Exenatide Is an Effective Antihyperglycaemic Agent in a Mouse Model of Wolfram Syndrome 1

Abstract

Wolfram syndrome 1 is a very rare monogenic disease resulting in a complex of disorders including diabetes mellitus. Up to now, insulin has been used to treat these patients. Some of the monogenic forms of diabetes respond preferentially to sulphonylurea preparations. The aim of the current study was to elucidate whether exenatide, a GLP-1 receptor agonist, and glipizide, a sulphonylurea, are effective in a mouse model of Wolfram syndrome 1. Wolframin-deficient mice were used to test the effect of insulin secretagogues. Wolframin-deficient mice had nearly normal fasting glucose levels but developed hyperglycaemia after glucose challenge. Exenatide in a dose of 10 μg/kg lowered the blood glucose level in both wild-type and wolframin-deficient mice when administered during a nonfasted state and during the intraperitoneal glucose tolerance test. Glipizide (0.6 or 2 mg/kg) was not able to reduce the glucose level in wolframin-deficient animals. In contrast to other groups, wolframin-deficient mice had a lower insulin-to-glucose ratio during the intraperitoneal glucose tolerance test, indicating impaired insulin secretion. Exenatide increased the insulin-to-glucose ratio irrespective of genotype, demonstrating the ability to correct the impaired insulin secretion caused by wolframin deficiency. We conclude that GLP-1 agonists may have potential in the treatment of Wolfram syndrome-related diabetes.

Preventive treatment with liraglutide protects against development of glucose intolerance in a rat model of Wolfram syndrome

“…Increased proinsulin:insulin ratio has been shown in mice lacking functional Wfs1 18 . Improper proinsulin processing may also explain the lack of blood glucose lowering effect of depolarizing medication in Wfs1 deficient mice 8 . As both insulin and C-peptide ELISAs used in current study may also cross-react with proinsulin (according to our inquiry to the manufacturer), the improved glycemic control may also in part result from properly processed insulin after liraglutide treatment.…”

“…An incretin peptide, GLP-1 regulates glucose homeostasis, metabolism, and neural survival directly on tissues expressing GLP-1 receptors and indirectly through neuronal and endocrine pathways 6 , 7 . Acute treatment with the GLP-1 agonist exenatide has shown a promising anti-diabetic effect in Wfs1 knock-out mice 8 . The GLP-1 agonist Exendin-4 was shown to reduce endoplasmic reticulum (ER) stress in cardiac myocytes and prevent a decrease in activity of sarco/endoplasmic reticulum Ca-ATPase-2a (SERCA2a) 9 .…”

Endoplasmic reticulum stress and eIF2α phosphorylation: The Achilles heel of pancreatic β cells

“…In vivo , exenatide attenuates ER stress and β cell apoptosis in Akita mice and improves glucose levels [181] . A recent study showed that exenatide administration reduces glycemia in exon 8 deleted wfs1 −/− mice [182] . While β cell ER stress was not examined in this study, the data suggest that GLP-1 analogs hold promise for the treatment of Wolfram syndrome diabetes.…”

Wolfram Syndrome: A Case Report and Review of Clinical Manifestations, Genetics Pathophysiology, and Potential Therapies

“…In 2006, Yusta et al showed that a glucagon-like peptide-1 receptor (GLP-1R) agonist interfered with the ER unfolded protein response, resulting in decreased apoptotic signalling and increased cell survival ( Figure 1 ) [ 44 , 45 ]. In a mouse model of classical WS, the GLP-1R agonist exenatide effectively treated hyperglycaemia [ 35 ]. Treatment of a patient with WS (type 2) with exenatide was associated with a 70% reduction in daily insulin dose, improved glycaemic control, and a 7-fold increase in maximal insulin secretion [ 46 ].…”

“…It is believed that increased cytoplasmic calcium levels activate the calcium-dependent protease, calpain-2, which promotes cellular apoptosis [ 16 , 34 ]. Potential therapeutic targets include molecules which inhibit calcium efflux from the ER, such as dantrolene, via inhibition of the RyR [ 35 ], and rapamycin and pioglitazone, via inhibition of IP3R [ 34 ]. In neuronal WS models, cytosolic calcium appears to be increased under resting conditions and reduced under stimulated conditions [ 28 ].…”