A vitamin B12 conjugate of exendin-4 improves glucose tolerance without associated nausea or hypophagia in rodents

Elizabeth G. Mietlicki-Baase, Claudia G. Liberini, Jayme L. Workinger, Ron L. Bonaccorso, Tito Borner, David J. Reiner, Kieran Koch-Laskowski, Lauren E. Mcgrath, Rinzin Lhamo, Lauren M. Stein, Bart C. De Jonghe, George G. Holz, Christian L. Roth, Robert Patrick Doyle, Matthew R. Hayes

Research output: Contribution to journalArticle

6 Citations (Scopus)

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 languageEnglish (US)
JournalDiabetes, Obesity and Metabolism
DOIs
StateAccepted/In press - Jan 1 2018

Fingerprint

Vitamin B 12
Nausea
Rodentia
Glucose
Penetrance
exenatide
Anorexia
Fluorescein
Type 2 Diabetes Mellitus
Insulin
Body Weight Changes
Brain
Insulin-Secreting Cells
Glucose Tolerance Test
Hypoglycemic Agents
Confocal Microscopy
Hypothalamus
cyanine dye 5
Pancreas

Keywords

  • Antidiabetic drug
  • Appetite control
  • Drug development
  • Exenatide

ASJC Scopus subject areas

  • Internal Medicine
  • Endocrinology, Diabetes and Metabolism
  • Endocrinology

Cite this

Mietlicki-Baase, E. G., Liberini, C. G., Workinger, J. L., Bonaccorso, R. L., Borner, T., Reiner, D. J., ... Hayes, M. R. (Accepted/In press). A vitamin B12 conjugate of exendin-4 improves glucose tolerance without associated nausea or hypophagia in rodents. Diabetes, Obesity and Metabolism. https://doi.org/10.1111/dom.13222

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 journalArticle

Mietlicki-Baase, EG, Liberini, CG, Workinger, JL, Bonaccorso, RL, Borner, T, Reiner, DJ, Koch-Laskowski, K, Mcgrath, LE, Lhamo, R, Stein, LM, De Jonghe, BC, Holz, GG, Roth, CL, Doyle, RP & Hayes, MR 2018, 'A vitamin B12 conjugate of exendin-4 improves glucose tolerance without associated nausea or hypophagia in rodents', Diabetes, Obesity and Metabolism. https://doi.org/10.1111/dom.13222
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. / A vitamin B12 conjugate of exendin-4 improves glucose tolerance without associated nausea or hypophagia in rodents. In: Diabetes, Obesity and Metabolism. 2018.
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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.",
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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.

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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.

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