Abstract
Biosynthesis of insulin - critical to metabolic homeostasis - begins with folding of the proinsulin precursor, including formation of three evolutionarily conserved intramolecular disulfide bonds. Remarkably, normal pancreatic islets contain a subset of proinsulin molecules bearing at least one free cysteine thiol. In human (or rodent) islets with a perturbed endoplasmic reticulum folding environment, non-native proinsulin enters intermolecular disulfide-linked complexes. In genetically obese mice with otherwise wild-type islets, disulfide-linked complexes of proinsulin are more abundant, and leptin receptor-deficient mice, the further increase of such complexes tracks with the onset of islet insulin deficiency and diabetes. Proinsulin-Cys(B19) and Cys(A20) are necessary and sufficient for the formation of proinsulin disulfide-linked complexes; indeed, proinsulin Cys(B19)-Cys(B19) covalent homodimers resist reductive dissociation, highlighting a structural basis for aberrant proinsulin complex formation. We conclude that increased proinsulin misfolding via disulfide-linked complexes is an early event associated with prediabetes that worsens with ß-cell dysfunction in type two diabetes.
Highlights
The progression of b-cell dysfunction with endoplasmic reticulum (ER) stress in prediabetes, to ß-cell failure with full-blown type two diabetes (T2D), has long been the subject of intensive investigation (Fonseca et al, 2011; Rabhi et al, 2014)
We examined proinsulin in the islet lysates of 5 additional prediabetic LepRdb/db mice — all were similar to the islets of two animals shown in Figures 4D (4 and 6 weeks of age with random blood glucose levels of 101 and 118 mg/dL, respectively) containing a large steady state level of proinsulin with >90% of molecules entangled in disulfide-linked dimers and higher-order complexes
It is indisputable that ß-cell ER stress can be triggered by proinsulin misfolding in the setting of INS gene coding sequence mutations (Liu et al, 2018) but there are strong reasons to think that even in the absence of INS gene mutations, proinsulin misfolding could be an early feature in the progression of T2D (Arunagiri et al, 2018; Riahi et al, 2018; Scheuner and Kaufman, 2008)
Summary
The progression of b-cell dysfunction with endoplasmic reticulum (ER) stress in prediabetes, to ß-cell failure with full-blown type two diabetes (T2D), has long been the subject of intensive investigation (Fonseca et al, 2011; Rabhi et al, 2014). Pancreatic sections of human subjects with T2D show a marked increase of ER volume density in b-cells with an induction of ER stress markers triggered by high glucose exposure (Marchetti et al, 2007). Similar indicators of ER stress have been established in the b-cells of animal models (Yang et al, 2016), such as leptin receptor-deficient diabetic mice [known as LepRdb/
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