Glucagon secretion and its association with glycaemic control and ketogenesis during sodium-glucose cotransporter 2 inhibition by ipragliflozin in people with type 1 diabetes: Results from the multicentre, open-label, prospective study.

AIM: Clinical trials showed the efficacy of sodium-glucose cotransporter 2 inhibitors for type 1 diabetes (T1D) by significant reductions in body weight and glycaemic variability, but elevated susceptibility to ketoacidosis via elevated glucagon secretion was a potential concern. The Suglat-AID evaluated glucagon responses and its associations with glycaemic control and ketogenesis before and after T1D treatment with the sodium-glucose cotransporter 2 inhibitor, ipragliflozin. METHODS: Adults with T1D (n = 25) took 50-mg open-labelled ipragliflozin daily as adjunctive to insulin. Laboratory/clinical data including continuous glucose monitoring were collected until 12 weeks after the ipragliflozin initiation. The participants underwent a mixed-meal tolerance test (MMTT) twice [before (first MMTT) and 12 weeks after ipragliflozin treatment (second MMTT)] to evaluate responses of glucose, C-peptide, glucagon and ß-hydroxybutyrate. RESULTS: The area under the curve from fasting (0 min) to 120 min (AUC0-120min) of glucagon in second MMTT were significantly increased by 14% versus first MMTT. The fasting and postprandial ß-hydroxybutyrate levels were significantly elevated in second MMTT versus first MMTT. The positive correlation between postprandial glucagon secretion and glucose excursions observed in first MMTT disappeared in second MMTT, but a negative correlation between fasting glucagon and time below range (glucose, <3.9 mmol/L) appeared in second MMTT. The percentage changes in glucagon levels (fasting and AUC0-120min) from baseline to 12 weeks were significantly correlated with those in ß-hydroxybutyrate levels. CONCLUSIONS: Ipragliflozin treatment for T1D increased postprandial glucagon secretion, which did not exacerbate postprandial hyperglycaemia but might protect against hypoglycaemia, leading to reduced glycaemic variability. The increased glucagon secretion might accelerate ketogenesis when adequate insulin is not supplied.

Æ©excessA1C index, the sum of yearly excess HbA1c values during the total period of diabetes, may have the potential to predict retinopathy by a linear regression setting regardless of duration in type 1 diabetes: a subgroup analysis of DCCT/EDIC data.

Aims: To find an index of glycemic exposure that predicts retinopathy by a simple regression setting regardless of duration in type 1 diabetes which might be useful for the care of diabetes. Materials and methods: To exclude the possible disturbing effect of metabolic memory, we examined a subgroup of patients with glycohemoglobin A1c (A1C) data for the total period of type 1 diabetes selected from the Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications data. Three indices-(1) mean value of yearly A1C (mA1C), (2) sum of yearly A1C values (Æ©A1C), and (3) sum of yearly A1C values above 6.5% (Æ©excessA1C)-were assessed as potential candidates. Development of retinopathy was defined by ≥ 3-steps' progression of retinopathy from baseline. Results: The areas under the receiver operating characteristics curves of the indices for development of retinopathy at years 5, 9, and 13 after the onset of diabetes were the same: 0.8481, 0.8762, and 0.8213, respectively, indicating that each index was substantially capable of predicting development of retinopathy at each timepoint. Linear regression analyses showed that each index had significant and substantial linear relations to retinopathy at each timepoint: all P < 0.0001 for slopes; contribution rate R2 = 0.21 (year 5), 0.46 (year 9), and 0.48 (year 13) for each index. But only Æ©excessA1C index appeared to have similar linear relations to retinopathy at all three timepoints (interactions by timepoint: for slopes: P = 0.1393; for intercepts: P = 0.9366). Conclusion: Æ©excessA1C may have the potential to predict retinopathy by just one linear regression setting regardless of duration in type 1 diabetes.

Correction: Æ©excessA1C index, the sum of yearly excess HbA1c values during the total period of diabetes, may have the potential to predict retinopathy by a linear regression setting regardless of duration in type 1 diabetes: a subgroup analysis of DCCT/EDIC data.

[This corrects the article DOI: 10.1007/s13340-023-00654-w.].

Impact of COVID-19 pandemic on behavioral changes and glycemic control and a survey of telemedicine in patients with diabetes: A multicenter retrospective observational study.

AIMS/INTRODUCTION: To investigate whether the COVID-19 pandemic affected behavioral changes and glycemic control in patients with diabetes and to conduct a survey of telemedicine during the pandemic. MATERIALS AND METHODS: In this retrospective study, a total of 2,348 patients were included from 15 medical facilities. Patients were surveyed about their lifestyle changes and attitudes toward telemedicine. Hemoglobin A1c (HbA1c) levels were compared among before (from June 1 to August 31, 2019) and in the first (from June 1 to August 31, 2020) and in the second (from June 1 to August 31, 2021) year of the pandemic. A survey of physician attitudes toward telemedicine was also conducted. RESULTS: The HbA1c levels were comparable between 2019 (7.27 ± 0.97%), 2020 (7.28 ± 0.92%), and 2021 (7.25 ± 0.94%) without statistical difference between each of those 3 years. Prescriptions for diabetes medications increased during the period. The frequency of eating out was drastically reduced (51.7% in 2019; 30.1% in 2020), and physical activity decreased during the pandemic (48.1% in 2019; 41.4% in 2020; 43.3% in 2021). Both patients and physicians cited increased convenience and reduced risk of infection as their expectations for telemedicine, while the lack of physician-patient interaction and the impossibility of consultation and examination were cited as sources of concern. CONCLUSIONS: Our data suggest that glycemic control did not deteriorate during the COVID-19 pandemic with appropriate intensification of diabetes treatment in patients with diabetes who continued to attend specialized diabetes care facilities, and that patients and physicians shared the same expectations and concerns about telemedicine.

Onset of type 1 diabetes during bone growth period is associated with increased prevalence of bone fracture: A post-hoc analysis of a cross-sectional study.

In this single-center, cross-sectional study, we demonstrated that the prevalence of fracture was significantly higher in patients who onset type 1 diabetes during 0-4 years, and 10-14 years compared with adult-onset type 1 diabetes. We are aware that this study contains a lot of limitations including non-prospective study design and a small number of participants. However, the results of this study, if followed by a larger cohort study, could provide important insights into the increased risk of fracture in patients with type 1 diabetes, and suggest the need for attention and perhaps early intervention for patients with type 1 diabetes who developed during these periods.

Fibroblast growth factor 23 and kidney function in patients with type 1 diabetes.

Diabetic kidney disease (DKD) is a key determinant of morbidity and mortality in patients with type 1 diabetes (T1D). Identifying factors associated with early glomerular filtration rate (GFR) decline in T1D is important in prevention or early intervention for DKD. This study investigated whether phosphate metabolism, including fibroblast growth factor 23 (FGF23) is associated with the kidney function of patients with T1D. We randomly recruited 118 patients with T1D with a normal or mildly impaired kidney function [chronic kidney disease (CKD) stages of G1/G2, A1/A2], and measured their serum FGF23 levels. Serum FGF23 was significantly negatively associated with the estimated GFR (eGFR) (r = -0.292, P = 0.0016), but not urinary albumin creatinine ratio (UACR), and positively associated with serum phosphate (Pi; r = 0.273, P = 0.0027). Serum FGF23 increased with decreasing eGFR quartiles (P for linear trend = 0.0371), while FGF23 was modestly higher in the higher quartiles of UACR (not statistically significant). The multiple linear regression analysis also showed a significant inverse association between FGF23 and eGFR (Model 1: ß = -0.149, P = 0.0429; Model 2: ß = -0.141, P = 0.0370). The association remained significant after adjustment for Pi. We identified that FGF23 was inversely associated with the eGFR in T1D patients with a normal or mildly impaired kidney function.

Prevalence of bone fracture and its association with severe hypoglycemia in Japanese patients with type 1 diabetes.

INTRODUCTION: Type 1 diabetes (T1D) is associated with higher fracture risk. However, few studies have investigated the relationship between severe hypoglycemia and fracture risk in patients with T1D, and the results are controversial. Besides, none has investigated the risk factors for fracture in Asian patients with T1D. The aim of the present study was to investigate the prevalence of bone fracture and its relationship between severe hypoglycemia and other risk factors in Japanese patients with T1D. RESEARCH DESIGN AND METHODS: The single-center cross-sectional study enrolled 388 Japanese patients with T1D (mean age, 45.2 years; women, 60.4%; mean duration of diabetes, 16.6 years) between October 2019 and April 2020. The occurrence and circumstances of any fracture after the diagnosis of T1D were identified using a self-administered questionnaire. The main outcomes were any anatomic site of fracture and fall-related fracture. Severe hypoglycemia was defined as an episode of hypoglycemia that required the assistance of others to achieve recovery. RESULTS: A total of 92 fractures occurred in 64 patients, and 59 fractures (64%) were fall-related. Only one participant experienced fracture within the 10 years following their diagnosis of diabetes. In logistic regression analysis, the multivariate-adjusted ORs (95% CIs) of a history of severe hypoglycemia were 2.11 (1.11 to 4.09) for any fracture and 1.91 (0.93 to 4.02) for fall-related fracture. Fourteen of 18 participants with multiple episodes of any type of fracture had a history of severe hypoglycemia (p<0.001 vs no fracture). CONCLUSIONS: We have shown that a history of severe hypoglycemia is significantly associated with a higher risk of bone fracture in Japanese patients with T1D.

Performance evaluation of case definitions of type 1 diabetes for health insurance claims data in Japan.

BACKGROUND: No case definition of Type 1 diabetes (T1D) for the claims data has been proposed in Japan yet. This study aimed to evaluate the performance of candidate case definitions for T1D using Electronic health care records (EHR) and claims data in a University Hospital in Japan. METHODS: The EHR and claims data for all the visiting patients in a University Hospital were used. As the candidate case definitions for claims data, we constructed 11 definitions by combinations of International Statistical Classification of Diseases and Related Health Problems, Tenth Revision. (ICD 10) code of T1D, the claims code of insulin needles for T1D patients, basal insulin, and syringe pump for continuous subcutaneous insulin infusion (CSII). We constructed a predictive model for T1D patients using disease names, medical practices, and medications as explanatory variables. The predictive model was applied to patients of test group (validation data), and performances of candidate case definitions were evaluated. RESULTS: As a result of performance evaluation, the sensitivity of the confirmed disease name of T1D was 32.9 (95% CI: 28.4, 37.2), and positive predictive value (PPV) was 33.3 (95% CI: 38.0, 38.4). By using the case definition of both the confirmed diagnosis of T1D and either of the claims code of the two insulin treatment methods (i.e., syringe pump for CSII and insulin needles), PPV improved to 90.2 (95% CI: 85.2, 94.4). CONCLUSIONS: We have established a case definition with high PPV, and the case definition can be used for precisely detecting T1D patients from claims data in Japan.

The Prognosis of Patients With Type 2 Diabetes and Nonalbuminuric Diabetic Kidney Disease Is Not Always Poor: Implication of the Effects of Coexisting Macrovascular Complications (JDDM 54).

OBJECTIVE: Nonalbuminuric diabetic kidney disease (DKD) has become the prevailing phenotype in patients with type 2 diabetes. However, it remains unclear whether its prognosis is poorer than that of other DKD phenotypes. RESEARCH DESIGN AND METHODS: A total of 2,953 Japanese patients with type 2 diabetes and estimated glomerular filtration rate (eGFR) ≥30 mL/min/1.73 m2, enrolled in an observational cohort study in 2004, were followed until 2015. On the basis of albuminuria (>30 mg/g creatinine) and reduced eGFR (<60 mL/min/1.73 m2) at baseline, participants were classified into the four DKD phenotypes-no-DKD, albuminuric DKD without reduced eGFR, nonalbuminuric DKD with reduced eGFR, and albuminuric DKD with reduced eGFR-to assess the risks of mortality, cardiovascular disease (CVD), and renal function decline. RESULTS: During the mean follow-up of 9.7 years, 113 patients died and 263 developed CVD. In nonalbuminuric DKD, the risks of death or CVD were not higher than those in no-DKD (adjusted hazard ratio 1.02 [95% CI 0.66, 1.60]) and the annual decline in eGFR was slower than in other DKD phenotypes. The risks of death or CVD in nonalbuminuric DKD without prior CVD were similar to those in no-DKD without prior CVD, whereas the risks in nonalbuminuric DKD with prior CVD as well as other DKD phenotypes were higher. CONCLUSIONS: Nonalbuminuric DKD did not have a higher risk of mortality, CVD events, or renal function decline than the other DKD phenotypes. In nonalbuminuric DKD, the presence of macrovascular complications may be a main determinant of prognosis rather than the renal phenotype.

Mental distress and health-related quality of life among type 1 and type 2 diabetes patients using self-monitoring of blood glucose: A cross-sectional questionnaire study in Japan.

AIMS/INTRODUCTION: The present multicenter, cross-sectional survey was initiated to evaluate self-monitoring of blood glucose (SMBG)-associated mental distress among patients with diabetes. MATERIALS AND METHODS: The survey was carried out in patients with type 1 diabetes and type 2 diabetes using SMBG recruited from 42 medical institutions. Profiles of Mood States 2 and diabetes therapy-related quality of life questionnaires were used to evaluate mood status and health-related quality of life. Two original questionnaires were also developed to evaluate SMBG 'importance,' 'painfulness' and 'confidence' among patients, and to evaluate physician attitudes to SMBG use. RESULTS: Questionnaires from 517 type 1 diabetes and 1,648 type 2 diabetes patients showed that 46.0% of type 1 diabetes and 37.5% of type 2 diabetes patients reported 'painfulness,' and that these patients reporting 'painfulness' showed significantly higher Profiles of Mood States 2 scores, lower diabetes therapy-related quality of life scores and higher glycated hemoglobin compared with those not reporting 'painfulness,' whereas the number of their daily SMBG tests were comparable. Patients reporting 'painfulness' also reported that SMBG use was significantly less important. Whether or not patients recognized the importance of SMBG use was well correlated with the frequency of physicians checking patient diaries. CONCLUSIONS: Type 1 diabetes and type 2 diabetes patients reporting 'painfulness' in SMBG use had more mental distress, lower health-related quality of life and higher glycated hemoglobin regardless of their number of daily SMBG tests. The importance of SMBG use was recognized less by patients experiencing pain, and the importance of SMBG use was recognized more in medical institutions in which physicians regularly checked SMBG diaries to provide meaningful feedback to patients in clinical settings.

Subtyping of Type 1 Diabetes as Classified by Anti-GAD Antibody, IgE Levels, and Tyrosine kinase 2 (TYK2) Promoter Variant in the Japanese.

OBJECTIVE: Type 1 diabetes (T1D) is known to be caused by Th1 cell-dependent autoimmunity. Recently, we reported that TYK2 promoter variant serves as a putative virus-induced diabetes susceptibility gene associated with deteriorated interferon-dependent antiviral response. TYK2 is also related to HIES, that is, Th2 cell-dependent. Therefore, TYK2 promoter variant may be also associated with the pathogenesis of T1D, modulating Th1/Th2 balance. RESEARCH DESIGN AND METHODS: We assessed the association between anti- GAD Ab, IgE levels, and TYK2 promoter variant among 313 T1D patients, 184 T2D patients, and 264 YH controls in the Japanese. RESULTS: T1D patients had elevated IgE (median, 56.7U/ml; p<0.0001) compared with T2D patients (22.5U/ml) and controls (43.3U/ml). Contrary to our expectations, there was no correlation between TYK2 promoter variant and IgE levels. We found that T1D could be subtyped as four groups based on anti-GAD Ab and IgE profile: Subtype 1, anti-GAD Ab positive and non-elevated IgE (47.0%); Subtype 2, anti-GAD Ab negative and non-elevated IgE (35.1%); Subtype 3, anti-GAD Ab positive and elevated IgE (10.9%); and Subtype 4, anti-GAD Ab negative and elevated IgE (7.0%). In Subtype 2, a significantly higher incidence was observed in T1D cases carrying the TYK2 promoter variant (OR, 2.60; 95%CI, 1.03-6.97; p=0.032), and also showing a flu-like syndrome at diabetes onset (OR, 2.34; 95%CI, 1.27-4.35; p=0.003). INTERPRETATION: Anti-GAD Ab and IgE profiling helps classifying T1D into four groups that recognize variable pathogenic bases of T1D.

Relationship between the efficacy of oral antidiabetic drugs and clinical features in type 2 diabetic patients (JDDM38).

AIMS/INTRODUCTION: We carried out an observational cohort study to examine the relationship between the efficacy of oral antidiabetic drugs and clinical features in type 2 diabetics. MATERIALS AND METHODS: We analyzed the CoDiC(®) database of the Japan Diabetes Data Management Study Group across 67 institutions in Japan. In a total of 3,698 drug-naïve patients who were initiated with metformin, dipeptidyl peptidase-4 inhibitor (DPP-4i) or sulfonylurea (SU) from 2007 to 2012, we evaluated body mass index (BMI) and hemoglobin A1c (HbA1c). The patients were stratified according to their clinical features, and matched using a propensity score to adjust for baseline factors. RESULTS: HbA1c was reduced with all drugs, with the largest effect elicited by DPP-4i and the smallest by SU (P = 0.00). HbA1c increased with SU after 6 months in the patients stratified by an age-of-onset of <50 years (P = 0.00). BMI increased with SU in the patients stratified by a BMI of <25 (P = 0.00), and decreased with metformin in the patients with a BMI >25 (P = 0.00). The reduction in HbA1c was larger in patients with HbA1c of ≥8%, compared with that in patients with HbA1c of <8% (P = 0.00). HbA1c during the study period was higher in patients who were added to or swapped with other drug(s), than in patients continued on the original drug (P = 0.00). CONCLUSIONS: The effect on bodyweight and glycemic control differed among metformin, DPP-4i and SU, and the difference was associated with clinical features.

TYK2 Promoter Variant and Diabetes Mellitus in the Japanese.

BACKGROUND: Recently, natural mutation of Tyrosine kinase 2 (Tyk2) gene has been shown to determine susceptibility to murine virus-induced diabetes. In addition, a previous human genome-wide study suggested the type 1 diabetes (T1D) susceptibility region to be 19p13, where the human TYK2 gene is located (19p13.2). METHODS: Polymorphisms of TYK2 gene at the promoter region and exons were studied among 331 healthy controls, and 302 patients with T1D and 314 with type 2 diabetes (T2D) in the Japanese. FINDINGS: A TYK2 promoter haplotype with multiple genetic polymorphisms, which are in complete linkage disequilibrium, named TYK2 promoter variant, presenting decreased promoter activity, is associated with an increased risk of not only T1D (odds ratio (OR), 2.4; 95% confidence interval (CI), 1.2 to 4.6; P = 0.01), but also T2D (OR, 2.1; 95% CI, 1.1 to 4.1; P = 0.03). The risk is high in patients with T1D associated with flu-like syndrome at diabetes onset and also those without anti-glutamic acid decarboxylase autoantibody. INTERPRETATION: The TYK2 promoter variant is associated with an overall risk for diabetes, serving a good candidate as a virus-induced diabetes susceptibility gene in humans. FUNDING: Ministry of Education, Culture, Sports, Science and Technology and of Health, Labor and Welfare of Japan.

Effect of a newly developed charging chamber for the treatment of hypotension during hemodialysis.

We developed a new method of hemodialysis using a charging chamber for treatment of hemodialysis patients with hypotension occurring during the latter half of hemodialysis (collapse). The purpose of this method was to recover systolic blood pressure (BP) by returning a part of blood within the chamber into the body circulation when hemodialysis collapse occurred. Using this method, systolic BP recovery (DeltaBP) in ten hemodialysis patients (4 males, 6 females, mean age 66.0 years old) was compared to a control group treated with intravenous administration of 20 ml of 10% NaCl. When hemodialysis collapse occurred, 60 ml of blood within the chamber in this method and 20 ml of 10% NaCl intravenously in the control group were administered and systolic BP was measured 20 minutes later. The results showed that DeltaBP using this method was 26.0 mm Hg (ANOVA: p = 0.0072), while in the control group it was 30.2 mm Hg (ANOVA: p = 0.0003), and there was no significant difference between the systolic BP recovery of both groups (paired t test: p = 0.4196).