Impaired function and reduced mass of pancreatic islet β-cells are two hallmarks of type 2 diabetes (T2D) (1,2). However, clinical onset of T2D does not occur until β-cells fail to secrete sufficient insulin to maintain normoglycemia in the face of insulin resistance (1,2). While studies performed on isolated human islets have identified multiple pathways that may contribute to β-cell failure in T2D, these studies lack the ability to investigate the initial steps that occur in vivo before or at early stages of onset of T2D and the sequence of events that result in β-cell failure in patients with T2D.
Growing evidence from recent studies suggests that chronic islet inflammation, in addition to its key role in the pathogenesis of type 1 diabetes, also plays an important role in β-cell dysfunction and failure in T2D (3–9). Impaired β-cell function precedes the clinical onset of T2D, suggesting an early role for islet inflammation in the process of β-cell failure in this disease. The association between chronic activation of the innate immune system and T2D has long been appreciated (10) but recently has gained high attention due to increasing evidence supporting its importance. The elevated number of islet-associated macrophages and increased expression of interleukin (IL)-1β have been reported in the pancreatic islets from patients with T2D (4,11). Moreover, it was recently demonstrated that depletion of resident islet macrophages in high fat–fed transgenic mice with islet amyloid formation can reduce IL-1β expression, improve β-cell insulin secretion, and restore glucose tolerance (8). Accordingly, animal studies and clinical trials targeting IL-1β signaling have been shown to improve β-cell function and glucose homeostasis in T2D (12–14). Taken together, these findings support the idea that IL-1β is likely a key proinflammatory mediator of β-cell damage in T2D. Thus, identifying the factors that contribute to local generation of IL-1β in the islets of patients with T2D is of great interest.
Increased islet IL-1β levels have been reported following chronic exposure of human islets to elevated glucose, fatty acids, or leptin—three factors that are closely associated with T2D (3,15,16). Moreover, it was recently shown that biosynthetic amyloid formation in human islets causes β-cell dysfunction and death via induction of Fas upregulation and activation of the Fas-mediated apoptotic pathway initiated by caspase-8, which closely correlates with increased islet IL-1β levels (6,9). These studies provided evidence that amyloid-induced Fas upregulation is likely mediated by IL-1β. In line with these findings, Westwell-Roper et al. (8) have reported β-cell dysfunction associated with increased islet IL-1β expression in high fat–fed transgenic mice with islet amyloid formation. These findings support the idea that local IL-1β production, likely induced by multiple factors during prediabetic state and/or early stages of T2D, may play a key role in β-cell failure in T2D. However, other factors that contribute to this process have yet to be identified.
In this issue of Diabetes, Sauter et al. (17) report another interesting mechanism that contributes to islet inflammation and local IL-1β production in patients with T2D. Using in vitro islet studies and a mouse model of T2D, the authors show that the renin-angiotensin system (RAS), a major system in blood pressure regulation, contributes to islet inflammation and β-cell dysfunction independent of its effects on glucose homeostasis mediated via vasoconstriction. The authors demonstrate that ex vivo exposure of human and mouse islets to angiotensin II induces expression of the chemokine MCP-1 and IL-6 (a marker of inflammation), impairs mitochondrial function and insulin secretion, and increases β-cell apoptosis. Using an IL-1 receptor antagonist, the authors further show that angiotensin II–induced IL-6 production in human islets is mediated by IL-1β signaling. It would be interesting to examine if angiotensin II at low (physiological) concentrations has similar or different effects on islet β-cells, such as the dual role of low and high IL-1β levels reported previously (18). Other questions to be addressed in future studies would be what the effects of angiotensin II on islet α-cells are and if the therapeutic strategies that aim to block RAS may potentiate glucagon release in patients.
Pharmacological inhibition of RAS has been reported to improve islet function and glucose tolerance in vivo (19,20). However, it is unclear if this improved glycemic control is a result of the normalization of vasoconstriction in tissues (e.g., muscle and pancreas) or due to the local inhibition of RAS. Sauter et al. (17) show that chronic treatment with angiotensin II in high fat–fed mice that also received the vasodilator hydralazine (to prevent hypertension) caused impaired glucose-stimulated insulin secretion and deteriorated glucose tolerance that was not due to the changes in insulin sensitivity, supporting the direct effects of angiotensin II on β-cell function. Interestingly, neutralizing IL-1β signaling reduced angiotensin II–mediated islet inflammation, restored glucose-stimulated insulin secretion, and improved glucose homeostasis. These findings also provide a mechanism to explain the β-cell protective effects reported for the antihypertensive drugs that target RAS.
The cellular sources of local IL-1β production in islets are still unclear. The findings from Westwell-Roper and colleagues (7,8) demonstrated increased IL-1β expression localized to islet-associated macrophages in high fat–fed, islet amyloid–forming mice, suggesting that macrophages are the major source of IL-1β production in islets. Moreover, the studies by Park and colleagues (6,9) and Maedler et al. (3) suggest that human islet β-cells per se can produce IL-1β in conditions associated with islet stress, such as elevated glucose or islet amyloid formation. Therefore, it appears that both islet macrophages and β-cells may contribute to IL-1β production. Further studies are required to identify the cell types that contribute to local islet IL-1β production in T2D.
In summary, islet inflammation and increased IL-1β levels contribute to loss of β-cell function and mass in T2D. IL-1β production in islets appears to be induced by multiple factors including angiotensin II, glucose, fatty acids, amyloid, and possibly other factors yet to be identified (Fig. 1). Thus, therapeutic strategies that target IL-1β signaling may provide a feasible approach to preserve β-cell function and mass during both prediabetic and diabetic states of T2D as well as in the metabolic syndrome.
See accompanying article, p. .
Article Information
Funding. The research work from the author’s laboratory presented in the manuscript is supported by an operating grant from the Canadian Institutes of Health Research (MOP-126204).
Duality of Interest. No potential conflicts of interest relevant to this article were reported.
