Associations between urinary 6-sulfatoxymelatonin excretion and diabetic vascular complications or arteriosclerosis in patients with type 2 diabetes

Aims/IntroductionThere are limited reports on the association between melatonin levels and vascular complications in patients with type 2 diabetes. The aim of this study was to determine the association between urinary 6‐sulfatoxymelatonin, which is a urinary metabolite of melatonin, and diabetic vascular complications or arteriosclerosis in patients with type 2 diabetes.Materials and MethodsThis retrospective study included patients (167 patients with type 2 diabetes and 27 patients without diabetes adjusted for age and sex) admitted to the hospital who underwent measurement of urinary 6‐sulfatoxymelatonin. The urinary 6‐sulfatoxymelatonin/creatinine ratio (6‐SMT) was calculated.ResultsThe natural logarithmically scaled 6‐SMT level (Ln 6‐SMT) was significantly lower in type 2 diabetes patients (1.9 ± 1.1) compared with patients without diabetes (2.8 ± 1.0, P < 0.001). Multivariate linear regression analysis identified duration of diabetes, smoking status, urinary albumin‐to‐creatinine ratio, retinopathy and coronary heart disease as factors that could influence Ln 6‐SMT levels in type 2 diabetes patients (R ² = 0.232, P < 0.001). Ln 6‐SMT was associated with decreased odds of diabetic retinopathy, even after adjustment for various confounding factors (odds ratio 0.559, 95% confidence interval 0.369–0.846, P = 0.006). Similarly, Ln 6‐SMT was associated with decreased odds of coronary heart disease (odds ratio 0.442, P = 0.030).ConclusionsOur results showed the presence of low levels of Ln 6‐SMT in type 2 diabetes patients relative to patients without diabetes. Furthermore, Ln 6‐SMT is an independent risk factor of diabetic retinopathy and coronary heart diseases. These findings suggest that 6‐SMT could be a useful biomarker for the prediction of micro‐ and macrovasculopathies in patients with type 2 diabetes.     

Impact of primary aldosteronism on renal function in patients with type 2 diabetes

Aims/IntroductionRenal dysfunction might quickly progress in patients with type 2 diabetes mellitus, when accompanied by hypertension. However, whether primary aldosteronism (PA), which autonomously over‐secretes aldosterone, causes additional renal damage in patients with type 2 diabetes mellitus is unclear. We evaluated the impact of PA on renal function in patients with type 2 diabetes mellitus.Materials and MethodsA retrospective review of all patients with type 2 diabetes mellitus who visited Yokohama Rosai Hospital’s (Yokohama Japan) outpatient department between April 2017 and March 2018 was carried out. Records of patients with PA who underwent PA treatment by adrenalectomy or mineralocorticoid receptor antagonists (PA group) and those without PA (non‐PA group) were extracted, and renal function was compared between the two groups. Untreated PA patients were excluded, as their renal function might be overestimated as a result of glomerular hyperfiltration.ResultsThere were 83 patients in the PA group and 1,580 patients in the non‐PA group. The PA group had significantly lower estimated glomerular filtration rates than the non‐PA group (66.3 [52.4–78.2] vs 70.5 [56.0–85.6] mL/min/1.73 m², P = 0.047). Multiple regression analysis showed that PA was a factor for decreased estimated glomerular filtration rate, independent of age, sex, glycated hemoglobin, diuretic use and hypertension (P = 0.025). PA induced a 3.7‐mL/min/1.73 m² (95% confidence interval 0.47–6.9) decrease in estimated glomerular filtration rate, equivalent to that induced by 4.4 years of aging.ConclusionsOur results show that in patients with type 2 diabetes mellitus, PA is an independent risk factor for renal dysfunction. To prevent the progression of renal failure, PA should not be overlooked.     

Thresholds for postprandial hyperglycemia and hypertriglyceridemia associated with increased mortality risk in type 2 diabetes patients: A real-world longitudinal study

Aims/IntroductionTo identify thresholds for postprandial hyperglycemia and hypertriglyceridemia predictive of all‐cause mortality in patients with type 2 diabetes.Materials and MethodsA total of 1,928 patients with type 2 diabetes visited our clinic for the first time from 1995 to 1999 and were followed up for ≥1 year. During the first year, 2‐h post‐breakfast blood glucose (2h‐BG) levels were measured in 1,122 patients (BG cohort) and postprandial serum triglyceride (ppTG) levels were measured in 1,826 patients (TG cohort). Patients were retrospectively followed until 2017 and administered questionnaires. Associations between 2h‐BG and ppTG levels and mortality risk were assessed by the multivariate Cox regression analysis.ResultsOver of 17,429 person‐years, 162 deaths occurred in the BG cohort, and over 28,026 person‐years, 253 deaths occurred in the TG cohort. Hazard ratios (HRs) with 95% confidence intervals for all‐cause mortality per 1‐standard deviation increases in 2h‐BG and ppTG were 1.34 (1.08–1.67) and 1.24 (1.06–1.45), respectively. HRs showed increasing trends across quintiles of 2h‐BG (P = 0.034) and ppTG (P = 0.007). The HR was significantly elevated (2.37, 1.26–4.47) in the fifth quintile of 2h‐BG (≥13.8 mmol/L) compared with the first quintile (<7.0 mmol/L; P = 0.008). The HR was also significantly elevated (1.63, 1.03–2.60) in the fifth quintile of ppTG (≥2.30 mmol/L) compared with the first quintile (<0.91 mmol/L; P = 0.038).ConclusionsPostprandial hyperglycemia and hypertriglyceridemia were associated with all‐cause mortality in patients with type 2 diabetes. We propose thresholds of 13.8 mmol/L 2h‐BG and 2.30 mmol/L ppTG to identify patients at increased risk of mortality.     

Clinical inertia in patients with type 2 diabetes treated with oral antidiabetic drugs: Results from a Japanese cohort study (JDDM53)

Aims/IntroductionTreatment intensification is commonly delayed in people with type 2 diabetes, resulting in poor glycemic control for an unacceptable length of time and increased risk of complications.Materials and MethodsThis retrospective study investigated clinical inertia in 33,320 Japanese adults with type 2 diabetes treated with oral antidiabetic drugs (OADs) between 2009 and 2018, using data from the Computerized Diabetes Care (CoDiC^®) database.ResultsThe median time from first reported glycated hemoglobin (HbA1c) ≥7.0% (≥53 mmol/mol) to treatment intensification was considerably longer and HbA1c levels were higher the more OADs the patient was exposed to. For patients receiving three OADs, the median times from HbA1c ≥7.0% (53 mmol/mol) to intensification with OAD, glucagon‐like peptide‐1 receptor agonist or insulin were 8.1, 9.1 and 6.7 months, with a mean HbA1c level at the time of intensification of 8.4%, 8.9% and 9.3%, respectively. The cumulative incidence for time since the first reported HbA1c ≥7.0% (≥53 mmol/mol) to intensification confirmed the existence of clinical inertia, identifying patients whose treatment was not intensified despite poor glycemic control. HbA1c levels ≥7.0% (≥53 mmol/mol) after ≥6 months on one, two or three OADs were observed in 42%, 51% and 58% of patients, respectively, showing that approximately 50% of patients are above HbA1c target regardless of how many OADs they take.ConclusionsReal‐world data here show clinical inertia in Japanese adults with type 2 diabetes from early diabetes stages when they are receiving OADs, and illustrate a need for earlier, more effective OADs or injectable treatment intensification and better communication around the existence of clinical inertia.     

Serum C-X-C motif chemokine ligand 14 levels are associated with serum C-peptide and fatty liver index in type 2 diabetes mellitus patients

Aims/IntroductionRecent studies have suggested C‐X‐C motif chemokine ligand 14 (CXCL14), secreted from adipose tissue, to play an important role in the pathogenesis of metabolic syndrome. However, the clinical significance of CXCL14 in humans has not been elucidated. This study aimed to assess correlations between serum CXCL14 levels and clinical parameters in patients with type 2 diabetes mellitus.Materials and MethodsIn total, 176 individuals with type 2 diabetes mellitus were recruited. Serum CXCL14 concentrations were determined by enzyme‐linked immunosorbent assay. We examined the associations of serum CXCL14 levels with laboratory values, abdominal computed tomography image information, surrogate markers used for evaluating the pathological states of diabetes, obesity and atherosclerosis.ResultsSerum CXCL14 levels correlated positively with body mass index, waist circumference, subcutaneous and visceral fat areas, and serum alanine transaminase, uric acid, total cholesterol, low‐density lipoprotein cholesterol, triglycerides and C‐peptide (CPR) levels. In contrast, CXCL14 levels correlated inversely with age, pulse wave velocity and serum adiponectin levels. Multiple linear regression analysis showed serum levels of CPR (β = 0.227, P = 0.038) and the fatty liver index (β = 0.205, P = 0.049) to be the only parameters showing independent statistically significant associations with serum CXCL14 levels.ConclusionsSerum CXCL14 levels were independently associated with serum CPR and fatty liver index in patients with type 2 diabetes mellitus. In these patients, a high serum CPR concentration might reflect insulin resistance rather than β‐cell function, because CXCL14 showed simple correlations with obesity‐related parameters. Collectively, these data suggested that serum CXCL14 levels in type 2 diabetes patients might be useful predictors of elevated serum CPR and hepatic steatosis.     

Impaired insulin secretion predicting unstable glycemic variability and time below range in type 2 diabetes patients regardless of glycated hemoglobin or diabetes treatment

Aims/IntroductionTo identify the coefficient of variation (CV) threshold for unstable glucose variability (GV) and hypoglycemia, and to characterize a patient population with unstable GV and hypoglycemia.Materials and MethodsThis was an observational study that enrolled 284 Japanese outpatients with type 2 diabetes who underwent continuous glucose monitoring. The C‐peptide index (CPI = [(fasting serum C‐peptide) / (plasma glucose)] × 100) was used as a marker of endogenous insulin secretion. The CV threshold between stable and unstable GV was defined as the upper limit of the CV distribution in the subgroup of patients who did not receive insulin nor insulin secretagogues (relatively stable GV subgroup, n = 104). The optimal CV range corresponding to time below target range ≥4% was determined for all patients using receiver operating characteristic curve analysis. Various characteristics of patients with unstable GV and hypoglycemia were extracted using multivariate logistic regression analysis.ResultsThe upper limit of the CV in the relatively stable GV subgroup was 40. The optimal CV range corresponding to time below target range ≥4% was also defined as CV ≥40 (area under the curve 0.85) for all patients. The CPI was an independent risk for CV ≥40 (odds ratio 0.17, 95% confidence interval 0.04–0.50, P < 0.01). The optimal cut‐off point for CPI to predict a CV cut‐off value of 40 was equivalent to 0.81 (area under the curve 0.80).ConclusionsA CV of 40 discriminates unstable GV and hypoglycemia from stable GV in Japanese outpatients with type 2 diabetes. Impaired insulin secretion might affect the stability of GV.     

Diagnostic value of combined islet antigen-reactive T cells and autoantibodies assays for type 1 diabetes mellitus

Aims/IntroductionType 1 diabetes mellitus is a T cell‐mediated autoimmune disease. However, the determination of the autoimmune status of type 1 diabetes mellitus relies on islet autoantibodies (Abs), as T‐cell assay is not routinely carried out. This study aimed to investigate the diagnostic value of combined assay of islet antigen‐specific T cells and Abs in type 1 diabetes mellitus patients.Materials and MethodsA total of 54 patients with type 1 diabetes mellitus and 56 healthy controls were enrolled. Abs against glutamic acid decarboxylase (GAD), islet antigen‐2 and zinc transporter 8 were detected by radioligand assay. Interferon‐γ‐secreting T cells responding to glutamic acid decarboxylase 65 and C‐peptide (CP) were measured by enzyme‐linked immunospot.ResultsThe positive rate for T‐cell responses was significantly higher in patients with type 1 diabetes mellitus than that in controls (P < 0.001). The combined positive rate of Abs and T‐cell assay was significantly higher than that of Abs assay alone (85.2% vs 64.8%, P = 0.015). A significant difference in fasting CP level was found between the T⁺ and T^– groups (0.07 ± 0.05 vs 0.11 ± 0.09 nmol/L, P = 0.033). Furthermore, levels of fasting CP and postprandial CP were both lower in the Ab⁻T⁺ group than the Ab⁻T⁻ group (fasting CP 0.06 ± 0.05 vs 0.16 ± 0.12 nmol/L, P = 0.041; postprandial CP 0.12 ± 0.13 vs 0.27 ± 0.12 nmol/L, P = 0.024).ConclusionsEnzyme‐linked immunospot assays in combination with Abs detection could improve the diagnostic sensitivity of autoimmune diabetes.     

Persons with type 2 diabetes and high insulin persistence were associated with a lower risk of mortality: A nationwide retrospective cohort study

Aims/IntroductionStudies assessing the long‐term outcomes of insulin persistence are scant. We compared the risk of all‐cause mortality among patients with different degrees of insulin persistence.Materials and MethodsIn total, 293,210 patients with type 2 diabetes mellitus undergoing insulin therapy were enrolled during 2002–2014. Insulin persistence was defined as continual insulin treatment without a 90‐day gap of discontinuation in the 2‐year observation period. Mortality rates were compared between 111,220 patients with ≥90% insulin persistence and 111,220 matched patients with <90% insulin persistence during the observational period.ResultsDuring the mean 5.37‐year follow‐up period, the mortality rates were 58.26 and 73.21 per 1,000 person‐years for patients with ≥90% and <90% of insulin persistence. The adjusted hazard ratio for mortality was 0.80 (95% confidence interval 0.79–0.81, P < 0.001). Patients with high insulin persistence had significantly lower risks than did those with low insulin persistence of death due to hypertension, diabetes, cardiovascular disease, liver disease, kidney disease, respiratory disease, sepsis and cancer.ConclusionsThis study showed that patients with ≥90% insulin persistence were associated with lower risks of all‐cause mortality than did patients with <90% insulin persistence.     

Randomized trial of an intensified,multifactorial intervention in patients with advanced-stage diabetic kidney disease: Diabetic Nephropathy Remission and Regression Team Trial in Japan (DNETT-Japan)

Aims/IntroductionWe evaluated the efficacy of multifactorial intensive treatment (IT) on renal outcomes in patients with type 2 diabetes and advanced‐stage diabetic kidney disease (DKD).Materials and MethodsThe Diabetic Nephropathy Remission and Regression Team Trial in Japan (DNETT‐Japan) is a multicenter, open‐label, randomized controlled trial with a 5‐year follow‐up period. We randomly assigned 164 patients with advanced‐stage diabetic kidney disease (urinary albumin‐to‐creatinine ratio ≥300 mg/g creatinine, serum creatinine level 1.2–2.5 mg/dL in men and 1.0–2.5 mg/dL in women) to receive either IT or conventional treatment. The primary composite outcome was end‐stage kidney failure, doubling of serum creatinine or death from any cause, which was assessed in the intention‐to‐treat population.ResultsThe IT tended to reduce the risk of primary end‐points as compared with conventional treatment, but the difference between treatment groups did not reach the statistically significant level (hazard ratio 0.69, 95% confidence interval 0.43–1.11; P = 0.13). Meanwhile, the decrease in serum low‐density lipoprotein cholesterol level and the use of statin were significantly associated with the decrease in primary outcome (hazard ratio 1.14; 95% confidence interval 1.05–1.23, P < 0.001 and hazard ratio 0.53, 95% confidence interval 0.28–0.998, P < 0.05, respectively). The incidence of adverse events was not different between treatment groups.ConclusionsThe risk of kidney events tended to decrease by IT, although it was not statistically significant. Lipid control using statin was associated with a lower risk of adverse kidney events. Further follow‐up study might show the effect of IT in patients with advanced diabetic kidney disease.     

Different interaction of onset age and duration of type 1 diabetes on the dynamics of autoantibodies to insulinoma-associated antigen-2 and zinc transporter 8

Aims/IntroductionThis study aimed to investigate the dynamics associated with autoantibodies to insulinoma‐associated antigen‐2 (IA‐2A) and zinc transporter 8 (ZnT8A) relating to the onset age and disease duration in patients with type 1 diabetes.MethodsUsing bridging‐type enzyme‐linked immunosorbent assay, IA‐2A, ZnT8A and glutamic acid decarboxylase autoantibodies were evaluated in 269 patients with type 1 diabetes (median onset age 18.2 years, range 0.8–86 years; median diabetes duration 7 years, range 0–58 years). We then compared the prevalence of these autoantibodies among the different age groups, along with the duration of diabetes using the Cochran–Armitage trend test and multivariate logistic regression analysis.ResultsThe prevalence of IA‐2A, ZnT8A and glutamic acid decarboxylase autoantibodies in patients with duration of ≤3 years was 41.1, 36.7 and 72.2%, respectively, with 80.0% expressing one or more of these autoantibodies. This prevalence declined according to the disease duration (P < 0.005). Both IA‐2A and ZnT8A were more frequently observed in younger patients, whereas glutamic acid decarboxylase autoantibodies was more common in older patients. Multivariate logistic regression analysis showed that there was a significant interaction between the onset age and duration of diabetes in patients diagnosed when aged ≤10 years regarding all anti‐islet autoantibodies (P < 0.05). However, for patients diagnosed in the middle tertile (aged 11–30 years), the interaction was significant only for ZnT8A, and for those with late‐onset diabetes (aged ≥31 years) only for IA‐2A.ConclusionsThe current study showed that the rate of disappearance of anti‐islet autoantibodies is faster in patients aged ≤10 years, and that even though both proteins are localized in the insulin granule membrane, humoral autoimmunity to IA‐2 and ZnT8 differs according to the age of onset.     

Serum vaspin levels are positively associated with diabetic retinopathy in patients with type 2 diabetes mellitus

Aims/IntroductionVaspin is linked to obesity and its metabolic abnormalities. However, the role of vaspin serum levels in diabetic retinopathy (DR) is unknown. In the present study, we investigated the association between serum levels of vaspin and both DR and vision‐threatening DR.Materials and MethodsThis was a cross‐sectional single‐center observational study from December 2018 to September 2019. We evaluated circulating serum levels of vaspin in 372 participants with type 2 diabetes. DR was screened through detailed ocular examination. DR patients were also divided two groups: vision‐threatening DR and non‐vision‐threatening DR. The relationship between vaspin and DR was investigated by univariate and multivariate logistic regression analyses, and the results are shown as odds ratios with 95% confidence intervals.ResultsThe vaspin serum levels of 372 patients were obtained, with a median value of 1.50 ng/mL (interquartile range 0.94–2.18 ng/mL). The median age of those patients was 53 years (interquartile range 44–62 years), and 44.4% were women. Patients with DR and VDTR had significantly increased vaspin serum levels (P < 0.001 andP < 0.001). A multivariable regression model found that patients with high levels of vaspin were approximately 1.85‐fold (odds ratio for per unit increase 1.85, 95% confidence interval 1.43–2.55; P < 0.001) more likely to experience DR, and 3.76‐fold (odds ratio for per unit increase 3.76, 95% confidence interval 2.05–6.55; P < 0.001) more likely to experience VTDR. The predictive value of vaspin was stronger in women than in men.ConclusionHigher vaspin serum levels were associated with an increased risk of DR and VDTR in patients with type 2 diabetes, which showed that vaspin is an important indicator factor for DR.     

High prevalence and clinical impact of dynapenia and sarcopenia in Japanese patients with type 1 and type 2 diabetes: Findings from the Impact of Diabetes Mellitus on Dynapenia study

Aims/IntroductionThe present study aimed to clarify the prevalence and clinical characteristics of sarcopenia and dynapenia, which are muscle weakness with and without low muscle mass, respectively, in Japanese patients with type 1 diabetes mellitus and type 2 diabetes mellitus.Materials and MethodsThis cross‐sectional study enrolled 1,328 participants with type 1 diabetes (n = 177), type 2 diabetes (n = 645) and without diabetes (n = 506). Sarcopenia was defined as a low grip strength and slow gait speed with low skeletal muscle mass index, whereas dynapenia was defined as low strengths of grip and knee extension with a normal skeletal muscle mass index. Participants without sarcopenia and dynapenia were defined as robust.ResultsAmong participants aged ≥65 years, sarcopenia and dynapenia were observed in 12.2% and 0.5% of individuals without diabetes, 42.9% and 11.4% of type 1 diabetes patients, and 20.9% and 13.9% of type 2 diabetes patients. In both type 1 diabetes and type 2 diabetes patients, sarcopenic patients were significantly older and thinner, and showed a significantly higher rate of diabetic neuropathy than robust patients. In patients with type 1 diabetes and type 2 diabetes, dynapenic patients were older, and showed a higher rate of diabetic neuropathy and lower estimated glomerular filtration rate than robust patients. Patients complicated with sarcopenia and dynapenia showed a significantly lower physical quality of life and higher rate of incidental falls than robust patients.ConclusionsSarcopenia and dynapenia were more frequent in patients with type 1 diabetes and type 2 diabetes than in individuals without diabetes, which might contribute to their impaired quality of life and incidental falls.     

High urinary glucose is associated with improved renal prognosis in patients with diabetes mellitus

Aims/IntroductionThe relationship between renal function and urinary glucose is poorly understood in diabetes patients who are not using sodium–glucose cotransporter 2 inhibitors. This study aimed to investigate the association of urinary glucose excretion with renal function prognosis in such patients.Materials and MethodsThis retrospective cohort study included 1,172 patients with type 1 or 2 diabetes mellitus. Patients were recruited and data were collected between 1 January 2007 and 31 December 2011; follow‐up data were collected until 30 June 2015. The primary outcome was set as a 30% decline in estimated glomerular filtration rate relative to baseline. The relationship between this outcome and urinary glucose was investigated using Cox proportional hazards model. For analysis, patients were categorized into two groups: urinary glucose <5 g/day or ≥5 g/day. Interaction terms were analyzed.ResultsMultivariate analysis showed that the prognosis of renal function was significantly better in patients with high urinary glucose (≥5 g/day; adjusted hazard ratio 0.58, 95% confidence interval 0.35–0.96; P = 0.034). Significant interactions were observed between high urinary glucose and male sex (hazard ratio 0.33, 95% confidence interval 0.14–0.74; P = 0.007), and between high urinary glucose and longer duration of diabetes (≥10 years; hazard ratio 0.25, 95% confidence interval 0.11–0.58; P = 0.001).ConclusionsThe present study suggests that high urinary glucose is associated with prognosis in diabetes patients not taking sodium–glucose cotransporter 2 inhibitors. Measurement of 24‐h urinary glucose excretion might have clinical utility for predicting renal prognosis.     

Association between the triglyceride–glucose index and diabetic nephropathy in patients with type 2 diabetes: A cross-sectional study

Aims/IntroductionThe triglyceride–glucose (TyG) index has been proposed as a reliable and simple marker of insulin resistance. We investigated the association between TyG index and diabetic nephropathy (DN) in patients with type 2 diabetes.Materials and MethodsA consecutive case series of 682 adult patients with type 2 diabetes hospitalized in the Department of Endocrinology at the Tongji Hospital (Wuhan, Hubei, China) from January 2007 to December 2009 was included in this cross‐sectional analysis. Receiver operating characteristics curve analysis, correlation analysis and multiple logistic regression analysis were carried out.ResultsA total of 232 (34.0%) participants were identified with DN. Compared with the non‐DN group, the DN group had longer disease duration, and higher bodyweight, systolic blood pressure, diastolic blood pressure, glycated hemoglobin, triglycerides, total cholesterol, serum uric acid, 24 h‐urinary albumin, TyG index and homeostasis model assessment 2 estimates for insulin resistance (HOMA2‐IR; P < 0.05 for each). The TyG index with an optimal cut‐off point >9.66 showed a higher area under the receiver operating characteristic curve of 0.67 (P = 0.002) than HOMA2‐IR (area under the curve 0.61, P = 0.029) on receiver operating characteristic curve analysis for DN identification. Additionally, the TyG index positively correlated with the levels of metabolic indicators (bodyweight, glycated hemoglobin, triglycerides, total cholesterol, serum uric acid, fasting glucose and HOMA2‐IR) and natural logarithmic 24 h‐urinary albumin (P < 0.05 for each), but not natural logarithm of estimated glomerular filtration rate. On multiple regression analysis, an increased TyG index was shown to be an independent risk factor (odds ratio 1.91, P = 0.001) for DN.ConclusionsThe TyG index was independently associated with DN in patients with type 2 diabetes, and was a better marker than HOMA2‐IR for identification of DN in type 2 diabetes patients.     

Two types of fulminant type 1 diabetes mellitus: Immune checkpoint inhibitor-related and conventional

Fulminant type 1 diabetes is characterized by a markedly rapid onset of hyperglycemia ¹ . According to the “criteria for the definite diagnosis of fulminant type 1 diabetes mellitus (2012)” ² , fulminant type 1 diabetes mellitus is confirmed when all the following three findings are present: (i) occurrence of diabetic ketosis or ketoacidosis soon after (within approximately 7 days) the onset of hyperglycemic symptoms (elevation of urinary and/or serum ketone bodies at the first visit); (ii) plasma glucose level ≥16.0 mmol/L (≥288 mg/dL) and glycated hemoglobin (HbA1c) level <8.7% (National Glycohemoglobin Standardization Program value; this value is not applicable for patients with previously diagnosed glucose intolerance) at the first visit; and (iii) urinary C‐peptide excretion <10 μg/day or fasting serum C‐peptide level <0.3 ng/mL (<0.10 nmol/L) and <0.5 ng/mL (<0.17 nmol/L) after intravenous glucagon (or after meal) load at onset. A rapid course in the medical history is being indicated by (i) and (ii); that is, (hyper) glycemia and almost normal HbA1c levels show a rapid rise in blood glucose concentration in the laboratory findings. This means that (i) and (ii) are synonymous with each other. The rapid rise in blood glucose concentration is indirectly proven by the relatively low (near normal) level of HbA1c at the onset, and in a few patients, the blood glucose levels before the onset were measured, and the rapid rise in blood glucose concentration was directly proven ³ . Of course, (iii) indicates complete destruction of β‐cells.Recently, antibodies to immune checkpoint inhibitors (ICIs) have been widely used as cancer immunotherapy, and many patients who were diagnosed with fulminant type 1 diabetes have been reported during the treatment ⁴ . Four patients have also been reported in this journal. The first patient is the first reported patient with fulminant type 1 diabetes in Asia that developed during ICI therapy ⁵ . The second patient developed fulminant type 1 diabetes during ICI treatment, but his endogenous insulin secretory capacity slightly improved with the discontinuation of ICI ⁶ . The third patient developed fulminant type 1 diabetes during the administration of ICI of programmed cell death 1 ligand 1 antibody, but not programmed cell death 1 (PD‐1) antibody ⁷ . The fourth patient showed a particularly rapid decrease in insulin secretory capacity during the development of fulminant type 1 diabetes ⁸ . In this article, we discuss the similarities and differences between fulminant type 1 diabetes after administration of ICIs and conventional fulminant type 1 diabetes.First, regarding the rate of β‐cell destruction, it might progress more rapidly in conventional fulminant type 1 diabetes than in ICI‐related fulminant type 1 diabetes. One rationale is that the rapid decline of C‐peptide levels was more frequently observed in conventional fulminant type 1 diabetes than in ICI‐related fulminant type 1 diabetes, when C‐peptide levels were directly and continuously measured. Sekine et al. ³ analyzed presymptomatic preserved serum with conventional fulminant type 1 diabetes patients, and reported that C‐peptide concentrations decreased from the normal value to below the measurement sensitivity in just 1 day in a patient. We have previously reported that a patient suffered from fulminant type 1 diabetes 6 days after hypoglycemia with endogenous hyperinsulinemia, which might be due to the destruction of β‐cells ⁹ . As the onset is almost unpredictable with conventional fulminant type 1 diabetes, there are few reports in which the course of C‐peptide levels can be followed, including before the onset. In contrast, in ICI‐related fulminant type 1 diabetes, there have been multiple reports in which blood C‐peptide levels decreased from the normal value to below the measurement sensitivity in approximately 2 weeks ⁴ , ⁵ , even though a patient whose insulin secretion decreased in just 1 day was also reported ⁸ . Another rationale is that, in a larger number of patients, HbA1c levels at the onset of diabetes were higher in ICI‐related type 1 diabetes patients than in conventional fulminant type 1 diabetes patients ⁴ . The former was 8.1% ⁴ , and the latter was 6.8% ² on average. It is speculated that low (near normal) HbA1c levels correlate with a high rate of blood glucose elevation and also with a high rate of β‐cell destruction at the onset of type 1 diabetes. In the aforementioned patient ³ , the HbA1c level at onset was 5.9%, indicating that β‐cell destruction progressed particularly rapidly. As there are some differences in HbA1c values at the onset of both conventional fulminant type 1 diabetes and ICI‐related fulminant type 1 diabetes, the rate of β‐cell destruction might vary within each subtype. It is also noted that a proportion of patients with ICI‐related diabetes fulfill the criteria for acute‐onset type 1 diabetes. Figure 1 illustrates type 1 diabetes in relation to the rapidness of progression and residual β‐cell mass at onset.Open in a separate windowFigure 1Schematic figure of type 1 diabetes in relation to the rapidness of progression and residual β‐cell mass at onset. β‐Cells are destroyed very rapidly and are almost absent at onset in conventional fulminant type 1 diabetes, but are destroyed and remain relatively slowly in acute‐onset type 1 diabetes. The immune checkpoint inhibitors (ICI)‐related fulminant type 1 diabetes is placed between the two established subtypes from both aspects. HbA1c, glycated hemoglobin.Next, the mechanism of β‐cell destruction might be common, at least in part, in both conventional fulminant type 1 diabetes and ICI‐related fulminant type 1 diabetes patients. Pathologically, mononuclear cell infiltration is observed both in the islets and exocrine areas, suggesting that cell‐mediated immunity is mainly involved ¹⁰ . As for the trigger, viral infection has been primarily considered in conventional fulminant type 1 diabetes patients (Table 1). Preceding common cold‐like symptoms is frequently observed in conventional fulminant type 1 diabetes ¹ . β‐Cell damage infected with encephalomyocarditis virus is a model in mice, and enterovirus and cytomegalovirus are candidates in humans ¹ . However, the molecular mechanism of β‐cell destruction has just begun to be elucidated. In contrast, in ICI‐related fulminant type 1 diabetes, blocking of the PD‐1/programmed cell death 1 ligand 1 pathway is the definite trigger (Table 1). As fulminant type 1 diabetes develops in programmed cell death 1 ligand 1 antibody administration, as well as in PD‐1 antibody ⁸ , it seems important to block this pathway, but not each molecule. Interestingly, β‐cell damage ensues after the initial dose of ICI, but often after repeated doses of ICI in ICI‐related fulminant type 1 diabetes ⁴ , ⁵ , ⁶ , ⁷ , ⁸ . This suggests that β‐cell destruction could be triggered only when an additional element overlaps with ICI administration. The next question was whether immune checkpoint molecules would be involved in the destruction of β‐cells in conventional fulminant type 1 diabetes. We have had no clear evidence of this issue, but it is reasonable to expect that these molecules are involved in T‐cell activation, even in conventional fulminant type 1 diabetes.Table 1Two subtypes of fulminant type 1 diabetes

Blood pressure after treatment with sodium–glucose cotransporter 2 inhibitors influences renal composite outcome: Analysis using propensity score-matched models

Aims/IntroductionSodium–glucose cotransporter 2 inhibitors (SGLT2i) improve renal outcome in patients with type 2 diabetes mellitus, but the mechanism is not fully understood. The aim of this retrospective study was to assess the association of achieved blood pressure with renal outcomes in Japanese type 2 diabetes mellitus patients with chronic kidney disease.Materials and MethodsWe assessed 624 Japanese type 2 diabetes mellitus patients with chronic kidney disease taking SGLT2i for >1 year. The patients were classified as those with post‐treatment mean arterial pressure (MAP) of ≥92 mmHg (n = 344) and those with MAP of <92 mmHg (n = 280) for propensity score matching (1:1 nearest neighbor match with 0.04 of caliper value and no replacement). The end‐point was a composite of progression of albuminuria or a decrease in the estimated glomerular filtration rate by ≥15% per year.ResultsBy propensity score matching, a matched cohort model was constructed, including 201 patients in each group. The incidence of renal composite outcome was significantly lower among patients with MAP of <92 mmHg than among patients with MAP of ≥92 mmHg (n = 11 [6%] vs n = 26 [13%], respectively, P = 0.001). The change in estimated glomerular filtration rate was similar in the two groups; however, the change in the albumin‐to‐creatinine ratio was significantly larger in patients with MAP of <92 mmHg.ConclusionsIn Japanese type 2 diabetes mellitus patients with chronic kidney disease, blood pressure after SGLT2i administration influences the renal composite outcome. Blood pressure management is important, even during treatment with SGLT2i.     

Appropriate physical activity and dietary intake achieve optimal metabolic control in older type 2 diabetes patients

Aims/Introduction

The aim of the present study was to investigate an appropriate level of physical activity and optimal dietary intake in older type 2 diabetes patients.

Materials and Methods

The cross‐sectional study enrolled 210 older type 2 diabetes patients. Participants were interviewed to obtain information on physical activity, 24‐h dietary recall and typical weekly dietary patterns. Anthropometric measurements, and biochemical analysis of blood and urine were determined.

Results

Moderate physical activity (either moderate leisure‐time physical activity or moderate physical activity level) and diet with protein intake of ≥0.8 g/kg/day were associated with lower glycated hemoglobin and triglyceride, higher high‐density lipoprotein, lower waist circumference, body mass index and body fat, as well as better serum magnesium and albumin levels in older diabetic patients. In contrast, inadequate protein intake was correlated with higher glycated hemoglobin, triglyceride, body fat percentage, waist circumference and body mass index. In addition, high physical activity with inadequate protein and magnesium intake might exacerbate magnesium deficiency, resulting in poor glycemic control in older diabetic patients. Furthermore, low physical activity and inadequate protein intake were linked with poor glycemic control, and lower high‐density lipoprotein, and higher triglyceride, body fat percentage, waist circumference and body mass index.

Conclusions

Moderate physical activity and adequate dietary protein intake (≥0.8 g/kg/day) might be the optimal recommendation for better metabolic control in older adults with type 2 diabetes.     

Recent evidence in the etiology and treatment for diabetic kidney disease

Etiology and therapeutic targets of diabetic nephropathy.

Diabetic kidney disease (DKD) is a microvascular complication of diabetes and the leading cause of end‐stage renal disease (ESRD) in many countries. Recently, accumulated evidence has provided new insights into the etiology and treatment for DKD.Albuminuria and decline of estimated glomerular filtration rate (eGFR) are characteristic features of DKD, and a risk factor for progression to ESRD and cardiovascular diseases (CVD). Baseline data of Japan Diabetes Complication and its A prevention prospective study showed that the prevalence of albuminuria is approximately 30% in Japanese patients with type 2 diabetes ¹ . This value is lower compared with the data of previous studies, suggesting that the prevalence of albuminuria has recently been decreasing. Yokoyama et al. ² analyzed the prognosis of DKD without albuminuria (non‐albuminuric DKD) in their follow‐up study (JDDM54). They divided Japanese patients with type 2 diabetes into four DKD phenotypes on the basis of albuminuria (>30 mg/g creatinine) and reduced eGFR (<60 mL/min/1.73 m²) at baseline: (i) no‐DKD; (ii) albuminuric DKD without reduced eGFR; (iii) non‐albuminuric DKD with reduced eGFR; and (iv) albuminuric DKD with reduced eGFR. As a result, in non‐albuminuric DKD, the risks of death or CVD were not higher than those with the no‐DKD phenotype, and the annual decline in eGFR was slower than in other DKD phenotypes during the mean follow‐up period of 9.7 years. They conclude that non‐albuminuric DKD did not have a higher risk of death, CVD or renal function decline than the other DKD phenotypes. It is important to measure albuminuria for early diagnosis of DKD, and prevention of ESRD and CVD in patients with diabetes.Hypertension and dyslipidemia are involved in the etiology of DKD, in addition to hyperglycemia ³ , ⁴ , ⁵ . As for the treatment of dyslipidemia, lowering of low‐density lipoprotein cholesterol by statin has been shown to reduce the risk of ESRD in type 2 diabetes patients with overt proteinuria ⁴ . Various mechanisms are believed to be involved in the pathogenesis of DKD, including genetic factors, activation of polyol pathway and protein kinase C, glomerular hypertension and hyperfiltration, accumulation of advanced glycation end‐products, oxidative stress, overexpression of transforming growth factor‐β, and the inflammatory process (microinflammation) ⁶ . These mechanisms are potential candidates for the therapeutic target of DKD (Figure 1). Recently, it has been reported that inflammasomes are implicated in the pathogenesis of renal inflammation in DKD ⁷ . Pattern recognition receptors, including nucleotide‐binding oligomerization domain‐like receptors, recognize exogeneous and endogenous ligands to stimulate inflammasome assembly followed by caspase‐1 activation, and secretion of interleukin‐1β and interleukin‐18. We previously found that serum and urinary levels of interleukin‐18 are elevated and positively corelated with albuminuria in patients with type 2 diabetes, suggesting that inflammasome plays a role in the pathogenesis of DKD ⁶ . Tumor necrosis factor is one of the major inflammatory cytokines. Gohda et al ⁸ . reported that increased concentrations of serum tumor necrosis factor receptors are positively associated with albuminuria, and negatively associated with the eGFR in patients with type 2 diabetes. They suggest that an increase in serum tumor necrosis factor receptors might result from their increased systemic production in the recent article.Open in a separate windowFigure 1Etiology and therapeutic targets of diabetic kidney disease (DKD). Hyperglycemia induces diabetic nephropathy through various mechanisms, including activation of the polyol pathway and protein kinase C (PKC), glomerular hypertension and hyperfiltration, glycation, oxidative stress, and the inflammatory process. These pathways are therapeutic targets of nephropathy. In addition to renin–angiotensin system (RAS) inhibitor, aldose reductase inhibitor (ARI), PKC inhibitor, advanced glycation end‐product (AGE) inhibitor, mineralocorticoid receptor (MR) antagonist and nuclear factor erythroid 2‐related factor 2 (NRF2) activator are potential therapeutic drugs, and sodium–glucose cotransporter 2 (SGLT2) inhibitor and glucagon‐like peptide‐1 (GLP‐1R) agonist have been shown to be effective for DKD. IL‐1β, interleukin‐1β; NF‐κB, nuclear factor‐kB; P2XR, purinergic P2X receptors; TGF‐β, transformation growth factor‐β; VEGF, vascular endothelial growth factor.There has been accumulating evidence of renoprotective effects of sodium–glucose cotransporter 2 (SGLT2) inhibitors in patients with type 2 diabetes by cardiovascular outcome trials, including the Empagliflozin Cardiovascular Outcome Event Trial in Type 2 Diabetes Mellitus Patients‐Removing Excess Glucose (EMPA‐REG OUTCOME) trial, Canagliflozin Cardiovascular Assessment Study (CANVAS) program and Dapagliflozin Effect on Cardiovascular Events – Thrombolysis in Myocardial Infarction 58 (DECLAER‐TIMI 58). These trials strongly suggest the renoprotective effects of SGLT2 inhibitor in patients with type 2 diabetes ⁹ . Kadowaki et al. ¹⁰ reported that empagliflozin reduces the risk of development or progression of DKD in Asian patients with type 2 diabetes. Furthermore, Canagliflozin and Renal Endpoints in Diabetes with Established Nephropathy Clinical Evaluation (CREDENCE) showed that canagliflozin reduced the risk of primary renal outcome consisting of ESRD, doubling of serum creatinine and death from renal or CVD in patients with type 2 diabetes with overt poteinuria ¹¹ . There have been several postulated mechanisms of renoprotective actions of SGLT2 inhibitors, including the improvement of the impaired tubuloglomerular feedback system, in addition to the improvement of metabolic abnormalities ⁹ . In an animal experiment, Kimura et al. ¹² showed that canagliflozin reduced oxidative stress in diabetic rats.Glucagon‐like peptide‐1 (GLP‐1) is an incretin hormone that enhances insulin secretion from pancreatic β‐cells. Recent studies have shown that GLP‐1 receptor is expressed not only in the pancreas, but also in many organs. GLP‐1 has been shown to exert anti‐inflammatory effects in in vitro and in vivo studies. We previously showed in vitro that exenatide exerts an anti‐inflammatory effect by decreasing the expression of intercellular cell adhesion molecule‐1 in glomerular endothelial cells. Furthermore, exendin‐4 – a GLP‐1 receptor agonist – ameliorated albuminuria, glomerular hyperfiltration, glomerular hypertrophy, and mesangial matrix expansion in type 1 diabetic rats with anti‐inflammatory and anti‐oxidative effects ¹³ . Weiqin et al. ¹⁴ reported that protein kinase C and protein kinase A are involved in renoprotective effects of GLP‐1 from their animal experiments. In clinical trials, liraglutide and semaglutide have shown renoprotective effects in patients with type 2 diabetes. In the Liraglutide Effect and Action In Diabetes: Evaluation of Cardiovascular Outcome Risks (LEADER) trial ¹⁵ , administration of liraglutide significantly suppressed the nephropathy‐related outcomes (onset of macroalbuminuria, doubling of the serum creatinine level and eGFR ≤45 mL/min/1.73 m², need for continuous renal replacement therapy or death from renal disease).Growing evidence has provided new insights and future direction for the etiology and treatment of DKD. This evidence might accelerate the development of new drugs for DKD, and GLP‐1 receptor agonist and SGLT2 inhibitor would improve the prognosis of DKD.     

East Asian diet-mimicking diet plan based on the Mediterranean diet and the Dietary Approaches to Stop Hypertension diet in adults with type 2 diabetes: A randomized controlled trial

Aims/IntroductionUsing an investigational diet plan based on the Mediterranean diet and the Dietary Approaches to Stop Hypertension diet comprised of substitute ingredients that mimic the average East Asian diet, this study assessed the glycemic benefits in comparison with a food exchange system‐based diet in established type 2 diabetes patients.Materials and MethodsThis was a 12‐week, open‐label randomized clinical trial carried out among 60 Korean adults with type 2 diabetes having a median body mass index of 23.5 kg/m². Glycemic benefits in the investigational diet (group A) were compared with those obtained with a food exchange system‐based diet, either in the form of ready meals provided to participants (group B) or not (group C). The primary end‐point was changes in glycated hemoglobin from baseline to week 12.ResultsChanges in glycated hemoglobin (%) from baseline to week 12 were −0.97 ± 0.97 in group A (vs group B, P = 0.085 in the full analysis set, and P = 0.028 in the per‐protocol set; vs group C, P = 0.030 in the full analysis set and P = 0.020 in the per‐protocol set), −0.51 ± 0.65 in group B (vs group C, P > 0.05 in the full analysis set and the per‐protocol set), and −0.36 ± 0.74 in group C. Decreases from baseline in body mass index, waist circumference and blood pressure were greater in group A than in group C.ConclusionWith the provision of ready meals, the glycemic benefits of the investigational diet plan were demonstrable over a self‐prepared food exchange system‐based diet in Korean adults with established type 2 diabetes.