IL-1 antagonism reduces hyperglycemia and tissue inflammation in the type 2 diabetic GK rat.
Recent studies suggest an inflammatory process, characterized by local cytokine/chemokine production and immune cell infiltration, regulates islet dysfunction and insulin resistance in type 2 diabetes. However, the factor initiating this inflammatory response is not known. Here, we characterized tissue inflammation in the type 2 diabetic GK rat with a focus on the pancreatic islet and investigated a role for IL-1. GK rat islets, previously characterized by increased macrophage infiltration, displayed increased expression of several inflammatory markers including IL-1beta. In the periphery, increased expression of IL-1beta was observed primarily in the liver. Specific blockade of IL-1 activity by the IL-1 receptor antagonist (IL-1Ra) reduced the release of inflammatory cytokines/chemokines from GK islets in vitro and from mouse islets exposed to metabolic stress. Islets from mice deficient in IL-1beta or MyD88 challenged with glucose and palmitate in vitro also produced significantly less IL-6 and chemokines. In vivo, treatment of GK rats with IL-1Ra decreased hyperglycemia, reduced the proinsulin/insulin ratio, and improved insulin sensitivity. In addition, islet-derived proinflammatory cytokines/chemokines (IL-1beta, IL-6, TNFalpha, KC, MCP-1, and MIP-1alpha) and islet CD68(+), MHC II(+), and CD53(+) immune cell infiltration were reduced by IL-1Ra treatment. Treated GK rats also exhibited fewer markers of inflammation in the liver. We conclude that elevated islet IL-1beta activity in the GK rat promotes cytokine and chemokine expression, leading to the recruitment of innate immune cells. Rather than being directly cytotoxic, IL-1beta may drive tissue inflammation that impacts on both beta cell functional mass and insulin sensitivity in type 2 diabetes.
Ehses
J A
JA
Division of Endocrinology, Diabetes, and Nutrition and Center for Integrated Human Physiology, University Hospital of Zurich, 8045 Zurich, Switzerland. jan.ehses@usz.ch
Lacraz
G
G
Giroix
M-H
MH
Schmidlin
F
F
Coulaud
J
J
Kassis
N
N
Irminger
J-C
JC
Kergoat
M
M
Portha
B
B
Homo-Delarche
F
F
Donath
M Y
MY
D000818:Animals; D015703:Antigens, CD / Q000096:biosynthesis; D015214:Antigens, Differentiation, Myelomonocytic / Q000096:biosynthesis; D000945:Antigens, Differentiation, T-Lymphocyte / Q000096:biosynthesis; D003921:Diabetes Mellitus, Experimental / Q000378:metabolism*; D003924:Diabetes Mellitus, Type 2 / Q000378:metabolism*; D006943:Hyperglycemia / Q000473:pathology*; D007249:Inflammation / Q000473:pathology*; D053590:Interleukin 1 Receptor Antagonist Protein / Q000378:metabolism; D007375:Interleukin-1 / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D053583:Interleukin-1beta / Q000378:metabolism; D015850:Interleukin-6 / Q000378:metabolism; D007515:Islets of Langerhans / Q000378:metabolism*; D008264:Macrophages / Q000378:metabolism; D051379:Mice; D053594:Myeloid Differentiation Factor 88 / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D060265:Tetraspanin 25; D000097382:CD68 Molecule
D015703:Antigens, CD; D015214:Antigens, Differentiation, Myelomonocytic; D000945:Antigens, Differentiation, T-Lymphocyte; D053590:Interleukin 1 Receptor Antagonist Protein; D007375:Interleukin-1; D053583:Interleukin-1beta; D015850:Interleukin-6; D053594:Myeloid Differentiation Factor 88; D060265:Tetraspanin 25; C554894:CD53 protein, human; C067980:CD68 antigen, human; D000097382:CD68 Molecule; C554895:Cd53 protein, mouse; C554896:Cd53 protein, rat; C507780:Myd88 protein, mouse