Naturally, most data concerning triggers of inflammation in human islets stem from in vitro cultures of isolated islets from organ donors. As such, exposure of islets to high glucose levels induced FAS expression [
59] and increased production and secretion of IL-1β, while secreted protein levels of other cytokines seemed to be less affected by glucose [
8,
10]. These glucose-induced effects could be mediated directly by acting on immune cells or via glucose-induced upregulation of the islet amyloid system, which is a strong activator of islet inflammation (see below). Saturated fatty acids also have been reported to trigger inflammation in human islets. Co-culture of islets from healthy donors with palmitate induced release of the proinflammatory cytokines IL-6 and IL-8 as well as the chemokine CXCL1 [
9,
12,
34]. Expression of other cytokines such as IL-1β and TNF-α were also increased by co-culture with palmitate [
12]. Oleate and stearate also increased expression levels of cytokines and chemokines [
34], although this was not observed in all studies [
12]. These free fatty acid-induced effects were blocked by adding IL-1Ra or anti-IL-1β antibodies [
34] suggesting that IL-1 signaling is mediating these deleterious effects. Combination of high glucose concentrations and free fatty acids even further stimulated IL-1β expression [
34] and the release of chemokines from human islets [
9], which may recruit additional macrophages to the islet. Further, IL-1β induces its own expression [
10] leading to a vicious cycle and eventually prolonged inflammation. One of the strongest inducers of IL-1β is islet amyloid polypeptide (IAPP, also called amylin), a β-cell-derived hormone that exerts beneficial properties on metabolism, mostly via central induction of satiety. However, under certain conditions, IAPP aggregates and forms toxic plaques (“islet amyloid deposits”). These deposits are found in most individuals with type 2 diabetes [
57,
60,
61] and correlate with β-cell apoptosis [
62] and reduced β-cell mass, a hallmark of type 2 diabetes [
57,
63]. Interestingly, both glucose [
64] and free fatty acids [
23] promote islet amyloidosis in human islets via upregulation of IAPP expression. IAPP and insulin are co-secreted from β-cells [
65,
66] and since insulin secretion is increased in prediabetes to compensate for increased insulin demand [
67], IAPP secretion is increased as well. Among other mechanisms, such as insufficiently processed IAPP that is found in failing human islet grafts [
68], the increased concentration of IAPP might be a trigger for amyloid deposition. Although in vitro work and studies using transgenic animal models have shed light on many aspects of islet amyloidosis (see “
What triggers islet inflammation in rodent models of T2D”), there is currently no therapy available to counteract this contributing factor to loss of β-cell mass in T2D. Further, anti-diabetic drugs that act as insulin secretagogues (like sulfonylurea, GLP-1 agonists, etc.) might partly promote amyloid-induced β-cell apoptosis by increasing β-cell secretion. The specific TLR2 receptor agonist Pam2 induced
IL1b,
IL6, and
IL8 expression in human islets and purified human β cells [
34]. LPS, a TLR4 receptor agonist, also induced cytokines, although to a lesser extent [
34]. TLR receptors are pattern recognition receptors and they are thus not very specific and typically induce an inflammatory response as a reaction to microbial pathogens or lipids, for instance contained in the food. Fatty acids also signal through TLR2 and 4 [
69]. Thus, the abovementioned fatty acid-induced increase in IL-1β expression in human islets might at least partly be mediated by TLR signaling. An additional mechanism of proinflammatory cytokine stimulation in human islets is the renin-angiotensin system. Indeed, exposure of human islets to angiotensin 2 induced gene expression of IL-6 and the chemokine MCP-1. These effects were independent of vasoconstriction but IL-1-dependent [
26]. Endocannabinoids were also shown to have proinflammatory properties in human tissues. Exposure of human macrophages to the endocannabinoid anandamide induced the expression of NLRP3 inflammasome components and the release of IL-1β and IL-18 [
25]. In contrast, exposure of whole human islets to anandamide only slightly induced the expression of proinflammatory factors [
25]. This suggests that endocannabinoids act on islets via CB1r signaling on islet macrophages. Finally, co-culture of human islets with the adipocyte-derived leptin reduced IL-1Ra expression and induced IL-1β release [
32], suggesting that leptin is also able to off shift the balance of IL-1β to IL-1Ra towards a more proinflammatory state.