Obesity and type 2 diabetes mellitus studies in a mouse model

Obesity and T2DM are metabolic diseases of major socioeconomic impact, morbidity and mortality. Worldwide, about one in every 10 adults are overweight and roughly 150 million people have T2DM. The risk factors for developing T2DM include: overweight, inactivity, genetic predisposition (family history and race) as well as aging. Cardinal features of T2DM are: obesity, insulin resistance, glucose intolerance, and low grade inflammation. Disease events originate in the gastrointestinal (GI) tract, and GI organs are a prime target for successful therapeutic intervention against obesity and T2DM. Recent studies indicate that the interaction between excessive calories and microorganisms in the GI tract, disrupted mucosal permeability, and chylomicron-mediated lipopolysaccharide (LPS) trans-epithelial transport causes endotoxemia. The latter induces fat deposition, inflammation and insulin resistance, the metabolic syndromes that ultimately develop into obesity and T2DM.

Diabetic neuronal cell death and altered neurochemistry (neuropathy) occur in the enteric nervous system (ENS; the “little brain” in the gut) because it is morphologically and functionally similar to the brain) of humans and experimental animals. Neuropathy is considered to be a key factor underlying bowel disorders that are common among obese and T2DM patients.  New research data indicate that enteric neural mechanisms have a crucial role in the development and in the therapeutic interventions against obesity and T2DM. The role of the ENS in the pathophysiology of obesity and T2DM is not fully understood.  The first long-term goal of  our research program  is to gain a better understanding of how excessive caloric intake, especially the consumption of fatty acids disrupts neurotransmission, and causes injury and death of enteric neurons. The second goal of this research is to utilize anti-inflammatory neural mechanisms to protect the ENS and preserve mucosal-barrier function, thus controlling the metabolic endotoxemia. These investigations will enhance understanding of the pathogenesis of GI motility disorders  that are widespread in type 2 diabetics and  shed light on how the enteric neuromuscular axis can be protected from damages induced by excessive calories and subsequent metabolic syndromes.  These breakthroughs will contribute to the development of effective treatments of neurological disorders, improving quality of life of obese and T2DM patients.

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