Inflammatory Cell Infiltration Into Islets Without PD-L1 Expression Is Associated With the Development of Immune Checkpoint Inhibitor-Related Type 1 Diabetes in Genetically Susceptible Patients.

Immune checkpoint inhibitors (ICIs) could cause type 1 diabetes (T1D). However, the underlying mechanism remains unclear. We immunohistochemically analyzed pancreatic specimens from three individuals with ICI-related T1D, and their histopathological data were compared those from three patients who had received ICI therapy but did not develop T1D (non-T1D) and seven normal glucose-tolerant subjects as control subjects. All ICI-related T1D patients had susceptible HLA haplotypes. In ICI-related T1D, the ß-cell area decreased and the α-cell area increased compared with non-T1D and control subjects. The number of CD3-positive cells around islets increased in ICI-related T1D and non-T1D compared with control subjects, while the number of CD68-positive cells around islets increased in ICI-related T1D compared with non-T1D and control subjects. The expression ratios of programmed death-ligand 1 (PD-L1) on islets decreased in non-T1D and almost completely disappeared in ICI-related T1D, while PD-L1 expression was observed in most cells of pancreatic islets in control subjects. This study, therefore, indicates that ICI therapy itself could reduce PD-L1 expression on islets in all subjects, which may be related to ß-cell vulnerability. In addition, we showed that absence of PD-L1 expression on ß-cells, genetic susceptibility, and infiltration of macrophages as well as T lymphocytes around islets might be responsible for T1D onset.

Consumption of two meals per day is associated with increased intrapancreatic fat deposition in patients with type 2 diabetes: a retrospective study.

INTRODUCTION: This study aimed to identify the associations between lifestyle factors and intrapancreatic fat deposition in patients with type 2 diabetes. RESEARCH DESIGN AND METHODS: The participants were 185 patients with type 2 diabetes who were hospitalized at Osaka University Hospital between 2008 and 2020 and underwent abdominal CT during hospitalization. Information regarding lifestyle factors, including the number of meals consumed per day, snacking habits, exercise habits, exercise at work, smoking habits, alcohol intake, insomnia, sleep apnea syndrome, and night-shift working, was acquired from self-administered questionnaires or medical records. We measured the mean CT values for the pancreas (P), liver (L), and spleen (S), and the visceral fat area (VFA), and quantified intrapancreatic and liver ectopic fat accumulation as P-S and L-S, respectively. RESULTS: After adjustment for age, sex, hemoglobin A1c, and body mass index (BMI), participants who consumed two meals per day had significantly lower P-S (higher intrapancreatic fat deposition, p=0.02) than those who consumed three meals per day. There were no significant associations between the number of meals consumed and liver ectopic fat accumulation and VFA (p=0.73 and p=0.67, respectively). CONCLUSIONS: Patients with diabetes who consumed two meals per day showed greater intrapancreatic fat deposition than those who consumed three meals per day, even after adjustment for BMI. These findings support the current guideline for diabetes treatment that skipping meals should be avoided.

Motivation for Treatment Correlating Most Strongly with an Increase in Satisfaction with Type 2 Diabetes Treatment.

INTRODUCTION: We previously reported several factors that cross-sectionally correlate with treatment satisfaction in Japanese patients with type 2 diabetes visiting diabetes clinics. The aim of this study is to identify factors associated with longitudinal changes in treatment satisfaction in patients with type 2 diabetes. METHODS: The study included 649 patients with type 2 diabetes treated with oral glucose-lowering agents who completed the first questionnaire in 2016. The collected data included scores from the Diabetes Treatment Satisfaction Questionnaire (DTSQ) and other parameters regarding diabetes treatment. We analyzed 1-year longitudinal changes in DTSQ scores and investigated factors associated with these changes. RESULTS: Univariate linear regression analyses showed that changes in body weight, adherence to diet therapy, adherence to exercise therapy, cost burden, motivation for treatment, regularity of mealtimes, and perceived hypoglycemia correlated with changes in DTSQ scores. On the basis of multiple linear regression analyses, a decrease in hypoglycemia (ß ± SE = - 0.394 ± 0.134, p = 0.0034), cost burden (ß ± SE = - 0.934 ± 0.389, p = 0.017), and an increase in treatment motivation (ß ± SE = 1.621 ± 0.606, p = 0.0077) correlated with DTSQ score increases, suggesting that motivation for treatment had the strongest impact on score increases. Subgroup analyses revealed that an increase in motivation for treatment most significantly correlated with a DTSQ score increase in obese and poor glycemic control groups, regardless of age. CONCLUSION: This is the first longitudinal study clarifying that an increase in motivation for treatment most strongly correlates with an increase in DTSQ score in patients with type 2 diabetes.

Maximum body mass index before onset of type 2 diabetes is independently associated with advanced diabetic complications.

INTRODUCTION: The maximum body mass index (BMI) before onset of type 2 diabetes (MBBO) might be used to estimate a patient's insulin secretion capacity. There have been few factors that can predict future diabetic complications at the time of diagnosis of diabetes mellitus. This study aimed to clarify the clinical usefulness of MBBO for predicting the development of advanced diabetic microvascular complications. RESEARCH DESIGN AND METHODS: This was a cross-sectional observational study. Of 1304 consecutively admitted patients with type 2 diabetes, we enrolled 435 patients for whom we could confirm their MBBO. Univariate and multivariate logistic regression analyses were performed to examine whether MBBO or BMI on admission was associated with advanced diabetic retinopathy or nephropathy. To evaluate the predictive performance of these indexes, we performed cross-validation in various models with MBBO or BMI and evaluated the areas under the curve (AUCs) yielded by these analyses. RESULTS: Univariate analyses suggested that MBBO was associated with advanced retinopathy and nephropathy, while BMI on admission was associated only with advanced nephropathy. In multivariate analyses, MBBO was significantly associated with advanced complications, while BMI on admission was not. For advanced diabetic retinopathy, the AUCs were 0.70-0.72, and for advanced nephropathy, the AUCs were 0.81-0.83. When comparing the AUCs among models, the models with MBBO sustained high predictive performance for diabetic complications. CONCLUSIONS: MBBO was independently associated with advanced diabetic complications, while BMI on admission was not. Diabetic microvascular complications in patients with high MBBO could progress more rapidly. At the time of the diagnosis of diabetes mellitus, MBBO would enable us to predict the progress of diabetic complications.

Amelioration of pancreatic fat accumulation in Japanese type 2 diabetes patients treated with sodium-glucose cotransporter 2 inhibitors: a retrospective study.

BACKGROUND: Prior reports have suggested that pancreatic fat is related to type 2 diabetes. Sodium-glucose co-transporter-2 (SGLT-2) inhibitors are expected to reduce ectopic fat accumulation. AIM: This study assessed the effect of SGLT-2 inhibitors on pancreatic and liver fat accumulations in patients with type 2 diabetes. MATERIALS AND METHODS: Retrospective analyses of indices of pancreatic and liver fat accumulations were conducted in 22 type 2 diabetes outpatients who were receiving SGLT-2 inhibitors for more than 12 weeks. The differences between the pancreatic (P) or liver (L) and splenic (S) computed tomography values were evaluated. RESULTS: Fatty pancreas was defined as P-S < -8 Hounsfield Unit (HU), and the number of patients with fatty pancreas was 11 (50%). Fatty pancreas significantly improved after SGLT-2 inhibitor use (median, -20.8; IQR, -34.8 to -14.3 HU vs. median, -14.6; IQR, -29.5 to -7.8 HU; p = 0.041). Fatty liver was defined as L-S ≤ 3.9 HU, and the number of patients with fatty liver was 11 (50%). Fatty liver significantly improved after SGLT-2 inhibitor use (median, -4.3; IQR, -23.0 to 3.0 HU vs. median, -0.7; IQR, -5.2 to 6.3 HU; p = 0.016). CONCLUSION: Pancreatic fat and liver fat accumulations might be reduced after treatment with SGLT-2 inhibitors in type 2 diabetes patients with intense cumulative fat depositions in these organs.

Clinical Significance of the Maximum Body Mass Index Before Onset of Type 2 Diabetes for Predicting Beta-Cell Function.

OBJECTIVE: This study aimed to clarify the clinical significance of the maximum body mass index (BMI) before the onset of type 2 diabetes (MBBO) for predicting pancreatic beta-cell function. METHODS: This was a cross-sectional observational study. Of 1304 consecutively admitted patients with type 2 diabetes, we enrolled 410 patients satisfying the criteria in this study. The correlations between the C-peptide index (CPI), which is one of the parameters that reflects beta-cell function, and various clinical parameters, including MBBO and duration of diabetes, were analyzed in multiple linear regression analyses. RESULTS: The analyses revealed that MBBO was correlated with CPI independently after adjustment for age, sex, HbA1c, and duration of diabetes. When we divided the subjects into three subgroups by MBBO (MBBO < 25 kg/m2; 25 kg/m2 ≤ MBBO < 30 kg/m2; MBBO ≥ 30 kg/m2), CPI was negatively correlated with duration of diabetes in each subgroup, while the rates of CPI based on the duration of diabetes were not different among the three MBBO subgroups. In contrast, the declining rates of CPI were higher in the BMI ≥ 25 kg/m2 group on admission than in the BMI < 25 kg/m2 group on admission. CONCLUSIONS: MBBO may be an independent factor correlating with beta-cell function and may predict insulin secretion capacity at diagnosis, but it does not seem to affect the rate of decline in insulin secretion capacity after diagnosis. It is important to preserve beta-cell function by decreasing a patient's BMI during treatment after diagnosis regardless of MBBO.

Pancreatic fat is related to the longitudinal decrease in the increment of C-peptide in glucagon stimulation test in type 2 diabetes patients.

AIMS/INTRODUCTION: The relationship between pancreatic fatty infiltration and diabetes is widely known, whereas the causal relationship is not clear. Furthermore, it is uncertain whether pathogenesis of pancreatic fat is similar to that of liver fat. We aimed to clarify the contribution of this type of fat to glucose metabolism in type 2 diabetes patients by cross-sectional and longitudinal analyses. MATERIAL AND METHODS: A total of 56 patients with type 2 diabetes who had been hospitalized twice were analyzed. We evaluated the mean computed tomography values of the pancreas (P), liver (L) and spleen (S). Lower computed tomography values indicate a greater fat content. We defined indices of pancreatic or liver fat content as the differences between P or L and S. We assessed the associations among fat content for the two organs (P-S, L-S) and clinical parameters at the first hospitalization, and then analyzed the associations between these fat contents and changes in glycometabolic markers (the second data values minus the first). RESULTS: In the cross-sectional study, P-S negatively correlated with the increment of C-peptide in the glucagon stimulation test (r = -0.71, P < 0.0001) and body mass index (r = -0.28, P = 0.034). L-S negatively correlated with homeostasis model assessment of insulin resistance (r = -0.73, P < 0.0001), body mass index (r = -0.62, P < 0.0001) and some other obesity-related indicators, but not with the increment of C-peptide in the glucagon stimulation test. In the longitudinal study, P-S positively correlated with the change of the increment of C-peptide in the glucagon stimulation test (r = 0.49, P = 0.021). CONCLUSIONS: In type 2 diabetes patients, pancreatic fat was less associated with obesity-related indicators than liver fat, but was more strongly associated with the longitudinal decrease in endogenous insulin-secreting capacity.

Asymptomatic Pontine Lesion and Diabetic Amyotrophy after Rapid Improvement of Poor Glycemic Control in a Patient with Type 1 Diabetes.

We herein report a 28-year-old woman with type 1 diabetes with an asymptomatic pontine lesion and diabetic amyotrophy. She had suffered from diabetes from 10 years old. Treatment in a hospital reduced the hemoglobin A1c level from 14.2% to 7.2% for approximately 2 months. She suffered from acute-onset pain and weakness of the lower limb muscles without central nervous system manifestations. Magnetic resonance imaging showed high-intensity lesions at the brainstem and lower limb muscles on T2-weighted images. These findings and symptoms gradually resolved. Rapid treatment of poor glycemic control might increase the risk of asymptomatic pontine lesions and diabetic amyotrophy.

Case of a novel PAX6 mutation with aniridia and insulin-dependent diabetes mellitus.

We present a case of a novel PAX6 heterozygous mutation with aniridia and insulin-dependent diabetes mellitus.To the best of our knowledge, this is the first case of its mutation with a complete loss of insulin secretory capacity. We believe that our letter will add new knowledge to diabetes mellitus associated with PAX6 mutations and might help us to understand the role of PAX6 in beta-cell development.

Suppression Failure of Cortisol Secretion by Dexamethasone May Occur in Glucagon-like Peptide-1 Receptor Agonist-treated Patients with Diabetic Autonomic Neuropathy.

Two diabetic women (case 1, 75 years old; case 2, 49 years old) being treated with glucagon-like peptide-1 (GLP-1) receptor agonists (GLP-1 RAs) showed no suppression of cortisol secretion on a dexamethasone suppression test (DST). However, its secretion was suppressed after switching from GLP-1 RAs to insulin. We also checked the cortisol secretion by a DST in five consecutive inpatients (case 3-7) being treated with GLP-1 RAs. The coefficients of R-R interval variation at rest and during deep breathing were lower in the two false-positive cases (case 1 and 2) than in the five true-negative cases (case 3-6). GLP-1 RAs can be switched to insulin in order to eliminate the slow absorption effect of dexamethasone by GLP-1 RAs if a DST is planned in diabetic patients receiving GLP-1 RAs.

Factors associated with treatment satisfaction in patients with type 2 diabetes mellitus using oral glucose-lowering agents: a cross-sectional study in urban districts in Japan.

Various oral glucose-lowering agents are available in Japan. Although the objective characteristics of these drugs are well described, little is known about treatment satisfaction by patients using these agents. The aim of this study was to assess treatment satisfaction of diabetic patients visiting diabetes clinics using the Diabetes Treatment Satisfaction Questionnaire (DTSQ) and to determine the association of the DTSQ scores with various factors including oral glucose-lowering agents. The study subjects were 754 outpatients who had been treated with one or more oral glucose-lowering agents, but not insulin or glucagon-like peptide-1 receptor agonist. The collected data included the response to DTSQ as completed by the patients, various parameters pertaining diabetes treatment including adherence, motivation, life style, social support, complications and cost burden from the patients and attending physicians. The associations among satisfaction scores and various parameters were analyzed by multiple linear regression analysis. In all subjects, use of sodium-glucose cotransporter 2 inhibitor (SGLT2i) were positively, and irregular diet time were negatively associated with satisfaction scores significantly as well as some factors which had been previously reported to be associated. Subgroup analysis showed that adherence to diet and use of SGLT2i were positively in obese (body mass index ≥25 kg/m2), and HbA1c and irregular work time were negatively in non-obese (<25 kg/m2) patients associated with satisfaction scores. These results suggest that SGLT2i is really used with high satisfaction, especially by obese patients and that factors associated with treatment satisfaction might differ between obese and non-obese patients using oral glucose-lowering agents.

Characteristics of sleep-wake cycle and sleep duration in Japanese type 2 diabetes patients with visceral fat accumulation.

Sleep pattern has been shown to be associated with type 2 diabetes mellitus. Here, we investigated the difference in bedtime, waking time and estimated sleep duration in type 2 diabetes mellitus patients with or without visceral fat accumulation, using a questionnaire on sleep patterns. The study participants were 59 Japanese type 2 diabetes mellitus patients (men/women 34/25, age 64.5 ± 12.1 years). Visceral fat accumulation was defined as estimated visceral fat area ≥100 cm2 . The patients with visceral fat accumulation (n = 40) showed significantly later bedtime (23.51 ± 01.27 h in the [+] group vs 22.49 ± 01.23 h in the [-] group) and shorter estimated sleep duration (6.6 ± 1.4 h in the [+] group vs 7.9 ± 1.0 h in the [-] group) on weekdays, compared with those without (n = 19). Later bedtime and shorter estimated sleep duration existed in the type 2 diabetes mellitus patients with visceral fat accumulation, compared with those without.

Predictors of postoperative bleeding after vitrectomy for vitreous hemorrhage in patients with diabetic retinopathy.

AIMS/INTRODUCTION: To clarify the association between perioperative variables and postoperative bleeding in pars plana vitrectomy for vitreous hemorrhage in diabetic retinopathy. MATERIALS AND METHODS: The present retrospective study enrolled 72 eyes of 64 patients who were admitted to Osaka University Hospital between April 2010 and March 2014, and underwent vitrectomy for vitreous hemorrhage as a result of diabetic retinopathy. RESULTS: Postoperative bleeding developed in 12 eyes. Using binomial logistic regression analysis, we found that the duration of operation was the only significant variable associated with postoperative bleeding within 12 weeks after vitrectomy. Furthermore, Poisson regression analysis identified fasting blood glucose just before vitrectomy, no treatment with antiplatelet drugs and treatment with antihypertensive drugs, as well as duration of operation, to be significantly associated with the frequency of bleeding within 52 weeks after vitrectomy. CONCLUSIONS: Long duration of operation can be used to predict bleeding within both 12 and 52 weeks after vitrectomy. In addition, fasting blood glucose just before vitrectomy, no treatment with antiplatelet drugs and treatment with antihypertensive drugs might be risk factors for postoperative bleeding up to 1 year after vitrectomy.

An Impaired Awareness of Hypoglycemia Improved After Vitamin B12 Treatment in a Type 1 Diabetic Patient.

An impaired awareness of hypoglycemia is a serious problem in diabetic patients, which can lead to life-threatening severe hypoglycemia. Recurrent hypoglycemia attenuates the function of the central, mainly hypothalamic, nervous system and it causes an impaired awareness of hypoglycemia. Vitamin B12 deficiency is also associated with the dysfunction of central nervous system. We report a 72-year-old type 1 diabetic patient with vitamin B12 deficiency whose impaired awareness of hypoglycemia improved after 4 weeks of vitamin B12 administration with an increased counter-hormone secretion in response to hypoglycemia. We should recognize vitamin B12 deficiency as one of the causes of an impaired awareness of hypoglycemia in diabetic patients.

Multiple Gouty Tophi with Bone Erosion and Destruction: A Report of an Early-onset Case in an Obese Patient.

A 27 year-old severely obese man (BMI, 35.1) had hyperuricemia and multiple gouty tophi with bone erosion and destruction, resulting in gait disturbance for 6 years after the early onset of gout at 21 years of age. His hyperuricemia was associated with hyperinsulinemia in obesity and a genetic variant of the ABCG2 gene. In addition, multiple gouty tophi with bone erosion and destruction might have been caused by hypoadiponectinemia and the elevation of the patient' s pro-inflammatory cytokine (IL-1ß) level with the accumulation of visceral fat. In this case, bone and Ga-67 scintigraphy were useful for detecting the location and magnitude of gouty tophi.

Insulin degludec is associated with less frequent and milder hypoglycemia in insulin-deficient patients with type 1 diabetes compared with insulin glargine or detemir.

INTRODUCTION: The aim of this study was to determine the efficacy of insulin degludec (IDeg) relative to insulin glargine (IGlar) or insulin detemir (IDet) in glycemic control, as evaluated by continuous glucose monitoring (CGM) in insulin-deficient patients with type 1 diabetes. METHODS: We studied 28 outpatients treated with IGlar or IDet (IGlar/IDet). Basal insulin was switched to IDeg when glycemic control was considered unstable, as judged by the dawn phenomenon or nocturnal hypoglycemia. Whole-day CGM data were also divided into daytime and nighttime data. RESULTS: The dawn phenomenon or nocturnal hypoglycemia under IGlar/IDet treatment was observed in all patients. Among 26 patients who completed the study, there were no significant differences in parameters representing glycemic variability, hyperglycemia, mean glycemic control, and HbA1c or insulin therapy-related quality of life at the night score. Measures of hypoglycemia [whole-day %Low and area under the curve (AUC) below 70] were significantly lower under IDeg treatment than under IGlar/IDet treatment (%Low, 9.6 ± 11.5 vs. 14.7 ± 14.9%, p = 0.045; AUC below 70, 85.5 ± 126.0 vs. 145.0 ± 178.6 mg/dl h, p = 0.030). Dividing patients into two groups according to percentage or degree of hypoglycemia under IGlar/IDet treatment, the whole-day, daytime and nighttime %Low in the high-percentage groups and AUC below 70 in the high-degree groups were significantly ameliorated, respectively (p < 0.05). CONCLUSION: Patients with unstable glycemic control under IGlar/IDet treatment did not improve glycemic control upon switching to IDeg, but the frequency and the degree of hypoglycemia was reduced in insulin-deficient outpatients with type 1 diabetes, especially in those suffering from severe hypoglycemia.

Treatment of Mitochondrial Diabetes with a Peroxisome Proliferator-activated Receptor (PPAR)-gamma Agonist.

The 3243 A>G mutation in mitochondrial DNA is the most common cause of monogenic diabetes mellitus in Japan. A 45-year-old woman with mitochondrial diabetes and significant insulin resistance presented with hypoadiponectinemia despite a normal amount of visceral fat. Three months of treatment with pioglitazone (PIO) improved her blood glucose profile and response to the 75-g oral glucose tolerance test. These changes were accompanied by the amelioration of her insulin resistance and the impairment of early-phase insulin secretion. Her serum adiponectin levels increased to the normal range. In this case of mitochondrial diabetes, PIO was effective for glycemic control.