Kazuyuki Miyashita's research while affiliated with Osaka University and other places

Immune checkpoint inhibitor (ICI)-related type 1 diabetes is an immune-related adverse event (irAE), occurring in slightly less than 1% of patients undergoing ICI therapy. Most cases develop during ICI treatment, with occurrences long after discontinuation being extremely rare. A 76-year-old woman, with no history of glucose tolerance issues, was diagnosed with lung adenocarcinoma with pleural invasion and underwent chemotherapy, including atezolizumab, an anti-programmed death-ligand 1 antibody. This treatment was discontinued due to disease progression, although she continued with other chemotherapy regimens. Approximately 5.5 months (166 days) after her last atezolizumab dose, she developed diabetic ketoacidosis, fulfilling the diagnostic criteria for fulminant type 1 diabetes. Anti-glutamic acid decarboxylase antibodies were positive. The patient carried susceptibility human leukocyte antigen (HLA) haplotypes, which are associated with type 1 diabetes. To date, including our patient, only nine cases of ICI-related type 1 diabetes developed after ICI discontinuation have been precisely reported. Eight cases originated from East Asia, with six exhibiting fulminant type 1 diabetes, and seven tested negative for islet-related autoantibodies. The reported cases were independent of ICI types, cycle number, or HLA haplotypes. Median time from the last ICI administration to diabetes onset was 4 months (range: 2–7 months). Although reports of cases occurring after ICI discontinuation are currently limited, their frequency may increase with the wider use of ICIs and improved survival rates of patients post-treatment. Therefore, it is crucial to remain vigilant for the development of ICI-related type 1 diabetes, not only during ICI administration, but also long after discontinuation.

Background This study aimed to evaluate the changes in glycemic control and diabetic complications over time in Japanese patients with juvenile‐onset type 1 diabetes mellitus and to clarify the factors associated with the progression of diabetic complications. Methods We tracked 129 patients with type 1 diabetes mellitus (21.8 ± 4.1 years old [mean ± SD] with a diabetes duration of 12.6 ± 5.7 years) for up to 19 years and analyzed data on glycated hemoglobin (HbA1c) and indicators related to the severity of diabetic complications (estimated glomerular filtration rate [eGFR], urinary albumin excretion rate [UAE], carotid intima‐media thickness [CIMT], and brachial‐ankle pulse wave velocity [baPWV]) using linear mixed model and decision tree analysis. Results Although the HbA1c and UAE levels improved over time, the eGFR, CIMT, and baPWV worsened. Decision tree analysis showed that HbA1c and the glycoalbumin/HbA1c ratio for eGFR; HbA1c and systolic blood pressure for UAE; low‐density lipoprotein cholesterol/high‐density lipoprotein cholesterol ratio, glycoalbumin/HbA1c ratio, and body mass index (BMI) for CIMT; and HbA1c for baPWV were associated factors. Conclusions In this retrospective observational study, glycemic control and albuminuria improved; however, renal function and arteriosclerosis worsened over time. HbA1c levels, glycemic excursion, and blood pressure are associated with nephropathy progression. HbA1c levels, glycemic excursion, lipid levels, and BMI are associated with the progression of atherosclerosis.

Aims/introduction: Hypertriglyceridemia is common in patients with diabetes. Although the fatty acid (FA) composition of triglycerides (TGs) is suggested to be related to the pathology of diabetes and its complications, changes in the fatty acid composition caused by diabetes treatment remain unclear. This study aimed to identify short-term changes in the fatty acid composition of plasma triglycerides after diabetes treatment. Materials and methods: This study was a sub-analysis of a prospective observational study of patients with type 2 diabetes aged between 20 and 75 years who were hospitalized to improve glycemic control (n = 31). A lipidomic analysis of plasma samples on the 2nd and 16th hospital days was conducted by supercritical fluid chromatography coupled with mass spectrometry. Results: In total, 104 types of triglycerides with different compositions were identified. Most of them tended to decrease after treatment. In particular, triglycerides with a lower carbon number and fewer double bonds showed a relatively larger reduction. The inclusion of FA 14:0 (myristic acid), as a constituent of triglyceride, was significantly associated with a more than 50%, and statistically significant, reduction (odds ratio 39.0; P < 0.001). The total amount of FA 14:0 as a constituent of triglycerides also decreased significantly, and its rate of decrease was the greatest of all the fatty acid constituents. Conclusions: A 2 week comprehensive risk management for diabetes resulted in decreased levels of plasma triglycerides and a change in the fatty acid composition of triglycerides, characterized by a relatively large reduction in FA 14:0 as a constituent of triglycerides.

To evaluate whether continuous subcutaneous insulin infusion attenuates the progression of diabetic complications, we retrospectively extracted data from 35 individuals who had developed type 1 diabetes mellitus under 20 years of age and whose treatment had been changed from multiple daily injections to continuous subcutaneous insulin infusion. The annual changes in estimated glomerular filtration rate, urinary albumin excretion rate, carotid intima‐media thickness, and brachial‐ankle pulse wave velocity during each treatment period were calculated. Although mean glycated hemoglobin under the continuous subcutaneous insulin infusion treatment was lower than that under the multiple daily injection treatment, there were no significant differences in annual changes in diabetic nephropathy and atherosclerosis between the two treatment periods. This pilot study indicated that, in Japanese patients with juvenile‐onset type 1 diabetes mellitus, there was no significant difference in the progression of diabetic nephropathy and atherosclerosis, at least in the early stage, between the two treatments.

Aims/Introduction Diabetes patients develop a variety of metabolic abnormalities in addition to hyperglycemia. However, details regarding change in various metabolites after comprehensive diabetes treatment remain unknown. This study aimed to identify the short-term change in metabolome in inpatients who were subject to comprehensive diabetes treatment, using GC/MS-based non-target metabolomics techniques. Materials and Methods Subjects of the present study were randomly recruited from the patients with type 2 diabetes hospitalized due to problems with glycemic control (n=31) and non-diabetic volunteers (n=30), both of whom were aged between 20 and 75 years. A metabolomic analysis of fasting plasma samples on the 2nd (pre-treatment) and 16th hospital (post-treatment) day with gas chromatography/mass spectrometry (GC/MS) using a multiple reaction monitoring (MRM) mode was conducted. Results A principal component analysis (PCA) indicated that metabolome of fasting plasma was different between subjects with and without diabetes. The metabolome of fasting plasma in diabetes patients after treatment was different from that of pre-treatment as well as subjects without diabetes. Many amino acids (proline, glycine, serine, threonine, methionine, pyroglutamic acid, glutamine, and lysine) were significantly increased by more than 10% after administering the inpatient diabetes treatment. A hierarchical clustering analysis revealed that in the case of patients with markedly decrease monosaccharide levels and increased 1,5-anhydroglucitol, the levels of amino acids increased more significantly. Conclusions After a 2-week comprehensive treatment, the plasma levels of various amino acids increased in conjunction with the reduction in monosaccharide levels in poorly controlled type 2 diabetes patients.

Recently, it is widely recognized that microinflammation plays important roles in the pathophysiology of metabolic diseases, especially obesity-related disorders, diabetes and their complications. Lipopolysaccharide-binding protein (LBP) is a liver-derived acute-phase protein responsive to lipopolysaccharides (LPS) produced by gram-negative bacteria, thus reflects the systemic inflammation caused by the infection of those bacteria including gut dysbiosis. In this study, we evaluated the plasma LBP levels and investigated its clinical significance in 67 Japanese patients with type 1 diabetes. Univariable analysis showed that LBP levels were significantly associated with body mass index (BMI; r = 0.43, p < 0.01) and serum high-sensitivity C-reactive protein (hs-CRP; r = 0.64, p < 0.001) levels. However, there was no significant association between plasma LBP levels and diabetic complications. Mediation analysis revealed that LBP had significant mediation effects on the association between hs-CRP and BMI (0.27 [95% confidence interval 0.10–0.48]). These results suggest that the systemic condition where the LBP level increases, such as gut dysbiosis, at least partly, impacts on chronic microinflammation in patients with type 1 diabetes.

Recent progress in research on glucagon and α-cells highlights their pathophysiological roles in diabetes. We previously showed that plasma glucagon levels measured by newly developed enzyme-linked immunosorbent assay were dysregulated in patients with type 1 diabetes with respect to plasma glucose levels, suggesting dysregulated secretion. In the current study, the annual change in plasma glucagon levels was assessed in these same patients. We found that the plasma glucagon levels in the 66 Japanese patients involved in the study were significantly correlated between both years. In addition, they were significantly associated with serum blood urea nitrogen (BUN) levels in a multivariate linear regression analysis, as reported in our previous paper. The statistical correlation in glucagon levels between annual checkups and the sustained significant correlation between glucagon and BUN suggest a constant dysregulation of glucagon in association with altered amino acid metabolism in patients with type 1 diabetes.

Pancreas transplantation (PTx) has been performed worldwide for patients with type 1 diabetes accompanied with end-stage renal disease or uncontrollable glycemic fluctuation. Nevertheless, risk factors of posttransplant glucose intolerance, which is responsible for progress of diabetic complications, remains unclear, especially in cases without pancreatic graft function loss. Therefore, this study was conducted to search for predictive factors of future glucose tolerance in PTx recipients without pancreatic graft function loss. Subjects were selected from among 41 Japanese patients with type 1 diabetes who received PTx between 2000 and 2016 in Osaka University Hospital, and 24 subjects free from rejections and thromboses were analyzed. Several examinations to evaluate insulin secretion and insulin sensitivity within 6 months after transplantation (initial examination) were performed. Glucose tolerance was evaluated by 120-minute post-load plasma glucose level during 75-g oral glucose tolerance tests (OGTT), referred to as PGOGTT120, at the initial examination and between 1 year and 2 years posttransplantation (maintenance period). The initial examination factors that were correlated with PGOGTT120 in the maintenance period were PGOGTT120 [r = 0.52 (p = 0.01)], insulinogenic index [r = –0.65 (p < 0.01)], and the ratio of incremental area under the curve of insulin to that of plasma glucose (iAUCR) calculated from data of OGTT [r = –0.65 (p < 0.01)]. Insulinogenic index [β = –0.28 (p = 0.02)] and iAUCR [β = –0.29 (p = 0.02)] were still significantly correlated with PGOGTT120 in the maintenance period after adjustment for PGOGTT120 at the initial examination. In conclusion, insulinogenic index and iAUCR from OGTT performed in the early posttransplantation period were predictive factors of future glucose intolerance.

The objective of the present study was to investigate the correlations between serum undercarboxylated osteocalcin (ucOC) or osteocalcin (OC) concentrations and %body fat, serum adiponectin and free-testosterone concentration, muscle strength and dose of exogenous insulin in patients with type 1 diabetes. We recruited 73 Japanese young adult patients with childhood-onset type 1 diabetes. All participants were receiving insulin replacement therapy. The correlations between logarithmic serum ucOC or OC concentrations and each parameter were examined. Serum ucOC and OC concentrations were inversely correlated with %body fat (r = -0.319, P = 0.007; r = -0.321, P = 0.006, respectively). Furthermore, multiple linear regression analyses were performed to determine whether or not serum ucOC or OC concentrations were factors associated with %body fat. Serum ucOC and OC concentrations remained significant factors even after adjusting for gender, HbA1c, body weight-adjusted total daily dose of insulin and duration of diabetes (β = -0.260, P = 0.027; β = -0.254, P = 0.031, respectively). However, serum ucOC and OC concentrations were not correlated with serum adiponectin or free-testosterone concentrations, muscle strength or dose of exogenous insulin. In conclusion, our study demonstrates the inverse correlation between serum ucOC or OC concentrations and body fat in patients with type 1 diabetes.

Correlations between dose of exogenous insulin and serum ucOC or OC concentration separately for MDI and CSII. (DOCX)