Bone fractures occur 5-7 times more often with type 1 diabetes, and type 2 diabetes was also recently identified as a risk factor for fractures (relative risk, 1.4-1.7). Moreover, poor blood glucose control results in a high prevalence of bone fracture in patients with type 2 diabetes. In addition to diabetic neuropathy, nephropathy, and retinopathy, arteriosclerotic diseases are also a common complication of diabetes. Therefore, osteoporosis should be considered as a complication or sequela of diabetes. Insulin secretion stimulates osteoblast maturation; in contrast, osteocalcin and sclerostin, which are involved in bone metabolism, affect insulin secretion and sensitivity. Furthermore, resting energy expenditure was associated with a serum bone turnover marker in postmenopausal women with type 2 diabetes in our cross-sectional study. An interplay between glucose metabolism and bone metabolism has been identified both in vitro and in vivo, and the pathology of osteoporosis differs between type 1 and type 2 diabetes. Although it is difficult to diagnose osteoporosis before a fracture, the early diagnosis of osteoporosis by considering glucose metabolism in patients with diabetes is important. In this review, the pathophysiology of osteoporosis in patients with diabetes and the effect of glucose metabolism are discussed.

This report summarizes articles and papers written on diabetic neuropathy patients treated at our department, with the aim of presenting a clinical picture of diabetic neuropathy. The clinical pictures of our cumulative diabetic neuropathy patient population indicated that prolonged disease state and long-term poor glycemic control increase the risk of developing diabetic neuropathy. However, the clinical pictures of some individual diabetic neuropathy cases did not follow these patterns, which suggests alternative factors and mechanisms that affect the risk of diabetic neuropathy besides diabetes duration and glycemic control.

There is a global consensus that early diabetic kidney disease (DKD) is characterized by persistent albuminuria. According to international guidelines, albuminuria is defined as a urinary albumin-to-creatinine ratio (ACR) ≥30 mg/g. Urinary albumin levels should be measured at least once a year. Moreover, albuminuria has been recognized as a predictor of cardiovascular disease.

In our cohort study including 3,231 diabetic patients, baseline albuminuria, defined as urinary ACR ≥30 mg/g, was found in 35.1 % of patients; and a decreased estimated glomerular filtration rate (eGFR), defined as eGFR <60 mL/min/1.73 m², was observed in 20.7 % of patients. The hazard ratio (HR) in each group stratified by albuminuria and eGFR was analyzed to simultaneously estimate the impact of these renal manifestations on renal outcomes. Compared to patients with normoalbuminuria and eGFR ≥60 mL/min/1.73 m², there was no significantly increased risk for renal endpoints among individuals with normoalbuminuria and eGFR <60 mL/min/1.73 m² [HR: 2.50; 95 % confidence interval (CI) : 0.99-6.33; p = 0.053]. In contrast, those with microalbuminuria and eGFR ≥60 mL/min/1.73 m² had a significantly increased risk for renal outcomes (HR: 4.98; 95 % CI: 2.82-8.80; p < 0.001). Therefore, albuminuria may be an independent predictor for the progression of DKD in Japanese patients with type 2 diabetes. In contrast, the level of eGFR is less likely to be associated with renal endpoints. Further studies are required to clarify the implications of albuminuria in diabetic patients.

The significance of foot care in diabetic patients is to salvage the limbs; that is, to prevent lower extremity amputation (LEA). Diabetic foot ulcers (DFUs) precede most non-traumatic LEA. Foot care in diabetic patients can therefore be split into two categories: foot care to prevent the development of DFUs; and wound care for patients who have already developed DFUs.

This review article provides an overview of the practice of foot care in diabetic patients. Next, based on a cohort study conducted in our department, risk factors for patients with DFUs were discussed. Predictors for the incidence of LEA in patients with DFUs included malnutrition and peripheral arterial disease, and lower levels of HDL cholesterol appeared to offer a novel clinical predictor. Moreover, mortality and severity of arteriosclerosis among diabetic patients after LEA are related, and baPWV appears to represent the best noninvasive index of the degree of arteriosclerosis.

Patients with type 1 diabetes and those undergoing total pancreatectomy have difficulties achieving normoglycemia even with the use of intensive insulin therapy. In these patients, pancreas and pancreatic islet transplantation can be a therapeutic option.

As of July 2017, a total of 302 patients received pancreas transplantation from brain-dead donors in Japan. The 5-year graft survival in 246 patients by 2015 was 73.9 %. Successful transplantation results in normal daily blood glucose profiles even after withdrawal of insulin therapy.

A total of 18 cases of islet transplantation were performed in Japan, between 2004 and 2007; 3 of them temporarily achieved insulin withdrawal. The 5-year islet graft survival was 22.2 %. A nationwide clinical trial examining the efficacy and safety of islet transplantation is now being conducted.

The currently developed artificial pancreas, to maintain tight blood glucose control automatically, combines insulin pump and real-time continuous blood glucose monitoring, adjusts insulin doses, and supplies glucose or glucagon to prevent hypoglycemia. Recent devices have been downsized to almost the same size as smart phones.

These therapeutic options are undergoing tremendous development; however, there are also advantages and disadvantages. Physicians and medical staff should support patients and their families in acquiring correct knowledge about these therapeutic options.

Aims: The aim of the study was to assess the efficacy of a 9-month dual therapy glucagon-like peptide-1 receptor agonist (GLP-1 RA), which comprises lixisenatide (Lix) and basal insulin glargine (IGla), and related factors in insulin-treated Japanese patients with type 2 diabetes (T2DM).

Methods: We retrospectively collected data from T2DM patients with HbA1c ≥7.0 % under insulin treatment at Diabetes Center, Tokyo Woman's Medical University Hospital from Feb. 2014 to April 2015. We selected 40 patients who had been switched from conventional insulin treatment to IGla+Lix, and body mass index (BMI), HbA1c, and total insulin doses matched 20 patients who continued the same treatment (C group).

Results: Of 40 patients with IGla+Lix treatment, 20 continued (M group) and 9 quitted IGla+Lix due to insufficient glycemic control (Q group) for 9-months. The 9-month change in BMI, and total insulin dose decreased and basal insulin dose increased significantly in M group compared to C group. Compared to Q group, M group had a significantly lower baseline 2-hour postprandial glucose but higher C-peptide reactivity and C-peptide index.

Conclusion: The 9-month observation study revealed the potential of IGla+Lix dual therapy as a new treatment option for insulin-treated patients with T2DM, especially those with sufficient endogenous insulin secretion.

Preconception counseling is very important for diabetic women to avoid maternal or fetal complications. For more effective preconception counseling, we investigated the actual levels of awareness regarding pregnancy and diabetes in diabetic women contemplating pregnancy.

We conducted a qualitative open-ended interview of 22 diabetic women contemplating a pregnancy. The interview comprised two major parts: knowledge of pregnancy and diabetes and the source of knowledge. We divided the first part, knowledge about pregnancy and diabetes, into eight categories and investigated the relationship between awareness and clinical characteristics.

With regard to knowledge of pregnancy and diabetes, 90 % of subjects were aware of planning a pregnancy; 73 %, of possible maternal complications; and 86 %, of possible fetal complications. We observed that 50 % of subjects had no knowledge regarding either dietary or insulin treatment during pregnancy. We found that their major sources of knowledge were books (45 %) and the internet (29 %).

There was a significant relationship between a lack of awareness regarding pregnancy and diabetes and a higher HbA1c level (p=0.002).

In conclusion, awareness regarding pregnancy and diabetes was found to affect good metabolic control. Preconception counseling for diabetic women is, therefore, necessary to decrease the risk of adverse pregnancy outcomes.

Aim: We aimed to investigate diabetic retinopathy and its association with clinical factors in Japanese patients with twin pregnancy.

Methods: Ten diabetic women had a twin pregnancy between 1977 and 2010. The incidence rate of deterioration in retinopathy was compared with 20 control patients with single pregnancy matched for diabetes type, age and retinopathy in early pregnancy. The clinical factor for diabetic retinopathy in twin pregnancy was also assessed.

Results: In the early pregnancy, 5 patients had simple retinopathy, 1 patient had proliferative retinopathy and the others had no retinopathy. In 4 patients, retinopathy deteriorated during pregnancy: from no retinopathy to simple retinopathy in 1 patient, from simple to preproliferative in 1 patient, and from simple to proliferative in 2 patients. There was no significant difference in the rate of deterioration in retinopathy as compared with control patients with single pregnancy (40 % vs 20 %). In twin pregnancy, the pre-pregnancy BMI in patients with deterioration in retinopathy was higher than that in patients without deterioration (25.6±3.0 vs 20.0±1.5, p<0.05).

Conclusion: This study did not show that twin pregnancy is a risk factor for the progression of retinopathy. Pre-pregnancy BMI was associated with deterioration in retinopathy.

Intraductal papillary mucinous neoplasm (IPMN) generally has a better prognosis than pancreatic ductal carcinoma. Therefore, postoperative diabetes mellitus (PODM) should be managed effectively. We investigated the glucose intolerance and treatment of diabetes before and after pancreatectomy in patients with IPMN. In our hospital, 160 patients underwent pancreatectomy, and only 96 were followed up. Twenty patients (21 %) had preoperative diabetes. Among the 59 patients who underwent pancreatectomy, 21 (59 %) had newly developed PODM. The preoperative HbA1c level was significantly higher (6.0 [5.8-6.3]% vs. 5.7 [5.6-5.9]%) in the PODM group than in the other groups. The incidence of PODM in patients undergoing pancreatic tail or body and tail resection (distal pancreatectomy) was significantly higher than that in those undergoing pancreatic head, body or body and tail, and uncinated process resection (tail, 60 %; head, 32 %; body or body and tail, 13 %; vs. uncinated process, 0 %). Patients requiring insulin therapy were older and had higher preoperative HbA1c levels. The rate of requiring insulin therapy was higher in patients undergoing tail or body and tail resection (tail or body and tail, 39 %; head, 21 %; body 0 %; vs. uncinated process, 0 %). These results suggest that development of PODM in patients with impaired preoperative glucose tolerance and those who have undergone pancreatic tail or body and tail resection should be closely monitored.

Objective: To investigate the incidence and severity of depression, and its association with diabetic complications, among Japanese patients with type 1 and type 2 diabetes.

Methods: This was a single-center cross-sectional study, performed as a part of the Diabetes Study from the Center of Tokyo Women's Medical University (DIACET), established in 2012 by the DIACET committee. All subjects received self-administered questionnaires which included questions regarding the diabetic condition, subjective symptoms associated with diabetic micro- and macroangiopathy, frequency of clinical visits due to vascular diseases, and the Patient Health Questionnaire-9 (PHQ-9), a measure of depression. We extracted data for patients with type 1 and type 2 diabetes. The incidence and severity of depression in patients with type 1 and type 2 diabetes, and the associations between the severity of depression and diabetic complications were examined using logistic regression analysis.

Results: A total of 7,036 patients with type 1 and type 2 diabetes were studied. The mean (±SD) age was 61±15 years, 1,196 patients had type 1 diabetes, and 3,009 patients were women. According to the PHQ-9 scores, patients were classified into the following 3 categories: 0-4 points, no depression (n=4,687); 5-9 points, mild depression (n=2,349); and 10 or more points, moderate or severe depression (n=823). Accordingly, 2,349 patients (33.4 %) of the patients with diabetes had depressive symptoms as indicated by a PHQ-9 score of 5 or more. Although frequency of depressive symptoms were significantly greater among patients with type 1 diabetes, the significance disappeared after adjustment for age and gender using multiple logistic regression analysis, yielding odds ratio (OR) of mild depression=0.94, 95 % confidence interval (CI) =0.78-1.12 (p=0.482) and OR of moderate or severe depression=0.89, 95 %CI=0.71-1.11 (p=0.293). Higher PHQ-9 scores were associated with increased ORs for retinopathy, neuropathy, and end-stage kidney disease requiring dialysis after adjustment for age, gender, and HbA1c in both type 1 and type 2 diabetes patients (p<0.001).

Conclusion: There were no differences in likelihood or severity of depression between type 1 and type 2 diabetes. Significant relationships were found between depression severity and chronic diabetic complications among patients with both type 1 and type 2 diabetes.

Objective: To assess the association between physical energy expenditure and the total and differential white blood cell (WBC) counts which reflect systemic inflammation.

Methods: This study included 953 and 277 apparently healthy middle-aged men and women who were employed and had participated in a general health examination in 2006-2007. They completed a questionnaire regarding their usual patterns of activity during the previous month. Such behaviors included occupational, locomotive, household, leisure, and exercise activities, as well as sleep and sedentary time.

Results: In men, the total WBC count decreased with increasing levels of exercise energy expenditure, after adjusting for confounders. A similar result was observed for neutrophil counts in both genders. A multivariate logistic regression model showed that exercise energy expenditure had significant negative linear relationships with the elevated WBC and neutrophil counts in men (p = 0.019 and 0.026, respectively). As compared to men who didn't exercise regularly the odds ratios of the elevated total WBC and neutrophil counts decreased significantly in the third tertile by 50 % and 51 %, respectively. However, no similar association was observed in women.

Conclusion: Exercise energy expenditure is inversely and independently associated with the WBC and neutrophil counts among healthy Japanese male workers.

Objective: This study compared the maximum body mass index (maxBMI) of patients (onset age: 15-30 years) before and at the onset of type 1 diabetes (T1D) based on the decade of their disease onset (1970-2009). In addition, risk factors for BMI changes after T1D onset were investigated.

Subjects and Methods: A total of 431 patients (157 men) who underwent medical examinations from 1970 to 2009 and developed T1D at 15-30 years of age were included. The patients were classified into 4 groups based on the decade of their T1D onset (group I: 1970-1979; group II: 1980-1989; group III: 1990-1999; and group IV: 2000-2009). BMI and HbA1c levels were measured after the administration of the patient's daily required insulin dose over a period of 5 years after T1D onset. Family history of diabetes and the patient's maxBMI were also compared. Study A compared patients with maxBMI of ≥22 kg/m² and <22 kg/m². Study B compared sHLA (-) patients with sHLA (+) patients who had T1D susceptibility based on a human leukocyte antigen (HLA) haplotype of DRB1*04:05-DQB1*04:01.

Results: In all, 0 % of men in group I, 21.6 % of men in group II, 22.0 % of men in group III, and 13.5 % of men in group IV were obese (i.e., maxBMI ≥25 kg/m²); the proportion of lean men (BMI <18.5 kg/m²) was similar in all groups. Furthermore, 0 % of women in group I, 13.2 % of women in group II, 13.4 % of women in group III, and 14.7 % of women in group IV were obese (i.e., maxBMI ≥25 kg/m²); the proportion of lean women (BMI <18.5 kg/m²) was similar in all groups. In study A, BMI was significantly higher for patients who had an maxBMI of ≥22 kg/m² for 5 years after T1D onset. In study B, the sHLA (+) group had a smaller increase in BMI after T1D onset compared with the sHLA (-) group.

Conclusion: Patients with T1D remained comparatively lean at disease onset over the 40-year period of our study. Moreover, sHLA (+) patients were not likely to have an increased BMI after T1D onset when compared with sHLA (-) patients.

Introduction: In patients with diabetes mellitus, hand stiffness is a common symptom, and is called diabetic hand syndrome (DHS). We conducted an observational study to investigate the prevalence and clinical backgrounds of hand stiffness in type 1 diabetes (T1D) compared with type 2 diabetes (T2D).

Materials and Methods: In this single-center observational cross-sectional study, participants completed a questionnaire, with questions on morning stiffness of hands and history of rheumatoid arthritis [RA]). Laboratory data and status of complications were collected from the participants' medical records. We analyzed the prevalence and clinical background of hand stiffness between the T1D and T2D cohorts.

Results: Participants were 1,360 patients with T1D and 6,254 with T2D. The frequency of hand stiffness was significantly higher in the T2D cohort (18.6 %) than in the T1D cohort (16.1 %). In patients aged 50 years and older, a longer duration and higher prevalence of hand stiffness were found in the T1D cohort than in the T2D cohort. Among the T1D cohort, the frequency of hand stiffness was significantly higher in female than in male participants. Patients with hand stiffness were older and had a longer duration of diabetes than patients without this symptom. In multivariate logistic regression analysis, age, sex, and proliferative retinopathy were independent risk factors.

Discussion: It was found that T1D patients tended to have hand stiffness while young. By age group, hand stiffness was more common in the T1D cohort. Long-term exposure to hyperglycemia may cause this symptom.

Conclusion: T1D patients are likely to have hand stiffness at a relatively younger age. Since hand stiffness is more common among female patients, it is necessary to discriminate DHS from connective tissue diseases.

Objective: To examine the time-dependent changes in the incidence of major amputation and re-amputation in diabetic patients who underwent lower extremity amputation (LEA).

Method: We recruited 188 consecutive patients who underwent LEA due to diabetic foot ulcers at the foot care unit in the Diabetes Center of Tokyo Women's Medical University Hospital between 1993 and 2016. Patients were classified into three groups according to the amputation date: group 1: 1993-2000 (n=37), group 2: 2001-2008 (n=64) and group 3: 2009-2016 (n=87). Major amputation was defined as an amputation above the ankle, and re-amputation was defined as LEA of the same limb within 6 months after the first LEA. The time-dependent changes in each group were compared by Jonckheere-Terpstra test.

Result: The ratio of the major amputation at the final LEA during each group were 81.1 % in group 1, 70.3 % in group 2 and 34.5 % in group 3, and it was significantly reduced over time (p for trend < 0.001). The ratio of the re-amputations during each group were 29.7 % in group 1, 26.6 % in group 2 and 33.3 % in group 3, and there were not any significant difference between 3 groups (p for trend = 0.510). As for the re-amputation parts of re-amputation patients, major amputations were performed 90.9 % in group 1, 82.4 % in group 2 and 41.4 % in group 3, and it was significantly reduced over time (p for trend = 0.001).

Conclusion: The incidence of major amputation in the diabetic patient who underwent LEA was reduced over time. Although there were not any significant change with the incidence of re-amputation, but the incidence of major amputation at the re-amputation parts was reduced.

Aim: To investigate the 6-month efficacy and safety of sodium-glucose co-transporter 2 inhibitors (SGLT2i) in obese patients with type 2 diabetes (T2DM) in Japan.

Methods: We retrospectively collected data from patients with T2DM with a body mass index (BMI) ≥25 kg/m² undergoing antidiabetic treatment at the Diabetes Center, Tokyo Women's Medical University Hospital, from April to October 2015. We selected 34 patients with SGLT2i added-on (S group), and 31 age-, BMI-, sex-, duration of diabetes-, HbA1c-propencity score matched patients who continued their treatment without SGLT2i (C group).

Result: After 6 months, the body weight (BW), BMI, and HbA1c decreased, and the hematocrit increased significantly in the S group compared to the C group. Sixty percent of patients in the S group showed a decrease in HbA1c and 90 % of them showed a decrease in BW. In the S group, patients who showed decreased HbA1c (n=23) had significantly higher baseline HbA1c, alanine transaminase (ALT), and aspartate transaminase (AST) levels than those without a decrease in HbA1c (n=11).

Conclusion: The 6-month evaluation revealed the potential of SGLT2i add-on therapy as a new treatment option for obese patients with T2DM, especially in those with visceral obesity with worse glycemic control.

Objective: This study aimed to assess the relationship between personality and obesity in patients with type 2 diabetes.

Research Design and Methods: Patients with type 2 diabetes (n=62) completed the Maudsley's Personality Inventory (MPI) questionnaire to assess their tendency for extraversion (E) and neuroticism (N) and their tendency to lie (L). Patients were categorized into three groups per measure and their clinical characteristics were compared.

Results: Half of the patients demonstrated a combination of high E scores and low N scores. An inverse correlation between body mass index (BMI) and E and N scores was observed, but was not significant. Patients in the highest BMI quartile (BMI ≥34.3 kg/m²) had the highest N scores compared to those in the lowest BMI quartile (BMI ≤22.7 kg/m²) (p<0.05). The same correlation was observed for leptin levels and N scores, which was significant. There were no differences in E, N and L scores across the adiponectin or alanine transaminase quartiles.

Conclusion: Obese Japanese patients with type 2 diabetes may be more introverted and neurotic than those with lower BMIs. Greater attention should be paid to treatment individualization for these diabetic patients.

Background/Aim: Low blood glucose index (LBGI), a predictor of hypoglycemia, is evaluated by self-measurement of blood glucose (SMBG). We investigated whether LBGI from short-term continuous glucose monitor (CGM) could also predict severe hypoglycemia (SH).

Subjects and Methods: Type 1 diabetic patients (n=250, 75 men) with HbA1c <10 % who consented to using a CGM were recruited. Twenty patients were treated with insulin pump and the rest with multiple daily injections of insulin. Blood glucose fluctuation index was compared between group A, with SH unawareness and group B with SH awareness, and the correlation factors with LGBI was investigated.

Results: Group A, with a longer duration of diabetes than group B, displayed significantly higher J-index, average daily risk range (ADRR), mean of daily difference of blood glucose (MODD), and LBGI. Both LBGI and MODD were independent risk factors for SH unawareness by multiple regression analysis (OR: 1.20, 1.04; p = 0.043, 0.002, respectively).

Discussion: The LBGI from CGM data can be predictive of SH. Even without SH, some patients in group B displayed high LBGI values. MODD and ADRR in group A were also significantly lower than in group B. This suggested that SH unawareness might occur in patients with larger daily and diurnal blood glucose variations.

Aim: Recently, artificially sweetened beverages (ASBs) have inundated the market because of their low calorie value. We examined the prevalence and related factors of ASB intake among patients with type 2 diabetes (T2DM) using questionnaires.

Methods: This study randomly selected 209 patients with T2DM who visited our center between December 1 and 20, 2016. For validation of questionnaires on ASB and sugar sweetened beverage (SSB) intake, 1-month beverages' record was performed in 40 patients with and without DM.

Results: The agreement between the recorded information and answers to the questionnaires on ASB/SSB intake was over 75 %. The prevalence of ASB and SSB intake was 27 % and 17 %, respectively. In total, 71 % of patients initiated ASB intake after T2DM onset. Multivariable logistic regression analysis showed that ORs (95 % CIs) for intake of ASB related to age 60-69 and ≥70 years old compared with <60 years old were 0.2 (0.1-0.5) and 0.1 (0.03-0.3). The corresponding values for HbA1c 6.5-7.1 and ≥7.2 % compared with <6.5 % were 2.6 (0.9-6.9) and 2.9 (1.1-7.6).

Conclusion: The prevalence of ASB intake anticipated from questionnaires was 27 %, with 71 % of these patients initiating ASB intake after T2DM onset. Not older age and a higher HbA1c were independently related to ASB intake.

Maturity onset diabetes of the young (MODY) is the most common form of monogenic diabetes mellitus that constitutes 1-2 % of the cases of diabetes mellitus. MODY3 is caused by mutations in the hepatocyte nuclear factor 1α gene (HNF1A) which are the most frequent cause of MODY in Japan. Characteristics of MODY3 are progressive insulin secretion defects and high sensitivity to sulfonylureas. Recently, incretin-related drugs such as GLP-1 receptor agonists and DPP-4 inhibitors are also indicated for the treatment of patients with MODY3. Here, we report two cases of MODY3 patients on insulin therapy who were given dipeptidyl peptidase-4 (DPP-4) inhibitors. Patient 1, a 38-year-old man carrying P291fsinsC mutation, showed a remarkable reduction in daily insulin dose (16 units to 8 units) without worsening of glycemic control after the administration of a DPP-4 inhibitor. Meal tolerance test (MTT) revealed improvement in insulin secretion and slight suppression of glucagon secretion. Patient 2, a 67-year-old woman, carrying L584S585fsinsTC showed improvement in glycemic control after the administration of a DPP-4 inhibitor, although the total daily insulin dose did not change (22 units to 20 units). MTT revealed the same tendency as observed in case 1. Reduction in daily insulin dose and improvement of insulin secretion were more significant in MODY3 patients than in patients with type 2 diabetes. In conclusion, administration of DPP-4 inhibitors to MODY3 patients who are on insulin treatment may be effective in improving glycemic control because of improved insulin secretion and suppression of glucagon secretion.