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.

Inhibition of calcium/calmodulin-dependent protein kinase IV in arthritis: dual effect on Th17 cell activation and osteoclastogenesis.

OBJECTIVE: To investigate the role of calcium/calmodulin-dependent protein kinase IV (CaMK4) in the development of joint injury in a mouse model of arthritis and patients with RA. METHODS: Camk4-deficient, Camk4flox/floxLck-Cre, and mice treated with CaMK4 inhibitor KN-93 or KN-93 encapsulated in nanoparticles tagged with CD4 or CD8 antibodies were subjected to collagen-induced arthritis (CIA). Inflammatory cytokine levels, humoral immune response, synovitis, and T-cell activation were recorded. CAMK4 gene expression was measured in CD4+ T cells from healthy participants and patients with active RA. Micro-CT and histology were used to assess joint pathology. CD4+ and CD14+ cells in patients with RA were subjected to Th17 or osteoclast differentiation, respectively. RESULTS: CaMK4-deficient mice subjected to CIA displayed improved clinical scores and decreased numbers of Th17 cells. KN-93 treatment significantly reduced joint destruction by decreasing the production of inflammatory cytokines. Furthermore, Camk4flox/floxLck-Cre mice and mice treated with KN93-loaded CD4 antibody-tagged nanoparticles developed fewer Th17 cells and less severe arthritis. CaMK4 inhibition mitigated IL-17 production by CD4+ cells in patients with RA. The number of in vitro differentiated osteoclasts from CD14+ cells in patients with RA was significantly decreased with CaMK4 inhibitors. CONCLUSION: Using global and CD4-cell-targeted pharmacologic approaches and conditionally deficient mice, we demonstrate that CaMK4 is important in the development of arthritis. Using ex vivo cell cultures from patients with RA, CaMK4 is important for both Th17 generation and osteoclastogenesis. We propose that CaMK4 inhibition represents a new approach to control the development of arthritis.

Exenatide challenge in oral glucose tolerance test is insufficient for predictions of glucose metabolism and insulin secretion after sleeve gastrectomy (SG) in obese patients with type 2 diabetes: a pilot study to establish a preoperative model to estimate ß-cell function following augmented glucagon-like peptide-1 secretion after SG.

The postoperative increase in glucagon-like peptide-1 (GLP-1) is the main factor to improve glucose metabolism following sleeve gastrectomy (SG) in obese patients with type 2 diabetes. We investigated whether the ß-cell responsiveness to an injection of exogenous GLP-1 in the preoperative period could determine the postoperative glucose tolerance in 18 patients underwent SG. In the preoperative period, a regular oral glucose tolerance test (OGTT) and an exenatide-challenge during OGTT (Ex-OGTT) were performed to evaluate the ß-cell function and its responsiveness to GLP-1. The postoperative glucose tolerance was evaluated by another regular OGTT performed at 3 months after SG. The significant decrease in glucose levels with enhanced secretions of insulin and GLP-1 was observed in OGTT at 3 months after SG. The area under the curve of glucose from 0 to 120 minutes (AUC glucose0-120 min) and the insulinogenic index (I.I.) in OGTT at 3 months post-SG were significantly improved compared to those in preoperative period, but comparable with those in Ex-OGTT. AUC glucose0-120 min and I.I. in OGTT at 3 months post-SG were significantly correlated with not only those in Ex-OGTT, but also those in the preoperative regular OGTT. Conversely, the correlations calculated by the Spearman's ρ were stronger in the latter than the former. This exenatide-challenge protocol might be useful to estimate glucose tolerance and insulin secretion after SG, however, it may be insufficient to improve predictability of a patient who is likely to achieve a significant benefit on glucose metabolism from receiving SG.

Bihormonal dysregulation of insulin and glucagon contributes to glucose intolerance development at one year post-delivery in women with gestational diabetes: a prospective cohort study using an early postpartum 75-g glucose tolerance test.

Gestational diabetes mellitus (GDM) is known to be a significant risk factor for the future development of type 2 diabetes. Here, we investigated whether a precise evaluation of ß- and α-cell functions helps to identify women at high risk of developing glucose intolerance after GDM. Fifty-six women with GDM underwent a 75-g oral glucose tolerance test (OGTT) at early (6-12 weeks) postpartum. We measured their concentrations of glucose, insulin, proinsulin and glucagon at fasting and 30, 60 and 120 min. At 1-year post-delivery, we classified the women into a normal glucose tolerance (NGT) group or an impaired glucose tolerance (IGT)/diabetes mellitus (DM) group. Forty-three of the 56 women completed the study. At 1-year post-delivery, 17 women had developed IGT/DM and 26 women showed NGT. In the early-postpartum OGTTs, the IGT/DM group showed a lower insulinogenic index, a less glucagon suppression evaluated by the change from fasting to 30 min (ΔGlucagon 30 min), and a higher glucagon-to-insulin ratio at 30 min compared to the NGT group. There were no significant between-group differences in proinsulin levels or proinsulin-to-insulin ratios. Insulinogenic index <0.6 and ΔGlucagon 30 min >0 pg/mL were identified as predictors for the development of IGT/DM after GDM, independent of age, body mass index, and lactation intensity. These results suggest that the bihormonal disorder of insulin and glucagon causes the postpartum development of glucose intolerance. The measurement of plasma insulin and glucagon during the initial OGTT at early postpartum period can help to make optimal decisions regarding the postpartum management of women with GDM.

A case of isolated hypothalamitis with a literature review and a comparison with autoimmune hypophysitis.

Idiopathic hypothalamitis is a rare condition that can cause anterior pituitary dysfunction and central diabetes insipidus (CDI), occasionally accompanied by a disturbance of autonomic regulation known as hypothalamic syndrome. This condition has been described as a subtype of autoimmune (lymphocytic) hypophysitis; however, some cases of isolated hypothalamic involvement with no inflammatory lesions in either the pituitary gland or infundibulum have been reported. The detailed epidemiology and pathophysiology of isolated hypothalamitis have not been clarified. We herein report a case of a solitary hypothalamic lesion in a young woman who showed spontaneous development of CDI and panhypopituitarism accompanied by hyperphagia. The hypothalamic lesion increased from 11 × 7 to 17 × 7 mm over 16 months based on the sagittal slices of magnetic resonance imaging examinations. The negative results for anti-pituitary antibodies and anti-Rabphilin-3A antibodies suggested that upward extension of lymphocytic adenohypophysitis or infundibulo-neurohypophysitis was unlikely. Infectious disease, granulomatosis, Langerhans cell histiocytosis, vasculitis, and systemic neoplastic diseases were excluded by the findings of a laboratory investigation, cerebrospinal fluid examination, and imaging studies. To make a definitive diagnosis, we performed a ventriculoscopic biopsy of the hypothalamic lesion. Histology revealed an infiltration of nonspecific lymphoplasmacytes with no evidence of neoplasm, which was consistent with a diagnosis of idiopathic hypothalamitis. Subsequently, the patient was treated with methylprednisolone pulse therapy followed by oral prednisolone. The hypothalamic lesion improved and remained undetectable after withdrawal of the prednisolone, suggesting that the glucocorticoid treatment was effective for isolated hypothalamitis while the patient remains dependent on the replacement of multiple hormones.

RENAL FUNCTION AND PLASMA RENIN ACTIVITY AS POTENTIAL FACTORS CAUSING HYPERKALEMIA IN PATIENTS WITH THYROID CARCINOMA UNDERGOING THYROID HORMONE WITHDRAWAL FOR RADIOACTIVE IODINE THERAPY.

Objective: Hypothyroidism is not commonly considered a cause of hyperkalemia. We previously reported that hyperkalemia was observed mainly in elderly patients treated with renin-angiotensin-aldosterone system (RAS) inhibitors when levothyroxine treatment was withdrawn for the thyroidectomized patients with thyroid carcinoma to undergo radioactive iodine treatment. Here, we investigated whether acute hypothyroidism causes hyperkalemia in patients who were not treated with RAS inhibitors. We also investigated factors influencing potassium metabolism in hypothyroid patients. Methods: We conducted a single-center, prospective cohort study of 46 Japanese patients with thyroid carcinoma undergoing levothyroxine withdrawal prior to radioiodine therapy. All patients were normokalemic before levothyroxine withdrawal. Blood samples were analyzed 3 times: before, and at 3 and 4 weeks after levothyroxine withdrawal. We investigated factors that may be associated with the elevation of serum potassium levels from a euthyroid state to a hypothyroid state. Results: None of the patients developed symptomatic hyperkalemia. The mean serum potassium level was significantly higher at 4 weeks after levothyroxine withdrawal compared to baseline. The serum sodium levels, the estimated glomerular filtration rate (eGFR), and the plasma renin activity (PRA) decreased significantly as hypothyroidism advanced. In contrast, the plasma levels of adrenocorticotropic hormone, cortisol, aldosterone, and antidiuretic hormone were not changed, while serum thyroid hormone decreased. At 4 weeks after their levothyroxine withdrawal, the patients' serum potassium values were significantly correlated with the eGFR and the PRA. Conclusion: Acute hypothyroidism can cause a significant increase in the serum potassium level, which may be associated with a decreased eGFR and decreased circulating RAS. Abbreviations: ACTH = adrenocorticotropic hormone; ADH = antidiuretic hormone; ATPase = adenosine triphosphatase; eGFR = estimated glomerular filtration rate; HbA1c = glycated hemoglobin; K+ = potassium; Na+ = sodium; PRA = plasma renin activity; RAS = renin-angiotensin-aldosterone system; T4 = thyroxine; TSH = thyroid-stimulating hormone.

Masked type 1 diabetes mellitus (T1DM) unveiled by glucocorticoid replacement: a case of simultaneous development of T1DM and hypophysitis in an elderly woman.

As a rare condition characterized by inflammation of the pituitary gland, hypophysitis usually results in hypopituitarism and pituitary enlargement. The most critical outcome of hypopituitarism is caused by secondary adrenal insufficiency. Glucocorticoid deficiency is a life-threatening condition, and patients who develop this deficiency require prompt diagnosis and treatment. However, a delayed diagnosis of hypopituitarism may occur due to its non-specific clinical manifestations. A common presenting sign of glucocorticoid deficiency is hypoglycemia. The amelioration of hyperglycemia has been observed in diabetic patients with adrenal insufficiency. We report the case of a 70-year-old Japanese woman who had suffered from fatigue and anorexia for several months; she was admitted based on refractory hyponatremia (sodium 125-128 mEq/L) and hypoglycemia (glucose 58-75 mg/dL). Laboratory findings and magnetic resonance imaging findings led to the diagnosis of panhypopituitarism caused by autoimmune hypophysitis. After receiving 10 mg/day of hydrocortisone, the patient developed severe hyperglycemia (glucose >500 mg/dL). Undetectable C-peptide levels and positive results of both insulinoma-associated antigen-2 antibodies and insulin autoantibodies indicated that she had experienced a recent onset of type 1 diabetes. The pathophysiological process indicated that overt hyperglycemia could be masked by the deficient action of glucocorticoids even in a diabetic patient with endogenous insulin deficiency. This uncommon case reinforces the importance of the prompt diagnosis and treatment of hypopituitarism. Clinicians should remain aware of the possibility of hidden diabetes when treating hypoglycemia in patients with adrenal insufficiency.

CD4+ CD52lo T-cell expression contributes to the development of systemic lupus erythematosus.

The cell-surface glycoprotein CD52 is widely expressed in lymphocytes. CD4+CD52hi T cells are functioning suppressor CD4+T cells. We investigated the role of the immune regulation of CD4+CD52 T cells in systemic lupus erythematosus (SLE). CD4+CD52lo T cells were increased in SLE patients, in positive correlation with SLEDAI, anti-ds-DNA antibody, and IgG concentration. Circulating follicular helper-like T cells (Tfh-like cells) were also increased in SLE, in positive correlation with CD4+CD52lo T cells. Chemokine receptor 8 (CCR8) expression in CD4+CD52lo T cells was increased. In vitro experiments using CD4 T cells of SLE patients showed that thymus and activation-regulated chemokine (TARC), a ligand of CCR8, contributed to the development of CD4+CD52hi T cells into CD4+CD52lo T cells. Our findings suggest that CD4+CD52lo T-cell upregulation is involved in the production of pathogens by autoantibodies, and TARC may contribute to the development of SLE through an aberrant induction of CD4+CD52lo T cells.

Postural Orthostatic Tachycardia in a Patient with Type 2 Diabetes with Diabetic Neuropathy.

A 24-year-old Japanese man with type 2 diabetes mellitus and diabetic neuropathy was admitted to our ward to evaluate the cause of orthostatic intolerance. During a head-up tilt test, his heart rate increased from 105 to 155 beats/minute within 3 minutes, and chest discomfort began. He was diagnosed with postural orthostatic tachycardia syndrome (POTS), and orthostatic intolerance disappeared after ß-blocker treatment. Scintigraphy using 123I-metaiodobenzylguanidine showed decreased cardiac uptake. Power spectral analysis of heart rate variability for 24 hours in Holter electrocardiography demonstrated decreases in both sympathetic and parasympathetic nervous system activities, with a greater decrease in parasympathetic activity than sympathetic activity. The relative sympathetic hyperactivity in the present patient with diabetic neuropathy seemed to be related to POTS.

Haploinsufficiency of interferon regulatory factor 4 strongly protects against autoimmune diabetes in NOD mice.

AIMS/HYPOTHESIS: Interferon regulatory factor (IRF)4 plays a critical role in lymphoid development and the regulation of immune responses. Genetic deletion of IRF4 has been shown to suppress autoimmune disease in several mouse models, but its role in autoimmune diabetes in NOD mice remains unknown. METHODS: To address the role of IRF4 in the pathogenesis of autoimmune diabetes in NOD mice, we generated IRF4-knockout NOD mice and investigated the impact of the genetic deletion of IRF4 on diabetes, insulitis and insulin autoantibody; the effector function of T cells in vivo and in vitro; and the proportion of dendritic cell subsets. RESULTS: Heterozygous IRF4-deficient NOD mice maintained the number and phenotype of T cells at levels similar to NOD mice. However, diabetes and autoantibody production were completely suppressed in both heterozygous and homozygous IRF4-deficient NOD mice. The level of insulitis was strongly suppressed in both heterozygous and homozygous IRF4-deficient mice, with minimal insulitis observed in heterozygous mice. An adoptive transfer study revealed that IRF4 deficiency conferred disease resistance in a gene-dose-dependent manner in recipient NOD/severe combined immunodeficiency mice. Furthermore, the proportion of migratory dendritic cells in lymph nodes was reduced in heterozygous and homozygous IRF4-deficient NOD mice in an IRF4 dose-dependent manner. These results suggest that the levels of IRF4 in T cells and dendritic cells are important for the pathogenesis of diabetes in NOD mice. CONCLUSIONS/INTERPRETATION: Haploinsufficiency of IRF4 halted disease development in NOD mice. Our findings suggest that an IRF4-targeted strategy might be useful for modulating autoimmunity in type 1 diabetes.

Association of the GCKR rs780094 polymorphism with metabolic traits including carotid intima-media thickness in Japanese community-dwelling men, but not in women.

BACKGROUND: The glucokinase regulator gene (GCKR) rs780094 has been shown to be strongly associated with some metabolic traits and atherosclerotic parameters, while the association between GCKR rs780094 and carotid intima-media thickness (CIMT) has not been fully investigated in the general population. The associations between the GCKR rs780094 genotype and metabolic traits including CIMT were examined in a Japanese community-dwelling population. METHODS: A total of 2491 Japanese adults (907 men and 1584 women) who participated in a medical screening program for the general population from 29 to 94 years of age during 2008 to 2010 were enrolled. GCKR rs780094 was genotyped by the TaqMan polymerase chain reaction method, and associations with metabolic markers including CIMT were evaluated. RESULTS: GCKR rs780094 AA genotype was significantly associated with higher TG (p<0.001 vs. GG), lower HDL-C (p=0.021 vs. GG), and lower HbA1c(p=0.023 vs. GG). The AA genotype showed significantly thinner CIMT (p=0.001 vs. GX). These associations were seen only in men. CONCLUSIONS: GCKR rs780094 was associated with TG, HDL-C, and HbA1c levels, as well as with CIMT in Japanese community-dwelling men, but not women.

The A>T polymorphism of the tribbles homolog 1 gene is associated with serum triglyceride concentrations in Japanese community-dwelling women.

Recent genome-wide association studies have identified Tribbles homolog 1 (TRIB1) as one of the candidate genes associated with lipid profiles. TRIB1 is known to interact with MAP kinases, thereby regulating their activities. The single nucleotide polymorphism rs2954029 of TRIB1 is located within an intron and is associated with lipid profiles. The aim of the present study is to investigate the TRIB1 rs2954029 (A>T polymorphism) with conventional predictors of coronary artery diseases such as carotid intima-media thickness (CIMT) and cardio-ankle vascular index (CAVI), and with lipid profiles in general population. This study enrolled 2,581 Japanese adults, 942 men and 1,639 women with a median age of 68 years (range 29 to 94 years), who participated in a screening program for the general population living in Goto City, Nagasaki Prefecture, Japan from 2008 to 2010. For the determination of TRIB1 rs2954029 genotypes, the polymerase chain reaction method was used. The differences in each parameter among the TRIB1 rs2954029 genotypes were evaluated using analysis of covariance. Genotype frequencies of TRIB1 rs2954029 in all participants were 25.5% for AA, 50.4% for AT, and 24.0% for TT. In women, the AA genotype showed significantly higher log triglyceride (TG) concentrations than the AT genotype (P = 0.004) and the AT + TT genotypes (P = 0.004). On the other hand, there were no associations with CIMT and CAVI among the TRIB1 rs2954029 genotypes. In conclusion, the TRIB1 rs2954029 is associated with serum TG concentrations in Japanese community-dwelling women.

Association between glycemic control and patient-reported outcomes in adults with type 1 diabetes in Japan: the SAGE study subanalysis.

Aims/introduction: Psychosocial aspects and the quality of life (QOL) of individuals with diabetes are important for achieving glycemic control and treatment goals. Here, we describe patient-reported outcomes (PROs) of Japanese adults with type 1 diabetes (T1D) and evaluate the association thereof with glycemic control. Materials and methods: This subanalysis of a subgroup of 528 Japanese participants in the SAGE study of adults with T1D used data on glycosylated hemoglobin (HbA1c) and PRO scores [Hypoglycemia Fear Survey-II (HFS-II), Problem Areas In Diabetes (PAID), Insulin Treatment Satisfaction Questionnaire (ITSQ), and Audit of Diabetes-Dependent QOL (ADDQoL)] and summarized the score by the predefined age groups (26-44-years: n = 208, 45-64-years: n = 217, and ≥ 65-years: n = 103). The association between PROs, achieving HbA1c < 7.0%, and individualized targets was explored using multivariate logistic regression analysis. Results: The HFS-II and PAID scores were lower, and the ITSQ score was higher in the ≥ 65-years group than in the younger groups with a linear trend of better scores with increasing age (P for trend < 0.05). ADDQoL scores were similar across the age groups, and present QOL (ADDQoL subscale) tended to improve with age (P for trend < 0.05). Achieving HbA1c < 7.0% and individualized targets were associated with satisfaction with insulin treatment regarding glycemic control. Conclusion: In Japanese adults with T1D, the impact on psychosocial aspects and QOL varied across age groups, with a trend of improving scores with age, potentially in relation to the less stringent glycemic control targets adopted in older individuals. Glycemic control was significantly associated with treatment satisfaction. Supplementary Information: The online version contains supplementary material available at 10.1007/s13340-023-00668-4.

Correction: Arimori et al. Association between Lifestyle Factors and Weight Gain among University Students in Japan during COVID-19 Mild Lockdown: A Quantitative Study. Healthcare 2023, 11, 2630.

In our published publication [...].

TYK2 signaling promotes the development of autoreactive CD8+ cytotoxic T lymphocytes and type 1 diabetes.

Tyrosine kinase 2 (TYK2), a member of the JAK family, has attracted attention as a potential therapeutic target for autoimmune diseases. However, the role of TYK2 in CD8+ T cells and autoimmune type 1 diabetes (T1D) is poorly understood. In this study, we generate Tyk2 gene knockout non-obese diabetes (NOD) mice and demonstrate that the loss of Tyk2 inhibits the development of autoreactive CD8+ T-BET+ cytotoxic T lymphocytes (CTLs) by impairing IL-12 signaling in CD8+ T cells and the CD8+ resident dendritic cell-driven cross-priming of CTLs in the pancreatic lymph node (PLN). Tyk2-deficient CTLs display reduced cytotoxicity. Increased inflammatory responses in ß-cells with aging are dampened by Tyk2 deficiency. Furthermore, treatment with BMS-986165, a selective TYK2 inhibitor, inhibits the expansion of T-BET+ CTLs, inflammation in ß-cells and the onset of autoimmune T1D in NOD mice. Thus, our study reveals the diverse roles of TYK2 in driving the pathogenesis of T1D.

New diagnostic criteria (2023) for slowly progressive type 1 diabetes (SPIDDM): Report from Committee on Type 1 Diabetes in Japan Diabetes Society (English version).

The diagnostic criteria for slowly progressive type 1 diabetes (slowly progressive insulin-dependent diabetes mellitus; SPIDDM) have been revised by the Committee on Type 1 Diabetes of the Japan Diabetes Society. All of the following three criteria must be met for "a definitive diagnosis of SPIDDM": (1) presence of anti-islet autoantibodies at some point in time during the disease course; (2) absence of ketosis or ketoacidosis at the diagnosis of diabetes with no requirement of insulin treatment to correct hyperglycemia immediately after diagnosis in principle; and (3) gradual decrease of insulin secretion over time, with insulin treatment required at more than 3 months after diagnosis, and presence of severe endogenous insulin deficiency (fasting serum C-peptide immunoreactivity < 0.6 ng/mL) at the last observed point in time. When a patient fulfills the only (1) and (2), but not (3), he/she is diagnosed with "SPIDDM (probable)" because the diabetes is non-insulin-dependent state.

New diagnostic criteria (2023) for slowly progressive type 1 diabetes (SPIDDM): Report from Committee on Type 1 Diabetes of the Japan Diabetes Society (English version).

The diagnostic criteria for slowly progressive type 1 diabetes (slowly progressive insulin-dependent diabetes mellitus; SPIDDM) have been revised by the Committee on Type 1 Diabetes of the Japan Diabetes Society. All of the following three criteria must be met for 'a definitive diagnosis of SPIDDM': (1) presence of anti-islet autoantibodies at some point in time during the disease course; (2) absence of ketosis or ketoacidosis at the diagnosis of diabetes with no requirement for insulin treatment to correct hyperglycemia immediately after diagnosis in principle; and (3) gradual decrease of insulin secretion over time, with insulin treatment required at more than 3 months after diagnosis, and the presence of severe endogenous insulin deficiency (fasting serum C-peptide immunoreactivity <0.6 ng/mL) at the last observed point in time. When a patient fulfills only (1) and (2), but not (3), he/she is diagnosed with 'SPIDDM (probable)' because the diabetes is non-insulin-dependent type.

Overlapping risk factors for diabetic ketoacidosis in patients with type 1 diabetes on ipragliflozin: case analysis of spontaneous reports in Japan from a pharmacovigilance safety database.

BACKGROUND: In patients with type 1 diabetes mellitus (T1D), sodium-glucose cotransporter 2 (SGLT2) inhibitors are associated with an increased risk of diabetic ketoacidosis (DKA). Ipragliflozin is an SGLT2 inhibitor approved in Japan in combination with insulin for patients with T1D. RESEARCH DESIGN AND METHODS: Spontaneous safety reports of ipragliflozin adverse drug reactions (ADRs) in patients with T1D were collected during early post-marketing phase vigilance (EPPV; 21 December 2018-20 June 2019). For patients with T1D prescribed ipragliflozin who experienced DKA, we examined DKA event data registered in the manufacturer's safety database (21 December 2018-31 December 2021), including patient background characteristics. RESULTS: During EPPV, there were 189 total events (45 serious) of ADRs, including 32 serious events of ketoacidosis. From 2018 to 2021, the major DKA risk factors were sick days, stopping or inappropriately decreasing insulin, insulin pump trouble, and low carbohydrate diet, with substantial overlap among these factors. CONCLUSIONS: In Japanese patients with T1D using ipragliflozin, DKA events were linked to several overlapping factors, including sick days and reduced dose/interruption of insulin, whether intentional or unexpected. These results highlight the need for improved patient education regarding ipragliflozin use and appropriate self-management of ketosis from an early stage.

Pilot Trial on the Effect of 5-Aminolevulinic Acid on Glucose Tolerance in Patients with Maternally Inherited Diabetes and Deafness.

INTRODUCTION: The amino acid 5-aminolevulinic acid (5-ALA) is the first heme biosynthetic precursor. The combination of 5-ALA with sodium ferrous citrate (SFC) enhances heme production, leading to increased adenosine triphosphate (ATP) production in mitochondria. We investigated whether administering 5-ALA/SFC improves glucose tolerance with an increase in insulin secretion in patients with maternally inherited diabetes and deafness (MIDD), which is characterized by an insulin secretory disorder due to impaired mitochondrial ATP production. METHODS: This was a single-arm, open-label, interventional study. We prospectively administered the oral glucose tolerance test (OGTT) twice in five patients with MIDD who had received intensive insulin therapy: before and 24 weeks after an administration of 5-ALA/SFC (200/232 mg per day). We measured the concentrations of glucose, insulin, C-peptide, and proinsulin at fasting, and 30, 60, and 120 min after glucose load in each OGTT. The primary endpoint was the changes in the area under the curve (AUC) of serum insulin from 0 to 120 min during OGTT from baseline to 24 weeks. RESULTS: The serum insulin AUC (µU/mL) during the 120-min OGTT tended to increase from baseline to 24 weeks but not significantly (17.1 ± 13.7 versus 22.3 ± 13.4, p = 0.077). The plasma glucose AUC (mg/dL) during the 120-min OGTT at 24 weeks was not significantly decreased; the late phase of glucose excursion from 60 to 120 min was significantly decreased compared with baseline (357 ± 42 versus 391 ± 50, p = 0.041). The mean level of glycated hemoglobin (HbA1c) decreased from 8.3 ± 1.2% at baseline to 7.9 ± 0.3% at 24 weeks (p = 0.36) without increasing the daily dose of insulin injections. CONCLUSION: The 24-week administration of 5-ALA/SFC did not demonstrate a significant improvement in insulin secretion in patients with MIDD. Further investigations with a larger number of patients and a placebo control group are required to clarify the potential efficacy of 5-ALA/SFC for ameliorating mitochondrial dysfunctions in MIDD. TRIAL REGISTRATION: UMIN-CTR000040581 and jRCT071200025.

Association between Lifestyle Factors and Weight Gain among University Students in Japan during COVID-19 Mild Lockdown: A Quantitative Study.

We aimed to investigate the lifestyle factors influencing weight gain among university students in Japan during the mild lockdown imposed due to the novel coronavirus disease pandemic. In this cross-sectional study, we conducted a questionnaire survey of students who underwent health examinations at Nagasaki University in 2021. Students reporting a weight gain of ≥3 kg were included in the weight gain group; the remaining students were included in the non-weight-gain group. Fisher's exact test and binary logistic regression were performed to determine the association between weight gain and each lifestyle factor. We included 3059 respondents (response rate: 45.7%), and 9.5% of them reported a weight gain of ≥3 kg. The following factors were associated with weight gain (odds ratio (95% confidence interval), p value based on Fisher's exact test): dining out for four times or more/week (2.16 (1.40, 3.32), p = 8.7 × 10-4) and gaming time of ≥4 h/day (2.26 (1.45, 3.47), p = 2.4 × 10-4). Binary logistic regression among the four highest odds ratios revealed that after adjusting for other factors, frequent dining out and prolonged gaming time were significantly associated with weight gain in students during the mild lockdown.