Aims/hypothesis
Although insulin resistance induces compensatory increases in beta cell mass and function to maintain normoglycaemia, it is
not clear whether insulin resistance can precipitate beta cell dysfunction and hyperglycaemia without a pre-existing beta
cell susceptibility. We therefore examined the beta cell phenotype in the MKR mouse, a model in which expression of a dominant-negative
IGF 1 receptor (IGF1R) in skeletal muscle leads to systemic insulin resistance and diabetes.
Materials and methods
Circulating glucose, insulin and glucagon concentrations were measured. Insulin sensitivity, glucose tolerance and insulin
release in vivo were assessed by i.p. insulin and glucose tolerance tests. Beta cell function was assessed via insulin secretion
from isolated islets and the glucose gradient in the perfused pancreas. Beta cell morphology was examined via immunohistochemistry.
MKR mice were fed a high-fat diet containing sucrose (HFSD) to test metabolic capacity and beta cell function.
Results
Insulin-resistant MKR mice developed hyperglycaemia and a loss of insulin responsiveness in vivo. Basal insulin secretion
from the perfused pancreas was elevated, with no response to glucose. Despite the demand on insulin secretion, MKR mice had
increased pancreatic insulin content and beta cell mass mediated through hyperplasia and hypertrophy. The HFSD worsened hyperglycaemia
in MKR mice but, despite increased food intake in these mice, failed to induce the obesity observed in wild-type mice.
Conclusions/interpretation
Our studies demonstrate that insulin resistance of sufficient severity can impair glucose-stimulated insulin secretion, thereby
undermining beta cell compensation and leading to hyperglycaemia. Moreover, because insulin stores were intact, the secretory
defects reflect an early stage of beta cell dysfunction.
Keywords Beta cell compensation - Beta cell dysfunction - Insulin resistance - Insulin secretion
Asghar and Chan contributed equally to this work.
An erratum to this article can be found at
http://dx.doi.org/10.1007/s00125-006-0157-z