Hiroshi Kajio

Immunogenetic and Clinical Characterization of Slowly Progressive IDDM

OBJECTIVE To examine the clinical and immunogenetic heterogeneity of IDDM. RESEARCH DESIGN AND METHODS We divided 207 IDDM patients into groups based on the interval from clinical onset to initiation of insulin therapy: group A (<3 mo, acute clinical-onset group, n = 134), group B (3–12 mo, intermediate group, n = 31), and group C (>13 mo, slowly progressive group, n = 42). Immunogenetic and clinical markers were compared between group A and group C. RESULTS The mode age of onset was higher in group C (52 yr) than group A (10 yr). Group C had a higher prevalence of islet cell antibodies (42.9%, 18 of 42) than group A (25.4%, 34 of 134, P = 0.05). Serum C-peptide immunoreactivity assayed by radioimmunoassay in response to a 100-g oral glucose tolerance test was significantly higher in group C uhan in group A. Group C patients were also more likely to have a family history of NIDDM (26.1%, 11 of 42) among their first-degree relatives than group A patients (11.2%, 15 of 134, P = 0.039). The prevalences of family history of IDDM and endocrine autoimmune diseases were not different between groups C and A. The frequency of complications of endocrine autoimmune disease was not different between group A (6.7%, 9 of 134) and group C (2.3%, 1 of 42). Significant associations with two class I major histocompatibility complex antigens (HLA-A24 and -Bw54) and one class II antigen (HLA-DR4) were observed in group A. Group A patients were assocciated with three diabetogenic HLA-DQ haplotypes including DQA1*0301-DQB1*0401, DQAl*0301-DQBl*0302, and DQA1 *0301-DQB 1*0303. In contrast, group C lacked the association with class I antigens, although HLA-DR4 and HLA-DQA1* 0301-DQB 1*0401 were more common in this group than in control subjects. CONCLUSIONS These results indicate that the clinical subtype with slowly progressive course (slowly progressive IDDM) has distinct findings including late-age onset, high prevalence of islet cell antibodies, preserved β-cell function, and high family history of NIDDM. An additive effect of class I and class II major histocompatibility complex antigens is suggested as an explanation for the acute clinical manifestations and more severe β-cell destruction in group A patients.

In Situ Characterization of Islets in Diabetes With a Mitochondrial DNA Mutation at Nucleotide Position 3243

Changes in the pancreas of diabetic patients with the A-to-G mitochondrial DNA (mtDNA) mutation at nucleotide position 3243 base pair (bp) have not previously been described. The clinical phenotypes of diabetes associated with the mtDNA 3243 mutation range from NIDDM to IDDM. We sought the presence of the mutation and studied volume of β-, α-, and δ-cells, mitochondrial enzyme activity, and presence of apoptosis in diabetic pancreases obtained at autopsy. Pancreases were obtained from 16 patients with IDDM, from 18 patients with NIDDM, and from 11 nondiabetic patients. Mitochondrial enzyme activity was determined for cytochrome c oxidase (COX), the subunits of which are partially encoded by mtDNA, and for succinate dehy-drogenase (SDH), the subunits of which are solely encoded by nuclear DNA. The volumes of islet β-, α-, and δ-cells were estimated by computerized morphometry. Pancreatic cells were examined for apoptosis by an in situ end-labeling procedure. The mtDNA 3243 mutation was detected in 1 of 16 (6%) pancreases from the IDDM patients; none of the pancreases from 18 NIDDM patients and 11 nondiabetic patients had the mutation. The single patient with the mtDNA 3243 mutation was a 56-year-old woman with IDDM, aged 39 years at diabetes onset, whose mother was diagnosed with NIDDM. The patient had a history of secondary failure of oral hypoglycemie agents and had a marked decrease in the number of β-cells. The islet β-cells and non-β-cells of the patient showed extremely decreased COX enzyme activity. The islet cells in the patient showed a high activity when examined for SDH. Some pancreatic exocrine cells also showed decreased COX activity with high SDH activity. In IDDM, NIDDM, and nondiabetic patients without the mtDNA 3243 mutation, only weak staining for SDH of the islet cells showed. The percentage of heteroplasmy of the mtDNA 3243 mutation in pancreatic micropunched islet specimens was 63 ± 5% (mean ± SD) in the islets, 32 ± 3% in the exocrine pancreas, and 8 ± 1% in peripheral polymorphonuclear cells. Apoptotic cells were not observed in the IDDM pancreas in the patient with the mtDNA 3243 mutation. The fact that higher levels of mutated mtDNA at 3243 bp were found in affected islets rather than in other tissue suggests that the distribution of the mutant may determine the effect on islet function. A characteristic decrease in the mitochondrial enzyme with COX activity and accelerated SDH activity of the affected islets may provide new insights into the pathogenesis of mitochondrial diabetes.

Vital Signs, QT Prolongation, and Newly Diagnosed Cardiovascular Disease during Severe Hypoglycemia in Type 1 and Type 2 Diabetic Patients

OBJECTIVE To assess vital signs, QT intervals, and newly diagnosed cardiovascular disease during severe hypoglycemia in diabetic patients. RESEARCH DESIGN AND METHODS From January 2006 to March 2012, we conducted a retrospective cohort study to assess type 1 and type 2 diabetic patients with severe hypoglycemia at a national center in Japan. Severe hypoglycemia was defined as the presence of any hypoglycemic symptoms that could not be resolved by the patients themselves in prehospital settings. RESULTS A total of 59,602 cases that visited the emergency room by ambulance were screened, and 414 cases of severe hypoglycemia were analyzed. The median (interquartile range) blood glucose levels were not significantly different between the type 1 diabetes mellitus (T1DM) (n = 88) and type 2 diabetes mellitus (T2DM) (n = 326) groups (32 [24–42] vs. 31 [24–39] mg/dL, P = 0.59). During severe hypoglycemia, the incidences of severe hypertension (≥180/120 mmHg), hypokalemia (<3.5 mEq/L), and QT prolongation were 19.8 and 38.8% (P = 0.001), 42.4 and 36.3% (P = 0.30), and 50.0 and 59.9% (P = 0.29) in the T1DM and T2DM groups, respectively. Newly diagnosed cardiovascular disease during severe hypoglycemia and death were only observed in the T2DM group (1.5 and 1.8%, respectively). Blood glucose levels between the deceased and surviving patients in the T2DM group were significantly different (18 [14–33] vs. 31 [24–39] mg/dL, P = 0.02). CONCLUSIONS T1DM and T2DM patients with severe hypoglycemia experienced many critical problems that could lead to cardiovascular disease, fatal arrhythmia, and death.

Comparison of characteristics and healing course of diabetic foot ulcers by etiological classification: Neuropathic, ischemic, and neuro-ischemic type

AIMS To identify differences in the characteristics of patients with diabetic foot ulcers (DFUs) according to their etiological classification and to compare their healing time. METHODS Over a 4.5-year period, 73 patients with DFUs were recruited. DFUs were etiologically classified as being of neuropathic, ischemic, or neuro-ischemic origin. Descriptive analyses were performed to characterize study subjects, foot-related factors, and healing outcome and time. Duration of healing was assessed using the Kaplan-Meier method. Healing time among the three types was compared using the log rank test. RESULTS The number of patients manifesting neuropathic, ischemic, and neuro-ischemic ulcers was 30, 20, and 14, respectively. Differences were identified for age, diabetes duration, body mass index, hypertension, and estimated glomerular filtration rate. Patients with neuro-ischemic ulcers had better ankle-brachial index, skin perfusion pressure (SPP), and transcutaneous oxygen pressure values compared to those with ischemic ulcers. The average time in which 50% of patients had healed wounds was 70, 113, and 233 days for neuropathic, neuro-ischemic, and ischemic ulcers, respectively. Main factors associated with healing were age and SPP values. CONCLUSIONS Based on the etiological ulcer type, DFU healing course and several patient factors differed. Failure to consider the differences in DFU etiology may have led to heterogeneity of results in previous studies on DFUs.

Asymptomatic coronary heart disease in patients with type 2 diabetes with vascular complications: a cross-sectional study

Background Recent studies have suggested that microvascular and macrovascular diseases are associated with coronary events. Objective To test the hypothesis that asymptomatic coronary heart disease (CHD) may be present in many patients with diabetes with vascular complications. Design From April 2009 to August 2010, the authors conducted a cross-sectional study to assess the prevalence of asymptomatic CHD among patients with type 2 diabetes with vascular complications at a national diabetes centre in Japan. Eligibility criteria included patients with type 2 diabetes with no known CHD and one or more of the following four criteria: (1) proliferative diabetic retinopathy or after photocoagulation; (2) estimated glomerular filtration rate <30 ml/min/1.73 m2 or an estimated glomerular filtration rate <45 ml/min/1.73 m2 plus albuminuria; (3) peripheral arterial disease; and (4) cerebrovascular disease. Each patient underwent a stress single-photon emission computed tomography; patients with myocardial perfusion abnormalities then underwent coronary angiography. Results A total of 1008 patients with type 2 diabetes were screened, and 122 eligible patients consented to participate. Stress single-photon emission computed tomography revealed myocardial perfusion abnormalities in 96 (79%) patients. Of the 112 patients who completed the study protocol, 59 (53%) had asymptomatic CHD with ≥50% diameter stenosis. Additionally, 35 (31%) patients had multivessel disease or left main disease, and 42 (38%) had a coronary artery with ≥75% diameter stenosis. In the multivariate logistic-regression analysis to identify coronary risk factors associated with asymptomatic CHD, the only significant predictor was male sex (OR 6.18; 95% CI 2.30 to 16.64; p<0.001). Conclusions Asymptomatic CHD with ≥50% diameter stenosis and myocardial perfusion abnormalities was detected in more than half of the patients with type 2 diabetes with vascular complications.

Risk of Cardiovascular Events in Patients With Diabetes Mellitus on β-Blockers

Although the use of &bgr;-blockers may help in achieving maximum effects of intensive glycemic control because of a decrease in the adverse effects after severe hypoglycemia, they pose a potential risk for the occurrence of severe hypoglycemia. This study aimed to evaluate whether the use of &bgr;-blockers is effective in patients with diabetes mellitus and whether its use is associated with the occurrence of severe hypoglycemia. Using the ACCORD trial (Action to Control Cardiovascular Risk in Diabetes) data, we performed Cox proportional hazards analyses with a propensity score adjustment. The primary outcome was the first occurrence of a cardiovascular event during the study period, which included nonfatal myocardial infarction, unstable angina, nonfatal stroke, and cardiovascular death. The mean follow-up periods (±SD) were 4.6±1.6 years in patients on &bgr;-blockers (n=2527) and 4.7±1.6 years in those not on &bgr;-blockers (n=2527). The cardiovascular event rate was significantly higher in patients on &bgr;-blockers than in those not on &bgr;-blockers (hazard ratio, 1.46; 95% confidence interval, 1.24–1.72; P<0.001). In patients with coronary heart disease or heart failure, the cumulative event rate for cardiovascular events was also significantly higher in those on &bgr;-blockers than in those not on &bgr;-blockers (hazard ratio, 1.27; 95% confidence interval, 1.02–1.60; P=0.03). The incidence of severe hypoglycemia was significantly higher in patients on &bgr;-blockers than in those not on &bgr;-blockers (hazard ratio, 1.30; 95% confidence interval, 1.03–1.64; P=0.02). In conclusion, the use of &bgr;-blockers in patients with diabetes mellitus was associated with an increased risk for cardiovascular events.

Seasonal variations of severe hypoglycemia in patients with type 1 diabetes mellitus, type 2 diabetes mellitus, and non-diabetes mellitus: clinical analysis of 578 hypoglycemia cases.

AbstractBlood glucose control in patients with diabetes mellitus (DM) is reportedly influenced by the seasons, with hemoglobin A1c (HbA1c) levels decreasing in the summer or warm season and increasing in the winter or cold season. In addition, several studies have shown that sepsis is also associated with the seasons. Although both blood glucose control and sepsis can strongly affect the occurrence of severe hypoglycemia, few studies have examined the seasonal variation of severe hypoglycemia. The aim of the present study is to examine the association between severe hypoglycemia and the seasons in patients with type 1 diabetes mellitus (T1DM), type 2 diabetes mellitus (T2DM), and non-diabetes mellitus (non-DM). We retrospectively reviewed all the patients with severe hypoglycemia at a national center in Japan between April 1, 2006 and March 31, 2012. A total of 57,132 consecutive cases that had visited the emergency room by ambulance were screened, and 578 eligible cases of severe hypoglycemia were enrolled in this study. The primary outcome was to assess the seasonality of severe hypoglycemia. In the T1DM group (n = 88), severe hypoglycemia occurred significantly more often in the summer than in the winter (35.2% in summer vs 18.2% in winter, P = 0.01), and the HbA1c levels were highest in the winter and lowest in the summer (9.1% [7.6%–10.1%] in winter vs 7.7% [7.1%–8.3%] in summer, P = 0.13). In the non-DM group (n = 173), severe hypoglycemia occurred significantly more often in the winter than in the summer (30.6% in winter vs 19.6% in summer, P = 0.01), and sepsis as a complication occurred significantly more often in winter than in summer (24.5% in winter vs 5.9% in summer, P = 0.02). In the T2DM group (n = 317), the occurrence of severe hypoglycemia and the HbA1c levels did not differ significantly among the seasons. The occurrence of severe hypoglycemia might be seasonal and might fluctuate with temperature changes. Patients should be treated more carefully during the season in which severe hypoglycemia is more common.

Improvement of glycemic control after periodontal treatment by resolving gingival inflammation in type 2 diabetic patients with periodontal disease.

Aims/Introduction:  Chronic inflammation aggravates glycemic control in patients with type 2 diabetes mellitus. An increase or decrease in the release and activities of various inflammatory mediators, such as tumor necrosis factor (TNF)‐α, interleukin (IL)‐6, and C‐reactive protein (CRP), are presumed to be responsible for inducing insulin resistance. The purpose of the present study was to examine the effects of non‐surgical periodontal treatment incorporating topical antibiotics on glycemic control and serum inflammatory mediators in patients with type 2 diabetes mellitus with periodontitis.

Association between hyperinsulinemia and increased risk of cancer death in nonobese and obese people: A population-based observational study

Obesity, metabolic syndrome and type 2 diabetes are associated with cancer‐related mortality. We assessed whether hyperinsulinemia is a risk factor for cancer death in nonobese people without diabetes. We conducted a prospective cohort study using data from the National Health and Nutrition Examination Survey 1999–2010 and followed up the participants until December 31, 2011. For the primary analysis of cancer mortality, we used Cox proportional hazard models to estimate hazard ratios (HRs) in the participants with hyperinsulinemia and those without. Hyperinsulinemia was defined as a fasting insulin level of ≥10 μU/mL. To identify causes of deaths, the International Classification of Diseases, Tenth Revision codes were used. This study included 9,778 participants aged 20 years or older without diabetes or a history of cancer: 6,718 nonobese participants (2,057 with hyperinsulinemia [30.6%]) and 3,060 obese participants (2,303 with hyperinsulinemia [75.3%]). A total of 99.9% completed follow‐up. Among all study participants, cancer mortality was significantly higher in those with hyperinsulinemia than in those without hyperinsulinemia (adjusted HR 2.04, 95% CI 1.24–3.34, p = 0.005). Similarly, among nonobese participants, multivariable analysis showed that cancer mortality was significantly higher in those with hyperinsulinemia than in those without (adjusted HR 1.89, 95% CI 1.07–3.35, p = 0.02). Considering that nonobese people with hyperinsulinemia were at higher risk of cancer mortality than those without hyperinsulinemia, improvement of hyperinsulinemia may be an important approach for preventing cancer regardless of the presence or absence of obesity.

Relationship between insulin-dependent diabetes mellitus (IDDM) and non-insulin-dependent diabetes mellitus: β-cell function, islet cell antibody, and haptoglobin in parents of IDDM patients

To examine the relationship between non-insulin-dependent diabetes mellitus (NIDDM) and insulin-dependent diabetes mellitus (IDDM), we studied beta-cell function, HLA type, and serologic markers of IDDM and NIDDM in the parents of IDDM patients. Fifty-two parents of 33 IDDM patients were examined in terms of islet-cell antibody (ICA) status, haptoglobin phenotype, HLA type, and insulin responses during an oral glucose tolerance test (OGTT). Twenty-seven parents were prospectively evaluated for up to 113 months. They were divided into the following three groups based on pattern of ICA positivity during the follow-up period: group 1, persistently positive ICA (n = 4); group 2, fluctuating ICA (n = 7); and group 3, persistently negative ICA (n = 16). Twenty-three percent (12 of 52) of the parents of IDDM patients had NIDDM, and 12% (six of 52) of the matched controls did. The prevalence of ICA in the parents (11 of 52, 21%) was greater than in normal controls (one of 112, P < .01). Diabetic parents tended to show a higher prevalence of ICA (six of 12, 50%) than nondiabetic parents (six of 40, 15%; P = .06). ICA-positive parents showed higher glucose levels and lower insulin responses than ICA-negative parents. Three of four parents in group 1 slowly progressed to an insulin-dependent state during 25 +/- 3 months of follow-up evaluation. Parents in group 2 and group 3 did not show any changes in glucose levels or insulin responses during the study.(ABSTRACT TRUNCATED AT 250 WORDS)