Efficacy and Safety of 6-Month High Dietary Protein Intake in Hospitalized Adults Aged 75 or Older at Nutritional Risk: An Exploratory, Randomized, Controlled Study.

The aim of this study was to investigate the effects of increased dietary protein in daily-life settings in Japan for 6 months on the activities of daily living (ADL) in adults aged 75 or older at nutritional risk. The study was an open-label, exploratory, randomized controlled trial conducted at seven hospitals in Japan. The study participants were adults aged 75 or older who were hospitalized for treatable cancer, pneumonia, fractures, and/or urinary-tract infection at nutritional risk. The primary outcome was change in grip strength, skeletal muscle, and ADL indices (Barthel index, Lawton score). One hundred sixty-nine patients were randomly assigned to the intensive care (IC) or standard care (SC) group; the protein intake goals (g/kgw/day) were 1.5 for IC and 1.0 for SC. There was a significant improvement in grip strength only in the IC group (1.1 kg: 95% CI 0.1 to 2.1) (p = 0.02). While the skeletal muscle index and ADL indices were not significantly improved in either group, the improvement ratio tended to be greater in the IC group. There was no decrease in renal function in either group. Thus, intervention of increased dietary protein in daily-life settings for 6 months in adults aged 75 or older with treatable cancer, pneumonia, fractures, and/or urinary-tract infection and at nutritional risk may be effective in ameliorating loss of muscle strength.

Voxel-based specific regional analysis system for Alzheimer's disease utility as a screening tool for unrecognized cognitive dysfunction of elderly patients in diabetes outpatient clinics: Multicenter retrospective exploratory study.

AIMS/INTRODUCTION: An efficient screening strategy for identification of cognitive dysfunction remains a clinical issue in the management of elderly adults with diabetes. A magnetic resonance imaging voxel-based specific regional analysis system for Alzheimer's disease (VSRAD) has been developed as an automated brain morphometry system that includes the hippocampus. We carried out a multicenter retrospective study to evaluate the utility of VSRAD for screening cognitive dysfunction in diabetes outpatient clinics. MATERIALS AND METHODS: We enrolled patients with diabetes aged >65 years who underwent brain magnetic resonance imaging scans for the purpose of a medical checkup between November 2018 and May 2019. Patients who were already suspected or diagnosed with mild cognitive impairment and/or dementia as well as those with a history of cerebrovascular disease were excluded. RESULTS: A total of 67 patients were enrolled. Five patients were diagnosed with mild cognitive impairment or dementia (clinical cognitive dysfunction). Patients with clinical cognitive dysfunction showed a significantly higher z-score in VSRAD analysis (2.57 ± 0.47 vs 1.15 ± 0.55, P < 0.01). The sensitivities and specificities for diagnosis of clinical cognitive dysfunction were 80 and 48% for the Mini-Mental State Examination, 100 and 89% for the z-score, and 100 and 90% for the combination of the Mini-Mental State Examination score and z-score, respectively. CONCLUSIONS: VSRAD analysis can distinguish patients with clinical cognitive dysfunction in the elderly with diabetes, and also shows reasonable sensitivity and specificity compared with the Mini-Mental State Examination alone. Thus, VSRAD analysis can be useful for early identification of clinical cognitive dysfunction in the elderly with diabetes.

Soluble tumor necrosis factor receptor 2 is independently associated with pulse wave velocity in nonobese Japanese patients with type 2 diabetes mellitus.

The aim of the present study was to investigate the factors contributing to pulse wave velocity (PWV) in patients with type 2 diabetes mellitus. We focused on tumor necrosis factor (TNF) including soluble TNF receptors (sTNF-R1, sTNF-R2) in this study because TNF seems to be associated with the progression of atherosclerosis and because the relationships between PWV and TNF were not yet examined in type 2 diabetic patients. Univariate regression analyses showed that PWV was positively correlated with age (r=0.492, P<.001), diabetes duration (r=0.251, P=.021), systolic (r=.595, P<.001) and diastolic (r=0.248, P=.022) blood pressure, antihypertensive medication (r=0.268, P=.013), and the concentrations of sTNF-R1 (r=0.354, P=.001) and sTNF-R2 (r=0.415, P<.001). Although there was a positive correlation between TNF-alpha and sTNF-R1 (r=0.382, P<.001) or sTNF-R2 (r=0.394, P<.001), TNF-alpha was not associated with PWV. Other variables including gender were not associated with PWV. Multiple regression analyses showed that PWV was independently predicted by the level of age (F=15.1), systolic blood pressure (F=31.6), and sTNF-R2 (F=5.2), which explained 49.2% of the variability of PWV. From these results, it can be concluded that serum soluble TNF receptor is an important independent factor associated with aortic PWV in type 2 diabetic patients.

Metabolic syndrome, insulin resistance, and atherosclerosis in Japanese type 2 diabetic patients.

The aim of the present study was to investigate the relationships between metabolic syndrome and atherosclerosis in 57 Japanese type 2 diabetic patients. Metabolic syndrome was diagnosed based on the criteria raised by the Japan Internal Medicine Society. Insulin resistance was estimated by the insulin resistance index of homeostasis model assessment. Ultrasonographically measured carotid atherosclerosis, brachial-ankle pulse wave velocity (ba-PWV), and ankle brachial index (ABI) were used to assess the degree of atherosclerosis. Of 57 patients, 25 were diagnosed as having metabolic syndrome. The patients with metabolic syndrome had significantly higher levels of waist circumference, insulin, insulin resistance index of homeostasis model assessment, systolic and diastolic blood pressures, and serum triglycerides, and lower concentrations of adiponectin. However, there was no significant difference in age, sex, glycosylated hemoglobin (hemoglobin A1c), fasting glucose, leptin, and tumor necrosis factor system activities including tumor necrosis factor alpha between the 2 groups. Furthermore, no significant difference was observed in the degree of carotid atherosclerosis (intimal-medial thickness in plaque-free segments: 0.72+/-0.03 vs 0.72+/-0.02 mm, P=.435; carotid stenosis in plaque segments: 6.6%+/-3.0% vs 6.6%+/-1.7%, P=.497), ba-PWV (1676+/-56 vs 1654+/-44, P=.380), and ABI (1.16+/-0.01 vs 1.15+/-0.01, P=.245) between the 2 groups. From these results, it can be suggested that metabolic syndrome, an insulin-resistant state, is not associated with carotid atherosclerosis, ba-PWV, or ABI in Japanese type 2 diabetic patients.

Early and late onset side effects of short-acting insulin analogue in seven Japanese diabetic patients.

Short-acting insulin analogue has previously shown to be equal to short-acting human regular insulin regarding in vitro characteristics, immunogenicity, and safety. But in the present study, we experienced seven patients who had mild to moderate side effects due to short-acting insulin analogue. These side effects could be divided into two types based on the appearance time; one with early onset and the other with late onset. Early onset side effects include rash, disturbances in walking and general fatigue that can not be explained by the swing in glucose levels. These symptoms appeared 2-3 days after the use of short-acting insulin analogue and disappeared several hours after switching short-acting human regular insulin. The late onset side effect is bilateral leg edema, which appeared 1-2 months after the induction of short-acting insulin analogue and disappeared after several hours by changing to short-acting human regular insulin. We should monitor the early and late onset side effects as diligently as possible when we use short-acting insulin analogue on diabetic patients.

Factors responsible for the evolution of insulin resistance in Japanese type 2 diabetic patients: association with atherosclerosis.

Type 2 diabetes is a heterogeneous syndrome characterized by defective insulin secretion and/or insulin resistance. In distinct from Caucasian populations, Japanese type 2 diabetic patients are divided into two categories: one with insulin resistance and the other with normal insulin sensitivity. This unique feature allows us to explore the factors responsible for the evolution of insulin resistance in Japanese type 2 diabetic patients. In this article, we describe the factors responsible for insulin resistance in Japanese type 2 diabetic patients and discuss the relationships between these factors and atherosclerosis. Japanese type 2 diabetic patients with insulin resistance had significantly higher concentrations of triglyceride, remnant-like particle cholesterol, subcutaneous and visceral abdominal fat areas, leptin, high sensitive C-reactive protein (hs-CRP), and soluble E-selectin and lower concentration of adiponectin when compared to those with normal insulin sensitivity. There were, however, no significant difference in tumor necrosis factor (TNF)-alpha and soluble TNF receptors between the two groups. Serum triglyceride was positively correlated to visceral abdominal fat area, while serum leptin was positively correlated with subcutaneous abdominal fat area. In contrast, serum adiponectin was negatively correlated to visceral abdominal fat area. High sensitive CRP was positively correlated to BMI, triglyceride, and leptin, but was negatively correlated to adiponectin. Tumor necrosis factor-alpha and soluble TNF receptors, however, were not associated with any of these factors. Thus, it may be hypothesized that Japanese type 2 diabetic patients are divided into two categories: one with normal insulin sensitivity and the other with insulin resistance. The former group has a low cardiovascular risk factor, whereas the latter one has a markedly increased cardiovascular disease risk factor. Furthermore, abdominal fat related insulin resistance seems to be associated with insulin resistance in Japanese type 2 diabetic patients. In this section, we would like to focus on the factors contributing to insulin resistance and discuss the association of these factors with atherosclerosis in Japanese type 2 diabetic patients.

Leptin, triglycerides, and interleukin 6 are independently associated with C-reactive protein in Japanese type 2 diabetic patients.

The aim of the present study was to investigate the factors contributing to the concentration of serum C-reactive protein in type 2 diabetic patients. One hundred and 48 Japanese type 2 diabetic patients were studied. In conjunction with C-reactive protein (CRP), BMI, systolic and diastolic blood pressure, glycosylated hemoglobin (HbA1c), fasting concentrations of plasma glucose, and serum lipids (triglycerides, HDL cholesterol, and total cholesterol), interleukin 6 (IL-6), and leptin were measured. Insulin resistance was also estimated by the insulin resistance index of homeostasis model assessment (HOMA-IR). With univariate analysis, serum CRP was positively correlated with BMI (r=0.281, P<0.001), diastolic blood pressure (r=0.176, P=0.048), triglycerides (r=0.293, P<0.001), HOMA-IR (r=0.294, P<0.001), IL-6 (r=0.323, P<0.001), and leptin (r=0.330, P<0.001), and negatively correlated with HDL cholesterol (r=-0.181, P=0.028). Multiple regression analyses showed that serum CRP was independently predicted by the level of IL-6 (P<0.001, F=4.04), leptin (P<0.001, F=7.09), and triglycerides (P<0.001, F=15.13), which explained 17.6% of the variability of serum CRP concentration in these patients. From these results, it can be concluded that along with IL-6 and triglycerides, leptin is another important independent factor that is associated with CRP in Japanese type 2 diabetic patients.

Interleukin 6, adiponectin, leptin, and insulin resistance in nonobese Japanese type 2 diabetic patients.

The aim of the present study was to investigate the relationships between interleukin 6 (IL-6) and insulin resistance, serum leptin, serum adiponectin, or serum lipids including triglycerides in 98 nonobese Japanese type 2 diabetic patients. Insulin resistance was estimated by the insulin resistance index of homeostasis model assessment (HOMA-IR). Serum IL-6 concentration was negatively correlated to high-density lipoprotein cholesterol (r = -0.295, P = .004), but was not associated with HOMA-IR (r = 0.016, P = .871), body mass index (BMI) (r = 0.090, P = .375), systolic (r = 0.169, P = .116) and diastolic (r = -0.061, P = .570) blood pressures, leptin (r = 0.062, P = .544), and adiponectin (r = -0.020, P = .841) in these patients. In contrast, serum leptin level was positively correlated to HOMA-IR (r = 0.291, P = .004), BMI (r = 0.338, P < .001), and systolic blood pressure (r = 0.241, P = .025). Serum adiponectin level was negatively correlated to HOMA-IR (r = -0.288, P = .005), BMI (r = -0.308, P = .002), diastolic blood pressure (r = -0.269, P = .012), and triglycerides (r = -0.338, P < .001), and positively correlated to high-density lipoprotein cholesterol (r = 0.300, P = .003) in our patients. From these results, it can be suggested that fasting serum IL-6 is not a major factor responsible for the evolution of insulin resistance in nonobese Japanese type 2 diabetic patients.

Soluble E-selectin, leptin, triglycerides, and insulin resistance in nonobese Japanese type 2 diabetic patients.

The aim of the present study was to investigate the relationships between insulin resistance and soluble E-selectin, body mass index (BMI), leptin, and serum lipid profile including triglycerides in nonobese Japanese type 2 diabetic patients. A total of 97 nonobese Japanese type 2 diabetic patients aged 43 to 84 years were examined. The duration of diabetes was 11.2 +/- 0.8 years. In conjunction with BMI and fasting concentrations of plasma glucose, serum lipids (triglycerides, total cholesterol, and high-density lipoprotein cholesterol) and serum insulin, soluble E-selectin, and leptin were also measured. The low-density lipoprotein (LDL) cholesterol level was calculated using the Friedewald formula. Insulin resistance was estimated by the homeostasis model assessment. The subjects were divided into 2 groups according to the value of insulin resistance estimated by the homeostasis model assessment. Values greater than 2.5 were indicative of the insulin-resistant state, and values less than 2.5 were indicative of the insulin-sensitive state. The insulin-resistant group had significantly higher levels of E-selectin, leptin, triglycerides, total and LDL cholesterol, and diastolic blood pressure as compared with the insulin-sensitive group. There was, however, no significant difference in age, sex, diabetes duration, BMI, systolic blood pressure, HbA1c, and high-density lipoprotein cholesterol between the 2 groups. Univariate regression analysis showed that insulin resistance was positively correlated to E-selectin (r = 0.305, P = .003), BMI (r = 0.283, P = .006), leptin (r = 0.296, P = .004), HbA1c (r = 0.241, P = .018), serum triglycerides (r = 0.385, P < .001), serum total (r = 0.240, P = .019) and LDL cholesterol (r = 0.254, P = .013) levels, and systolic (r = 0.247, P = .024) and diastolic (r = 0.305, P = .006) blood pressure. Multiple regression analyses showed that insulin resistance was independently predicted by serum E-selectin (F = 18.4), serum leptin (F = 14.0) and serum triglycerides (F = 20.0) levels, which explained 45.0% of the variability of insulin resistance. From these results, it can be concluded that in conjunction with serum triglycerides and serum leptin, serum E-selectin is another important independent factor associated with insulin resistance in nonobese Japanese type 2 diabetic patients.

Three measures of tumor necrosis factor alpha activity and insulin resistance in nonobese Japanese type 2 diabetic patients.

The aim of the present study was to investigate the relationship between insulin resistance and tumor necrosis factor alpha (TNF-alpha) as well as soluble TNF receptors (sTNF-R), body mass index (BMI), leptin, adiponectin, and serum lipid profile including triglycerides in nonobese Japanese patients with type 2 diabetes. A total of 88 nonobese Japanese type 2 diabetic patients were studied. The duration of diabetes was 11.0 +/- 0.8 years. In conjunction with BMI, glycosylated hemoglobin (HbA1c), fasting concentrations of plasma glucose, serum lipids (triglycerides, high-density lipoprotein cholesterol, and total cholesterol), serum leptin, serum adiponectin, serum TNF-alpha, and soluble TNF receptors (sTNF-R1 and sTNF-R2) were also measured. Insulin resistance was estimated by the insulin resistance index of homeostasis model assessment. Insulin resistance was positively correlated with BMI, triglycerides, leptin, and total cholesterol and negatively correlated with adiponectin and high-density lipoprotein cholesterol. In contrast, insulin resistance was not associated with TNF-alpha, nor sTNF-R (sTNF-R1 and sTNF-R2) in our diabetic patients. There was no significant relationship between the 3 measures of TNF-alpha system (TNF-alpha, sTNF-R1, and sTNF-R2) and BMI, serum triglycerides, leptin, or adiponectin in these patients. From these results, it can be concluded that peripheral levels of TNF-alpha system activity are not a major factor responsible for insulin resistance in nonobese Japanese type 2 diabetic patients.

Factors responsible for development from normal glucose tolerance to isolated postchallenge hyperglycemia.

OBJECTIVE: Isolated postchallenge hyperglycemia (IPH), defined as fasting plasma glucose (FPG) level <7.0 mmol/l and 2-h plasma glucose (PG) level >/=11.1 mmol/l, is a subtype of early-stage diabetes. This study evaluates the metabolic profiles of insulin secretion and insulin sensitivity in IPH to clarify the factors responsible for development of this form of type 2 diabetes. RESEARCH DESIGN AND METHODS: We conducted cross-sectional analysis of 231 Japanese men aged 20-70 years. The subjects were classified into the following three groups, based on the results of a 75-g oral glucose tolerance test (OGTT): 1) normal glucose tolerance (NGT), defined as FPG level <6.1 mmol/l and 2-h PG level <7.8 mmol/l (n = 89); 2) impaired glucose tolerance (IGT), defined as FPG level <7.0 mmol/l and 2-h PG level of 7.8-11.1 mmol/l (n = 94); and 3) IPH (n = 48). We compared the three groups for insulin secretion (insulinogenic index) and insulin sensitivity (index of insulin resistance using homeostasis model assessment [HOMA-IR]). RESULTS: The insulinogenic index in IPH was the lowest of the three groups (P < 0.001 versus NGT). The HOMA-IR in the IGT and IPH groups were significantly higher than in the NGT group (P < 0.001), but both were similar. By linear regression analysis, the insulinogenic index rather than fasting insulin or HOMA-IR was the more significant factor in the 2-h PG level in IGT and IPH. CONCLUSIONS: Subjects with IPH exhibited distinctly impaired early-phase insulin secretion and only mild insulin resistance, indicating that reduced insulin secretion is the primary determinant of deterioration from NGT to IGT and IPH in development of type 2 diabetes in these subjects.

Early phase glucagon and insulin secretory abnormalities, but not incretin secretion, are similarly responsible for hyperglycemia after ingestion of nutrients.

AIMS: Hypersecretion of glucagon and reduced insulin secretion both contribute to hyperglycemia in type 2 diabetes (T2DM). However, the relative contributions of impaired glucagon and insulin secretions in glucose excursions at the various stages of T2DM development remain to be determined. METHODS: The responses of glucagon and insulin as well as those of glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) were examined before and after ingestion of glucose or mixed meal in Japanese subjects with normal or impaired glucose tolerance (NGT and IGT) and in non-obese, untreated T2DM of short duration. RESULTS: In OGTT, T2DM showed a rise in glucagon at 0-30 min, unlike NGT and IGT, along with reduced insulin. In MTT, all three groups showed a rise in glucagon at 0-30 min, with that in T2DM being highest, while T2DM showed a significant reduction in insulin. Linear regression analyses revealed that glucose area under the curve (AUC)0-120 min was associated with glucagon-AUC0-30 min and insulin-AUC0-30 min in both OGTT and MTT. Total and biologically intact GIP and GLP-1 levels were similar among the three groups. CONCLUSIONS: Disordered early phase insulin and glucagon secretions but not incretin secretion are involved in hyperglycemia after ingestion of nutrients in T2DM of even a short duration.

Hypoadiponectinemia is associated with visceral fat accumulation and insulin resistance in Japanese men with type 2 diabetes mellitus.

The aim of the present study was to investigate the association of serum adiponectin concentration with regional adiposity and insulin resistance in subjects with type 2 diabetes mellitus. A total of 73 Japanese men with type 2 diabetes (aged 59 +/- 11 years and body mass index [BMI] 23.8 +/- 3.0 kg/m(2), mean +/- SD) were studied. Fasting serum adiponectin and leptin concentrations were determined by radioimmunoassay. Regional adiposity was measured by abdominal computed tomography (CT) at the umbilical level, and insulin resistance was estimated by homeostasis model assessment (HOMA-R). Univariate regression analysis showed that serum adiponectin levels were negatively correlated with subcutaneous and visceral fat areas. With multivariate regression analysis, visceral fat area was a predominant determinant of serum adiponectin levels. In contrast, subcutaneous fat area was strongly associated with serum leptin concentrations. Among subcutaneous and visceral fat areas, BMI, and serum leptin levels, both subcutaneous and visceral fat areas were independently associated with HOMA-R. In another model incorporating serum adiponectin levels, serum adiponectin levels were selected as an independent determinant of HOMA-R instead of visceral fat area. In conclusion, hypoadiponectinemia was associated with visceral fat accumulation rather than subcutaneous fat depot in Japanese men with type 2 diabetes mellitus. Both subcutaneous and visceral fat accumulation contribute to insulin resistance in these subjects, and the contribution of visceral fat may be mediated, in part, by hypoadiponectinemia.

Porphyromonas gingivalis infection is associated with carotid atherosclerosis in non-obese Japanese type 2 diabetic patients.

The aim of the present study was to investigate whether non-obese Japanese type 2 diabetic patients with porphyromonas gingivalis infection have atherosclerotic vascular diseases. A total of 134 non-obese Japanese type 2 diabetic patients (96 men and 38 women, aged 36 to 84 years, body mass index [BMI] 20.1 to 26.9 kg/m(2)) were studied. In conjunction with BMI, glycosylated hemoglobin (HbA(1c)), fasting glucose, and serum lipids (triglycerides, total cholesterol, high-density lipoprotein [HDL] cholesterol, low-density lipoprotein [LDL] cholesterol) were measured. LDL cholesterol was calculated using the Friedewald formula. Using high-resolution B-mode ultrasound scan, we measured intimal medial thickness (IMT) in plaque-free segments of bilateral common carotid arteries, and the mean of IMT in 2 vessels was used for the analysis. Furthermore, we calculated the degree of stenosis in plaque segments of bilateral common carotid arteries. The degree of carotid atherosclerosis was expressed as a percentage ratio between the area of plaque and that of the lumen using the formula (Lumen Area Residual - Lumen Area)/Lumem Area x 100. Both the areas were automatically measured by the system on a frozen transverse scanning plane at the site of maximal narrowing. When 2 or more plaques were present in the vessel, only that causing the greatest degree of stenosis was considered for analysis. Values represent mean+/-SEM unless otherwise stated. Immunoglobulin G (IgG) titer against porphyromonas gingivalis was 245 +/- 65 (mean +/- 2 SD) in nondiabetic healthy subjects. In contrast, there was a wide variation in IgG titer against porphyromonas gingivalis in type 2 diabetic patients studied (range, 16 to 26,800). Thus, we classified our type 2 diabetic patients into 2 subpopulations according to the value of mean +/- 2 SD (= 310) of nondiabetic healthy subjects: one with high IgG titer against porphyromonas gingivalis (>310) (1,422 +/- 408) and the other with normal IgG titer against porphyromonas gingivalis (<310) (152 +/- 10, P =.002). The populations did not differ with respect to age, sex, BMI, fasting glucose, HbA(1c), serum triglycerides, total, HDL, and LDL cholesterol levels. Although the mean IMT in plaque-free segments was not different between the 2 groups (0.73 +/-0.03 v 0.68 +/- 0.02 mm, P =.098), the degree of stenosis in plaque segments was significantly higher in the high IgG titer group (12.0% +/- 2.2%) than in normal one (5.5% +/- 1.4%, P =.009). From these results, it can be concluded that porphyromonas gingivalis infection, although still a subclinical infection, is associated with atherosclerotic vascular disease in non-obese Japanese type 2 diabetic patients.

Platelet count is independently associated with insulin resistance in non-obese Japanese type 2 diabetic patients.

The aim of the present study was to investigate the relationship between platelet count and insulin resistance in non-obese Japanese type 2 diabetic patients. A total of 163 non-obese Japanese type 2 diabetic patients (112 men and 51 women, aged 36 to 84 years, body mass index [BMI] 16.2 to 26.9 kg/m(2)) were studied. In conjunction with BMI, glycosylated hemoglobin (HbA(1c)), fasting concentrations of plasma glucose and serum lipids (triglycerides, low-density lipoprotein [LDL] cholesterol, high-density lipoprotein [HDL] cholesterol, and total cholesterol), and hematological parameters (platelets, white blood cell count, red blood cell count, hematocrit, hemoglobin) were measured. LDL cholesterol was calculated using the Friedewald formula. Insulin resistance was estimated by the insulin resistance index of homeostasis model assessment (HOMA-IR). Univariate regression analysis showed that HOMA-IR was positively correlated to BMI (r = 0.465, P <.0001), HbA(1c) (r = 0.423, P <.0001), platelet count (r = 0.310, P <.0001), triglycerides (r = 0.277, P <.0005), white blood cell count (r =.222, P =.005), red blood cell count (r = 0.210, P =.008), hematocrit (r = 0.156, P =.047), total cholesterol (r = 0.178, P =.023), and systolic (r = 0.216, P =.011) and diastolic (r = 0.263, P =.002) blood pressure, and inversely correlated to HDL cholesterol (r = -0.312, P <.0001) level in our diabetic patients. Multiple regression analysis showed that HOMA-IR was independently predicted by BMI (P <.0001, F = 22.45), HbA(1c) (P <.0001, F = 16.15), platelet count (P <.0001, F = 10.75), and serum triglycerides (P <.0001, F = 10.47) levels, which explained 34% of the variability of HOMA-IR in non-obese Japanese type 2 diabetic patients. These results indicate that not only BMI, HbA(1c), and triglycerides levels but also platelet counts are independent predictor of insulin resistance in non-obese Japanese type 2 diabetic patients.

C-reactive protein and insulin resistance in non-obese Japanese type 2 diabetic patients.

The aim of the present study was to investigate the relationship between C-reactive protein (CRP) and insulin resistance in non-obese Japanese type 2 diabetic patients. A total of 135 non-obese Japanese type 2 diabetic patients (96 men and 39 women, aged 36 to 83 years, with a body mass index [BMI] of 16.2 to 26.8 kg/m2) were studied. BMI, glycosylated hemoglobin (HbA(1c)), fasting concentrations of plasma glucose, serum lipids (triglycerides, low-density lipoprotein [LDL] cholesterol, high-density lipoprotein [HDL] cholesterol, and total cholesterol), CRP, and fibrinogen were measured. LDL cholesterol was calculated using the Friedewald formula. Insulin resistance was estimated by the insulin resistance index of homeostasis model assessment (HOMA-IR). Univariate regression analysis showed that CRP value was positively correlated to age (r = 0.218, P =.012), BMI (r = 0.239, P =.006), HOMA-IR (r = 0.397, P <.0001), triglycerides (r= 0.310, P <.005), LDL cholesterol (r= 0.179, P =.038), and fibrinogen (r = 0.371, P <.0001) levels and inversely correlated to HDL cholesterol (r = 0.174, P =.044) level in our diabetic patients. Multiple regression analysis showed that CRP was independently predicted by HOMA-IR (P<.0001, F = 11.6) and fibrinogen (P<.0001, F = 34.2), which explained 23.5% of the variability of CRP in our non-obese Japanese type 2 diabetic patients. These results indicate that insulin resistance and fibrinogen level are independent predictors of CRP in non-obese Japanese type 2 diabetic patients.

The role of the TSC-22 (-396) A/G variant in the development of diabetic nephropathy.

TSC-22 is a leucine zipper transcriptional factor and expression of the TSC-22 gene is highly induced by TGF-beta treatment. We estimated the frequency of the -396 A/G polymorphism of the TSC-22 gene with an Alu I-Restriction fragment length polymorphism (RFLP) method in 498 Japanese subjects with type 2 diabetes mellitus. We also determined the promoter activity. The diabetic patients with the AA genotype had a significantly higher incidence of the diabetic nephropathy (vs. the AG genotype, P<0.05, odds ratio: 1.95; 95% confidence intervals 1.14-3.33). There was no significant difference in the promoter activity between the fragments with -396A and -396G. These findings suggest that the TSC-22 gene (-396) A allele is associated with an increasing risk of the diabetic nephropathy.

Impaired beta-cell function and insulin sensitivity in Japanese subjects with normal glucose tolerance.

The development of type 2 diabetes mellitus is characterized by both impaired beta-cell function and increasing insulin resistance. To clarify the roles of them in developing type 2 diabetes, we evaluated insulin resistance by HOMA-IR and insulin secretion by HOMA beta-cell in 453 Japanese subjects whose fasting plasma glucose (FPG) and HbA(1c) levels were within normal range. HOMA beta-cell was found to decrease in the over 30 years groups, while HOMA-IR increased with body mass index (BMI). To analyze the reserve capacity of insulin secretion and insulin sensitivity, the 67 of them, who underwent a standard oral glucose tolerance test and were diagnosed with normal glucose tolerance (NGT), were divided into four degrees of BMI age-adjusted to 50 years. They were compared for insulinogenic index and ISI composite proposed by Matsuda and DeFronzo across the range of BMI. ISI composite was significantly less in the highest BMI group, while insulin secretion did not increase in the higher BMI groups. The subjects with higher BMI had remarkably lower insulinogenic indices than those with lower BMI. These data suggest that insulin secretory reserve is insufficient to compensate for increased insulin resistance in Japanese people with NGT at about 50 years of age.

Factors influencing the durability of the glucose-lowering effect of sitagliptin combined with a sulfonylurea.

We analyzed the changes of glycemic control over 12 months and the factors influencing blood glucose in 162 Japanese patients with type 2 diabetes having inadequate glycemic control despite sulfonylurea-based therapy who received add-on sitagliptin. Hemoglobin A1c (HbA1c) decreased significantly after 4 weeks of treatment, and this improvement was maintained for 1 year, although HbA1c was slightly higher in week 52 than in week 24. Comparison of the patients showing a ≥0.4% increase of HbA1c between weeks 24 and 52 (n = 57) with the others (n = 105) showed a significant difference in the change of bodyweight, as well as the dose of glibenclamide (both P < 0.01). Although combined therapy with sitagliptin and a sulfonylurea seems to be effective for at least 1 year, blood glucose levels are more likely to increase again in patients who show greater weight gain after 24 weeks of treatment and those receiving a higher dose of glibenclamide.