Miglitol Treatment Research Articles

Relationships among Postprandial Plasma Active GLP-1 and GIP Excursions, Skeletal Muscle Mass, and Body Fat Mass in Patients with Type 2 Diabetes Treated with Either Miglitol, Sitagliptin, or Their Combination: A Secondary Analysis of the MASTER Study.

We previously conducted a pilot randomized controlled trial "the MASTER study" and demonstrated that alpha-glucosidase inhibitor miglitol and a dipeptidyl peptidase-4 inhibitor sitagliptin modified postprandial plasma excursions of active glucagon-like peptide-1 (aGLP-1) and active gastric inhibitory polypeptide (aGIP), and miglitol treatment decreased body fat mass in patients with type 2 diabetes (T2D). However, the details regarding the relationships among postprandial plasma aGLP-1 and aGIP excursions, skeletal muscle mass, and body fat mass are unclear. We conducted a secondary analysis of the relationships among skeletal muscle mass index (SMI), total body fat mass index (TBFMI), and the incremental area under the curves (iAUC) of plasma aGLP-1 and aGIP excursions following mixed meal ingestion at baseline and after 24-week add-on treatment with either miglitol alone, sitagliptin alone, or their combination in T2D patients. SMI was not changed after the 24-week treatment with miglitol and/or sitagliptin. TBFMI was reduced and the rates of aGIP-iAUC change were lowered in the two groups treated with miglitol, although their correlations did not reach statistical significance. We observed a positive correlation between the rates of aGIP-iAUC and TBFMI changes and a negative correlation between the rates of TBFMI and SMI changes in T2D patients treated with sitagliptin alone whose rates of aGIP-iAUC change were elevated. Collectively, although T2D patients treated with miglitol and/or sitagliptin did not show altered SMI after 24-week treatment, the current study suggests that there are possible interrelationships among postprandial plasma aGIP excursion modified by sitagliptin, skeletal muscle mass, and body fat mass.

Protective effect of SGL5213, a potent intestinal sodium–glucose cotransporter 1 inhibitor, in nonalcoholic fatty liver disease in mice

BackgroundNonalcoholic fatty liver disease (NAFLD) is the most common chronic disease. SGL5213, which is minimally absorbed and is restricted to the intestinal tract, is a potent intestinal sodium–glucose cotransporter 1 (SGLT1) inhibitor. In this study, we investigated the protective effect of SGL5213 in a rodent model of NAFLD. MethodsUsing a rodent model of NAFLD, we compared SGL5213 efficacy with miglitol, which is an α-glucosidase inhibitor. We used a high-fat and high-sucrose diet-induced NAFLD model. ResultsSGL5213 and miglitol improved obesity, liver dysfunction, insulin resistance, and the NAFLD severity. To further investigate the effects of SGL5213, we analyzed the mRNA expression of genes involved in lipid metabolism, inflammation, and liver fibrosis, and cecal pH levels. SGL5213 and miglitol treatment significantly decreased mRNA expression of factors involved in inflammation and liver fibrosis. SGL5213 treatment significantly decreased cecal pH levels, which did not occur with miglitol. ConclusionsSGL5213 had a protective effect on the pathogenesis of NAFLD in a rodent model. We considered that inhibiting glucose absorption and increasing glucose content in the gastrointestinal tract with SGL5213 might have contributed to the protective effect in NAFLD. SGL5213 is a promising therapeutic agent for NAFLD with obesity and insulin resistance.

395-P: N-hydroxyethyl-1-deoxynojirimycin (Miglitol) Restores the Sympathoadrenal Response to Hypoglycemia following Antecedent Hypoglycemia in Diabetic Rats

Antecedent hypoglycemia leads to a reduction in the sympathoadrenal response during subsequent hypoglycemia, i.e., HAAF. We’ve shown previously that this can be corrected in nondiabetic rats by portal vein infusion of N-hydroxyethyl-1-deoxynojirimycin (NEOH-DNJ; miglitol). In the current study we examined the efficacy of portal vein NEOH-DNJ infusion in restoring the sympathoadrenal response for diabetic animals. Diabetes was induced in rats via streptozotocin (STZ) injection (65mg/kg) 4 weeks prior to experiments. Conscious, unrestrained STZ-diabetic rats underwent hyperinsulinemic-hypoglycemic clamps on two consecutive days with a glycemic nadir of 2.6 ± 0.04 mM. On Day 2 animals received portal vein miglitol infusions (1.45 μmol/kg/min) either upstream, (PORups) or liver adjacent (PORadj), while hypoglycemic controls (HYPO) received normal saline infusion. Serial plasma samples were assayed for glucose, insulin, epinephrine (EPI) and norepinephrine (NE). On Day1 peak epinephrine (22.7 ± 2.1 nM) and norepinephrine (2.92 ± 0.3 nM) values were not significantly different between HYPO, PORups and PORadj (P>0.38). On Day 2, EPI values for untreated HYPO controls were suppressed by 85% relative to Day 1 (P < 0.0001). In contrast, EPI responses for miglitol infused groups, PORups (21.3 ± 2.2 nM) and PORadj (16.1 ± 2.01 nM) were not significantly different from Day 1 values (P = 0.75 and 0.50, respectively). NE demonstrated similar responses with HYPO suppressed by 63% on Day 2 (P<0.05), while miglitol treated groups, PORups and PORadj, demonstrated Day 2 NE values not significantly different from Day 1 (P>0.85). Conclusion: The impaired sympathoadrenal response following antecedent hypoglycemia is restored in STZ-diabetic rats by miglitol (NEOH-DNJ) treatment during subsequent hypoglycemia. As with nondiabetic rats, STZ-diabetic animals demonstrated no differences between portal miglitol infusion sites. Disclosure C. Donovan: None. A.J. Jokiaho: None. Funding JDRF (3-SRA-2017-486-S-B)

The alpha-glucosidase inhibitor miglitol increases hepatic CYP7A1 activity in association with altered short-chain fatty acid production in the gut of obese diabetic mice

PurposeBile acids (BAs) have been shown to contribute to glucose and energy homeostasis. We have recently reported that miglitol, an alpha-glucosidase inhibitor, increases fecal BA excretion and ameliorate insulin resistance and obesity in mice. The aim of this study was to clarify the mechanisms by which miglitol affects BA metabolism. The expression of genes regulating BA metabolism, gut microbiome and short-chain fatty acids (SCFA) were examined. ProceduresNSY mice, representing an obese type 2 diabetic model, were fed with a high-fat diet with or without miglitol for 4 weeks. The expression of BA-related genes in the liver and the lower intestine were measured. Alterations in fecal microbiome, fecal SCFA along with plasma lipid levels were also evaluated. Major findingsMiglitol significantly increased fecal BA secretion and markedly upregulated the mRNA expression, protein levels and enzyme activity of hepatic cholesterol 7α-hydroxylase, a rate-limiting enzyme of BA synthesis. In the intestine, miglitol treatment significantly suppressed the mRNA expression of apical sodium-dependent bile acid transporter and ATP-binding cassette transporter G5 and G8. In fecal microbiome, the prevalence of prevotella was remarkably reduced and that of clostridium subcluster XIVa was increased by miglitol. Miglitol elevated formic and n-butyric acids along with total SCFA concentration in feces, while succinic acid was decreased. There was no change in plasma total cholesterol levels. ConclusionsCollectively, miglitol may affect BA metabolism via enhanced CYP7A1 activity resulting from at least in part the alterations in gut microbiome and SCFA production in obese diabetic mice.

16-LB: N-Hydroxylethyl-1-Deoxynojirimycin (Miglitol) Infusion Rescues the Sympathoadrenal Response to Hypoglycemia following Antecedent Hypoglycemia in Rats

Antecedent hypoglycemia leads to a blunting of the sympathoadrenal response during subsequent hypoglycemia, which can largely be prevented by normalizing portal-mesenteric vein (PMV) glycemia during the antecedent bout. As SGLT3 has recently been implicated in PMV glucosensing, we hypothesized that PMV infusion of the imino sugar N-hydroxylethyl-1-deoxynojirimycin (miglitol), a potent SGLT3 agonist, during hypoglycemia would prevent or rescue the sympathoadrenal response to subsequent hypoglycemia. Wistar rats underwent hyperinsulinemic-hypoglycemic clamps on two consecutive days. Control animals were exposed to either euglycemia (EUG-CON: 5.73 ± 0.37 mM) or hypoglycemia (HYPO-CON: 2.39 ± 0.07 mM) on Day 1 without miglitol infusion, followed by a hypoglycemic bout on Day 2. Treatment groups were exposed to hypoglycemia (2.52 ± 0.07 mM) on both days with miglitol (1.45 μmol/kg/min) infused either upstream, perfusing the PMV glucosensors (PORups), or adjacent to the liver, bypassing the PMV glucosensors (PORadj), on Day 1 (PORups1, PORadj1) or Day2 (PORups2, PORadj2). Serial plasma samples drawn on the Day 2 experiment were assayed for glucose, insulin, epinephrine (EPI) and norepinephrine (NE). Compared to EUG-CON, peak EPI responses for HYPO-CON on Day 2 were significantly blunted (34.1 ± 4.3 vs. 15.4 ± 3.5 nmol/L; P < 0.05). EPI responses for PORups1 (11.8 ± 4.7 nmol/L) and PORadj1 (12.83 ± 3.4 nmol/L) were also suppressed on Day 2 compared with HYPO-CON (P<0.05). In contrast, EPI responses for PORups2 (31.5 ± 8.2 nmol/L) and PORadj2 (32.9 ± 13.2 nmol/L) were not significantly different from HYPO-CON (P = 0.74 and 0.90, respectively). NE demonstrated a similar trend to EPI. Conclusion: The impaired sympathoadrenal response following antecedent hypoglycemia in rats is restored by miglitol (NEOH-DNJ) treatment during a subsequent bout of hypoglycemia. Whether this is mediated via PMV glucosensors remains unclear. Disclosure A.J. Jokiaho: None. M. Winchester: None. C. Donovan: None. Funding JDRF

Miglitol attenuates non-alcoholic steatohepatitis in diabetic patients.

Postprandial hyperglycemia is frequently accompanied by non-alcoholic fatty liver disease (NAFLD) and steatohepatitis (NASH). Although α-glucosidase inhibitors (αGIs) can slow glucose absorption from the intestine and suppress the surge of circulating glucose concentration after meals, it remains unclear whether αGIs are also beneficial for NASH. The aim of this prospective study was to examine the efficacy and safety of miglitol, a typical αGI, for NASH. Seventeen patients with histologically confirmed NASH and hemoglobin A1c (HbA1c) >6.5% were treated with miglitol (150mg/day) for 12months. The changes in clinical parameters and liver histology were analyzed. All patients completed the 12-month miglitol treatment course with no severe adverse events. The treatment significantly decreased body mass index, serum alanine aminotransferase levels, and HbA1c (all P < 0.001). Post-treatment liver biopsy of 11 patients revealed significant improvements in steatosis (from 2.2 ± 0.6 to 1.5 ± 0.7, P = 0.001), lobular inflammation (from 1.8 ± 0.8 to 1.3 ± 0.5, P = 0.014), portal inflammation scores (from 0.6 ± 0.5 to 0.1 ± 0.3, P = 0.025), and NAFLD activity score (from 5.5 ± 1.5 to 3.9 ± 1.4, P = 0.012). Fibrosis and hepatocyte ballooning scores were unchanged. Miglitol appears to safely ameliorate NASH activity by attenuation of steatosis and lobular/portal inflammation. Appropriately powered controlled trials are warranted to validate our results.

Effect of miglitol on the suppression of nonalcoholic steatohepatitis development and improvement of the gut environment in a rodent model

BackgroundThe gut environment has been considered to play a role in the development of nonalcoholic steatohepatitis (NASH). α-glucosidase inhibitors (α-GIs) delay carbohydrate absorption and may change the gut environment. We considered that the protective effect of α-GIs against NASH development is related to changes in the gut environment and thus investigated the effects of miglitol, an α-GI, on NASH development and the gut environment.MethodsMice were divided into three groups and fed a normal chow diet (NCD), a high-fat high-sucrose diet (HFHSD), or HFHSD plus 0.04% miglitol (HFHSD plus M) for 12 weeks.ResultsInsulin resistance developed more in the HFHSD group than in the NCD group, whereas it was suppressed in the HFHSD plus M group. NASH was evaluated histologically, biochemically, and on the basis of messenger RNA expression levels. Miglitol treatment suppressed HFHSD-induced NASH development with the suppression of hepatic Toll-like receptor 4 expression, increased glucagon-like peptide 1 (GLP-1) concentration, and reduced lipopolysaccharide concentration in portal plasma. Regarding the gut environment, the intestinal transit time was shortened and colon inflammation was suppressed in the HFHSD plus M group compared with the HFHSD group. Regarding the gut microbiota, the abundances of Erysipelotrichaceae and Coriobacteriaceae were increased in the HFHSD group compared with the NCD group, whereas the increase was suppressed in the HFHSD plus M group.ConclusionsWe demonstrated that miglitol has a protective effect against HFHSD-induced NASH development. The increased GLP-1 secretion and the suppression of endotoxemia, associated with the changes in the gut environment, including the gut microbiota, could contribute to the underlying mechanisms.

Improvement of both fasting and postprandial glycemic control by the two-step addition of miglitol and mitiglinide to basal insulin therapy: a pilot study

BackgroundCombination therapy consisting of basal insulin and oral hypoglycemic agents (OHAs) is effective for the treatment of type 2 diabetes (T2DM) that cannot be adequately controlled using OHAs alone. Though basal insulin with metformin or sulfonylurea is an effective therapy, it cannot reduce postprandial glycemia without the risk of hypoglycemia. We examined a two-step regimen consisting of the addition of postprandial hypoglycemic agents (an alpha-glucosidase inhibitor and a glinide) in patients whose T2DM was poorly controlled using basal insulin therapy.MethodsInpatients between the ages of 30–79 years who had T2DM and an HbA1c level of more than 7.0% were recruited. The patients were treated with once-daily insulin glargine with or without metformin, depending on the patient’s age and renal function. Insulin glargine was titrated to achieve a target fasting glucose level of 70–130 mg/dL as a first step (STEP0). If the 2-hour postprandial glucose (PBG) level was higher than the target of 180 mg/dL, miglitol treatment (150 mg/day) was initiated, with dose adjustments (75–225 mg) allowed depending on abdominal symptoms and the PBG (STEP1). If the PBG of the patients remained higher than the target after 3 days of treatment, mitiglinide (30 mg/day, titrated up to 60 mg) was added (STEP2). We then evaluated the proportion of patients who achieved the target PBG before and after the two-step regimen. Continuous Glucose Monitoring (CGM) was performed throughout the two-step protocol in most of the patients.ResultsOf the 16 patients who were recruited (median age, 67.0 [58.0-71.0] years; body mass index, 25.0 [22.0-27.9] kg/m2; HbA1c level at admission, 9.1% [8.35-10.4%]), 1 patient (6.25%) achieved the target PBG at STEP 0 and 14 patients (87.5%) had achieved the target PBG at the end of the treatment protocol (P = 0.002). CGM showed a significant decrease in the glucose level at each step of the protocol. The standard deviations in the CGM glucose levels for 24 hours, MAGE, and M-value also improved.ConclusionsThe two-step addition of postprandial hypoglycemic agents to basal insulin therapy is potentially effective and safe for decreasing both the fasting and postprandial glucose levels.

Miglitol improves postprandial endothelial dysfunction in patients with acute coronary syndrome and new-onset postprandial hyperglycemia

BackgroundHyperglycemia, a risk factor for development of cardiovascular disease, causes endothelial dysfunction. Alpha-glucosidase inhibitors (α-GIs) improve postprandial hyperglycemia (PPHG) and may have favorable effects on associated cardiovascular disease. Effects of α-GIs in patients with acute coronary syndrome (ACS) and PPHG remain unclear; thus, we assessed the effect of α-GI miglitol on endothelial function in such patients by digital reactive hyperemia peripheral arterial tonometry (RH-PAT).MethodsFifty-four patients with ACS who underwent primary percutaneous coronary intervention were enrolled in the study: 36 with new-onset PPHG and 18 with normal glucose tolerance. Eighteen PPHG patients were given 50 mg of miglitol with each meal for 1 week. Endothelial function was assessed on the basis of the RH-PAT index (RHI) before and after the 1-week miglitol treatment. The other 18 PPHG patients and the 18 NGT patients were not given any anti-diabetic agent for 1 week, and endothelial function was assessed.ResultsPostprandial RHI decreased significantly in patients with PPHG. Miglitol improved PPHG significantly; postprandial RHI also improved (p = 0.007). Significant inverse correlation was found between the postprandial change in RHI and postprandial fasting-to-60-minutes surge in glucose (r = -0.382, p = 0.009). Moreover, the improvement in endothelial function correlated with the reduced postprandial glucose surge achieved with miglitol (r = -0.462, p = 0.001).ConclusionsPostprandial changes in glucose are related to endothelial dysfunction in ACS. Miglitol-based improvement in PPHG appears to improve endothelial function. The effect of miglitol on glucose-dependent endothelial function might improve outcomes of ACS.

Lipid Deposition in Various Sites of the Skeletal Muscles and Liver Exhibits a Positive Correlation with Visceral Fat Accumulation in Middle-aged Japanese Men with Metabolic Syndrome

Objective In addition to excess visceral fat, lipid deposition in the liver and skeletal muscle has been implicated in the pathophysiology of type 2 diabetes and metabolic syndrome. This study was designed to explore the relationship between hepatic and muscular lipid deposition and visceral fat accumulation in 105 middle-aged men with metabolic syndrome. Methods Abdominal computed tomography (CT) was used to simultaneously evaluate the visceral fat area (VFA) and CT Hounsfield unit (HU) values of three different portions of skeletal muscle and the liver. Results A significant inverse correlation was observed between the VFA and the CT HU values of the iliopsoas muscle, back muscle, rectus abdominis muscle and liver. Three types of interventions, i.e., lifestyle modification and treatment with antidiabetic drugs, such as Pioglitazone or Miglitol, caused significant decreases in visceral fat accumulation. The extent of lipid deposition in the liver was strongly correlated with the levels of glucose-lipid metabolic markers, which decreased significantly following Pioglitazone treatment. On the other hand, the amount of lipid deposition in the three skeletal muscles and the liver did not decrease after Miglitol treatment. Conclusion Visceral fat accumulation is accompanied by excess lipid deposition in skeletal muscle and the liver in patients with metabolic syndrome. The CT-based simultaneous, concise evaluations of ectopic lipid deposition and visceral fat mass used in the present study may provide unique information for assessing cardiometabolic risks and the therapeutic impact in patients with diabetes-obesity syndrome.

Miglitol prevents diet-induced obesity by stimulating brown adipose tissue and energy expenditure independent of preventing the digestion of carbohydrates

Miglitol is an alpha-glucosidase inhibitor that improves post-prandial hyperglycemia, and it is the only drug in its class that enters the bloodstream. Anecdotally, miglitol lowers patient body weight more effectively than other alpha-glucosidase inhibitors, but the precise mechanism has not been addressed. Therefore, we analyzed the anti-obesity effects of miglitol in mice and in the HB2 brown adipocyte cell line. Miglitol prevented diet-induced obesity by stimulating energy expenditure without affecting food intake in mice. Long-term miglitol treatment dose-dependently prevented diet-induced obesity and induced mitochondrial gene expression in brown adipose tissue. The anti-obesity effect was independent of preventing carbohydrate digestion in the gastrointestinal tract. Miglitol effectively stimulated energy expenditure in mice fed a high-fat high-monocarbohydrate diet, and intraperitoneal injection of miglitol was sufficient to stimulate energy expenditure in mice. Acarbose, which is a non-absorbable alpha glucosidase inhibitor, also prevented diet-induced obesity, but through a different mechanism: it did not stimulate energy expenditure, but caused indigestion, leading to less energy absorption. Miglitol promoted adrenergic signaling in brown adipocytes in vitro. These data indicate that circulating miglitol stimulates brown adipose tissue and increases energy expenditure, thereby preventing diet-induced obesity. Further optimizing miglitol's effect on brown adipose tissue could lead to a novel anti-obesity drug.

Effects of miglitol in platelet-derived microparticle, adiponectin, and selectin level in patients with type 2 diabetes mellitus

Background:Platelet-derived microparticles (PDMP), selectins, and adiponectin play an important role in the development of atherosclerosis in diabetes. Miglitol has been shown to have a beneficial effect on postprandial hyperglycemia in diabetic patients. However, its influence on platelet activation markers (PDMP and soluble CD40 ligand [sCD40L]), selectins, and adiponectin in these patients is poorly understood.Aim:We investigated the effect of miglitol on circulating levels of PDMP, sCD40L, selectins, and adiponectin in patients with type 2 diabetes.Methods:Miglitol (150 mg/day) was administered for 4 months. Levels of PDMP, sCD40L, soluble P-selectin (sP-selectin), soluble E-selectin (sE-selectin), soluble L-selectin (sL-selectin), and adiponectin were measured by enzyme-linked immunosorbent assay at baseline, and after 1 and 4 months of treatment.Results:The levels of PDMP, sCD40L, sP-selectin, sE-selectin, and sL-selectin were higher in diabetic patients than in hypertensive patients, while there were no significant differences between hypertensive and hyperlipidemic patients. Before miglitol treatment, the adiponectin level of diabetic patients was lower than that of hypertensive patients. Miglitol therapy significantly decreased the plasma PDMP and sCD40L levels relative to baseline. Miglitol also caused a significant decrease of sP-selectin, sE-selectin, and sL-selectin. On the other hand, miglitol therapy led to a significant increase in adiponectin after 4 months of administration compared with baseline. Furthermore, the reduction of platelet activation markers and selectins during miglitol therapy was significantly greater in the responder (adiponectin-improved) group than the nonresponder group of diabetic patients.Conclusion:Miglitol has an adiponectin-dependent anti-atherothrombotic effect that may be beneficial for primary prevention of atherothrombosis in patients with type 2 diabetes.

Comparing the Efficacy of α-Glucosidase Inhibitors in Suppressing Postprandial Hyperglycemia Using Continuous Glucose Monitoring: A Pilot Study—The MAJOR Study

This study aimed to compare glucose variability in patients given the α-glucosidase inhibitors miglitol and acarbose using continuous glucose monitoring (CGM). Ten type 2 diabetes patients were hospitalized for 4 days, and their glucose levels were measured using CGM. Patients were given miglitol (50 mg) or acarbose (100 mg) before each meal on Day 2, and vice versa on Day 3, in a randomized crossover design. The patients had three identical test meals on Days 2 and 3. The CGM data were used to compare each parameter for glycemic variability after each of the three meals. No significant differences were observed between miglitol treatment or acarbose treatment in regard to the range of increase in glucose levels from baseline to peak, time to peak postprandial glucose levels from the preprandial period, and area under the curve for glycemic variability from the preprandial period to 3 h after each meal. However, the range of increase in glucose levels at 30 min (0.4 vs. 30.7 mg/dL, P < 0.0001) and 60 min (32.8 vs. 67.5 mg/dL, P <0.0001) after lunch and 30, 60, and 90 min after dinner (3.3 vs. 22.2 mg/dL, P = 0.0249; 36.6 vs. 67.5 mg/dL, P < 0.0001; and 60.5 vs. 81.6 mg/dL, P = 0.0073, respectively) was significantly smaller in miglitol treatment compared with acarbose treatment. In a pilot study with a crossover design in 10 type 2 diabetes patients, it was shown that although there was no significant difference in glucose variability with miglitol or acarbose after a fat-rich diet, glucose increases was significantly reduced with miglitol after a meal comprising typical Japanese diet 60-90 min postprandially.

Evaluation of the efficacy and tolerability of miglitol in Chinese patients with type 2 diabetes mellitus inadequately controlled by diet and sulfonylureas

The objective of this study is to examine the efficacy and tolerability of miglitol with respect to improving glycemic control in Chinese patients with type 2 diabetes mellitus inadequately controlled by diet and sulfonylurea treatment. This was a randomized, double-blinded, placebo-controlled, multicenter study. A total of 105 patients were randomized to receive 24 weeks of treatment with miglitol (n = 52; titrated from 50 mg to 100 mg 3 times daily) or placebo (n = 53). Concomitant sulfonylurea treatment and diet remained unchanged. The primary endpoint was change in glycated hemoglobin (HbA1c) from baseline at 24 weeks. Secondary endpoints were changes in fasting plasma glucose (FPG), postprandial plasma glucose (PPG), and postprandial serum insulin (PSI). The miglitol treatment group showed significantly greater reductions in HbA1c and PPG levels compared with the placebo group. With respect to adverse events, abdominal discomfort, diarrhea, and hypoglycemia occurred with similar frequency in both groups. Results of this study indicate that miglitol significantly improves metabolic control in Chinese patients with type 2 diabetes mellitus. Miglitol is safe and well tolerated, with the exception of abdominal discomfort. Therefore, miglitol may be a useful adjuvant therapy for Chinese patients with type 2 diabetes mellitus inadequately controlled by diet and sulfonylurea treatment.

Efficacy of combined use of miglitol in Type 2 diabetes patients receiving insulin therapy-placebo-controlled double-blind comparative study

Combination therapy with an α-glucosidase inhibitor and insulin is commonly performed for type 2 diabetes mellitus. We conducted a placebo-controlled double-blind comparative study to investigate the efficacy of combination therapy with miglitol and insulin. The patients with T2DM on insulin therapy were randomly assigned to either a miglitol treatment group (Group M) or a placebo group (Group P) and treated for 12weeks. Meal tolerance tests were conducted at the observation period, week 0 and week 12 of the treatment period. Mean values of decrease in 1-h- and 2-h postprandial plasma glucose level were significantly larger in Group M than in Group P (60.3±70.1mg/dl vs. -5.1±68.2mg/dl (P<0.001)), as was HbA1c as well (0.36±0.66% vs. -0.03±0.56% (P<0.001)). Adverse events included abdominal distension and flatulence, which were significantly more frequent in Group M. The frequency of nocturnal hypoglycemia events tended to be reduced in Group M. Combined use of insulin and miglitol is useful for postprandial glucose regulation and improves glycemic control.

Changes in α-glucosidase activities along the jejunal-ileal axis of normal rats by the α-glucosidase inhibitor miglitol

Miglitol, an α-glucosidase inhibitor that inhibits postprandial hyperglycemia by delaying carbohydrate digestion and absorption along the jejunal-ileal axis, has recently been approved for use in patients with type 2 diabetes mellitus. Miglitol treatment may lead to increased α-glucosidase activities toward the ileum because carbohydrate flow toward the ileum increases. However, it is not yet known if miglitol treatment alters the α-glucosidase activities along the jejunal-ileal axis. In this study, we examined the effects of miglitol supplementation for 3 or 7 days on α-glucosidase activities along the jejunal-ileal axis of Wistar rats. Supplementation with miglitol for 3 or 7 days in rats increased tissue weights of the lower jejunum and ileum, but did not alter tissue weights of the upper jejunum and cecum or the contents of the cecum. Furthermore, supplementation with miglitol for 7 days reduced the activities of isomaltase and maltase in the upper jejunum and increased the activities of sucrase, isomaltase, and maltase in the lower jejunum and ileum. These results suggest that the delay in carbohydrate digestion and absorption along the jejunal-ileal axis by miglitol supplementation in rats is associated with increased α-glucosidase activities toward the ileum.

Effects of miglitol, an α-glucosidase inhibitor, on glycaemic status and histopathological changes in islets in non-obese, non-insulin-dependent diabetic Goto-Kakizaki rats

Miglitol, a 1-deoxynojirimycin derivative, is an alpha-glucosidase inhibitor. In the present study, the effects of acute (single-dose) and chronic (8-week) oral administration of miglitol in Goto-Kakizaki (GK) rats, an animal model of type 2 diabetes, were investigated. Dose-dependent decreases in incremental blood glucose concentrations integrated over a period of 2 h (deltaAUC0-2 h) for values of blood glucose after sucrose-loading in miglitol-treated GK rats were observed following an acute oral administration of miglitol (1, 3 or 10 mg/kg body weight). At 10 mg/kg, the deltaAUC0-2 h of blood glucose was decreased by 45 % compared with the control group. Following the oral administration of miglitol in a dietary mixture (10 mg, 20 mg or 40 mg miglitol/100 g control diet) for 8 weeks, the ratio of HbA1c at 8 weeks compared with 0 weeks in GK rats treated with 40 mg miglitol/100 g control diet miglitol was significantly decreased compared with control GK rats without changes in body weight. In oral glucose tolerance testing, miglitol caused a slight decrease in the deltaAUC0-2 h of plasma glucose concentration. In addition, miglitol treatment slightly inhibited the reduction in beta-cell mass, and lessened the irregular contours and fibrosis of the islets in GK rats. These results indicate that miglitol ameliorates the hyperglycaemic state of GK rats and the impaired function of the pancreatic islets, as well as preventing the degeneration of islets in GK rats.

Miglitol: a review of its therapeutic potential in type 2 diabetes mellitus.

Miglitol, the first pseudomonosaccharide alpha-glucosidase inhibitor, smooths postprandial peak plasma glucose levels and thus improves glycaemic control, which is reflected in a reduced glycosylated haemoglobin (HbA1c) level. This oral antihyperglycaemic agent is indicated for the treatment of patients with type 2 diabetes mellitus. Miglitol is generally well tolerated and, unlike the sulphonylurea agents, is not associated with bodyweight gain or hypoglycaemia when administered as monotherapy. The drug is systemically absorbed but is not metabolised and is rapidly excreted via the kidneys. Clinical trials with miglitol (usually 50 or 100 mg 3 times daily) in patients with type 2 diabetes mellitus consistently demonstrated a significant improvement in glycaemic control for periods of 6 to 12 months. There were also marked reductions in postprandial serum insulin levels, although miglitol generally had no effect on fasting insulin levels. In comparative studies miglitol had similar efficacy to acarbose, but at lower therapeutic doses (50 and 100 mg 3 times daily, respectively). In addition, although sulphonylurea agents provided superior reductions in HbA1c levels, miglitol provided similar or superior reductions in fasting and postprandial plasma glucose levels. In combination with other oral antidiabetic agents or insulin, miglitol improved glycaemic control in patients in whom metabolic control was suboptimal despite dietary and pharmacological intervention. Most adverse events associated with miglitol treatment involve disturbances of the gastrointestinal tract (most common effects are flatulence, abdominal pain and diarrhoea). These symptoms are usually dose dependent, mild to moderate in severity, occur at the onset of treatment, decline with time and resolve promptly on discontinuation of the drug or with dosage adjustment. As monotherapy, miglitol is not associated with hypoglycaemia, but concomitant use with other oral antidiabetic agents may necessitate dosage adjustment of the other agents. Miglitol had no significant effects on renal, cardiovascular, respiratory or haematological parameters in long term studies. No dosage adjustments are required in elderly patients, in those with hepatic impairment or in those with mild to moderate renal insufficiency. In long term, well designed trials miglitol reduces fasting and postprandial plasma glucose levels, thus improving glycaemic control, which is reflected in a reduced HbA1c level in patients with type 2 diabetes mellitus. Most adverse events associated with miglitol involve disturbances of the gastrointestinal tract. This agent is a useful first-line therapy in patients with type 2 diabetes mellitus insufficiently controlled by diet alone and as second-line or as adjuvant therapy in those insufficiently controlled with diet and sulphonylurea agents. Miglitol may prove particularly beneficial in elderly patients and those with hepatic impairment or mild to moderate renal impairment, in whom other oral antidiabetic agents are contraindicated or need to be used with caution.

Miglitol (BAY m 1099) treatment of diabetic hypothalamic-dietary obese rats improves islet response to glucose.

The well-absorbed alpha-glucosidase inhibitor, miglitol (BAY m 1099), was included in the diets of hypothalamic-dietary obese diabetic rats to investigate its ability to improve glycemia and thereby reverse glucotoxic effects on islet secretory response. Female rats received bilateral electrolytic lesions of the ventromedial hypothalamus and were fed high-fat, sucrose-supplemented diets until hyperinsulinemia and hyperglycemia were observed after 3 hours of food deprivation (nonfed). Diabetic animals were assigned to miglitol-treated (40 mg/100 g of diet) or untreated groups for 3 weeks; pancreatic islets were isolated for incubation experiments. No differences in food intake, body weights, or nonfed plasma glucose or insulin levels were seen between treated and untreated diabetic rats. Islets isolated from untreated diabetic rats showed elevated basal insulin release and no insulin secretory response to an elevation in glucose concentration. In contrast, islets obtained from miglitol-treated rats showed more normal basal release and a significant insulin secretory response to glucose. Incubation of islets, obtained from normal control rats or untreated diabetic rats, in media containing miglitol at levels estimated to exist in plasma of treated rats had no effect on islet insulin secretory responses to glucose. Islet secretory response was improved despite continued hyperglycemia and severe insulin resistance. Miglitol treatment may improve islet sensitivity to glucose either through effects on islet metabolism requiring prolonged exposure or by improvement in postmeal glycemia, despite persistent hyperglycemia.

Effect of miglitol administration to non-insulin-dependent diabetic rats

1. 1. The effect of the acute or chronic oral administration of miglitol (Bay M 1099 α-glucosidase inhibitor) to non-insulin-dependent diabetic rats was studied. 2. 2. The acute oral administration of miglitol (10 mg/kg b.w.) reduced significantly the increment of blood glucose after oral maltose (2 g/kg b.w.) overload (364 ± 58 and 205 ± 12 mmol/90 min, without and with miglitol respectively; P<0.05). 3. 3. Under chronic oral administration of miglitol (10 mg/kg b.w.), two days after the start of treatment the blood glucose dropped from 7.53 ± 9.59 to 4.40 ± 5.50 mmol/l. The plasma insulin, cholesterol, or triglycerides levels were not modified. 4. 4. A significant reduction ( P<0.01) in water and food intake was observed. Normal rats values were not affected by miglitol treatment.