Metabolic syndrome; associations with adverse outcome after colorectal surgery. A systematic review and meta-analysis.

BACKGROUND: Increasing evidence shows that patients with Metabolic Syndrome (MetS) are at risk for adverse outcome after abdominal surgery. The aim of this study was to investigate the impact of MetS and preoperative hyperglycemia, as an individual component of MetS, on adverse outcome after colorectal surgery. METHODS: A literature review was systematically performed according to the PRISMA guidelines. Inclusion criteria were observational studies that evaluated the relationship between MetS or preoperative hyperglycemia and outcomes after colorectal surgery (i.e. any complication, severe complication defined as Clavien-Dindo grade ≥ III, anastomotic leakage, surgical site infection, mortality and length of stay). RESULTS: Six studies (246.383 patients) evaluated MetS and eight studies (9.534 patients) reported on hyperglycemia. Incidence rates of MetS varied widely from 7% to 68% across studies. Meta-analysis showed that patients with MetS are more likely to develop severe complications than those without MetS (RR 1.62, 95% CI 1.01-2.59). Moreover, a non-significant trend toward increased risks for any complication (RR 1.35, 95% CI 0.91-2.00), anastomotic leakage (RR 1.67, 95% CI 0.47-5.93) and mortality (RR 1.19, 95% CI 1.00-1.43) was found. Furthermore, preoperative hyperglycemia was associated with an increased risk of surgical site infection (RR 1.35, 95% CI 1.01-1.81). CONCLUSION: MetS seem to have a negative impact on adverse outcome after colorectal surgery. As a result of few studies meeting inclusion criteria and substantial heterogeneity, evidence is not conclusive. Future prospective observational studies should improve the amount and quality in order to verify current results.

Breakfast partly restores the anti-inflammatory function of high-density lipoproteins from patients with type 2 diabetes mellitus.

Background and aims: High-density lipoproteins (HDL) of patients with type 2 diabetes mellitus (T2DM) have impaired anti-inflammatory activities. The anti-inflammatory activity of HDL has been determined ex vivo after isolation by different methods from blood mostly obtained after overnight fasting. We first determined the effect of the HDL isolation method, and subsequently the effect of food intake on the anti-inflammatory function of HDL from T2DM patients. Methods: Blood was collected from healthy controls and T2DM patients after an overnight fast, and from T2DM patients 3 h after breakfast (n = 17 each). HDL was isolated by a two-step density gradient ultracentrifugation in iodixanol (HDLDGUC2), by sequential salt density flotation (HDLSEQ) or by PEG precipitation (HDLPEG). The anti-inflammatory function of HDL was determined by the reduction of the TNFα-induced expression of VCAM-1 in human coronary artery endothelial cells (HCAEC) and retinal endothelial cells (REC). Results: HDL isolated by the three different methods from healthy controls inhibited TNFα-induced VCAM-1 expression in HCAEC. With apoA-I at 0.7 µM, HDLDGUC2 and HDLSEQ were similarly effective (16% versus 14% reduction; n = 3; p > 0.05) but less effective than HDLPEG (28%, p < 0.05). Since ultracentrifugation removes most of the unbound plasma proteins, we used HDLDGUC2 for further experiments. With apoA-I at 3.2 µM, HDL from fasting healthy controls and T2DM patients reduced TNFα-induced VCAM-1 expression in HCAEC by 58 ± 13% and 51 ± 20%, respectively (p = 0.35), and in REC by 42 ± 13% and 25 ± 18%, respectively (p < 0.05). Compared to preprandial HDL, postprandial HDL from T2DM patients reduced VCAM-1 expression by 56 ± 16% (paired test: p < 0.001) in HCAEC and by 34 ± 13% (paired test: p < 0.05) in REC. Conclusions: The ex vivo anti-inflammatory activity of HDL is affected by the HDL isolation method. Two-step ultracentrifugation in an iodixanol gradient is a suitable method for HDL isolation when testing HDL anti-inflammatory function. The anti-inflammatory activity of HDL from overnight fasted T2DM patients is significantly impaired in REC but not in HCAEC. The anti-inflammatory function of HDL is partly restored by food intake.

A genetic variant in SLC6A20 is associated with Type 2 diabetes in white-European and Chinese populations.

AIMS: To investigate whether polymorphisms in SLC6A20 are associated with susceptibility to Type 2 diabetes. METHODS: In the Rotterdam Study, a prospective, population-based cohort (n = 5974), 22 tagging polymorphisms with minor allele frequencies>0.05 across SLC6A20 were studied. Replication studies were performed in an independent Dutch case-control study (DiaGene-Rotterdam Study 2 n = 3133), and in a Chinese Han case-control population (n = 2279). A meta-analysis of the results was performed. RESULTS: In the Rotterdam study, the minor alleles of rs13062383, rs10461016 and rs2286489 increased the risk of Type 2 diabetes (hazard ratio 1.37, 95% CI 1.15-1.63, hazard ratio 1.30 95% CI 1.09-1.54 and hazard ratio 1.20, 95% CI 1.07-1.35, respectively). In the DiaGene/Rotterdam Study 2, the A allele of rs13062383 increased the risk of Type 2 diabetes (odds ratio 1.45, 95% CI 1.19-1.76). In the Chinese Han study, the rs13062383 A allele also increased the risk of Type 2 diabetes (odds ratio 1.21, 95% CI 1.03-1.42). Meta-analysis showed a highly significant association of rs13062383 with Type 2 diabetes (odds ratio 1.35, 95% CI 1.21-1.47; P = 3.3 × 10⁻8). CONCLUSIONS: In conclusion, rs13062383 in SLC6A20 increased the susceptibility to Type 2 diabetes in populations with different genetic backgrounds.

Association of an APOC3 promoter variant with type 2 diabetes risk and need for insulin treatment in lean persons.

AIMS/HYPOTHESIS: An APOC3 promoter haplotype has been previously associated with type 1 diabetes. In this population-based study, we investigated whether APOC3 polymorphisms increase type 2 diabetes risk and need for insulin treatment in lean participants. METHODS: In the Rotterdam Study, a population-based prospective cohort (n = 7,983), Cox and logistic regression models were used to analyse the associations and interactive effects of APOC3 promoter variants (-482C > T, -455T > C) and BMI on type 2 diabetes risk and insulin treatment. Analyses were followed by replication in an independent case-control sample (1,817 cases, 2,292 controls) and meta-analysis. RESULTS: In lean participants, the -482T allele was associated with increased risk of prevalent and incident type 2 diabetes: OR -482CT 1.47 (95% CI 1.13-1.92), -482TT 1.40 (95% CI 0.83-2.35), p = 0.009 for trend; HR -482CT 1.35 (95% CI 0.96-1.89), -482TT 1.68 (95% CI 0.91-3.1), p = 0.03 for trend, respectively. These results were confirmed by replication. Meta-analysis was highly significant (-482T meta-analysis p = 1.1 × 10(-4)). A borderline significant interaction was observed for insulin use among participants with type 2 diabetes (-482CT*BMI p = 0.06, -455TC*BMI p = 0.02). CONCLUSIONS/INTERPRETATION: At a population-based level, the influence of APOC3 promoter variants on type 2 diabetes risk varies with the level of adiposity. Lean carriers of the -482T allele had increased type 2 diabetes risk, while such an effect was not observed in overweight participants. Conversely, in overweight participants the -455C allele seemed protective against type 2 diabetes. The interaction of the variants with need for insulin treatment may indicate beta cell involvement in lean participants. Our findings suggest overlap in the genetic backgrounds of type 1 diabetes and type 2 diabetes in lean patients.

Influence of acute exercise on hyperglycemia in insulin-treated type 2 diabetes.

INTRODUCTION: The impact of exercise on blood glucose homeostasis has not been assessed in long-standing type 2 diabetes patients receiving exogenous insulin treatment. PURPOSE: To study the effects of an acute bout of exercise on the subsequent 24-h blood glucose excursions under free-living conditions in insulin-treated type 2 diabetes patients. METHODS: Eleven male type 2 diabetes patients (59 +/- 2 yr) performed an acute bout of exercise. One day before the exercise bout, a continuous glucose monitoring system (GlucoDay, A. Menarini Diagnostics) was inserted subcutaneously in the periumbilical region. The glucose sensor continuously measured glucose concentrations in the dialysate during a 48-h period. RESULTS: The prevalence of hyperglycemic glucose excursions was reduced by 39% during a 24-h period (equivalent to 3 h) after an acute bout of exercise (P < 0.05). Average glucose concentrations 24 h before and after the exercise bout did not differ (NS). Mean dialysate glucose concentrations and the prevalence of hyperglycemic periods correlated strongly with baseline blood HbA1c concentrations (Pearson's R = 0.69, P < 0.05). CONCLUSION: An acute bout of exercise effectively reduces the prevalence of hyperglycemia during a 24-h period under free-living conditions in long-standing type 2 diabetes patients on exogenous insulin therapy.

Glycaemic instability is an underestimated problem in Type II diabetes.

The aim of the present study was to assess the level of glycaemic control by the measurement of 24 h blood glucose profiles and standard blood analyses under identical nutritional and physical activity conditions in patients with Type II diabetes and healthy normoglycaemic controls. A total of 11 male patients with Type II diabetes and 11 healthy matched controls participated in a 24 h CGMS (continuous subcutaneous glucose-monitoring system) assessment trial under strictly standardized dietary and physical activity conditions. In addition, fasting plasma glucose, insulin and HbA(1c) (glycated haemoglobin) concentrations were measured, and an OGTT (oral glucose tolerance test) was performed to calculate indices of whole-body insulin sensitivity, oral glucose tolerance and/or glycaemic control. In the healthy control group, hyperglycaemia (blood glucose concentration >10 mmol/l) was hardly present (2+/-1% or 0.4+/-0.2/24 h). However, in the patients with Type II diabetes, hyperglycaemia was experienced for as much as 55+/-7% of the time (13+/-2 h over 24 h) while using the same standardized diet. Breakfast-related hyperglycaemia contributed most (46+/-7%; P<0.01 as determined by ANOVA) to the total amount of hyperglycaemia and postprandial glycaemic instability. In the diabetes patients, blood HbA(1c) content correlated well with the duration of hyperglycaemia and the postprandial glucose responses (P<0.05). In conclusion, CGMS determinations show that standard measurements of glycaemic control underestimate the amount of hyperglycaemia prevalent during real-life conditions in Type II diabetes. Given the macro- and micro-vascular damage caused by postprandial hyperglycaemia, CGMS provides an excellent tool to evaluate alternative therapeutic strategies to reduce hyperglycaemic blood glucose excursions.

Lack of specific renal haemodynamic effects of different doses of dopamine after infrarenal aortic surgery.

Dopamine is administered frequently in the operating theatre and intensive care unit patients undergoing mechanical ventilation with the aim of specifically enhancing renal blood flow. In an uncontrolled, open study, we administered sequentially different doses of dopamine (0, 2, 4, 8 and 0 microgram kg-1 min-1) during a 1-h period each. Systemic haemodynamic and renal haemodynamic variables were measured simultaneously using a pulmonary artery catheter and radiopharmaceuticals, respectively. We studied seven haemodynamically stable patients (mean age 66 yr), with a serum creatinine concentration < 160 mumol litre-1, after elective infrarenal abdominal aortic reconstruction. All patients received extradural analgesia with bupivacaine and sufentanil, and none had a previous history of heart failure. Dopamine induced a dose-dependent increase in cardiac index which returned to baseline after cessation of the dopamine infusion. Glomerular filtration rate (GFR) increased with all doses of dopamine, whereas renal blood flow (RBF) increased significantly only with the 2- and 4-microgram kg-1 min-1 doses. However, the ratio RBF/cardiac output remained unchanged with the 2- and 4-microgram kg-1 min-1 doses, but decreased with 8 micrograms kg-1 min-1 from 14 (1.5)% to 10 (1.3)%. We conclude that dopamine increased RBF and GFR as a result of an increase in cardiac output.

The effects of ibopamine on glomerular filtration rate and plasma norepinephrine remain preserved during prolonged treatment in patients with congestive heart failure.

UNLABELLED: In acute studies ibopamine, an a selective dopamine agonist, induces moderate increases of GFR and ERPF, and a fall in plasma norepinephrine levels in patients with congestive heart failure (CHF). We evaluated acute and chronic effects of ibopamine on renal haemodynamics, sodium excretion, PRA, plasma aldosterone (ALD) and norepinephrine levels in an open controlled study in 10 patients aged (51-79 years) with mild CHF, NYHA class II-III. All patients used digoxin and frusemide. After a control study day, the second study day involved the administration of 100 mg ibopamine. Subsequently the patients continued to take ibopamine 100 mg three times daily for one month, at which time the chronic effects were measured on the third study day. RESULTS: On the second day ERPF rose from a baseline of 288 +/- 32 to a mean of 308 +/- 32 ml.min-1 x 1.73 m-2 (P < 0.05) during the 4 h after the first administration of ibopamine and GFR rose from 77 +/- 8 to a mean of 84 +/- 8 ml.min-1 x 1.73 m-2 (P < 0.05). The ratio GFR/ERPF, representing the filtration fraction (FF) remained unchanged. On the third study day GFR and ERPF at baseline were similar to those before ibopamine treatment. After the acute on chronic administration we observed an increase in GFR (from 76 +/- 6 to a mean of 85 +/- 7 ml.min-1 x 1.73 m-2 (P < 0.05)), and in ERPF (from 279 +/- 27 to a mean of 293 +/- 29 ml.min-1 x 1.73 m-2 (P < 0.05)). Plasma norepinephrine levels fell from 2.63 +/- 0.48 to 1.92 +/- 0.27 nmol.l-1 (P < 0.05) after the acute administration of ibopamine, and remained unchanged after the acute on chronic ibopamine administration (C: 1.80 +/- 0.42 nmol.l-1). No changes in sodium excretion were observed, either in blood pressure, heart rate, PRA or ALD. We conclude that renal function is preserved during chronic ibopamine treatment and the acute moderate increase of ERPF and GFR after a single dose of 100 mg of ibopamine is still present after one month of treatment with ibopamine in patients with CHF. Ibopamine lowered plasma norepinephrine levels in our patients with CHF, and these values remained unchanged after the acute on chronic administration of ibopamine.

Dopaminergic modulation of physiological and pathological neurohumoral activation in man.

Close relations exist between the peripheral dopaminergic system, and the sympathetic nervous and renin-angiotensin-aldosterone system: D1 dopamine receptor stimulation-induced vasodilation may activate the sympathetic nervous and renin-angiotensin system in vivo, presynaptic D2 dopamine receptor stimulation is known to inhibit stimulated norepinephrine release from sympathetic nerve terminals, in experimental conditions both in vitro and in vivo. Endogenous dopamine has a tonic inhibitory effect on aldosterone release. Conversely, basal sympathetic activity has been found to be required for the natriuretic effect of dopamine in proximal renal tubules. Other relations include the conversion of dopamine to other catecholamines, and co-release. This review considers the reflection of some of these relations and their clinical significance in man in physiological and pathophysiological conditions, especially congestive heart failure. An inhibitory effect of the nonselective dopamine agonist ibopamine on plasma norepinephrine levels was found in normal man during exercise but not at rest, and in patients with several degrees of congestive heart failure, both at rest and during exercise. Infusions of dopamine 1 microgram/kg/min, but not 3 micrograms/kg/min were found to lower plasma norepinephrine levels during sympathetic stimulation by exercise or by a cold pressor test in normal man. Dopamine antagonists enhance the rise in plasma norepinephrine levels during exercise, indicating that endogenous dopamine also inhibits norepinephrine release. Both phentolamine and prazosin abolish the natriuretic effects of dopamine in man, even when the renal hemodynamic effect of dopamine is unaffected. In conclusion, it is important to be aware of clinically significant interactions between the peripheral dopaminergic and sympathetic nervous system at different levels.

The effects of different doses of dopamine and domperidone on increases of plasma norepinephrine induced by cold pressor test in normal man.

The effect of dopamine 1 and 3 micrograms/kg/min i.v., of dopamine 1 and 3 micrograms/kg/min i.v. combined with domperidone 30 mg per os and of placebo infusion on plasma norepinephrine concentration before and during sympathetic stimulation by a cold pressor test was investigated in 10 healthy volunteers (1 female, 9 males, mean age 28, range 19-41). Dopamine 1 microgram/kg/min resulted in a blunting of the rise in plasma norepinephrine concentration during the cold pressor test, compared with placebo infusion. The addition of domperidone to dopamine 1 microgram/kg/min abolished this effect. Plasma norepinephrine levels during dopamine 3 micrograms/kg/min infusion, both with and without domperidone, were not different from placebo, but significantly higher compared to dopamine 1 microgram/kg/min infusion. Dopamine 1 and 3 micrograms/kg/min infusion, both with and without domperidone resulted in a blunted increase in blood pressure compared to placebo infusion. Dopamine 1 microgram/kg/min infusion resulted in a lower systolic blood pressure during the cold pressor test compared to dopamine 3 micrograms/kg/min infusion. No significant changes in heart rate occurred during the cold pressor test comparing the different circumstances. We conclude that in healthy volunteers only dopamine 1 microgram/kg/min, but not dopamine 3 micrograms/kg/min, blunts the increase in plasma norepinephrine concentration during a cold pressor test; this effect is abolished by pretreatment with domperidone. We presume that for dopamine 1 microgram/kg/min the inhibitory effects of presynaptic DA-2 receptor or alpha-2 adrenoceptor stimulation on plasma norepinephrine concentration predominate. When dopamine 3 micrograms/kg/min is infused, the inhibitory effects might be counteracted by uptake-1 inhibition or enhanced synthesis and release of norepinephrine, either directly or indirectly.

Renal and systemic hemodynamic effects of ibopamine in patients with mild to moderate congestive heart failure.

To study the hemodynamic and renal effects of the orally (p. o.) active dopamine (DA) agonist ibopamine, we examined 10 patients with mild to moderate congestive heart failure (CHF), who were stable while treated with digoxin and diuretics. All patients were in New York Heart Association (NYHA) functional class II-III; their mean age was 63 years (range 51-79 years), and mean left ventricular ejection fraction (LVEF) was 28% (range 18-36%). The protocol consisted of a control study-day with measurements of renal characteristics including glomerular filtration rate (GFR), effective renal plasma flow (ERPF), and filtration fraction (FF). One week later, systemic and renal hemodynamics were measured simultaneously before and after patients received one 100-mg tablet of ibopamine. Ibopamine caused a slight but significant increase in both ERPF (from 288 +/- 32 ml/min/1.73 m2 at baseline to 316 +/- 32 ml/min/1.73 m2 after ibopamine) and GFR (from 77 +/- 8 to 85 +/- 8 ml/min/1.73 m2; both p < 0.05); FF was not affected (mean value 0.26 +/- 0.02). Sodium excretion was not influenced by ibopamine, but diuresis increased significantly. Cardiac output (CO) increased significantly (from 4.0 +/- 0.4 L/min at baseline to a maximum of 5.0 L/min after ibopamine, p < 0.05), mainly due to decreased systemic vascular resistance (SVR). Heart rate (HR) and blood pressure (BP) were unchanged throughout the studies. The percentage of contribution of CO to renal blood flow (RBF) was not significantly affected by ibopamine.(ABSTRACT TRUNCATED AT 250 WORDS)

Familial increased serum intestinal alkaline phosphatase: a new variant associated with Gilbert's syndrome.

Investigation of mild, inherited increased serum alkaline phosphatase activity partially combined with Gilbert's syndrome in one family showed, apart from a normal liver fraction, an intestinal isoenzyme pattern and an extra band in the agar electrophoresis. Analysis by agarose electrophoresis before and after incubation of neuraminidase showed that the extra fraction was an intestinal variant isoenzyme. The precise genetic background of the two disorders in this family could not be determined from the available data. Abnormal activities of (regular) intestinal alkaline phosphatase isoenzyme caused the increase in serum alkaline phosphatase in the absence of disease.