Abstract Insulin treatment should be introduced in patients with slowly progressive type 1 diabetes (SPIDDM; definite), according to the revised diagnostic criteria of SPIDDM (2023). In contrast, SPIDDM (probable) patients are in a non‐insulin‐dependent state; therefore, a more flexible treatment can be considered, although sulfonylurea agents should be avoided. Insulin treatment has been shown to maintain endogenous insulin secretion capacity in SPIDDM (probable); however, this does not mean that all SPIDDM (probable) patients should use insulin from the early phase. Dipeptidyl peptidase‐4 inhibitors and biguanides might be the treatment of choice for SPIDDM (probable), but no evidence exists for other hypoglycemic agents. In any case, careful monitoring of the endogenous insulin secretion capacity should be carried out, and if a decrease in insulin secretion capacity is suspected, a change in treatment should be considered to prevent progression to an insulin‐dependent state.

Abstract Aims/Introduction This study aimed to identify risk factors that contribute to the progression of slowly‐progressive type 1 diabetes by evaluating the positive predictive value (PPV) of factors associated with the progression to an insulin‐dependent state. Materials and Methods We selected 60 slowly‐progressive type 1 diabetes patients who tested positive for glutamic acid decarboxylase autoantibodies (GADA) at diagnosis from the Japanese Type 1 Diabetes Database Study. GADA levels in these patients were concurrently measured using both radioimmunoassay (RIA) and enzyme‐linked immunosorbent assay (ELISA) techniques. Results Compared with the non‐progressor group (fasting C‐peptide [F‐CPR] levels maintained ≥0.6 ng/mL), the progressor group showed a younger age at diagnosis, lower body mass index (BMI), lower F‐CPR levels and a higher prevalence of insulinoma‐associated antigen‐2 autoantibodies (IA‐2A). The PPV of RIA‐GADA increased from 56.3 to 70.0% in the high titer group (≥10 U/mL), and further increased to 76.9, 84.2, 81.0 and 75.0% when combined with specific thresholds for age at diagnosis <47 years, BMI <22.6 kg/m², F‐CPR <1.41 ng/mL and IA‐2A positivity, respectively. In contrast, the PPV of ELISA‐GADA (71.8%) remained the same at 73.1% in the high titer group (≥180 U/mL), but increased to 81.8, 82.4 and 79.0% when evaluated in conjunction with age at diagnosis, BMI and F‐CPR level, respectively. Conclusions Our findings show that, unlike RIA‐GADA, ELISA‐GADA shows no association between GADA titers and the risk of progression to an insulin‐dependent state. The PPV improves when age at diagnosis, BMI and F‐CPR levels are considered in combination.

Abstract Context Glucose tolerance worsens after distal pancreatectomy (DP); however, the long-term incidence and factors affecting interindividual variation in this worsening are unclear. Objective To investigate the changes in diabetes-related traits before and after DP and to clarify the incidence of diabetes and its predictors. Methods Among 493 registered patients, 117 underwent DP. Among these, 56 patients without diabetes before surgery were included in the study. Glucose and endocrine function were prospectively assessed using a 75-g oral glucose tolerance test preoperatively, 1 month after DP, and every 6 months thereafter for up to 36 months. Pancreatic volumetry was performed using multidetector row computed tomography before and after surgery. Results Insulin secretion decreased and blood glucose levels worsened after DP. Residual pancreatic volume was significantly associated with the reserve capacity of insulin secretion but not with blood glucose levels or the development of diabetes. Among 56 patients, 33 developed diabetes mellitus. The cumulative incidence of diabetes at 36 months after DP was 74.1%. Multivariate Cox regression analysis showed that impaired glucose tolerance as a preoperative factor as well as a decreased insulinogenic index and impaired glucose tolerance at 1 month postoperatively were identified as risk factors for diabetes following DP. Conclusion Impaired glucose tolerance and reduced early-phase insulin response to glucose are involved in the development of new-onset diabetes after DP; the latter is an additional factor in the development of diabetes and becomes apparent when pancreatic beta cell mass is reduced after DP.

Abstract Continuous glucose monitoring (CGM) values obtained from CGM systems using the same sensor but with different internal algorithms (the first- and third-generation FreeStyle Libre (1st-gen-libre and 3rd-gen-libre, respectively)) were compared. We used 19,819 paired and simultaneously measured CGM values of 13 patients with diabetes. The average CGM value was significantly higher (P < 0.0001) and the time below range (CGM value < 70 mg/dL) was significantly lower (P < 0.0001) with the 3rd-gen-libre than with the 1st-gen-libre. There was a significant correlation (P < 0.0001) between the CGM values of the 3rd-gen-libre (y-axis, mg/dL) and 1st-gen-libre (x-axis, mg/dL) using the following formula: y = 0.9728x + 10.024. On assessing the association between glycated hemoglobin (HbA1c (%), y-axis) and the average CGM values (x-axis, mg/dL) by applying the obtained equation to previously reported 1st-gen-libre data and converting it to 3rd-gen-libre data, we obtained the equation y = 0.02628x + 3.233, indicating that the glucose management indicator reported in the West may be underestimated compared with the laboratory-measured HbA1c in the Japanese population. Glucose values from the same sensor were found to be significantly different between readers with different algorithms, and the calculation of CGM-related indices may need to be individualized for each device.

Abstract 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.

Abstract We previously reported that four hyperglycemia loci are located on three chromosomes in the Nagoya-Shibata-Yasuda (NSY) mouse model, commonly used to study type 2 diabetes. However, we did not search for hyperglycemia loci across all chromosomes. In this study, we performed quantitative trait loci (QTLs) mapping of longitudinal phenotypes from crosses between NSY (hyperglycemic) and C3H (normoglycemic) mice. We identified four new QTLs for hyperglycemia, namely Nidd5nsy, Nidd6nsy, Nidd1c3h, and Nidd2c3h, on Chromosome 1, 4, 10, and 13, respectively. These QTLs were associated with hyperglycemia in young mice and had attenuated effects in older mice. Nidd5nsy and Nidd6nsy were hyperglycemic with NSY alleles, and Nidd1c3h and Nidd2c3h were hyperglycemic with C3H alleles. We further bred Nidd5nsy congenic mice and demonstrated that Nidd5nsy has a strong effect on hyperglycemia when young, accompanied by insulin resistance and visceral fat accumulation. These results showed that the effects of individual QTLs strengthened or weakened with age, and that the sum of the effects of QTLs captured the age-related deterioration of glucose tolerance in individuals. Our results support the importance of longitudinal phenotypes in the genetic analysis of polygenic traits and have implications for the genetic basis and pathogenesis of type 2 diabetes in humans.

Abstract Context The glucose tolerance of patients changes considerably from before to after pancreaticoduodenectomy wherein approximately half of the pancreas is resected. Objective The aim of this prospective study was to investigate the incidence of and risk factors for diabetes after pancreaticoduodenectomy. Methods This study is a part of an ongoing prospective study, the Kindai Prospective Study on Metabolism and Endocrinology after Pancreatectomy (KIP-MEP) study. Of the 457 patients enrolled to date, 96 patients without diabetes who underwent pancreaticoduodenectomy were investigated in this study. Preoperatively, 1 month post-pancreaticoduodenectomy, and every 6 months thereafter, the glucose metabolism and endocrine function were evaluated using the 75 g oral glucose tolerance test. Various other metabolic, endocrine, and exocrine indices were also examined over a period of up to 36 months. Results Of the 96 patients analyzed in this study, 33 were newly diagnosed with diabetes. The cumulative diabetes incidence at 36 months following pancreaticoduodenectomy was 53.8%. The preoperative insulinogenic index and ΔC-peptide in the glucagon stimulation test were significantly lower in the progressors to diabetes than in the nonprogressors. Multivariate Cox regression analysis demonstrated that the insulinogenic index was the only significant risk factor for new-onset diabetes. Conclusion The majority of patients developed new-onset diabetes after pancreaticoduodenectomy, and a low value of the insulinogenic index was suggested to be a risk factor for diabetes. Preoperative assessment for the prediction of the onset of diabetes serves as useful information for patients and is important for postoperative glycemic control and diabetes management in patients who require pancreaticoduodenectomy.

The targets for continuous glucose monitoring (CGM)-derived metrics were recently set; however, studies on CGM data over a long period with stable glycemic control are limited. We analyzed 194,279 CGM values obtained from 19 adult Japanese patients with type 1 diabetes. CGM data obtained during stable glycemic control over four months were analyzed. CGM-related metrics of different durations “within 120, 90, 60, 30, and 7 days” were calculated from baseline. Time in range (TIR; glucose 70–180 mg/dL), time above range (TAR; glucose ≥ 181 mg/dL), and average glucose levels, but not time below range (TBR; glucose ≤ 69 mg/dL), strongly correlated with glycated hemoglobin (HbA1c) values (P < 0.0001). TBR correlated with glucose coefficient of variation (CV) (P < 0.01). Fasting serum C-peptide levels negatively correlated with glucose CV (P < 0.01). HbA1c of approximately 7% corresponded to TIR of 74% and TAR of 20%. The shorter the CGM period, the weaker was the relationship between HbA1c and CGM-related metrics. TIR, TAR, and average glucose levels accurately reflected HbA1c values in Japanese patients with type 1 diabetes with stable glycemic control. Glucose CV and TBR complemented the limitation of HbA1c to detect glucose variability and hypoglycemia. Stable glycemic control with minimal hypoglycemia depended on residual β-cell function.

Abstract Adrenocortical carcinoma (ACC) is a rare tumor, and some histological variants (oncocytic, myxoid, and sarcomatoid ACCs) have been reported in addition to the conventional ACC. Among these subtypes, oncocytic ACC is histologically characterized by the presence of abundant eosinophilic granular cytoplasm in the carcinoma cells owing to the accumulation of mitochondria, which generally yields high 18F-fluorodeoxyglucose (FDG) uptake on positron emission tomography (PET). Herein, we report the case of a 21-year-old woman with oncocytic ACC with low FDG uptake on PET scan. Her circulating levels of androgens were high, and androgen-synthesis enzymes were detected in carcinoma cells. The patient also had hypocholesterolemia. However, glucose transporter 1 (GLUT1) was not detected in the tumor, which was considered to account for the low FDG uptake by the tumor. To the best of our knowledge, this is the first case of low FDG uptake by oncocytic ACC without GLUT1 expression. Additionally, since hypocholesterolemia was reported in 3 previous reports of androgen-producing tumors, a possible correlation between androgenicity in adrenal tumors and the development of hypocholesterolemia could be postulated; however, further investigations are needed for clarification. This case highlights important information regarding the diversity of ACC and its impact on hypocholesterolemia.

Mixed corticomedullary tumors (MCMTs) are rare and comprise medullary and cortical cells in a single adrenal tumor. The mechanisms underlying their development have not been fully elucidated. Here, we report a case of MCMT in a 42-year-old woman. Based on the preoperative clinical findings, the patient was diagnosed as having a pheochromocytoma with subclinical Cushing syndrome. Postoperative pathological diagnosis revealed that the tumor demonstrated morphologically distinct medullary and cortical components, which produced catecholamines and cortisol, respectively. Hybrid tumor cells producing both catecholamines and cortisol were not detected. Adrenocorticotropin (ACTH)-positive tumor cells were identified to be present in the pheochromocytoma. This ectopic production of ACTH can contribute to an autonomous cortisol production in a paracrine manner. In addition, micronodules producing aldosterone were detected in the adrenal tissue adjacent to the tumor. The simultaneous development of these 2 lesions may not be correlated with each other; however, this case confirms the importance of a detailed histopathological examination of the adrenal lesions harboring complicated hormonal abnormalities by providing pivotal and indispensable information on their pathogenesis and the possible interaction of the hormones produced in the adrenal gland.

The rate of glucose metabolism changes drastically after partial pancreatectomy. This work aims to analyze changes in patients’ glucose metabolism and endocrine and exocrine function before and after partial pancreatectomy relative to different resection types (Kindai Prospective Study on Metabolism and Endocrinology after Pancreatectomy: KIP-MEP study). A series of 278 consecutive patients with scheduled pancreatectomy were enrolled into our prospective study. Of them, 109 individuals without diabetes, who underwent partial pancreatectomy, were investigated. Data were compared between patients with pancreaticoduodenectomy (PD, n = 73) and those with distal pancreatectomy (DP, n = 36). Blood glucose levels during the 75-g oral glucose tolerance test (75gOGTT) significantly decreased after pancreatectomy in the PD group (area under the curve [AUC] –9.3%, P &lt; .01), and significantly increased in the DP population (AUC + 16.8%, P &lt; .01). Insulin secretion rate during the 75gOGTT and glucagon stimulation test significantly decreased after pancreatectomy both in the PD and DP groups (P &lt; .001). Both groups showed similar homeostasis model assessment of insulin resistance (HOMA-IR) values after pancreatectomy. Decrease in exocrine function quality after pancreatectomy was more marked in association with PD than DP (P &lt; .01). Multiple regression analysis indicated that resection type and preoperative HOMA-IR independently influenced glucose tolerance-related postoperative outcomes. Blood glucose levels after the OGTT differed markedly between PD and DP populations. The observed differences between PD and DP suggest the importance of individualization in the management of metabolism and nutrition after partial pancreatectomy.

Characterization of adrenocortical disorders is challenging because of varying origins, laterality, the presence or absence of hormone production, and unclarity about the benign or malignant nature of the lesion. Histopathological examination in conjunction with immunohistochemistry is generally considered mandatory in this characterization. We report a rare case of bilateral adrenocortical adenomas associated with unilateral adrenal endothelial cysts in a 65-year-old woman whose condition was not diagnosed before surgery. Detailed histological examination of the resected adrenal glands revealed hyperplasia in the zona glomerulosa. Despite hyperplasia, the patient had normal serum aldosterone levels and renin activity without clinical evidence of hypertension. The patient was treated with a sodium-glucose cotransporter protein 2 (SGLT2) inhibitor. This may have stimulated the renin-angiotensin-aldosterone system. To the best of our knowledge, this is the first case in which both relatively large bilateral adrenocortical adenomas and unilateral adrenal endothelial cysts were detected. This case also highlights the complexity and difficulty of preoperative diagnosis. Furthermore, this case reports the first detailed histopathological examination of adrenal lesions with SGLT2 treatment and the possibility of SGLT2 inhibitor treatment resulting in histological hyperplasia in the zona glomerulosa; however, it is difficult to prove a causative relationship between SGLT2 inhibitors and hyperplasia of the zona glomerulosa based on the data of this case. It can be confirmed only under limited conditions; therefore, further studies on adrenal gland histology employing SGLT2 inhibition are warranted.

OBJECTIVE: Glomerular filtration rate (GFR) decreases without or prior to the development of albuminuria in many patients with diabetes. Therefore, albuminuria and/or a low GFR in patients with diabetes is referred to as diabetic kidney disease (DKD). A certain proportion of patients with diabetes show a rapid progressive decline in renal function in a unidirectional manner and are termed early decliners. This study aimed to elucidate the prevalence of DKD and early decliners and clarify their risk factors. RESEARCH DESIGN AND METHODS: This combination cross-sectional and cohort study included 2385 patients with diabetes from 15 hospitals. We defined DKD as a urinary albumin to creatinine ratio (ACR) ≥30 mg/gCr and/or estimated glomerular filtration rate (eGFR) <60 mL/min/1.73 m². We classified patients into four groups based on the presence or absence of albuminuria and a decrease in eGFR to reveal the risk factors for DKD. We also performed a trajectory analysis and specified the prevalence and risk factors of early decliners with sequential eGFR data of 1955 patients in five facilities. RESULTS: Of our cohort, 52% had DKD. Above all, 12% with a low eGFR but no albuminuria had no traditional risk factors, such as elevated glycated hemoglobin, elevated blood pressure, or diabetic retinopathy in contrast to patients with albuminuria but normal eGFR. Additionally, 14% of our patients were early decliners. Older age, higher basal eGFR, higher ACR, and higher systolic blood pressure were significantly associated with early decliners. CONCLUSIONS: The prevalence of DKD in this cohort was larger than ever reported. By testing eGFR yearly and identifying risk factors in the early phase of diabetes, we can identify patients at high risk of developing end-stage renal disease.

AIMS/INTRODUCTION: Patients with a total pancreatectomy and type 1 diabetes are similar in regard to absolute insulin deficiency, but different in regard to glucagon, providing a unique opportunity to study the contribution of glucagon to glucose metabolism in an insulin-dependent state. The aim of the present study was to investigate the contribution of glucagon to glucose homeostasis in complete insulin deficiency in vivo. METHODS: A total of 38 individuals with a complete lack of endogenous insulin (fasting C-peptide <0.0066 nmol/L) and whose glycemic control was optimized with an insulin pump during hospitalization were retrospectively studied. The basal insulin requirement, time-to-time adjustment of the basal insulin infusion rate, prandial insulin requirement and fasting plasma glucagon were compared between patients with a total pancreatectomy (n = 10) and those with type 1 diabetes (n = 28) after achievement of optimal glycemic control. RESULTS: Total daily insulin (P = 0.03) and basal insulin (P = 0.000006), but not prandial insulin requirements, were significantly lower in total pancreatectomy patients than in type 1 diabetes patients. The basal percentage (basal insulin/total daily insulin) was also significantly lower in total pancreatectomy patients than in type 1 diabetes patients (15.8 ± 7.8 vs 32.9 ± 10.1%, P = 0.00003). An increase in the insulin infusion rate early in the morning was not necessary in most patients with a pancreatectomy. The fasting plasma glucagon concentration was significantly lower in total pancreatectomy patients than in type 1 diabetes patients (P = 0.00007), and was positively correlated with the basal insulin requirement (P = 0.038). CONCLUSIONS: The difference in insulin requirements between total pancreatectomy and type 1 diabetes patients suggests a contribution of glucagon to the basal insulin requirement and dawn phenomenon.

[抄録]目的: 円形脱毛症患者における甲状腺自己免疫および膵島自己免疫の臨床的・遺伝的実態を明らかにする. 方法: 円形脱毛症患者110例について臨床的特徴および自己免疫疾患の合併率を検討し, 血清学的に抗サイログロブリン（Tg）抗体, 抗甲状腺ペルオキシダーゼ（TPO）抗体, 甲状腺刺激ホルモン受容体抗体（TRAb)抗glutamic acid decarboxylase（GAD）抗体, 抗insulinoma-associated antigen2（IA-2抗体）, インスリン自己抗体（IAA）を測定した. またHLA-DRB1, -DQB1, -A, -B, -C 遺伝子型を決定した. 結果: 円形脱毛症患者は健常対照者に比し, 抗Tg抗体, 抗IA-2抗体, IAA, 抗GAD抗体陽性率は同等であったが, 抗TPO抗体（29.1％ vs. 11.6％, P＜0.001）, TRAb（42.7％ vs. 1.2％, P＜0.001）の陽性率は有意に高値を示した. 膵島関連自己抗体価の比較では抗GAD抗体, 抗IA-2抗体, IAAはいずれも健常対照者との間に差を認めず, 自己免疫性甲状腺疾患患者に比し有意に低値であった. 遺伝子解析において円形脱毛症患者は健常対照者に比し, A, 33: 03 が有意に低頻度であり（3.2％ vs. 9.7％, Pc＝0.036）, DRB1, 04: 05 -DQB1, 04:01 は低頻度の傾向, DRB1, 15: 01-DQB1, 06: 02 は高頻度の傾向を示した. 結語: 円形脱毛症には甲状腺自己免疫を高率に合併するが, 膵島自己免疫・１型糖尿病の合併は稀であること、遺伝子解析でも円形脱毛症では１型糖尿病の疾患感受性ハプロタイプが低頻度、疾患抵抗性ハプロタイプが高頻度であるという今回の結果から、円形脱毛症が自己免疫性甲状腺疾患とは共通性を有するのに対し、１型糖尿病とは臨床的にも遺伝的にも異質性を有することが示唆された.

[抄録]目的：自己免疫性甲状腺疾患（AITD）発症へのHLAクラスII領域とクラスI領域の関与を明らかにする． 方法：AITD患者281人と健常対照者198人を対象に，HLAクラスII領域のDRB1 とDQB1 アリルおよびクラスI領域のA，B とC アリルを決定し，アリル頻度およびハプロタイプ頻度を比較検討した．成績：DRB1 についてはDRB1*08:03 がAITD患者において有意に高頻度（14.4％ vs.7.6％，Pc＜0.01），DRB1*01:01 は有意に低頻度（2.3％ vs.8.8％，Pc＜0.0001）であった．DQB1 については，DQB1*05:01 が患者群において有意に低頻度（2.7％ vs.10.6％，Pc＜0.00001）であった．DRB1-DQB1 ハプロタイプについては，DRB1*08:03 -DQB1*06:01 が患者群において有意に高頻度（14.2％ vs.7.3％，Pc＜0.01），DRB1*01:01-DQB1*05:01が有意に低頻度（2.3％ vs.8.8％，Pc＜0.0001）であった．A については，いずれのアリルについても統計学的有意差を認めなかった．B についてはB *35:01 が患者群において有意に高頻度（13.2％ vs.6.8％，Pc＝0.04），B*07:02 が有意に低頻度（1.6％ vs.6.8％，Pc＜0.01）であった．C については，C *03:03 が患者群において有意に高頻度（17.4％ vs.8.1％，Pc＜0.01）であった．B -C ハプロタイプについては，B*35:01-C*03:03 が患者群において有意に高頻度（11.9％ vs.4.7％，Pc＜0.001），B *07:02 -C*07:02 が患者群で有意に低頻度（1.6％ vs.6.6％，Pc＝0.02）であった．DRB1

[抄録] 低Na血症は臨床上遭遇する電解質異常のなかでも頻度が高く，軽症では倦怠感や食欲不振の訴えにとどまるが，ひとたび重症化すると，けいれんや意識障害をきたし，生命維持に危機に関わる重要な病態である．今回我々は著明な低Na血症に加えて低血糖を伴った症例を経験し，速やかに加療を開始すると共に鑑別診断を行い，下垂体性副腎皮質機能低下症と診断し得たので報告する．

[抄録] 目的：自己免疫性甲状腺疾患（AITD）患者における膵島自己免疫の実態を明らかにする．方法：AITD 患者866人（バセドウ病患者546人，橋本病患者320人）と非自己免疫性甲状腺疾患患者221人を対象にGAD 抗体陽性率と抗体価を比較するとともに，抗体陽性AITD 患者の臨床的特徴及びHLA-DRB1，DQB1 とCTLA4 の遺伝子型を陰性者と比較．成績：GAD 抗体陽性率はAITD 患者で対照者に比し有意に高率（5.8％ vs. 0.6％，P＜0.001）．糖尿病有病率はGAD 抗体陽性者において陰性者に比し有意に高率（40.0％ vs. 10.1％，p＜0.0001），陽性者の中では高抗体価群で低抗体価群に比し有意に高率（64％ vs. 16％，p＝0.001）．GAD 抗体陽性AITD 患者は陰性患者に比し，糖尿病発症年齢が有意に若く，BMIが有意に低く，HbA1c値，インスリン使用率が有意に高値．DRB1＊0405-DQB1＊0401ハプロタイプはGAD 抗体陽性AITD 患者で抗体陰性者，対照者に比し有意に高頻度．CTLA4 の6230G＞A 多型（rs3087243）はAITD と有意の関連を示したが，GAD 抗体の有無とは関連を認めなかった．結論：AITD 患者ではGAD 抗体が高率に陽性を示し，抗体陽性者は１型糖尿病の臨床的，遺伝的特徴を有することが示された．

[抄録]高齢者糖尿病の治療においても血糖の正常化に努めるべきであるが，同時に治療がQOL を低下させることがないよう，患者の身体的，精神・心理的，社会的背景を十分に考慮した治療を実施すべきである．今回，我々は，血糖コントールのため一旦インスリンを導入したが，在宅自己注射が困難な状況を考慮し，経口薬でのコントロールに戻し得た高齢者２型糖尿病の１症例を経験したので報告する．

【目的】AITDにおける膵島自己免疫の実態やその臨床的・遺伝的背景を明らかにする。【方法】当科通院中のAITD患者 816例について病態、臨床背景、GAD抗体価、HLA遺伝子型（DRB1、DQB1）を比較検討した。【結果】AITD患者のGAD抗体陽性率は5.6%と高率であった。GAD抗体陽性AITD患者の糖尿病発症率は、GAD抗体陰性AITD患者に比し有意に高頻度であった。糖尿病合併AITD患者において、GAD抗体陽性者は陰性者に比し糖尿病発症年齢が有意に若く（、AITD発症年齢も有意に若齢であり、BMIが有意に低かった。非糖尿病AITD患者にける同様の比較では有意差を認めなかった。HLA解析ではDRB1*0405-DQB1*0401ハプロタイプが、GAD抗体陽性バセドウ病患者において、抗体陰性者及び健常対照者に比し有意に高頻度であった。GAD抗体陰性AITD患者では健常対象者に比し、DRB1*0803-DQB1*0601ハプロタイプ頻度が高頻度であった。【総括】AITD患者、特にバセドウ病ではGAD抗体陽性率が高く、糖尿病発症との関連が認められた。GAD抗

糖尿病を発症するマウス(Nagoya-Shibata-Yasuda mouse：NSY)の糖尿病感受性遺伝子を有する染色体を、非糖尿病マウス(C3H)へ導入した系統であるコンソミックマウス/コンジェニックマウスの作製により、糖尿病および糖尿病関連形質の疾患感受性領域を特定の染色体/領域に絞り込んできた(Kobayashi M, Babaya N, et al., BMC Genet 2020、Babaya N et al., Int J Endocrinol 2018、Babaya N et al., BMC Genet 2014、Babaya N et al., J Diabetes Res 2013、Babaya N et al., Diabetologia 2010 など)。今年度は、1番染色体コンジェニック系統の表現型解析を行い、加齢に伴う遺伝子座の影響を検討した。 ヒトにおいては２型糖尿病患者の表現型パネル作成を行っているが、その過程で副腎腫瘤をもつ個人を2例同定し、病理学的解析を行い報告した（Babaya N et al., J Endocr Soc 2021、Yoshida S, Babaya N et al., J Endocr Soc 2021、今村、馬場谷他, 第22回日本内分泌学会近畿支部学術集会）。また、ヒト糖尿病における新たな臨床ツールcontinuous glucose monitoring(CGM)の関連指標とHbA1c・残存膵β細胞機能との関連解析についての発表を行った（馬場谷他, 第94回日本内分泌学会学術集会）。さらには、膵部分切除術（膵頭十二指腸切除術と膵尾部切除術）後の糖尿病発症率の解析を行い、術式の違いによる糖尿病発症率に差があることを明らかにし報告した(Niwano F, Babaya N, et al., J Clin Endocrinol Metab)。

本研究では、１型糖尿病において治療困難の原因となる膵β細胞機能の完全廃絶を規定する遺伝因子を同定し、その分子メカニズムを明らかにするとともに、膵β細胞機能の完全廃絶を予知・予測するバイオマーカーを探索・同定することにより、内因性インスリンの完全廃絶阻止に資する基盤情報を得ることを目的として研究を進めている。 １）膵β細胞機能の完全廃絶を規定する遺伝因子の解析： 膵β細胞が発症時から完全廃絶する劇症１型糖尿病のゲノムワイド関連解析（GWAS）でゲノムワイド有意水準をクリアしたHLA領域とCSAD領域のターゲットリシークエンスを進め、劇症化・膵β細胞機能完全廃絶の直接原因となる変異・多型の同定・抽出を進めている。また、自己免疫性１型糖尿病（急性発症・緩徐進行）を対象としたGWASを新たに進めており、劇症１型糖尿病のGWAS結果と対比した解析を行うことで、１型糖尿病の劇症化・膵β細胞機能の完全廃絶に関与する遺伝子を抽出・同定し、膵β細胞機能完全廃絶を規定する体質・遺伝子の全貌解明へと展開する。 ２）膵β細胞機能の完全廃絶を予知・予測するバイオマーカーの探索： 劇症１型糖尿病のGWASで同定した染色体12q13.13のCSADがコードする遺伝子の機能に関連する血中バイオマーカーの探索を進めた結果、CSADが律速酵素として生合成する産物Taurineがバイオマーカーとなりうる可能性が示唆された。これと並行して血中メタボローム解析を施行し、アミノ酸以外の各種メタボライトも含めた解析で膵β細胞完全廃絶に関与するバイオマーカーの探索を進めている。

本研究は１型糖尿病の濃厚発症家系を対象とした責任遺伝子変異の解明を目的としている。我が国における１型糖尿病の有病率は欧米に比べて低いため、濃厚発症家系の集積は容易ではないが、本研究申請時以降も新規4家系13名の検体を上乗せすることに成功し、合計で13家系54名（罹患者35名、非罹患者19名）について、既に全エクソームシーケンス作業は完了している。本研究の解析対象者を選別する際に、糖尿病の病型診断として確実な１型糖尿病に限定して効率的に解析を進める必要がある。この目的のためには、高額な次世代シーケンス工程に入る前に、HLA遺伝子型タイピングをおこない、１型糖尿病の疾患感受性ハプロタイプを有することを確認するスクリーニング工程が非常に有効な手段であると考えられる。確実な１型糖尿病を選別するため、多数検体に対するHLAタイピングが必要であるが、不確実な病型診断を回避することにより、さらに高額な次世代シーケンス行程を必要かつ最小限に抑制するに足る十分な効果があった。また、独立基盤形成支援にともなう交付決定後増額を得たことにより各家系の発端者に対して全ゲノムシーケンス（WGS）を実施することができ、全エクソームシーケンス（WES）だけでは検出し得ない、染色体上の大きな構造変異の探索の探索やミスアライメントの検証など変異解析の精度を飛躍的に向上させることができた。 また次世代シーケンス解析によって同定された遺伝子変異が、技術的に生じるノイズではなく、実際に遺伝子配列の変異があることを検証するため、Taqman法を用いて遺伝子型を決定することにより、次世代シーケンスの結果を随時検証した。 上記の結果を、18th Immunology of Diabetes Society Congress(2021.11.2. Virtual conference)にて発表し、現在論文執筆中である。

本研究は１型糖尿病の濃厚発症家系を対象とした責任遺伝子変異の解明を目的としている。我が国における１型糖尿病の有病率は欧米に比べて低いため、濃厚発症家系の集積は容易ではないが、本研究申請時以降も新規4家系13名の検体を上乗せすることに成功し、合計で13家系54名（罹患者35名、非罹患者19名）について、既に全エクソームシーケンス作業は完了している。本研究の解析対象者を選別する際に、糖尿病の病型診断として確実な１型糖尿病に限定して効率的に解析を進める必要がある。この目的のためには、高額な次世代シーケンス工程に入る前に、HLA遺伝子型タイピングをおこない、１型糖尿病の疾患感受性ハプロタイプを有することを確認するスクリーニング工程が非常に有効な手段であると考えられる。確実な１型糖尿病を選別するため、多数検体に対するHLAタイピングが必要であるが、不確実な病型診断を回避することにより、さらに高額な次世代シーケンス行程を必要かつ最小限に抑制するに足る十分な効果があった。また、独立基盤形成支援にともなう交付決定後増額を得たことにより各家系の発端者に対して全ゲノムシーケンス（WGS）を実施することができ、全エクソームシーケンス（WES）だけでは検出し得ない、染色体上の大きな構造変異の探索の探索やミスアライメントの検証など変異解析の精度を飛躍的に向上させることができた。 また次世代シーケンス解析によって同定された遺伝子変異が、技術的に生じるノイズではなく、実際に遺伝子配列の変異があることを検証するため、Taqman法を用いて遺伝子型を決定することにより、次世代シーケンスの結果を随時検証した。 上記の結果を、18th Immunology of Diabetes Society Congress(2021.11.2. Virtual conference)にて発表し、現在論文執筆中である。

In this study, we identified susceptibility genes for type 2 diabetes-related traits using a mouse model of the disease. We mapped streptozotocin susceptibility (pancreatic β-cell vulnerability) loci to the telomeric side of mouse chromosome 14 (Int J Endocrinol 2018) and to the central region on chromosome 11 (Mamm Genome 2018). We also identified and reported hyperglycemia-sensitive, insulin deficient, and fat accumulation loci on chromosome 11 (BMC Genet 2020). In human studies, we are creating a phenotypic panel of type 2 diabetic patients, and in the process, we discovered and reported unique cases (J Endocr Soc 2018, J Endocr Soc 2021). We also performed phenotyping and genetic analysis in a large number of cases in type 1 diabetes, type 2 diabetes, and endocrine disorders (J Diabetes Investig 2018, J Diabetes Investig 2020, Sci Rep 2021).

To clarify pathogenesis of type 1 diabetes for the development of effective methods for prediction, prevention and cure of type 1 diabetes, we performed molecular genetic analysis of type 1 diabetes by using two approaches. 1) Common variants: genome-wide association study on fulminant type 1 diabetes, 2) Rare variants: whole-exome sequencing in rare multiplex families with type 1 diabetes in Japanese population. GWAS identified two loci associated with fulminant type 1 diabetes with genome-wide significance: HLA on chromosome 6 and CSAD/lnc-ITGB7-1 on chromosome 12q13.13. In multiplex families, existence of two categories of susceptibility genes, genes specific to each family and genes common in multiple families, were found to be present, indicating the importance of precision medicine based on susceptibility genes in each family.

Type 1 diabetes is an incurable disease characterized by specific destruction of pancreatic beta cells, leading to absolute exhaustion of insulin secretion. Fulminant, acute-onset, and slowly progressive type 1 diabetes were clinically classified by Japan Diabetes Society. It is still difficult to predict the insulin secretion by exact diagnosis of diabetes at the onset of disease, because the mechanisms and pathogenesis of 3 types of type 1 diabetes is largely unkown. We aimed to clarify the genetic factors of type 1 diabetes to select high-risk individuals who develop insulin-dependent state, and identify novel biomarker of beta-cell destruction at early-stage of disease.

Type 2 diabetes is multifactorial diseases caused by a complex interaction of multiple susceptibility genes and environmental factors. In this study, we localized the diabetes-related regions in mice. In addition, we constructed the phenotype panel in human. During the course of constructing the panel, a rare case was found and reported (Babaya N, et al., BMC Endocrine Disorders 17、2017、1-6). We also reported the susceptible loci of type 1 diabetes and Grave’s disease (Babaya N, et al., Hum Immunol 78、2017、185-189, and Babaya N, et al., J Clin Endocrinol Metab 100、2015、1976-1983).

The purpose of this study was to identify genes responsible for both autoimmuninty and organ-specificity of type 1 diabetes. Type 1 diabetes and autoimmune thyroid diseases (AITD), alopecia areata and AITD, are often develop in the same individuals, whereas type 1 diabetes and AA are very rare to be observed in the same individuals. HLA-DR4 haplotype (DRB1*04:05-DQB1*04:01) was found to be responsible for beta-cell specificity in autoimmune diseases. targeted disruption of MafA in NOD mice resulted in protection, but not accerelation, of beta-cell autoimmunity and type 1 diabetes. Accumulation of regulatory T-cells in insulitis legion was suggested to be possible mechanism of protection from beta-cell autoimmunity and type 1 diabetes.

More than 50 genetic loci have been associated with type 1 diabetes in multiple studies among Caucasian populations, but they have been able to explain only 70-80% of the heritability for type 1 diabetes. Rare variants with high permeability are likely to explain a part of the remaining missing heritability. In Japan, where the prevalence of type 1 diabetes is very low, it is extremely rare for type 1 diabetes to develop in three or more siblings within a family. We found a family, in which type 1 diabetes occurred in three siblings among four sisters and the fourth sister was positive for GAD antibody but had not developed diabetes. To search the rare causative genetic variants, we performed whole-exome sequencing, using parents and four sisters. We narrowed down all exome variants to 11 candidate variants. Moreover, we performed whole-genome linkage analysis. By combining whole-exome sequencing and linkage analysis, we extracted one locus as candidate regions to type 1 diabetes.

This study aimed to clarify the mechanism of specific destruction of insulin-producing pancreatic beta cells and to prevent beta cell specific destruction. As for human study, genes related to organ specificity were clarified by association study of patients with type 1 diabetes, Graves disease and alopecia areata. Whole exome sequence analysis identified causal variant for familial, as well as sporadic type 1 diabetes in the Japanese population. As for mouse study, disruption of Mafa gene caused accelerated infiltration of lymphocytes into pancreatic islets, but suppressed spontaneous development of diabetes in the NOD mouse. Immunohistochemical staining by Foxp3 antibody suggested the involvement of a regulatory mechanism in benign insulitis.

Type 1 diabetes mellitus is the organ-specific autoimmune disease that β cell in pancreatic islets is destroyed by immune mechanism and to clarify the mechanism of immunoregulation leads to treatment of type 1 diabetes mellitus. To clarify the immunoregulation in the type 1 diabetes mellitus, we identify new genes susceptibility to type 1 diabetes mellitus and analyze correlation between autoimmune diseases in different organs. As a result, we clarified intergenic correlation between autoimmune genes.Then, we established the Mafa(which is the new genes susceptibility to type 1 diabetes mellitus) knockout NOD mouse, it was revealed that the Mafa gene affected the diabetes onset and insulitis.

Type 2 diabetes are multifactorial diseases caused by a complex interaction of environmental and genetic factors, with the latter consisting of multiple susceptibility genes, making it difficult to clarify their functions and interactions in conferring susceptibility to type 2 diabetes in humans. In this study, we constructed consomic and congenic strains, in which the NSY-derived diabetogenic region was introgressed onto the genetic background of control mice. We succeeded to localize and characterize the function of diabetogenic region in the NSY.

The aim of this study was to clarify the molecular mechanisms why only beta-cells are destroyed in type 1 diabetes. Insulin-specific transcription factor, MafA, affects expression of insulin in the thymus and induction of immunological tolerance to insulin. Functional polymorphisms of MAFA were associated with type 1 diabetes. Alopecia areata, organ-specific autoimmune disease to hair follicle, was associated with autoimmune thyroid diseases, but not with type 1 diabetes, which correlated with class II HLA haplotypes susceptible or resistant to each autoimmune disease.

To clarify genetic susceptibility to type 1 diabetes in the major histocompatibility complex , we robustly investigated the association of HLA-DRB1, DQB1, A, B, C loci with type 1 diabetes. This study showed that the frequency of the combination of DRB1*04:05-DQB1*04:01 and DRB1*08:02-DQB1*03:02 was low in Japanese population, but this was very high risk combination to type 1 diabetes. Several alleles of B, C loci were associated with type 1 diabetes, but most of them appeared to be secondary to linkage disequilibrium between these alleles and disease-related class II alleles. Taken the result with autoimmune thyroid disease in consideration, these data suggest that HLA Class II and Class I might contribute to the genetic susceptibility in the different manner, for each specific target organ.

Type 1 diabetes is a tissue-specific autoimmune disease against insulin-producing beta cells in pancreatic islets. To clarify the mechanisms of beta cell-specific destruction and the application of treatment for type 1 diabetes, we identified genetic factors, including Mafa gene, for islet-specific autoimmune response by association studies of candidate genes for type 1 diabetes with multiple organ-specific autoimmune diseases (type 1 diabetes, Graves' disease, Hashimoto thyroiditis and alopecia areata). Then, we established the Mafa knockout NOD mouse by speed congenic protocol. The cumulative incidence of type 1 diabetes in Mafa knockout NOD mouse was significantly protected in homozygotes of knockout allele in comparison with heterozygotes and wild type, suggesting the critical role of Mafa gene on the development of type 1 diabetes in vivo.

Susceptibility genes for type 1 diabetes were studied by using syntenic homology between mouse and human. Contribution of HLA to type 1 diabetes was shown to be different among three subtypes of type 1 diabetes : qualitative difference between fulminant and other subtypes, and quantitative difference between slowly progressive and acute-onset. Functional polymorphisms of MafA, an insulin transactivator, were associated with reduced expression of insulin in the thymus and susceptibility to type 1 diabetes both in mice and humans through the reduced expression of insulin in the thymus.

The etiology of type 1 and type 2 diabetes is thought to be different. However, type 2 diabetes is often observed in the family of patients with type 1 diabetes, suggesting the common genetic basis among them. We identified the susceptibility genes to type 1 diabetes, as well as type 2 diabetes, in the Japanese individuals, and susceptibility loci to glucose tolerance, body weight, and insulin resistance in the mouse model of type 2 diabetes, in order to establish the screening panel of association study of common susceptibility genes to type 1 and type 2 diabetes. We reported a newly identified susceptibility gene to type 1 diabetes in both mice and human, and the association study with type 2 diabetes was performed.