Hemoglobin concentration in men with type 2 diabetes mellitus

Anemia is a common but often overlooked complication of diabetes. We investigated the relationship between hemoglobin concentration and various factors as well as markers of subclinical atherosclerosis in men with type 2 diabetes mellitus. Hemoglobin concentration was measured in 319 men with type 2 diabetes mellitus. We evaluated the relationship between hemoglobin concentration and various factors including age, body mass index, and glycemic control, as well as between hemoglobin concentration and pulse wave velocity or ankle-brachial index (n = 209) and between hemoglobin concentration and carotid intima-media thickness or plaque score (n = 125). Mean hemoglobin concentration was 14.2 ± 0.80 g/dL. Body mass index (r = 0.340, P < .0001) and estimated glomerular filtration rate (r = 0.219, P = .0011) were positively associated with hemoglobin concentration, whereas age (r = −0.388, P < .0001), glycated albumin (r = −0.148, P = .0121), serum creatinine concentration (r = −0.206, P = .0019), and log (urinary albumin excretion) (r = −0.188, P = .0010) were negatively associated with hemoglobin concentration. Multiple regression analysis identified age (β = −0.222, P = .0019), body mass index (β = 0.145, P = .0432), systolic blood pressure (β = 0.214, P = .0015), total cholesterol concentration (β = 0.170, P = .0077), and serum creatinine concentration (β = −0.181, P = .0045) as independent determinants of hemoglobin concentration. No significant association was observed between hemoglobin concentration and serum erythropoietin concentration (r = −0.079, P = .2980). Negative correlations were found between hemoglobin concentration and pulse wave velocity (r = −0.289, P < .0001) and between hemoglobin concentration and plaque score (r = −0.275, P = .0024). In conclusion, hemoglobin concentration was associated with various factors; and decreased hemoglobin concentration was associated with subclinical markers of atherosclerosis in men with type 2 diabetes mellitus.     

Association between serum testosterone concentration and collagen degradation fragments in men with type 2 diabetes mellitus

The aim of the present study was to evaluate relationships between serum endogenous androgens and urinary concentration of cross-linked N-telopeptides of type I collagen (NTx), a bone resorption marker, in men with type 2 diabetes mellitus because low androgen concentrations are associated with both osteoporosis and cardiovascular disease. Relationships between serum free testosterone and urinary NTx concentrations were investigated in 246 consecutive men with type 2 diabetes mellitus. In addition, relationships between urinary NTx concentration and other variables including age, duration of diabetes, blood pressure, serum lipid concentration, hemoglobin A(1c), and body mass index were evaluated. Urinary NTx concentrations were 27.8 (26.4-29.3) nmol of bone collagen equivalent per millimole of creatinine, correlating inversely with serum free testosterone (r = -0.263, P < .0001). Multiple regression analysis identified serum free testosterone (beta = -.292, P < .0001), hemoglobin A(1c) (beta = .144, P = .0404), and smoking status (beta = .143, P = .0402) as independent determinants of urinary NTx. In conclusion, serum free testosterone concentration correlated inversely with urinary NTx concentration, which may partly account for an observed link between osteoporosis and cardiovascular disease in men with type 2 diabetes mellitus.     

Relationship between low serum endogenous androgen concentrations and arterial stiffness in men with type 2 diabetes mellitus

The aim of this study was to evaluate the relationship between arterial stiffness determined by pulse wave velocity (PWV) and serum endogenous androgen concentrations as well as major cardiovascular risk factors in men with type 2 diabetes mellitus. Serum free testosterone and dehydroepiandrosterone sulfate (DHEA-S) concentrations were measured in 268 men with type 2 diabetes mellitus. Relationships between PWV and serum endogenous androgen concentrations as well as major cardiovascular risk factors, including age, blood pressure, serum lipid concentration, glycemic control (hemoglobin A(1c)), body mass index, and degree of albuminuria, were evaluated. Positive correlations were found between PWV and age (r = 0.491, P < .0001), duration of diabetes (r = 0.320, P < .0001), systolic blood pressure (r = 0.292, P < .0001), and log (urinary albumin excretion) (r = 0.269, P < .0001). Inverse correlations were found between serum free testosterone concentration and PWV (r = -0.228, P = .0003) and between serum DHEA-S concentration and PWV (r = -0.252, P = .0002) in men with type 2 diabetes mellitus. Pulse wave velocity was significantly greater in patients with lower concentrations of free testosterone (<10 pg/mL) than in patients with higher concentrations of free testosterone (1864 +/- 359 vs 1736 +/- 327 cm/s; P = .0053). Pulse wave velocity also was significantly greater in patients with lower concentrations of DHEA-S (<1000 ng/mL) than in patients with higher concentrations of DHEA-S (1843 +/- 371 vs 1686 +/- 298 cm/s; P = .0008). Multiple regression analysis identified both serum free testosterone concentration (beta = -.151, P = .0150) and serum DHEA-S concentration (beta = -.200, P = .0017) as independent determinants of PWV. In conclusion, serum endogenous androgen concentrations are inversely associated with arterial stiffness determined by PWV in men with type 2 diabetes mellitus, which is true for men in general based on other works.     

Helicobacter pylori infection and arterial stiffness in patients with type 2 diabetes mellitus

Epidemiologic studies have suggested possible atherogenic roles for such pathogens as Chlamydia pneumoniae, Helicobacter pylori (Hp), cytomegalovirus, and herpes simplex virus. The aim of the present study was to examine the relationship between seropositivity of antibodies to Hp (Hp infection) and arterial stiffness determined by pulse wave velocity (PWV) in 130 patients (73 men and 57 women) with type 2 diabetes mellitus without a history of cardiovascular disease. The prevalence of Hp infection in patients with type 2 diabetes mellitus was 53.8%. Age (66.7 ± 11.3 vs 60.0 ± 12.2 years, P = .0014) and systolic blood pressure (138 ± 19 vs 131 ± 22 mm Hg, P = .0420) were significantly higher in patients with Hp infection than in those without. Serum C-reactive protein was higher in patients with Hp infection than in those without, although it did not reach statistical significance (0.23 ± 0.27 vs 0.18 ± 0.20 mg/dL, P = .2205). Pulse wave velocity was significantly higher in patients with Hp infection than in those without (1877 ± 550 vs 1585 ± 331 cm/s, P = .0005). Multiple regression analysis demonstrated that age (β = .388, P < .0001), mean arterial pressure (β = .289, P = .0006), hypertensive treatment (β = .185, P = .0282), and presence of Hp infection (β = .169, P = .0220) were independent determinants of PWV. In conclusion, Hp infection is associated with arterial stiffness determined by PWV in patients with type 2 diabetes mellitus.     

Improvement of postprandial hyperglycemia and arterial stiffness upon switching from premixed human insulin 30/70 to biphasic insulin aspart 30/70

Postprandial hyperglycemia is known to be associated with increasing cardiovascular mortality in type 2 diabetes mellitus patients. Cardio-ankle vascular index (CAVI) reflects arterial stiffness and is more useful for predicting coronary atherosclerosis than intima-media thickness. Premixed human insulin 30/70 (BHI30) containing rapid-acting insulin has been used conventionally as a biphasic insulin. Recently, a biphasic insulin analogue preparation, biphasic insulin aspart 30/70 (BIAsp30), containing ultrarapid-acting insulin has been approved and expected to improve postprandial hyperglycemia. The aim of this study was to clarify the effects of switching the biphasic insulin from BHI30 to BIAsp30 on arterial stiffness in type 2 diabetes mellitus patients. Twenty-six type 2 diabetes mellitus patients (glycosylated hemoglobin >6.5%) who were already receiving biphasic insulin therapy with BHI30 twice daily were observed for 3 months. Afterward, BHI30 was switched to BIAsp30. At 3 months after switching, relative mobility of the peak of LDL fraction decreased significantly (from 0.3462 ± 0.041 to 0.3356 ± 0.035, P < .01); and CAVI also decreased significantly (from 9.77 ± 1.11 to 9.35 ± 1.17 m/s, P < .005). A significant negative correlation was observed between the change in CAVI and change in 1,5-anhydroglucitol (1,5-AG) (r = −0.3929, P < .05). A stronger correlation between change in CAVI and change in 1,5-AG was observed in the subgroup of patients whose 1,5-AG levels were elevated after switching (r = −0.6261, P < .05) compared with all subjects. These results suggest that switching biphasic insulin from BHI30 to BIAsp30 improves arterial stiffness, and the improvement of arterial stiffness may be associated with improvement of postprandial hyperglycemia.     

Correlation of serum testosterone with insulin resistance in elderly male type 2 diabetes mellitus patients with osteoporosis

Aims/Introduction

The present study was designed to investigate the correlations between the serum testosterone level and insulin sensitivity in elderly male type 2 diabetes patients with osteoporosis.

Materials and Methods

A total of 35 elderly male patients with type 2 diabetes (type 2 diabetes group), 30 elderly male type 2 diabetes patients combined with osteoporosis (DO group) and 30 healthy elderly men (normal control group) participated in the present study. The fasting plasma glucose, fasting insulin, testosterone (T) and estradiol (E₂) were measured. The insulin sensitivity index (ISI), homeostasis model assessment of insulin resistance (HOMA-IR) and E₂/T were calculated. Then, the correlations of serum testosterone level with ISI and HOMA-IR were analyzed by statistical methods.

Results

The HOMA-IR, E₂ and E₂/T of the type 2 diabetes group and DO group were significantly increased, whereas the bone mineral density, ISI, T and sex hormone binding globulin were decreased compared with those of the normal control group. Serum testosterone levels of the type 2 diabetes group and DO group were negatively correlated to the HOMA-IR (r = −0.496, −0.506; P < 0.05), whereas they were positively correlated to the fasting insulin (r = 0.281, 0.292; P < 0.05) and ISI (r = 0.364, 0.403; P < 0.05).

Conclusions

The reduced level of serum testosterone in elderly male type 2 diabetes patients with osteoporosis might promote insulin resistance.     

Diabetic retinopathy is associated with visceral fat accumulation in Japanese type 2 diabetes mellitus patients

The presence of diabetic retinopathy (DR) and increased of visceral fat accumulation (VFA) are associated with high mortality in type 2 diabetes mellitus patients. This preliminary study was therefore designed to test the hypothesis that DR is associated with insulin resistance and VFA in type 2 diabetes mellitus patients without insulin treatment. A total of 102 type 2 diabetes mellitus patients were divided into 2 groups: DR group (age, 60 ± 6 years [mean ± SD]; n = 31) and no diabetic retinopathy (NDR) group (59 ± 5 years, n = 71). The level of blood glucose was assessed by fasting plasma glucose, fasting immunoreactive insulin, homeostasis model assessment index, and hemoglobin A_1c. The fat distribution was evaluated by measuring the VFA by abdominal computed tomography at the umbilical level. The body mass index and waist circumference were higher in the DR group than in the NDR group (P < .001 and P < .0005, respectively). Plasma levels of triglyceride were higher, whereas high-density lipoprotein cholesterol was lower, in the DR group than in the NDR group (P < .005 and P < .0001, respectively). Fasting plasma glucose (P < .0005), insulin concentrations (P < .0001), homeostasis model assessment index (P < .0001), and VFA (P < .0001) levels were higher in the DR group than in the NDR group. Multivariate logistic analysis revealed that DR was independently predicted by high VFA and insulin resistance. The results of this preliminary study indicate that the presence of DR was associated with high VFA and insulin resistance in Japanese patients with type 2 diabetes mellitus.     

Baseline serum total adiponectin level is positively associated with changes in bone mineral density after 1-year treatment of type 2 diabetes mellitus

Although recent clinical studies have shown that serum adiponectin level was negatively associated with bone mineral density (BMD), serum adiponectin action on bone metabolism in humans is still unclear. We investigated the relationships between serum levels of total and high-molecular weight (HMW) adiponectin and its ratio (HMW-total ratio) vs chronological changes in BMD at the lumbar spine, femoral neck (FN), and one third of the radius after 1-year treatment of type 2 diabetes mellitus in 32 Japanese patients. Serum total adiponectin, but not HMW adiponectin or HMW-total ratio, was significantly and positively correlated with percentage change in FN-BMD (r = 0.35, P < .05). Multiple regression analysis adjusted for age, duration of diabetes, sex, body height, body weight, waist circumference, serum creatinine, and hemoglobin A_1c showed that serum total adiponectin was still significantly and positively correlated with percentage change in FN-BMD (r = 0.65, P < .01). On the other hand, no significant relationships were found between serum levels of hemoglobin A_1c, pentosidine, bone formation markers (bone-specific alkaline phosphatase and osteocalcin), or a bone resorption marker (urinary N-terminal cross-linked telopeptide of type-I collagen) vs percentage change in BMD at any site. These findings suggest that serum total adiponectin could be clinically useful for predicting BMD change during treatment of type 2 diabetes mellitus. Adiponectin might protect against BMD reduction in patients with type 2 diabetes mellitus.     

Insulin resistance and inflammation may have an additional role in the link between cystatin C and cardiovascular disease in type 2 diabetes mellitus patients

Recent studies suggest that serum cystatin C level is not only a sensitive marker for renal dysfunction but also a predictive marker for cardiovascular disease (CVD). However, the mechanism of this connection is not fully understood. We aimed to determine whether insulin resistance or various biomarkers of cardiovascular risk have a role in the link between cystatin C and CVD in type 2 diabetes mellitus patients. Anthropometric measurements and biochemical studies including inflammatory biomarkers were performed in 478 patients with type 2 diabetes mellitus. The degree of insulin resistance was assessed by homeostasis model assessment (HOMA-IR) and indicators of metabolic syndrome. Estimated glomerular filtration rate (eGFR) was derived from the Modification of Diet in Renal Disease study equation. After adjusting for age, sex, body mass index, and eGFR, the cystatin C level increased significantly in proportion to the number of metabolic syndrome components present (1.08 ± 0.06, 1.19 ± 0.04, 1.20 ± 0.04, 1.23 ± 0.04, and 1.37 ± 0.06 mg/L; P < .0001); and HOMA-IR increased significantly in proportion to cystatin C quartiles (1.16 ± 0.15, 1.40 ± 0.13, 1.49 ± 0.13, and 2.00 ± 0.17; P < .0001) (means ± SE). Albumin-creatinine ratio, fibrinogen, uric acid, homocysteine, high-sensitivity C-reactive protein, and lipoprotein(a) all showed significant correlations with cystatin C that were generally higher than those with eGFR. Cystatin C level was independently associated with HOMA-IR (β = 0.0380, P = .0082), albumin-creatinine ratio (β = 0.0004, P < .0001), uric acid (β = 0.0666, P < .0001), and homocysteine (β = 0.0087, P = .0004). In conclusion, cystatin C level was significantly associated with insulin resistance and biomarkers reflecting inflammation independent of renal function. These components may have a role in addition to that of eGFR in explaining the link between cystatin C and CVD in type 2 diabetes mellitus patients.     

Bone mass and bone resorption in postmenopausal women with type 2 diabetes mellitus

The aim of the present study was to examine the relationships between bone mass or bone resorption evaluated by urinary cross-linked N-telopeptides of type I collagen (NTx) concentration and known and potential contributors to bone mass or bone resorption such as sex hormones, age, duration of diabetes, glycemic control (hemoglobin A(1c) [HbA(1c)]), body mass index (BMI), severity of diabetic complications, smoking status, and current treatment of diabetes in postmenopausal women with type 2 diabetes mellitus (n = 196). In addition, the relationship of bone mass to pulse wave velocity, which is an earlier indicator of cardiovascular disease, was investigated in a subgroup of patients (n = 120). Bone mass was evaluated by the quantitative ultrasound method. A higher stiffness index indicates higher bone mass. Inverse correlations were found between the stiffness index and age (r = -0.374, P < .0001) and between the stiffness index and log (urinary albumin excretion) (r = -0.170, P = .0398), and a positive correlation was found between the stiffness index and serum dehydroepiandrosterone sulfate (DHEA-S) concentration (r = 0.201, P = .0136). No significant correlations were found between the stiffness index and duration of diabetes, HbA(1c), BMI, or serum estradiol concentration. No significant correlations were found between urinary NTx concentration and age, duration of diabetes, HbA(1c), BMI, serum estradiol concentration, or serum DHEA-S concentration. The stiffness index correlated inversely with urinary NTx concentration (r = -0.262, P = .0002). No significant correlation was found between the stiffness index and pulse wave velocity (r = -0.165, P = .0714). Multiple regression analysis demonstrated that serum DHEA-S concentration was an independent determinant of the stiffness index (beta = .207, P = .0428). In conclusion, serum DHEA-S concentration correlated positively with bone mass, whereas glycemic control, BMI, or duration of diabetes did not correlate with bone mass or urinary NTx concentration in postmenopausal women with type 2 diabetes mellitus.     

Addition of metformin to exogenous glucagon-like peptide-1 results in increased serum glucagon-like peptide-1 concentrations and greater glucose lowering in type 2 diabetes mellitus

Glucagon-like peptide-1 (GLP-1) is an incretin hormone that lowers blood glucose after meals in type 2 diabetes mellitus. The therapeutic potential of GLP-1 in diabetes is limited by rapid inactivation by the enzyme dipeptidylpeptidase-4 (DPP-4). Metformin has been reported to inhibit DPP-4. Here we investigated the acute effects of metformin and GLP-1 alone or in combination on plasma DPP-4 activity, active GLP-1 concentrations, and glucose lowering in type 2 diabetes mellitus. Ten subjects with type 2 diabetes mellitus (8 male and 2 female; age, 68.7 ± 2.6 years [mean ± SEM]; body mass index, 29.6 ± 1.7 kg/m²; hemoglobin A_1c, 7.0% ± 0.1%) received 1 of 3 combinations after an overnight fast in a randomized crossover design: metformin 1 g orally plus subcutaneous injection saline (Metformin), GLP-1 (1.5 nmol/kg body weight subcutaneously) plus placebo tablet (GLP-1), or metformin 1 g plus GLP-1(Metformin + GLP-1). At 15 minutes, glucose was raised to 15 mmol/L by rapid intravenous infusion of glucose; and responses were assessed over the next 3 hours. This stimulus does not activate the enteroinsular axis and secretion of endogenous GLP-1, enabling the effect of exogenously administered GLP-1 to be examined. Mean area under curve (AUC) _{0-180 minutes} plasma glucose responses were lowest after Metformin + GLP-1 (mean ± SEM, 1629 ± 90 mmol/[L min]) compared with GLP-1 (1885 ± 86 mmol/[L min], P < .002) and Metformin (2045 ± 115 mmol/[L min], P < .001). Mean AUC serum insulin responses were similar after either Metformin + GLP-1 (5426 ± 498 mU/[L min]) or GLP-1 (5655 ± 854 mU/[L min]) treatment, and both were higher than Metformin (3521 ± 410 mU/[L min]; P < .001 and P < .05, respectively). Mean AUC for plasma DPP-4 activity was lower after Metformin + GLP-1 (1505 ± 2 μmol/[mL min], P < .001) and Metformin (1508 ± 2 μmol/[mL min], P < .002) compared with GLP-1 (1587 ± 3 μmol/[mL min]). Mean AUC measures for plasma active GLP-1 concentrations were higher after Metformin + GLP-1 (820 × 10⁴ ± 51 × 10⁴ pmol/[L min]) compared with GLP-1 (484 × 10⁴ ± 31 × 10⁴ pmol/[L min], P < .001) and Metformin (419 × 10⁴ ± 34 × 10⁴ pmol/[L min], P < .001), respectively. In patients with type 2 diabetes mellitus, metformin inhibits DPP-4 activity and thus increases active GLP-1 concentrations after subcutaneous injection. In combination with GLP-1, metformin significantly lowers plasma glucose concentrations in type 2 diabetes mellitus subjects compared with GLP-1 alone, whereas insulin responses were similar. Metformin enhances serum concentrations of injected active GLP-1(7-36)amide, and the combination results in added glucose-lowering potency.     

White matter lesions are associated with the results of I-metaiodobenzylguanidine myocardial scintigraphy in type 2 diabetes mellitus patients

White matter lesions (WMLs) and cardiovascular autonomic dysfunction are associated with high mortality in type 2 diabetes mellitus patients. This preliminary study was therefore designed to test the hypothesis that WML is associated with insulin resistance and cardiovascular autonomic dysfunction in type 2 diabetes mellitus patients without insulin treatment. Based on brain magnetic resonance imaging findings, 55 type 2 diabetes mellitus patients were divided into 2 groups: a WML-positive group (59 ± 5 years [mean ± SD], n = 21) and a WML-negative group (58 ± 6 years, n = 34). Cardiovascular autonomic function was assessed by baroreflex sensitivity, heart rate variability, plasma norepinephrine concentrations, and cardiac ¹²³I-metaiodobenzylguanidine (MIBG) scintigraphy. Baroreflex sensitivity was lower in the WML-positive group than in the WML-negative group (P < .01). Early and delayed ¹²³I-MIBG myocardial uptake values were lower (P < .005 and P < .001, respectively) and the percentage washout rate (WR) of ¹²³I-MIBG was higher (P < .0001) in the WML-positive group than in the WML-negative group. The fasting plasma glucose (P < .005) and insulin concentrations (P < .0001) and the homeostasis model assessment (HOMA) index values (P < .0001) were higher in the WML-positive group than in the WML-negative group. Multiple logistic regression analysis revealed that HOMA index and percentage WR of ¹²³I-MIBG were associated with WML patients. Our results suggested that WML was associated with depressed cardiovascular autonomic function and insulin resistance and that HOMA index and the percentage WR of ¹²³I-MIBG were independent associations for WML in Japanese patients with type 2 diabetes mellitus.     

Association of serum lycopene and brachial-ankle pulse wave velocity with metabolic syndrome

Metabolic syndrome (MetS) is known to inversely correlate with antioxidant status. Recently, it has been reported that MetS is associated with arterial stiffness, a composite risk factor for early atherosclerosis. In addition, our recent study for healthy women showed an inverse relationship between arterial stiffness and circulating lycopene. Therefore, this study aimed to investigate the interrelationship between arterial stiffness, antioxidant status, and the risk of MetS. Korean men (N = 299) were subgrouped according to the number of MetS risk factors (RF 0, RF 1-2, RF ≥3). Anthropometric parameters, brachial-ankle pulse wave velocity (baPWV; a marker of arterial stiffness), antioxidants (lycopene, β-carotene, α-tocopherol), lipid profiles, glucose, insulin, and oxidative stress (low-density lipoprotein [LDL] particle size, oxidized LDL) were measured. Corresponding to the number of MetS RF, baPWV (1306 ± 17, 1364 ± 16, and 1420 ± 33 cm/s; P < .001) and insulin resistance (1.5 ± 0.1, 1.9 ± 0.1, and 2.7 ± 0.2; P < .001) gradually increased after adjustment for age, body mass index, smoking, and drinking, whereas serum lycopene among antioxidants and LDL particle size gradually decreased (0.036 ± 0.001, 0.031 ± 0.001, and 0.028 ± 0.001 mmol/L; P = .004 and 23.9 ± 0.1, 23.7 ± 0.1, and 23.3 ± 0.1 nm; P < .001, respectively). Brachial-ankle pulse wave velocity inversely correlated with serum lycopene after adjustment for the above confounders, blood pressure, insulin resistance, and oxidative stress (r = −0.136, P < .05). Oxidative stress markers also significantly correlated with baPWV as well as serum lycopene. Study subjects were divided into 2 groups by the median level of serum lycopene. When serum lycopene was lower than median level (≤0.0294 mmol/L), baPWV was significantly higher in MetS subjects than non-MetS subjects (1436 ± 41 vs 1367 ± 23 cm/s) after adjustment for age, body mass index, smoking, drinking, and oxidative stress (P = .041). However, when serum lycopene levels were high, no statistically significant difference was observed between the 2 subject groups (1386 ± 36 vs 1326 ± 13 cm/s). In conclusion, our result shows the interrelationship between circulating lycopene, baPWV, and MetS. In addition, much enhanced baPWV in MetS may be associated with lower lycopene concentration.     

The contribution of race and diabetes status to metabolic flexibility in humans

Factors controlling metabolic flexibility (MF), the ability of the body to switch from fat to carbohydrate oxidation in response to feeding or with insulin administration, are being actively investigated. We sought to determine the effects of race (African American vs Caucasian) and diabetes status (nondiabetic vs type 2 diabetes mellitus individuals) on MF to glucose in humans. Respiratory quotient (RQ) and macronutrient substrate utilization were evaluated by indirect calorimetry during baseline (fasting) and hyperinsulinemic-euglycemic clamp (insulin infusion of 120 mU·m⁻²·min⁻¹); ΔRQ (MF) = clamp RQ − fasting RQ. The study included 168 human subjects of different races (55 African Americans, 113 Caucasians), sex (73 men, 95 women), ages (18-73 years), body mass index (19.3-47.7 kg/m²), and diabetes status (89 nondiabetic, 79 type 2 diabetes mellitus subjects). Metabolic flexibility was negatively correlated (P < .01) with age (r = − 0.41), fasting RQ (r = −0.22), fasting glucose (r = −0.55), insulin (r = −0.40), and triglyceride (r = −0.44) concentrations; whereas a positive association was observed with insulin sensitivity (r = 0.69, P < .0001). Insulin sensitivity, fasting RQ, triglyceride concentrations, diabetes status, and race accounted for 71% of the variability in MF with insulin sensitivity being the main determinant factor (model R² = 0.48, P < .0001). After controlling for the significant predictors, MF was higher in African Americans vs Caucasians (mean ± SEM 0.080 ± 0.004 vs 0.069 ± 0.002, P = .008) and in nondiabetic vs type 2 diabetes mellitus subjects (P = .003). This study confirms that insulin sensitivity is the major contributor to MF in humans, but provides the novel findings that African Americans have significantly greater MF than Caucasians even after adjusting for insulin sensitivity and diabetes status.     

High-sensitivity C-reactive protein is associated with hippocampus volume in nondementia patients with type 2 diabetes mellitus

The elevated level of high-sensitivity C-reactive protein (HSCRP) is associated with cognitive dysfunction, for which changes in the hippocampus plausibly play a pivotal role. We tested the hypothesis that an elevated level of HSCRP correlates with hippocampus volume and insulin resistance in nondementia patients with type 2 diabetes mellitus. Subjects included 45 nondementia patients with type 2 diabetes mellitus, who were divided into 2 groups: high-HSCRP group (age, 65 ± 6 years [mean ± SD]; n = 17) and normal-HSCRP group (65 ± 7 years, n = 28). Hippocampus volume has been quantitated with computer-assisted analysis using a magnetic resonance imaging voxel-based specific regional analysis system developed for the study of Alzheimer disease (VSRAD), which yields a z score as the end point for assessment of hippocampal volume. The z score was higher in the high-HSCRP group than in the normal-HSCRP group (P < .0001). The fasting plasma glucose (P < .05) and insulin concentrations (P < .0001) and the homeostasis model assessment (HOMA) index (P < .0001) were higher in the high-HSCRP group than in the normal-HSCRP group. Multiple regression analysis showed that HSCRP levels were independently predicted by z score and HOMA index. Our results indicate that the elevated level of HSCRP in Japanese nondementia patients with type 2 diabetes mellitus is characterized by increased hippocampus volume and insulin resistance, and that the z score and HOMA index are independent predictors of HSCRP.     

Adiponectin, total antioxidant status, and urine albumin excretion in the low-risk “Golden Years” type 1 diabetes mellitus cohort

Adiponectin is associated with inflammation and oxidative stress. Levels are reduced in type 2 diabetes mellitus and coronary heart disease. Conversely, levels are elevated in type 1 diabetes mellitus (T1DM) and associated with microalbuminuria and diabetic nephropathy. An explanation may be that elevated adiponectin in T1DM represents a beneficial counterregulatory response to disease. Our aim was to examine adiponectin in relation to urinary albumin excretion and plasma total antioxidant status (TAOS) in subjects with long-standing T1DM. Serum adiponectin and plasma TAOS were measured in 338 samples from the Golden Years cohort. These subjects have T1DM for at least 50 years and are at low risk of complications. Subjects were divided into normoalbuminuria, microalbuminuria, and macroalbuminuria groups. Adiponectin was elevated in women (20.53 ± 5.94 vs 11.8 ± 3.6 mg/L, P < .001); therefore, the samples were sex stratified. Within men, adiponectin was higher in those with macroalbuminuria (normoalbuminuria vs microalbuminuria vs macroalbuminuria: 10.97 ± 3.26 vs 11.55 ± 3.50 vs 23.63 ± 7.07 mg/L, P = .002). In women, no difference was observed (20.48 ± 5.61 vs 20.75 ± 7.04 vs 29.62 ± 7.81 mg/L, respectively; P = .42). Plasma TAOS did not differ by groups. The correlation between adiponectin and TAOS showed a linear increase from normoalbuminuria, microalbuminuria, to macroalbuminuria in men (r = 0.33, P = .001; r = 0.48, P < .001; r = 0.59, P = .04) and women (r = 0.25, P = .01; r = 0.63, P < .001; r = 0.79, P = .08). Adiponectin was higher in women. Within men, levels were significantly higher in the presence of macroalbuminuria. In both sexes, adiponectin and TAOS were correlated, which was most marked with micro-/macroalbuminuria. The increase in adiponectin in the face of an insult may be a compensatory mechanism to reduce oxidative burden.     

Osteoprotegerin in relation to type 2 diabetes mellitus and the metabolic syndrome in postmenopausal women

Osteoprotegerin (OPG) is an inhibitor of bone resorption. Circulating levels of OPG seem to be elevated in patients with cardiovascular disorders and diabetes. The relationship between OPG and the metabolic syndrome has never been studied in postmenopausal women. In a population-based study, 382 Iranian postmenopausal women were randomly selected. Cardiovascular risk factors, high-sensitivity C-reactive protein, and OPG were measured. The diabetes classification and the metabolic syndrome definition were based on the criteria of the American Diabetes Association and the National Cholesterol Education Program-Adult Treatment Panel III, respectively. The mean serum OPG level was higher in those with type 2 diabetes mellitus than those without diabetes (4.33 ± 1.70 vs 3.84 ± 1.76 pmol/L, P = .016). In multiple logistic regression analysis, type 2 diabetes mellitus showed a significant association with serum OPG levels when adjustments were made for age, high-sensitivity C-reactive protein, and cardiovascular risk factors (odds ratio = 2.21; confidence interval, 1.34-3.66; P = .002). No significant difference was found between the mean serum OPG levels of those with the metabolic syndrome and those without the metabolic syndrome. Mean OPG levels did not differ significantly between subjects with and without hypertension, dyslipidemia, glucose intolerance, or abdominal obesity according to the National Cholesterol Education Program-Adult Treatment Panel III criteria. In conclusion, circulating OPG levels are significantly associated with diabetes, independent of cardiovascular risk factors in postmenopausal women. However, OPG levels have no correlation with the metabolic syndrome or its components. Further studies are warranted to determine the pathophysiologic origin of elevated OPG in type 2 diabetes mellitus.     

Plasma serotonin is a predictor for deterioration of urinary albumin excretion in men with type 2 diabetes mellitus

We performed an observational study to investigate if plasma 5-hydroxyindole-3-acetic acid (5-HIAA), a derivative end product of serotonin (5-hydroxytryptamine), concentration could be a predictor for deterioration of urinary albumin excretion. The relationship between baseline plasma 5-HIAA concentration and changes in urinary albumin excretion for 24 months was investigated in 162 male patients with type 2 diabetes mellitus. Patients were divided into tertiles according to plasma 5-HIAA concentration. Greater changes in urinary albumin excretion were seen in patients with high plasma 5-HIAA concentration (112.8 ± 36.2 mg/g creatinine) than in patients with low plasma 5-HIAA concentration (7.6 ± 8.0 mg/g creatinine, P = .0011) or in patients with intermediate plasma 5-HIAA concentration (25.6 ± 15.0 mg/g creatinine, P = .0070) after adjustment for baseline values of urinary albumin excretion. A positive correlation was observed between log (plasma 5-HIAA concentration) and changes in urinary albumin excretion (r = 0.314, P < .0001). Multiple regression analysis demonstrated that log (plasma 5-HIAA concentration) (β = .284, P = .0013) was an independent determinant of changes in urinary albumin excretion. In conclusion, plasma 5-HIAA concentration was positively correlated with changes in urinary albumin excretion, which may indicate causality in diabetic nephropathy in male patients with type 2 diabetes mellitus and high plasma 5-HIAA concentration.     

Glimepiride increases high-density lipoprotein cholesterol via increasing adiponectin levels in type 2 diabetes mellitus

The aims of the present study are to investigate the effect of glimepiride 1 mg/d on plasma adiponectin and to assess the contribution of adiponectin in changing high-density lipoprotein cholesterol (HDL-c) levels after glimepiride treatment. Forty patients with type 2 diabetes mellitus were included. Plasma adiponectin, fasting plasma glucose, insulin, hemoglobin A_1c, and cholesterol were measured at study entry and after 3 months of treatment with glimepiride. Both plasma adiponectin level (7.5 ± 4.5 vs 8.3 ± 4.5 μg/mL, P = .040) and HDL-c level increased significantly (50 ± 11 vs 53 ± 10 mg/dL, P = .041) in the all-subjects group. In the low-adiponectin group (initial plasma adiponectin level <6 μg/mL), both plasma adiponectin level (4.5 ± 0.9 vs 5.9 ± 2.0 μg/mL, P = .004) and HDL-c level increased significantly (44 ± 8 vs 49 ± 9 mg/dL, P = .011). There was no significant change in the high-adiponectin group (initial plasma adiponectin level ≥6 μg/mL). Change in plasma adiponectin level was an independent factor for change in HDL-c level after adjustment for other factors (β = .574, P = .009, R² = 0.524, P = .036). In conclusion, glimepiride improved plasma adiponectin level, especially in the subjects with type 2 diabetes mellitus with low adiponectin level before treatment, and may directly contribute to improving HDL-c level.     

Carotid intima-media thickness and stiffness in relation to type 2 diabetes in Chinese

We investigated carotid intima-media thickness (IMT) and quantitative carotid stiffness (QCS) index in relation to plasma glycosylated hemoglobin A_1C (HbA_1C) and duration of diabetes mellitus in 337 Chinese diabetic patients. In categorical analyses, carotid IMT was 710 μm in subjects with a duration of diabetes mellitus ≤2 years, 760 μm in subjects with a duration of diabetes mellitus more than two years and with plasma HbA_1C < 6.5% (P < 0.05), and 790 μm in subjects with a duration of diabetes mellitus more than two years but with plasma HbA_1C ≥ 6.5% (P < 0.01). The corresponding values for QCS values were 4.5, 4.6 and 5.1 (P < 0.05), respectively. In multiple stepwise regression analyses carotid IMT was significantly associated with the duration of diabetes mellitus, systolic blood pressure and serum concentration of total cholesterol, whereas QCS was significantly associated with age, HbA_1C, systolic and diastolic blood pressure (P < 0.05). In conclusion, carotid IMT as a structural measure of arterial wall is increased in patients with a longer history of diabetes mellitus, whereas QCS as functional index is mainly influenced by the quality of blood glucose control.