Glucokinase Activation Repairs Defective Bioenergetics of Islets of Langerhans Isolated From Type 2 Diabetics

Am J Physiol Endocrinol Metab. 2012 Jan 1;302(1):E87-E102. doi: 10.1152/ajpendo.00218.2011. Epub 2011 Sep 27.

Abstract

It was reported previously that isolated human islets from individuals with type 2 diabetes mellitus (T2DM) show reduced glucose-stimulated insulin release. To assess the possibility that impaired bioenergetics may contribute to this defect, glucose-stimulated respiration (Vo(2)), glucose usage and oxidation, intracellular Ca(2+), and insulin secretion (IS) were measured in pancreatic islets isolated from three healthy and three type 2 diabetic organ donors. Isolated mouse and rat islets were studied for comparison. Islets were exposed to a "staircase" glucose stimulus, whereas IR and Vo(2) were measured. Vo(2) of human islets from normals and diabetics increased sigmoidally from equal baselines of 0.25 nmol/100 islets/min as a function of glucose concentration. Maximal Vo(2) of normal islets at 24 mM glucose was 0.40 ± 0.02 nmol·min(-1)·100 islets(-1), and the glucose S(0.5) was 4.39 ± 0.10 mM. The glucose stimulation of respiration of islets from diabetics was lower, V(max) of 0.32 ± 0.01 nmol·min(-1)·100 islets(-1), and the S(0.5) shifted to 5.43 ± 0.13 mM. Glucose-stimulated IS and the rise of intracellular Ca(2+) were also reduced in diabetic islets. A clinically effective glucokinase activator normalized the defective Vo(2), IR, and free calcium responses during glucose stimulation in islets from type 2 diabetics. The body of data shows that there is a clear relationship between the pancreatic islet energy (ATP) production rate and IS. This relationship was similar for normal human, mouse, and rat islets and the data for all species fitted a single sigmoidal curve. The shared threshold rate for IS was ∼13 pmol·min(-1)·islet(-1). Exendin-4, a GLP-1 analog, shifted the ATP production-IS curve to the left and greatly potentiated IS with an ATP production rate threshold of ∼10 pmol·min(-1)·islet(-1). Our data suggest that impaired β-cell bioenergetics resulting in greatly reduced ATP production is critical in the molecular pathogenesis of type 2 diabetes mellitus.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Adult
  • Animals
  • Benzeneacetamides / pharmacology*
  • Calcium Signaling / drug effects
  • Cell Respiration / drug effects
  • Diabetes Mellitus, Type 2 / drug therapy
  • Diabetes Mellitus, Type 2 / metabolism*
  • Enzyme Activators / pharmacology*
  • Exenatide
  • Female
  • Glucagon-Like Peptide 1 / analogs & derivatives
  • Glucokinase / chemistry
  • Glucokinase / metabolism*
  • Glucose / metabolism*
  • Glycolysis / drug effects
  • Humans
  • Hypoglycemic Agents / pharmacology
  • Insulin / metabolism*
  • Insulin Secretion
  • Islets of Langerhans / drug effects*
  • Islets of Langerhans / metabolism
  • Male
  • Mice
  • Middle Aged
  • Oxidative Phosphorylation / drug effects
  • Peptides / pharmacology
  • Rats
  • Species Specificity
  • Tissue Culture Techniques
  • Venoms / pharmacology

Substances

  • Benzeneacetamides
  • Enzyme Activators
  • Hypoglycemic Agents
  • Insulin
  • Peptides
  • Venoms
  • Glucagon-Like Peptide 1
  • Exenatide
  • piragliatin
  • Glucokinase
  • Glucose