Alpha-cells and therapy of diabetes: Inhibition, antagonism or death?
Peptides
; 157: 170877, 2022 11.
Article
in En
| MEDLINE
| ID: mdl-36108978
ABSTRACT
Absolute or relative hyperglucagonaemia is a characteristic of both Type 1 and Type 2 diabetes, resulting in fasting hyperglycaemia due in part to increased hepatic glucose production and lack of postprandial suppression of circulating glucagon concentrations. Consequently, therapeutics that target glucagon secretion or biological action may be effective antidiabetic agents. In this regard, specific glucagon receptor (GCGR) antagonists have been developed that exhibit impressive glucose-lowering actions, but unfortunately may cause off-target adverse effects in humans. Further to this, several currently approved antidiabetic agents, including GLP-1 mimetics, DPP-4 inhibitors, metformin, sulphonylureas and pramlintide likely exert part of their glucose homeostatic actions through direct or indirect inhibition of GCGR signalling. In addition to agents that inhibit the release of glucagon, compounds that enhance the transdifferentiation of glucagon secreting alpha-cells towards an insulin positive beta-cell phenotype could also help curb excess glucagon secretion in diabetes. Use of alpha-cell toxins represents another possible strategy to address hyperglucagonaemia in diabetes. In that respect, research from the 1920 s with diguanides such as synthalin A demonstrated effective glucose-lowering with alpha-cell ablation in both animal models and humans with diabetes. However, further clinical use of synthalin A was curtailed due its adverse effects and the increased availability of insulin. Overall, these observations with therapeutics that directly target alpha-cells, or GCGR signaling, highlight a largely untapped potential for diabetes therapy that merits further detailed consideration.
Key words
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
Diabetes Mellitus, Type 2
/
Dipeptidyl-Peptidase IV Inhibitors
/
Metformin
Type of study:
Prognostic_studies
Limits:
Animals
/
Humans
Language:
En
Journal:
Peptides
Year:
2022
Document type:
Article
Affiliation country:
Reino Unido