Sotirios A. Raptis

Effect of valsartan on the incidence of diabetes and cardiovascular events

BACKGROUND It is not known whether drugs that block the renin-angiotensin system reduce the risk of diabetes and cardiovascular events in patients with impaired glucose tolerance. METHODS In this double-blind, randomized clinical trial with a 2-by-2 factorial design, we assigned 9306 patients with impaired glucose tolerance and established cardiovascular disease or cardiovascular risk factors to receive valsartan (up to 160 mg daily) or placebo (and nateglinide or placebo) in addition to lifestyle modification. We then followed the patients for a median of 5.0 years for the development of diabetes (6.5 years for vital status). We studied the effects of valsartan on the occurrence of three coprimary outcomes: the development of diabetes; an extended composite outcome of death from cardiovascular causes, nonfatal myocardial infarction, nonfatal stroke, hospitalization for heart failure, arterial revascularization, or hospitalization for unstable angina; and a core composite outcome that excluded unstable angina and revascularization. RESULTS The cumulative incidence of diabetes was 33.1% in the valsartan group, as compared with 36.8% in the placebo group (hazard ratio in the valsartan group, 0.86; 95% confidence interval [CI], 0.80 to 0.92; P<0.001). Valsartan, as compared with placebo, did not significantly reduce the incidence of either the extended cardiovascular outcome (14.5% vs. 14.8%; hazard ratio, 0.96; 95% CI, 0.86 to 1.07; P=0.43) or the core cardiovascular outcome (8.1% vs. 8.1%; hazard ratio, 0.99; 95% CI, 0.86 to 1.14; P=0.85). CONCLUSIONS Among patients with impaired glucose tolerance and cardiovascular disease or risk factors, the use of valsartan for 5 years, along with lifestyle modification, led to a relative reduction of 14% in the incidence of diabetes but did not reduce the rate of cardiovascular events. (ClinicalTrials.gov number, NCT00097786.)

Effect of nateglinide on the incidence of diabetes and cardiovascular events

BACKGROUND The ability of short-acting insulin secretagogues to reduce the risk of diabetes or cardiovascular events in people with impaired glucose tolerance is unknown. METHODS In a double-blind, randomized clinical trial, we assigned 9306 participants with impaired glucose tolerance and either cardiovascular disease or cardiovascular risk factors to receive nateglinide (up to 60 mg three times daily) or placebo, in a 2-by-2 factorial design with valsartan or placebo, in addition to participation in a lifestyle modification program. We followed the participants for a median of 5.0 years for incident diabetes (and a median of 6.5 years for vital status). We evaluated the effect of nateglinide on the occurrence of three coprimary outcomes: the development of diabetes; a core cardiovascular outcome that was a composite of death from cardiovascular causes, nonfatal myocardial infarction, nonfatal stroke, or hospitalization for heart failure; and an extended cardiovascular outcome that was a composite of the individual components of the core composite cardiovascular outcome, hospitalization for unstable angina, or arterial revascularization. RESULTS After adjustment for multiple testing, nateglinide, as compared with placebo, did not significantly reduce the cumulative incidence of diabetes (36% and 34%, respectively; hazard ratio, 1.07; 95% confidence interval [CI], 1.00 to 1.15; P=0.05), the core composite cardiovascular outcome (7.9% and 8.3%, respectively; hazard ratio, 0.94, 95% CI, 0.82 to 1.09; P=0.43), or the extended composite cardiovascular outcome (14.2% and 15.2%, respectively; hazard ratio, 0.93, 95% CI, 0.83 to 1.03; P=0.16). Nateglinide did, however, increase the risk of hypoglycemia. CONCLUSIONS Among persons with impaired glucose tolerance and established cardiovascular disease or cardiovascular risk factors, assignment to nateglinide for 5 years did not reduce the incidence of diabetes or the coprimary composite cardiovascular outcomes. (ClinicalTrials.gov number, NCT00097786.)

Circulating tumor necrosis factor alpha concentrations are higher in abdominal versus peripheral obesity

Fat tissue is a significant source of endogenous tumor necrosis factor alpha (TNFalpha), the pluripotent cytokine that plays an important role as a mediator of the peripheral insulin resistance found in obesity. The majority of evidence for this role of TNFalpha is from studies in animal models of obesity. To explore further the role of TNFalpha in the pathogenesis of obesity-related insulin resistance in humans, we compared plasma levels of TNFalpha and the other main endocrine cytokine, interleukin-6 ([IL-6] both measured by enzyme-linked immunosorbent assay), in 26 obese women (body mass index [BMI] > 30 kg/m2) and 13 female controls (BMI < 26 kg/m2) without a history of recent or active infection. Glucose and insulin levels were measured at 0, 1, and 2 hours after a 75-g oral glucose load. There was no significant difference in plasma TNFalpha or IL-6 levels between obese and non-obese subjects overall (2.10 +/- 0.19 v 1.65 +/- 0.18 pg/mL and 2.06 +/- 0.29 v 1.50 +/- 0.17 pg/mL, respectively). However, TNFalpha levels were significantly elevated in obese subjects with a 2-hour glucose level more than 140 mg/dL (n = 8) compared with the other obese subjects (n = 18) and the non-obese controls (2.88 +/- 0.46 v 1.75 +/- 0.10 and 1.65 +/- 0.18 pg/mL, respectively, P < .01). Furthermore, the TNFalpha level correlated significantly with the waist to hip ratio ([WHR] r = .53, P < .01) and fasting and post-oral glucose tolerance test (OGTT) insulin levels (r = .47, P < .02), but not with the BMI, and was higher in obese women with a WHR more than 0.90 (n = 14) in comparison to those with a WHR less than 0.90 (n = 12, 2.47 +/- 0.29 v 1.66 +/- 0.18 pg/mL, respectively, P < .03). The corresponding plasma leptin level was significantly higher in obese women versus the control group (41.6 +/- 2.5 v22.3 +/- 2.9 ng/mL, P < .001) and was related to the BMI (r = .60, P < .01) but not to TNFalpha or the WHR. There were no significant differences in the corresponding IL-6 concentration between groups, and IL-6 did not correlate with TNFalpha, leptin, BMI, WHR, or insulin levels. In conclusion, circulating TNFalpha levels are higher in abdominal obesity compared with peripheral obesity, and may contribute to the insulin resistance that more commonly complicates the former pattern of fat distribution.

Studies of insulin resistance in patients with clinical and subclinical hyperthyroidism

OBJECTIVE Although clinical hyperthyroidism (HR) is associated with insulin resistance, the information on insulin action in subclinical hyperthyroidism (SHR) is limited. DESIGN AND METHODS To investigate this, we assessed the sensitivity of glucose metabolism to insulin in vivo (by an oral glucose tolerance test) and in vitro (by measuring insulin-stimulated rates of glucose transport in isolated monocytes) in 12 euthyroid subjects (EU), 16 patients with HR, and 10 patients with SHR. RESULTS HR and SHR patients displayed higher postprandial glucose levels (area under the curve, AUC(0)(-)(300) 32,190±1067 and 31,497±716,mg/dl min respectively) versus EU (27,119±1156 mg/dl min, P<0.05). HR but not SHR patients displayed higher postprandial insulin levels (AUC(0)(-)(300) 11,020±985 and 9565±904 mU/l min respectively) compared with EU subjects (AUC(0)(-)(300) 7588±743 mU/l min, P<0.05). Homeostasis model assessment index was increased in HR and SHR patients (2.81±0.3 and 2.43±0.38 respectively) compared with EU subjects (1.27±0.16, P<0.05), while Matsuda and Belfiore indices were decreased in HR (4.21±0.41 and 0.77±0.05 respectively, P<0.001) and SHR patients (4.47±0.33 and 0.85±0.05 respectively, P<0.05 versus EU (7.76±0.87 and 1 respectively). At 100 μU/ml insulin, i) GLUT3 levels on the monocyte plasma membrane were increased in HR (468.8±7 mean fluorescence intensity (MFI)) and SHR patients (522.2±25 MFI) compared with EU subjects (407±18 MFI, P<0.01 and P<0.05 respectively), ii) glucose transport rates in monocytes (increases from baseline) were decreased in HR patients (37.8±5%) versus EU subjects (61.26±10%, P<0.05). CONCLUSIONS Insulin-stimulated glucose transport in isolated monocytes of patients with HR was decreased compared with EU subjects. Insulin resistance was comparable in patients with both HR and SHR.

Insulin effects in muscle and adipose tissue

The major effects of insulin on muscle and adipose tissue are: (1) Carbohydrate metabolism: (a) it increases the rate of glucose transport across the cell membrane, (b) it increases the rate of glycolysis by increasing hexokinase and 6-phosphofructokinase activity, (c) it stimulates the rate of glycogen synthesis and decreases the rate of glycogen breakdown. (2) Lipid metabolism: (a) it decreases the rate of lipolysis in adipose tissue and hence lowers the plasma fatty acid level, (b) it stimulates fatty acid and triacylglycerol synthesis in tissues, (c) it increases the uptake of triglycerides from the blood into adipose tissue and muscle, (d) it decreases the rate of fatty acid oxidation in muscle and liver. (3) Protein metabolism: (a) it increases the rate of transport of some amino acids into tissues, (b) it increases the rate of protein synthesis in muscle, adipose tissue, liver, and other tissues, (c) it decreases the rate of protein degradation in muscle (and perhaps other tissues). These insulin effects serve to encourage the synthesis of carbohydrate, fat and protein, therefore, insulin can be considered to be an anabolic hormone.

Relationship of Helicobacter pylori CagA status to gastric cell proliferation and apoptosis.

Despite the fact that the association ofHelicobacterpylori with an increased risk of gastriccancer is well documented, the exact mechanisms of thisassociation have not been elucidated. Our aim was to shed some light on these mechanisms by studyingThe relationship of H. pylori CagA status to gastriccell proliferation and apoptosis, since both play animportant role in gastrointestinal epithelial cell turnover and carcinogenesis. We studied fiftypatients [32 men, 18 women, median age 39.5 years (range18-67)], referred for upper gastrointestinal endoscopy,from whom antral biopsies were taken. On biopsy specimens gastritis was estimated byscoring the severity of inflammatory infiltrate, and thepresence of atrophy and intestinal metaplasia were alsonoted. The gastric cell proliferation index (PI) was estimated by AgNOR staining, the epithelialapoptotic index (AI) was measured by special stainingfor apoptosis, and CagA status was determinedserologically by immunoblotting the sera of patientsagainst H. pylori antigens. Thirty-eight (76%) of the50 patients were H. pylori (positive) and 12 (24%) H.pylori (negative). Among the 38 H. pylori (+) patients,28 (73.6%) were CagA(+) and 10 (24.6%) CagA(-). In the H. pylori CagA(+) and CagA(-) groups,the PI values [median (ranges)] were 5 (4-7) and 3.7(3.5-5.5), respectively (P < 0.05). In addition thedifference in PI between the H. pylori CagA(+) and H. pylori (-) groups was highly significant (P< 0.001). Concerning apoptosis, in the H. pyloriCagA(+) and CagA(-) groups, the values for AI were 1(1-30) and 5.5 (1-35), respectively (P < 0.05). In addition, the difference in AI between theH. pylori CagA(-) and H. pylori (-) groups, wassignificant (P < 0.05). We conclude that H. pyloriCagA(+) strains induce increased gastric cellproliferation, which is not accompanied by a parallel increasein apoptosis. This might explain the increased risk forgastric carcinoma that is associated with infection byH. pylori CagA(+) strains.

Long‐term effectiveness of a new α‐glucosidase inhibitor (BAY m1099‐miglitol) in insulin‐treated Type 2 diabetes mellitus

In a double‐blind, randomized study, miglitol (BAY m 1099), an α‐glucosidase inhibitor, 100 mg tds or placebo was given orally with meals for a period of 24 weeks in 117 patients with Type 2 (non‐insulin‐dependent) diabetes mellitus (DM) treated with insulin. Fasting and 1 h postprandial plasma glucose and C‐peptide were measured at the beginning and at the end of each 4‐week interval and glycosylated haemoglobin was determined at day 0 and at the end of the 12th and 24th week. One hour postprandial plasma glucose was significantly lower in the miglitol group at the end of the 24th week (placebo: 11.6 ± 1.5 vs miglitol: 8.2 ± 1.5 mmol l−1, mean ± SD, p = 0.001). Diabetes control improved in the same group as the HbA1 was lowered by 16 % (p = <0.0001) at the end of the treatment. Mild reversible adverse effects were observed in 37 patients of the miglitol group (mainly flatulence and mild hypoglycaemia) and 2 of the placebo group. Urinary glucose was rendered negative in 41 patients in the miglitol group only. Thus miglitol appears to be a safe and effective adjunct in the management of Type 2 DM, in association with insulin.

Advanced glycoxidation products and impaired diabetic wound healing

Impaired wound healing is an important diabetic complication associated with increased morbidity and mortality. It appears to be the net result of micro‐ and macrovascular disease. Diabetic neuropathy and the resulting loss of protective sensation (LOPS) has been recognized as one of the major causes for delayed healing in diabetic foot ulcer patients. In addition, hyperglycemia and a number of hyperglycemia‐related factors have been linked to impaired diabetic wound healing, including advanced glycation end products (AGE). A large body of evidence from in vitro and in vivo studies and also data from studies using anti‐AGE agents, indicate that AGE may play a role in the pathogenesis of impaired diabetic wound healing. AGE affect the wound healing process either directly by their interference with a variety of components involved or indirectly through their association with diabetic neuropathy and/or angiopathy. However, further studies need to be performed, mostly clinical studies, to evaluate the exact role of AGE in the impaired diabetic wound healing, suggesting new therapeutic approaches.

Close adherence to a Mediterranean diet improves endothelial function in subjects with abdominal obesity

BACKGROUND Abdominal obesity (AO) is associated with increased risk of cardiovascular disease and type 2 diabetes, whereas the Mediterranean diet exerts a cardioprotective effect. OBJECTIVE We examined whether a close adherence to a Mediterranean-style diet improves endothelial function in individuals with AO. DESIGN We recruited 90 subjects with AO without cardiovascular disease or type 2 diabetes. Participants were randomly assigned to the intervention or control group. Both groups were instructed to follow a Mediterranean-style diet for 2 mo. Subjects in the intervention group additionally had to follow a specific relevant daily and weekly food plan with close supervision by a dietitian and provision of basic foods. Flow-mediated dilatation (FMD), lipids, C-reactive protein (CRP), and insulin resistance with the homeostasis model assessment (HOMA-IR) were measured. RESULTS After 2 mo, subjects in the intervention group increased their intake of total fat due to higher consumption of monounsaturated fatty acids as well as intakes of dietary fiber, vitamin C, and alcohol compared with the control group (all P < 0.05). The intervention group also increased FMD ( 2.05%; 95% CI: 0.97, 3.13%), whereas no effect was found in the control group (-0.32%; 95% CI: -1.31, 0.67%). Changes in lipids and CRP concentrations did not differ between the 2 groups, whereas diastolic blood pressure decreased in the intervention group (-6.44 mm Hg; 95% CI: -8.57, -4.31 mm Hg) compared with the control group (-0.76 mm Hg; 95% CI: -2.83, 1.31 mm Hg). Finally, there was a trend for a reduction in HOMA-IR in the intervention group compared with the control group (P = 0.072). CONCLUSION Close adherence to a Mediterranean-style diet achieved by close dietetic supervision improves endothelial function in subjects with AO.

Gastric phytobezoars may be treated by nasogastric Coca- Cola lavage

Large gastric phytobezoars may occur in patients with gastric dysmotility disorders. Treatment options include dissolution with enzymes, endoscopic fragmentation with removal or aspiration, and surgery. We report our experience with nasogastric cola lavage therapy. Over an 8-year period, five consecutive patients were referred to our unit for endoscopic treatment of large gastric phytobezoars. They included one patient with lobectomy for lung cancer and four patients with diabetic gastroparesis. An initial attempt of endoscopic fragmentation and removal was unsuccessful. Patients were treated with 3 l of Coca-Cola nasogastric lavage over 12 h. Nasogastric lavage was very well tolerated by the patients. Complete phytobezoar dissolution was achieved in one session in all cases. There were no procedure-related complications. The dissolution of large gastric phytobezoars with cola nasogastric lavage is a safe, rapid and effective method. Patients may be treated in the medical ward, avoiding therapeutic endoscopy or surgery.