title: Glucokinase activation repairs defective bioenergetics of islets of Langerhans isolated from type 2 diabetics.
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.
authors.affiliation: Department of Biochemistry and Biophysics, University of Pennsylvania, 415 Curie Blvd., Philadelphia, PA 19104-6140, USA.
authors.forename: Nicolai M
authors.initials: NM
authors.lastname: Doliba
authors.forename: Wei
authors.initials: W
authors.lastname: Qin
authors.forename: Habiba
authors.initials: H
authors.lastname: Najafi
authors.forename: Chengyang
authors.initials: C
authors.lastname: Liu
authors.forename: Carol W
authors.initials: CW
authors.lastname: Buettger
authors.forename: Johanna
authors.initials: J
authors.lastname: Sotiris
authors.forename: Heather W
authors.initials: HW
authors.lastname: Collins
authors.forename: Changhong
authors.initials: C
authors.lastname: Li
authors.forename: Charles A
authors.initials: CA
authors.lastname: Stanley
authors.forename: David F
authors.initials: DF
authors.lastname: Wilson
authors.forename: Joseph
authors.initials: J
authors.lastname: Grimsby
authors.forename: Ramakanth
authors.initials: R
authors.lastname: Sarabu
authors.forename: Ali
authors.initials: A
authors.lastname: Naji
authors.forename: Franz M
authors.initials: FM
authors.lastname: Matschinsky
mesh_terms: D000328:Adult; D000818:Animals; D044482:Benzeneacetamides / Q000494:pharmacology*; D020013:Calcium Signaling / Q000187:drug effects; D019069:Cell Respiration / Q000187:drug effects; D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy / Q000378:metabolism*; D020536:Enzyme Activators / Q000494:pharmacology*; D000077270:Exenatide; D005260:Female; D052216:Glucagon-Like Peptide 1 / Q000031:analogs & derivatives; D005941:Glucokinase / Q000737:chemistry / Q000378:metabolism*; D005947:Glucose / Q000378:metabolism*; D006019:Glycolysis / Q000187:drug effects; D006801:Humans; D007004:Hypoglycemic Agents / Q000494:pharmacology; D007328:Insulin / Q000378:metabolism*; D000078790:Insulin Secretion; D007515:Islets of Langerhans / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D051379:Mice; D008875:Middle Aged; D010085:Oxidative Phosphorylation / Q000187:drug effects; D010455:Peptides / Q000494:pharmacology; D051381:Rats; D013045:Species Specificity; D046509:Tissue Culture Techniques; D014688:Venoms / Q000494:pharmacology
chemical_list: D044482:Benzeneacetamides; D020536:Enzyme Activators; D007004:Hypoglycemic Agents; D007328:Insulin; D010455:Peptides; D014688:Venoms; D052216:Glucagon-Like Peptide 1; D000077270:Exenatide; C553963:piragliatin; D005941:Glucokinase; D005947:Glucose