MANAGEMENT OF INSULIN-DEPENDENT DIABETES MELLITUS BY PREPROINSULIN AND PREPROTACHYKININ SUBSTANCE P: EXPERIMENTAL EVIDENCE AND THERAPEUTIC PROSPECTS

Prof. Sandeep Paithane*

Insulin-dependent diabetes mellitus (IDDM), currently termed type 1 diabetes mellitus (T1DM), is a chronic autoimmune disorder characterized by immune-mediated destruction of pancreatic β-cells, progressive loss of endogenous insulin secretion, and lifelong dependence on exogenous insulin. Although modern insulin formulations and glucose-monitoring technologies have substantially improved disease management, they do not directly eliminate β-cell autoimmunity or regenerate functional β-cell mass. Consequently, therapeutic strategies aimed at restoring endogenous insulin production while simultaneously modifying the pancreatic inflammatory microenvironment have attracted considerable interest. Two experimental approaches relevant to this objective are preproinsulin-based gene therapy and modulation of the preprotachykinin–Substance P pathway. Preproinsulin gene delivery attempts to provide non-pancreatic tissues with the genetic information required for sustained insulin production, whereas Substance P (SP), an 11-amino-acid tachykinin derived principally from the TAC1/preprotachykinin-A precursor, influences neuroimmune signaling, pancreatic inflammation, insulin sensitivity, and β-cell survival. Experimental studies in non-obese diabetic (NOD) and streptozotocin-induced diabetic mice demonstrate that Substance P can reduce insulitis, preserve pancreatic β-cell mass, promote compensatory β-cell proliferation, and delay hyperglycemia. Separately, preproinsulin gene-transfer studies have demonstrated prolonged production of insulin-like peptides and improvement of hyperglycemia in diabetic rodents. This review discusses the pathophysiological basis of T1DM, preproinsulin biosynthesis, preprotachykinin/Substance P biology, experimental evidence for their therapeutic effects, possible complementary mechanisms, limitations, and translational prospects. Importantly, preproinsulin and Substance P should presently be regarded as two complementary experimental strategies rather than an established combined treatment for T1DM.