Macrophages play a dynamic role in tissue repair following injury. Here we found that following streptozotocin (STZ)-induced beta-cell death, mouse islet macrophages had increased Igf1 expression, decreased proinflammatory cytokine expression, and transcriptome changes consistent with macrophages undergoing efferocytosis and having an enhanced state of metabolism. Macrophages were the major, if not sole, contributors to islet insulin-like growth factor-1 (IGF-1) production. Adoptive transfer experiments showed that macrophages can maintain insulin secretion in vivo following beta-cell death with no effects on islet cell turnover. IGF-1 neutralization during STZ treatment decreased insulin secretion without affecting islet cell apoptosis or proliferation. Interestingly, high-fat diet (HFD) combined with STZ further skewed islet macrophages to a reparative state. Finally, islet macrophages from db/db mice also expressed decreased proinflammatory cytokines and increased Igf1 mRNA. These data have important implications for islet biology and pathology and show that islet macrophages preserve their reparative state following beta-cell death even during HFD feeding and severe hyperglycemia.

No abstract

Dysregulated glucagon secretion accompanies islet inflammation in type 2 diabetes. We recently discovered that interleukin (IL)-6 stimulates glucagon secretion from human and rodent islets. IL-6 family cytokines require the glycoprotein 130 (gp130) receptor to signal. In this study, we elucidated the effects of a-cell gp130 receptor signaling on glycemic control in type 2 diabetes. IL-6 family cytokines were elevated in islets in rodent models of this disease. gp130 receptor activation increased STAT3 phosphorylation in primary a-cells and stimulated glucagon secretion. Pancreatic a-cell gp130 knockout (agp130KO) mice showed no differences in glycemic control, a-cell function, or a-cell mass. However, when subjected to streptozotocin plus high-fat diet to induce islet inflammation and pathophysiology modeling type 2 diabetes, agp130KO mice had reduced fasting glycemia, improved glucose tolerance, reduced fasting insulin, and improved a-cell function. Hyperinsulinemic-euglycemic clamps revealed no differences in insulin sensitivity. We conclude that in a setting of islet inflammation and pathophysiology modeling type 2 diabetes, activation of a-cell gp130 receptor signaling has deleterious effects on a-cell function, promoting hyperglycemia. Antagonism of a-cell gp130 receptor signaling may be useful for the treatment of type 2 diabetes.Islet inflammation (1,2) and pancreatic a-cell dysfunction (3-6) contribute to hyperglycemia in patients with type 2 diabetes. Pancreatic islets from patients with type 2 diabetes are infiltrated with macrophages (7,8), express elevated proinflammatory cytokines (9,10), and express features of fibrosis (11), consistent with reports from animals and primates with this disease (7,(12)(13)(14)(15)(16)(17)(18). The detrimental effects of inflammation on islet b-cell function were recently confirmed, when the interleukin (IL)-1 receptor antagonist reduced hyperglycemia and improved b-cell insulin secretion in patients with type 2 diabetes (1).Pancreatic a-cell dysfunction is detectable in the early stages of type 2 diabetes, where the inverse relationship between pulsatile insulin and glucagon secretion is lost (19). This dysregulation is associated with relative hyperglucagonemia, which contributes to the development of fasting hyperglycemia associated with frank type 2 diabetes (6). Indeed, inhibition of glucagon action by various means reduces hyperglycemia in rodent models of this disease (5,6).