In:
American Journal of Physiology-Endocrinology and Metabolism, American Physiological Society, Vol. 302, No. 1 ( 2012-01-01), p. E87-E102
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 (V̇o 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 V̇o 2 were measured. V̇o 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 V̇o 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 V̇o 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.
Type of Medium:
Online Resource
ISSN:
0193-1849
,
1522-1555
DOI:
10.1152/ajpendo.00218.2011
Language:
English
Publisher:
American Physiological Society
Publication Date:
2012
detail.hit.zdb_id:
1477331-4
SSG:
12
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