Osteoprotegerin (OPG) protects pancreatic beta cells from Interleukin-1 induced cell death

Abstract. To investigate the hypothesis that interleukin 1 initially stimulates and then suppresses beta-cell function and that this sequential effect is directly related to interleukin 1 dose, duration of exposure, and ambient glucose concentration, insulin release was measured from cultured newborn rat islets exposed for 6 h to 6 days to interleukin 1 at doses ranging from 20 to 2000 ng/l at glucose concentrations of 3.3, 5.5 and 11 mmol/l. After 6 h of exposure and at all three glucose levels, all doses of interleukin 1 stimulated insulin release, maximal stimulation (370% of control) being observed at 5.5 mmol/l glucose and 100 ng/l interleukin 1. In contrast, after 6 days, all doses of interleukin 1 were inhibitory irrespective of glucose level, maximal inhibition (90%) being observed at 11 mmol/l glucose and 2000 ng/l interleukin 1. At 24 and 48 h of exposure, the biphasic effect of interleukin 1 was observed: lower doses of interleukin 1 at lower glucose concentrations at 24 h being more stimulatory with transition to inhibition directly related to higher glucose levels, higher interleukin 1 doses, and longer exposure. After 48 h, 200 ng/l of interleukin 1 increased insulin release to 220% at 3.3 mmol/l glucose, but at 11 mmol/l glucose a 60% suppression was seen. On the basis of these data we suggest that interleukin l's effect on beta-cells is bimodal: stimulation followed by inhibition. Increasing interleukin 1 dose and ambient glucose concentration shift this response to the left. Experimental results will, and in vivo effects may, depend upon these three variables.

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Commentary: The Effects of Inflammation, Aging, and Oxidative Stress on the Pathogenesis of Type II Diabetes

10.36502/2020/hcr.6169 ◽

2020 ◽

Vol 1 (2) ◽

pp. 119-124

Author(s):

Halim M ◽

Halim A

Keyword(s):

Oxidative Stress ◽

Beta Cells ◽

Type Ii Diabetes ◽

Pancreatic Beta Cells ◽

Interleukin 1 ◽

Pancreatic Beta Cell ◽

Low Grade ◽

Type Ii ◽

Peripheral Tissues ◽

Critical Pathways

Type II Diabetes Mellitus (T2DM) is a high-risk metabolic condition associated with high mortality due to hyperglycemia. Many studies have focused on how inflammation, aging, or oxidative stress influences the pathogenesis of T2DM. The functional anomalies of the pancreatic beta cells attribute to insulin resistance which is the primary cause of T2DM manifestations and complications. This is evidenced in polymorphism in the TNF-α gene which inhibits insulin production, metabolism, and utilization during T2DM development. The dysregulation of insulin signaling involves multiple pathways. Various factors such as epigenetics, oxygen radicals, and glucolipotoxicity are implicated in the pathogenesis. Low-grade inflammation mediated by pro-inflammatory cytokines and chemokines such as interleukin-1 attack peripheral tissues and mediates the activation of critical pathways involved in T2DM pathogenesis via transcriptional factors. The core factor resulting in inflammation is hyperglycemia. The result is the release of inflammatory mediators which then affect neurons in the nervous system and alter microvascular and enzymatic pathways to elicit severe complications such as neuropathy. Oxidative stress and inflammation share an intertwined relationship in the pathogenesis of T2DM. High levels of reactive oxygen species increase the level of DNA damage markers and expose pancreatic beta-cell lines to dysregulation through reduced expression of the insulin gene. The link between the interaction of oxidative stress and inflation in the human body increases the level of interleukin-6 which triggers superoxide radicles and oxidative stressors increase which have been shown to affect free fatty acids metabolism inversely Finally, the aspect of cellular senescence in adipocytes and pancreatic beta cells explain why age is a critical factor in T2DM pathogenesis. Overall, the three factors discussed have a crucial role in T2DM disease states, progressions, and complications.

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