Glucose values from the same continuous glucose monitoring sensor significantly differ among readers with different generations of algorithm.

Continuous glucose monitoring (CGM) values obtained from CGM systems using the same sensor but with different internal algorithms (the first- and third-generation FreeStyle Libre (1st-gen-libre and 3rd-gen-libre, respectively)) were compared. We used 19,819 paired and simultaneously measured CGM values of 13 patients with diabetes. The average CGM value was significantly higher (P < 0.0001) and the time below range (CGM value < 70 mg/dL) was significantly lower (P < 0.0001) with the 3rd-gen-libre than with the 1st-gen-libre. There was a significant correlation (P < 0.0001) between the CGM values of the 3rd-gen-libre (y-axis, mg/dL) and 1st-gen-libre (x-axis, mg/dL) using the following formula: y = 0.9728x + 10.024. On assessing the association between glycated hemoglobin (HbA1c (%), y-axis) and the average CGM values (x-axis, mg/dL) by applying the obtained equation to previously reported 1st-gen-libre data and converting it to 3rd-gen-libre data, we obtained the equation y = 0.02628x + 3.233, indicating that the glucose management indicator reported in the West may be underestimated compared with the laboratory-measured HbA1c in the Japanese population. Glucose values from the same sensor were found to be significantly different between readers with different algorithms, and the calculation of CGM-related indices may need to be individualized for each device.

High Incidence of Diabetes Mellitus After Distal Pancreatectomy and Its Predictors: A Long-term Follow-up Study.

CONTEXT: Glucose tolerance worsens after distal pancreatectomy (DP); however, the long-term incidence and factors affecting interindividual variation in this worsening are unclear. OBJECTIVE: To investigate the changes in diabetes-related traits before and after DP and to clarify the incidence of diabetes and its predictors. METHODS: Among 493 registered patients, 117 underwent DP. Among these, 56 patients without diabetes before surgery were included in the study. Glucose and endocrine function were prospectively assessed using a 75-g oral glucose tolerance test preoperatively, 1 month after DP, and every 6 months thereafter for up to 36 months. Pancreatic volumetry was performed using multidetector row computed tomography before and after surgery. RESULTS: Insulin secretion decreased and blood glucose levels worsened after DP. Residual pancreatic volume was significantly associated with the reserve capacity of insulin secretion but not with blood glucose levels or the development of diabetes. Among 56 patients, 33 developed diabetes mellitus. The cumulative incidence of diabetes at 36 months after DP was 74.1%. Multivariate Cox regression analysis showed that impaired glucose tolerance as a preoperative factor as well as a decreased insulinogenic index and impaired glucose tolerance at 1 month postoperatively were identified as risk factors for diabetes following DP. CONCLUSION: Impaired glucose tolerance and reduced early-phase insulin response to glucose are involved in the development of new-onset diabetes after DP; the latter is an additional factor in the development of diabetes and becomes apparent when pancreatic beta cell mass is reduced after DP.

Metabolic signatures of ß-cell destruction in type 1 diabetes.

AIMS/INTRODUCTION: In the development of type 1 diabetes, metabolites are significantly altered and might be involved in ß-cell destruction and protection. We aimed to identify new metabolic markers of ß-cell destruction in type 1 diabetes patients. MATERIALS AND METHODS: A total of 33 participants were recruited for this cross-sectional observational study: 23 with type 1 diabetes, seven with type 2 diabetes and three healthy controls. Those with type 1 diabetes were further subdivided into three groups: new-onset, microsecretors and complete lack of endogenous insulin in type 1 diabetes. RESULTS: Metabolomic analysis identified a total of 737 peaks, and partial least square analysis was successful in discriminating between the three groups of type 1 diabetes. Among the factor loadings discriminating type 1 diabetes, 3-phenylpropionic acid (r = 0.80, P = 4.7E-6 ) and hypotaurine (r = -0.484, P = 1.9E-2 ) strongly contributed to identifying new-onset type 1 diabetes, and 5-methylcytosine to identifying complete-lack type 1 diabetes (r = 0.586, P = 6.5E-3 ). Reporter operating characteristics analysis, including all type 1 diabetes, type 2 diabetes and healthy controls, showed that high 3-phenylpropionic acid (Pc <0.0001) and low hypotaurine (Pc <0.0001) were useful for identifying new-onset type 1 diabetes, and high 5-methylcytosine (Pc = 0.002) for the complete-lack type 1 diabetes. CONCLUSIONS: In the present study, metabolic signatures were shown to be useful in identifying type 1 diabetes at different clinical stages, and 3-phenylpropionic acid and hypotaurine are novel biomarkers for identifying new-onset type 1 diabetes, suggesting the involvement of the gut bacterial environment, anti-oxidant mechanisms through the hypotaurine-taurine pathway and methylated deoxyribonucleic acid fragmentation in the process of ß-cell destruction.

Glycemic Excursion and Insulin Action Revealed in a Rare Case of Type 1 Diabetes Complicated with Short Bowel Syndrome.

We herein report a 52-year-old woman with a rare combination of short bowel syndrome due to massive resection of the small intestine and complete loss of endogenous insulin due to type 1 diabetes. To provide nutritional support, she was treated with total parenteral nutrition with co-administration of insulin, requiring careful matching of insulin and glucose levels. This case report provides insights on glycemic excursion and insulin action in type 1 diabetes, even when both insulin and glucose are administered directly into circulation, and the usual obstacles caused by subcutaneous injection of insulin and oral intake of nutrients are eliminated.

Three-Year Observation of Glucose Metabolism After Pancreaticoduodenectomy: A Single-Center Prospective Study in Japan.

CONTEXT: The glucose tolerance of patients changes considerably from before to after pancreaticoduodenectomy wherein approximately half of the pancreas is resected. OBJECTIVE: The aim of this prospective study was to investigate the incidence of and risk factors for diabetes after pancreaticoduodenectomy. METHODS: This study is a part of an ongoing prospective study, the Kindai Prospective Study on Metabolism and Endocrinology after Pancreatectomy (KIP-MEP) study. Of the 457 patients enrolled to date, 96 patients without diabetes who underwent pancreaticoduodenectomy were investigated in this study. Preoperatively, 1 month post-pancreaticoduodenectomy, and every 6 months thereafter, the glucose metabolism and endocrine function were evaluated using the 75 g oral glucose tolerance test. Various other metabolic, endocrine, and exocrine indices were also examined over a period of up to 36 months. RESULTS: Of the 96 patients analyzed in this study, 33 were newly diagnosed with diabetes. The cumulative diabetes incidence at 36 months following pancreaticoduodenectomy was 53.8%. The preoperative insulinogenic index and ΔC-peptide in the glucagon stimulation test were significantly lower in the progressors to diabetes than in the nonprogressors. Multivariate Cox regression analysis demonstrated that the insulinogenic index was the only significant risk factor for new-onset diabetes. CONCLUSION: The majority of patients developed new-onset diabetes after pancreaticoduodenectomy, and a low value of the insulinogenic index was suggested to be a risk factor for diabetes. Preoperative assessment for the prediction of the onset of diabetes serves as useful information for patients and is important for postoperative glycemic control and diabetes management in patients who require pancreaticoduodenectomy.

Associations between genetic loci related to lean mass and body composition in type 2 diabetes.

AIM: Several genetic loci related to lean mass have been identified in healthy individuals by genome-wide association studies; however, the contribution of these loci to body composition in type 2 diabetes remains to be investigated. Here, we aimed to clarify the genetic determinants of body composition in individuals with type 2 diabetes. METHODS: A total of 176 Japanese outpatients (70 women and 106 men) with type 2 diabetes were studied using a cross-sectional design. Body composition was measured using bioimpedance analysis with a commercially available device (InBody770). Single-nucleotide polymorphisms in IRS1 (rs2943656), HSD17B11 (rs9991501), VCAN (rs2287926), ADAMTSL3 (rs4842924) and FTO (rs9936385) were evaluated by genotyping. The contributions of single-nucleotide polymorphisms to body composition were examined, considering known clinical determinants. RESULTS: Sex, body composition and age were identified as clinical predictors. IRS1 rs2934656 was identified as an independent predictor of skeletal muscle mass (ß = 0.11, P = 0.026), and ADAMTSL3 rs4842924 was an independent predictor of body fat mass (ß = 0.15, P = 0.0095) and appendicular lean mass (ß = -0.13, P = 0.017). CONCLUSIONS: The findings clarified the contribution of genetic factors - IRS1 and ADAMTSL3 - to interindividual variation in body composition, independent of clinical factors, in type 2 diabetes patients. These data will contribute to the establishment of effective methods for the prediction, prevention, and intervention of sarcopenia and frailty in diabetes patients. Geriatr Gerontol Int 2021; 21: 932-938.

Oncocytic Adrenocortical Carcinoma With Low 18F-FDG Uptake and the Absence of Glucose Transporter 1 Expression.

Adrenocortical carcinoma (ACC) is a rare tumor, and some histological variants (oncocytic, myxoid, and sarcomatoid ACCs) have been reported in addition to the conventional ACC. Among these subtypes, oncocytic ACC is histologically characterized by the presence of abundant eosinophilic granular cytoplasm in the carcinoma cells owing to the accumulation of mitochondria, which generally yields high 18F-fluorodeoxyglucose (FDG) uptake on positron emission tomography (PET). Herein, we report the case of a 21-year-old woman with oncocytic ACC with low FDG uptake on PET scan. Her circulating levels of androgens were high, and androgen-synthesis enzymes were detected in carcinoma cells. The patient also had hypocholesterolemia. However, glucose transporter 1 (GLUT1) was not detected in the tumor, which was considered to account for the low FDG uptake by the tumor. To the best of our knowledge, this is the first case of low FDG uptake by oncocytic ACC without GLUT1 expression. Additionally, since hypocholesterolemia was reported in 3 previous reports of androgen-producing tumors, a possible correlation between androgenicity in adrenal tumors and the development of hypocholesterolemia could be postulated; however, further investigations are needed for clarification. This case highlights important information regarding the diversity of ACC and its impact on hypocholesterolemia.

Glucose Metabolism After Pancreatectomy: Opposite Extremes Between Pancreaticoduodenectomy and Distal Pancreatectomy.

CONTEXT: The rate of glucose metabolism changes drastically after partial pancreatectomy. OBJECTIVE: This work aims to analyze changes in patients' glucose metabolism and endocrine and exocrine function before and after partial pancreatectomy relative to different resection types (Kindai Prospective Study on Metabolism and Endocrinology after Pancreatectomy: KIP-MEP study). METHODS: A series of 278 consecutive patients with scheduled pancreatectomy were enrolled into our prospective study. Of them, 109 individuals without diabetes, who underwent partial pancreatectomy, were investigated. Data were compared between patients with pancreaticoduodenectomy (PD, n = 73) and those with distal pancreatectomy (DP, n = 36). RESULTS: Blood glucose levels during the 75-g oral glucose tolerance test (75gOGTT) significantly decreased after pancreatectomy in the PD group (area under the curve [AUC] -9.3%, P < .01), and significantly increased in the DP population (AUC + 16.8%, P < .01). Insulin secretion rate during the 75gOGTT and glucagon stimulation test significantly decreased after pancreatectomy both in the PD and DP groups (P < .001). Both groups showed similar homeostasis model assessment of insulin resistance (HOMA-IR) values after pancreatectomy. Decrease in exocrine function quality after pancreatectomy was more marked in association with PD than DP (P < .01). Multiple regression analysis indicated that resection type and preoperative HOMA-IR independently influenced glucose tolerance-related postoperative outcomes. CONCLUSIONS: Blood glucose levels after the OGTT differed markedly between PD and DP populations. The observed differences between PD and DP suggest the importance of individualization in the management of metabolism and nutrition after partial pancreatectomy.

Relationship of continuous glucose monitoring-related metrics with HbA1c and residual ß-cell function in Japanese patients with type 1 diabetes.

The targets for continuous glucose monitoring (CGM)-derived metrics were recently set; however, studies on CGM data over a long period with stable glycemic control are limited. We analyzed 194,279 CGM values obtained from 19 adult Japanese patients with type 1 diabetes. CGM data obtained during stable glycemic control over four months were analyzed. CGM-related metrics of different durations "within 120, 90, 60, 30, and 7 days" were calculated from baseline. Time in range (TIR; glucose 70-180 mg/dL), time above range (TAR; glucose ≥ 181 mg/dL), and average glucose levels, but not time below range (TBR; glucose ≤ 69 mg/dL), strongly correlated with glycated hemoglobin (HbA1c) values (P < 0.0001). TBR correlated with glucose coefficient of variation (CV) (P < 0.01). Fasting serum C-peptide levels negatively correlated with glucose CV (P < 0.01). HbA1c of approximately 7% corresponded to TIR of 74% and TAR of 20%. The shorter the CGM period, the weaker was the relationship between HbA1c and CGM-related metrics. TIR, TAR, and average glucose levels accurately reflected HbA1c values in Japanese patients with type 1 diabetes with stable glycemic control. Glucose CV and TBR complemented the limitation of HbA1c to detect glucose variability and hypoglycemia. Stable glycemic control with minimal hypoglycemia depended on residual ß-cell function.

Clinical and genetic determinants of urinary glucose excretion in patients with diabetes mellitus.

AIMS/INTRODUCTION: Glucosuria is a representative symptom in diabetes patients with poor glycemic control and in those treated with sodium-glucose cotransporter 2 inhibitors. Renal threshold levels of glucose excretion are known to vary among individuals, but factors contributing to glucosuria are not well characterized. The present study aimed to clarify clinical and genetic determinants of glucosuria in individuals with diabetes mellitus. MATERIALS AND METHODS: The 24-h urinary glucose excretion was measured in 135 hospitalized patients on admission, with continuous measurement for five consecutive days in 75 patients. Genetic and clinical factors contributing to glucosuria were studied. As a genetic factor, SLC5A2 polymorphism was genotyped. A total of 476 participants (266 participants with type 2 diabetes and 210 healthy controls) were additionally genotyped for the association study of SLC5A2 with type 2 diabetes. A meta-analysis was carried out with the present study and previous association studies. RESULTS: Multiple regression analysis showed that the independent variables of average blood glucose (ß = 0.41, P = 1.4 × 10-7 ), estimated glomerular filtration rate (ß = 0.28, P = 6.0 × 10-5 ), sex (ß = 0.28, P = 5.7 × 10-5 ) and SLC5A2 rs9934336 polymorphism (ß = 0.17, P = 0.02) were significantly correlated with urinary glucose excretion. The frequency of the A allele of rs9934336 tended to be lower in participants with type 2 diabetes than in controls (odds ratio 0.78, 95% confidence interval 0.53-1.13, not significant), and meta-analysis showed a significant association between the A allele and type 2 diabetes (summary odds ratio for minor allele [A] 0.86, 95% confidence interval 0.78-0.94, P < 0.002). CONCLUSIONS: Blood glucose, estimated glomerular filtration rate, sex and SLC5A2 polymorphism were independent determinants of glucosuria in diabetes mellitus.

Mixed Corticomedullary Tumor Accompanied by Unilateral Aldosterone-Producing Adrenocortical Micronodules: a Case Report.

Mixed corticomedullary tumors (MCMTs) are rare and comprise medullary and cortical cells in a single adrenal tumor. The mechanisms underlying their development have not been fully elucidated. Here, we report a case of MCMT in a 42-year-old woman. Based on the preoperative clinical findings, the patient was diagnosed as having a pheochromocytoma with subclinical Cushing syndrome. Postoperative pathological diagnosis revealed that the tumor demonstrated morphologically distinct medullary and cortical components, which produced catecholamines and cortisol, respectively. Hybrid tumor cells producing both catecholamines and cortisol were not detected. Adrenocorticotropin (ACTH)-positive tumor cells were identified to be present in the pheochromocytoma. This ectopic production of ACTH can contribute to an autonomous cortisol production in a paracrine manner. In addition, micronodules producing aldosterone were detected in the adrenal tissue adjacent to the tumor. The simultaneous development of these 2 lesions may not be correlated with each other; however, this case confirms the importance of a detailed histopathological examination of the adrenal lesions harboring complicated hormonal abnormalities by providing pivotal and indispensable information on their pathogenesis and the possible interaction of the hormones produced in the adrenal gland.

A Rare Case of Adrenal Cysts Associated With Bilateral Incidentalomas and Diffuse Hyperplasia of the Zona Glomerulosa.

Characterization of adrenocortical disorders is challenging because of varying origins, laterality, the presence or absence of hormone production, and unclarity about the benign or malignant nature of the lesion. Histopathological examination in conjunction with immunohistochemistry is generally considered mandatory in this characterization. We report a rare case of bilateral adrenocortical adenomas associated with unilateral adrenal endothelial cysts in a 65-year-old woman whose condition was not diagnosed before surgery. Detailed histological examination of the resected adrenal glands revealed hyperplasia in the zona glomerulosa. Despite hyperplasia, the patient had normal serum aldosterone levels and renin activity without clinical evidence of hypertension. The patient was treated with a sodium-glucose cotransporter protein 2 (SGLT2) inhibitor. This may have stimulated the renin-angiotensin-aldosterone system. To the best of our knowledge, this is the first case in which both relatively large bilateral adrenocortical adenomas and unilateral adrenal endothelial cysts were detected. This case also highlights the complexity and difficulty of preoperative diagnosis. Furthermore, this case reports the first detailed histopathological examination of adrenal lesions with SGLT2 treatment and the possibility of SGLT2 inhibitor treatment resulting in histological hyperplasia in the zona glomerulosa; however, it is difficult to prove a causative relationship between SGLT2 inhibitors and hyperplasia of the zona glomerulosa based on the data of this case. It can be confirmed only under limited conditions; therefore, further studies on adrenal gland histology employing SGLT2 inhibition are warranted.

Flash glucose monitoring in type 1 diabetes: A comparison with self-monitoring blood glucose.

AIMS/INTRODUCTION: A flash glucose monitoring (FGM) system has become available. To clarify the relationship between FGM and self-monitoring blood glucose (SMBG) values, we compared the two values after simultaneous measurement in Japanese patients with type 1 diabetes, under daily life settings. MATERIALS AND METHODS: A total of 20 outpatients with type 1 diabetes were analyzed. When FGM and SMBG were carried out simultaneously (within ±3 min), the values were adopted and each FGM value was matched and compared with the corresponding SMBG value. In addition, we analyzed other cases of simultaneity defined as "within ±2 min," "within ±1 min" and "at the exact same time." RESULTS: The percentage of SMBG and FGM values in the clinically acceptable zone A + B in Clarke and consensus error grid analyses were 97.9 and 99.2%, respectively. Deming regression (x-axis: FGM values, y-axis: SMBG values) determined a slope of 0.9128 (95% confidence interval 0.9008-0.9247) and an intercept of +15.94 mg/dL (95% confidence interval 14.05-17.84). FGM values were lower than SMBG values in the lower glucose range, and higher in the higher glucose range. The shorter the time lag between measurements, the higher the rate of concordance between FGM and SMBG values. CONCLUSIONS: The results of this study provided evidence on the reliability of FGM in Japanese patients with type 1 diabetes in home conditions. Based on the results, if an abnormal glucose value is detected by FGM, SBMG should then be used to confirm the result.

Contribution of Asian Haplotype of KCNJ18 to Susceptibility to and Ethnic Differences in Thyrotoxic Periodic Paralysis.

CONTEXT AND OBJECTIVES: Thyrotoxic periodic paralysis (TPP) is an acute complication of thyrotoxicosis that can be lethal. TPP is rare in Caucasians but often affects young men in East Asian populations. This study aimed to clarify the contribution of KCNJ18 to susceptibility to TPP in East Asian populations. PARTICIPANTS AND METHODS: The study comprised 635 participants including 13 Japanese patients with TPP, 208 Japanese patients with Graves disease without TPP, and 414 healthy control subjects from the Japanese (n = 208), Korean (n = 111), and Caucasian populations (n = 95). DNA samples from 29 participants (13 with TPP, 8 with Graves disease, and 8 controls) were sequenced for KCNJ18, and all participants (n = 635) were genotyped for six variants of KCNJ18 and a polymorphism of KCNJ2 (rs312691). RESULTS: Six single-nucleotide variants (SNVs) with amino acid substitutions were identified by direct sequencing of KCNJ18. Among these, four SNVs comprised three haplotypes under strong linkage disequilibrium. Haplotype 1 (AAAG) of KCNJ18 was significantly associated with susceptibility to TPP in the Japanese population (OR = 19.6; 95% CI, 1.5 to 256.9; P = 0.013). Haplotype frequencies in the general East Asian (Japanese and Korean) and Caucasian populations differed significantly (haplotype 1: 80.8% vs 48.4%, P = 1.1×10-27). CONCLUSION: A major haplotype of KCNJ18 in East Asian populations is significantly associated with susceptibility to TPP. The haplotype is much more common in East Asian than Caucasian populations, suggesting its contribution to the high prevalence of TPP in East Asian populations.

Insulin deficiency with and without glucagon: A comparative study between total pancreatectomy and type 1 diabetes.

AIMS/INTRODUCTION: Patients with a total pancreatectomy and type 1 diabetes are similar in regard to absolute insulin deficiency, but different in regard to glucagon, providing a unique opportunity to study the contribution of glucagon to glucose metabolism in an insulin-dependent state. The aim of the present study was to investigate the contribution of glucagon to glucose homeostasis in complete insulin deficiency in vivo. METHODS: A total of 38 individuals with a complete lack of endogenous insulin (fasting C-peptide <0.0066 nmol/L) and whose glycemic control was optimized with an insulin pump during hospitalization were retrospectively studied. The basal insulin requirement, time-to-time adjustment of the basal insulin infusion rate, prandial insulin requirement and fasting plasma glucagon were compared between patients with a total pancreatectomy (n = 10) and those with type 1 diabetes (n = 28) after achievement of optimal glycemic control. RESULTS: Total daily insulin (P = 0.03) and basal insulin (P = 0.000006), but not prandial insulin requirements, were significantly lower in total pancreatectomy patients than in type 1 diabetes patients. The basal percentage (basal insulin/total daily insulin) was also significantly lower in total pancreatectomy patients than in type 1 diabetes patients (15.8 ± 7.8 vs 32.9 ± 10.1%, P = 0.00003). An increase in the insulin infusion rate early in the morning was not necessary in most patients with a pancreatectomy. The fasting plasma glucagon concentration was significantly lower in total pancreatectomy patients than in type 1 diabetes patients (P = 0.00007), and was positively correlated with the basal insulin requirement (P = 0.038). CONCLUSIONS: The difference in insulin requirements between total pancreatectomy and type 1 diabetes patients suggests a contribution of glucagon to the basal insulin requirement and dawn phenomenon.

Common phenotype and different non-HLA genes in Graves' disease and alopecia areata.

Our previous observations clarified that Graves' disease (GD) is the most frequent autoimmune disease in patients with alopecia areata (AA), and 42.7% of patients with AA were positive for thyrotropin receptor antibody (TRAb). A class II HLA haplotype DRB1∗15:01-DQB1∗06:02 was suggested to contribute to autoimmunity against the thyroid gland in AA. To further clarify the genetic factors contributing to organ specificity in autoimmune diseases, we studied the contribution of non-HLA genes to organ specificity in GD and AA. A high frequency of AA (13.4%) was observed in patients with GD, indicating strong phenotypic association between GD and AA. CTLA4 and TSHR were significantly associated with GD (Pc=0.007 and Pc<0.002, respectively), but not with AA, even in TRAb-positive patients. The difference in the association between GD and AA suggests that the CTLA4 and TSHR are not main factors contributing to determining common genetic basis among GD and AA.

Effects of dosage and dosing frequency on the efficacy and safety of high-dose metformin in Japanese patients with type 2 diabetes mellitus.

AIMS/INTRODUCTION: Differences in the efficacy and safety of antidiabetic drugs among different ethnic groups are well documented. Metformin is widely used in the treatment of type 2 diabetes in Western countries, but high doses of metformin have been approved only recently for clinical use in Japan. The aim of the present study was to investigate the effects of dosage and dosing frequency on the efficacy and safety of high-dose metformin in Japanese patients. MATERIALS AND METHODS: A total of 71 Japanese patients with type 2 diabetes were prospectively studied for the effects of dosage and dosing frequency on the efficacy and safety of metformin during hospitalization. Dose effects were studied in 27 patients treated with 0, 500, 1,000, 1,500 and 2,250 mg/day of metformin. The effect of dosing frequency was compared in 56 patients with 1,500 mg/day of metformin administered either two or three times per day. RESULTS: Significant dose-dependent improvement in daily profiles of blood glucose was observed with metformin dosages up to 1,500 mg/day, with a trend towards further improvement observed at 2,250 mg/day. The efficacy of 1,500 mg of metformin was comparable when the drug was administered either two or three times per day. The most frequently reported side-effects were gastrointestinal symptoms, which were not affected by the dosage or dosing frequency of metformin. CONCLUSIONS: These results show that the efficacy of high-dose metformin is dose-dependent in Japanese patients. The efficacy and safety of metformin were similar when the drug was administered either two or three times per day.