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 3

SEL1L expression in pancreatic samples from NGT and IGT individuals.

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SEL1L expression in pancreatic samples from NGT and IGT individuals. Rep...
Representative immunofluorescence images of pancreatic section from 1 individual with NGT (A–D) and 1 with IGT (E–H), stained for nuclei DAPI in blue (A–H), insulin in green (A–E), SEL1L in red (B–F), and glucagon in magenta (C–G). Merged images show the localization of SEL1L in relation to insulin- and glucagon+ cells in individuals with NGT (D) and IGT (H), respectively. SEL1L immunoreactivity appears higher in IGT islets compared with NGT islets. Scale bar: 100 μm. Original magnification, ×40; ×80 (insets). I showed the quantification of total SEL1L+ cells within islets, assessed across entire pancreatic sections (at least 10 islets per section) in individuals with NGT (green box) compared with those with IGT (red box). J showed the quantification of total SEL1L+ cells within exocrine cells, as assessed across entire pancreatic sections in individuals with NGT (green box) compared with those with IGT (red box). Data are expressed as mean ± SEM ***P < 0.01.