Abstract
Type 2 diabetes (T2D) is evolving into a global disease and patients have a systemic low-grade inflammation, yet the role of this inflammation is still not established. One plausible mechanism is enhanced expression and activity of the innate immune system. Therefore, we evaluated the expression and the function of the toll-like receptor 4 (TLR4) on pancreatic β-cells in primary mouse islets and on the murine β-cell line MIN6 in the presence or absence of macrophages. Diabetic islets have 40% fewer TLR4 positive β-cells, but twice the number of TLR4 positive macrophages as compared to healthy islets. Healthy and diabetic islets respond to a TLR4 challenge with enhanced production of cytokines (5–10-fold), while the TLR4 negative β-cell line MIN6 fails to produce cytokines. TLR4 stimulation induces β-cell dysfunction in mouse islets, measured as reduced glucose stimulated insulin secretion. Diabetic macrophages from 4-months old mice have acquired a transient enhanced capacity to produce cytokines when stimulated with LPS. Interestingly, this is lost in 6-months old diabetic mice. TLR4 activation alone does not induce apoptosis in islets or MIN-6 cells. In contrast, macrophages mediate TLR4-dependent cell-contact dependent (3-fold) as well as cell-contact independent (2-fold) apoptosis of both islets and MIN-6 cells. Importantly, diabetic macrophages have a significantly enhanced capacity to induce β-cell apoptosis compared to healthy macrophages. Taken together, the TLR4 responsiveness is elevated in the diabetic islets and mainly mediated by newly recruited macrophages. The TLR4 positive macrophages, in both a cell-contact dependent and independent manner, induce apoptosis of β-cells in a TLR4 dependent fashion and TLR4 activation directly induces β-cell dysfunction. Thus, targeting either the TLR4 pathway or the macrophages provides a novel attractive treatment regime for T2D.
Highlights
The global epidemic of Type 2 diabetes (T2D), tied to the rising obesity rate is considered to be one of the major public health problems of the 21st century and the fifth leading cause of death worldwide [1,2].T2D is characterized by defective insulin secretion from the pancreatic b-cells and diminished insulin sensitivity in peripheral tissues leading to hyperglycemia [2]
We have previously demonstrated two distinct populations of macrophages infiltrating the diabetic islets based on CD68 and F4/80 expression i.e. CD68+F480+ and CD68+F4/802 subsets [18]
A non-significant trend towards reduced frequency of toll-like receptor 4 (TLR4) positive b-cells was observed in diabetic islets (Fig. 1A, B, E)
Summary
T2D is characterized by defective insulin secretion from the pancreatic b-cells and diminished insulin sensitivity in peripheral tissues leading to hyperglycemia [2]. The metabolic overload in these patients triggers a low grade chronic inflammation resulting in a progressive loss of pancreatic b-cells [3]. There is an intimate relationship between the immune and metabolic response systems with overlapping metabolic and inflammatory signaling and sensing pathways. Factors such as lipids and cytokines provide cross-talk between inflammatory and metabolic signaling pathways that contribute to the risk of developing diabetes. Overproduction of IL-1b in adipose tissue is an important feature of obesity and contributes significantly to insulin resistance [4]. In human and animal models, elevated free fatty acid (FFA) levels have been observed in obesity and T2D [4,5] where toll-like receptors (TLRs) are thought to participate in sensing extracellular
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