Targeting innate immune mediators in type 1 and type 2 diabetes

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Abstract

Type 1 and type 2 diabetes are characterized by chronic inflammation; both diseases involve pancreatic islet inflammation, while systemic low-grade inflammation is a feature of obesity and type 2 diabetes. Long-term activation of the innate immune system impairs insulin secretion and action, and inflammation also contributes to macrovascular and microvascular complications of diabetes. However, despite strong preclinical evidence and proof-of-principle clinical trials demonstrating that targeting inflammatory pathways can prevent cardiovascular disease and other complications in patients with diabetes, there are still no approved treatments for diabetes that target innate immune mediators. Here, we review recent advances in our understanding of the inflammatory pathogenesis of type 1 and type 2 diabetes from a translational angle and point out the critical gaps in knowledge that need to be addressed to guide drug development.

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Fig. 1: Model for targeting IL-1β in islets of patients with type 2 diabetes.
Fig. 2: Transition from innate immune metabolic homeostasis via systemic low-grade inflammation to local disease.
Fig. 3: Pathogenesis of type 2 diabetes and its associated complications.

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The authors contributed equally to all aspects of the article.

Correspondence to Marc Y. Donath.

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Competing interests

M.Y.D. is listed as the inventor on a patent filed in 2003 for the use of an IL-1 receptor antagonist for the treatment of or prophylaxis for type 2 diabetes. C.A.D. and T.M.-P. declare no competing interests.

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Glossary

Glucagon-like peptide 1

(GLP1). An intestinal incretin hormone that induces satiety and potentiates glucose-stimulated insulin secretion on oral feeding.

Sodium–glucose cotransporter 2 (SGLT2) inhibitors

Antidiabetic drugs that lower blood glucose levels by inhibiting renal reuptake of glucose.

Metabolic syndrome

A condition characterized by increased blood pressure, impaired glucose metabolism (prediabetes or type 2 diabetes), excess body weight and abnormal blood levels of lipids (cholesterol and triglycerides). It is associated with increased risk of cardiovascular diseases.

β-cell ‘rest’

Concept implying that inactive β-cells are resistant to metabolic, inflammatory and oxidative stress.

Haemoglobin A1c

(HbA1c). HbA1c (or glycated haemoglobin) level represents the average amount of glucose attached to haemoglobin and reflects the average level of blood glucose over the past 2–3 months.

Canakinumab

A human monoclonal antibody targeting IL-1β.

Homeostatic model assessment

Model assessment of insulin sensitivity and secretion.

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