Abstract
The FDA’s approval of peptide drugs such as Ziconotide or Exendin for pain relief and diabetes treatment, respectively, enhanced the interest to explore novel conotoxins from Conus species venom. In general, conotoxins can be used in pathologies where voltage-gated channels, membrane receptors, or ligands alter normal physiological functions, as in metabolic diseases such as Type 2 diabetes. In this study, the synthetic cal14.2b (s-cal14.2b) from the unusual Californiconus californicus demonstrated bioactivity on NIT-1 insulinoma cell lines stimulating insulin secretion detecting by high performance liquid chromatography (HPLC). Accordingly, s-cal14.2b increased the CaV1.2/1.3 channel-current by 35 ± 4% with a recovery τ of 10.3 ± 4 s in primary cell culture of rat pancreatic β-cells. The in vivo results indicated a similar effect of insulin secretion on mice in the glucose tolerance curve model by reducing the glucose from 500 mg/dL to 106 mg/dL in 60 min, compared to the negative control of 325 mg/dL at the same time. The PET-SCAN with radiolabeling 99mTc-s-cal14.2b demonstrated biodistribution and accumulation in rat pancreas with complete depuration in 24 h. These findings show the potential therapeutic use of s-cal14.2b in endocrinal pathologies such as early stages of Type 2 Diabetes where the pancreas’s capability to produce insulin is still effective.
Highlights
Type 2 diabetes mellitus (T2DM) is the most common endocrinological disorder worldwide
Findings from this study suggest s-cal14.2b is a promising therapeutic for treating T2DM
The native peptide of conotoxin cal14.2b was isolated from Californiconus californicus
Summary
Type 2 diabetes mellitus (T2DM) is the most common endocrinological disorder worldwide. Biomedicines 2021, 9, 936 the number of cases in the last few decades in industrialized countries and spreading to low and medium-income countries where the microvascular complications represent an. The chronic degenerative nature of diabetes implies an economic impact associated to healthcare resources deviated to provide proper attention in the cases where complications occur such as renal diseases, amputations or blindless, and lack of productivity [2,4,5,6]. The global diabetes prevalence will rise to 578 million by 2030 and 700 million by 2045 [7,8]. The pathophysiology is defined as an inherited or acquired deficiency in insulin production and secretion of insulin in pancreatic β cells, or by the ineffectiveness of the insulin produced, resistance at peripheral level mainly in fat tissue, liver and muscle reflecting on high glucose blood levels damaging microvascular vessels, vision, renal function, and others [11,12,13]
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