Omeprazole and PGC-Formulated Heparin Binding Epidermal Growth Factor Normalizes Fasting Blood Glucose and Suppresses Insulitis in Multiple Low Dose Streptozotocin Diabetes Model

Castillo, Gonzalo; Nishimoto-Ashfield, Akiko; Banerjee, Aryamitra; Landolfi, Jennifer A.; Lyubimov, Alexander V.; Bolotin, Elijah M.

doi:10.1007/s11095-013-1112-6

Cited by 6 publications

(4 citation statements)

References 36 publications

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“…The third component of the A+B+C combination, the PPI, omeprazole increases endogenous gastrin levels, which stimulates b-cell regeneration and improves glucose tolerance (59). Here, we investigated the addition of a PPI in form of omeprazole because it was previously reported to improve glycemic control by increasing gastrin levels in the blood and pancreas and has been shown to act as an adjuvant with hypoglycemic drugs (60)(61)(62). Additionally, omeprazole was reported to simultaneously increase insulin secretion by inhibiting the V-ATPase proton pump in b-cell insulin granules (63).…”

Section: Discussionmentioning

confidence: 99%

Triple drug therapy with GABA, sitagliptin, and omeprazole prevents type 1 diabetes onset and promotes its reversal in non-obese diabetic mice

et al. 2022

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Previous studies have reported that dual drug combinations consisting of γ-aminobutyric acid (GABA) together with a dipeptidyl-peptidase-4 inhibitor (DPP-4i), also a DPP-4i with a proton pump inhibitor (PPI), could improve pancreatic β-cell function and ameliorate diabetes in diabetic mice. In this study, we sought to determine if a triple drug combination of GABA, a DPP-4i and a PPI might have superior therapeutic effects compared with double drug therapies in the prevention and reversal of diabetes in the non-obese diabetic (NOD) mouse model of human type 1 diabetes (T1D). In a diabetes prevention arm of the study, the triple drug combination of GABA, a DPP-4i, and a PPI exhibited superior therapeutic effects in preventing the onset of diabetes compared with all the double drug combinations and placebo. Also, the triple drug combination significantly increased circulating C-peptide and serum insulin levels in the mice. In a diabetes reversal arm of the study, the triple drug combination was superior to all of the double drug combinations in reducing hyperglycemia in the mice. In addition, the triple drug combination was the most effective in increasing circulating levels of C-peptide and serum insulin, thereby significantly reducing exogenous insulin needs. The combination of GABA, a DPP-4i and a PPI appears to be a promising and easily scalable therapy for the treatment and prevention of T1D.

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Section: Discussionmentioning

confidence: 99%

Triple drug therapy with GABA, sitagliptin, and omeprazole prevents type 1 diabetes onset and promotes its reversal in non-obese diabetic mice

et al. 2022

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“…In contrast to its effects on β-cell proliferation, acute and extended (24-h) exposure to HB-EGF did not alter insulin secretion or insulin content in rat islets ex vivo. However, positive, antidiabetic effects of HB-EGF on the β-cell were demonstrated in multiple low-dose streptozotocin diabetic mice by which combined treatment of gastrin and HB-EGF led to improved islet function due in part to a reduction in insulitis ( 36 ). Further studies will be required to fully elucidate the pleotropic effects of HB-EGF on pancreatic islets.…”

Section: Discussionmentioning

confidence: 99%

HB-EGF Signaling Is Required for Glucose-Induced Pancreatic β-Cell Proliferation in Rats

et al. 2020

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The molecular mechanisms of β-cell compensation to metabolic stress are poorly understood. We previously observed that nutrient-induced β-cell proliferation in rats is dependent on epidermal growth factor receptor (EGFR) signaling. The aim of this study was to determine the role of the EGFR ligand heparin-binding EGF-like growth factor (HB-EGF) in the β-cell proliferative response to glucose, a β-cell mitogen and key regulator of β-cell mass in response to increased insulin demand. We show that exposure of isolated rat and human islets to HB-EGF stimulates β-cell proliferation. In rat islets, inhibition of EGFR or HB-EGF blocks the proliferative response not only to HB-EGF but also to glucose. Furthermore, knockdown of HB-EGF in rat islets blocks β-cell proliferation in response to glucose ex vivo and in vivo in transplanted glucose-infused rats. Mechanistically, we demonstrate that HB-EGF mRNA levels are increased in β-cells in response to glucose in a carbohydrate-response element–binding protein (ChREBP)–dependent manner. In addition, chromatin immunoprecipitation studies identified ChREBP binding sites in proximity to the HB-EGF gene. Finally, inhibition of Src family kinases, known to be involved in HB-EGF processing, abrogated glucose-induced β-cell proliferation. Our findings identify a novel glucose/HB-EGF/EGFR axis implicated in β-cell compensation to increased metabolic demand.

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“…However, other ERBB ligands could be involved in regulating ERBB activation in db/db mice. Indeed, other ligands, which have been involved in metabolic disorders, can modulate ERBB phosphorylation state 25 , such as NRG4 26 , 27 , betacellulin 28 , 29 , epiregulin 30 or proheparin-binding EGF-like growth factor (HB-EGF) 31 , 32 . As many biological processes can be regulated through ERBB, the functional consequences of the modified ERBB abundance and phosphorylation state in diabetes are difficult to predict.…”

Section: Discussionmentioning

confidence: 99%

Neuregulin 1 improves complex 2-mediated mitochondrial respiration in skeletal muscle of healthy and diabetic mice

Ennequin

Capel

Caillaud

et al. 2017

Sci Rep

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It has been reported that neuregulin1 (NRG1) improves glucose tolerance in healthy and diabetic rodents. In vitro studies also suggest that NRG1 regulates myocyte oxidative capacity. To confirm this observation in vivo, we evaluated the effect on mitochondrial function of an 8-week treatment with NRG1 in db/db diabetic mice and C57BL/6JRJ healthy controls. NRG1 treatment improved complex 2-mediated mitochondrial respiration in the gastrocnemius of both control and diabetic mice and increased mitochondrial complex 2 subunit content by 2-fold. This effect was not associated with an increase in mitochondrial biogenesis markers. Enhanced ERBB4 phosphorylation could mediate NRG1 effects on mitochondrial function through signalling pathways, independently of ERK1/2, AKT or AMPK.

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Omeprazole and PGC-Formulated Heparin Binding Epidermal Growth Factor Normalizes Fasting Blood Glucose and Suppresses Insulitis in Multiple Low Dose Streptozotocin Diabetes Model

Cited by 6 publications

References 36 publications

Triple drug therapy with GABA, sitagliptin, and omeprazole prevents type 1 diabetes onset and promotes its reversal in non-obese diabetic mice

Triple drug therapy with GABA, sitagliptin, and omeprazole prevents type 1 diabetes onset and promotes its reversal in non-obese diabetic mice

HB-EGF Signaling Is Required for Glucose-Induced Pancreatic β-Cell Proliferation in Rats

Neuregulin 1 improves complex 2-mediated mitochondrial respiration in skeletal muscle of healthy and diabetic mice

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