Association of Impaired Awareness of Hypoglycemia with Driving Safety and Hypoglycemia Problem-solving Abilities among Patients with Type 1 Diabetes in Japan: The PR-IAH Study.

Objective Patients with type 1 diabetes (T1D) and impaired awareness of hypoglycemia (IAH) are at an elevated risk of experiencing automobile accidents. We therefore investigated the association of IAH with driving safety and hypoglycemia problem-solving abilities in adults with T1D. Methods This cross-sectional survey used Gold's method in adult patients with T1D at the National Hospital Organization (NHO) Hospital from February 14, 2020, to October 31, 2021. The participants were divided into control and IAH groups. The data included information on demographics, worries and distress regarding hypoglycemia, hypoglycemia problem-solving abilities, and adverse driving events. Patients We enrolled 233 participants (mean age: 48.5±12.8 years old, mean hemoglobin A1c level: 7.6%±0.9%) from NHO collaborating centers in Japan. Results Among a total of 233 participants (mean age: 48.5±12.8 years old, mean hemoglobin A1c level: 7.6%±0.9%), the prevalence rate of IAH was 11.6% [95% confidence interval (CI): 7.8-16.4%]. IAH was significantly associated with near-miss car accidents (odds ratio: 5.41; 95% CI:1.64-17.80). Diabetic peripheral neuropathy was associated with an increased risk of IAH, while treatment with continuous subcutaneous insulin infusion was not associated with a decreased risk of IAH. The average hypoglycemia problem-solving perception, detection control, and seeking preventive strategies scores in the IAH group were significantly reduced compared with those in the control group. Conclusion IAH was associated with an increased risk of near-miss car accidents among adults with T1D. Furthermore, good hypoglycemia problem-solving abilities were associated with a decreased risk of IAH.

Protective and risk factors of impaired awareness of hypoglycemia in patients with type 1 diabetes: a cross-sectional analysis of baseline data from the PR-IAH study.

BACKGROUND: Hypoglycemia in type 1 diabetes (T1D) is associated with mortality and morbidity, especially when awareness of hypoglycemia is impaired. This study aimed to investigate the protective and risk factors for impaired awareness of hypoglycemia (IAH) in adults with T1D. METHODS: This cross-sectional study enrolled 288 adults with T1D (mean age, 50.4 ± 14.6 years; male, 36.5%; diabetes duration, 17.6 ± 11.2 years; mean HbA1c level, 7.7 ± 0.9%), who were divided into IAH and non-IAH (control) groups. A survey was conducted to assess hypoglycemia awareness using the Clarke questionnaire. Diabetes histories, complications, fear of hypoglycemia, diabetes distress, hypoglycemia problem-solving abilities, and treatment data were collected. RESULTS: The prevalence of IAH was 19.1%. Diabetic peripheral neuropathy was associated with an increased risk of IAH (odds ratio [OR] 2.63; 95% confidence interval [CI] 1.13-5.91; P = 0.014), while treatment with continuous subcutaneous insulin infusion and hypoglycemia problem-solving perception scores were associated with a decreased risk of IAH (OR, 0.48; 95% CI, 0.22-0.96; P = 0.030; and OR, 0.54; 95% CI, 0.37-0.78; P = 0.001, respectively). There was no difference in continuous glucose monitoring use between the groups. CONCLUSION: We identified protective factors in addition to risk factors for IAH in adults with T1D. This information may help manage problematic hypoglycemia. TRIAL REGISTRATION: University hospital Medical Information Network (UMIN) Center: UMIN000039475). Approval date 13 February 2020.

Higher Serum Soluble TREM2 as a Potential Indicative Biomarker for Cognitive Impairment in Inadequately Controlled Type 2 Diabetes Without Obesity: The DOR-KyotoJ-1.

Objective: Type 2 diabetes is a risk factor for dementia. We investigated whether serum levels of soluble triggering receptor expressed on myeloid cell 2 (sTREM2), a soluble form of the cell surface receptor TREM2, were predictive of cognitive impairment in type 2 diabetes without obesity. Methods: A total of 166 Japanese patients with type 2 diabetes without obesity were followed-up for 2 years. We measured clinical parameters, assessed cognitive function using the mini-mental state examination (MMSE), quantified and divided serum sTREM2 levels into quartiles, and examined the longitudinal associations. Results: During the follow-up, HbA1c levels were elevated in 98 patients and decreased in 68 patients. In the HbA1c-elevated group, higher sTREM2 levels at baseline showed a significant association with a greater tendency for reduction in MMSE scores (P for trend = 0.015), whereas they were not significantly associated with other examined parameters. In the HbA1c-decreased group, there was no significant association between sTREM2 levels at baseline and changes in MMSE scores, but higher sTREM2 levels at baseline were significantly associated with a greater tendency for reduction in waist circumference (P for trend = 0.027), homeostasis model assessment of insulin resistance (P for trend = 0.039), and sTREM2 levels (P for trend = 0.023). Conclusions: Glycemic control is suggested to be important in preventing cognitive impairment in patients with type 2 diabetes without obesity. Higher serum sTREM2 levels would be a predictive marker for cognitive impairment in inadequately controlled type 2 diabetes without obesity.

Cardio-ankle vascular index predicts for the incidence of cardiovascular events in obese patients: a multicenter prospective cohort study (Japan Obesity and Metabolic Syndrome Study: JOMS).

OBJECTIVE: The cardio-ankle vascular index (CAVI) is an index of arterial stiffness less dependent on blood pressure and an indicator suitable for assessing the arterial dysfunction. However, it remains unclear whether CAVI can predict the outcome of cardiovascular diseases (CVD) in obese patients. METHODS: A total of 425 obese Japanese outpatients (189 men and 236 women, mean age: 51.5 years) were enrolled in a multicenter prospective cohort Japan, the Japan Obesity and Metabolic Syndrome Study (JOMS). Primary analysis regarding measurements of cardiovascular risk factors including CAVI and the occurrence of macrovascular complications was based on following the participants over a 5-year period. RESULTS: Of the eligible patients, 300 (78%) were followed into the fifth year. During the study period, 15 coronary heart disease, 7 stroke, and 6 arteriosclerosis obliterans events occurred. All events occurred in 28 patients, and CVD incidence rate was 15.8 per 1000 person-years. In the analysis of adjusted models for traditional risk factors, CAVI was a significant factor for the incidence of events. In addition, high CAVI and low HDL-cholesterol were significant factors for the incidence of events in Cox stepwise multivariate analysis when age- and sex-adjusted (CAVI [per 1]: HR = 1.44 [1.02-2.02], p = 0.037; HDL-cholesterol [per 1 mmol/L]: HR = 0.20 [0.06-0.69], p = 0.011). In addition, CAVI added value to atherosclerotic cardiovascular disease risk score in predicting the development of CVD. CONCLUSION: This study demonstrates for the first time that CAVI is an effective predictor of CVD events in obese patients.

Comparison of cystatin C- and creatinine-based estimated glomerular filtration rate to predict coronary heart disease risk in Japanese patients with obesity and diabetes.

The aim of this study is to determine which indicator of chronic kidney disease most closely correlates with 10-year Framingham coronary heart disease (CHD) risk among serum creatinine, serum cystatin C (S-CysC), urine albumin-creatinine ratio (UACR), estimated creatinine-based GFRs (eGFRcre), and estimated CysC-based GFRs (eGFRcys) in patients with obesity and diabetes. Serum creatinine, S-CysC, UACR, and cardio-ankle vascular index (CAVI) were examined in 468 outpatients with obesity and type 2 diabetes, free of severe renal dysfunction or previous history of cardiovascular disease, as a cross-sectional survey using baseline data from the multi-centered Japan Diabetes and Obesity Study. S-CysC and eGFRcys had significantly stronger correlations with the 10-year Framingham CHD risk than serum creatinine, eGFRcre, and UACR (creatinine, ρ = 0.318; S-CysC, ρ = 0.497; UACR, ρ = 0.174; eGFRcre, ρ = -0.291; eGFRcys, ρ = -0.521; P < 0.01 by Fisher's z-test). S-CysC and eGFRcys had significantly stronger correlations with CAVI than serum creatinine, eGFRcre, and UACR (creatinine, ρ = 0.198; S-CysC, ρ = 0.383; UACR, ρ = 0.183; eGFRcre, ρ = -0.302; eGFRcys, ρ = -0.444; P < 0.05 by Fisher's z-test). The receiver operating characteristic curves to distinguish the high-risk patients for CHD revealed significantly larger areas under the curve of S-CysC and eGFRcys than those of serum creatinine, UACR, and eGFRcre (serum creatinine, 0.64; S-CysC, 0.75; UACR, 0.56; eGFRcre, 0.63; eGFRcys, 0.76; P < 0.01). The data suggested that eGFRcys can be more predictive of the 10-year CHD risk than eGFRcre in Japanese patients with obesity and diabetes.

Efficacy and safety of sitagliptin in Japanese patients with type 2 diabetes switched from glinides.

AIMS/INTRODUCTION: The efficacy and safety of sitagliptin, a dipeptidyl peptidase (DPP)-4 inhibitor, were compared with those of glinides in Japanese patients with type 2 diabetes. MATERIALS AND METHODS: The participants were 82 patients with type 2 diabetes (glycated hemoglobin [HbA1c] ≥6.0% and <10%) under treatment with glinides for glucose control. The participants were randomly assigned to a group (n = 44) receiving continuous treatment with glinides and a group (n = 38) switched to sitagliptin. Patients were followed for 12 weeks to evaluate glucose control. A meal tolerance test was carried out in weeks 0 and 12 to examine the pancreatic secretory response to postprandial hyperglycemia. RESULTS: The changes in HbA1c from week 0 to week 12 were -0.25 and -0.05% in the sitagliptin and glinide groups, respectively, with a significant improvement with sitagliptin. The differences in fasting plasma glucose (FPG), glycoalbumin and 1,5-anhydroglucitol between the two groups were 14.2 mg/dL, 0.7% and 1.7 µg/mL, respectively, showing significant improvements with sitagliptin. In the meal tolerance test, glucose at 0 min was lower in the sitagliptin group; however, there were no differences in glucose elevation at 30 and 60 min compared with 0 min. Plasma insulin and glucagon secretion at week 12 were significantly lower than at baseline in the sitagliptin group. Adverse events including hypoglycemia did not differ between the groups. CONCLUSIONS: FPG decreased and glucose control improved in patients who switched from glinides to sitagliptin. Sitagliptin decreased secretion of insulin and glucagon in a meal tolerance test compared with glinides, whereas the agents showed similar inhibition of postprandial hyperglycemia. This trial was registered with UMIN (UMIN-CTR no. 000003479).

Remnant-like particle cholesterol and serum amyloid A-low-density lipoprotein levels in obese subjects with metabolic syndrome.

BACKGROUND: Although the circulating levels of remnant-like particle cholesterol (RLP-C) or serum amyloid A-low-density lipoprotein (SAA-LDL) can individually be increased in subjects with metabolic syndrome (MetS), the correlation between the two markers has not yet been previously studied. In the present study, we aimed to investigate the correlation between RLP-C and SAA-LDL in obese subjects with MetS in comparison to those without MetS. METHODS: A total of 436 obese subjects were divided into groups with MetS and without MetS (male/female 75/143, mean age 49 years, current smokers 16% in both groups) by applying the age-, gender-, and smoking habit-matching method based on the database in the multicenter Japan Obesity and Metabolic Syndrome Study (JOMS). The data, including RLP-C and SAA-LDL, were compared in each group. RESULTS: Significantly greater levels of RLP-C or SAA-LDL were observed in subjects with MetS in comparison with those without MetS. There was a significantly positive correlation between RLP-C and SAA-LDL, with a relatively greater correlation in subjects with MetS (coefficient = 0.290, P < .01) in comparison with those without MetS (coefficient = 0.181, P < .01). Multivariate-adjusted correlation analyses showed a greater correlation between RLP-C and SAA-LDL in subjects with MetS, relative to those without MetS, although the significant correlation decreased in both groups when the hypertriglyceridemic states were taken into account. CONCLUSIONS: A relatively greater and positive correlation between greater levels of RLP-C and SAA-LDL in obese subjects with MetS, in comparison with those without MetS, may be linked to the development of MetS-related cardiovascular disease.

Multi-center study on the prevalence of hypothyroidism in patients with hypercholesterolemia.

Hypercholesterolemia is one of the most representative disorders of the common diseases. To evaluate the prevalence of hypothyroidism in the population of adult hypercholesterolemia, we prospectively examined the thyroid function in patients with untreated or treated hypercholesterolemia as a multi-center survey. Subjects were the patients who were treated with some antilipemic agents or the untreated patients whose total cholesterol (TC) was over 220 mg/dL and/or LDL-cholesterol (LDL-C) over 140 mg/dL. Among 737 cases recruited, 725 cases (300 males and 425 females) participated in the survey including the thyroid function test. The patient's backgrounds include hypertension (51%), diabetes mellitus (49%), fatty liver (17%), smoking (15%), and habitual drinking (10%). The 72% of the patients were treated with some antilipemic agents and the mean values of TC, LDL-C, triglyceride (TG), HDL-cholesterol (HDL-C), and LDL-C/HDL-C ratio (L/H) were 204.5 mg/dL, 119.6 mg/dL, 144.4 mg/dL, 60.7 mg/dL and 2.25, respectively. The primary hypothyroidism was seen in 27 cases (3.7%) (11 males, 16 females) with subclinical hypothyroidism in 17 cases (2.4%) and overt hypothyroidism in 10 cases (1.4%). The central hypothyroidism was seen in 4 cases (0.6%). The prevalence of hypothyroidism was 4.3% in patients with hypercholesterolemia. Taking account of the large number of patients with dyslipidemia and importance of avoiding unnecessary administration and associated adverse effects, evaluation of the thyroid function could be warranted in patients with dyslipidemia although cost-benefit issues waits further investigation.

Urinary cystatin C as a potential risk marker for cardiovascular disease and chronic kidney disease in patients with obesity and metabolic syndrome.

BACKGROUND AND OBJECTIVES: Obesity and metabolic syndrome (MS) increase the risk of cardiovascular disease (CVD), chronic kidney disease (CKD), and all-cause mortality. Serum cystatin C (S-CysC), a marker of GFR, has been shown to be associated with CVD and CKD. This study was designed to elucidate the association of urinary CysC (U-CysC), a marker of renal tubular dysfunction, with CVD and CKD risk factors in patients with obesity and MS. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: The U-CysC-creatinine ratio (UCCR) was examined in 343 Japanese obese outpatients enrolled in the multi-centered Japan Obesity and Metabolic Syndrome Study. RESULTS: UCCR was positively correlated with urine albumin-creatinine ratio (UACR) and S-CysC and negatively correlated with estimated GFR (eGFR). Among obese patients, UCCR was significantly higher in MS patients than in non-MS patients. UCCR had significant correlations with the number of components of MS and arterial stiffness, all of which are CVD predictors, similarly to UACR (P<0.05). Interestingly, diet- and exercise-induced weight reduction for 3 months significantly decreased only UCCR among all of the renal markers examined (P<0.01), in parallel with the decrease in BMI, HbA1c, and arterial stiffness, suggesting the beneficial effect of weight reduction on renal tubular dysfunction. CONCLUSIONS: This study demonstrates that UCCR is significantly associated with renal dysfunction, the severity of MS, arterial stiffness, and weight change in obese patients. The data of this study suggest that U-CysC could serve as a CVD and CKD risk factor in patients with obesity and MS.

A novel oxidized low-density lipoprotein marker, serum amyloid A-LDL, is associated with obesity and the metabolic syndrome.

BACKGROUND: The putative association between the novel oxidized low-density lipoprotein markers, serum amyloid A-LDL (SAA-LDL) and alpha1-antitrypsin-LDL (AT-LDL), and obesity and the metabolic syndrome (MetS) has not been previously studied. In the present report, we investigated the levels of SAA-LDL and AT-LDL in relation to the components of the MetS. We also assessed the effect of weight reduction therapy on serum SAA-LDL and AT-LDL levels among obese subjects. METHODS: The study population included 421 obese Japanese outpatients (185 men and 236 women, mean age: 51.1 years) enrolled in the multicenter Japan Obesity and Metabolic Syndrome Study (JOMS). The novel oxidized low-density lipoprotein markers, serum SAA-LDL and AT-LDL, were measured in all participants. RESULTS: Circulating SAA-LDL levels were independently associated with the presence and the number of components of the MetS. SAA-LDL levels were also significantly and independently correlated with high-sensitivity C-reactive protein. Notably, successful weight reduction resulted in a significant decrease in circulating SAA-LDL concentrations. Levels of AT-LDL were not associated with the MetS. CONCLUSIONS: We documented, for the first time, that serum SAA-LDL levels correlate positively with the number of components of the MetS and weight reduction. Whether SAA-LDL may be involved in the pathophysiology of MetS and atherosclerosis deserves further investigation.

Evaluation of the cardio-ankle vascular index, a new indicator of arterial stiffness independent of blood pressure, in obesity and metabolic syndrome.

Aortic stiffness is predictive of cardiovascular diseases (CVD) and mortality in lifestyle-related diseases. The cardio-ankle vascular index (CAVI), a new index of arterial stiffness, was recently developed by measuring of pulse wave velocity (PWV) and blood pressure (BP). CAVI is adjusted for BP based on stiffness parameter beta and is less influenced by BP, suggesting its superiority over brachial-ankle PWV (baPWV). However, there are currently no reports on the usefulness of CAVI as an atherogenic index in obesity and metabolic syndrome (MS). Among the 325 obese Japanese outpatients enrolled in the multi-centered Japan Obesity and Metabolic Syndrome Study, 216 patients (67%) met the criteria of MS according to the modified National Cholesterol Education Program-Adult Treatment Panel III. CAVI values were significantly higher in MS than in non-MS patients, whereas there was no significant difference in body mass index, total cholesterol, and low-density lipoprotein-cholesterol between both groups. CAVI values were weakly correlated with BP but closely correlated with the severity of MS and MS-related parameters such as hypoadiponectinemia, relative to baPWV. Furthermore, weight-reduction therapy through diet and exercise over a 3-month period significantly decreased CAVI values in parallel with increasing adiponectin. This study demonstrates for the first time that CAVI is a good indicator of arterial stiffness. It is closely correlated with the severity of MS and CVD risks in obesity and independent of BP, and is thus superior to baPWV. Therefore, the determination of arterial stiffness by CAVI may be useful for evaluating and managing the CVD risks of MS patients.

Monocyte chemoattractant protein-1 promoter -2518 polymorphism is associated with post-challenge insulin and glucose levels in non-diabetic Japanese subjects.

We investigated that the association of MCP-1 polymorphism at position -2518 with insulin sensitivity and insulin secretion by measuring the fasting and post-challenge glucose and insulin levels during 75g OGTT in 409 non-diabetic Japanese subjects. The blood sampling was performed before glucose loading and after 30 and 120 min. Polymorphism was evaluated by PCR-RFLP method by genomic DNA isolated from peripheral blood leukocytes. The genotype distribution was 44.8% for G/G, 46.0% for G/A and 9.2% for A/A. The plasma glucose levels were significantly increased in A/A as compared to G/G (p<0.05), but it was not compared with G/A at 120 min. The serum insulin levels were significantly increased in A/A as compared to G/A (p<0.05) or G/G (p<0.05) at 30 min. Moreover, the serum insulin levels in A/A were significantly increased compared with G/A (p<0.02) or G/G (p<0.005) at 120 min. Elevation in post-challenge glucose (120 min) and insulin levels (30 and 120 min) suggests that reduced insulin sensitivity during glucose loading occurs in subjects with A/A polymorphism. The present study demonstrates that the A/A polymorphism of the MCP-1 gene at position -2518 is associated with insulin resistance during glucose loading in non-diabetic Japanese subjects.

Different metabolic correlations of thrombin-activatable fibrinolysis inhibitor and plasminogen activator inhibitor-1 in non-obese type 2 diabetic patients.

We investigated the plasma levels of thrombin-activatable fibrinolysis inhibitor (TAFI), plasminogen activator inhibitor-1 (PAI-1) and their relation with clinical and metabolic parameters in non-obese type 2 diabetic patients. The plasma levels of TAFI and PAI-1 were evaluated in 47 non-obese type 2 diabetic patients and 31 normal subjects. The intra-abdominal visceral and subcutaneous fat areas were measured by computed tomography (CT). The degree of insulin resistance was evaluated by the euglycemic-hyperinsulinemic clamp technique using artificial pancreas. The plasma levels of TAFI (169.0+/-108.8% versus 103.7+/-52.3%; p<0.001, mean+/-S.D.) and PAI-1 (82.7+/-54.5ng/ml versus 52.9+/-51.7ng/ml; p<0.05) were significantly higher in non-obese type 2 diabetic patients than in normal subjects. Univariate analysis showed that the plasma TAFI levels are significantly and inversely correlated with the glucose infusion rate (GIR) (r=-0.42, p<0.005) in all diabetic patients. Moreover, the plasma levels of TAFI were significantly correlated with fasting plasma glucose levels (r=0.47, p<0.001) and HbA(1c) (r=0.38, p<0.005) in all subjects. The plasma levels of PAI-1 were significantly and proportionally correlated with the visceral fat area (r=0.42, p<0.005) and body mass index (r=0.33, p<0.05). There was no significant correlation between plasma levels of TAFI and PAI-1 (r=0.04). These results show that the plasma levels of TAFI and PAI-1 differently correlate with insulin resistance and visceral fat accumulation, suggesting that different factors are implicated in the plasma elevation of TAFI and PAI-1 in non-obese type 2 diabetes mellitus.