Negative correlation between organ heteroplasmy, particularly hepatic heteroplasmy, and age at death revealed by post-mortem studies of m.3243A > G cases.

Mitochondrial DNA m.3243A > G mutation causes mitochondrial encephalopathy, lactic acidosis, and stroke-like episodes (MELAS) and its associated multi-organ disorders, including diabetes. To clarify associations between m.3243A > G organ heteroplasmy and clinical phenotypes, including the age at death, we combined genetic and pathological examinations from seven unreported and 36 literature cases of autopsied subjects. Clinical characteristics of subjects were as follows: male, 13; female, 28; unknown, 2; the age at death, 36.9 ± 20.2 [4-82] years; BMI, 16.0 ± 2.9 [13.0-22.3]; diabetes, N = 21 (49%), diabetes onset age 38.6 ± 14.2 years; deafness, N = 27 (63%); stroke-like episodes (StLEp), N = 25 (58%); congestive heart failure (CHF), N = 15 (35%); CHF onset age, 51.3 ± 14.5 years. Causes of death (N = 32) were as follows: cardiac, N = 13 (41%); infection, N = 8 (25%); StLEp, N = 4 (13%); gastrointestinal, N = 4 (13%); renal, N = 2 (6%); hepatic, N = 1 (2%). High and low heteroplasmies were confirmed in non-regenerative and regenerative organs, respectively. Heteroplasmy of the liver, spleen, leukocytes, and kidney for all subjects was significantly associated with the age at death. Furthermore, the age at death was related to juvenile-onset (any m.3243A > G-related symptoms appeared before 20) and stroke-like episodes. Multiple linear regression analysis with the age at death as an objective variable showed the significant contribution of liver heteroplasty and juvenile-onset to the age at death. m.3243A > G organ heteroplasmy levels, particularly hepatic heteroplasmy, are significantly associated with the age at death in deceased cases.

Clinical manifestations of a sporadic maturity-onset diabetes of the young (MODY) 5 with a whole deletion of HNF1B based on 17q12 microdeletion.

We report a sporadic case of maturity-onset diabetes of the young type 5 (MODY5) with a whole-gene deletion of the hepatocyte nuclear factor-1beta (HNF1B) gene. A 44-year-old Japanese man who had been diagnosed with early-onset non-autoimmune diabetes mellitus at the age of 23 was examined. He showed multi-systemic symptoms, including a solitary congenital kidney, pancreatic hypoplasia, pancreatic exocrine dysfunction, elevation of the serum levels of liver enzymes, hypomagnesemia, and hyperuricemia. These clinical characteristics, in spite of the absence of a family history of diabetes, prompted us to make the diagnosis of maturity-onset diabetes of the young 5 (MODY 5). One allele deletion of the entire HNF1B gene revealed by multiplex ligation-dependent probe amplification (MLPA) led us to the diagnoses of 17q12 microdeletion syndrome even though there were negative chromosomal analyses with array comparative genomic hybridization (CGH). 17q12 microdeletion syndrome, which is not rare especially in sporadic cases since 17q12 is a typical hot spot for chromosomal deletion, could have complicated the clinical heterogeneity of MODY5.

Fragmented QRS on electrocardiography as a predictor for diastolic cardiac dysfunction in type 2 diabetes.

AIMS/INTRODUCTION: Diastolic cardiac dysfunction in type 2 diabetes (DD2D) is a critical risk of heart failure with preserved ejection fraction. However, there is no established biomarker to detect DD2D. We aimed to investigate the predictive impact of fragmented QRS (fQRS) on electrocardiography on the existence of DD2D. MATERIALS AND METHODS: We included in-hospital patients with type 2 diabetes without heart failure symptoms who were admitted to our institution for glycemic management between November 2017 and April 2021. An fQRS was defined as an additional R' wave or notching/splitting of the S wave in two contiguous electrocardiography leads. DD2D was diagnosed according to the latest guidelines of the American Society of Echocardiography. RESULTS: Of 320 participants, 122 patients (38.1%) had fQRS. DD2D was diagnosed in 82 (25.6%). An fQRS was significantly associated with the existence of DD2D (odds ratio 4.37, 95% confidence interval 2.33-8.20; p < 0.0001) adjusted for seven potential confounders. The correlation between DD2D and diabetic microvascular disease was significant only among those with fQRS. Classification and regression tree analysis showed that fQRS was the most relevant optimum split for DD2D. CONCLUSIONS: An fQRS might be a simple and promising predictor of the existence of DD2D. The findings should be validated in a larger-scale cohort.

Perioperative C-peptide index is associated with the status of diabetes management after pancreatectomy.

AIMS/INTRODUCTION: This study aimed to identify the clinical factors affecting postoperative residual pancreatic ß-cell function, as assessed by the C-peptide index (CPI), and to investigate the association between perioperative CPI and the status of diabetes management after pancreatectomy. MATERIALS AND METHODS: The associations between perioperative CPI and clinical background, including surgical procedures of pancreatectomy, were analyzed in 47 patients who underwent pancreatectomy, and were assessed for pre-and postoperative CPI. The association between perioperative CPI and glycemic control after pancreatectomy was investigated. RESULTS: The low postoperative CPI group (CPI <0.7) had longer duration of diabetes (17.5 ± 14.5 vs 5.5 ± 11.0 years, P = 0.004), a higher percentage of sulfonylurea users (41.7 vs 8.7%, P = 0.003) and a greater number of drug categories used for diabetes treatment (1.9 ± 1.1 vs 0.8 ± 0.8, P <0.001) than did the high postoperative CPI group. Postoperative CPI was higher (1.4 ± 1.2 vs 0.7 ± 0.6, P = 0.039) in patients with low glycosylated hemoglobin (<7.0%) at 6 months after pancreatectomy; preoperative (2.0 ± 1.5 vs 0.7 ± 0.5, P = 0.012) and postoperative CPI (2.5 ± 1.4 vs 1.4 ± 1.1, P = 0.020) were higher in non-insulin users than in insulin users at 6 months after surgery. CONCLUSIONS: The duration of diabetes and preoperative diabetes treatment were associated with residual pancreatic ß-cell function after pancreatectomy. Furthermore, perioperative ß-cell function as assessed by CPI was associated with diabetes management status after pancreatectomy.

Type 1 diabetes woman with repeated miscarriages successfully gave birth after introducing an insulin pump with a predictive low glucose suspend feature.

Sensor-augmented insulin pump therapy with a predictive low glucose suspend (SAP-PLGS) feature is a remarkably progressed modality for the glycemic management of patients with type 1 diabetes. This technology avoids nocturnal hypoglycemia and severe hypoglycemia. A Brazilian woman developed type 1 diabetes at age 11 and was treated with multiple daily insulin injections. At age 20, she was admitted to our internal medicine department for her first pregnancy. Her HbA1c was 7.9% in the 6 weeks of gestation. Although the combination of continuous subcutaneous insulin infusion and a sensor-augmented pump was introduced, she had a miscarriage in the next week. After 6 months, she became pregnant again. Despite an HbA1c of 7.2%, she had another miscarriage. Thereafter, she returned to multiple daily insulin injections and began using intermittently scanned continuous glycemic monitoring. At age 22, she had her third pregnancy. Her HbA1c was 7.3%. SAP-PLGS was then introduced, which reduced her frequent hypoglycemic events and blood glucose fluctuations. She gave birth to a 4137 g boy at 39 weeks without significant complications. Successful delivery can be obtained in women with type 1 diabetes following repeated miscarriages after introducing SAP-PLGS. We hypothesize that the modality might contributed to our patient's miscarriage avoidance by reducing her glycemic fluctuations.

High prevalence of fragmented QRS on electrocardiography in Japanese patients with diabetes irrespective of metabolic syndrome.

AIMS/INTRODUCTION: Fragmented QRS (fQRS) on electrocardiography is a marker of myocardial fibrosis and myocardial scar formation. This study aimed to clarify the relationship of fQRS with diabetes mellitus and metabolic syndrome (MetS) in Japanese patients. MATERIALS AND METHODS: Approximately 702 individuals who had a routine health checkup at the Hokuriku Health Service Association (Toyama, Japan) in October 2014 were enrolled and categorized into one of the following four groups based on MetS and diabetes mellitus status: with diabetes mellitus (+) MetS+ (164 participants); diabetes mellitus+ without MetS (Mets-; 103 participants); diabetes mellitus- MetS+ (133 participants); and diabetes mellitus- MetS- (302 participants). fQRS was assessed using the results of electrocardiography. RESULTS: The prevalence of fQRS was statistically higher in patients with diabetes mellitus+ MetS+ (37%) and diabetes mellitus+ MetS- (35%), than those with diabetes mellitus- MetS+ (14%) or diabetes mellitus- MetS- (10%; P < 0.0001). Significant differences were observed between the fQRS(+) and fQRS(-) groups for age, sex, waist circumference, heart rate, hypertension, hemoglobin A1c, total cholesterol, MetS and diabetes mellitus. The area under the receiver operating characteristic curve for traditional risk factors and diabetes mellitus was 0.72 (P = 0.0007, 95% confidence interval 0.67-0.76), and for traditional risk factors and MetS it was 0.67 (P = 0.28, 95% confidence interval 0.62-0.72). Patients with diabetes mellitus had more than threefold higher likelihood of showing fQRS (odds ratio 3.41; 95% confidence interval 2.25-5.22; P < 0.0001) compared with the reference group without diabetes mellitus, after adjusting for age, sex, dyslipidemia, hypertension and waist circumference. CONCLUSIONS: fQRS was observed more frequently in diabetes mellitus patients than in MetS and control individuals. Diabetes mellitus was the most significant determinant for fQRS among MetS and other traditional metabolic risk factors.

Diastolic Cardiac Function Improvement by Liraglutide Is Mainly Body Weight Reduction Dependent but Independently Contributes to B-Type Natriuretic Peptide Reduction in Patients with Type 2 Diabetes with Preserved Ejection Fraction.

OBJECTIVES: A single-arm prospective study was conducted among Japanese patients with type 2 diabetes having preserved ejection fraction. The aim was to investigate (1) whether liraglutide therapy could improve B-type natriuretic peptide (BNP) levels and diastolic cardiac function assessed by the E-wave to E' ratio (E/E') using transthoracic echocardiography (TTE), and (2) whether E/E' contributed to BNP improvement independent of bodyweight reduction (UMIN000005565). METHODS: Patients with type 2 diabetes and left ventricular ejection fraction (LVEF) ≥ 40% without heart failure symptoms were enrolled, and daily injection with liraglutide (0.9 mg) was introduced. Cardiac functions were assessed by TTE before and after 26 weeks of liraglutide treatment. Diastolic cardiac function was defined as septal E/E' ≥ 13.0. RESULTS: Thirty-one patients were analyzed. BNP and E/E' improved, with BNP levels declining from 36.8 ± 30.5 pg/mL to 26.3 ± 25.9 pg/mL (p = 0.0014) and E/E' dropping from 12.7 ± 4.7 to 11.0 ± 3.3 (p = 0.0376). The LVEF showed no significant changes. E/E' improved only in patients with E/E' ≥ 13.0. Favorable changes in E/E' were canceled when adjusted for body mass index (BMI). Multivariate linear regression analysis revealed that the left ventricular diastolic diameter and ∆E/E'/∆BMI contributed to ∆BNP/baseline BNP (p = 0.0075, R 2 = 0.49264). CONCLUSIONS: Liraglutide had favorable effects on BNP and E/E' but not on LVEF. E/E' improvement was only seen in patients with diastolic cardiac function. Body weight reduction affected the change of E/E'. The BMI-adjusted E/E' significantly contributed to the relative change of BNP. GLP-1 analog treatment could be considered a therapeutic option against diabetic diastolic cardiac dysfunction regardless of body weight. This trial is registered with the University Hospital Medical Information Network in Japan, with clinical trial registration number: UMIN000005565.

Family history of diabetes in both parents is strongly associated with impaired residual ß-cell function in Japanese type 2 diabetes patients.

AIMS/INTRODUCTION: The objective of the present study was to clarify the association of the type and number of first-degree family history of diabetes (FHD) with the clinical characteristics, especially with residual ß-cell function, in type 2 diabetes patients. MATERIALS AND METHODS: A total of 1,131 type 2 diabetes patients were recruited and divided into four groups according to FHD information as follows: (i) patients without FHD (FHD-); (ii) those with at least one sibling who had diabetes without parental diabetes (FHD+); (iii) those with one parent (FHD++); or (iv) those with both parents (FHD+++) who had diabetes with or without a sibling with diabetes. RESULTS: The percentages of the FHD-, FHD+, FHD++ and FHD+++ groups were 49.4%, 13.4%, 34.0% and 3.2%, respectively. Patients in the FHD++ and FHD+++ groups were significantly younger at the time of diabetes diagnosis (P < 0.001) than those in the FHD- and FHD+ groups, even after adjusting for confounding factors. In addition, the levels of insulin secretion were significantly lower in the patients in the FHD+, FHD++ and FHD+++ groups than those in the FHD- group (P < 0.05) after adjusting for confounding factors, and the patients in the FHD+++ group presented with the lowest levels of insulin secretion among the four groups. CONCLUSIONS: Our results showed that in type 2 diabetes patients, the degree of the associations between FHD and clinical characteristics differs according to the number and the type of FHD. In particular, FHD in both parents is most strongly associated with impaired residual ß-cell function.

Ratio of low molecular weight serum adiponectin to the total adiponectin value is associated with type 2 diabetes through its relation to increasing insulin resistance.

AIM: Among the three adiponectin isoforms, a lower ratio of high molecular weight (HMW) adiponectin to total adiponectin (TA) is well known to cause insulin resistance and type 2 diabetes (T2D). However, how the levels of other adiponectin isoforms, such as the middle molecular weight (MMW) and low molecular weight (LMW) isoforms, and their relative ratio to TA change in T2D subjects has not been determined. Therefore, we investigated the association of these adiponectin-related parameters with T2D. METHODS: We examined the associations between adiponectin-related parameters and diabetes in a group of 394 T2D subjects and 374 controls (1st group) randomly selected from among the participants in our previous study. The associations between these parameters and the HOMA-IR in a 2nd group, consisting of the subjects remaining in the 1st group after the exclusion of subjects receiving diabetic medication, were also examined. RESULT: In the 1st group, after adjusting for confounding factor, the levels of all the adiponectin isoforms and the HMW/TA ratio were significantly lower among the diabetic subjects than among the controls (all P values < 0.01). On the contrary, the LMW/TA ratio was significantly higher among the diabetic subjects (P < 0.01) and was positively associated with T2D (odds ratio = 8.64, P < 0.01). In the 2nd group, the HMW/TA ratio was inversely associated with the HOMA-IR; however, the LMW/TA ratio was positively associated with the HOMA-IR (ß for LMW/TA ratio = 0.89, SE = 0.24, P < 0.001), similar to the association with T2D. The MMW/TA ratio was not associated with T2D or the HOMA-IR. CONCLUSION: The current investigation demonstrated that, unlike the reduction in the levels of all the adiponectin isoforms and the HMW/TA ratio, an increased LMW/TA ratio was associated with T2D through its relation to insulin resistance.

FTO Gene Polymorphism Is Associated with Type 2 Diabetes through Its Effect on Increasing the Maximum BMI in Japanese Men.

AIM: Several studies have demonstrated that polymorphisms within the fat-mass and obesity-associated gene (FTO) are associated with type 2 diabetes (T2D). However, whether the effects of the FTO locus on T2D susceptibility are independent of fat-mass increases remains controversial. To investigate this issue, we examined the association of FTO variants with T2D and various aspects of BMI history during adult life in a Japanese population. METHODS: We genotyped SNPs within FTO (rs1121980 and rs1558902) in 760 Japanese patients with T2D who had reached a lifetime maximum BMI (BMImax) before or at the time of diagnosis and 693 control individuals with information regarding their BMImax. RESULTS: The BMImax showed the strongest association with T2D risk among the BMIs evaluated in this study. In the sex-combined analysis, FTO SNPs were not associated with any of the BMI variables or with T2D, but in sex-stratified analyses, both SNPs were significantly associated with the BMImax and rs1558902 was associated with T2D in men. The association of the SNPs with T2D remained significant after adjustments for the current BMI and age, whereas the T2D association of the SNP was no longer significant after adjustments for BMImax and age. CONCLUSIONS: These results suggest that the effects of FTO polymorphisms on T2D susceptibility in Japanese men are mediated through their effect on increasing the BMImax before or at the time of diagnosis.

[Marked improvement of Lambert-Eaton myasthenic syndrome resulting from treatment for small cell lung carcinoma].

A 68-year-old man was admitted to our hospital because of muscle weakness. A complete medical examination led to a diagnosis of small cell lung carcinoma (SCLC) with Lambert-Eaton myasthenic syndrome (LEMS) and the syndrome of inappropriate secretion of antidiuretic hormone (SIADH). Four courses of chemotherapy (carboplatin + etoposide) and one of radiotherapy with a total dose of 45 Gy to the mediastinum were performed and resulted in a partial response in the SCLC. After the second course of chemotherapy, the serum level of antivoltage-gated Ca2+ channel (VGCC) antibody decreased from 190 pg/ml to 120 pg/ml. Marked improvement of the muscle weakness was recognized only after 3 courses of chemotherapy. The patient, who had had difficulty in standing, recovered enough to be able to climb stairs after 4 courses of chemotherapy. Marked improvement of LEMS was achieved by treatment for small cell lung carcinoma.

Secretory units of islets in transplantation index is a useful predictor of insulin requirement in Japanese type 2 diabetic patients.

AIMS/INTRODUCTION: The objective of the present study was to clarify the validity of ß-cell function-related parameters for predicting the insulin requirement of Japanese type 2 diabetic patients. MATERIALS AND METHODS: In 188 patients with type 2 diabetes who had been admitted to the University of Toyama Hospital (Toyama, Japan) without receiving insulin therapy, we carried out a cross-sectional study examining the relationship between the homeostasis model assessment of ß-cell function (HOMA-ß) and C-peptide-based indices, and also carried out a retrospective study to examine the utility for predicting insulin requirement of several ß -cell function-related indices using a receiver operating characteristic (ROC) curve analysis. RESULTS: The secretory units of islets in transplantation index (SUIT) had the strongest correlation with HOMA-ß, followed by the fasting serum C-peptide immunoreactivity index (CPI); the fasting serum C-peptide immunoreactivity itself (F-CPR) had the least correlation. The CPI, HOMA-ß and SUIT were significantly lower in the insulin-requiring group than in the non-insulin-requiring group, even after adjustments for confounding factors (P < 0.01). The areas under the ROC curve for insulin requirement were 0.622, 0.774, 0.808, and 0.759 for F-CPR, CPI, SUIT, and HOMA-ß, respectively. The cut-off values of SUIT, CPI, and HOMA-ß for an over 80% specificity for the prediction of insulin therapy were 23.5, 1.00, and 14.9, respectively. CONCLUSIONS: The present study shows that SUIT is the best predictor of insulin requirement among these ß-cell function-related markers.