Zinc and iron dynamics in human islet amyloid polypeptide-induced diabetes mouse model

Abstract

Metal homeostasis is tightly regulated in cells and organisms, and its disturbance is frequently observed in some diseases such as neurodegenerative diseases and metabolic disorders. Previous studies suggest that zinc and iron are necessary for the normal functions of pancreatic β cells. However, the distribution of elements in normal conditions and the pathophysiological significance of dysregulated elements in the islet in diabetic conditions have remained unclear. In this study, to investigate the dynamics of elements in the pancreatic islets of a diabetic mouse model expressing human islet amyloid polypeptide (hIAPP): hIAPP transgenic (hIAPP-Tg) mice, we performed imaging analysis of elements using synchrotron scanning X-ray fluorescence microscopy and quantitative analysis of elements using inductively coupled plasma mass spectrometry. We found that in the islets, zinc significantly decreased in the early stage of diabetes, while iron gradually decreased concurrently with the increase in blood glucose levels of hIAPP-Tg mice. Notably, when zinc and/or iron were decreased in the islets of hIAPP-Tg mice, dysregulation of glucose-stimulated mitochondrial respiration was observed. Our findings may contribute to clarifying the roles of zinc and iron in islet functions under pathophysiological diabetic conditions.

A practical and robust method to evaluate metabolic fluxes in primary pancreatic islets

“…Since pancreatic β-cells efficiently couple glucose metabolism to insulin release through mitochondrial electron transport and ATP production [ 2 , 3 ], studying oxygen consumption rates (OCR) in ex vivo islets is of great interest. Most studies use cell lines, while few existing studies with primary islets [ [4] , [5] , [6] , [7] , [8] , [9] , [10] ] use specific equipment and consumables that are expensive, complicated to use, and yield poorly reproducible results. While cell lines are an important tool, primary islets are a much more robust model to evaluate β-cell function.…”

Beta Cell Dysfunction in Youth- and Adult-Onset Type 2 Diabetes: An Extensive Narrative Review with a Special Focus on the Role of Nutrients

“…Regarding micronutrients, iron has been implicated in IAPP formation and deposition [260]. In addition, iron in the form of heme has been shown to form a complex with IAPP which leads to hydrogen peroxide formation and β-cell death through oxidative stress [261,262].…”

Copper binding and protein aggregation: a journey from the brain to the human lens

“…aResidues involved in metal ion binding are highlighted on each protein. References: Prion protein, 18–20 amyloid-β, 18,21–24 α-synuclein, 25 Huntingtin, 18 IAPP, 26,27 Crystallin. 26,28–30 …”

“…References: Prion protein, 18–20 amyloid-β, 18,21–24 α-synuclein, 25 Huntingtin, 18 IAPP, 26,27 Crystallin. 26,28–30…”

“…As summarized in Table 1, most proteinopathies are also associated with the loss of essential metal ion homeostasis. 18,21,26,28–30,43 In Alzheimer's disease, copper is decreased in degenerated tissue, 44–46 increased in the serum, 47,48 and accumulated in amyloid plaques. 49–52 Similarly, copper is elevated in serum of diabetic patients and is raised in lenses with cataracts.…”