Patient case: 11-year-old male with Peutz-Jeghers syndrome; genetic feature: STK11

Clinical trial: The Role of Arachidonic Acid Metabolites, From Patients With Metabolic Syndrome

Summary: The purpose of this study is to determine whether an increase in lipid bodies in leukocytes will lead to an increase in eicosanoid production. The 2nd purpose is to determine if there is a significant correlation between lipid body formation and enhanced generation of both Lipoxygenase (LO) and COX derived eicosanoids. The 3rd purpose is, if lipid bodies are involved in arachidonic acid (AA) metabolism, then AA present in these lipid rich structure must be released by phospholipases and the free Arachidonic Acid (AA) must have access to the eicosanoid forming enzyme. The fourth objective is to determine the compartmentalisation of cPLA2 and MAP kinases including ERK1, ERK2, p85 and p38 are involved in AA liberation within lipid bodies.

Detailed description: Metabolic syndrome is a cluster of biochemical and physiological abnormalities associated with the development of cardiovascular disease and type 2 diabetes mellitus. The current study focused on type 2 Diabetes Mellitus(T2DM). T2DM is a chronic disease in which people have problems regulating their blood sugar. This disorder consists of an array of dysfunctions characterized by hyperglycemia and resulting from the combination of resistance of insulin action, inadequate insulin secretion and excessive or inappropriate glucagon secretion. Insulin resistance results from a complex interplay between nutrient overload, systemic fatty acid excess, inflammation of the adipose tissue, endoplasmic reticulum and oxidative stress.
  At the molecular lever, inflammatory cytokines, fatty acid derivatives such as ceramides, diacylglycerols and reactive oxygen species (ROS), activate several serine/threonine kinases, that have emerged as important negative regulators of insulin signaling. Because of their ability to directly oxidize DNA, protein and lipid damage, ROS are believed to play a key role in the metabolic syndrome and the possible development of T2DM. It is possible that ROS and oxidative stress, induced by elevations in glucose and possibly free fatty acid levels play a key role in causing insulin resistance, and beta cell dysfunction by their ability to activate stress sensitive signaling pathways.
  Lipids as signaling intermediates encompass a vast range of molecules with distinct function. The characteristics includes, lipid bodies(LB) are sites for the production of inflammatory mediators and LB within inflammatory cells contain arachidonyl lipids which serve as precursors for eicosanoids. In addition, formation of LB within inflammatory macrophages was positively correlated with augmented increase in prostaglandin E2 (PGE2) in changes. LB also could function as a draining compartment to rapidly uptake and re-acetylate free arachidonic acid with the potentially detrimental outcomes for the host cell.
  Macrophage from cells with lipid bodies involves complex and multi step mechanisms that depend on different signaling pathways regulating lipid influx, metabolism storage and mobilization. In view of these clues the investigators have reason to believe that organic anion transporters might be resident or upon stimulation trans located to lipid bodies in order to export the newly synthesized lipid mediators into the cytoplasmic space. Once outside the lipid bodies the eicosanoids can exert intracrine functions or be exported to plasma membrane resident transporters to the extracellular space. Free fatty acids have adverse effects on the mitochondrial function including uncoupling of oxidative phosphorylation and the generation of ROS. Beta cell lipotoxicity has an amplifying effect only if mediated by concurrent hyperglycemia. The association of obesity, fatty acids and oxidative stress with insulin action clearly merits further attention with particular focus on the molecular mechanism.

Eligibility: Inclusion Criteria:
  -  age ≥ 18 to ≤ 60
  -  Patient diagnosed with Type 2 Diabetes Mellitus within 1 year
  Exclusion Criteria:
  -  Patients < 18 years
  -  Patients with uncontrolled diabetes, heart failure and sepsis

Relevance to patient case: not relevant