Mariko Suetsugu

Serum level of soluble CD26/dipeptidyl peptidase-4 (DPP-4) predicts the response to sitagliptin, a DPP-4 inhibitor, in patients with type 2 diabetes controlled inadequately by metformin and/or sulfonylurea

Dipeptidyl peptidase 4 (DPP-4) inhibitors is a new class of antihyperglycemic agents that is now available for the treatment of type 2 diabetes. We investigated the relationship between the baseline serum level of soluble CD 26/DPP-4 and the response to treatment with sitagliptin, a DPP-4 inhibitor, over 24 weeks in patients who had type 2 diabetes inadequately controlled by metformin and/or sulfonylurea therapy. We studied 52 consecutive patients with type 2 diabetes who had poor glycemic control despite treatment with metformin and/or sulfonylurea. All patients were given 50 mg/day of sitagliptin and were followed at monthly intervals for 24 weeks. Treatment with sitagliptin decreased significantly hemoglobin A1c (HbA1c) from 7.91 ± 1.08% at baseline to 6.96 ± 1.18% at 8 weeks, 7.04 ± 0.77% at 16 weeks, and 7.08 ± 0.80% at 24 weeks. The baseline serum level of sCD26 was correlated positively with HbA1c at both 16 weeks and 24 weeks. Furthermore, the serum sCD26 level at baseline was also correlated positively with the changes from baseline of HbA1c at 16 and 24 weeks (r = 0.318, P = 0.0296 and r = 0.516, P = 0.0003, respectively). In a multivariate logistic regression model that explained 56.1% (R(2) = 0.561) of the variation of the changes from baseline of HbA1c at 24 weeks, the baseline HbA1c (β = -0.638, P < 0.001) and serum sCD26 (β = 0.357, P = 0.041) were independent determinants of the change of HbA1c at 24 weeks. In conclusions, a higher serum level of sCD26 is associated with a worse response to sitagliptin in patients with type 2 diabetes controlled inadequately by metformin and/or sulfonylurea therapy.

Relation between serum high molecular weight adiponectin and serum ferritin or prohepcidin in patients with type 2 diabetes

An increase of serum ferritin, an indicator of body iron store, is associated with insulin resistance and with an increased risk of type 2 diabetes in the general population. A low serum adiponectin is also associated with insulin resistance. Recently, hepcidin was identified as a regulator of iron metabolism. We investigated whether serum adiponectin was associated with serum ferritin or prohepcidin, a precursor of hepcidin, in healthy subjects and patients with type 2 diabetes. We studied 65 healthy subjects and 104 patients with type 2 diabetes. A serum ferritin concentration ≥ 300 ng/ml for men or ≥ 150 ng/ml for women was defined as hyperferritinemia. Serum ferritin was significantly higher and serum prohepcidin was significantly lower in diabetic patients than in control subjects. Serum total and high molecular weight (HMW) adiponectin correlated negatively with serum ferritin in control subjects or diabetic patients, while serum total and HMW adiponectin correlated positively with serum prohepcidin in diabetic patients, but not in control subjects. Serum total and HMW adiponectin were lower in patients with hyperferritinemia than in those without it. In conclusion, serum ferritin was increased in type 2 diabetic patients, while serum prohepcidin was decreased. A high serum ferritin was associated with insulin resistance, and with low serum total and HMW adiponectin in patients with type 2 diabetes.

Low-dose pioglitazone increases serum high molecular weight adiponectin and improves glycemic control in Japanese patients with poorly controlled type 2 diabetes

We investigated the effects of low-dose pioglitazone (7.5mg/day) on serum high molecular weight (HMW) adiponectin and fluid retention (estimated from hematocrit) in 14 male and 16 female patients with type 2 diabetes. All of them were being treated with sulfonylureas and had poor glycemic control. Patients were given 7.5 mg/day of pioglitazone and were followed for 12 weeks at monthly intervals. In all 30 patients, HbA1c was significantly decreased after 12 weeks of treatment with pioglitazone (8.2+/-0.7% vs. 7.4+/-0.8%, P<0.0001). Serum HMW adiponectin increased markedly from 5.2 (2.4, 8.6) microg/ml at baseline to 9.8 (4.1, 12.6) microg/ml at the end of pioglitazone treatment (P<0.0001). When the changes were evaluated separately for each sex, diabetic men showed no increase of body weight or BMI after treatment, while HbA1c decreased significantly, and did Hct. Serum HMW adiponectin increased significantly after treatment. In diabetic women, neither body weight nor BMI increased after treatment with pioglitazone, as was the case for the men. HbA1c decreased significantly, and did Hct. Serum HMW adiponectin increased significantly after treatment. In conclusion, low-dose pioglitazone therapy could significantly improved glycemic control and markedly increased serum HMW adiponectin in both male and female Japanese patients with type 2 diabetes.

Effects of Rosuvastatin and Colestimide on Metabolic Parameters and Urinary Monocyte Chemoattractant Protein-1 in Type 2 Diabetic Patients with Hyperlipidemia

Background: Rosuvastatin, a strong statin, and colestimide, a new anion exchange resin, are both clinically beneficial drugs for treatment of hypercholesterolemia. The main purpose of the study was to compare the effects of rosuvastatin and colestimide on metabolic parameters, adipokines, and markers of oxidative stress and diabetic nephropathy in patients with type 2 diabetes complicated by hyperlipidemia. Design: A total of 40 patients with type 2 diabetes complicated by hyperlipidemia were recruited prospectively and consecutively. The patients were assigned randomly in equal numbers to rosuvastatin (2.5 mg/day) and colestimide (3.0 g/day) groups. Blood and urine tests were performed at the beginning of the study and after 12 weeks. Results: Rosuvastatin significantly decreased the level of serum retinol-binding protein (RBP)-4, an insulin-resistant adipokine, in a subgroup of patients with poor glycemic control, in addition to exerting a strong low-density lipoprotein (LDL-C)-lowering effect. Colestimide significantly decreased HbA1c, even in patients treated with a sulfonylurea at a more than moderate dose, without influencing insulin resistance or adiponectin (an insulin-sensitive adipokine) and RBP4. Colestimide also significantly decreased the levels of urinary 8-iso-prostaglandin (PG) F2&agr; (a marker of oxidative stress) and urinary monocyte chemoattractant protein-1 (MCP-1) (a marker of diabetic nephropathy). Conclusion: Our results show that rosuvastatin and colestimide exert different beneficial effects in type 2 diabetic patients complicated by hyperlipidemia. Therefore, concomitant use of these drugs may be useful for prevention of progression of diabetic complications.

Comparison of the effects of pioglitazone and voglibose on circulating total and high‐molecular‐weight adiponectin, and on two fibrinolysis inhibitors, in patients with Type 2 diabetes

Background  To investigate short‐term effects of pioglitazone and voglibose on serum concentrations of both total and high‐molecular‐weight (HMW) adiponectin measured with a novel sandwich enzyme‐linked immunosorbent assay (ELISA) ,and on plasma fibrinolysis indicators, in Type 2 diabetic patients with inadequate glycaemic control on sulphonylureas.

Anemia is associated with an elevated serum level of high-molecular-weight adiponectin in patients with type 2 diabetes independently of renal dysfunction

Low serum adiponectin is associated with a high incidence of type 2 diabetes or coronary artery disease in the general population. Paradoxically, serum adiponectin is elevated in patients with chronic kidney disease (CKD), such as overt diabetic nephropathy. The current study aimed to investigate whether anemia was independently associated with the serum level of high-molecular-weight (HMW) adiponectin in patients with type 2 diabetes. We studied 207 type 2 diabetic patients (92 women and 115 men). Anemia was defined as a hemoglobin (Hb) <13.0g/dL in men and <12.0g/dL in women according to the guidelines of the World Health Organization (WHO). Overt nephropathy (CKD) was defined as clinical proteinuria and /or estimated glomerular filtration rate (eGFR) lower than 60mL/min for more than 3 months. The diabetic patients were divided into 4 groups according to the presence or absence of anemia and/or CKD. Serum HMW adiponectin levels were measured by a sandwich enzyme-linked immunosorbent assay. In all 207 patients with type 2 diabetes, serum total and HMW adiponectin levels were correlated positively with age, the duration of diabetes, high-density lipoprotein (HDL) cholesterol, urinary albumin, and serum erythropoietin, whereas negative correlations were found with body mass index, triglyceride, eGFR, Hb, hematocrit, and high sensitivity C-reactive protein. A stepwise regression analysis demonstrated that among several significant variables, Hb had the strongest independent influence on HMW adiponectin (beta =-0.487, P < 0.001). Diabetic patients of both sexes with anemia and CKD had the highest serum levels of HMW adiponectin among the 4 groups. In conclusion, anemia is associated with marked elevation of serum HMW adiponectin levels in diabetic patients who have CKD, and this elevation is independent of renal function.

Serum high-molecular weight adiponectin decreases abruptly after an oral glucose load in subjects with normal glucose tolerance or impaired fasting glucose, but not those with impaired glucose tolerance or diabetes mellitus.

Adiponectin exists in the blood as 3 forms, which are a trimer, a hexamer, and a high-molecular weight (HMW) form. We investigated whether circulating HMW adiponectin levels were altered by oral glucose or fat ingestion. Forty male subjects underwent a 75-g oral glucose loading test (OGTT), and 11 healthy subjects (5 women and 6 men) received a fat loading test. Serum levels of HMW and total adiponectin were measured during the OGTT and the fat loading test. The fat loading test was performed for at least 8 hours. Among the 40 male subjects, 11 had normal glucose tolerance (NGT), 9 had impaired fasting glucose (IFG), 11 had impaired glucose tolerance, and 9 had diabetes mellitus (DM). In all 40 subjects, the serum total adiponectin level did not change significantly, whereas serum HMW adiponectin decreased significantly after a glucose load and reached 92.2% of the basal level at 120 minutes after the OGTT (P < .01). The HMW to total adiponectin ratio decreased significantly from 0.47 +/- 0.15 at baseline to 0.43 +/- 0.13 at 120 minutes after a glucose load (P < .05). Serum HMW adiponectin measured at 120 minutes after the OGTT decreased significantly to 86.0% and 85.6% of the basal level in subjects with NGT or IFG, respectively (both P < .01). In subjects with impaired glucose tolerance or DM, however, serum HMW adiponectin did not change. The area under the curve for insulin at 30 minutes after a glucose load during the OGTT was significantly larger in subjects with NGT or IFG than in those with DM (P < .05). In addition, the insulinogenic index (DeltaI(0-30)/DeltaG(0-30)) was significantly higher in subjects with NGT or IFG than in those with DM (P < .001). Percentage changes in serum HMW adiponectin of the baseline at 120 minutes correlated negatively with those in serum insulin (r = -0.468, P = .0023), but not plasma glucose, of the baseline at 30 minutes in 40 subjects. On the other hand, serum triglycerides increased significantly after an oral fat load in 11 healthy subjects; but neither serum total nor HMW adiponectin changed. In conclusion, serum HMW adiponectin (but not total adiponectin) decreased rapidly after glucose loading in subjects with NGT or IFG; and the decrease of HMW adiponectin may be associated with an increase of serum insulin at 30 minutes.

Association between diabetic microangiopathy and vascular endothelial function evaluated by flow-mediated vasodilatation in patients with type 2 diabetes

The main purpose of the study was to investigate the association between vascular endothelial function and diabetic microangiopathy (nephropathy, retinopathy and neuropathy) in patients with type 2 diabetes. In addition, the association between endothelial function and macroangiopathy evaluated by intimal–medial complex thickness (IMT) was also investigated. Endothelial function was evaluated non‐invasively by the measurement of flow‐mediated vasodilatation (FMD) of the brachial artery. Diabetic nephropathy and neuropathy were assessed by urinary albumin excretion (UAE) and motor or sensory nerve conduction velocity (MCV, SCV), respectively, and retinopathy was evaluated by an ophthalmologist using the Davis classification. FMD was measured in 102 patients with type 2 diabetes and in 20 control subjects, and showed a tendency to be lower in the diabetic patients. There was a significant decrease in FMD in patients with proliferative diabetic retinopathy, compared with those in patients with no diabetic retinopathy. FMD showed significant positive correlations with MCV and SCV, and significant negative correlations with log UAE, systolic blood pressure and diabetic duration, but no correlation was obtained between FMD and IMT. In stepwise regression analysis, MCV alone showed a significant association with FMD. In conclusion, our results show that in patients with type 2 diabetes FMD is closely associated with all types of microangiopathy, with neuropathy being most strongly associated with FMD; however, FMD is not associated with macroangiopathy evaluated by IMT.

Correlation of high-sensitivity C-reactive protein and plasma fibrinogen with individual complications in patients with type 2 diabetes.

Objective: We investigated the correlation between acute-phase reactants, ie, high-sensitivity C-reactive protein (hsCRP) or fibrinogen and diabetic complications. Methods: In 73 patients with type 2 diabetes, we investigated associations between both markers and carotid artery intimal medial complex thickness (IMT), heart rate variability, or urinary albumin excretion (UAE). Results: Log hsCRP and fibrinogen correlated significantly with each other (r = 0.3701, P = 0.0013). Fibrinogen correlated negatively with the coefficient of variation of RR intervals (CVRR) and positively with log UAE (r = −0.2433, P = 0.0381; r = 0.4815, P < 0.0001), while log hsCRP did not. Furthermore both log hsCRP and fibrinogen did not correlate with IMT. Conclusion: We concluded that despite their close correlation, fibrinogen compared with hsCRP might be closely associated with diabetic microangiopathy and that both markers might not correlate with IMT as a marker of macroangiopathy.

Alterations of plant sterols, lathosterol, oxidative stress and inflammatory markers after the combination therapy of ezetimibe and statin drugs in type 2 diabetic patients

UNLABELLED The elevation of serum plant sterols in addition to serum LDL-cholesterol (LDL-C) is one of the important risk factors for coronary heart disease. We investigated how to alterations of serum hepatic synthesised cholesterol and plant sterols levels, clinical markers for inflammation and oxidative stress after combination therapy with ezetimibe, an inhibitor of cholesterol transporter in the small intestinal colon, and statin drugs in type 2 diabetic patients. Studies were conducted in 28 patients with type 2 diabetes mellitus complicated with dyslipidemia. Patients were divided into 3 groups as follows: the 1st group is 7 patients treated with 10mg ezetimibe sequent on pretreatment with mild statin drug (MS+E group), and the 2nd group is 7 patients treated with 10mg ezetimibe sequent on pretreatment with strong statin drug (SS+E group), and then the 3rd group is 14 patients treated with 10mg ezetimibe alone without pretreatment with any statin drugs (naïve E group). In addition to various metabolic markers, serum plant sterols such as sitosterol and campesterol, and hepatic synthesised cholesterol such as lathosterol were measured by the gas liquid chromatography. Serum highly sensitive CRP (hsCRP) as an inflammation marker, and then malonyldealdehyde (MDA) and carbonyl-modified protein (CMP) as an oxidative stress were assayed by the conventional method, respectively. Fasting plasma glucose and serum glucosylated HbA1c (JDS value) did not show any significant changes after administration of ezetimibe in whole groups. Serum LDL-C was reduced significantly and serum triglyceride exhibited a tendency of reduction in whole groups. Serum sitosterol and campesterol were decreased significantly, while serum lathosterol was increased significantly or markedly in whole patients and also in each group. There were no significant changes in serum hsCRP in whole groups. Both serum MDA and CMP revealed significant or marked reductions in each group. CONCLUSIONS The present investigation suggests that the combination therapy of the ezetimibe and statin drugs is potential to remarkably reduce serum LDL-C, plant sterols, MDA and CMP, and therefore might lead to prevent atherosclerosis.