title: Modulation of β-cell function: a translational journey from the bench to the bedside.
abstract: Both decreased insulin secretion and action contribute to the pathogenesis of type 2 diabetes (T2D) in humans. The insulin receptor and insulin signalling proteins are present in the rodent and human β-cell and modulate cell growth and function. Insulin receptors and insulin signalling proteins in β-cells are critical for compensatory islet growth in response to insulin resistance. Rodents with tissue-specific knockout of the insulin receptor in the β-cell (βIRKO) show reduced first-phase glucose-stimulated insulin secretion (GSIS) and with aging develop glucose intolerance and diabetes, phenotypically similar to the process seen in human T2D. Expression of multiple insulin signalling proteins is reduced in islets of patients with T2D. Insulin potentiates GSIS in isolated human β-cells. Recent studies in humans in vivo show that pre-exposure to insulin increases GSIS, and this effect is diminished in persons with insulin resistance or T2D. β-Cell function correlates to whole-body insulin sensitivity. Together, these findings suggest that pancreatic β-cell dysfunction could be caused by a defect in insulin signalling within β-cell, and β-cell insulin resistance may lead to a loss of β-cell function and/or mass, contributing to the pathophysiology of T2D.
authors.affiliation: Section of Clinical Research, Joslin Diabetes Center, Boston, MA 02215, USA. allison.goldfine@joslin.harvard.edu
authors.forename: A B
authors.initials: AB
authors.lastname: Goldfine
authors.forename: R N
authors.initials: RN
authors.lastname: Kulkarni
mesh_terms: D000818:Animals; D049109:Cell Proliferation; D003924:Diabetes Mellitus, Type 2 / Q000235:genetics / Q000378:metabolism*; D004195:Disease Models, Animal; D015536:Down-Regulation; D006801:Humans; D007328:Insulin / Q000378:metabolism*; D007333:Insulin Resistance / Q000235:genetics; D050417:Insulin-Secreting Cells / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D008817:Mice, Mutant Strains; D011972:Receptor, Insulin / Q000494:pharmacology*; D015398:Signal Transduction / Q000235:genetics
chemical_list: D007328:Insulin; D011972:Receptor, Insulin