Ultra-stable insulin-glucagon fusion protein exploits an endogenous hepatic switch to mitigate hypoglycemic risk.
Nicolás VarasRachel GrabowskiMark A JarosinskiNingwen TaiRaimund I HerzogFaramarz Ismail-BeigiYanwu YangAlan D CherringtonMichael A WeissPublished in: bioRxiv : the preprint server for biology (2024)
The therapeutic goal of insulin replacement therapy in diabetes is normalization of blood-glucose concentration, which prevents or delays long-term complications. A critical barrier is posed by recurrent hypoglycemic events that results in short- and long-term morbidities. An innovative approach envisions co-injection of glucagon (a counter-regulatory hormone) to exploit a glycemia-dependent hepatic switch in relative hormone responsiveness. To provide an enabling technology, we describe an ultra-stable fusion protein containing insulin- and glucagon moieties. Proof of principle was obtained in rats. A single-chain insulin moiety provides glycemic control whereas a lactam-stabilized glucagon extension mitigates hypoglycemia. This dual-hormone fusion protein promises to provide a basal formulation with reduced risk of hypoglycemia. Resistance to fibrillation may circumvent the cold chain required for global access.
Keyphrases
- glycemic control
- blood glucose
- type diabetes
- replacement therapy
- weight loss
- insulin resistance
- cardiovascular disease
- high resolution
- smoking cessation
- transcription factor
- drug delivery
- adipose tissue
- metabolic syndrome
- risk factors
- skeletal muscle
- multidrug resistant
- radiation therapy
- mass spectrometry
- ultrasound guided