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Background: This ANAFIE Registry sub-analysis investigated 2-year outcomes and oral anticoagulant (OAC) use stratified by glycated hemoglobin (HbA1c) levels among Japanese patients aged ≥ 75 years with non-valvular atrial fibrillation (NVAF) with and without clinical diagnosis of diabetes mellitus (DM). Methods: The ANAFIE Registry was a large-scale multicenter, observational study conducted in Japan; this sub-analysis included patients with baseline HbA1c data at baseline. The main endpoints evaluated (stroke/systemic embolic events [SEE], major bleeding, intracranial hemorrhage, cardiovascular death, all-cause death, and net clinical outcome [a composite of stroke/SEE, major bleeding, and all-cause death]) were stratified by HbA1c levels (< 6.0%; 6.0% to < 7.0%; 7.0% to < 8.0%; and ≥ 8.0%). Results: Of 17,526 patients with baseline HbA1c values, 8725 (49.8%) patients had HbA1c < 6.0%, 6700 (38.2%) had 6.0% to < 7.0%, 1548 (8.8%) had 7.0% to < 8.0%, and 553 (3.2%) had ≥ 8.0%. Compared with other subgroups, patients with HbA1c ≥ 8.0% were more likely to have lower renal function, higher CHA2DS2-VASc and HAS-BLED scores, higher prevalence of non-paroxysmal AF, and lower direct OAC (DOAC) administration, but higher warfarin administration. The HbA1c ≥ 8.0% subgroup had higher event rates for all-cause death (log-rank P = 0.003) and net clinical outcome (log-rank P = 0.007). Similar trends were observed for stroke/SEE. In multivariate analysis, risk of all-cause death (adjusted hazard ratio [aHR]: 1.46 [95% confidence interval 1.11–1.93]) and net clinical outcome (aHR 1.33 [1.05–1.68]) were significantly higher in the HbA1c ≥ 8.0% subgroup. No significant differences were observed in risks of major bleeding or other outcomes in this and other subgroups. No interaction was observed between HbA1c and OACs. Use/non-use of antidiabetic drugs was not associated with risk reduction; event risks did not differ with/without injectable antidiabetic drugs. Conclusions: Among elderly Japanese patients with NVAF, only HbA1c ≥ 8.0% was associated with increased all-cause death and net clinical outcome risks; risks of the events did not increase in other HbA1c subgroups. Relative event risks between patients treated with DOACs and warfarin were not modified by HbA1c level. Trial registration: UMIN000024006; date of registration: September 12, 2016. [ABSTRACT FROM AUTHOR]

Aims: To evaluate, through exploratory post hoc subgroup analyses, the efficacy and safety of oral semaglutide versus comparators in Japanese patients enrolled in the global PIONEER 1, 3, 4 and 8 clinical trials. Materials and Methods: Patients were randomized to once‐daily oral semaglutide 3, 7 or 14 mg or comparator (placebo, sitagliptin 100 mg or liraglutide 1.8 mg). Change from baseline in glycated haemoglobin (HbA1c) and body weight, and proportions of patients attaining HbA1c <7.0% (53 mmol/mol) and body weight loss ≥5%, were analysed at week 26 for all Japanese patients in each trial separately using the treatment policy estimand (regardless of treatment discontinuation or rescue medication use). Adverse events (AEs) were analysed descriptively. Results: Reductions in HbA1c from baseline in Japanese patients were 1.0% to 1.2% (11.3 mmol/mol to 13.3 mmol/mol) and 1.4% to 1.7% (15.7 mmol/mol to 18.3 mmol/mol) for oral semaglutide 7 mg and 14 mg, respectively. HbA1c reductions were similar or greater than with comparators. Body weight reductions were 1.0% to 2.7% and 3.7% to 4.7% for oral semaglutide 7 mg and 14 mg, respectively, and were generally greater with oral semaglutide than comparators. As expected, the main class of AEs was gastrointestinal, and these AEs comprised most commonly mild‐to‐moderate constipation, nausea and diarrhoea. Conclusions: Oral semaglutide appears efficacious and well tolerated in Japanese patients across the type 2 diabetes spectrum. [ABSTRACT FROM AUTHOR]

New gene regions involved in type 2 diabetes in East Asian individuals have been identified6, and a family history of diabetes also has a substantial influence on the pathophysiology of diabetes. Thus, maternal and paternal family histories of diabetes appear to have differing influences on the pathogenesis of diabetes. The main pathophysiological features of type 2 diabetes are impaired insulin secretion and insulin resistance. Family history of diabetes in both parents is strongly associated with impaired residual -cell function in Japanese type 2 diabetes patients. [Extracted from the article]

Aims: To explore the impact of baseline characteristics on clinical outcomes in the phase 3 LixiLan JP trials which evaluated the efficacy and safety of iGlarLixi, a titratable fixed‐ratio combination of insulin glargine 100 units/mL (iGlar) and GLP‐1 RA lixisenatide (Lixi), vs Lixi (JP‐O1, NCT02749890) or iGlar (LixiLan JP‐O2, NCT02752828; JP‐L, NCT02752412) in Japanese people with type 2 diabetes uncontrolled on oral antidiabetes drugs (OADs; JP‐O1, JP‐O2) or OADs and basal insulin (JP‐L). Materials and methods: Glycated haemoglobin (HbA1c) change from baseline to week 26 was assessed within patient subgroups. Subgroups were defined by dipeptidyl peptidase‐4 inhibitor use at screening (JP‐O1, JP‐O2 only), baseline HbA1c (<8%, ≥8%), baseline BMI (<25, ≥25 kg/m2) and age (<65, ≥65 years). Incidences of hypoglycaemia (baseline HbA1c, BMI and age subgroups) and gastrointestinal disorders (age subgroup) were evaluated over 52 (JP‐O1) or 26 weeks (JP‐O2, JP‐L). Time to control (first HbA1c <7% or fasting plasma glucose [FPG] ≤130 mg/dL; JP‐O2 only) was also assessed. Results: HbA1c reductions were consistently greater with iGlarLixi vs iGlar or Lixi across all subgroups, and iGlarLixi was equally effective in all subgroups. Incidences of documented symptomatic hypoglycaemia (plasma glucose ≤3.9 mmol/L) were higher with iGlarLixi vs Lixi and generally comparable with iGlar. Across age subgroups, incidences of gastrointestinal disorders with iGlarLixi were higher vs iGlar, but lower vs Lixi. Median time to HbA1c or FPG control was shorter with iGlarLixi vs iGlar. Conclusions: iGlarLixi was consistently effective across all baseline characteristic subgroups, with more patients achieving glycaemic control vs iGlar early in treatment. [ABSTRACT FROM AUTHOR]

Aims: To assess efficacy and safety of 26‐week treatment with insulin glargine/lixisenatide fixed‐ratio combination (iGlarLixi) compared with insulin glargine U100 (iGlar) in Japanese patients with type 2 diabetes mellitus (T2DM) inadequately controlled on oral antidiabetic drugs (OADs). Materials and Methods: This phase 3, multicentre, open‐label, 1:1 randomized, parallel‐group study compared efficacy of iGlarLixi and iGlar in patients with T2DM, HbA1c of ≥7.5% to ≤9.5% and fasting plasma glucose ≤10.0 mmol/L (180 mg/dL). The primary endpoint was change in HbA1c from baseline to week 26. Results: Patients were randomized to iGlarLixi (n = 260) or iGlar (n = 261) (mean age 59.7 years, baseline BMI 26.04 kg/m2, and HbA1c 8.04% [64.4 mmol/mol]). HbA1c reduction was significantly greater with iGlarLixi (−1.40% [−15.3 mmol/mol]) than with iGlar (−0.76% [−8.3 mmol/mol]). Significantly more iGlarLixi patients reached HbA1c <7% at week 26 (71.5% vs 38.5%, P <.0001), with significantly lower weight gain (LS mean difference −1.06 kg, P <.0001). Documented symptomatic hypoglycemia (plasma glucose ≤3.9 mmol/L [70 mg/dL]) was recorded in 14.2% of patients with iGlarLixi and 12.3% with iGlar. No severe hypoglycemia was reported in either group. Other than the expected gastrointestinal issues associated with glucagon‐like peptide 1 receptor agonists, we found no major difference in the incidence of TEAEs. Conclusions: HbA1c reduction was significantly greater with iGlarLixi than with iGlar; significantly more patients achieved HbA1c <7%, with no additional risk of hypoglycemia and without weight gain. iGlarLixi (1:1) provided an effective treatment option for Japanese patients with T2DM inadequately controlled on OADs. Clinical Trial Number: NCT02752828 [ABSTRACT FROM AUTHOR]

Aims/Introduction: Tofogliflozin is a potent and highly selective sodium–glucose cotransporter 2 inhibitor that is currently used to treat patients with type 2 diabetes mellitus. The aim of the present study was to evaluate the safety and efficacy of tofogliflozin add‐on to glucagon‐like peptide‐1 (GLP‐1) receptor agonist monotherapy. Materials and Methods: In this 52‐week, prospective, multicenter, single arm, post‐marketing clinical study, Japanese patients who had already been receiving GLP‐1 receptor agonist monotherapy for ≥8 weeks, glycated hemoglobin ≥7.0 and <10.5%, and body mass index ≥18.5 and <35.0 kg/m2 were enrolled. Tofogliflozin 20 mg was orally administered once daily for 52 weeks with GLP‐1 receptor agonist. Primary end‐points were safety and change in glycated hemoglobin from baseline to week 52. Safety was assessed on the basis of the adverse events. Changes from baseline in fasting plasma glucose, bodyweight, blood pressure, uric acid and lipid parameters were assessed as secondary efficacy end‐points. Results: Of the 67 patients enrolled, 63 patients completed the study. Overall, 26 adverse drug reactions occurred in 17 patients (25.4%). Adverse drug reactions with a frequency of two or more patients (3.0%) were constipation, thirst, dehydration and pollakiuria. Hypoglycemia (n = 1) was limited. With the addition of tofogliflozin to GLP‐1 receptor agonist, the subsequent mean (standard deviation) reduction in glycated hemoglobin was −0.6% (1.0%; P < 0.0001). Fasting plasma glucose, bodyweight and blood pressure were significantly improved. Conclusions: Tofogliflozin add‐on to GLP‐1 receptor agonist monotherapy is an effective treatment option with an acceptable safety profile. [ABSTRACT FROM AUTHOR]

Introduction: Empagliflozin, a highly selective sodium-glucose cotransporter 2 (SGLT2) inhibitor, improves glycaemic control in patients with type 2 diabetes mellitus (T2DM) by inducing urinary glucose excretion. Combination therapy with empagliflozin and glucagon-like peptide-1 (GLP-1) receptor agonists had not previously been assessed, so we investigated the safety, tolerability and efficacy of empagliflozin as an add-on therapy to liraglutide, a GLP-1 receptor agonist. Methods: This was a randomised, double-blind, parallel-group phase 4 trial of empagliflozin (10 mg or 25 mg) for 52 weeks as an add-on therapy to liraglutide (0.9 mg/day) in Japanese patients with T2DM insufficiently controlled by liraglutide alone. Results: 59.4% (19/32) and 66.7% (22/33) of patients in the empagliflozin 10 mg and 25 mg groups, respectively, reported at least one adverse event (AE). 9.4% (3/32) and 21.2% (7/33) of patients, respectively, reported drug-related AEs (primary endpoint). From baseline to week 52, adjusted mean changes with empagliflozin 10 mg and 25 mg, respectively, were: − 0.55 (standard error: 0.15) and − 0.77 (0.14)% for glycated haemoglobin; − 32.5 (4.6) and − 36.0 (4.5) mg/dL for fasting plasma glucose; − 2.6 (0.4) and −3.1 (0.3) kg for body weight; − 6.7 (2.2) and − 8.4 (2.1) mmHg for systolic blood pressure; and − 3.0 (1.2) and − 4.7 (1.1) mmHg for diastolic blood pressure. Conclusion: Empagliflozin as an add-on to liraglutide for 52 weeks was well tolerated and led to clinically meaningful and sustained improvements in glycaemic control, body weight and blood pressure in Japanese patients with T2DM. Trial Registration: ClinicalTrials.gov with the identifier NCT02589626. Funding: Nippon Boehringer Ingelheim Co. Ltd. [ABSTRACT FROM AUTHOR]

Aim: This study aims to examine the humanistic and economic burden of cardiovascular disease (CVD)-related comorbidities and hypoglycaemia among respondents with type 2 diabetes (T2D) in Japan.Methods: This study used the Japan National Health and Wellness Survey 2016 database. Respondents who self-reported a physician-diagnosed T2D were included. Respondents with or without the condition of interest (CVD-related comorbidities or hypoglycaemia) were compared via generalized linear models in terms of the outcome variables: (1) health-related quality of life (HRQoL), (2) work productivity and activity impairment, (3) healthcare resource utilization and (4) economic costs.Results: A total of 1478 survey respondents reported a diagnosis of T2D (mean age 63.6 ± 10.6 years, mean HbA1c 6.91 ± 1.1%). Of whom, 804 subjects (54.4%) had at least one CVD related comorbidities, and 369 subjects (29.3%) reported experiences of hypoglycaemia episodes. Patients with CVD-related comorbidities or hypoglycaemia episodes had worse HRQoL, more work and activity impairment, increased health care visits, and higher costs.Conclusions: CVD related comorbidities and hypoglycaemia remains a significant humanistic and economic burden in patients with T2D. The findings suggested that appropriate T2D management with proper medication choice are important to control CVD related comorbidities and hypoglycaemia among T2D patients to alleviate the burden. [ABSTRACT FROM AUTHOR]

Aim: To explore if clinical effects and hypoglycaemia risks associated with insulin glargine 300 U/mL (Gla‐300) and 100 U/mL (Gla‐100) differed by sulphonylurea and/or glinide (SU/G) treatment. Methods: A post hoc subgroup analysis of 12‐month treatment data from the EDITION Japan 2 trial, a randomized, open‐label, phase 3 study of Japanese people with type 2 diabetes receiving once‐daily Gla‐300/Gla‐100 + oral antihyperglycaemic drugs. Participants previously receiving SU/G (+SU/G) were compared with those not taking SU/G (‐SU/G). Endpoints included HbA1c, hypoglycaemia and body weight. Results: For +SU/G (n = 152, 63%), HbA1c was reduced from baseline to month 12 for Gla‐300 (8.1% to 7.6%) and Gla‐100 (8.2% to 7.8%). For ‐SU/G (n = 89, 37%), reductions were 7.8% to 7.4%, and 7.9% to 7.5% for Gla‐300 and Gla‐100, respectively. A lower annualized rate of hypoglycaemia with Gla‐300 versus Gla‐100 was observed at night (00:00–05:59 hours; p = 0.0001) and any time of day (24 hour; p = 0.0015). Irrespective of the insulin used, the incidence and rate of confirmed (≤3.9 mmol/L [≤70 mg/dL]) or severe hypoglycaemia appeared higher in +SU/G versus ‐SU/G; overall, a reduced incidence of nocturnal hypoglycaemia, and rate of hypoglycaemia at any time, was observed in ‐SU/G versus +SU/G. In the ‐SU/G subgroup, body weight gain differences were observed between Gla‐300 and Gla‐100 (p < 0.0001). Conclusions: Participants with prior and continued SU/G use had similar therapeutic responses with basal insulin but greater risk of hypoglycaemia than those not using SU/G; hypoglycaemia risk was lower with Gla‐300 than Gla‐100 in both subgroups. [ABSTRACT FROM AUTHOR]

Introduction: We evaluated the efficacy and safety of DS‐8500a as add‐on therapy to sitagliptin in Japanese type 2 diabetes mellitus patients. Materials and Methods: This multicenter, randomized, double‐blind, placebo‐controlled, phase 2 trial randomized patients aged ≥20 years with hemoglobin A1c ≥7.0% and <9.0%, and inadequate glycemic control with sitagliptin 50‐mg monotherapy to receive 25 or 75 mg DS‐8500a, or a placebo, orally. The primary end‐point was change from baseline to day 28 in 24‐h weighted mean glucose. Secondary end‐points included change from baseline in fasting plasma glucose, 2‐h postprandial plasma glucose and lipid profiles. Results: Overall, 29, 28 and 27 patients in the placebo, 25‐ and 75‐mg groups, respectively, were analyzed. A significant dose‐dependent reduction was observed in 24‐h weighted mean glucose (linear: P = 0.0006, saturated at 25 mg: P = 0.0003, responded from 75 mg: P = 0.0176) when compared with the placebo (25 mg: −13.19 mg/dL [−0.73 mmol/L], P = 0.0044 vs placebo and 75 mg: −16.12 mg/dL [−0.89 mmol/L], P = 0.0006 vs placebo). A significant reduction in fasting plasma glucose at 75 mg vs placebo was observed (P < 0.001). At 25 and 75 mg, significant reductions of 2‐h postprandial plasma glucose (after breakfast), total cholesterol, low‐cholesterol and triglycerides were observed (all P < 0.05), with a (non‐significant) trend towards increased high‐density lipoprotein cholesterol. Both doses of DS‐8500a were well tolerated. There were no significant treatment‐emergent adverse events leading to discontinuation during the study. Conclusions: DS‐8500a was well tolerated, and showed significant glycemic benefits and favorable changes in lipid profile in Japanese type 2 diabetes mellitus patients with inadequate glycemic control with sitagliptin therapy. We evaluated the efficacy and safety of the G protein‐coupled receptor 119 agonist DS‐8500a as add‐on therapy for Japanese patients with type 2 diabetes mellitus currently receiving once‐daily sitagliptin 50‐mg monotherapy. In this multicenter, double‐blind, placebo‐controlled, phase 2 trial, patients were randomized to receive 25‐ or 75‐mg DS‐8500a, or placebo. A significant dose‐dependent reduction from baseline to day 28 was observed in 24‐h weighted mean glucose (primary endpoint) compared with placebo; DS‐8500a treatment was well tolerated and elicited significant glycemic benefits and favorable changes in lipid profile. [ABSTRACT FROM AUTHOR]

DPP-4 inhibitors also increase the levels of endogenous DPP-4 substrates, such as neuropeptide Y or substance P, and might thereby have effects on the immune system through DPP-4, DPP-8 or DPP-9. At least for now, we need to pay attention to early detection and treatment of pancreatitis and pancreatic cancer in patients receiving DPP-4 inhibitors. Measurement of serum amylase or lipase levels is not sufficient for the prediction of pancreatitis, because mild elevation in the levels of these enzymes is seen in patients receiving DPP-4 inhibitors or GLP-1RAs. [Extracted from the article]

Aims: To evaluate the long‐term safety and efficacy of tofogliflozin as an add‐on treatment to insulin over 52 weeks. Materials and methods: This 52‐week, multicentre, Phase 4 study consisted of a 16‐week, randomized, double‐blind, placebo‐controlled phase and a 36‐week open label extension phase (NCT02201004). Japanese patients with type 2 diabetes mellitus, aged 20 to 75 years, with suboptimal glycaemic control (7.5%‐10.5%) receiving insulin monotherapy (basal‐bolus, bolus, premix [low and high] and basal) or receiving combination therapy with basal insulin and dipeptidyl peptidase‐4 inhibitor were eligible for participation. Patients who received tofogliflozin throughout the study (52 weeks) were referred to as the ‘tofo‐tofo group’ and patients who received placebo and tofogliflozin (36 weeks) were referred to as the ‘pla‐tofo group’. Results: A total of 210 patients received treatment per randomization. Hypoglycaemia was the most common treatment‐emergent adverse event (AE) (42.9% in the tofo‐tofo group and 29.4% in the pla‐tofo group). Patients reported genital infection, urinary tract infection, excessive urination and AEs related to volume depletion (2.1%, 2.1%, 7.1% and 10.0% of patients in the tofo‐tofo group, and 0%, 1.5%, 2.9% and 7.4% of patients in the pla‐tofo group, respectively). Mean HbA1c and body weight at baseline (mean changes ± standard error from baseline to Week 52) in the tofo‐tofo and pla‐tofo groups were 8.53% (−0.76% ± 0.077) and 8.40% (−0.73% ± 0.102); 68.84 kg (−1.52 kg ± 0.207) and 72.24 kg (−2.13 kg ± 0.313), respectively. Conclusions: This study demonstrates the safety and efficacy of tofogliflozin as add‐on to insulin therapy in type 2 diabetes mellitus patients, offering a new therapeutic solution to diabetes management. [ABSTRACT FROM AUTHOR]

Aims: To assess the safety and efficacy of monotherapy with once‐weekly subcutaneous (s.c.) semaglutide vs sitagliptin in Japanese people with type 2 diabetes (T2D). Methods: In this phase IIIa randomized, open‐label, parallel‐group, active‐controlled, multicentre trial, Japanese adults with T2D treated with diet and exercise only or oral antidiabetic drug monotherapy (washed out during the run‐in period) received once‐weekly s.c. semaglutide (0.5 or 1.0 mg) or once‐daily oral sitagliptin 100 mg. The primary endpoint was number of treatment‐emergent adverse events (TEAEs) after 30 weeks. Results: Overall, 308 participants were randomized and exposed to treatment, with similar baseline characteristics across the groups. In total, 2.9% of participants in both the semaglutide 0.5 mg and the sitagliptin group prematurely discontinued treatment, compared with 14.7% in the semaglutide 1.0 mg group. The majority of discontinuations in the semaglutide 0.5 and 1.0 mg groups were attributable to adverse events (AEs). More TEAEs were reported in semaglutide‐ vs sitagliptin‐treated participants (74.8%, 71.6% and 66.0% in the semaglutide 0.5 mg, semaglutide 1.0 mg and sitagliptin groups, respectively). AEs were mainly mild to moderate. Gastrointestinal AEs, most frequently reported with semaglutide, diminished in frequency over time. The mean glycated haemoglobin (HbA1c [baseline 8.1%]) decreased by 1.9% and 2.2% with semaglutide 0.5 and 1.0 mg, respectively, vs 0.7% with sitagliptin (estimated treatment difference [ETD] vs sitagliptin −1.13%, 95% confidence interval [CI] −1.32; −0.94, and −1.44%, 95% CI −1.63; −1.24; both P < .0001). Body weight (baseline 69.3 kg) was reduced by 2.2 and 3.9 kg with semaglutide 0.5 and 1.0 mg, respectively (ETD −2.22 kg, 95% CI −3.02; −1.42 and −3.88 kg, 95% CI −4.70; −3.07; both P < .0001). Conclusions: In Japanese people with T2D, more TEAEs were reported with semaglutide than with sitagliptin; however, the semaglutide safety profile was similar to that of other glucagon‐like peptide‐1 receptor agonists. Semaglutide significantly reduced HbA1c and body weight compared with sitagliptin. [ABSTRACT FROM AUTHOR]

Aim/Introduction To assess the overall safety of lixisenatide monotherapy in Japanese patients with type 2 diabetes mellitus. Materials and Methods Patients with type 2 diabetes mellitus, previously treated with ≤1 oral antidiabetic drug, were enrolled in an uncontrolled, open-label, single-arm study over 24 and 52 weeks. Any oral antidiabetic drug treatment was stopped at the start of the 6-week run-in period. From baseline, patients received once-daily lixisenatide monotherapy (10 μg for 1 week, 15 μg for 1 week, 20 μg thereafter) for 52 weeks (first 140 patients enrolled) or 24 weeks (subsequently enrolled patients). The primary end-point was safety over 24 and 52 weeks. Secondary efficacy end-points included absolute change in glycated hemoglobin, fasting plasma glucose and bodyweight from baseline. Results Of 428 patients screened, 361 and 140 were treated for 24 and 52 weeks, respectively; 88.4 and 90.0% completed treatment. During the 24- and 52-week treatment periods, 268/361 (74.2%) and 117/140 (83.6%) patients, respectively, had treatment-emergent adverse events; the most frequently reported was nausea (33.2 and 31.4%, respectively). The risk of severe hypoglycemia was low; only one case was reported. Lixisenatide treatment resulted in a decrease in mean glycated hemoglobin A1c (−0.98 and −0.86%), fasting plasma glucose (−1.05 and −0.85 mmol/L), and bodyweight (−1.33 and −1.48 kg) for the 24- and 52-week treatment periods, respectively. Conclusions Once-daily lixisenatide monotherapy was associated with a safety profile in line with the glucagon-like peptide-1 receptor agonist class, and improved glycemic control in Japanese patients with type 2 diabetes mellitus. [ABSTRACT FROM AUTHOR]

Aims To assess the effects of 16 weeks of tofogliflozin (sodium-glucose co-transporter-2 [ SGLT2] inhibitor) treatment vs placebo on glycated haemoglobin ( HbA1c) levels in Japanese patients with type 2 diabetes mellitus ( T2DM) inadequately controlled with insulin monotherapy or insulin plus a dipeptidyl peptidase-4 ( DPP-4) inhibitor. Methods The study comprised a 16-week, multicentre, double-blind, placebo-controlled period and a 36-week extension ( NCT02201004). Men and women (aged ≥20 and ≤75 years) with T2DM ( HbA1c ≥7.5% and ≤10.5%) were randomized 2:1 to tofogliflozin 20 mg once/day or placebo. The primary endpoint was change in HbA1c from baseline. Insulin reduction was not permitted during this study. Results A total of 211 patients were randomized (141 tofogliflozin, 70 placebo). Addition of tofogliflozin to insulin therapy was significantly superior to placebo for lowering HbA1c (−0.59 vs +0.48%; P < .0001), fasting plasma glucose (−27.2 vs +5.3 mg/ dL; P < .0001), postprandial plasma glucose (−65.0 vs +3.2 mg/ dL; P < 0.0001), serum uric acid (−0.18 vs +0.07 mg/ dL; P = .0062), body weight (−1.34 vs +0.03 kg; P < .0001) and daily insulin dose (−1.3 vs −0.2 U, P = .0152). Hypoglycaemia occurred in 30.7% of patients receiving tofogliflozin vs 21.4% for placebo. Two patients treated with tofogliflozin each had a genital or urinary tract infection. Conclusions This 16-week double-blind study indicated that, in patients with T2DM whose HbA1c levels were poorly controlled with insulin monotherapy or insulin plus a DPP-4 inhibitor, addition of tofogliflozin was an effective treatment option with an acceptable safety profile. [ABSTRACT FROM AUTHOR]

Aims/Introduction: The Dementia Assessment Sheet for Community‐based Integrated Care System 8‐items (DASC‐8) assesses memory, orientation, instrumental activities of daily living and basic activities of daily living. Category I (DASC‐8 score ≤10), category II (11 ≤ DASC‐8 score ≤16) and category III (DASC‐8 score ≥17) have been defined. Based on these categories, the glycemic targets in diabetes patients aged ≥65 years have been proposed by the Japan Diabetes Society and the Japan Geriatrics Society Joint Committee. DASC‐8 is difficult to apply to patients without family members or supportive persons. We propose a verbal fluency test as the screening tool. Materials and Methods: We enrolled 69 inpatients aged ≥65 years with type 2 diabetes, who were administered the DASC‐8 and VF tests, which included recalling animal names and common nouns starting with a specified letter in 1 min. The relationship between DASC‐8 and verbal fluency test scores was investigated. Results: Animal fluency correlated with DASC‐8 scores after adjustment for patient characteristics. Animal scores correlated with orientation, instrumental activities of daily living and basic activities of daily living scores of DASC‐8, and tended to show a relationship with DASC‐8 memory scores. An animal score ≥8 predicted category I with a sensitivity of 89% and a specificity of 57%. An animal score ≤6 predicted category III with a sensitivity of 85% and a specificity of 67%. Conclusions: Animal scores would be useful in predicting the categories of DASC‐8. Animal fluency could be a screening tool of DASC‐8 when a patient's family member or supportive person is absent. We enrolled 69 inpatients aged ≥65 years with type 2 diabetes, who were administered the Dementia Assessment Sheet for Community‐based Integrated Care System 8‐items and verbal fluency tests, which included recalling animal names and common nouns starting with a specified letter in 1 min. Animal fluency would be useful in predicting the categories of Dementia Assessment Sheet for Community‐based Integrated Care System 8‐items. [ABSTRACT FROM AUTHOR]

Glucokinase is one of four members of the hexokinase family of enzymes. Its expression is limited to the major organs (such as the pancreas, liver, brain and the gastrointestinal tract) that are thought to have an integrated role in glucose sensing. In the liver, phosphorylation of glucose by glucokinase promotes glycogen synthesis, whereas in the β-cells, it results in insulin release. Studies of glucokinase-linked genetically-modified mice and mutations in humans have illustrated the important roles played by glucokinase in whole-body glucose homeostasis, and suggest that the use of pharmacological agents that augment glucokinase activity could represent a viable treatment strategy in patients with type 2 diabetes. Since 2003, many glucokinase activators ( GKAs) have been developed, and their ability to lower the blood glucose has been shown in several animal models of type 2 diabetes. Also, we and others have shown in mouse models that GKAs also have the effect of stimulating the proliferation of β-cells. However, the results of recent phase II trials have shown that GKAs lose their efficacy within several months of use, and that their use is associated with a high incidence of hypoglycemia; furthermore, patients treated with GKAs frequently developed dyslipidemia. A better understanding of the role of glucokinase in metabolic effects is required to resolve several issues identified in clinical trials. [ABSTRACT FROM AUTHOR]

Glucose‐ or insulin resistance‐mediated β‐cell replication serves as a useful physiological model of β‐cell mass expansion to study the pathophysiology of type 2 diabetes. Lakshmipathi et al. (2016) report that PKCζ activation is crucial for compensatory β‐cell proliferation induced by glucose stimulation or high‐fat diet‐feeding. [ABSTRACT FROM AUTHOR]

Aims/Introduction Our primary objective was to assess changes in quality of life ( QOL) associated with changes in insulin regimen in patients with type 2 diabetes mellitus. Secondary objectives were to assess the reasons for and patterns of changes in insulin regimen, and the effects on glycemic control. Materials and Methods This 12-week, observational study included patients with type 2 diabetes mellitus ( n = 625) who planned to change insulin regimen (type of insulin, injection device and/or number of injections). The primary outcome measure was a change from baseline in QOL assessed by the Insulin Therapy- Related ( ITR) QOL questionnaire. The secondary outcome measures included change from baseline in plasma glycated hemoglobin ( Hb A1c) level, the reasons for and pattern of insulin regimen change, and change from baseline in QOL assessed by Diabetes Treatment Satisfaction Questionnaire ( DTSQ). Results QOL did not worsen during the study. Improvements were seen in the ITR- QOL 'daily activities' subscale score (baseline: 12.7 ± 2.3; week 12: 12.9 ± 2.3; P = 0.038, n = 568) and the DTSQ 'perceived frequency of hyperglycemia' subscale score (baseline: 3.4 ± 1.6; week 12: 3.0 ± 1.7; P < 0.001, n = 573). Glycemic control improved, as evidenced by decreased plasma Hb A1c levels (baseline: 8.21 ± 1.47%; week 12: 7.85 ± 1.31%; P < 0.001, n = 606). Conclusions It was suggested that insulin regimen changes might improve glycemic control in Japanese patients with type 2 diabetes mellitus without worsening QOL. This trial was registered with ClinicalTrials.gov (no. NCT01055808). [ABSTRACT FROM AUTHOR]

Glucokinase (Gck) functions as a glucose sensor for insulin secretion, and in mice fed standard chow, haploinsufficiency of β cell-specific Gck (Gck+/-) causes impaired insulin secretion to glucose, although the animals have a normal β cell mass. When fed a high-fat (HF) diet, wild-type mice showed marked β cell hyperplasia, whereas Gck+/- mice demonstrated decreased β cell replication and insufficient β cell hyperplasia despite showing a similar degree of insulin resistance. DNA chip analysis revealed decreased insulin receptor substrate 2 (Irs2) expression in HF diet-fed Gck+/- mouse islets compared with wild-type islets. Western blot analyses confirmed upregulated Irs2 expression in the islets of HF diet-fed wild-type mice compared with those fed standard chow and reduced expression in HF diet-fed Gck+/- mice compared with those of HF diet-fed wild-type mice. HF diet-fed Irs2+/- mice failed to show a sufficient increase in β cell mass, and overexpression of Irs2 in β cells of HF diet-fed Gck+/- mice partially prevented diabetes by increasing β cell mass. These results suggest that Gck and Irs2 are critical requirements for β cell hyperplasia to occur in response to HF diet-induced insulin resistance. [ABSTRACT FROM AUTHOR]

Thiazolidinediones have been shown to up-regulate adiponectin expression in white adipose tissue and plasma adiponectin levels, and these up-regulations have been proposed to be a major mechanism of the thiazolidinedione-induced amelioration of insulin resistance linked to obesity. To test this hypothesis, we generated adiponectin knock-out (adipo-/-) ob/ob mice with a C57B/6 background. After 14 days of 10 mg/kg pioglitazone, the insulin resistance and diabetes of ob/ob mice were significantly improved in association with significant up-regulation of serum adiponectin levels. Amelioration of insulin resistance in ob/ob mice was attributed to decreased glucose production and increased AMP-activated protein kinase in the liver but not to increased glucose uptake in skeletal muscle. In contrast, insulin resistance and diabetes were not improved in adipo-/- ob/ob mice. After 14 days of 30 mg/kg pioglitazone, insulin resistance and diabetes of ob/ob mice were again significantly ameliorated, which was attributed not only to decreased glucose production in the liver but also to increased glucose uptake in skeletal muscle. Interestingly, adipo ob/ob mice also displayed significant amelioration of insulin resistance and diabetes, which was attributed to increased glucose uptake in skeletal muscle but not to decreased glucose production in the liver. The serum-free fatty acid and triglyceride levels as well as adipocyte sizes in ob/ob and adipo-/- ob/ob mice were unchanged after 10 mg/kg pioglitazone but were significantly reduced to a similar degree after 30 mg/kg pioglitazone. Moreover, the expressions of TNFα and resistin in adipose tissues of ob/ob and adipo-/- ob/ob mice were unchanged after 10 mg/kg pioglitazone but were decreased after 30 mg/kg pioglitazone. Thus, pioglitazone-induced amelioration of insulin resistance and diabetes may occur adiponectin dependently in the liver and adiponectin independently in skeletal muscle. [ABSTRACT FROM AUTHOR]

Heterozygous peroxisome proliferator-activated receptor-gamma (PPAR-gamma)-deficient (PPARgamma(+/-)) mice were protected from high-fat diet-induced insulin resistance. To determine the impact of systemic reduction of PPAR-gamma activity on beta-cell function, we investigated insulin secretion in PPARgamma(+/-) mice on a high-fat diet. Glucose-induced insulin secretion in PPARgamma(+/-) mice was impaired in vitro. The tissue triglyceride (TG) content of the white adipose tissue, skeletal muscle, and liver was decreased in PPARgamma(+/-) mice, but it was unexpectedly increased in the islets, and the increased TG content in the islets was associated with decreased glucose oxidation. Administration of a PPAR-gamma agonist, pioglitazone, reduced the islet TG content in PPARgamma(+/-) mice on a high-fat diet and ameliorated the impaired insulin secretion in vitro. Our results demonstrate that PPAR-gamma protects islets from lipotoxicity by regulating TG partitioning among tissues and that a PPAR-gamma agonist can restore impaired insulin secretion under conditions of islet fat accumulation. [ABSTRACT FROM AUTHOR]

We previously demonstrated that insulin receptor substrate 2 (Irs2) KO mice develop diabetes associated with hepatic insulin resistance, lack of compensatory β cell hyperplasia, and leptin resistance. To more precisely determine the roles of lrs2 in β cells and the hypothalamus, we generated β cell-specific Irs2 KO and hypothalamus-specific Irs2 knockdown (I3HT-IRS2) mice. Expression of Irs2 mRNA was reduced by approximately 90% in pancreatic islets and was markedly reduced in the arcuate nucleus of the hypothalamus. By contrast, Irs2 expression in liver, muscle, and adipose tissue of βHT-IRS2 mice was indistinguishable from that of control mice. The βHT-IRS2 mice displayed obesity and leptin resistance. At 4 weeks of age, the βHT-IRS2 mice showed normal insulin sensitivity, but at 8 and 12 weeks, they were insulin resistant with progressive obesity. Despite their normal insulin sensitivity at 8 weeks with caloric restriction, the βHT-IRS2 mice exhibited glucose intolerance and impaired glucose-induced insulin secretion. β Cell mass and βcell proliferation in the βHT-IRS2 mice were reduced significantly at 8 and 12 weeks but not at 10 clays. Insulin secretion, normalized by cell number per islet, was significantly increased at high glucose concentrations in the βHT-IRS2 mice. We conclude that, in β cells and the hypothalamus, Irs2 is crucially involved in the regulation of β cell mass and leptin sensitivity. [ABSTRACT FROM AUTHOR]

Mice lacking the p85alpha regulatory subunit of phosphoinositide (PI) 3-kinase (Pik3r1(-/-)) showed increased glucose uptake in white adipose tissue (WAT) and skeletal muscle due to increased phosphatidylinositol (3,4,5)-triphosphate [PtdIns(3,4,5)P3] production and on a normal diet had a body weight and fat mass similar to wild-type mice. After 3 months on a high-fat diet, Pik3r1(-/-) mice still had increased insulin sensitivity and better glucose tolerance than wild-type mice, but showed markedly greater increases in body weight and WAT mass than wild-type mice. On the normal diet, serum leptin levels of Pik3r1(-/-) mice were significantly higher than in wild-type mice as a result of increased leptin secretion from adipocytes, presumably due to the increased PtdIns(3,4,5)P3 production in adipocytes. Leptin (5 microg/g body wt per day) caused a reduction in food intake and decrease in body weight by the wild-type mice as well as Pik3r1(-/-) mice, suggesting Pik3r1(-/-) mice having leptin sensitivity similar to wild-type mice. The slightly increased serum leptin compensated for the increased glucose uptake by adipocytes in Pik3r1(-/-) mice, thereby preventing adiposity on the normal diet. On the high-fat diet, leptin (5 microg/g body wt per day) failed to decrease food intake or body weight in either genotype, indicating that both genotypes had indeed become severely leptin resistant. Consequently, leptin secretion was unable to sufficiently compensate for the severe leptin resistance caused by the high-fat diet, thereby failing to prevent obesity in Pik3r1(-/-) mice. Our findings suggest that primary increase in serum leptin on the normal diet play a role in the protection from adiposity in Pik3r1(-/-) mice. [ABSTRACT FROM AUTHOR]

Phosphoinositide 3-kinases (PI3Ks) are a family of lipid kinases essential for diverse physiological reactions. In recent years a series of gene-targeted mice lacking different types of PI3Ks and related molecules have been generated which enable us to understand the role of PI3K pathways, particularly class I members, in vivo. Analyses of such gene-targeted mice have led to major discoveries in the physiological roles of PI3K signaling in mast cell biology. In particular the role of PI3Ks has been extensively studied in signaling through the high-affinity IgE receptor (FcεRI), since mast cells are the main effector cells in type I allergic reaction associated with IgE-dependent mechanisms. Furthermore, the knockout mice have provided significant information concerning the role of PI3K signals in mast cell differentiation. This review presents several new insights into mast cell biology, which have been elucidated by the analyses of these knockout mice. [ABSTRACT FROM AUTHOR]

Examines the impact of genetic background and ablation of insulin receptor substrate (IRS)-3 on IRS-2 knock-out mice. Pathogenesis of type 2 diabetes; Glucose homeostasis; Analysis of glucose and insulin tolerance tests.

Low birth weight has been reported to be associated with impaired insulin secretion and insulin resistance. It has been proposed that this association results from fetal programming in response to the intrauterine environment (the thrifty phenotype hypothesis). To elucidate the relationship between birth weight and genetically determined defects in insulin secretion, we measured the birth weights of neonates derived from crosses of male pancreatic beta-cell type glucokinase knockout (Gck+/-) mice and female wild-type (WT) or Gck+/- mice. In 135 offspring, birth weights were lower in the presence of a fetal heterozygous mutation and higher in the presence of a maternal heterozygous mutation. Moreover, Gck-/- neonates had significantly smaller birth weights than WT or Gck+/- neonates (means +/- SE 1.49+/-0.03 [n = 30] vs. 1.63+/-0.03 [n = 30] or 1.63+/-0.02 [n = 50] g, respectively; P<0.01). Thus, Gck mutations in beta-cells may impair insulin response to glucose and alter intrauterine growth as well as glucose metabolism after birth. This study has confirmed the results of a previous report that human subjects carrying mutations in Gck had reduced birth weights and has provided direct evidence for a link between insulin and fetal growth. Moreover, birth weights were reduced in insulin receptor substrate-1 knockout mice despite normal insulin levels. Taken together, these results suggest that a genetically programmed insulin effect during embryogenesis determines fetal growth and provides a possible molecular link between birth weight and susceptibility to type 2 diabetes. [ABSTRACT FROM AUTHOR]

Introduction: As treatment agents for diabetes, liraglutide is a long-acting glucagon-like peptide 1 receptor agonist, and dipeptidyl peptidase 4 (DPP4) inhibitors are widely used because of their safety and tolerability. Regular treatment with liraglutide has been reported to significantly reduce blood glucose levels, but the impact of low-dose (0.3 mg) liraglutide on blood glucose levels immediately after treatment switching from a DPP4 inhibitor remains unknown. Methods: We conducted a single-arm, retrospective, observational study in 55 inpatients with type 2 diabetes (T2D) to investigate the changes (Δ) in their blood glucose levels at six time points (6-point) from the day before (day −1) to the day after (day 1) by switching the antidiabetic treatment from a DPP4 inhibitor to liraglutide 0.3 mg (low-dose liraglutide) once daily. We also attempted to identify factors associated with the blood glucose-lowering effects of liraglutide. Results: The median values of the changes in fasting, preprandial, and postprandial blood glucose levels and the fluctuations in the blood glucose levels expressed as the standard deviation of the 6-point blood glucose levels were significantly lower on day 1 than on day −1 (P < 0.05, P < 0.0001, P < 0.0001, P < 0.01, respectively); there were no cases of severe hypoglycemia. The Δ blood glucose levels were not associated with the baseline serum hemoglobin A1c values or with any markers of the insulin secreting capacity. There were no associations between the previously used blood glucose-lowering drug and the Δ blood glucose levels. Conclusion: Switching from a DPP4 inhibitor to low-dose (0.3 mg) liraglutide once daily significantly reduced the blood glucose levels and excursions of the blood glucose levels even from the very day after the treatment switch, with no serious adverse events. [ABSTRACT FROM AUTHOR]

The hallmark of type 2 diabetes, the most common metabolic disorder, is a defect in insulin-stimulated glucose transport in peripheral tissues. Although a role for phosphoinositide-3kinase (PI3K) activity in insulin-stimulated glucose transport and glucose transporter isoform 4 (Glut4) translocation has been suggested in vitro, its role in viva and the molecular link between activation of PI3K and translocation has not yet been elucidated. To determine the role of PI3K in glucose homeostasis, we generated mice with a targeted disruption of the gene encoding the p85α regulatory subunit of PI3K (Pik3r1; refs 3-5). Pik3r1[sup -/-] mice showed increased insulin sensitivity and hypoglycaemia due to increased glucose transport in skeletal muscle and adipocytes. Insulin-stimulated PI3K activity associated with insulin receptor substrates (IRSs) was mediated via full-length p85α in wild-type mice, but via the p50α alternative splicing isoform of the same gene in Pik3r1[sup -/-] mice. This isoform switch was associated with an increase in insulin-induced generation of phosphatidylinositol(3,4,5)triphosphate (Ptdlns(3,4,5)P[sub 3]) in Pik3r1[sup -/-] adipocytes and facilitation of Glut4 translocation from the low-density microsome (LDM) fraction to the plasma membrane (PM). This mechanism seems to be responsible for the phenotype of Pik3r1[sup -/-] mice, namely increased glucose transport and hypoglycaemia. Our work provides the first direct evidence that PI3K and its regulatory subunit have a role in glucose homeostasis in vivo. [ABSTRACT FROM AUTHOR]

Presents research which showed that the protein p85 participates in the cell death process that is induced in response to oxidative stress without involving the signaling protein phosphatidyl-3-OH kinase (PI(3)K). Effects of reactive oxygen species on cells; Disruption of p85 by homologous recombination; Relation between p85 and the protein p53; Methods; p85 acting as a signal transducer and mediating cell death regulated by p53.

Inactivation of β‐cell transcriptional factors in the development of diabetes. [ABSTRACT FROM AUTHOR]

Aim: α-Glucosidase inhibitors (αGIs) primarily modify postprandial plasma glucose levels and should be taken just before meals. We previously demonstrated that a single administration of miglitol within 30 min after the start of a meal was equally effective as when administered just before a meal. We here compared pre- vs. postmeal administration of miglitol for 3 months in type 2 diabetic patients. Methods: Thirty-one type 2 diabetic outpatients who had never been treated with insulin injections or αGIs were randomized to two groups: patients in group A were asked to take miglitol just before meals, while patients in group B were asked to take miglitol after meals. We measured 1,5-anhydroglucitol (1,5-AG) and HbA1C levels in these patients. Results: The administration of miglitol after meals for a 3-month period decreased HbA1C and increased 1,5-AG levels to the same extent as when administered just before meals. The incidence of adverse effects seemed to be unrelated to the timing of the miglitol administration. Conclusions: Our results suggest that if patients have difficulty remembering to take miglitol just before meal, they should be instructed to take the medicine together with other medicine(s) after the meal; this instruction may improve the treatment compliance of diabetic patients. [ABSTRACT FROM AUTHOR]

Introduction: The ultimate goal of antihyperglycemic treatment for people with diabetes is to have a similar longevity and quality of life (QOL) as those without diabetes. No study has specifically aimed at assessing the association between glycemic control and QOL in general type 2 diabetes patients in Japan. We therefore wanted to evaluate QOL in Japanese type 2 diabetes (T2DM) patients using a validated diabetes treatment related-QOL (DTR-QOL) questionnaire. The aim of this study was to investigate the association between glycemic controls and QOL among Japanese patients with T2DM. We presented its interim report on 77th scientific session in June, 2017. We will finally submit our final report this time. Methods: We conducted a large-scale multi-centered, cross-sectional study and analyzed a total of 3,259 type 2 diabetes patients who provided valid answers to the DTR-QOL questionnaire. Results: Among 3,259 patients, 61% were male and 39% were female. The mean age was 63.0 ± 11.8 years, the mean BMI was 25.3 ± 4.8 kg/m2, and the mean HbA1c was 7.5 ± 1.6%. There was a significant negative correlation between the total DTR-QOL score and HbA1c (ρ =-0.325, p<0.0001). The total DTR-QOL score increased with increasing age (p < 0.0001) and decreased with increased BMI (p < 0.0001) and increased HbA1c levels (p < 0.0001). In multiple regression analysis, adjusted for age, sex and BMI, HbA1c (β=-0.229, p<0.0001), neuropathy (β=0.082, p<0.0001), macroangiopathy (β=0.050, p=0.0027), and insulin injection (β=0.196, p<0.0001) were found to be independent factors with significant effects on DTR-QOL. Conclusions: Our results show that poor blood glucose control, diabetic neuropathy, macroangiopathy, and insulin injections are factors that lead to reduced QOL in type 2 diabetes patients. In routine practice, healthcare professionals should not forget to evaluate the patient's QOL in addition to assessing blood glucose control status and other factors. Disclosure: K. Takahashi: None. Y. Terauchi: Advisory Panel; Self; AstraZeneca, Boehringer Ingelheim Pharmaceuticals, Inc., Daiichi Sankyo, Eli Lilly Japan K.K., Novo Nordisk A/S, Sanofi. Consultant; Self; Astellas Pharma Inc. Research Support; Self; Boehringer Ingelheim Pharmaceuticals, Inc., Daiichi Sankyo, Eli Lilly Japan K.K., Merck Sharp & Dohme Corp., Novartis Pharmaceuticals Corporation, Novo Nordisk A/S, Ono Pharmaceutical Co., Ltd., Sumitomo Dainippon Pharma Co., Ltd., Takeda Pharmaceutical Company Limited. Speaker's Bureau; Self; Astellas Pharma Inc., AstraZeneca, Boehringer Ingelheim Pharmaceuticals, Inc., Daiichi Sankyo, Eli Lilly Japan K.K., Kowa Company, Ltd., Medscape, Medtronic, Merck Sharp & Dohme Corp., Mitsubishi Tanabe Pharma Corporation, Novartis Pharmaceuticals Corporation, Novo Nordisk A/S, Ono Pharmaceutical Co., Ltd., Sanofi, Sanwa Kagaku Kenkyusho, Sumitomo Dainippon Pharma Co., Ltd., Taisho Pharmaceutical Co., Ltd., Takeda Pharmaceutical Company Limited, Terumo Medical Corporation. T. Yamakawa: None. [ABSTRACT FROM AUTHOR]

Introduction: The real-world SPARTA Japan study confirmed the effectiveness and safety of the fixed-ratio combination of insulin glargine 100 U/mL plus lixisenatide (iGlarLixi) once daily over 6 months in Japanese people with type 2 diabetes (T2D). This post hoc analysis examined the impact of participant characteristics on the achievement of age-defined glycaemic targets with iGlarLixi therapy. Methods: The retrospective, observational SPARTA Japan study included adults with T2D who initiated iGlarLixi. In this analysis, data from insulin-naïve and insulin-experienced participants were separately assessed to compare glycated haemoglobin (HbA1c), body weight and safety outcomes between those who achieved ('achieved' group) and those who did not achieve ('not-achieved' group) age-defined glycaemic targets after 6 months of iGlarLixi. The not-achieved group was further stratified by whether or not their iGlarLixi dose was increased during treatment. Results: In total, 418 participants were included in this analysis (138 insulin naïve and 280 insulin experienced). Among both insulin-naïve and insulin-experienced participants, those in the achieved group were older and had lower baseline HbA1c than those in the not-achieved group. Compared with the not-achieved group, the achieved group showed significantly greater HbA1c reductions from baseline (in both insulin-naïve and insulin-experienced participants) and significantly greater body weight reductions (in insulin-naïve participants), despite some participants in the not-achieved group receiving significantly higher insulin glargine doses than those in the achieved group. In both insulin-naïve and insulin-experienced participants, the incidence of hypoglycaemia and gastrointestinal-related adverse events was similar in the achieved and not-achieved groups. In a multivariate analysis, glycaemic target achievement was significantly more likely in older individuals and those who lost weight during iGlarLixi treatment. Conclusions: Achievement of age-defined glycaemic targets with iGlarLixi treatment for 6 months was significantly affected by increased age and body weight loss, regardless of prior insulin exposure. Trial Registration: UMIN-CTR Trials Registry, UMIN000044126; registered 10 May 2021. Plain Language Summary: iGlarLixi is an injectable product used to treat type 2 diabetes that contains a fixed combination of two drugs, insulin glargine (at a concentration of 100 U/mL) and lixisenatide. The SPARTA Japan study investigated the effectiveness of controlling blood glucose levels and the safety of iGlarLixi in Japanese people when taken once daily for over 6 months as part of their routine medical care. The analysis reported in this article looked back at data from SPARTA Japan to assess whether certain characteristics of the people who took part in the study affected how well blood glucose targets were met. People who had previously taken insulin and those who had not were identified, and their results were assessed separately. The people were divided into those who had met their blood glucose level target (with the target defined as the glycated haemoglobin level for each person based on their age) and those who had not met their target. It was found that people who achieved their blood glucose target while receiving iGlarLixi were more likely to be older, to have had a lower glycated haemoglobin level before starting iGlarLixi, and to have lost weight during treatment than those who did not achieve their target, whether or not they had previously been treated with insulin. Side effects of excessively low blood glucose levels or gastrointestinal upset with iGlarLixi treatment occurred in a similar number of people who achieved or did not achieve their blood glucose target. [ABSTRACT FROM AUTHOR]

Aims/Introduction: This study evaluated the effects of the Medtronic MiniMed 770G hybrid closed‐loop system on glycemic control and psychological aspects in persons with type 1 diabetes mellitus. Materials and Methods: This 3‐month prospective observational study included 22 participants with type 1 diabetes mellitus who used the Medtronic MiniMed 640G predictive low‐glucose suspend system and were switched to the 770G system. Time in the range of 70–180 mg/dL and glycated hemoglobin levels were evaluated; satisfaction, emotional distress and quality of life were assessed using self‐reported questionnaires, including the Diabetes Treatment Satisfaction Questionnaire Status, Problem Area in Diabetes and Diabetes Therapy‐Related Quality of Life. Results: Time in the range of 70–180 mg/dL increased (63.5 ± 13.4 to 73.0 ± 10.9% [mean ± standard deviation], P = 0.0010), and time above the range of 181–250 mg/dL decreased (26.9 ± 8.9 to 19.6 ± 7.1%, P < 0.0005). Glycated hemoglobin levels decreased (7.7 ± 1.0 to 7.2 ± 0.8%, P = 0.0021). The percentage of participants with time below the range of 54–69 mg/dL <4% of readings increased from 91% to 100% (P < 0.0005). No significant changes were detected in the satisfaction, emotional distress and quality of life levels, but increased sensor calibration might be related to worsened emotional distress and quality of life. Conclusions: The hybrid closed‐loop system decreased hyperglycemia and minimized hypoglycemia, but did not improve psychological aspects compared with the predictive low‐glucose suspend system, probably because sensor calibration was increased. [ABSTRACT FROM AUTHOR]

Glucokinase, which phosphorylates glucose to form glucose‐6‐phosphate, plays a critical role in regulating blood glucose levels. On the basis of data of glucokinase‐knockout and transgenic mice and humans with glucokinase mutations, glucokinase was targeted for drug development aiming to augment its activity, and thereby reduce hyperglycaemia in patients with diabetes. In fact, various small molecule compounds have been developed and clinically tested as glucokinase activators. However, some have been discontinued because of efficacy and safety issues. One of these issues is loss of the drug's efficacy over time. This unsustained glycaemic efficacy may be associated with the excess glycolysis by glucokinase activation in pancreatic beta cells, resulting in beta‐cell failure. Recently, we have shown that glucokinase haploinsufficiency ameliorated glucose intolerance by increasing beta‐cell function and mass in a mouse model of diabetes. Given that a similar phenotype has been observed in glucokinase‐activated beta cells and diabetic beta cells, glucokinase inactivation may be a new therapeutic target for type 2 diabetes. [ABSTRACT FROM AUTHOR]

Presents research which studied mice with targeted gene disruption of p85-alpha. Effects of the gene disruption; Role of p85-alpha; Comparison of phenotypes; Evidence that p85-alpha is linked to the Btk pathway in signal transduction; p85-alpha in B cell development and function.

The cover image, by Yutaka Seino et al., is based on the Original Article Safety and efficacy of semaglutide once weekly vs sitagliptin once daily, both as monotherapy in Japanese people with type 2 diabetes, DOI: 10.1111/dom.13082. [ABSTRACT FROM AUTHOR]

The aim of this study was to evaluate the efficacy and safety of sitagliptin administered to elderly patients with type 2 diabetes mellitus ( T2DM) for 1 year as compared with glimepiride. Patients aged ≥60 years with T2DM and inadequately controlled blood glucose were randomly assigned to sitagliptin 50 mg once daily or glimepiride 0.5 mg once daily for 52 weeks. The primary efficacy endpoint was the change in glycated haemoglobin ( HbA1c) from baseline to week 52. Secondary efficacy endpoints included self-monitored blood glucose and weight. Safety endpoints were adverse events including hypoglycaemia. Administration of sitagliptin or glimepiride to elderly patients with T2DM resulted in a significant decrease in HbA1c change from baseline. At 52 weeks, the least squares mean difference between the treatments was 0.11% (95% confidence interval [ CI] −0.02 to 0.24; P = .087) (1.2 mmol/mol [−0.2 to 2.6]). The upper limit of the CI was below the predefined non-inferiority margin (0.3% [3.3 mmol/mol]), demonstrating non-inferiority of sitagliptin to glimepiride for the primary endpoint. Sitagliptin resulted in a significantly lower incidence rate of non-serious hypoglycaemia than glimepiride during the 52 weeks (4.7% vs 16.1%; P = .002); thus, sitagliptin is a useful therapeutic option for elderly patients with T2DM. [ABSTRACT FROM AUTHOR]

Objective: This trial compared the efficacy and safety of the first oral glucagon-like peptide 1 (GLP-1) receptor agonist, oral semaglutide, as monotherapy with placebo in patients with type 2 diabetes managed by diet and exercise alone. Two estimands addressed two efficacy-related questions: a treatment policy estimand (regardless of trial product discontinuation or rescue medication use) and a trial product estimand (on trial product without rescue medication use) in all randomized patients.Research Design and Methods: This was a 26-week, phase 3a, randomized, double-blind, placebo-controlled, parallel-group trial conducted in 93 sites in nine countries. Adults with type 2 diabetes insufficiently controlled with diet and exercise were randomized (1:1:1:1) to once-daily oral semaglutide 3 mg, 7 mg, 14 mg, or placebo. The primary end point was change from baseline to week 26 in HbA1c. The confirmatory secondary end point was change from baseline to week 26 in body weight.Results: In the 703 patients randomized (mean age 55 years, 50.8% male, and mean baseline HbA1c 8.0% [64 mmol/mol]), oral semaglutide reduced HbA1c (placebo-adjusted treatment differences at week 26: treatment policy estimand, -0.6% [3 mg], -0.9% [7 mg], and -1.1% [14 mg]; trial product estimand, -0.7% [3 mg], -1.2% [7 mg], and -1.4% [14 mg]; P < 0.001 for all) and body weight (treatment policy, -0.1 kg [3 mg], -0.9 kg [7 mg], and -2.3 kg [14 mg, P < 0.001]; trial product, -0.2 kg [3 mg], -1.0 kg [7 mg, P = 0.01], and -2.6 kg [14 mg, P < 0.001]). Mild-to-moderate transient gastrointestinal events were the most common adverse events with oral semaglutide. Trial product discontinuations occurred in 2.3-7.4% with oral semaglutide and 2.2% with placebo.Conclusions: In patients with type 2 diabetes, oral semaglutide monotherapy demonstrated superior and clinically relevant improvements in HbA1c (all doses) and body weight loss (14 mg dose) versus placebo, with a safety profile consistent with other GLP-1 receptor agonists. [ABSTRACT FROM AUTHOR]

Background: Antithyroid drugs (ATDs) are frequently used to achieve euthyroidism in patients with hyperthyroidism. ATDs cause characteristic common and rare adverse events; however, comprehensive comparisons between methimazole (MMI) and propylthiouracil (PTU) in terms of adverse events are limited. Methods: In this study, we thoroughly explored adverse events in association with MMI and PTU use with a disproportionality analysis using the Japanese Adverse Drug Event Report (JADER) database and evaluated the prevalence of MMI and PTU prescriptions using the National Database of Health Insurance Claims and Specific Health Checkups (NDB) Open Data Japan. We analyzed 3271 cases of MMI use and 1029 cases of PTU use with respect to 9789 preferred terms (PTs) for adverse events registered in the JADER database by calculating and comparing reporting odds ratios (RORs). Results: We found that 8 PTs, including agranulocytosis (p < 0.0001, 4.01-fold), aplasia cutis congenita (p < 0.0001, 123.22-fold), and exomphalos (p = 0.0002, 22.17-fold), demonstrated significantly higher RORs (more than 4-fold) for MMI use than for PTU use. Nineteen PTs, including anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (p < 0.0001, 29.84), rapidly progressive glomerulonephritis (p < 0.0001, 6.44), and pulmonary alveolar hemorrhage (p < 0.0001, 7.77), had RORs for PTU use more than four times those for MMI use. NDB Open Data Japan showed more frequent PTU prescriptions than MMI prescriptions for women of reproductive age. Conclusions: This large-scale study confirmed that a variety of congenital malformations were identified as having significantly high RORs for MMI use, while diseases related to ANCA-associated vasculitis were specific to PTU. [ABSTRACT FROM AUTHOR]

Aims/Introduction: We carried out a cross‐sectional study of people with type 2 diabetes mellitus to elucidate the association between sleep duration and food intake. Materials and Methods: Overall, 2,887 participants with type 2 diabetes mellitus (mean age 63.0 years; 61.1% men; mean glycated hemoglobin level 7.5%) were included in this study. The participants' self‐reported dietary habits and sleep duration were evaluated using a brief self‐administered dietary history questionnaire and Pittsburgh Sleep Quality Index, respectively. The participants were categorized into the following four groups based on sleep duration: <6, 6–6.9, 7–7.9 (reference) and ≥8 h. Results: No significant differences were observed between the groups regarding energy intake (kcal/day), absolute intake (g/day) or relative intake (% energy) of carbohydrates, total fat, proteins and fibers. However, confectionery intake was higher in the <6 h group and lower in the ≥8 h group than in the reference group after adjustment for confounding factors. In multivariate analysis, sleep durations <6 h and ≥8 h significantly correlated with increased (95% confidence interval 0.55 to 3.6; P = 0.0078) and decreased (95% confidence interval −4.0 to −0.32; P = 0.021) confectionery intake, respectively. Confectionery intake was positively correlated with female sex, glycated hemoglobin level and dyslipidemia, whereas it was negatively correlated with alcohol consumption and current smoking status. Conclusions: Short sleep duration is associated with high confectionery intake in people with type 2 diabetes mellitus; this might disturb their glycemic control. Therefore, short sleepers with type 2 diabetes mellitus could improve their glycemic control by avoiding confectionery intake and maintaining adequate sleep duration. [ABSTRACT FROM AUTHOR]

Introduction: iGlarLixi, a fixed-ratio combination of insulin glargine 100 U/mL and the glucagon-like peptide 1 receptor agonist (GLP-1 RA) lixisenatide, is one option for treatment intensification in individuals with type 2 diabetes (T2D) who are unable to achieve targeted glycaemic control with their current glucose-lowering agent. Real-world data on the impact of prior treatment on the effectiveness and safety of iGlarLixi may be useful to guide individualised treatment decisions. Methods: This analysis of the 6-month, retrospective, observational SPARTA Japan study compared glycated haemoglobin (HbA1c), body weight and safety for pre-specified subgroups defined by prior treatment: post oral antidiabetic agent (OAD), GLP-1 RA, basal insulin (BI) + OADs (BOT), GLP-1 RA + BI or multiple daily injections (MDI). The post BOT and MDI subgroups were further divided on the basis of prior dipeptidyl peptidase 4 inhibitor (DPP-4i) use, and the post MDI group was divided on the basis of whether participants continued bolus insulin. Results: Of the 432 participants in the full analysis set (FAS), 337 were included in this subgroup analysis. Across subgroups, mean baseline HbA1c ranged from 8.49% to 9.18%. iGlarLixi significantly (p < 0.05) reduced mean HbA1c from baseline in all but the post GLP-1 RA + BI group. At 6 months, these significant reductions ranged from 0.47% to 1.27%. Prior DPP-4i exposure had no impact on the HbA1c-lowering effect of iGlarLixi. Mean body weight decreased significantly in the FAS (0.5 kg) and the post BOT (1.2 kg) and MDI (1.5 and 1.9 kg) subgroups but increased in the post GLP-1 RA subgroup (1.3 kg). iGlarLixi treatment was generally well tolerated, with very few participants discontinuing because of hypoglycaemia or gastrointestinal events. Conclusion: In participants with suboptimal glycaemic control on various regimens, 6 months of iGlarLixi treatment improved HbA1c in all but one prior treatment subgroup (GLP-1 RA + BI), and was generally well tolerated. Trial Registration: UMIN-CTR Trials Registry, UMIN000044126; registered 10 May 2021. Plain Language Summary: Despite initially receiving oral treatment for their diabetes, many individuals with type 2 diabetes are unable to achieve their blood glucose targets and require treatment intensification as their disease progresses. In these individuals, options for treatment intensification include adding an injectable therapy, such as a glucagon-like peptide 1 receptor agonist or basal insulin, or the combination of both. However, the impact of previously received treatments on the ability of treatment intensification to improve outcomes in these individuals has yet to be evaluated. Here, we report the findings of an analysis that aimed to determine the influence of different treatment backgrounds on the effectiveness and safety of iGlarLixi, a fixed-ratio combination (i.e. combined as a single subcutaneous injection) of the glucagon-like peptide 1 receptor agonist lixisenatide and basal insulin glargine 100 U/mL, in Japanese individuals with type 2 diabetes. We found that iGlarLixi improved glycaemic control and was well tolerated in most individuals, regardless of previously received treatments. These results suggest that iGlarLixi may offer an effective option for improving outcomes in Japanese individuals with type 2 diabetes who require treatment intensification. [ABSTRACT FROM AUTHOR]

Introduction: Many individuals with type 2 diabetes (T2D) experience suboptimal glycemic control. Treatment intensification options include fixed-ratio combination products containing a basal insulin and a glucagon-like peptide-1 receptor agonist, such as iGlarLixi (insulin glargine 100 U/mL and lixisenatide). This study aimed to provide real-world evidence of the effect of iGlarLixi in Japanese clinical practice. Methods: SPARTA Japan was a non-comparative, observational study conducted at 27 institutions in Japan. Anonymized individual-level data from adults with T2D receiving iGlarLixi in routine clinical practice were retrospectively collected. The primary study objective was to assess the impact of iGlarLixi on the change in glycated hemoglobin (HbA1c) at 6 months' post-treatment initiation, with preplanned subanalyses to determine the influence of baseline characteristics. Secondary and exploratory endpoints included assessment of the proportion of individuals achieving HbA1c targets, change in body weight, and incidence and severity of hypoglycemia and gastrointestinal events. Results: The full analysis set included 432 individuals, with data available at 6 months for 426. Of the 432 individuals, the mean (SD) age at baseline was 61.6 (12.8) years and the majority had a T2D duration of ≥ 10 years [mean (SD) 13.3 (10.4) years]. At 6 months, HbA1c had significantly decreased versus baseline (–0.85%; P < 0.0001), with a greater decrease in those aged < 65 years, with a shorter duration of T2D and higher baseline HbA1c. A significant increase in the proportion of participants achieving age-specific HbA1c versus baseline was observed. Mean body weight decreased by 0.5 kg (P = 0.0034 versus baseline). There were few hypoglycemia and gastrointestinal events (in individuals with HbA1c data); no severe hypoglycemic events were reported. Conclusions: The results of this real-world study indicate that iGlarLixi may improve glycemic control without serious adverse events in Japanese individuals with T2D who have suboptimal glycemic control on current treatment regimens and switch to iGlarLixi. Trial registration: UMIN-CTR Trials Registry, UMIN000044126; registered 10 May 2021. Plain Language Summary: The first medicines for treating diabetes that many individuals with type 2 diabetes receive are administered orally; however, for most individuals, these oral drugs are not enough to achieve blood glucose targets as their disease progresses. Treatment intensification options include adding an injectable therapy, such as a glucagon-like peptide-1 receptor agonist or basal insulin, or the combination of both, the use of which has been studied extensively and has been shown to be a simple and well-tolerated option. Here, we report the findings of a study that retrospectively evaluated the outcomes of 432 Japanese individuals who took iGlarLixi, which consists of the glucagon-like peptide-1 receptor agonist lixisenatide and basal insulin glargine 100 U/mL as a fixed-ratio combination (i.e., combined as a single subcutaneous injection), over 6 months of treatment. We found that iGlarLixi improved blood glucose levels in these individuals, and was associated with few hypoglycemia or gastrointestinal adverse events. These results suggest that iGlarLixi may offer an effective option for improving glycemic control in Japanese individuals with type 2 diabetes who require treatment intensification because their blood glucose goals have not been achieved with oral drugs alone or co-administered with a glucagon-like peptide-1 receptor agonist or basal insulin. [ABSTRACT FROM AUTHOR]

Aims/Introduction: This study was designed and carried out to investigate the association of dipeptidyl peptidase‐4 inhibitor (DPP‐4i) use with pancreatic cancer (PC) in individuals with diabetes in Japan. Materials and Methods: The JMDC Claims Database, which contains the medical and prescription information of Japanese employment‐based health insurance programs, was used. The primary outcome was duration to the first occurrence of PC (International Classification of Diseases 10th Revision code C25), both all and hospitalized, from prescription of DPP‐4is or other oral glucose‐lowering agents (GLAs). Results: Individuals with diabetes who received DPP‐4is (n = 61,430) or other oral GLAs (n = 83,304) were analyzed. Follow‐up periods (median [interquartile range]) were 17 months (8–33) for DPP‐4is and 14 months (7–28) for other oral GLAs. Kaplan–Meier curve analysis to determine the duration of first use of DPP4i or other oral GLA to diagnosis of PC disclosed no differences between the two groups in duration to all or hospitalized PC (log‐rank test: all, P = 0.7140; hospitalized, P = 0.3446). Cox proportional hazards models showed that use of DPP‐4is did not affect the PC risk adjusted for medications, age, sex and risk comorbidities (all, hazard ratio 1.1, 95% confidence interval 0.8–1.3, P = 0.6518; hospitalized, hazard ratio 1.1, 95% confidence interval 0.8–1.4, P = 0.6662). Similar results were obtained when individuals with ≥2 years oral GLA treatment and those with medical checkup data (e.g., smoking or drinking habit) available were analyzed. Conclusion: This database study shows that there is not a significant PC risk due to DPP‐4i treatment in individuals with diabetes in Japan, but larger studies with longer follow up are required to confirm these findings. [ABSTRACT FROM AUTHOR]

Summary: This study aimed to evaluate the diagnostic accuracy of home sleep apnea testing using peripheral arterial tonometry for sleep apnea as an alternative to polysomnography. We conducted a systematic review and meta‐analysis of observational studies, randomized controlled trials, and diagnostic case–control studies examining the diagnostic accuracy of peripheral arterial tonometry by searching the CENTRAL, MEDLINE, EMBASE, ICTRP and ClinicalTrials.gov databases on 5 October 2021. We assessed the risk of bias of the included studies using the Quality Assessment of Diagnostic Accuracy Studies‐2 tool. A bivariate random‐effects model was generated to derive the summary point estimates of sensitivity and specificity with 95% confidence intervals at different apnea–hypopnea index cutoffs. This meta‐analysis included 13 studies (1227 participants, median prevalence of sleep apnea with apnea–hypopnea index ≥ 5 events per hr: 85%). The risk of bias in the included studies was low to moderate. The pooled sensitivity and specificity estimates were 96% (95% confidence interval: 93%–97%) and 44% (95% confidence interval: 32%–56%) at apnea–hypopnea index ≥ 5 events per hr, 88% (85%–91%) and 74% (63%–83%) at apnea–hypopnea index ≧ 15 events per hr, and 80% (66%–89%) and 90% (83%–95%) at apnea–hypopnea index ≧ 30 events per hr, respectively. Peripheral arterial tonometry resulted in a significant number of false negatives and false positives at any apnea–hypopnea index cutoff when applied to the median prevalence setting of the included studies. The inadequate sensitivity and specificity of peripheral arterial tonometry render it an unsuitable alternative to polysomnography for detecting sleep apnea for apnea–hypopnea index ≧ 5, 15 and 30 events per hr. [ABSTRACT FROM AUTHOR]

Plasma and liver SerpinB1 levels are elevated in mice with insulin resistance and promote β-cell proliferation in human islets. We measured serum SerpinB1 levels in Japanese subjects with or without type 2 diabetes (T2DM). We enrolled 12 normal glucose tolerance (NGT) and 51 T2DM subjects. There was no difference in serum SerpinB1 levels between the 2 groups (T2DM, 1.3 ± 0.9 ng/mL vs. NGT, 1.8 ± 1.7 ng/mL; P = 0.146). After adjusting for age and sex, the serum SerpinB1 levels were positively correlated with HOMA2-%S (β = 0.319, P = 0.036), and negatively correlated with fasting blood glucose (β = -0.365, P = 0.010), total cholesterol (β = -0.396, P = 0.006), low-density lipoprotein (LDL) cholesterol (β = -0.411, P = 0.004), triglycerides (β = -0.321, P = 0.026), and γGTP (β = -0.322, P = 0.026) in subjects with T2DM. Thus, circulating SerpinB1 is possibly associated with insulin sensitivity and better blood glucose level in Japanese subjects with T2DM. Trial registration: UMIN Clinical Trials Registry, UMIN000020453. [ABSTRACT FROM AUTHOR]

Aims/Introduction: This study aimed to clarify the nature of the relationship between the abdominal aortic calcification (AAC) grade and the presence of cardiovascular diseases, and determine factors related to AAC grade in people with type 2 diabetes mellitus. Materials and Methods: This retrospective cross‐sectional study enrolled 264 inpatients with type 2 diabetes mellitus. The AAC score and length were measured using the lateral abdominal radiographs. Logistic regression models were used to assess the associations between AAC scores/lengths and the presence of coronary artery disease (CAD), cerebral infarction (CI) and peripheral artery disease (PAD). The correlation between AAC scores/lengths and other clinical factors were evaluated using linear regression models. Results: The AAC score was significantly correlated with prevalent CAD and CI independent of age and smoking, but not with the prevalence of PAD. AAC length was not significantly correlated with the presence of CAD, CI or PAD; however, the sample size was insufficient to conclude, probably due to low prevalence. Both the AAC score and length were correlated inversely with body mass index (BMI) and, with the Fibrosis‐4 (Fib‐4) index >2.67; these correlations were significant after adjusting for cardiovascular risk factors and BMI, although AAC was not associated with ultrasonography‐diagnosed fatty liver. There was a significant interaction between BMI and Fib‐4 index; lower BMI and Fib‐4 index >2.67 showed a synergistic association with high AAC grade. Conclusions: AAC score is associated with CAD and CI morbidity in participants with type 2 diabetes mellitus. Low BMI and Fib‐4 index >2.67 can be valuable indicators of AAC in people with type 2 diabetes mellitus. [ABSTRACT FROM AUTHOR]

Pharmacological agents are now available that primarily modify post-prandial plasma glucose levels. The alpha-glucosidase inhibitors (αGIs) represent one such class of agents whose intake is recommended just before a meal; however, adherence to these drugs has been reported to be lower than that to other oral hypoglycemic agents. When we interviewed 100 diabetic patients who had been prescribed αGIs, 48 of the 100 reported forgetting to take the medicine more than once in a week and 54% of these patients did not take the medicine at all in the case of missing it at the appointed hour. Miglitol, the first pseudomonosaccharide αGI, was shown to be more effective at reducing blood glucose levels at 30 and 60 min after a meal than other αGIs. We therefore hypothesized that administration of miglitol even after the start of a meal may be effective, and evaluated the timing of administration of miglitol on plasma glucose and serum insulin levels in 13 type 2 diabetic patients. Miglitol was administered in four different intake manners in each patient (control: no miglitol, intake 1: just before breakfast; intake 2:15 min after the beginning of breakfast; intake 3:30 min after the beginning of breakfast). The areas under the curve (AUC) of plasma glucose from 0 min to 180 min was significantly decreased under all of the intake 1, 2 and 3 conditions, compared with the AUC in the control, and there were no significant differences among the three intake groups. Thus, administration of miglitol anytime within 30 min after the start of a meal is effective for reducing the plasma glucose concentrations. The AUC of serum insulin from 0 min to 180 min tended to be lower in all the three groups than that in the control, although not statistically significant. However, when we carried out a similar study in subjects with normal glucose tolerance (n= 15), the AUCs of serum insulin from 0 min to 180 min under the intake 1, 2 and 3 conditions were significantly smaller than the AUC under the control conditions. These results suggest that, if patients miss taking miglitol at the beginning of a meal, the drug can still be taken until 30 min after the start of a meal. [ABSTRACT FROM AUTHOR]