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 5

Differentially expressed proteins in the LOW-βGS group compared with HIGH-βGS group.

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Differentially expressed proteins in the LOW-βGS group compared with HIG...
Proteins involved in the major detected molecular pathway are grouped according to their function: apoptosis and proliferation (A) or insulin secretion and release (B). Islets of participants with LOW-βGS show increased levels of proteins involved cell proliferation (CKAP4) and transdifferentiation from endocrine precursors (SEL1L) compared with islets of participants with HIGH-βGS; however islets of individuals with LOW-βGS show reduced levels of proteins involved in apoptosis (SKP1), insulin maturation (ERO1B), and cell response to glucose stimuli (CREB1). The LOW-βGS group is represented as blue boxes, and the HIGH-βGS group is represented as yellow boxes. *P = interaction between HIGH-βGS vs. LOW-βGS. **P < 0.01, ***P < 0.001. βGS, β cell glucose sensitivity.