Therapeutic Approaches for Preserving or Restoring Pancreatic β-Cell Function and Mass

Abstract

The goal for the treatment of patients with diabetes has today shifted from merely reducing glucose concentrations to preventing the natural decline in β-cell function and delay the progression of disease. Pancreatic β-cell dysfunction and decreased β-cell mass are crucial in the development of diabetes. The β-cell defects are the main pathogenesis in patients with type 1 diabetes and are associated with type 2 diabetes as the disease progresses. Recent studies suggest that human pancreatic β-cells have a capacity for increased proliferation according to increased demands for insulin. In humans, β-cell mass has been shown to increase in patients showing insulin-resistance states such as obesity or in pregnancy. This capacity might be useful for identifying new therapeutic strategies to reestablish a functional β-cell mass. In this context, therapeutic approaches designed to increase β-cell mass might prove a significant way to manage diabetes and prevent its progression. This review describes the various β-cell defects that appear in patients with diabetes and outline the mechanisms of β-cell failure. We also review common methods for assessing β-cell function and mass and methodological limitations in vivo. Finally, we discuss the current therapeutic approaches to improve β-cell function and increase β-cell mass.

Keywords: Therapeutic agents; β-Cell function; β-Cell mass.

Fig. 1

Regulation of the pancreatic β-cell mass dynamics.

Fig. 2

Regulation of the pancreatic β-cell by peroxisome proliferator-activated receptor-gamma (PPARγ). RXR, retinoid X receptor; GLP-1R, glucagon-like peptide-1R; PI3K, phosphatidylinositol-3 kinase; IRS, insulin receptor substrate; PDX-1, pancreas duodenum homeobox-1; GLUT2, glucose transporter 2.

Fig. 3

Regulation of the pancreatic β-cell by glucagon-like peptide-1 (GLP-1). GLUT2, glucose transporter 2; K-ATP, ATP-sensitive potassium channel; TCA, tricarboxylic acid; EGFR, epidermal growth factor receptor; VDCC, voltage-dependent calcium channels; PI3K, phosphatidylinositol-3 kinase; IRS, insulin receptor substrate; PKC, protein kinase C; MAPK, mitogen-activated protein kinase; ER, endoplasmic reticulum; cAMP, cyclic adenosine monophosphate; PKA, protein kinase A; AC, adenylate cyclase; Epac, exchange protein activated by cAMP.

Fig. 4

Insulin-induced inactivation of glycogen synthase kinase 3 β (GSK3β). IRS, insulin receptor substrate; PI3K, phosphatidylinositol-3 kinase.

Fig. 5

Regulation of the pancreatic β-cell by G protein-coupled receptor 40 (GPR40). GLUT2, glucose transporter 2; K-ATP, ATP-sensitive potassium channel; TCA, tricarboxylic acid; VDCC, voltage-dependent calcium channels; PLC, phospholipase C; DAG, diacylglycerol; PKC, protein kinase C; IP3, 1,4,5-trisphosphate; PIP2, 4,5-bisphosphate; ER, endoplasmic reticulum; cAMP, cyclic adenosine monophosphate; PKA, protein kinase A; Epac, exchange protein activated by cAMP; AC, adenylate cyclase; GLP-1, glucagon-like peptide-1.