C-peptide improves neuropathy in type 1 diabetic BB/Wor-rats.
ABSTRACT The spontaneously diabetic BB/Wor-rat is a close model of human type 1 diabetes and develops diabetic polyneuropathy (DPN) similar to that seen in type 1 patients. Here we examine the therapeutic effects of C-peptide, delivered as continuous infusion or once daily subcutaneous injections on established DPN.
Diabetic rats were treated from four to seven months duration of diabetes with full continuous replacement dose of rat C-peptide via (a) osmopumps (OS), (b) full replacement dose (HSC) or (c) one-third of full replacement dose (LSC) by once daily injections.
Diabetic rats treated with OS showed improvements in motor nerve conduction velocity (p < 0.001), sural nerve myelinated fibre number (p < 0.005), size (p < 0.05), axonal area (p < 0.001), regeneration (p < 0.001) and overall neuropathy score (p < 0.001). The progressive decline in sensory nerve conduction velocity was fully prevented. The frequencies of Wallerian degeneration were decreased (p < 0.005). HSC-treated rats showed prevention of further progression of DPN (p < 0.001), whereas LSC-treated rats showed a milder progression of DPN (p < 0.001) compared to untreated rats as assessed by neuropathy score.
We conclude that (1) C-peptide is effective in the treatment of established DPN, (2) its effect is dose-dependent and (3) replacement by continuous infusion is the most effective administration of C-peptide.
Médecine des Maladies Métaboliques 09/2007; 1(3). DOI:10.1016/S1957-2557(07)92001-5
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ABSTRACT: Connecting Peptide, or C-peptide, is a product of the insulin prohormone, and is released with and in amounts equimolar to those of insulin. While it was once thought that C-peptide was biologically inert and had little biological significance beyond its role in the proper folding of insulin, it is now known that C-peptide binds specifically to the cell membranes of a variety of tissues and initiates specific intracellular signaling cascades that are pertussis toxin-sensitive. Although it is now clear that C-peptide is a biologically active molecule, controversy still remains as to the physiological significance of the peptide. Interestingly, C-peptide appears to reverse the deleterious effects of high glucose in some tissues, including the kidney, the peripheral nerves and the vasculature. C-peptide is thus a potential therapeutic target for the treatment of diabetes-associated long-term complications. This review addresses the possible physiologically relevant roles of C-peptide in both normal and disease states, and discusses the effects of the peptide on sensory nerve, renal, and vascular function. Furthermore, we will highlight the intracellular effects of the peptide and present novel strategies for the determination of the C-peptide receptor(s). Finally, a hypothesis is offered concerning the relationship between C-peptide and the development of microvascular complications of diabetes.AJP Endocrinology and Metabolism 09/2014; 307(11). DOI:10.1152/ajpendo.00130.2014 · 4.09 Impact Factor
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ABSTRACT: This study was undertaken to examine if C-peptide may interact with hexameric insulin and facilitate its disaggregation into the physiologically active monomeric form. Regular insulin (I) or an insulin analogue (IA) were injected subcutaneously (s.c) in rats together with C-peptide (C) or its C-terminal pentapeptide (PP). I or IA and C or PP were administered either as a physical mixture or into two separate s.c. depots. Whole body glucose utilization was evaluated using euglycemic clamp technique. Phosphorylation of Akt/PKB and GSK in liver and skeletal muscle and (86) Rb(+) uptake by L6 cells were measured. S.c. injection of a mixture of I and C or I and PP resulted in a 30 - 55% greater (P < 0.01-0.001) and 15-27% (P < 0.05-0.001) longer stimulation of whole body glucose utilization than after separate injections. Insulin-stimulated phosphorylation of Akt/PKB in liver increased 35% more after injection of I and C in mixture compared to after separate injections. Phosphorylation of GSK3 was augmented by 50% (P < 0.05) following injection of I and C in mixture compared to separate injections. Stimulation of myotubes with pre-mixed I and C (1nM) elicited 20% additional increase in ouabain-sensitive (86) Rb(+) uptake (P < 0.05) in comparison to the effect when I and C were added separately. Subcutaneous co-administration of insulin and C-peptide results in augmented insulin bioactivity at the level of tissue glucose uptake and intracellular signaling and enzyme activation. These effects may be attributed to augmented C-peptide mediated disaggregation of hexameric insulin into its physiologically active monomeric form. This article is protected by copyright. All rights reserved.Diabetes/Metabolism Research and Reviews 02/2014; 30(2). DOI:10.1002/dmrr.2471 · 3.59 Impact Factor