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Insulin: how its structure and function are affected by metals (dietary or not)

Metals play a role in many biochemical processes. As an example, hemoglobin contains iron and carries oxygen in the blood; zinc and copper are involved in a third to a half of all body functions, as cofactors of important enzymes involved in metabolism. But while scientists know the overall amount of an element in a given component of the body, such as blood, they generally don’t know the exact location of these metals, the state they are in or their biological role in the body. Metals such as zinc, copper and chromium bind to and influence a peptide involved in insulin production, according to new work from chemists at the University of California, Davis. The research is part of a new field of “metalloendocrinology” that takes a detailed look at the role of metals in biological processes in the body. Dr. Marie Heffern, assistant professor of Chemistry and senior author on the paper, to be published in the journal ChemBioChem, in her laboratory at UC Davis is using new techniques to understand how metals are distributed inside and outside cells, how they bind to proteins and other molecules and the subtle influences they have on those molecules.
The new study looked at C-peptide, or connecting peptide, a short chain of aminoacids that is released after pro-insulin is processed to became a mature protein. When the pancreas makes insulin, C-peptide connects two chains of insulin in a preliminary step. C-peptide is then cut out, stored along with insulin and released at the same time. C-peptide used to be considered a byproduct of insulin production but now scientists know that it acts as a hormone in its own right. C-peptide is now being investigated for potential in treating kidney disease and nerve damage in diabetes, so any better understanding of how it behaves in different conditions could be useful in drug development. The researchers measured how readily zinc, copper and chromium bound to C-peptide in test tubes, and how the metals affected the ability of cells to take up C-peptide. The metals had subtle effects on the structure of C-peptide, notably on its ability to curl into a helix in some conditions. Copper and chromium prevented cells from taking up the hormone, but other metals such as zinc, cobalt and manganese did not have such an effect.
However, cobalt ions may interfere with insulin release, as demonstrated may years ago (Wollheim et al., 1984) on rat pancreatic islets. The effect was not dependent on cellular calcium or cyclic nucleotides, typically involved in vesicle secretion. Insulin biological activity is reported also to have some relationship with other metal ions, like vanadium. Almost 25 years ago vanadate salts found interest because they mimic insulin actions, apparently with three mechanisms: a) vanadate interferes with phosphatases (PTP-1B) that turn off insulin receptor activity; b) enhances insulin sensitivity especially when the hormone is at very low levels; and c) prolonged insulin biological response. However, no direct interaction of vanadium ions (V3+ or V5+) has been reported up to date with insulin or C-peptide. Nonetheless, vanadium has always been considered a micronutrient, despite its diffusion in foods is scarce. That is why, like other metal ions is labeled as “micro”-nutrient, meaning that body needs daily amounts lesser than 1 milligram.
Another enigmatic question is why an “industrial” element like chromium must find a role in hormone biology. Is not news to biochemists or biologists and endocrinologists that chromium is required to some insulin actions. Specifically, it enhances the so-called “glucose tolerance” or the complex set of metabolic reactions that prepare the terrain to glucose metabolism. More than 20 years ago, it was demonstrated that chromium when complexed with short sequences of aminoacids (peptides), is able to enhance the biological function of insulin receptor. Insulin must be required for this mechanism, though no mechanism has ever been clarified. However, the presence of chromium ion was essential. As found the current research, instead, free chromium ions interfere with insulin uptake from target cells. This creates a dichotomy of effects between the dietary chromium intake (as peptide complex where available) and the free chromium that may derive from professional exposures.Anyway, results of this latest research confirm that metals can potentially “tune” the activity of hormones, or their processing such as C-peptide for insulin, by altering their structure or affecting uptake into cells.

This is an additional reason why daily diet must pay attention on the intake of several micronutrients that regulate such an important hormonal system. It might, in turn, affects a lot more that looks like.

– Edited by Dr. Gianfrancesco Cormaci, PhD, specialist in Clinical Biochemistry.
Scientific references
Ishihara H, Wollheim CB. Diabetol Int. 2016; 7(2):106-110. 
Davis CM, Vincent JB. Biochemistry 1997; 36(15):4382-85.
Wollheim CB, Janjic D. Am J Physiol. 1984; 246:57-62.
Saggerson ED et al. Biochem J. 1976 Feb; 154(2):349-57.
Dormer RL et al. Biochem J. 1974 May; 140(2):135-42.

Dott. Gianfrancesco Cormaci
- Laurea in Medicina e Chirurgia nel 1998 (MD Degree in 1998) - Specialista in Biochimica Clinica nel 2002 (Clinical Biochemistry residency in 2002) - Dottorato in Neurobiologia nel 2006 (Neurobiology PhD in 2006) - Ha soggiornato negli Stati Uniti, Baltimora (MD) come ricercatore alle dipendenze del National Institute on Drug Abuse (NIDA/NIH) e poi alla Johns Hopkins University, dal 2004 al 2008. - Dal 2009 si occupa di Medicina personalizzata. - Guardia medica presso strutture private dal 2010 - Detentore di due brevetti sulla preparazione di prodotti gluten-free a partire da regolare farina di frumento immunologicamente neutralizzata (owner of patents concerning the production of bakery gluten-free products, starting from regular wheat flour). - Responsabile del reparto Ricerca e Sviluppo per la società CoFood s.r.l. (leader of the R&D for the partnership CoFood s.r.l.) - Autore di un libro riguardante la salute e l'alimentazione, con approfondimenti su come questa condizioni tutti i sistemi corporei. - Autore di articoli su informazione medica e salute sui siti web salutesicilia.com, medicomunicare.it e in lingua inglese sul sito www.medicomunicare.com
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