Effect of canagliflozin on circulating active GLP-1 levels in patients with type 2 diabetes: a randomized trial.

Canagliflozin has a robust inhibitory effect on sodium glucose transporter (SGLT)-2 and a mild inhibitory effect on SGLT1. The main purpose of this study was to investigate the effect of canagliflozin on circulating active glucagon-like peptide 1 (GLP-1) levels in patients with type 2 diabetes. Patients were randomly divided into a control group (n =15) and a canagliflozin-treated group (n =15). After hospitalization, the canagliflozin-treated group took 100 mg/day canagliflozin for the entire study, and after 3 days both groups took 20 mg/day teneligliptin for an additional 3 days. In a meal test, canagliflozin significantly decreased the area under curve (AUC) (0-120 min) for plasma glucose (PG) after 3 days when compared with that at baseline, and addition of teneligliptin to the canagliflozin-treated group further decreased it. A significant decrease in the AUC (0-120 min) for serum insulin by canagliflozin was obtained, but the addition of teneligliptin elevated the AUC, and thus abolished the significant difference from baseline. A significant increase in the AUC (0-120 min) of plasma active GLP-1 by canagliflozin-treatment compared with that at baseline was observed, and the addition of teneligliptin resulted in a further increase. However, canagliflozin-treatment did not change the AUC (0-120 min) of plasma active glucose-dependent insulinotropic peptide (GIP). In conclusions, canagliflozin-administration before meals decreased PG and serum insulin, and increased plasma active GLP-1 levels in patients with type 2 diabetes. Canagliflozin did not greatly influence plasma active GIP levels.

Effect of combination therapy with alogliptin and lansoprazole on glycemic control in patients with type 2 diabetes.

The main purpose of the current study was to investigate the effect of a combination of alogliptin [a dipeptydil peptidase (DPP)-4 inhibitor] and lansoprazole [a proton pump inhibitor (PPI)] compared with alogliptin mono-therapy on glycemic control in patients with type 2 diabetes. This study was a multicenter randomized open-label study. One hundred type 2 diabetic patients were randomly assigned to either the alogliptin with lansoprazole group or the alogliptin mono-therapy group. After 3 months of treatment, the changes in hemoglobin (Hb)A1c, fasting plasma glucose (FPG), serum gastrin, homeostasis model assessment (HOMA)-ß, and HOMA-insulin resistance (IR) were evaluated. A significant decrease in HbA1c and FPG, and a significant increase in HOMA-ß were observed in both groups (all with P <0.0001). However, there were no significant differences in changes in HbA1c, FPG, or HOMA-ß before and after therapy between the combination and alogliptin mono-therapy group (P =0.2945, P =0.1901, P =0.3042, respectively). There was a significant elevation of serum gastrin in the combination group compared with the alogliptin mono-therapy group (P =0.0004). This study showed that, although combination therapy with alogliptin and lansoprazole more effectively elevated serum gastrin levels compared with alogliptin mono-therapy, the effect of the combination therapy on glycemic control was equal to that of alogliptin mono-therapy during a 3-month study period.

Association of the Hermansky-Pudlak syndrome type 4 (HPS4) gene variants with cognitive function in patients with schizophrenia and healthy subjects.

BACKGROUND: The Hermansky-Pudlak Syndrome Type 4 (HPS4) gene, which encodes a subunit protein of the biogenesis of lysosome-related organelles complex (BLOC)-3, which is involved in late endosomal trafficking, is associated with schizophrenia; however, its clinical relevance in schizophrenia remains unknown. The purpose of the present study was to investigate whether HPS4 is associated with cognitive functions in patients with schizophrenia and healthy controls and with the clinical profiles of patients with schizophrenia. METHODS: We investigated the association of variants of HPS4 with clinical symptoms and cognitive function in Japanese patients with schizophrenia (n = 240) and age-matched healthy control subjects (n = 240) with single nucleotide polymorphisms (SNP)- or haplotype-based linear regression. We analyzed five tagging SNPs (rs4822724, rs61276843, rs9608491, rs713998, and rs2014410) of HPS4 and 2-5 locus haplotypes of these five SNPs. The cognitive functions of patients and healthy subjects were evaluated with the Brief Assessment of Cognition in Schizophrenia, Japanese-language version, and the patients were assessed for their symptomatology with the Positive and Negative Symptom Scale (PANSS). RESULTS: In patients with schizophrenia, rs713998 was significantly associated with executive function under the dominant genetic model (P = 0.0073). In healthy subjects, there was a significant association between working memory and two individual SNPs under the recessive model (rs9608491: P = 0.001; rs713998: P = 0.0065) and two haplotypes (rs9608491-713998: P = 0.0025; rs61276843-9608491-713998: P = 0.0064). No significant association was found between HPS4 SNPs and PANSS scores or premorbid IQ, as measured by the Japanese version of the National Adult Reading Test. CONCLUSIONS: These findings suggested the involvement of HPS4 in the working memory of healthy subjects and in the executive function deficits in schizophrenia.

[Symptomatic obesity--classification, pathogenesis, diagnosis and therapy].

Obesity is mainly classified by two types, such as simple obesity and symptomatic obesity. Symptomatic obesity is not so rare, which occupies by approximately 10-20% among whole obese patients. Especially, when we encounter high-grade obese patients with BMI more than 35 kg/m2, we have to carefully find out masked symptomatic obesity through medical examinations. Symptomatic obesity is divided into 4 groups according to its pathogenesis, that include endocrinological-, hereditary-, central- and pharmacological obesity. Therapy to the disorder is, in principle, the treatment to original diseases leading to obesity, in addition to dietary-, exercise-, behavioral therapy required to simple obesity. We want to emphasize that the adequate discovery of symptomatic obesity, by our careful medical checks and various laboratory examinations could determine QOL and life prognosis of those obese patients.

Effects of retinol binding protein-4 on vascular endothelial cells.

The study was designed to investigate the effect of retinol binding protein (RBP)-4 on the phosphatidylinositol 3-kinase (PI3K) and mitogen-activated protein kinase (MAPK) pathways, which mediate the effects of insulin in vascular endothelial cells. The effects of RBP4 on nitric oxide (NO) and insulin-stimulated endothelin-1 (ET-1) secretion and on phosphorylation (p) of Akt, endothelial NO synthetase (eNOS), and extracellular signal-regulated kinase (ERK)1/2 were investigated in bovine vascular aortic endothelial cells (BAECs). RBP4 showed an acute vasodilatatory effect on aortic rings of rats within a few minutes. In BAECs, RBP4-treatment for 5min significantly increased NO production, but inhibited insulin-stimulated ET-1 secretion. RBP4-induced NO production was not inhibited by tetraacetoxymethylester (BAPTA-AM), an intracellular calcium chelator, but was completely abolished by wortmannin, a PI3K inhibitor. RBP4 significantly increased p-Akt and p-eNOS production, and significantly inhibited p-ERK1/2 production. Triciribine, an Akt inhibitor, and wortmannin significantly inhibited RBP4-induced p-Akt and p-eNOS production. Inhibition of Akt1 by small interfering RNA decreased p-eNOS production enhanced by RBP4 in human umbilical vein endothelial cells. In conclusion, RBP4 has a robust acute effect of enhancement of NO production via stimulation of part of the PI3K/Akt/eNOS pathway and inhibition of ERK1/2 phosphorylation and insulin-induced ET-1 secretion, probably in the MAPK pathway, which results in vasodilatation.

Comparison of effects of insulin aspart three times a day versus insulin detemir once a day on oxidative stress in patients with type 2 diabetes.

The main purpose of this study was to investigate whether treatment with long-acting insulin once a day or short-acting insulin three times before each meal daily has a stronger antioxidative effect in patients with type 2 diabetes. These patients had not been treated previously with insulin and were hospitalized for initiation of glycemic control by insulin injection. The patients (n=43) were assigned consecutively and alternately to a group treated with insulin aspart injection three times daily just before each meal and a group treated with insulin detemir injection once daily before bedtime. The results showed that insulin aspart three times a day produced a greater improvement in plasma glucose, and particularly in mean postprandial plasma glucose, compared with insulin detemir once a day (p = 0.0006 for comparison of changes between the two insulin treatments). The amount of insulin needed to approach the target levels of plasma glucose was larger in the insulin aspart group (26.0 ± 10.7 U/day vs. 13.7 ± 4.9 U/day; p < 0.0001). However, only insulin detemir significantly decreased oxidative stress evaluated based on the level of urinary 8-iso-prostaglandin F2α (p = 0.0079), although the mechanisms are not fully evident.

Effects of short-term calorie restriction on circulating DPP-4/sCD26 concentrations and body composition in patients with type 2 diabetes.

Previous studies have shown that dipeptidyl peptidase (DPP)-4, is released from adipocytes in a differentiation-dependent manner and a marker for insulin resistance in obese individuals who have particularly high circulating DPP-4/soluble CD26 (sCD26) concentrations. In this study, we have evaluated the effects of short-term hospitalization with calorie restriction on body composition and circulating DPP-4/sCD26 concentrations in patients with type 2 diabetes. A total of 47 Japanese adults with type 2 diabetes were recruited to the study (age; 56.6 ± 13.0 years, body mass index (BMI); 27.3 ± 5.6 kg/m2). Body composition, circulating DPP-4/sCD26 concentrations and metabolic parameters were assessed upon admission and at discharge from hospital (average of the period: 13.0 ± 2.5 days). Visceral fat area (VFA) was also assessed by dual impedance method. During hospitalization, there was a significant reduction in body weight, BMI, lean body mass, VFA and circulating DPP-4/sCD26 concentrations, but not in body fat mass. Fasting circulating DPP-4/sCD26 concentrations were significantly correlated with fasting insulin, aspartate aminotransferase, γ-glutamyltransferase (γ-GTP) levels, and HOMA-IR (r = 0.477, 0.423, 0.415, 0.548, respectively), but not with VFA (r = - 0.056) by liner regression analyses at base line. It was also observed a positive correlation between changes in circulating DPP-4/sCD26 concentrations and γ-GTP level, HOMA-IR, and a negative correlation between the changes in circulating DPP-4/sCD26 concentrations and VFA significantly (r = 0.300, 0.633, - 0.343, respectively). In conclusion, our observations suggest that liver enzymes as well as VFA might be associated with the response of DPP-4/sCD26 concentrations.

Association of circulating soluble lectin-like oxidized low-density lipoprotein receptor-1 with inflammatory markers and urinary albumin excretion in patients with type 2 diabetes.

OBJECTIVES: The main purpose of the study was to study the association between circulating soluble lectin-like oxidized low-density lipoprotein receptor-1 levels and various markers, including inflammatory markers such as high-sensitivity C-reactive protein and fibrinogen, serum lipids, and renal function, in patients with poorly controlled type 2 diabetes. METHODS: The subjects were 70 patients (men 45, women 25) who were hospitalized for treatment of poor glycemic control. Plasma soluble lectin-like oxidized low-density lipoprotein receptor-1 levels were assayed using a sandwich chemiluminescence enzyme immunoassay. RESULTS: Circulating soluble lectin-like oxidized low-density lipoprotein receptor-1 was significantly positively correlated with lectin-like oxidized low-density lipoprotein-1 ligands containing apolipoprotein B, reflecting modified low-density lipoprotein, and with inflammatory markers such as high-sensitivity C-reactive protein and fibrinogen. In addition, there was a significant positive correlation between soluble lectin-like oxidized low-density lipoprotein receptor-1 and urinary albumin excretion. CONCLUSIONS: Soluble lectin-like oxidized low-density lipoprotein receptor-1 may serve as a marker reflecting the degrees of inflammation and albuminuria in patients with poorly controlled type 2 diabetes.

Effects of androgens and estrogens on sirtuin 1 gene expression in human aortic endothelial cells.

OBJECTIVES: To investigate the effect of androgens and estrogens on surtuin 1 (SIRT1) expression in human aortic endothelial cells (HAECs). METHODS: Real-time polymerase chain reaction analysis of SIRT-1 expression over 48 hours (h) was performed in HAECs treated with various concentrations of dehydroepiandrostendione (DHEA), androstenedione and testosterone (androgens), estrone (E1), estradiol (E2), and estriol (E3) (estrogens) to investigate the dose-dependency of time courses. The influence of high glucose on SIRT1 expression induced by the androgens and estrogens was also examined. RESULTS: Dehydroepiandrostendione, androstenedione, and testosterone remarkedly produced a dose-dependent increase in SIRT1 expression in the range of 10 to 20 µg/ml. High glucose (40mM) medium had significantly inhibitory effects on 10 µg/ml DHEA-induced SIRT1 expression (p=0.024). Estrone and E2, but not E3, caused a marked dose-dependent increase in SIRT1 expression from 10 to 20 µg/ml. Treatment with 20 mM or 40 mM glucose medium did not significantly inhibit E1- and E3-induced SIRT1 expression in control medium; however, both high glucose mediums significantly emphasized E2-induced SIRT1 expression in control medium (p=0.007, p=0.005). CONCLUSION: These results suggest that DHEA, androstenedione, testosterone, E1, and E2 definitely activate SIRT1 expression in HAECs. A high glucose medium is potent to inhibit the basal gene expression; however, it could not reduce powerful androgen- and estrogen-induced SIRT1 expression in HAECs.

Hb Phnom Penh Showing Falsely High or Reasonable HbA1c Values Depending on the Type of High-performance Liquid Chromatography System.

We herein report a 50-year-old Chinese woman with Hb Phnom Penh (α117Phe-Ile-α118Thr) showing high or reasonable HbA1c values depending on the type of high-performance liquid chromatography (HPLC) system. A high HbA1c value of 7.5% (HPLC assay: G9) and a reasonable HbA1c value of 5.2% (assay unknown) were observed. Therefore, the patient was refereed to our hospital; the oral glucose tolerance test showed normal glucose tolerance. The HbA1c values measured by an enzymatic assay, immunoassay, and affinity assay, as well as most HPLC assays were within the reference range, whereas those measured by the Tosoh HPLC systems were high.

Severe Non-Islet Cell Hypoglycemia From Ileum-Origin Gastrointestinal Stromal Tumor Producing Insulin-Like Growth Factor-2 in a Patient With Liver Cirrhosis Due to Chronic Hepatitis B.

Non-islet cell tumor hypoglycemia (NICTH) is a rare paraneoplastic syndrome, and NICTH associated with gastrointestinal stromal tumor (GIST) is even more rare. Herein, we describe a patient with severe NICTH due to GIST who had developed liver cirrhosis as a consequence of chronic hepatitis B. Although circulating insulin, C-peptide, and insulin-like growth factor-1 (IGF-1) levels were significantly decreased, in contrast to our expectations, the growth hormone (GH) level was slightly elevated. Steroid therapy with prednisolone appeared to be effective for the prevention of severe and continuous hypoglycemia.

Increase of osteopontin plasma concentrations after bariatric surgery independent from inflammation and insulin resistance.

BACKGROUND: Osteopontin (OPN) is a multifunctional matrix glycoprotein associated with bone metabolism and has been linked to chronic inflammation, insulin resistance, and atherosclerosis. Diet-induced weight loss decreases elevated OPN concentrations in obese patients. The aim of the current study was to investigate the role of OPN after bariatric surgery, where not only improvements of chronic inflammation, insulin resistance and comorbidities, but also malabsorption and altered bone metabolism have been reported. METHODS: OPN plasma concentrations were determined in 31 morbidly obese patients (5 men, 26 women, BMI 46.2+/-7.1 kg/m2, age 41+/-11 years; mean+/-SD) before and 18 months after bariatric surgery, together with parameters of bone metabolism and inflammation. RESULTS: OPN concentrations increased by +20.3+/-26.6 ng/ml (mean+/-SD, p<0.01), concomitant to a weight loss of -38+/-22 kg, and a decrease in BMI by -13.1+/-7.7 kg/m2 (both p<0.01). HOMA-index improved from 5.2+/-3.4 to 1.5+/-1.0 (p<0.01). Calcium concentrations slightly decreased, and phosphate increased (-0.06+/-0.13 mmol/l and +0.08+/-0.16 mmol/l, respectively; both p<0.05), while 25-OH-Vitamin D3 remained unchanged and PTH tended to increase (+5.1+/-14.0 pg/ml, p=0.054). Monocyte chemoattractant protein 1 and interleukin 18 were significantly decreased and associated with HOMA both before and after bariatric surgery. DeltaOPN was correlated with DeltaPTH, but not with other parameters. CONCLUSIONS: OPN plasma concentrations increased concomitant to weight loss after bariatric surgery, which was independent from an improvement of insulin sensitivity and a decrease of inflammatory markers. Further studies are needed to differentiate whether these changes in bone metabolism after bariatric surgery are secondary to calcium deficiency or an adaptation to weight loss.

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) F2alpha (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.

Association between angiopoietin-like protein 2 and lectin-like oxidized low-density lipoprotein receptor 1 ligand containing apolipoprotein B in patients with type 2 diabetes.

Objective This study was performed to evaluate the association of the serum level of angiopoietin-like protein 2 (ANGPTL2) with circulating inflammatory markers and oxidized and modified low-density lipoprotein (LDL) cholesterol as evaluated by lectin-like oxidized LDL receptor 1 ligand containing apolipoprotein B (LAB) in patients with type 2 diabetes. Methods The study included 70 patients with type 2 diabetes hospitalized for glycemic control and 9 control subjects. Results The serum level of ANGPTL2 was significantly higher in the patients with type 2 diabetes than in the healthy controls. There was a significant positive correlation between ANGPTL2 and the high-sensitivity C-reactive protein, fibrinogen, and LAB levels and a significant negative correlation between ANGPTL2 and the estimated glomerular filtration rate (eGFR). Conclusions These results suggest that the serum ANGPTL2 level has a close positive association with inflammatory markers, especially fibrinogen and oxidized and modified LDL as evaluated by LAB. The data also suggest that the serum ANGPTL2 level is influenced by renal function as reflected by the eGFR.

Isolated Adrenocorticotropic Hormone Deficiency and Severe Hypercalcemia After Destructive Thyroiditis in a Patient on Nivolumab Therapy With a Malignant Melanoma.

We describe a 58-year-old man with a malignant melanoma metastasis to the liver. After initiation of nivolumab therapy, he developed destructive thyroiditis and subsequently simultaneous isolated adrenocorticotropic hormone (ACTH) deficiency and severe hypercalcemia. Although isolated ACTH deficiency and hypercalcemia due to nivolumab therapy are both rare occurrences, these conditions can often cause a severe clinical course accompanied by a disturbance of consciousness. Therefore, clinicians should pay attention to these possible side effects of nivolumab if the patients have clinical symptoms, such as fatigue and a disturbance of consciousness.

Retinol binding protein-4 levels and clinical features of type 2 diabetes patients.

CONTEXT: Retinol binding protein (RBP)-4 is a recently identified adipocytokine that is associated with insulin resistance. OBJECTIVES: The aim was to investigate the association between RBP4 and various markers related to insulin resistance and diabetic complications in type 2 diabetic patients. The effect on RBP4 of the addition of pioglitazone to other diabetic medications was also examined. DESIGN, SETTING, PATIENTS, INTERVENTION, AND MAIN OUTCOME MEASURES: RBP4 levels were measured in 101 hospitalized patients with type 2 diabetes and in 22 nonhospitalized control subjects. Endothelial function was evaluated using flow-mediated vasodilatation. In a further 22 nonhospitalized type 2 diabetic patients, pioglitazone (30 mg/d) was administered for 12 wk while other medications for diabetes were continued. RESULTS: There was a significant elevation of RBP4 levels in diabetic patients compared with healthy subjects. RBP4 showed significant positive correlations with triglyceride, systolic blood pressure, and log urinary albumin excretion, and significant negative correlations with high-density lipoprotein cholesterol and flow-mediated vasodilatation. In stepwise regression analysis, log urinary albumin excretion, triglyceride, and gender showed a significant association with RBP4. RBP4 was significantly elevated in patients with proliferative-diabetic retinopathy compared with nondiabetic retinopathy and simple-diabetic retinopathy patients. The addition of pioglitazone for 12 wk to other diabetic medications the patients were already taking did not affect the serum RBP4 concentration. CONCLUSIONS: The current study shows that RBP4 is associated with variables related to insulin resistance and diabetic complications. The addition of pioglitazone for 12 wk to other diabetic medications the patients were already taking did not affect serum RBP4 levels.

Comparison of serum high-molecular weight (HMW) adiponectin with total adiponectin concentrations in type 2 diabetic patients with coronary artery disease using a novel enzyme-linked immunosorbent assay to detect HMW adiponectin.

Adiponectin (Acrp30), an adipocyte-derived protein, exists in serum as a trimer, a hexamer, and a high-molecular weight (HMW) form, including 12-18 subunits. Because HMW adiponectin may be biologically active, we measured it in serum using a novel enzyme-linked immunosorbent assay (ELISA) confirmed by gel filtration chromatography that the ELISA detected mainly adiponectin with 12-18 subunits, and we compared HMW with total adiponectin concentration in patients with type 2 diabetes. We next investigated the relationship between serum HMW and coronary artery disease (CAD) in 280 consecutive type 2 diabetic patients, including 59 patients with angiographically confirmed CAD. Total adiponectin was measured in serum by a commercially available ELISA. Like serum total adiponectin, HMW adiponectin correlated positively with HDL cholesterol and negatively with triglyceride, insulin sensitivity, creatinine clearance, and circulating inflammatory markers. Total and HMW adiponectin were significantly higher in women than in men, as was the HMW-to-total adiponectin ratio. Serum HMW and the HMW-to-total adiponectin ratio were significantly lower in men with than without CAD (P < 0.05, respectively). In women, the ratio, but neither total nor HMW adiponectin, tended to be lower when CAD was present. In conclusion, determination of HMW adiponectin, especially relative to total serum adiponectin, is useful for evaluating CAD in type 2 diabetic patients.

High molecular weight adiponectin as a predictor of long-term clinical outcome in patients with coronary artery disease.

Adiponectin is an adipocyte-specific secretory protein that is highly and specifically expressed in adipose tissue, and low plasma levels of adiponectin are associated with coronary artery disease (CAD). It has been suggested that high molecular weight (HMW) adiponectin is more important for vascular protection than total amount of adiponectin. To establish the clinical relevance of HMW adiponectin, we measured its serum levels in 149 patients with CAD. The levels were lower in vasospastic angina pectoris (3.4 +/- 2.4 microg/ml, p <0.01), stable angina pectoris (3.3 +/- 2.6 microg/ml, p <0.001), and healed myocardial infarction (3.8 +/- 2.9 microg/ml, p <0.01) than chest pain syndrome (controls) (6.6 +/- 5.4 microg/ml). The levels were also lower in multivessel CAD (3.4 +/- 2.4 microg/dl) compared with single vessel CAD (4.2 +/- 2.7 microg/ml, p <0.05) or no organic stenosis (5.1 +/- 3.5 microg/ml, p <0.01). In univariate analysis, diabetes mellitus (p = 0.03), insulin resistance (p = 0.06), high-sensitivity C-reactive protein levels (p = 0.0012), and low HMW adiponectin levels (p = 0.0001) predicted cardiovascular events during 7 years of follow-up. However, multivariate analysis showed that only HMW adiponectin levels were an independent predictor of cardiovascular events (relative risk 2.79, 95% confidence interval 1.49 to 5.24, p = 0.0014). In conclusion, serum HMW adiponectin levels may serve as a predictor of future cardiovascular events in patients with CAD as well as a marker for severity of CAD.

Association between plasma visfatin and vascular endothelial function in patients with type 2 diabetes mellitus.

Visfatin is a newly identified adipocytokine that mimics insulin action. However, the pathophysiological role of visfatin in diabetic patients is not fully understood. The main purpose of this study was to investigate the association of plasma visfatin with endothelial function in patients with type 2 diabetes mellitus. In addition, the relationships of visfatin with oxidative stress, low-grade inflammation, atherosclerosis, adiponectin, plasma renin activity, and aldosterone were also explored, and the effect of pioglitazone on visfatin was examined. Visfatin levels were measured in 80 patients with type 2 diabetes mellitus and in 28 age-matched healthy subjects. Endothelial function was evaluated by using flow-mediated vasodilatation (FMD), oxidative stress was assessed by the level of urinary 8-iso-prostaglandin F2alpha, and atherosclerosis and inflammation were measured by using the intimal-medial complex thickness and the levels of high-sensitivity C-reactive protein and fibrinogen. Pioglitazone was administered for 12 weeks at a dose of 30 mg/d in a further 20 patients with type 2 diabetes mellitus. There was a significant negative correlation between the log10-transformed (log) plasma visfatin concentration and FMD or creatinine clearance (R=-0.2672, P=.0167; R=-0.2750, P=.0136). Log visfatin was also positively correlated with log urinary albumin excretion (R=0.2305, P=.0397). In addition, it was also found that visfatin had a significant negative correlation with plasma aldosterone (R=-0.2432, P=.0297). In stepwise regression analysis, creatinine clearance, log aldosterone, FMD, and sex showed a significant association with log visfatin (P=.0040, P=.0069, P=.0444, and P=.0487, respectively), and log 8-iso-prostaglandin F2alpha showed a tendency for an association (P=.0515). Pioglitazone therapy did not affect the visfatin concentration in the 20 pioglitazone-treated patients with diabetes, although a significant elevation of visfatin was obtained in a subgroup of 11 female patients (P=.0381). In conclusion, the current study showed that visfatin is negatively associated with vascular endothelial function evaluated by FMD and creatinine clearance, and positively associated with log urinary albumin excretion. Visfatin was also negatively correlated with circulating aldosterone. Pioglitazone therapy for 12 weeks did not affect the plasma visfatin concentration significantly in all diabetic patients, but a significant elevation in visfatin was obtained in women only.

Effect of Sodium Glucose Cotransporter 2 Inhibitors With Low SGLT2/SGLT1 Selectivity on Circulating Glucagon-Like Peptide 1 Levels in Type 2 Diabetes Mellitus.

Sodium glucose cotransporter 2 (SGLT2) inhibitors are a new class of antidiabetic drugs that improve glycemic control by inhibiting reabsorption of glucose filtered through the renal glomerulus. Use of drugs in this class has increased because of their effect of decreasing body weight and a low risk for hypoglycemia, in addition to a relatively strong glucose-lowering effect. SGLT2 inhibitors such as canagliflozin and sotagliflozin (a SGLT1/SGLT2 dual inhibitor) also have a mild or moderate intestinal and renal SGLT1 inhibitory effect because of their relatively weak selectivity for SGLT2 over SGLT1. Recent evidence shows that these SGLT2 inhibitors with low SGLT2/SGLT1 selectivity elevate the level of circulating glucagon like peptide-1 (GLP-1), an incretin hormone that promotes insulin secretion in pancreatic ß cells. This effect probably occurs partly via inhibition of intestinal SGLT1, and the elevation of active GLP-1 levels is especially apparent when these drugs are co-administered with dipeptidyl peptidase 4 (DPP4) inhibitors. These findings suggest that a combination of canagliflozin or sotagliflozin and a DPP4 inhibitor can provide a beneficial effect associated with elevation of circulating active GLP-1 and may serve as a treatment for patients with type 2 diabetes.