Central obesity, type 2 diabetes and insulin: exploring a pathway full of thorns.

The prevalence of type 2 diabetes (T2D) is rapidly increasing. This is strongly related to the contemporary lifestyle changes that have resulted in increased rates of overweight individuals and obesity. Central (intra-abdominal) obesity is observed in the majority of patients with T2D. It is associated with insulin resistance, mainly at the level of skeletal muscle, adipose tissue and liver. The discovery of macrophage infiltration in the abdominal adipose tissue and the unbalanced production of adipocyte cytokines (adipokines) was an essential step towards novel research perspectives for a better understanding of the molecular mechanisms governing the development of insulin resistance. Furthermore, in an obese state, the increased cellular uptake of non-esterified fatty acids is exacerbated without any subsequent ß-oxidation. This in turn contributes to the accumulation of intermediate lipid metabolites that cause defects in the insulin signaling pathway. This paper examines the possible cellular mechanisms that connect central obesity with defects in the insulin pathway. It discusses the discrepancies observed from studies organized in cell cultures, animal models and humans. Finally, it emphasizes the need for therapeutic strategies in order to achieve weight reduction in overweight and obese patients with T2D.

Thiazolidinediones and type 2 diabetes: from cellular targets to cardiovascular benefit.

The prevalence of type 2 diabetes is evolving globally at an alarming rate. This fact is mainly the result of our global lifestyle "modernization" that has resulted in overweight and obesity. Dysfunction of peroxisome proliferator activated receptor-gamma (PPAR-gamma) has been implicated in the development of insulin resistance, while a reduce expression of many PPAR-gamma regulated genes has been observed in an obese diabetic state. Thiazolidinediones (TZDs) are potent exogenous agonists of PPAR-gamma, which augment the effects of insulin to its cellular targets and mainly at the level of adipose tissue. Preclinical and clinical studies have demonstrated that apart from their glucose-lowering activity, these drugs also regulate the production of inflammatory mediators by cells that play a pivotal role in the pathogenesis of atherosclerosis. This paper summarizes the evolving changes observed in an enlarged adipose tissue and examines the activity of TZDs in their main cellular targets. It also discusses whether these cellular pleiotropic effects can result in a clinically meaningful outcome, in terms of cardiovascular benefit, in this population.

Arterial stiffness: determinants and relationship to the metabolic syndrome.

This study aimed to investigate independent determinants of arterial stiffness and evaluate the association of arterial stiffness with the presence of metabolic syndrome (MS). Demographic characteristics, hemodynamic parameters, and cardiovascular (CV) risk factors were assessed in Greek food industry employees with no history of diabetes or CV disease in order to isolate multiple correlates of arterial stiffness as assessed by pulse wave velocity (PWV). Subsequently, logistic regression analysis was performed using as end point the presence of MS, defined according to the National Cholesterol Education Program. Data from 424 participants (mean age 45.3 -/+ 15.5 years, 298 [70.3%] males, average PWV 8.5 -/+ 3.6 m/s) were analyzed. PWV was higher in men (8.8 -/+ 3.1 m/s) compared to women (7.7 -/+ 2.9 m/s, p < 0.01). Age, systolic blood pressure, and heart rate were isolated as multivariate determinants of PWV (adjusted R2 0.511 [p < 0.0001] in men and 0.538 [p < 0.0001] in women). The overall prevalence of the MS was 14.6%, being similar in both genders. Four variables were shown to be independent predictors of the presence of MS: waist circumference >102 cm (men)/88 cm (women) (OR 8.6, [95% CI 2.8, 20.6], p < 0.001), insulin resistance (homeostasis model assessment >4) (6.3, [2.1, 17.6], p < 0.001), total cholesterol >240 mg/dL (5.5, [1.7, 12.4], p < 0.01), PWV >9 m/s (4.1, [1.5, 9.9], p < 0.01). High PWV, which was found to be mostly determined by advanced age, elevated systolic BP, and accelerated heart rate, appeared to exhibit a strong independent association with the presence of MS together with adiposity and insulin resistance. This index should be considered as a useful marker for CV risk stratification.

Prognostic significance of plasma resistin levels in patients with atherothrombotic ischemic stroke.

BACKGROUND: Resistin (RSN) is an adipocytokine involved in insulin resistance, obesity and atherosclerosis. This study aimed to investigate the association between plasma RSN and outcome after ischemic stroke. METHODS: RSN measured within 24 h after the event was related to functional outcome and 5-year survival in 211 subjects with first-ever atherothrombotic ischemic stroke. Prognosis was assessed by the Kaplan Meier and the Cox techniques. RESULTS: The probabilities of death were 80.4%, 46.2% and 15.7% (p<0.001) for patients stratified according to tertiles of RSN (>30 ng/mL, 20-30 ng/mL and<20 ng/mL, respectively). The proportion of dependency (modified Rankin Scale score>or=3) was greater in 5-year survivors with RSN in the upper tertile (6/11 [54.5%]) compared to the middle (20/56 [35.7%]) and the lowest tertile (8/43 [18.6%]; p<0.01). C-reactive protein levels (hazard ratio [HR] 3.96 [95% CI 2.06, 8.91]; p<0.001), coronary heart disease (2.69 [1.62, 6.23]; p<0.001), RSN levels (2.12 [1.31, 5.08] p<0.001), National Institute of Health Stroke Scale score (2.02 [1.23, 4.49]; p<0.01) and age (1.84 [1.19, 3.93]; p<0.01) were independent predictors of death. CONCLUSIONS: High plasma RSN appears to be associated with increased risk of 5-year mortality or disability after atherothrombotic ischemic stroke, independently of other adverse predictors.

A mortality prediction model in diabetic ketoacidosis.

AIM: To assess the value of clinical and laboratory parameters in predicting mortality in patients presenting with diabetic ketoacidosis (DKA). METHODS: The records of all DKA admissions within 10 years were reviewed. Eighteen variables were evaluated at initial presentation and 20 variables at 4, 12 and 24 h from admission. A scoring system derived from these variables was compared to the APACHE III scoring system. RESULTS: Among 154 patients (52 males, mean age 58 +/- 12 years), 20 (13%) died in hospital. Multivariate analysis yielded six variables as significant independent predictors (P < 0.05) of mortality: severe coexisting diseases (SCD) and pH < 7.0, at presentation; units of regular insulin required in the first 12 h > 50 and serum glucose > 16.7 mmo/l, after 12 h; depressed mental state and fever, after 24 h. An integer-based scoring system was derived, as follows: number of points = 6 (SCD at presentation) + 4 (pH < 7.0 at presentation) + 4 (regular insulin required > 50 IU after 12 h) + 4 (serum glucose > 16.7 mmo/l after 12 h) + 4 (depressed mental state after 24 h) + 3 (fever after 24 h). Patients with 0-14 points had 0.86% risk of death, whereas for those with 19-25 points the risk was 93.3%. Median APACHE III scores differed significantly (P < 0.001) among groups of patients stratified according to the above scoring system. CONCLUSIONS: Risk stratification of patients with diabetic ketoacidosis is possible from simple clinical and laboratory variables available during the first day of hospitalization.