Inflammation in obesity, diabetes, and related disorders

Abstract

Obesity leads to chronic, systemic inflammation and can lead to insulin resistance (IR), β-cell dysfunction, and ultimately type 2 diabetes (T2D). This chronic inflammatory state contributes to long-term complications of diabetes, including non-alcoholic fatty liver disease (NAFLD), retinopathy, cardiovascular disease, and nephropathy, and may underlie the association of type 2 diabetes with other conditions such as Alzheimer's disease, polycystic ovarian syndrome, gout, and rheumatoid arthritis. Here, we review the current understanding of the mechanisms underlying inflammation in obesity, T2D, and related disorders. We discuss how chronic tissue inflammation results in IR, impaired insulin secretion, glucose intolerance, and T2D and review the effect of inflammation on diabetic complications and on the relationship between T2D and other pathologies. In this context, we discuss current therapeutic options for the treatment of metabolic disease, advances in the clinic and the potential of immune-modulatory approaches.

Figure 1. Chronic tissue inflammation in obesity.

In normal lean conditions, tissue macrophages in the liver, adipose tissue, pancreatic islets, intestine, and muscle generally display an anti-inflammatory M2-like (blue) polarization state. Obesity induces monocyte recruitment into the tissue and resident macrophage proliferation with a switch toward a more pro-inflammatory M1-like state (red), promoting systemic IR and glucose intolerance. Obesity also causes accumulation of lipid associated macrophages (green; Trem2⁺CD9⁺ LAMs). In the lean liver, Kupffer cells (KCs) represent ^~10% of all cells. Obesity increases the recruitment of monocytes also into the liver, which differentiate into M1-like recruited hepatic macrophages (RHMs). In the progression to non-alcoholic steatohepatitis (NASH), KC genes involved in tissue repair, inflammation, and lipid metabolism, such as Trem2 and CD9, are upregulated.

Figure 2. Exosomes as regulators of intercellular and interorgan crosstalk in metabolism.

The release of exosomes from adipose tissue macrophages (ATMs), hepatocytes and islet β-cells have systemic metabolic effects. Exosomal miRNA (miR)-690 from M2-like ATMs improves insulin sensitivity, while miR-155 from M1-like ATMs can cause insulin resistance. In early stage HFD, hepatocytes secrete exosomes containing miR-3075, which produces beneficial metabolic effects. In contrast, the hepatocyte exosomes in chronically obese mice contain miR-434-5p, which promotes inflammation and insulin resistance. Exosomes from steatotic hepatocytes also contain pathogenic miRs, such as miR-128 and miR-1, that can induce inflammation or cause hepatic stellate cell activation, promoting NASH. β-cells stressed by pro-inflammatory stimuli release exosomes containing miR-21-5p, which can induce apoptosis in neighboring β-cells.

Figure 3. Islet inflammation.

In a normal state, pro-inflammatory cytokines released from macrophages and the anti-inflammatory IL-1 receptor antagonist (IL-1Ra) released from immune- and β-cells keep the IL-1 system balanced. In pre-diabetes, islet function is increased, the number of immune cells increases and the overall inflammatory balance is tilted towards pro-inflammation. A self-amplified prolonged pro-inflammatory milieu and amyloid polypeptide promotes deterioration of β-cell mass and function, eventually leading to type 2 diabetes.

Figure 4. Immunomodulatory targets for the treatment of diabetes and its complications.

Targeting the IL-1 pathway in patients with type 2 diabetes was shown to have beneficial effects on insulin sensitivity and secretion as well as atherosclerosis, heart failure and retinopathy. Future clinical studies building on preclinical work blocking TNF-α, the IL-1 system or other pro-inflammatory mediators may uncover novel routes to counteract type 2 diabetes and its complications.