Abstract
Aims: While pharmacological glucagon-like peptide-1 receptor (GLP-1R) agonists are FDA-approved for treating type 2 diabetes mellitus (T2DM) and obesity, a major side effect is nausea/malaise. We recently developed a conjugate of vitamin B12 (B12) bound to the GLP-1R agonist exendin-4 (Ex4), which displays enhanced proteolytic stability and retention of GLP-1R agonism. Here, we evaluate whether the conjugate (B12-Ex4) can improve glucose tolerance without producing anorexia and malaise. Materials and methods: We evaluated the effects of systemic B12-Ex4 and unconjugated Ex4 on food intake and body weight change, oral glucose tolerance and nausea/malaise in male rats, and on intraperitoneal glucose tolerance in mice. To evaluate whether differences in the profile of effects of B12-Ex4 vs unconjugated Ex4 are the result of altered CNS penetrance, rats received systemic injections of fluorescein-Ex4 (Flex), Cy5-B12 or Cy5-B12-Ex4 and brain penetrance was evaluated using confocal microscopy. Uptake of systemically administered Cy5-B12-Ex4 in insulin-containing pancreatic beta cells was also examined. Results: B12-Ex4 conjugate improves glucose tolerance, but does not elicit the malaise and anorexia produced by unconjugated Ex4. While Flex robustly penetrates into the brain (dorsal vagal complex, paraventricular hypothalamus), Cy5-B12 and Cy5-B12-Ex4 fluorescence were not observed centrally, supporting an absence of CNS penetrance, in line with observed reduction in CNS-associated Ex4 side effects. Cy5-B12-Ex4 colocalizes with insulin in the pancreas, suggesting direct pancreatic action as a potential mechanism underlying the hypoglycaemic effects of B12-Ex4. Conclusion: These novel findings highlight the potential clinical utility of B12-Ex4 conjugates as possible future T2DM therapeutics with reduced incidence of adverse effects.
| Original language | English (US) |
|---|---|
| Journal | Diabetes, Obesity and Metabolism |
| DOIs | |
| State | Accepted/In press - Jan 1 2018 |
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Keywords
- Antidiabetic drug
- Appetite control
- Drug development
- Exenatide
ASJC Scopus subject areas
- Internal Medicine
- Endocrinology, Diabetes and Metabolism
- Endocrinology
Cite this
A vitamin B12 conjugate of exendin-4 improves glucose tolerance without associated nausea or hypophagia in rodents. / Mietlicki-Baase, Elizabeth G.; Liberini, Claudia G.; Workinger, Jayme L.; Bonaccorso, Ron L.; Borner, Tito; Reiner, David J.; Koch-Laskowski, Kieran; Mcgrath, Lauren E.; Lhamo, Rinzin; Stein, Lauren M.; De Jonghe, Bart C.; Holz, George G.; Roth, Christian L.; Doyle, Robert Patrick; Hayes, Matthew R.
In: Diabetes, Obesity and Metabolism, 01.01.2018.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - A vitamin B12 conjugate of exendin-4 improves glucose tolerance without associated nausea or hypophagia in rodents
AU - Mietlicki-Baase, Elizabeth G.
AU - Liberini, Claudia G.
AU - Workinger, Jayme L.
AU - Bonaccorso, Ron L.
AU - Borner, Tito
AU - Reiner, David J.
AU - Koch-Laskowski, Kieran
AU - Mcgrath, Lauren E.
AU - Lhamo, Rinzin
AU - Stein, Lauren M.
AU - De Jonghe, Bart C.
AU - Holz, George G.
AU - Roth, Christian L.
AU - Doyle, Robert Patrick
AU - Hayes, Matthew R.
PY - 2018/1/1
Y1 - 2018/1/1
N2 - Aims: While pharmacological glucagon-like peptide-1 receptor (GLP-1R) agonists are FDA-approved for treating type 2 diabetes mellitus (T2DM) and obesity, a major side effect is nausea/malaise. We recently developed a conjugate of vitamin B12 (B12) bound to the GLP-1R agonist exendin-4 (Ex4), which displays enhanced proteolytic stability and retention of GLP-1R agonism. Here, we evaluate whether the conjugate (B12-Ex4) can improve glucose tolerance without producing anorexia and malaise. Materials and methods: We evaluated the effects of systemic B12-Ex4 and unconjugated Ex4 on food intake and body weight change, oral glucose tolerance and nausea/malaise in male rats, and on intraperitoneal glucose tolerance in mice. To evaluate whether differences in the profile of effects of B12-Ex4 vs unconjugated Ex4 are the result of altered CNS penetrance, rats received systemic injections of fluorescein-Ex4 (Flex), Cy5-B12 or Cy5-B12-Ex4 and brain penetrance was evaluated using confocal microscopy. Uptake of systemically administered Cy5-B12-Ex4 in insulin-containing pancreatic beta cells was also examined. Results: B12-Ex4 conjugate improves glucose tolerance, but does not elicit the malaise and anorexia produced by unconjugated Ex4. While Flex robustly penetrates into the brain (dorsal vagal complex, paraventricular hypothalamus), Cy5-B12 and Cy5-B12-Ex4 fluorescence were not observed centrally, supporting an absence of CNS penetrance, in line with observed reduction in CNS-associated Ex4 side effects. Cy5-B12-Ex4 colocalizes with insulin in the pancreas, suggesting direct pancreatic action as a potential mechanism underlying the hypoglycaemic effects of B12-Ex4. Conclusion: These novel findings highlight the potential clinical utility of B12-Ex4 conjugates as possible future T2DM therapeutics with reduced incidence of adverse effects.
AB - Aims: While pharmacological glucagon-like peptide-1 receptor (GLP-1R) agonists are FDA-approved for treating type 2 diabetes mellitus (T2DM) and obesity, a major side effect is nausea/malaise. We recently developed a conjugate of vitamin B12 (B12) bound to the GLP-1R agonist exendin-4 (Ex4), which displays enhanced proteolytic stability and retention of GLP-1R agonism. Here, we evaluate whether the conjugate (B12-Ex4) can improve glucose tolerance without producing anorexia and malaise. Materials and methods: We evaluated the effects of systemic B12-Ex4 and unconjugated Ex4 on food intake and body weight change, oral glucose tolerance and nausea/malaise in male rats, and on intraperitoneal glucose tolerance in mice. To evaluate whether differences in the profile of effects of B12-Ex4 vs unconjugated Ex4 are the result of altered CNS penetrance, rats received systemic injections of fluorescein-Ex4 (Flex), Cy5-B12 or Cy5-B12-Ex4 and brain penetrance was evaluated using confocal microscopy. Uptake of systemically administered Cy5-B12-Ex4 in insulin-containing pancreatic beta cells was also examined. Results: B12-Ex4 conjugate improves glucose tolerance, but does not elicit the malaise and anorexia produced by unconjugated Ex4. While Flex robustly penetrates into the brain (dorsal vagal complex, paraventricular hypothalamus), Cy5-B12 and Cy5-B12-Ex4 fluorescence were not observed centrally, supporting an absence of CNS penetrance, in line with observed reduction in CNS-associated Ex4 side effects. Cy5-B12-Ex4 colocalizes with insulin in the pancreas, suggesting direct pancreatic action as a potential mechanism underlying the hypoglycaemic effects of B12-Ex4. Conclusion: These novel findings highlight the potential clinical utility of B12-Ex4 conjugates as possible future T2DM therapeutics with reduced incidence of adverse effects.
KW - Antidiabetic drug
KW - Appetite control
KW - Drug development
KW - Exenatide
UR - http://www.scopus.com/inward/record.url?scp=85042172847&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85042172847&partnerID=8YFLogxK
U2 - 10.1111/dom.13222
DO - 10.1111/dom.13222
M3 - Article
C2 - 29327400
AN - SCOPUS:85042172847
JO - Diabetes, Obesity and Metabolism
JF - Diabetes, Obesity and Metabolism
SN - 1462-8902
ER -