Molecular pathways dysregulated by Pb 2+ exposure prompts pancreatic beta-cell dysfunction.

Type 2 diabetes mellitus (T2DM) is a metabolic disease characterized by reduced insulin sensitivity and dysfunction of β-cells. Although the increasing prevalence of diabetes worldwide is largely attributed to genetic predisposition or lifestyle factors (insufficient physical activity), and caloric intake. Environmental factors, exposure to xenobiotics and heavy metals have also been reported to be causative factors of T2DM. At this juncture, we, through our work unveil a plausible link between Pb ²⁺ exposure and diabetes mellitus, and delineated a comprehensive understanding of the potential mechanisms of Pb ²⁺ -induced β-cells dysfunction. In our in vivo observations, we found that Pb ²⁺ exposure strongly reduced glucose-stimulated insulin secretion and diminished functional pancreatic β-cell mass. Mechanistically, we found that Pb ²⁺ downregulates intracellular cAMP level via hyper-activating Ca ²⁺ /calmodulin-dependent 3',5'-cyclic nucleotide phosphodiesterase 1C and thereby reduces glucose-stimulated insulin secretion. Further, we report that Pb ²⁺ inhibited mitochondrial adenosine triphosphate production and also identified Pb ²⁺ as a negative regulator of β-cell proliferation via Ca ²⁺ /calmodulin-dependent protein kinase kinases-pAMPK-pRaptor axis. Together, our findings strongly reinforce Pb ²⁺ to hijack the physiological role of calcium ions, by mimicking Ca ²⁺ within pancreatic β-cell and thereby stands as a diabetogenic xenobiotic.
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