A diabetic patient in whom Hb Weesp was incidentally detected when her HbA1c level was measured Abstract The level of glycated hemoglobin A1c (HbA1c) is widely used to monitor long-term glycemic control in patients with diabetes mellitus. There are more than 30 methods for measuring HbA1c levels. In recent times, high-performance liquid chromatography (HPLC) has become the most commonly used method in Japan. However, HPLC-based HbA1c level measurements do not accurately reflect glycemic control in the presence of Hb variants. We report the case of a patient with type 2 diabetes mellitus, who was incidentally found to having an extremely rare Hb variant. A 69-year-old Japanese female visited our clinic and was diagnosed with diabetes mellitus. Her HbA1c level, which was measured using HPLC at our clinic, could not be determined. DNA sequencing revealed a heterozygous mutation in the α1 globin gene (HBA1: c.301C > T, p.Leu101Phe). Hb Weesp was detected. Many Hb variants have been reported; however, to the best of our knowledge, this is only the second report about Hb Weesp in the world and the first from Japan. Clinicians should consider the possibility of Hb variants in cases in which abnormal elution patterns are detected during the measurement of HbA1c using HPLC.

Clinical background of Japanese patients with type 1 diabetes mellitus who have received insulin therapy for 50 years or longer Abstract Aims We clarified the clinical background of Japanese patients with type 1 diabetes mellitus (T1DM) who have received insulin therapy for 50 years or longer. Methods Of 1,412 patients diagnosed with T1DM at an age younger than 30 years old between 1962 and 2000, 29 had a 50-year or longer history of diabetes. We investigated the mean values of HbA1c and systolic blood pressure (SBP) during follow-up, as well as diabetic retinopathy, diabetic nephropathy, and macroangiopathy. Results The mean age of the subjects at the time of diagnosis was 10 years and that at the completion of this survey was 66 years. The mean follow-up period was 43 years. The mean HbA1c value and SBP during the follow-up period were 8.2% and 130 mmHg, respectively. Seventeen percent of patients did not have diabetic retinopathy, 59% had proliferative retinopathy, and 66% had undergone photocoagulation. Fifty-four percent of patients did not have microalbuminuria and 11% had end-stage renal disease. Macroangiopathy was observed in 46%, cardiovascular disease (CVD) in 25%, and ischemic stroke in 18%. Conclusions It became possible for patients with T1DM to live more than 50 years in Japan.

Albuminuria, C-reactive protein, and socioeconomic factors are associated with periodontal status in subjects with type 2 diabetes Abstract Diabetes and periodontitis may increase risk of cardiovascular disease. Whether albuminuria, C-reactive protein (CRP), and socioeconomic factors, known as cardiovascular risks in subjects with poorly controlled diabetes, are independently associated with periodontal status in well-controlled diabetes remains to be elucidated. In 503 subjects with type 2 diabetes, the cross-sectional associations of clinical and socioeconomic factors with periodontal parameters were investigated. Periodontal parameters on all teeth included the probing pocket depth at 6 sites per tooth, bleeding on probing, the plaque score, tooth mobility, and the number of teeth. The subjects had a mean HbA1c value of 6.85% and a median CRP value of 0.06 mg/dL, and 27.9% of the subjects had albuminuria. Albuminuria and CRP values had significant associations with several periodontal parameters, whereas other variables including HbA1c did not. Subjects with albuminuria had significantly higher HbA1c, CRP, and % sites of pocket depth ≥ 4 mm than subjects with normoalbuminuria; additionally, those with high CRP (≥ median) had significantly higher body mass index, HbA1c, % sites of pocket depth ≥ 4 mm, and plaque score than those with low CRP. In multiple linear regression analysis, albuminuria, CRP, education, smoking, and dental attendance exhibited significant associations with periodontal parameters, independent of the effect of age, sex, body mass index, and diabetes therapy. Albuminuria, CRP, education, smoking, and dental attendance were independently associated with periodontal parameters even in subjects with a mean of HbA1c of 6.85%, implying the importance of these factors for the prevention of cardiovascular disease.

Low resting energy expenditure in postmenopausal Japanese women with type 2 diabetes mellitus Abstract Objective Resting energy expenditure (REE) is an important tool in nutrition management, especially in type 2 diabetes mellitus (T2DM). The predicted REE (pREE) was reported to be inaccurate, compared with measured REE (mREE) in Japanese T2DM patients. Despite the accuracy of REE, measured via indirect calorimetry (mREE), the technique is demanding. This study evaluated the associated clinical factors of the difference between pREE and mREE in Japanese patients with T2DM. Methods Forty-nine Japanese patients with T2DM but no severe complications (32 men and 17 women) were enrolled. mREE was determined via indirect calorimetry. Results Participants average age was 56.3 ± 11.0 years, body mass index was 25.2 ± 3.6 kg/m2, and HbA1c was 9.6 ± 1.6%. The mean mREE was 1099 ± 212 kcal/day. Age, body mass index, hemoglobin, and uric acid levels were all associated with mREE by simple regression; of these, body weight was the significant factor in the multiple regression analysis. When the patients were divided into tertiles, the average mREE values were lower than the pREE values for each group. The difference between mREE and pREE was largest in the lowest value group, whose subjects were mostly women aged over 50 years. This group of women showed significantly lower mREE (904 ± 121 kcal) in comparison with men in the same age group, with 26% overestimation of pREE, even when the equation that yielded the closest mREE value was used. Conclusion The previously reported pREE overestimates mREE in Japanese patients with T2DM, especially in postmenopausal women.

A case of mediastinal teratoma with pancreatic islets accompanied by discontinuation of insulin treatment in insulin-dependent diabetes mellitus Abstract A 74-year-old woman of insulin-dependent diabetes mellitus presented with gradually improvement of blood glucose control and finally discontinuation of insulin therapy, for some unknown reason. During follow-up period, she was admitted with hemoptysis. CT imaging showed a heterogeneous enhancement mass in the middle mediastinum with cyst and calcification, suggesting the diagnosis of mediastinal teratoma. Immediately after excision of the tumor, her plasma glucose levels again increased, and she required insulin therapy for glycemic control. Immunohistochemical examination showed that the tumor contained pancreatic tissue with both exocrine and endocrine components consisted with the islet cells of Langerhans with insulin-positive cells. Accordingly, we diagnosed insulin-producing mediastinal teratoma. Although hypoglycemic agents are the commonest cause of hypoglycemia in diabetic patients, an insulin-producing tumor should be considered in the patients who have dramatic improvement of diabetes mellitus, particularly after withdrawal of all hypoglycemic treatment. Mediastinal teratomas should be considered in differential diagnosis as etiology in undiagnosed case of hypoglycemia or blood glucose fluctuations.

Pathophysiological roles of nutrient-sensing mechanisms in diabetes and its complications Abstract Diabetic nephropathy, which is characterized by increased albuminuria, has been the most common cause of end-stage kidney disease for many years in Japan and many other countries. Although the renal prognosis of the disease has been improving in recent years because of the clinical implementation of strict glucose, blood pressure, and lipid controls, some diabetes patients continue to exhibit treatment-resistant macroalbuminuria leading to end-stage kidney disease. Furthermore, renal function decline without macroalbuminuria in diabetes is an emerging issue in Japan, which might be partly due to aging. Thus, a novel therapeutic strategy is needed to further improve renal outcome in diabetes patients. We have recently reported the involvement of dysregulation of intracellular nutrient-sensing signals and the related cellular process, autophagy, in the pathogenesis of diabetic nephropathy and abnormal insulin secretion pattern in type 2 diabetes. This review discusses potential roles of intracellular nutrient-sensing signals and autophagy as novel therapeutic targets for type 2 diabetes and diabetic nephropathy.

Temporal trends in the prevalence of albuminuria and reduced eGFR in Japanese patients with type 2 diabetes Abstract Changes over time have been shown in renal manifestations in individuals with diabetes in the United States; however, whether the trends are shared across ethnicities is unknown. We conducted this single-center serial cross-sectional study to determine temporal changes in albuminuria and reduced kidney function in Japanese patients with type 2 diabetes. This study included adult Japanese patients with type 2 diabetes who first visited our institute between 2004 and 2013. Temporal changes during the 10 years in the frequency of albuminuria ( ≥ 30 mg/g creatinine) and reduced eGFR ( < 60 mL/min/1.73 m2) were analyzed using the univariate and multivariate logistic regression analyses and Granger causality test. 5331 Japanese patients with type 2 diabetes, 1892 women and 3439 men, with the mean age of 56 ± 13 years, were studied. There was no change in the prevalence of albuminuria in the univariate analysis; however, a significantly decreasing trend was observed after adjustment for several covariates. On the other hand, patients with reduced eGFR significantly increased over time, although the statistical significance disappeared after adjustment for the covariates, including levels of serum uric acid and hemoglobin and use of renin–angiotensin inhibitors. The Granger causality test showed that time series for use of RAS inhibitors and BMI had a causative role in time series for reduced eGFR. In conclusion, prevalence of albuminuria decreased and that of reduced eGFR remained stable after adjustment for clinical characteristics in Japanese patients with type 2 diabetes during the last decade.

Drug development research for novel adiponectin receptor-targeted antidiabetic drugs contributing to healthy longevity Abstract It is well recognized that the decrease of adiponectin associated with high-fat diet and lack of exercise accounts for the onset of insulin resistance, type 2 diabetes, the metabolic syndrome, and cardiovascular disease. Our research efforts have led to the identification of adiponectin receptors, AdipoR1 and AdipoR2, with the former shown to activate AMP kinase in the liver and the latter shown to activate peroxisome proliferator-activated receptor-α signaling thereby increasing fatty acid oxidation. Again, adiponectin upregulates mitochondrial function in the skeletal muscle thereby improving glucose/lipid metabolism and insulin resistance. These findings suggested that activation of adiponectin/AdipoR signaling could represent a viable therapeutic approach to lifestyle-linked diseases associated with prevalent obesity thus contributing to healthy longevity in humans. Indeed, they have led to the successful discovery of AdipoRon, a small-molecule AdipoR-activating compound. Thus far, AdipoRon has been found not only to improve insulin resistance in mice but to prolong their lifespan shortened by high-fat diet. Additionally, our structure-based drug discovery research has led to AdipoR being identified as an entirely novel structure having a zinc iron bound within its seven-transmembrane domain as well as an opposite orientation to that of G protein-coupled receptors. It is expected that increasing insight into AdipoR signaling will facilitate the structure-based optimization of candidate small-molecule AdipoR-activating compounds for human use as well as the development of molecularly targeted and calorie-limiting/exercise-mimicking agents for lifestyle-linked diseases.

Prospective study of cancer in Japanese patients with type 2 diabetes: the Fukuoka Diabetes Registry Abstract Background Although the association between type 2 diabetes and cancer has been reported, few epidemiological studies have been conducted in Japanese patients whose leading cause of death is cancer. We prospectively studied the incidence of site-specific cancer, risk factors for developing cancer, cancer death, and survival in Japanese patients with type 2 diabetes. Methods We followed 4923 participants (mean age, 65 years) with type 2 diabetes attending an outpatient diabetes clinic for a median of 5.3 years (follow-up rate, 99.0%). Results During the follow-up period, cancer occurred in 450 participants (incidence rate, 22.3/1000 person-years in men and 12.2/1000 person-years in women). In men, prostate cancer was the most common cancer (4.3/1000 person-years), colorectal cancer was the second (3.6/1000 person-years), and gastric cancer was the third (3.3/1000 person-years). In women, colorectal cancer was the most common cancer (2.6/1000 person-years), gastric cancer was the second (2.0/1000 person-years), and breast cancer was the third (1.4/1000 person-years). Smoking, male sex, low-density lipoprotein cholesterol, family history of cancer, and reduced intake of isoflavone daidzein were significant risk factors for developing cancer using multivariable Cox proportional hazards models. The leading cancer death was lung cancer in men and pancreatic cancer in women. The survival was the best for prostate cancer and the worst for pancreatic cancer (2-year cancer-specific survival 95.4%, 30.0%, respectively). Conclusions Since the leading cause of death in patients with type 2 diabetes is cancer in Japan, clinicians should be aware of epidemiological data regarding cancer besides diabetic complications.

The hypoglycemia-prevention effect of sensor-augmented pump therapy with predictive low glucose management in Japanese patients with type 1 diabetes mellitus: a short-term study Abstract Aims/introduction The predictive low glucose management (PLGM) system was introduced in March 2018 in Japan. Although there are some reports demonstrating the benefit of PLGM in preventing hypoglycemia, no data are currently available in Japanese patients with type 1 diabetes mellitus (T1DM). The aim of the present study is to evaluate the effect of PLGM with sensor-augmented pump therapy in the prevention of hypoglycemia in Japanese patients. Materials and methods We included 16 patients with T1DM who used the MiniMed®640G system after switching from the MiniMed®620G system. We retrospectively analysed the data of the continuous glucose monitoring system in 1 month after switching to MiniMed®640G. Results The area under the curve (AUC) of hypoglycemia of < 70 mg/dL was lowered from 0.42 ± 0.43 mg/dL day to 0.18 ± 0.18 mg/dL day (P = 0.012). Correspondingly, the duration of severe hypoglycemia (< 54 mg/dL) was reduced significantly from 15.3 ± 21.7 min/day to 4.8 ± 6.9 min/day (P = 0.019). The duration of hypoglycemia was reduced, but the reduction was not significant. Regarding the AUC for hyperglycemia > 180 mg/dL and the duration of hyperglycemia did not change. With the PLGM function, 79.3% of the predicted hypoglycemic events were avoided. Conclusions The hypoglycemia avoidance rate was comparable to those in previous reports. In addition, we demonstrated that PLGM can markedly suppress severe hypoglycemia without deteriorating glycemic control in Japanese T1DM patients. It is necessary to further investigate the effective use of the PLGM feature such as establishing a lower limit and the timing of resumption.