Proteomic analyses of human islets reveal potential markers of β cell dysfunction during prediabetes
Chiara Maria Assunta Cefalo, Teresa Mezza, Giuseppe Quero, Sergio Alfieri, Donatella Lucchetti, Filomena Colella, Alessandro Sgambato, Wei-Jun Qian, Andrea Mari, Alfredo Pontecorvi, Andrea Giaccari, Rohit N. Kulkarni
Chiara Maria Assunta Cefalo, Teresa Mezza, Giuseppe Quero, Sergio Alfieri, Donatella Lucchetti, Filomena Colella, Alessandro Sgambato, Wei-Jun Qian, Andrea Mari, Alfredo Pontecorvi, Andrea Giaccari, Rohit N. Kulkarni
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Research Article Endocrinology Metabolism

Proteomic analyses of human islets reveal potential markers of β cell dysfunction during prediabetes

Abstract

The mechanisms driving progressive β cell dysfunction in type 2 diabetes remain incompletely understood. This study aimed to identify pancreatic islet proteome changes that could predict diabetes onset. We isolated islets from individuals without diabetes undergoing partial pancreatectomy, previously characterized for glucose tolerance, insulin sensitivity, and insulin secretion, using laser capture microdissection, and analyzed them via high-performance liquid chromatography–mass spectrometry. Proteomic analysis revealed that individuals with impaired glucose tolerance (IGT) had reductions in proteins regulating glycolysis (PGK1, G3P), lipid metabolism (ACBP, ARF1), glucose transport (14-3-3B), and insulin secretion (STARD10, CAPDS) compared with normal glucose-tolerant (NGT) individuals. Additionally, IGT islets showed impaired expression of proteins involved in glucose- and incretin-stimulated insulin response (CREB1, IQGA1). Stratification by β cell glucose sensitivity (βGS) indicated that individuals with lower βGS exhibited reduced levels of insulin maturation (ERO1B) and antiapoptotic proteins (CASP8, PAK2, SKP1), along with increased SEL1L, a factor promoting endocrine precursor differentiation. These findings suggest that early defects in glucose metabolism and insulin secretion characterize IGT, while reduced βGS may trigger compensatory mechanisms, through enhanced β cell survival or neogenesis, to delay type 2 diabetes progression. Overall, proteomic alterations in prediabetic islets provide potential early predictive markers and targets for interventions aimed at preserving β cell function.

Authors

Chiara Maria Assunta Cefalo, Teresa Mezza, Giuseppe Quero, Sergio Alfieri, Donatella Lucchetti, Filomena Colella, Alessandro Sgambato, Wei-Jun Qian, Andrea Mari, Alfredo Pontecorvi, Andrea Giaccari, Rohit N. Kulkarni

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Figure 1

Gene ontology enrichment for differential genes between NGT islets and IGT islets.

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Gene ontology enrichment for differential genes between NGT islets and I...
Categories were determined based on information provided by the online PANTHER classification system resource (https://pantherdb.org/validateHuman.jsp). All proteins were grouped based on biological process (A); molecular function (B); and pathways analysis (C). Data are expressed as the number of genes coding for the proteins identified in each group. NGT islets are represented as black bars, and IGT islets are represented as gray bars. In C, the underlying pathways represent those not expressed in IGT islets compared with NGT islets. NGT, normal glucose tolerant profile; IGT, impaired glucose tolerant profile.