Glucose transporter inhibitor-conjugated insulin mitigates hypoglycemia.
Proc Natl Acad Sci U S A
; 116(22): 10744-10748, 2019 05 28.
Article
in En
| MEDLINE
| ID: mdl-31097579
ABSTRACT
Insulin therapy in the setting of type 1 and advanced type 2 diabetes is complicated by increased risk of hypoglycemia. This potentially fatal complication could be mitigated by a glucose-responsive insulin analog. We report an insulin-facilitated glucose transporter (Glut) inhibitor conjugate, in which the insulin molecule is rendered glucose-responsive via conjugation to an inhibitor of Glut. The binding affinity of this insulin analog to endogenous Glut is modulated by plasma and tissue glucose levels. In hyperglycemic conditions (e.g., uncontrolled diabetes or the postprandial state), the in situ-generated insulin analog-Glut complex is driven to dissociate, freeing the insulin analog and glucose-accessible Glut to restore normoglycemia. Upon overdose, enhanced binding of insulin analog to Glut suppresses the glucose transport activity of Glut to attenuate further uptake of glucose. We demonstrate the ability of this insulin conjugate to regulate blood glucose levels within a normal range while mitigating the risk of hypoglycemia in a type 1 diabetic mouse model.
Key words
Full text:
1
Database:
MEDLINE
Main subject:
Blood Glucose
/
Glucose Transport Proteins, Facilitative
/
Hypoglycemia
/
Hypoglycemic Agents
/
Insulin
Limits:
Animals
Language:
En
Journal:
Proc Natl Acad Sci U S A
Year:
2019
Type:
Article