Kazuyuki Miyashita

Patients with diabetes often develop abnormalities in lipid metabolism that can promote diabetic complications. Lipidomic studies have demonstrated that certain plasma lipid species are associated with the development of cardiovascular diseases. However, the plasma lipids associated with endothelial dysfunction remain unclear. To identify the lipids associated with flow-mediated vasodilation (FMD), an indicator of endothelial function, in patients with diabetes, we performed a cross-sectional analysis as a subanalysis of a previous lipidomic study. In total, 200 patients with type 2 diabetes were included in the analysis. A total of 55.0% were men, and the mean age (±standard deviation) was 61.1 ± 11.3 years. Their HbA1c and FMD values were 9.04 ± 1.79% (75.3 ± 19.5 mmol/mol) and 5.77 ± 2.55%, respectively. Supercritical fluid chromatography/mass spectrometry-based semi-targeted lipidomic analysis identified 349 lipids belonging to 16 lipid classes. We selected 13 distinctive lipids potentially associated with FMD, according to a sparse-group least absolute shrinkage and selection operator regularized regression model. Of these, seven phospholipids, including three phosphatidylethanolamine (PE) plasmalogens and three phosphatidylinositols (PIs), showed a positive association with FMD after adjusting for atherosclerotic risk factors. These findings may contribute to improving the assessment and management of endothelial dysfunction in patients with diabetes.

Abnormalities in plasma lipoproteins observed in patients with diabetes promote atherosclerosis. However, the association between various lipid species and classes and atherosclerosis remains unclear. Here, we aimed to identify the plasma lipid characteristics associated with atherosclerosis progression in patients with diabetes. We performed semi-targeted lipidomic analysis of fasting plasma samples using supercritical fluid chromatography coupled with mass spectrometry in two independent patient groups with type 2 diabetes (n = 223 and 31) and evaluated cross-sectional associations between plasma lipids and carotid intima-media thickness (CIMT). Ten plasma lipid species, including eight diacylglycerols (DGs), and total DG levels were significantly associated with CIMT in both groups. Patients of the former group were partly observed for 5 years, and we investigated associations between DGs and CIMT progression in these patients (n = 101). As a result, 22 DGs among the 26 identified DGs and total DG (β = 0.398, p < 0.001) were significantly associated with the annual change in CIMT. Furthermore, plasma DG levels improved the predictive ability for CIMT progression, with an adjusted R-squared increase of 0.105 [95% confidence interval: 0.010, 0.232] in the models. Plasma DGs are associated with CIMT progression in patients with type 2 diabetes. Measurement of total plasma DG levels may be beneficial in assessing the risk of atherosclerosis progression.

Introduction: Despite the increasing number of studies using machine learning to develop individualized treatment strategies, only a few have been conducted in patients with type 1 diabetes. This study aimed to identify the characteristics of Japanese patients with type 1 diabetes, classified into subgroups using data‐driven cluster analysis based on pancreatic beta‐cell function, obesity, and glycemic control, and clarify the association between these subgroups and diabetic complications.Materials and Methods: In this cross‐sectional study, a cluster analysis using three variables (C‐peptide, body mass index, and glycated hemoglobin) in 206 Japanese patients with type 1 diabetes was performed. Multivariate logistic regression analysis was performed to compare the risk of diabetic complications by subgroup.Results: The cluster analysis identified four subgroups. Group 2 (n = 58), characterized by high body mass index levels, had a higher risk of hepatic steatosis than the control group (Group 1, n = 90). Meanwhile, Group 3 (n = 44), characterized by high glycated hemoglobin levels, had higher risks of retinopathy, polyneuropathy, elevated brachial–ankle pulse wave velocity, and hepatic steatosis than Group 1 and Group 4 (n = 14), characterized by residual endogenous insulin, had a higher risk of chronic kidney disease than Group 1.Conclusions: The risks of diabetic complications differed between subgroups of Japanese patients with type 1 diabetes. Tailored treatment approaches based on subgroup characteristics are a potential treatment option for reducing the risks of diabetic complications in this population.

Pheochromocytoma/paraganglioma (PPGL) is a rare neuroendocrine tumor with metastatic potential. Peptide receptor radionuclide therapy with 177Lu-DOTATATE, a radiolabeled somatostatin analog, has been used for the treatment of somatostatin receptor-positive PPGLs and has shown promising efficacy and generally mild toxicity. However, rare instances of fatal crises following treatment have been reported. A 50-year-old man with pheochromocytoma was admitted for 177Lu-DOTATATE therapy. At the age of 49, he received 131I-MIBG therapy for the recurrence of pheochromocytoma with bone metastasis. He rejected additional radionuclide treatment because of work commitments. However, the patient’s plasma normetanephrine levels increased to >7,200 pg/mL, which worsened his pain from bone metastasis. Therefore, the patient resumed radionuclide treatment. Because his markedly elevated catecholamine levels might have induced a hypertensive crisis, 177Lu-DOTATATE therapy was applied to reduce staff radiation exposure in an emergency. He developed a fever and tachycardia approximately 30 hours after 177Lu-DOTATATE administration followed by cardiopulmonary arrest with hemoptysis approximately 35 hours after the administration. He was not revived. Postmortem imaging suggested alveolar hemorrhage. 177Lu-DOTATATE administration might induce a fatal crisis, alveolar hemorrhage, and subsequent death. This is the first detailed report of a patient with PPGL who died shortly after 177Lu-DOTATATE therapy. A review of five reported cases of fatal crises after 177Lu-DOTATATE treatment suggests that high catecholamine levels are associated with a risk of crisis. In conclusion, while 177Lu-DOTATATE therapy is generally considered safe, our findings underscore the potential risks of fatal crisis after therapy. Careful monitoring of patients with PPGL should be performed after treatment.

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 aged <= 20 years 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 showed 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 gas chromatography/mass spectrometry‐based non‐target metabolomics techniques.Materials and Methods: Participants of the present study were randomly recruited from the patients with type 2 diabetes hospitalized due to problems with glycemic control (n = 31) and volunteers without diabetes (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 using a multiple reaction monitoring mode was carried out.Results: A principal component analysis showed that metabolome of fasting plasma was different between individuals with and without diabetes. The metabolome of fasting plasma in diabetes patients after treatment was different from that of pre‐treatment, as well as individuals without diabetes. Many amino acids (proline, glycine, serine, threonine, methionine, pyroglutamic acid, glutamine and lysine) were significantly increased by >10% after administering the inpatient diabetes treatment. A hierarchical clustering analysis showed that in the case of patients with markedly decreased 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.

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.

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.

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.