Zinc in Pancreatic Islet Biology, Insulin Sensitivity, and Diabetes

Abstract

About 20 chemical elements are nutritionally essential for humans with defined molecular functions. Several essential and nonessential biometals are either functional nutrients with antidiabetic actions or can be diabetogenic. A key question remains whether changes in the metabolism of biometals and biominerals are a consequence of diabetes or are involved in its etiology. Exploration of the roles of zinc (Zn) in this regard is most revealing because 80 years of scientific discoveries link zinc and diabetes. In pancreatic β- and α-cells, zinc has specific functions in the biochemistry of insulin and glucagon. When zinc ions are secreted during vesicular exocytosis, they have autocrine, paracrine, and endocrine roles. The membrane protein ZnT8 transports zinc ions into the insulin and glucagon granules. ZnT8 has a risk allele that predisposes the majority of humans to developing diabetes. In target tissues, increased availability of zinc enhances the insulin response by inhibiting protein tyrosine phosphatase 1B, which controls the phosphorylation state of the insulin receptor and hence downstream signalling. Inherited diseases of zinc metabolism, environmental exposures that interfere with the control of cellular zinc homeostasis, and nutritional or conditioned zinc deficiency influence the patho-biochemistry of diabetes. Accepting the view that zinc is one of the many factors in multiple gene-environment interactions that cause the functional demise of β-cells generates an immense potential for treating and perhaps preventing diabetes. Personalized nutrition, bioactive food, and pharmaceuticals targeting the control of cellular zinc in precision medicine are among the possible interventions.

Keywords: biometals; diabetes; insulin resistance; pancreas; zinc.

Fig. 1

Biometals/biominerals interact with food bioactives and micronutrients. Metal ions bind to molecules affecting the metabolism of both. For those metal ions with high affinity binding, actions can be at very low concentrations (Fig. 2). In addition to the interaction with biomolecules, some free (unbuffered) metal ions have unique chemical reactivities. Bioactive food is rarely screened for metal content and metal binding capacity nor are the effects on control of metal homeostasis addressed.

Fig. 2

The cellular concentrations of biometals and biominerals. Essential metal ions occur at concentrations that cover many orders of magnitude. Controlled fluctuations make them important regulators of biological function, especially the redox-inert metal ions calcium and zinc as intracellular messengers/signalling ions. Some non-essential metal ions occur at concentrations commensurate with those of essential metal ions. ppm, parts per million; ppb, parts per billion; ppt, part per trillion.

Fig. 3

Complexity of zinc circuits in pancreatic islet biology. In addition to intracellular functions in about 3,000 proteins, zinc ions have hormone-like functions in islet biology. They are secreted from matured insulin and glucagon vesicles in β- and α-cells by exocytosis and have autocrine functions. Zinc ions secreted from β-cell together with insulin affect glucagon secretion from α-cells (paracrine function) and have been suggested to have an endocrine function on hepatic insulin clearance. A, autocrine effects; B, paracrine effect.