Role of IL-1beta in type 2 diabetes.
OBJECTIVE
To understand the role of inflammation as the fundamental cause of type 2 diabetes and specifically to examine the contribution of IL-1beta.


RESULTS
Recent studies from animals, in-vitro cultures and clinical trials provide evidence that support a causative role for IL-1beta as the primary agonist in the loss of beta-cell mass in type 2 diabetes. In vitro, IL-1beta-mediated autoinflammatory process results in beta-cell death. The autoinflammation is driven by glucose, free fatty acids, leptin, and IL-1beta itself. Caspase-1 is required for IL-1beta activity and the release of free fatty acids from the adipocyte. An emerging hypothesis gains support from patients with type 2 diabetes in which an imbalance in the amount of IL-1beta agonist activity versus the specific countering by the naturally occurring IL-1 receptor antagonist (IL-1Ra) determines the outcome of islet inflammation. An important confirmation comes from clinical trials. Blockade of IL-1 receptor with anakinra, the recombinant form of IL-1Ra, or neutralizing anti-IL-1beta antibodies, provides proof-of-principle data that reducing IL-1beta activity is sufficient for correcting dysfunctional beta-cell production of insulin in type 2 diabetes, including a possibility that suppression of IL-1beta-mediated inflammation in the microenvironment of the islet allows for regeneration.


CONCLUSIONS
Monotherapy or add-on therapy targeting IL-1beta in type 2 diabetes holds promise for long-term benefits in glycemic control and possibly reducing cardiovascular events.
Dinarello
Charles A
CA
Department of Medicine, University of Colorado, Aurora, Colorado 80045, USA. cdinare333@aol.com
Donath
Marc Y
MY
Mandrup-Poulsen
Thomas
T
D000818:Animals; D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy / Q000209:etiology* / Q000235:genetics / Q000378:metabolism; D006801:Humans; D007249:Inflammation / Q000209:etiology / Q000473:pathology; D053583:Interleukin-1beta / Q000235:genetics / Q000378:metabolism / Q000502:physiology* / Q000627:therapeutic use; D007515:Islets of Langerhans / Q000276:immunology / Q000473:pathology; D008954:Models, Biological
D053583:Interleukin-1beta