The present study examined the association between the onset of micro- and macroangiopathy in type 2 diabetes mellitus patients and levels of glycated hemoglobin (HbA1c) described in the Evidence-based Practice Guideline for the Treatment for Diabetes in Japan 2013 or those indicated in the Japan Diabetes Society and the Japan Geriatrics Society Joint Committee on Improving Care for Elderly Patients with Diabetes.Patients with type 2 diabetes mellitus who visited the outpatient clinic at Kawasaki Medical School Hospital between 2000 and 2016 and received follow up for >2 years were eligible for the present study. Two datasets, comprising 2,424 or 3,316 patients without micro- or macroangiopathy at the start of follow up, were used, respectively. The Cox model was used in two categories of patients, younger and elderly, with the dividing line set at the age of 65 years.For the prevention of microangiopathy, in all patients, there was found to be no advantage in controlling HbA1c at a level of <6.0% based on the categories in the Evidence-based Practice Guideline for the Treatment for Diabetes in Japan 2013, and there was found to be a disadvantage in maintaining HbA1c ≥8.5% based on the categories in the Japan Diabetes Society and the Japan Geriatrics Society Joint Committee on Improving Care for Elderly Patients with Diabetes guideline. For the prevention of macroangiopathy in younger patients, there seemed to be an advantage in maintaining HbA1c within the range of 6.0-6.9% and <7.0% based on the Evidence-based Practice Guideline for the Treatment for Diabetes in Japan 2013 and the Japan Diabetes Society and the Japan Geriatrics Society Joint Committee on Improving Care for Elderly Patients with Diabetes, respectively.In all type 2 diabetes mellitus patients, average HbA1c should be maintained <7.0% to prevent microangiopathy. However, in elderly patients, no optimal target for preventing macroangiopathy was found, in contrast to the younger patients in the present study.
The clinical usefulness of once weekly GLP-1 receptor agonists, dulaglutide (D) and semaglutide (S), on domestically approved doses in Japan, was assessed by the multicenter RCT to compare the efficacy, safety and patient satisfaction of D at a dose of 0.75mg and S at a dose of 0.25-1.0mg in patients with type 2 diabetes. The study protocol was approved by the IRB of Kawasaki Medical School (No.5276-01). A total 120 patients eligible for the criteria with HbA1c of 7% or more were randomly assigned to groups D and S (D:S = 59:61), and 107 subjects completed the trial for 24 weeks (D:S=53:54). Backgrounds of 107 subjects were age 62.7 ± 10.7 years, disease duration 13.9 ± 7.4 years, BMI 29.3 ± 5.9 kg/m2, HbA1c 8.0 ± 0.6%. There were no differences in these parameters between 2 groups. Dose of S was escalated by 4 weeks from 0.25mg to adequate dose for each, and average dose was 0.63±0.24mg. The primary endpoint was the difference of HbA1c level between 2 groups at 24 weeks. The HbA1c level at 24 weeks was significantly lower in S than D (D: 8.1±0.6→7.4±0.8 vs S: 7.9±0.5→ 6.7±0.5%, p<0.0001). Reduction in BMI and VFA levels were also more significant in S (D vs. S), BMI: 29.2→28.8 vs. 29.4→28.1 kg/m2, VFA: 174.5→164.6 vs. 175.8→153.2cm2, respectively (p< 0.05). The achievement rate of HbA1c <7% was higher in S (D vs S; 30.8% vs 70.4%, p<0.0001). The parameters such as LDL-C, ALT, γGTP, and apo B/A1 were decreased, and the L/S ratio was increased only in S. Compared the changes in L/S ratio less than 0.9 at baseline, which is diagnosed as NAFLD by CT, between two groups, the ratio was significantly elevated only in the S, but not in D at 24weeks. Gastrointestinal symptoms were observed in 13.2% of D and 46.3% of S (p<0.01). DTR-QoL scores related to pain and gastrointestinal symptoms were superior in D. This prospective trial demonstrated that S has more pronounced effects on glucose and BMI lowering, as well as a reduction in liver fat percentage and visceral fat area. Disclosure T. Kimura: Speaker's Bureau; Sanwa Kagaku Kenkyusho, Kowa Research Institute, Inc., Taisho Pharmaceutical Holdings Co., Ltd., Boehringer Ingelheim Japan, Inc., Sumitomo Dainippon Pharma Co., Ltd., Sanofi, MSD Life Science Foundation, Lilly, Daiichi Sankyo, Novo Nordisk. Y. Katakura: Speaker's Bureau; Abbott. M. Shimoda: Speaker's Bureau; Sanofi, Lilly, AstraZeneca, Ono Pharmaceutical Co., Ltd., Kowa Company, Ltd., Novo Nordisk, Sumitomo Dainippon Pharma Co., Ltd., Taisho Pharmaceutical Holdings Co., Ltd., MSD Life Science Foundation, Mitsubishi Tanabe Pharma Corporation. F. Kawasaki: None. M. Yamabe: Speaker's Bureau; Novo Nordisk, Eli Lilly Japan K.K., Abbott Japan Co., Ltd., Sanofi, Boehringer Ingelheim Japan, Inc., Kowa Company, Ltd., Ono Pharmaceutical Co., Ltd., Mitsubishi Tanabe Pharma Corporation, Sumitomo Dainippon Pharma Co., Ltd., Terumo Corporation. F. Tatsumi: Speaker's Bureau; Abbott Japan Co., Ltd., Kowa Company, Ltd., Novo Nordisk. M. Matsuki: None. Y. Iwamoto: Speaker's Bureau; Kowa Company, Ltd. T. Anno: None. Y. Fushimi: None. S. Kamei: None. Y. Kimura: None. J. Sanada: Speaker's Bureau; Lilly, Kowa Company, Ltd. Y. Hirata: None. S. Nakanishi: Speaker's Bureau; Boehringer Ingelheim Japan, Inc., Novo Nordisk, Sanofi, Taisho Pharmaceutical Holdings Co., Ltd., Ono Pharmaceutical Co., Ltd., Daiichi Sankyo, Kowa Company, Ltd., Abbott, Mitsubishi Tanabe Pharma Corporation. T. Mune: None. K. Kaku: Speaker's Bureau; Astellas Pharma Inc., Daiichi Sankyo, Eli Lilly Japan K.K., Boehringer Ingelheim Japan, Inc., Kowa Company, Ltd., Mitsubishi Tanabe Pharma Corporation. Advisory Panel; Novo Nordisk. Consultant; Sanwa Kagaku Kenkyusho. Speaker's Bureau; Taiho Pharmaceutical Co. Ltd., Takeda Pharmaceutical Co., Ltd. H. Kaneto: Research Support; Sumitomo Dainippon Pharma Co., Ltd., Taiho Pharmaceutical Co. Ltd., Boehringer Ingelheim Japan, Inc. Speaker's Bureau; Lilly, Sanofi, Boehringer Ingelheim Japan, Inc., Novo Nordisk, Sumitomo Dainippon Pharma Co., Ltd. Research Support; Abbott.
Aims: Effects of DPP-4 inhibitor or SGLT2 inhibitor on human β-cell function are not well understood, and there is no report showing the difference between the two agents. The aim of this study is to compare the effects of these drugs on β-cell function in patients with type 2 diabetes. Methods: The study protocol was approved by the IRB of Kawasaki Medical School (No. jRCTs061190008). A total of 103 patients met the inclusion criteria (age; 20 to 79 years, HbA1c; ≥7.0% and <9.0%). Subjects were randomly assigned to luseogliflozin (L) group (n=49) or teneligliptin (T) group (n=54) and received 24 wks of intervention followed by 1-2 wks of drug washout. The primary endpoint was the change in log-transformed (Ln) disposition index (DI) 0-120 from baseline. Subjects underwent 75gOGTT before and after treatment. Results: The main baseline backgrounds of L and T groups were as follows; age: 60.8±11.1 vs. 62.6±11.2 years (p=0.4), diabetes duration: 10.1±7.9 vs. 9.2±7.6 years (p=0.6), BMI: 27.0±4.2 vs. 27.2±5.4 kg/m2 (p=0.8), HbA1c: 7.6±0.4 vs. 7.5±0.5 % (p=0.5), DI 0-120: 0.80±0.60 vs. 0.92±0.59 (p=0.1). HbA1c levels were significantly decreased in both groups, but the amount of change was greater in the T group (-0.2%, p=0.02). Body weight was significantly decreased only in the L group, with a group difference of -2.5 kg (p<0.001). Ln DI 0-120 were improved in both groups: -0.46±0.66 to -0.15±0.59 (p=0.01) in L group and -0.26±0.60 to -0.02±0.60 (p=0.003) in T group. The change in Ln serum proinsulin/CPR ratio, a marker of β-cell dysfunction, was reduced in L group (1.63±0.63 to 1.56±0.68, p=0.16), but rather increased in T group (1.70±0.75 to 1.90±0.51, p=0.01), with significant difference between the 2 groups (-0.27; p=0.004). Conclusion: Improvement effects on DI 0-120 were almost identical between luseogliflozin and teneligliptin. On the other hand, burden on β-cells was mitigated only in luseogliflozin group. Disclosure M.Shimoda: Speaker's Bureau; Sanofi, Lilly, AstraZeneca, Ono Pharmaceutical Co., Ltd., Kowa Company, Ltd., Novo Nordisk, Sumitomo Dainippon Pharma Co., Ltd., Taisho Pharmaceutical Holdings Co., Ltd., MSD Life Science Foundation, Mitsubishi Tanabe Pharma Corporation. A.Obata: None. T.Kimura: Speaker's Bureau; Sanwa Kagaku Kenkyusho, Kowa Research Institute, Inc., Taisho Pharmaceutical Holdings Co., Ltd., Boehringer Ingelheim Japan, Inc., Sumitomo Dainippon Pharma Co., Ltd., Sanofi, MSD Life Science Foundation, Lilly, Daiichi Sankyo, Novo Nordisk. F.Kawasaki: None. F.Tatsumi: Speaker's Bureau; Abbott Japan Co., Ltd., Kowa Company, Ltd., Novo Nordisk. S.Nakanishi: Speaker's Bureau; Boehringer Ingelheim Japan, Inc., Novo Nordisk, Sanofi, Taisho Pharmaceutical Holdings Co., Ltd., Ono Pharmaceutical Co., Ltd., Daiichi Sankyo, Kowa Company, Ltd., Abbott, Mitsubishi Tanabe Pharma Corporation. T.Mune: None. K.Kaku: Advisory Panel; Novo Nordisk, Consultant; Sanwa Kagaku Kenkyusho, Speaker's Bureau; Astellas Pharma Inc., Daiichi Sankyo, Eli Lilly Japan K.K., Boehringer Ingelheim Japan, Inc., Kowa Company, Ltd., Mitsubishi Tanabe Pharma Corporation, Taiho Pharmaceutical Co. Ltd., Takeda Pharmaceutical Co., Ltd. H.Kaneto: Research Support; Sumitomo Dainippon Pharma Co., Ltd., Taiho Pharmaceutical Co. Ltd., Boehringer Ingelheim Japan, Inc., Abbott, Speaker's Bureau; Lilly, Sanofi, Boehringer Ingelheim Japan, Inc., Novo Nordisk, Sumitomo Dainippon Pharma Co., Ltd. Y.Katakura: Speaker's Bureau; Abbott. M.Iwamoto: Speaker's Bureau; Mitsubishi Tanabe Pharma Corporation, Novo Nordisk, Boehringer Ingelheim Inc., Eli Lilly Japan K.K., Sumitomo Dainippon Pharma Co., Ltd. Y.Kimura: None. T.Anno: None. H.Isobe: None. Y.Iwamoto: Speaker's Bureau; Kowa Company, Ltd. Y.Fushimi: None. J.Sanada: Speaker's Bureau; Lilly, Kowa Company, Ltd. Funding Taisho Pharmaceutical Holdings Co., Ltd.
Pituitary inflammation due to IgG4-related disease is a rare condition and is sometimes accompanied by central diabetes insipidus. Central diabetes insipidus produces a strong thirst sensation, which may be difficult to distinguish when complicated by salivary insufficiency. A 45-year-old man was admitted to our department for a thorough examination of his thirst and polyuria. He had suddenly developed these symptoms more than one year earlier and visited an oral surgeon. Swelling of the left submandibular gland, right parotid gland, and cervical lymph nodes had been observed. Since his IgG4 level was relatively high at 792 mg/dL and a lip biopsy showed high plasmacytoid infiltration around the gland ducts, he had been diagnosed with IgG4-related disease. He had started taking 0.4 mg/kg/day of prednisolone, and his chief complaint temporarily improved. However, since the symptom recurred, he was referred to our institution. After admission, to examine the cause of his thirst and polyuria, we performed a water restriction test, vasopressin loading test, hypertonic saline loading test and pituitary magnetic resonance imaging. Based on the findings, we diagnosed him with central diabetes insipidus due to IgG4-related hypophysitis. We increased the dose of prednisolone to 0.6 mg/kg/day and started 10 μg/day of intranasal desmopressin. His symptoms were subsequently alleviated, and his serum IgG4 level finally normalized. We should remember that IgG4-related disease can be accompanied by hypophysitis and that central diabetes insipidus is brought about by IgG4-related hypophysitis. This case report should remind physicians of the fact that pituitary inflammation due to IgG4-related disease is very rare and can be masked by symptoms due to salivary gland inflammation, which can lead to pitfalls in the diagnosis in clinical practice.
Non-alcoholic fatty liver disease (NAFLD) is often observed in individuals with type 2 diabetes mellitus, and it is known that the presence of type 2 diabetes mellitus leads to the aggravation of NAFLD. The aim of this study was to compare the possible effects of three kinds of oral hypoglycemic agents on NAFLD in individuals with type 2 diabetes mellitus.We carried out a prospective clinical trial (a randomized and open-label study) in patients with type 2 diabetes mellitus and NAFLD. A total of 98 patients were randomly allocated either to the dapagliflozin (n = 32), pioglitazone (n = 33) or glimepiride (n = 33) group, and the patients took these drugs for 28 weeks. The primary end-point was the change of the liver-to-spleen ratio on abdominal computed tomography.There was no difference in baseline clinical characteristics among the three groups. Dapagliflozin, pioglitazone and glimepiride ameliorated hyperglycemia similarly. Bodyweight and visceral fat area were significantly decreased only in the dapagliflozin group. Serum adiponectin levels were markedly increased in the pioglitazone group compared with the other two groups. Dapagliflozin and pioglitazone, but not glimepiride, significantly increased the liver-to-spleen ratio, and the effects of dapagliflozin and pioglitazone on the liver-to-spleen ratio were comparable.The present study showed that the decrease of visceral fat area and the increase of adiponectin level contributed to the improvement of NAFLD in patients with type 2 diabetes mellitus. Furthermore, dapagliflozin and pioglitazone exerted equivalent beneficial effects on NAFLD in patients with type 2 diabetes mellitus, although it seemed that these two drugs had different mechanisms of action.
The db gene homozygous, but not heterozygous, mice develop diabetes with severe beta-cell damage. We investigated the molecular mechanism underlying db gene-associated pancreatic beta-cell dysfunction. Islet morphology, beta-cell function, and gene expression profiles specific for pancreatic islet cells were compared among db gene homozygous(db/db), heterozygous (db/m) and unrelated m/m mice. The beta-cell ratio decreased in db/db mice with age, but not in non-diabetic db/m and m/m mice. The islet insulin content was lower, but the triglyceride content was higher in db/db than other mice. The islet cell specific gene expression profiles analyzed by laser capture microdissection method and morphological findings suggested an augmentation of beta-cell apoptosis, oxidative stress and ER stress in db/db mice. Interestingly, insulin I and II, anti-apoptotic bcl-2, and proliferation promoting ERK-1 gene expressions were significantly upregulated in db/m mice. An impaired glucose tolerance was shown in m/m mice fed a high fat diet, but not in db/m mice, in which a higher insulin response and increased beta-cell mass were observed. Expressions of insulin I and II, bcl-2, and ERK-1 gene were increased in db/m mice, but not in m/m fed a high fat diet. The present results strongly suggest that the db gene heterozygote, but not homozygote, acquires a compensatory mechanism suppressing beta-cell apoptosis and augmenting the capacity of beta-cell function.
A 58-year-old Japanese man was brought to the emergency room due to disturbance of consciousness. He regained consciousness on the day of admission and started taking hospital meals, but he needed intravenous glucose administration for eight days. The total amount of glucose administration was 4,464 g. It took over three weeks for exogenous insulin to be almost undetectable. While degludec binds to albumin and exerts glucose-lowering effects for a long time, the above-mentioned period of three weeks was consistent with the half-life of albumin. Hypoglycemia induced by massive dose of insulin degludec is persistent and prominent.
Acute necrotic esophagitis is characterized by blacking in the esophageal mucosa and is rarely accompanied by diabetes mellitus, especially under severe hyperglycemic conditions. Here we show a very rare case of a patient who had acute and extremely severe necrotic esophagitis accompanied by hyperglycemic hyperosmolar syndrome.
Abstract Aim Recently, the development of the oral glucagon‐like peptide‐1 receptor agonist semaglutide has drawn a great deal of attention. This study aimed to compare the effectiveness of oral glucagon‐like peptide‐1 receptor agonist semaglutide and dipeptidyl peptidase‐4 (DPP‐4) inhibitors on glycaemic control and several metabolic parameters in patients with type 2 diabetes mellitus over a 6‐month period. Methods Fifty‐nine participants were included, and we compared various clinical parameters between before and after switching from DPP‐4 inhibitors to oral semaglutide in ‘study 1’ (pre‐post comparison) and set the control group using the propensity score matching method in ‘study 2’. Results In ‘study 1’, 6 months after the switching, the glycated haemoglobin value was significantly reduced from 7.5% to 7.0%, and the body mass index was also decreased from 29.7 kg/m 2 to 28.8 kg/m 2 . Such effects were more clearly observed in participants whose glycaemic control was poor. In ‘study 2’, after 1:1 propensity score matching, 51 participants from each group were matched, and glycaemic control as well as body weight management were improved in the switching group compared with the DPP‐4 inhibitor continuation group over the 6‐month observation period. Conclusion In this study, including obese participants with poor glycaemic control, switching DPP‐4 inhibitors to oral semaglutide showed more beneficial effects on both glycaemic and weight control, irrespective of age, body weight and diabetes duration. Therefore, we should bear in mind that it would be better to start using an oral semaglutide in clinical practice, particularly in obese participants with poor glycaemic control with DPP‐4 inhibitors.
Abstract Primary aldosteronism (PA) is a well-known cause of secondary hypertension. We have long performed the simple standing test in patients with PA. On the other hand, there are few reports on the usefulness of the simple standing test in PA. This study is a single-center, retrospective, observational study. A total of 173 patients with hypertension or adrenal tumor admitted to Kawasaki Medical School were included. Eighty patients who met the exclusion criteria were excluded, and 31 patients without PA (non-PA), 26 patients with unilateral PA, and 36 patients with bilateral PA were included in the study. The simple standing test was performed after 120 min of standing or sitting followed, and the aldosterone/renin ratio (ARR) and percentage of increase plasma aldosterone concentration (%increase of PAC) was calculated. The mean ARR in the simple standing test in unilateral PA (1143 (528–2200)) and bilateral PA subjects (521 (374–765)) were significantly higher compared to non-PA subjects (152 (102–240)) ( p < 0.0001, p = 0.0013, respectively). The percentage increase of PAC after standing loading was significantly lower in unilateral PA subjects (110 (96–140)) compared to non-PA subjects (187 (155–244)) ( p = 0.0003), with no difference between non-PA and bilateral PA subjects ( p = 0.99). The cutoff value of the ARR in the simple standing test for diagnosis of PA in this study was 364 (AUC = 0.948, sensitivity = 83.8%, specificity = 93.5%, false positive rate = 3.7%, false negative rate = 25.6%, p < 0.001), which was not inferior to the diagnostic performance of the captopril loading test. The diagnostic performance of the simple standing test for PA was not inferior to that of the captopril loading test. The percentage increase of PAC in unilateral PA subjects was significantly lower compared to bilateral PA subjects. These results demonstrate the usefulness of the simple standing test, which can be performed simultaneously with general screening tests of PA.
