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
View: Text | PDF
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

×

Figure 6

Correlation between expression of selected proteins and metabolic features of individuals with NGT versus those with IGT in vivo.

Options: View larger image (or click on image) Download as PowerPoint
Correlation between expression of selected proteins and metabolic featur...
In A, glucose tolerance is inversely correlated to expression of proteins involved in glycolysis (G3P); in B, insulin resistance (measured as M value during a hyperinsulinemic euglycemic clamp) is directly correlated to expression of proteins regulating insulin secretion upon glucose stimulus (CREB1); in C, insulin resistance (express as M value during a hyperinsulinemic euglycemic clamp) is inversely correlated to the expression of proteins involved in GLP-1–induced insulin production (IQGA1); in D, β cell glucose sensitivity is directly correlated to a protein involved in glucose homeostasis in response to insulin stimulus (14-3-3T); and in E, glucose sensitivity is inversely correlated to the expression of a protein increasing endocrine precursors differentiation (SEL1L) and directly correlated to a protein with reducing apoptosis function (PAK2). AUC glycemia, area under the curve of glucose.