Gevokizumab in type 1 diabetes mellitus: extreme remedies for extreme diseases?

Pafili, Kalliopi; Παπάνας, Νικόλαος; Maltezos, Efstratios

doi:10.1517/13543784.2014.947026

Cited by 12 publications

(9 citation statements)

References 72 publications

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“…The extent of protection provided by IL-1bAb was associated with the duration of the treatment, demonstrating pronounced protection when IL-1bAb was injected every day during the 15 days of HSD feeding and a weaker effect when IL-1bAb was given during only the first 5 days of HSD feeding. As shown in our previous studies (5)(6)(7)11,14,15) and confirmed in the current study, IL1b is the sole proinflammatory cytokine expressed by macrophages infiltrating the pancreas. An expression of other proinflammatory markers such as the chemokine MCP1 or the cytokines IL-2, IL-6, TNF-a, and IFN-g could not be detected in the infiltrating macrophages.…”

Section: Discussionsupporting

confidence: 90%

“…In conclusion, our study supports the concept that inflammation in close vicinity to islets may have a detrimental effect on the ability of b-cells to secret insulin in response to glucose stimulation (14,15). Moreover, it illustrates the complexity of the interrelationships between inflammation, b-cell dysfunction, and diabetes development and supports the notion that preventing pancreatic inflammation is important to preserve b-cell function and avoid diabetes development.…”

Section: Discussionsupporting

confidence: 85%

“…In these studies IL-1bAb treatment improved inflammation, glucose metabolism, and b-cell function (3,9,(17)(18)(19)(20). Thus the cumulative evidence from the literature and our current observations reinforce the important role that IL-1b plays in mediating b-cell toxicity in T2DM (14,15).…”

Section: Discussionsupporting

confidence: 83%

“…Therefore the current observations showing that specific IL-1bAbs are able to fully counteract the deleterious process triggered exclusively by IL-1b provide convincing evidence linking IL-1b toxicity and diabetes development in this animal model. Notably, the IL-1bAb dose selected in our study was comparable with the dose that successfully counteracted the deleterious effects of IL-1b on glucose homeostasis and b-cell function in diabetic patients (14,15). The extent of protection provided by IL-1bAb was associated with the duration of the treatment, demonstrating pronounced protection when IL-1bAb was injected every day during the 15 days of HSD feeding and a weaker effect when IL-1bAb was given during only the first 5 days of HSD feeding.…”

Section: Discussionmentioning

confidence: 75%

“…Normoglycemic CDs rats fed an RD for 15 days and treated with saline were studied as a normoglycemic reference group. In this study we used the dose range of IL-1bAb used in various human studies (13)(14)(15).…”

Section: Methodsmentioning

confidence: 99%

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Antidiabetic Effect of Interleukin-1β Antibody Therapy Through β-Cell Protection in the Cohen Diabetes-Sensitive Rat

et al. 2014

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Interleukin (IL)-1b, the sole proinflammatory cytokine released from pancreas-infiltrating macrophages, inhibits glucose-stimulated insulin secretion (GSIS), causing hyperglycemia in Cohen diabetes-sensitive (CDs) rats fed a diabetogenic-diet (CDs-HSD). Because IL-1b blockade is a potential therapeutic target in diabetes, we examined whether treating CDs rats with IL-1b antibody (IL-1bAb; 0.5 mg/kg body weight) could counteract the inhibition of GSIS and hyperglycemia. We found that daily IL-1bAb injections had a beneficial effect on glucose tolerance and insulin secretion in CDs-HSD rats. In the oral glucose tolerance test, IL-1bAb-treated CDs-HSD rats showed lower blood glucose concentrations (P < 0.001) and higher GSIS (P < 0.05) compared with nontreated CDs-HSD rats. IL-1bAb treatment also protected the exocrine pancreas; the number of infiltrating macrophages decreased by 70% (P < 0.01) and IL-1b expression decreased by 85% (P < 0.01). In parallel, a 50% reduction (P < 0.01) in the rate of apoptosis and in fat infiltration (P < 0.05) was noted in the exocrine parenchyma of IL-1bAb-treated CDs-HSD rats compared with nontreated CDs-HSD rats. Altogether, these data demonstrate that blocking IL-1b action by IL-1bAb counteracted b-cell dysfunction and glucose intolerance, supporting the notion that prevention of pancreas infiltration by macrophages producing IL-1b is of crucial importance for the preservation of b-cell function and prevention of diabetes.Recent studies suggest that interleukin (IL)-1b is an important player in b-cell dysfunction and death in type 1 and type 2 diabetes mellitus (T2DM) (1-7). IL-1b has been shown to reduce glucose-stimulated insulin secretion (GSIS) in isolated islets (4,5). In vivo studies of patients with T2DM and animal models have shown evidence of elevated IL-1b expression in the pancreas, in insulin target tissues, as well as in the circulation (1,3,4,6,7). Moreover, IL-1b antibody (IL-1bAb) treatment has improved glycemic control in animals and humans (3,4,8,9), supporting the notion that efficient targeting of IL-1b with a specific monoclonal antibody may prevent hyperglycemia.The Cohen diabetes-sensitive (CDs) rat is a genetic model of nutritionally induced diabetes that maintains normoglycemia on a regular diet (RD) but develops impaired GSIS and hyperglycemia when fed a high-sucrose, low-copper diet (HSD). In this animal model the development of hyperglycemia is associated with a mild pancreatic inflammation, that is, peri-islet infiltration with fat and macrophages expressing the proinflammatory cytokine 7). In a recent in vitro study we demonstrated that IL-1b modulates GSIS by inhibiting the activity of the islet mitochondrial respiratory chain enzyme cytochrome c-oxidase (COX) (5). In the current study we analyzed the role of IL-1b in b-cell dysfunction by neutralizing IL-1b in vivo and examined whether treating CDs rats with a rat-specific IL-1bAb counteracts GSIS inhibition and hyperglycemia. The CDs rat is a unique animal model for this purpose because IL-1b is t...

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