The "metabolic syndrome" (MetS) is a clustering of components that reflect overnutrition, sedentary lifestyles, and resultant excess adiposity. The MetS includes the clustering of abdominal obesity, insulin resistance, dyslipidemia, and elevated blood pressure and is associated with other comorbidities including the prothrombotic state, proinflammatory state, nonalcoholic fatty liver disease, and reproductive disorders. Because the MetS is a cluster of different conditions, and not a single disease, the development of multiple concurrent definitions has resulted. The prevalence of the MetS is increasing to epidemic proportions not only in the United States and the remainder of the urbanized world but also in developing nations. Most studies show that the MetS is associated with an approximate doubling of cardiovascular disease risk and a 5-fold increased risk for incident type 2 diabetes mellitus. Although it is unclear whether there is a unifying pathophysiological mechanism resulting in the MetS, abdominal adiposity and insulin resistance appear to be central to the MetS and its individual components. Lifestyle modification and weight loss should, therefore, be at the core of treating or preventing the MetS and its components. In addition, there is a general consensus that other cardiac risk factors should be aggressively managed in individuals with the MetS. Finally, in 2008 the MetS is an evolving concept that continues to be data driven and evidence based with revisions forthcoming.

The Metabolic Syndrome

The National Cholesterol Education Program’s Adult Treatment Panel III (ATP III) report [1] added the metabolic syndrome, a multidimensional risk factor for cardiovascular disease (CVD), as a coequal partner of elevated low-density lipoprotein (LDL) cholesterol for risk-reduction therapies. Interest in the metabolic syndrome has increased greatly since the publication of the ATP III report. There are several aspects to the metabolic syndrome that deserve consideration for clinical practice: 1) major clinical outcomes, 2) metabolic components, 3) pathogenesis, 4) clinical criteria for diagnosis, 5) risk for clinical outcomes, and 6) therapeutic interventions.

https://www.thelancet.com/pdfs/journals/lancet/PIIS0140-6736(05)66378-7.pdf

OBJECTIVE —This study evaluated the ability of the incretin mimetic exenatide (exendin-4) to improve glycemic control in patients with type 2 diabetes failing maximally effective doses of a sulfonylurea as monotherapy RESEARCH DESIGN AND METHODS —This was a triple-blind, placebo-controlled, 30-week study conducted at 101 sites in the US After a 4-week, single-blind, placebo lead-in period, 377 subjects were randomized (60% men, age 55 ± 11 years, BMI 33 ± 6 kg/m 2 , HbA 1c 86 ± 12% [±SD]) and began 4 weeks at 5 μg subcutaneous exenatide twice daily (before breakfast and dinner; arms A and B) or placebo Subsequently, subjects in arm B were escalated to 10 μg bid exenatide All subjects continued sulfonylurea therapy RESULTS —At week 30, HbA 1c changes from baseline were −086 ± 011, −046 ± 012, and 012 ± 009% (±SE) in the 10-μg, 5-μg, and placebo arms, respectively (adjusted P 1c > 7% ( n = 237), 41% (10 μg), 33% (5 μg), and 9% (placebo) achieved HbA 1c ≤ 7% ( P P P CONCLUSIONS —Exenatide significantly reduced HbA 1c in patients with type 2 diabetes failing maximally effective doses of a sulfonylurea Exenatide was generally well tolerated and was associated with weight loss

https://care.diabetesjournals.org/content/diacare/27/11/2628.full.pdf

Effects of Exenatide (Exendin-4) on Glycemic Control Over 30 Weeks in Sulfonylurea-Treated Patients With Type 2 Diabetes

Type 2 diabetes mellitus is a chronic metabolic disorder that results from defects in both insulin secretion and insulin action. An elevated rate of basal hepatic glucose production in the presence of hyperinsulinemia is the primary cause of fasting hyperglycemia; after a meal, impaired suppression of hepatic glucose production by insulin and decreased insulin-mediated glucose uptake by muscle contribute almost equally to postprandial hyperglycemia. In the United States, five classes of oral agents, each of which works through a different mechanism of action, are currently available to improve glycemic control in patients with type 2 diabetes. The recently completed United Kingdom Prospective Diabetes Study (UKPDS) has shown that type 2 diabetes mellitus is a progressive disorder that can be treated initially with oral agent monotherapy but will eventually require the addition of other oral agents, and that in many patients, insulin therapy will be needed to achieve targeted glycemic levels. In the UKPDS, improved glycemic control, irrespective of the agent used (sulfonylureas, metformin, or insulin), decreased the incidence of microvascular complications (retinopathy, neuropathy, and nephropathy). This review examines the goals of antihyperglycemic therapy and reviews the mechanism of action, efficacy, nonglycemic benefits, cost, and safety profile of each of the five approved classes of oral agents. A rationale for the use of these oral agents as monotherapy, in combination with each other, and in combination with insulin is provided.

Pharmacologic Therapy for Type 2 Diabetes Mellitus

The Asian Pacific Association for the Study of the Liver (APASL) set up a working party on acute-on-chronic liver failure (ACLF) in 2004, with a mandate to develop consensus guidelines on various aspects of ACLF relevant to disease patterns and clinical practice in the Asia-Pacific region. Experts predominantly from the Asia–Pacific region constituted this working party and were requested to identify different issues of ACLF and develop the consensus guidelines. A 2-day meeting of the working party was held on January 22–23, 2008, at New Delhi, India, to discuss and finalize the consensus statements. Only those statements that were unanimously approved by the experts were accepted. These statements were circulated to all the experts and subsequently presented at the Annual Conference of the APASL at Seoul, Korea, in March 2008. The consensus statements along with relevant background information are presented in this review.

/pdf/acute-on-chronic-liver-failure-consensus-recommendations-of-41vjck9vv5.pdf

Acute-on-chronic liver failure: consensus recommendations of the Asian Pacific Association for the study of the liver (APASL)

Glyburide (GB) and glipizide (GZ) differ in their pharmacokinetics, but it is not known whether they also differ in mode of action. To examine this question, 10 young healthy subjects and 6 non-insulin-dependent diabetic (NIDDM) patients participated in each of three studies: 1) infusion of saline for 120 min followed by a 100-min hyperglycemic (125 mg/dl) clamp; 2) 120-min primed continuous infusion of GZ followed by a 100-min hyperglycemic clamp; and 3) 120-min primed continuous infusion of GB followed by a 100-min hyperglycemic clamp. The GB and GZ infusions were continued throughout the hyperglycemic clamp. Similar plasma concentrations of GB and GZ were obtained in both groups. All studies were performed with [3-3H]glucose to allow quantification of hepatic glucose production. When administered under basal conditions of glycemia, the acute phase (0-10 min) of plasma insulin and C-peptide increase in both control and NIDDM subjects was twice as great with GZ compared with GB (P less than .01). During the hyperglycemic-clamp studies performed in normal subjects, both GB and GZ increased the first- (1.6-fold) and second- (2.2-fold) phase plasma insulin responses more than hyperglycemia alone. During the hyperglycemic clamp in NIDDM subjects, the first-phase plasma insulin response was absent, and the second-phase insulin response was markedly impaired. Neither GB nor GZ improved first-phase insulin secretion in the NIDDM patients. In both NIDDM and control subjects, the effects of hyperglycemia and sulfonylurea drugs (both GB and GZ) on the first- and second-phase plasma insulin responses were simply additive.(ABSTRACT TRUNCATED AT 250 WORDS)

Different Effects of Glyburide and Glipizide on Insulin Secretion and Hepatic Glucose Production in Normal and NIDDM Subjects

To determine the impact of fish-oil supplementation on glucose and lipid metabolism in patients with impaired glucose tolerance (IGT), 30 ml fish oil containing 3.8 g eicosapentaenoic acid (EPA; 20:5 ω 3) and 2.5 g docosahexaenoic acid (DHA; 22:5 ω 3) were given to eight obese subjects with IGT (mean ± SD age 50.3 ± 8.0 yr) in addition to their regular diet for 2 wk. Studies were performed in randomized order versus an isocaloric control period with a washout phase of 3 wk. Hyperinsulinemic clamp examinations (1 and 10 mU · kg −1 · min −1 ) were performed. Glucose disposal rate (M value) rose from basal 14.3 ± 5.1 to 17.9 ± 4.4 μmol · kg −1 · min −1 after fish oil ( P −1 · min −1 ; with fish oil, 45.1 ± 9.8 μmol · kg −1 · min −1 ;NS). Basal hepatic glucose output remained unaffected by fish oil, whereas fractional glucose clearance after intravenous glucose loading (2.4 mmol/kg body wt, t = 30 min) tended to increase ( K value: without fish oil, 2.15 ± 1.02%/min; with fish oil, 2.74 ± 1.26%/min; NS). Neither the fasting concentrations of glucose and insulin nor induced glycemia and insulin response during intravenous glucose loading calculated as incremental area under the curve changed after fish-oil supplementation. Supplementation of ω-3 fatty acids led to a mean decrease in total cholesterol of 15.2% (5.78 ± 1.19 to 4.90 ± 0.83 mM, P P P P

Metabolic effects of fish-oil supplementation in patients with impaired glucose tolerance.

Objective: Sensory evoked potential (SEP) peak latencies were recorded in order to evaluate the incidence and severity of septic encephalopathy, testing the hypothesis that the occurrence of septic encephalopathy is more frequent than generally assumed. Design: Prospective cohort study. Setting: Medical intensive care unit of a university hospital. Patients: Sixty-eight critically ill patients were studied within 48 hrs after the development of severe sepsis (n = 41) or septic shock (n = 27). Interventions: None. Measurements and Main Results: Septic encephalopathy was defined as prolongation of SEP peak latencies beyond the upper limit of the reference range of subcortical (N13-N20 interpeak latency) and cortical SEP pathways (N20-N70 interpeak latency), as well as asymmetry of peak latencies marked by the presence of subclinical cerebral focal signs. Subcortical SEP pathways were impaired in 34% and cortical SEP pathways in 84% of all patients. The prolongation of the cortical SEP pathway correlated with the Acute Physiology and Chronic Health Evaluation III score (r 2 = 0.23; p <.0001). SEP peak latencies did not differ in patients with severe sepsis compared with those with septic shock. Subclinical cerebral focal signs were present in 24% of the subcortical SEP pathways and in 6% of the cortical SEP pathways. Conclusions: Septic encephalopathy occurs more frequently than generally assumed, and its severity is associated with the severity of illness. The impairment of subcortical and cortical SEP pathways was not different between patients with severe sepsis and those with septic shock.

Impaired subcortical and cortical sensory evoked potential pathways in septic patients

Objective To examine the relationship between plasma glyburide concentrations (0, 50, 100, 200, 400, and 800 nM) and the insulin response and glucose metabolism during euglycemic (4.6 ± 0.1 mM) and hyperglycemic (11.6 ± 0.2 mM) conditions. Research Design and Methods Nine healthy subjects participated in the study. Steady-state plasma glyburide concentrations were achieved by primed continuous intravenous infusion of glyburide. Results During both euglycemia and hyperglycemia, glyburide enhanced insulin secretion and glucose disposal only to drug levels of 100–200 nM corresponding to an oral dose ≤ 10 mg. Conclusions The data suggest that glyburide (and probably other sulfonylureas), operates within a narrow range of plasma concentrations (50–200 nM), which can be achieved with very low doses of the drug. It remains to be shown whether the threshold of maximal effect also in clinical practice is achieved with lower sulfonylurea doses than that currently used.

Dose-Dependent Effects of Glyburide on Insulin Secretion and Glucose Uptake in Humans

Objective The mortality of patients with liver cirrhosis admitted to an intensive care unit (ICU) has been found to be high. This study was performed to assess the physiological and laboratory parameters which are able to identify on ICU admission the cirrhotic patients who are most likely to die. Design Prospective clinical trial. Methods Two groups of patients were analysed. Group A consisted of 196 consecutive cirrhotic patients admitted to our medical ICU for various reasons. For the detection of independent outcome predictors, we used a multiple logistic regression model. Based on these variables, the 'intensive care cirrhosis outcome (ICCO) score' was calculated. The ability to discriminate between survivors and non-survivors was determined by receiver operating characteristic curves, and the area under the curve was calculated. Group B consisted of 70 consecutive cirrhotic patients for prospective validation of the ICCO score. Results Applying multiple logistic regression analysis, bilirubin, cholesterol, creatinine clearance and lactate were found to be independently associated with the hospital mortality. The ICCO score was 0.3707 + (0.0773 x bilirubin (mg/dl)) - (0.00849 x cholesterol (mg/dl)) -(0.0155 x creatinine clearance (ml/min)) + (0.1351 x lactate (mmol/l)), giving an area under a receiver operating characteristic curve of 0.9. Increasing score values were associated with an increase in mortality. All patients with an ICCO score > +2.6 died. Conclusions Application of the ICCO score is rapid and available at the patient's bedside, and its application is simple and reproducible. In cirrhotic patients, the ICCO score has a high ability to discriminate between survivors and non-survivors. The ICCO score may facilitate estimation on ICU admission of the prognosis of critically ill cirrhotic patients.

Klaus Ratheiser

Papers

Different Effects of Glyburide and Glipizide on Insulin Secretion and Hepatic Glucose Production in Normal and NIDDM Subjects

Metabolic effects of fish-oil supplementation in patients with impaired glucose tolerance.

Impaired subcortical and cortical sensory evoked potential pathways in septic patients

Dose-Dependent Effects of Glyburide on Insulin Secretion and Glucose Uptake in Humans

Short-term prognosis in critically ill patients with liver cirrhosis: an evaluation of a new scoring system.