Metabolic syndrome and type 2 diabetes mellitus: focus on peroxisome proliferator activated receptors (PPAR)

Abstract

The metabolic syndrome is a highly prevalent clinical entity. The recent Adult Treatment Panel (ATP III) guidelines have called specific attention to the importance of targeting the cardiovascular risk factors of the metabolic syndrome as a method of risk reduction therapy. The main factors characteristic of this syndrome are abdominal obesity, atherogenic dyslipidemia, elevated blood pressure, insulin resistance (with or without glucose intolerance), prothrombotic and proinflammatory states. An insulin resistance following nuclear peroxisome proliferator activated receptors (PPAR) deactivation (mainly obesity-related) is the key phase of metabolic syndrome initiation. Afterwards, there are 2 principal pathways of metabolic syndrome development: 1) with preserved pancreatic beta cells function and insulin hypersecretion which can compensate for insulin resistance. This pathway leads mainly to the macrovascular complications of metabolic syndrome; 2) with massive damage of pancreatic beta cells leading to progressively decrease of insulin secretion and to hyperglycemia (e.g. overt type 2 diabetes). This pathway leads to both microvascular and macrovascular complications. We suggest that a PPAR-based appraisal of metabolic syndrome and type 2 diabetes may improve our understanding of these diseases and set a basis for a comprehensive approach in their treatment.

Figure 1

The relationship between metabolic syndrome, insulin resistance, hyperinsulinemia and hyperglycemia (overt type 2 diabetes). An insulin-resistant state following nuclear peroxisome proliferator activated receptors (PPAR) deactivation is the key phase of metabolic syndrome initiation. Afterwards, there are 2 principal pathways of metabolic syndrome development: 1) With preserved pancreatic beta cells function and insulin hypersecretion which can compensate for insulin resistance. This pathway leads mainly to the macrovascular complications of metabolic syndrome; 2) With massive damage of pancreatic beta cells leading to progressively decrease of insulin secretion and to hyperglycemia (e.g. overt type 2 diabetes). This pathway leads both to microvascular and macrovascular complications. Time-related scheme.

Figure 2

The peroxisome proliferator activated receptors (PPARs) in the framework of the nuclear receptors superfamily.

Figure 3

The atherogenesis tree, showing the complex interrelationship between hereditary and environmental factors in the pathogenesis of metabolic syndrome and atherothrombotic events. The central role of an insulin-resistant state following adipogenesis and nuclear peroxisome proliferator activated receptors (PPAR) deactivation is emphasized. CAD – coronary artery disease; AP – angina pectoris; ACS – acute coronary syndromes; CHF – congestive heart failure; PVD – peripheral vascular disease; HDL – high density lipoproteins cholesterol; IGT – impaired glucose tolerance; IFG – impaired fasting glucose.

Figure 4

The protection of patients with metabolic syndrome and diabetes: focus on treatment of PPAR-related risk factors.