tetrodotoxin and Diabetes-Mellitus

Diabetes mellitus (DM) is a common chronic medical problem worldwide; one of its complications is painful peripheral neuropathy, which can substantially erode quality of life and increase the cost of management. Despite its clinical importance, the pathogenesis of painful diabetic neuropathy (PDN) is complex and incompletely understood. Voltage-gated sodium channels (VGSCs) link many physiological processes to electrical activity by controlling action potentials in all types of excitable cells. Two isoforms of VGSCs, NaV1.3 and NaV1.7, which are encoded by the sodium voltage-gated channel alpha subunit 3 and 9 (Scn3A and Scn9A) genes, respectively, have been identified in both peripheral nociceptive neurons of dorsal root ganglion (DRG) and pancreatic islet cells. Recent advances in our understanding of tetrodotoxin-sensitive (TTX-S) sodium channels NaV1.3 and NaV1.7 lead to the rational doubt about the cause-effect relation between diabetes and painful neuropathy. In this review, we summarize the roles of NaV1.3 and NaV1.7 in islet cells and DRG neurons, discuss the link between DM and painful neuropathy, and present a model, which may provide a starting point for further studies aimed at identifying the mechanisms underlying diabetes and painful neuropathy.

Topics: Animals; Diabetes Mellitus; Diabetic Neuropathies; Humans; Islets of Langerhans; NAV1.3 Voltage-Gated Sodium Channel; NAV1.7 Voltage-Gated Sodium Channel; Sodium Channel Blockers; Tetrodotoxin

To explore the pathogenic mechanism of diabetic gastropathy, we investigated differences in response to electrical field stimulation (EFS) of gastric muscles from diabetic and non-diabetic (control) patients. Gastric specimens were obtained from 34 patients and 45 controls who underwent gastrectomy for early gastric cancer. Using organ bath techniques, we examined peak and nadir values of contraction under EFS. To examine responses to purinergic and nitrergic inhibition without cholinergic innervation, atropine, MRS2500, and N-nitro-L-arginine (L-NNA) were added sequentially to the organ bath. Tetrodotoxin (TTX) was used to confirm that the responses to EFS were mediated via neural stimulation. In the absence of pharmacological agents, peak contraction amplitude was greater in non-diabetic controls compared to diabetics only in the distal longitudinal gastric muscles. However, the nadir was greater in controls than in patients in both proximal and distal gastric circular muscles. Addition of MRS2500 could not decrease the nadir in both controls and patients, both in the proximal and distal stomach. However, L-NNA completely reversed the relaxation. TTX had no further effect on nadir. In conclusion, impaired inhibitory nitrergic neural pathway in both proximal and distal stomach and impaired excitatory cholinergic neural pathway in the distal stomach may contribute to the pathogenic mechanism underlying diabetic gastropathy.

Topics: Aged; Atropine; Diabetes Complications; Diabetes Mellitus; Electric Stimulation; Female; Humans; Male; Middle Aged; Muscle Contraction; Muscle Relaxation; Muscle, Smooth; Neural Pathways; Organ Culture Techniques; Stomach; Tetrodotoxin