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Proinsulin misfolding is an early event in the progression to type 2 diabetes.

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.

SUBMITTER: Arunagiri A

PROVIDER: S-EPMC6559786 | biostudies-literature | 2019 Jun

REPOSITORIES: biostudies-literature

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Proinsulin misfolding is an early event in the progression to type 2 diabetes.

Arunagiri Anoop A Haataja Leena L Pottekat Anita A Pamenan Fawnnie F Kim Soohyun S Zeltser Lori M LM Paton Adrienne W AW Paton James C JC Tsai Billy B Itkin-Ansari Pamela P Kaufman Randal J RJ Liu Ming M Arvan Peter P

eLife 20190611

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 mi ...[more]

PMID: 31184302

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Project description:ObjectiveBiomarkers are needed to characterize heterogeneity within populations at risk for type 1 diabetes. The ratio of proinsulin to C-peptide (PI:C ratio), has been proposed as a biomarker of beta cell dysfunction and is associated with progression to type 1 diabetes. However, relationships between PI:C ratios and autoantibody type and number have not been examined. We sought to characterize PI:C ratios in multiple islet autoantibody positive, single autoantibody positive and autoantibody negative relatives of individuals with type 1 diabetes.MethodsWe measured PI:C ratios and autoantibodies with both electrochemiluminescence (ECL) assays (ECL-IAA, ECL-GADA and ECL-IA2A) and radiobinding (RBA) assays (mIAA, GADA, IA2A and ZnT8A) in 98 relatives of individuals with type 1 diabetes followed in the TrialNet Pathway to Prevention Study at the Barbara Davis Center for a mean of 7.4 ± 4.1 years. Of these subjects, eight progressed to T1D, 31 were multiple autoantibody (Ab) positive, 37 were single Ab positive and 22 were Ab negative (by RBA).ResultsIn cross-sectional analyses, there were no significant differences in PI:C ratios between type 1 diabetes and/or multiple Ab positive subjects (4.16 ± 4.06) compared to single Ab positive subjects (4.08 ± 4.34) and negative Ab subjects (3.72 ± 3.78) (p = 0.92) overall or after adjusting for age, sex and BMI. Higher PI:C ratios were associated with mIAA titers (p = 0.03) and showed an association with ECL-IA2A titers (p = 0.09), but not with ECL-IAA, GADA, ECL-GADA, IA2A nor ZnT8A titers. In mixed-effects longitudinal models, the trajectories of PI:C ratio over time were significantly different between the Ab negative and multiple Ab positive/type 1 diabetes groups, after adjusting for sex, age, and BMI (p = 0.04).ConclusionsPI:C ratio trajectories increase over time in subjects who have multiple Ab or develop type 1 diabetes and may be a helpful biomarker to further characterize and stratify risk of progression to type 1 diabetes over time.

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Proinsulin misfolding is an early event in the progression to type 2 diabetes.

Publications

Proinsulin misfolding is an early event in the progression to type 2 diabetes.

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