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Zinc transporters, mechanisms of action and therapeutic utility: implications for type 2 diabetes mellitus.

ABSTRACT: Zinc is an essential trace element that plays a vital role in maintaining many biological processes and cellular homeostasis. Dysfunctional zinc signaling is associated with a number of chronic disease states including cancer, cardiovascular disease, Alzheimer's disease, and diabetes. Cellular homeostasis requires mechanisms that tightly control the uptake, storage, and distribution of zinc. This is achieved through the coordinated actions of zinc transporters and metallothioneins. Evidence on the role of these proteins in type 2 diabetes mellitus (T2DM) is now emerging. Zinc plays a key role in the synthesis, secretion and action of insulin in both physiological and pathophysiological states. Moreover, recent studies highlight zinc's dynamic role as a "cellular second messenger" in the control of insulin signaling and glucose homeostasis. This suggests that zinc plays an unidentified role as a novel second messenger that augments insulin activity. This previously unexplored concept would raise a whole new area of research into the pathophysiology of insulin resistance and introduce a new class of drug target with utility for diabetes pharmacotherapy.

SUBMITTER: Myers SA

PROVIDER: S-EPMC3530793 | biostudies-literature | 2012

REPOSITORIES: biostudies-literature

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Zinc transporters, mechanisms of action and therapeutic utility: implications for type 2 diabetes mellitus.

Myers Stephen A SA Nield Alex A Myers Mark M

Journal of nutrition and metabolism 20121212

Zinc is an essential trace element that plays a vital role in maintaining many biological processes and cellular homeostasis. Dysfunctional zinc signaling is associated with a number of chronic disease states including cancer, cardiovascular disease, Alzheimer's disease, and diabetes. Cellular homeostasis requires mechanisms that tightly control the uptake, storage, and distribution of zinc. This is achieved through the coordinated actions of zinc transporters and metallothioneins. Evidence on t ...[more]

PMID: 23304467

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Project description:Diabetes mellitus (DM) is a chronic progressive metabolic disease that involves uncontrolled elevation of blood glucose levels. Among various therapeutic approaches, GLP-1 prevents type 2 diabetes mellitus (T2DM) patients from experiencing hyperglycemic episodes. However, the short half-life (<?5 min) and rapid clearance of GLP-1 often limits its therapeutic use. Here, we developed an oral GLP-1 gene delivery system to achieve an extended antidiabetic effect.Human IgG1 (hIgG1)-Fc-Arg/pDNA complexes were prepared by an electrostatic complexation of the expression plasmid with various ratios of the positively modified Fc fragments of an antibody (hIgG1-Fc-Arg) having a targeting ability to FcRn receptor. The shape and size of the complexes were examined by atomic force and field emission electron microscope. The stability of the complexes was tested in simulated gastrointestinal pH and physiological serum condition. Cellular uptake, transport, and toxicity of the complexes were tested in the Caco-2 cells. Biodistribution and antidiabetic effect of the complexes were observed in either Balb/c mice or Lepdb/db mice.A 50/1 ratio of the hIgG1-Fc-Arg/pDNA produced a complex structure having approximately 40 ~?60 nm size and also demonstrated protection of pDNA in the complex from the physiological pH and serum conditions. Cellular uptake and transport of the complex were demonstrated in Caco-2 cells having FcRn receptor expression and forming the monolayer-polarized structure. The cellular toxicity of both delivery vehicle and the complex revealed their minimal toxicity comparable with nontoxicity of a commercial transfection reagent. Biodistribution of the complex showed the detectable distribution of the complex in the most parts of gastrointestinal tract due to ubiquitous expression of the FcRn receptors. An in vivo type 2 diabetes treatment study of oral administration of hIgG1-Fc-9Arg/pGLP-1 complexes showed absorption and expression in GI tract of either Balb/c mice or Lepdb/db mice.In this study, we developed an oral GLP-1 gene delivery system on the platform of cationic hIgG1-Fc-9Arg. Prolonged t1/2, less immunoactivity, and better bioactivities of hIgG-Fc-9Arg/pGLP-1 complexes appeared to be a promising approach to achieve potent treatment of type 2 diabetes treatment.

Dataset Information

Zinc transporters, mechanisms of action and therapeutic utility: implications for type 2 diabetes mellitus.

Publications

Zinc transporters, mechanisms of action and therapeutic utility: implications for type 2 diabetes mellitus.

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