Obesity and T2DM are metabolic diseases with 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 diet, microorganisms and GI (host), disrupted mucosal permeability, and chylomicron-mediated lipopolysaccharide (LPS) trans-epithelial transport causes endotoxemia. The latter induces inflammation, obesity, insulin resistance and ultimately T2DM.
Nerve cell damage (neuropathy) is one of the major causes of debilitating complications and disability in diabetes patients. Diabetic neuronal cell death and altered neurochemistry (neuropathy) occur in the enteric nervous system (ENS; the “little brain” in the gut) of humans and experimental animals. Neuropathy affects 60-75% of over diabetic patients causing devastating GI motility disorders including gastroparesis, constipation, diarrhea, and pain in T2DM patients. Unfortunately, we know very little about the pathophysiology of diabetic ENS neuropathy and GI dysmotility. Dysmotility is thought to be caused by structural and physiological changes in the ENS that disrupt ENS regulation of GI motility. ENS neuropathy and subsequent dysmotility contribute to the pathogenesis of T2D by causing dysbiosis of gut microbiota, altered mucosal barrier function and ENS-brain signaling, leading to disruption of glucose metabolism in the body.
New research data indicate that enteric neural mechanisms have a crucial role in the development and in the therapeutic interventions against obesity and T2DM (Figure 1). 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 fat disrupts neurotransmission, and causes injury and death of ENS neurons. The second goal of this research is to explore traditional herbal medicine to identify novel molecules for protecting the ENS against high fat diet/diabetes-induced neuropathy. These crucial research objectives because they will enhance understanding of the pathogenesis of GI motility disorders that are widespread in type 2 diabetics; shed light on the mechanisms underlying neuropathy and dismotility; and identify new molecules to mitigate/protect the ENS from excessive calories and subsequent metabolic disorders. These breakthroughs will contribute to the development of effective treatments of neurological disorders, improving quality of life of obese and T2DM patients.