compound differs from miglitol in that it does not influence oligosaccharide processing and the maturation of glycoproteins. A molecular docking study of maltase-glucoamylase suggested that the interaction modes and the orientations of α-1-C-butyl-LAB and miglitol are clearly different. Furthermore, α-1-C-butyl-LAB strongly suppressed postprandial hyperglycemia at an early phase, similar to miglitol in vivo. It is noteworthy that the effective dose was about 10-fold lower than that for miglitol. α-1-C-Butyl-LAB therefore represents a new class of promising compounds that can improve postprandial hyperglycemia.

Topics: Administration, Oral; Animals; Enzyme Inhibitors; Glycoside Hydrolase Inhibitors; Humans; Hyperglycemia; Hypoglycemic Agents; Imino Sugars; Inhibitory Concentration 50; Male; Mice; Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization

The aim of this study was to clarify the influence of hyperglycemia on the deposition of aggregated protein in the glomeruli of diabetic mice. KK-A(y) mice injected with aggregated bovine serum albumin accumulated more of it in the glomeruli than did ICR mice. There were no histological alterations in the glomeruli of KK-A(y) mice. KK-A(y) mice given voglibose in mouse-chow for 2 weeks had significantly reduced blood glucose, glycated albumin, and hemoglobin A(1C) levels compared with control mice. The voglibose-treated KK-A(y) mice were injected with aggregated bovine serum albumin and accumulated significantly less albumin in the glomeruli than did the control mice. Pioglitazone decreased blood glucose levels compared with the control, and reduced the glomerular deposition of aggregated albumin. Glomerular aggregated bovine serum albumin levels and blood glucose levels were reduced significantly by the injection of insulin. Six times more advanced glycation endproducts were produced from aggregated bovine albumin than from non-aggregated bovine albumin on incubation with glucose and L-lysine in vitro. Glucose-loaded ICR mice generated more advanced glycation endproducts from aggregated albumin, and had more aggregated bovine albumin in the glomeruli. It was suggested that hyperglycemia contributes to an increase in the deposition of aggregated protein in glomeruli even early on in diabetes.

Topics: Animals; Blood Glucose; Diabetes Mellitus; Glucose; Glycated Hemoglobin; Glycated Serum Albumin; Glycation End Products, Advanced; Hyperglycemia; Hypoglycemic Agents; Inositol; Insulin; Kidney Glomerulus; Lysine; Male; Mice; Mice, Inbred ICR; Pioglitazone; Serum Albumin; Serum Albumin, Bovine; Thiazolidinediones

E3024 (3-but-2-ynyl-5-methyl-2-piperazin-1-yl-3,5-dihydro-4H-imidazo[4,5-d]pyridazin-4-one tosylate) is a dipeptidyl peptidase IV (DPP-IV) inhibitor. Since the target of both DPP-IV inhibitors and alpha-glucosidase inhibitors is the lowering of postprandial hyperglycemia, we compared antihyperglycemic effects for E3024 and alpha-glucosidase inhibitors in various oral carbohydrate and meal tolerance tests using normal mice. In addition, we investigated the combination effects of E3024 and voglibose on blood glucose levels in a meal tolerance test using mice fed a high-fat diet. ER-235516-15 (the trifluoroacetate salt form of E3024, 1 mg/kg) lowered glucose excursions consistently, regardless of the kind of carbohydrate loaded. However, the efficacy of acarbose (10 mg/kg) and of voglibose (0.1 mg/kg) varied with the type of carbohydrate administered. The combination of E3024 (3 mg/kg) and voglibose (0.3 mg/kg) improved glucose tolerance additively, with the highest plasma active glucagon-like peptide-1 levels. This study shows that compared to alpha-glucosidase inhibitors, DPP-IV inhibitors may have more consistent efficacy to reduce postprandial hyperglycemia, independent of the types of carbohydrate contained in a meal, and that the combination of a DPP-IV inhibitor and an alpha-glucosidase inhibitor is expected to be a promising option for lowering postprandial hyperglycemia.

Topics: Acarbose; Administration, Oral; Animals; Area Under Curve; Blood Glucose; Carbohydrate Metabolism; Diabetes Mellitus, Type 2; Dietary Sucrose; Dipeptidyl-Peptidase IV Inhibitors; Drug Therapy, Combination; Enzyme Inhibitors; Food, Formulated; Glucagon-Like Peptide 1; Glucose Tolerance Test; Glycoside Hydrolase Inhibitors; Hyperglycemia; Hypoglycemic Agents; Imidazoles; Injections, Intravenous; Inositol; Insulin; Male; Mice; Mice, Inbred C57BL; Postprandial Period; Pyridazines; Tosyl Compounds

It has been suggested that reduction in glucose levels contributes to the prolongation of life span of rodents in conjunction with restricted food intake, and hyperglycemia has been confirmed as a risk factor for cardiovascular disease (CVD), raising the possibility that better glycemic control could slow the progression of CVD. This study was designed to determine whether impaired glucose tolerance develops during the progression of cardiac hypertrophy and heart failure, and whether tight glycemic control could reduce the severity of heart failure.. In male C57BL/6 mice, transverse aortic constriction (TAC) was employed to create cardiac hypertrophy and heart failure. The involvement of NADPH in TAC mice and cardiac myocytes in the neonatal rat was investigated.. The random-fed plasma glucose concentration was higher in TAC mice, and it was reduced to about 100 mg/dL by voglibose (an alpha-glycosidase inhibitor). Four weeks after TAC, both the heart weight/body weight ratio and the lung weight/body weight ratio were lower in the voglibose group than in the TAC group. Echocardiographic and invasive hemodynamic examination showed improvement of left ventricular function in voglibose-treated mice. Voglibose treatment decreased the myocardial expression of an NADPH oxidase subunit (p47phox). Glucose dose-dependently increased both neonatal rat myocyte protein synthesis and the expression of p47phox protein, while apocynin (an NADPH oxidase inhibitor) blocked the enhancement of protein synthesis by high glucose.. Improvement of glycemic control through voglibose therapy inhibited cardiac remodeling by decreasing myocardial oxidative stress in mice with cardiac pressure overload.

Topics: Acetophenones; Animals; Blotting, Western; Body Weight; Cells, Cultured; Disease Progression; Echocardiography; Fatty Acids, Nonesterified; Glucose; Glycoside Hydrolase Inhibitors; Heart Failure; Hyperglycemia; Inositol; Insulin; Lung; Male; Mice; Mice, Inbred C57BL; Models, Animal; Myocardium; Myocytes, Cardiac; NADPH Oxidases; Organ Size; Oxidative Stress; Rats; Reverse Transcriptase Polymerase Chain Reaction; Ventricular Dysfunction, Left

To assess the possible difference in effectiveness of 2 alpha-glucosidase inhibitors, voglibose and acarbose, the relationship between postprandial hyperglycemia and subjective abdominal symptoms was investigated. A total of 21 inpatients with type 2 diabetes were recruited to a single-center, 2-period, crossover trial. The subjects were given acarbose (150 mg/d) or voglibose (0.9 mg/d) under an isocaloric diet, and the postprandial (2 hours) increment in blood glucose level, M value which is a marker for fluctuation of blood glucose levels, and subjective abdominal symptom score were monitored. There was no significant difference between the 2 agents in postprandial increment in blood glucose level, M value, and subjective symptom score. When patients were divided according to subjective symptoms, however, the sum postprandial glucose increments were significantly different according to the agent (P = .03), with favorable efficacy in patients in whom the alpha-glucosidase inhibitor caused abdominal symptoms, demonstrating a significant interaction (P = .04) between treatment and symptomatic grouping. The results demonstrated that 50 mg acarbose and 0.3 mg voglibose had similar overall effects on postprandial hyperglycemia as well as subjective symptoms, but marked interindividual variation existed. Subjective symptoms may be a predictor of the divergent clinical response to each agent.

Topics: Acarbose; Aged; Blood Glucose; Cross-Over Studies; Diabetes Mellitus, Type 2; Enzyme Inhibitors; Female; Flatulence; Food; Gastrointestinal Tract; Glycoside Hydrolase Inhibitors; Humans; Hyperglycemia; Inositol; Male; Middle Aged

Reactive oxygen species are involved in a diversity of biological phenomena such as inflammation, carcinogenesis, aging, and atherosclerosis. We and other investigators have shown that the level of 8-hydroxy-2'-deoxyguanosine (8-OHdG), a marker for oxidative stress, is increased in either the urine or the mononuclear cells of the blood of type 2 diabetic patients. However, the association between type 2 diabetes and oxidative stress in the pancreatic beta-cells has not been previously described. We measured the levels of 8-OHdG and 4-hydroxy-2-nonenal (HNE)-modified proteins in the pancreatic beta-cells of GK rats, a model of nonobese type 2 diabetes. Quantitative immunohistochemical analyses with specific antibodies revealed higher levels of 8-OHdG and HNE-modified proteins in the pancreatic beta-cells of GK rats than in the control Wistar rats, with the levels increasing proportionally with age and fibrosis of the pancreatic islets. We further investigated whether the levels of 8-OHdG and HNE-modified proteins would be modified in the pancreatic beta-cells of GK rats fed with 30% sucrose solution or 50 ppm of voglibose (alpha-glucosidase inhibitor). In the GK rats, the levels of 8-OHdG and HNE-modified proteins, as well as islet fibrosis, were increased by sucrose treatment but reduced by voglibose treatment. These results indicate that the pancreatic beta-cells of GK rats are oxidatively stressed, and that chronic hyperglycemia might be responsible for the oxidative stress observed in the pancreatic beta-cells.

Topics: 8-Hydroxy-2'-Deoxyguanosine; Aldehydes; Animals; Blood Glucose; Deoxyguanosine; Diabetes Mellitus, Type 2; Enzyme Inhibitors; Hyperglycemia; Immunohistochemistry; Inositol; Insulin; Islets of Langerhans; Oxidative Stress; Proteins; Rats; Rats, Inbred Strains; Solutions; Sucrose