The metabolic syndrome

Replacement of the methyl-thiazole moiety of GW501516 (a PPARδ selective agonist) with [1,2,4]thiadiazole gave compound 21 which unexpectedly displayed submicromolar potency as a partial agonist at PPARα in addition to the high potency at PPARδ. A structure–activity relationships study of 21 resulted in the identification of 40 as a potent and selective PPARα/δ dual agonist. Compound 40 and its close analogs represent a new series of PPARα/δ dual agonists. The high potency, high selectivity, significant gene induction, excellent PK profiles, low P450 inhibition or induction, and good in vivo efficacy in four animal models support 40 being selected as a pre-clinical study candidate, and may render 40 as a valuable pharmacological tool in elucidating the complex roles of PPARα/δ dual agonists, and the potential usage for the treatment of metabolic syndrome.

The dental literature contains little information about metabolic syndrome (MetS) and its dental implications.

The authors conducted a MEDLINE search for the period 2000 through 2005, using the term “metabolic syndrome” to define its pathophysiology, medical treatment and dental implications.

MetS is the co-occurrence of abdominal obesity, hyper-triglyceridemia, reduced high-density lipoprotein cholesterol levels, hypertension and impaired fasting glucose, which results from consumption of a high-calorie diet and decreased levels of physical activity superimposed on the appropriate genetic setting. Components of MetS synergistically promote the development of atherosclerosis, resulting in myocardial infarction and stroke.

Deteriorating oral health status is associated with worsening of the atherogenic profile. Tooth loss often results in chewing difficulties because of inadequate occlusive surfaces and may lead to alterations in food selection and dietary quality. This, in turn, adversely affects body composition and nutritional status, both of which are related to vascular health. Dentists should develop treatment plans that preserve and restore the dentition, thus ensuring maximum masticatory efficiency and affording patients the optimum opportunity to consume food that will not foster atherogenesis.

We report the identification of a novel series of trisubstituted isoxazoles as PPAR activators from a high-throughput screen. A series of structural optimizations led to improved efficacy and excellent functional receptor selectivity for PPARδ. The isoxazoles represent a series of agonists which display a scaffold that lies outside the typical PPAR agonist motif.

Metabolic syndrome (MetS), the co-occurrence of abdominal obesity, hypertriglyceridemia, reduced HDL cholesterol, hypertension, and insulin resistance promotes carotid atherosclerosis and stroke. The objective of this study was to determine if the presence of calcified atheromas detected on panoramic radiographs of individuals free of overt vascular disease may herald occult MetS.

Ninety-four individuals (mean age 65.6 years) with a calcified atheroma detected by a VA dental clinic were evaluated. A like-aged group was used for comparative analysis.

Fifteen percent of individuals (mean age 64 years) with an atheroma had occult MetS. Mean waist circumference was 116 cm, BMI 32.7 kg/m², triglycerides 250 mg/dL, HDL cholesterol 35 mg/dL, blood pressure 147/87 mm Hg, and glucose 117 mg/dL. Only 6% of controls had occult MetS but this difference in prevalence was not proven to be statistically significant (P = .059).

Some individuals with a calcified atheroma may have undiagnosed MetS and should be referred to their physician because aggressive management may preclude a stroke.