Abstract
Aims/hypothesisFinding new treatment alternatives for individuals with diabetes with severe insulin resistance is highly desired. To identify novel mechanisms that improve glucose uptake in skeletal muscle, independently from insulin levels and signalling, we have explored the therapeutic potential of a short peptide sequence, RG54, derived from apolipoprotein A-I (ApoA-I).MethodsINS-1E rat clonal beta cells, C2C12 rat muscle myotubes and J774 mouse macrophages were used to study the impact of RG54 peptide on glucose-stimulated insulin secretion, glucose uptake and cholesterol efflux, respectively. GTTs were carried out on diet-induced insulin-resistant and Leprdb diabetic mouse models treated with RG54 peptide, and the impact of RG54 peptide on atherosclerosis was evaluated in Apoe−/− mice. Control mice received ApoA-I protein, liraglutide or NaCl.ResultsThe synthetic RG54 peptide induced glucose uptake in cultured muscle myotubes by a similar amount as insulin, and also primed pancreatic beta cells for improved glucose-stimulated insulin secretion. The findings were verified in diet-induced insulin-resistant and Leprdb diabetic mice, jointly confirming the physiological effect. The RG54 peptide also efficiently catalysed cholesterol efflux from macrophages and prevented the formation of atherosclerotic plaques in Apoe−/− mice.Conclusions/interpretationThe RG54 peptide exhibits good prospects for providing glucose control and reducing the risk of cardiovascular disease in individuals with severe insulin resistance.
Highlights
Diabetes treatment has substantially improved in recent years
RG54 peptide displays high solubility/stability and forms rHDL The peptide RG54 was synthesised with natural amino acids and modified with an acetylation cap on the Nterminus in order to reduce the susceptibility for proteolytic degradation by endoproteases (ESM Fig. 3a)
Solubilisation of multilamellar vesicles (MLV) made from DMPC phospholipids by RG54 peptide, or by recombinant apolipoprotein A-I (ApoA-I) protein as control, was assayed by light scattering (ESM Fig. 4a)
Summary
Diabetes treatment has substantially improved in recent years. Significant numbers of individuals with diabetes still do not meet their treatment goals or experience undesired side effects. None of the major diabetes drugs currently in use addresses the inadequate muscular glucose uptake in individuals with insulin-resistant disease. As about 80% of blood glucose in the postprandial state is disposed in skeletal muscle in healthy individuals [1], a lack of this function results in hyperglycaemia and increased risk of muscle fatigue. Individuals with diabetes are at significantly higher risk of developing chronic complications, including microvascular nephropathy, neuropathy and retinopathy, and macrovascular diabetic foot, as well as cardiovascular disease. (CVD) [2, 3]. Novel treatment alternatives that adequately address several aspects of this complex disease are required
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