Functional and morphological alterations of mitochondria in pancreatic beta cells from type 2 diabetic patients.
OBJECTIVE
Little information is available on the insulin release properties of pancreatic islets isolated from type 2 diabetic subjects. Since mitochondria represent the site where important metabolites that regulate insulin secretion are generated, we studied insulin release as well as mitochondrial function and morphology directly in pancreatic islets isolated from type 2 diabetic patients.


METHODS
Islets were prepared by collagenase digestion and density gradient purification, and insulin secretion in response to glucose and arginine was assessed by the batch incubation method. Adenine nucleotides, mitochondrial membrane potential, the expression of UCP-2, complex I and complex V of the respiratory chain, and nitrotyrosine levels were evaluated and correlated with insulin secretion.


RESULTS
Compared to control islets, diabetic islets showed reduced insulin secretion in response to glucose, and this defect was associated with lower ATP levels, a lower ATP/ADP ratio and impaired hyperpolarization of the mitochondrial membrane. Increased protein expression of UCP-2, complex I and complex V of the respiratory chain, and a higher level of nitrotyrosine were also found in type 2 diabetic islets. Morphology studies showed that control and diabetic beta cells had a similar number of mitochondria; however, mitochondrial density volume was significantly higher in type 2 diabetic beta cells.


CONCLUSIONS
In pancreatic beta cells from type 2 diabetic subjects, the impaired secretory response to glucose is associated with a marked alteration of mitochondrial function and morphology. In particular, UCP-2 expression is increased (probably due to a condition of fuel overload), which leads to lower ATP, decreased ATP/ADP ratio, with consequent reduction of insulin release.
Anello
M
M
Internal Medicine, Department of Internal and Specialistic Medicine, University of Catania, Ospedale Cannizzaro, Catania, Italy.
Lupi
R
R
Spampinato
D
D
Piro
S
S
Masini
M
M
Boggi
U
U
Del Prato
S
S
Rabuazzo
A M
AM
Purrello
F
F
Marchetti
P
P
D000227:Adenine Nucleotides / Q000378:metabolism; D001120:Arginine / Q000494:pharmacology; D002469:Cell Separation; D003924:Diabetes Mellitus, Type 2 / Q000473:pathology*; D005947:Glucose / Q000494:pharmacology; D006801:Humans; D007328:Insulin / Q000378:metabolism; D000078790:Insulin Secretion; D007515:Islets of Langerhans / Q000187:drug effects / Q000378:metabolism / Q000473:pathology*; D008928:Mitochondria / Q000473:pathology*; D012016:Reference Values
D000227:Adenine Nucleotides; D007328:Insulin; D001120:Arginine; D005947:Glucose