Pancreatic β-cell dysfunction in type 2 diabetes: Implications of inflammation and oxidative stress

Abstract

Insulin resistance and pancreatic β-cell dysfunction are major pathological mechanisms implicated in the development and progression of type 2 diabetes (T2D). Beyond the detrimental effects of insulin resistance, inflammation and oxidative stress have emerged as critical features of T2D that define β-cell dysfunction. Predominant markers of inflammation such as C-reactive protein, tumor necrosis factor alpha, and interleukin-1β are consistently associated with β-cell failure in preclinical models and in people with T2D. Similarly, important markers of oxidative stress, such as increased reactive oxygen species and depleted intracellular antioxidants, are consistent with pancreatic β-cell damage in conditions of T2D. Such effects illustrate a pathological relationship between an abnormal inflammatory response and generation of oxidative stress during the progression of T2D. The current review explores preclinical and clinical research on the patho-logical implications of inflammation and oxidative stress during the development of β-cell dysfunction in T2D. Moreover, important molecular mechanisms and relevant biomarkers involved in this process are discussed to divulge a pathological link between inflammation and oxidative stress during β-cell failure in T2D. Underpinning the clinical relevance of the review, a systematic analysis of evidence from randomized controlled trials is covered, on the potential therapeutic effects of some commonly used antidiabetic agents in modulating inflammatory makers to improve β-cell function.

Keywords: Inflammation; Insulin resistance; Oxidative stress; Type 2 diabetes; β-cell dysfunction.

Figure 1

An overview of the pathological implications of adipose tissue hypertrophy and insulin resistance during the development and progressive loss of β-cell function in conditions of obesity to type 2 diabetes. Briefly, adipose tissue expansion (usually seen in obesity or type 2 diabetes) is associated with enhanced secretion of pro-inflammatory markers and generation of oxidative stress that directly or indirectly cause pancreatic β-cell loss, leading to impaired insulin secretion. CRP: C-reactive protein; TNF-α: Tumor necrosis factor-alpha; IL: Interleukin; FFAs: Free fatty acids.

Figure 2

An overview of the pathological mechanisms linking impaired immune function and inflammation during β-cell dysfunction in conditions of type 2 diabetes (characterized by hyperglycemia and hyperlipidemia). Briefly, CD4+ T cells can be activated by interleukin-12 produced from macrophages and dendritic cells, and this consequence occurs as part of a vicious process involving cytotoxic T cells and recruitment by the pancreatic islets. Notably, elevated levels of tumor necrosis factor-alpha are linked with activation of pro-inflammatory signals such as Janus kinase/signal transducer and activator of transcription that promote β-cell failure. IL-12: Interleukin-12; TNF-α: Tumor necrosis factor-alpha; INFs: Interferons; IAPP: Islet amyloid polypeptide; ROS: Reactive oxygen species; ER stress: Endoplasmic reticulum stress; JAK/STAT: Janus kinase/signal transducer and activator of transcription.

Figure 3

An overview of some pathophysiological mechanisms that highlight the interrelated link between inflammation and oxidative stress during β-cell dysfunction in type 2 diabetes. Briefly, elevated levels of glucose (hyperglycemia) and lipids (hyperlipidemia) are consistent with an abnormal inflammatory response (due to increased levels of tumor necrosis factor-alpha, interferon-gamma, and interleukin 1 beta) and impaired mitochondrial electron transport chain that causes enhanced generation of reactive oxygen species implicated in β-cell dysfunction. Both inflammation and oxidative stress are responsible for activating cellular destructive mechanisms such as the c-Jun N-terminal kinase pathway and suppressing intracellular antioxidant responses (e.g., nuclear factor erythroid 2-related factor 2, catalase, superoxide dismutase and others), leading to accelerated β-cell injury. ROS: Reactive oxygen species; SOD: Superoxide dismutase; CAT: Catalase; Gpx: Glutathione peroxidase; NQO1: NAD(P)H quinone dehydrogenase 1; NAD(H): Nicotinamide adenine dinucleotide; FADH: Flavin adenine dinucleotide; Nrf2: Nuclear factor erythroid 2-related factor 2; JNK: c-Jun N-terminal kinase; PDX-1: Pancreatic duodenal homeobox 1; ARE: Antioxidant response element; TNF-α: Tumor necrosis factor-alpha; IL-1β: Interleukin 1 beta; INF-γ: Interferon-gamma; ADP: Adenosine diphosphate; ATP: Adenosine triphosphate; ROS: Reactive oxygen species; T2D: Type 2 diabetes; FFAs: Free fatty acids.