C‐peptide and Retinal Microangiopathy in Diabetes

Abstract

Increased extracellular matrix (ECM) protein deposition and capillary basement membrane (BM) thickening are characteristic features of diabetic retinal microangiopathy. Recent observations in the authors' laboratories suggest that high glucose in endothelial cells as well as diabetes causes up-regulation of total fibronectin (FN), as well as extradomain-B (EDB) containing the spliced variant of FN, oncofetal FN, in the retina. This splice variant is normally absent in mature adult tissues and is believed to be involved in angiogenesis. In this study, the authors have investigated the role of C-peptide in the production of ECM proteins and capillary BM thickening in the retina of diabetic rats. They investigated retinas from poorly controlled diabetic BB/Wor rats with or without C-peptide treatment as well as those from age-matched nondiabetic control rats after 8 months of diabetes. In addition, the authors investigated retinas from BBDRZ/Wor rats, a model of type 2 diabetes. Following a treatment period of 8 months, retinal tissues were harvested for gene expression and histological analyses. In the retinas of diabetic BB/Wor rats, a significant increase of oncofetal FN was demonstrated compared to control rats. C-peptide treatment of BB/Wor rats completely prevented such increase. Furthermore, retinas from BBDRZ/Wor rats, did not exhibit any such alteration in oncofetal FN expression. The authors further examined retinal capillary BM thickening using ultrastructural morphometry. C-peptide treatment was ineffective in preventing the diabetes-induced increase in capillary BM thickness. The authors' previous studies of cultured endothelial cells demonstrated that oncofetal FN synthesis is, at least in part, mediated via transforming growth factor-β (TGF-β) and endothelin-1 (ET-1). Hence, they examined these two transcripts in the retina of these animals. Diabetes caused significant increase in mRNA expression of ET-1 and TGF-β, which was not prevented by C-peptide treatment. Hence it appears that C-peptide is effective in preventing diabetes-induced oncofetal FN expression and that these effects are not mediated via ET-1 or TGF-β. In conclusion, these data suggest that C-peptide is involved in regulating ECM protein composition. Furthermore, normalization of diabetes-induced oncofetal FN up-regulation may suggest importance of C-peptide in advanced alterations in diabetic retinopathy such as angiogenesis.

Proinsulin C-peptide: Friend or foe in the development of diabetes-associated complications?

“…C-peptide increases eNOS and NO activity (Johansson et al 2003; Tsimaratos et al 2003; Walcher et al 2004; Maezawa et al 2006). In smooth muscle cells (Chakrabarti et al 2004) and aortic endothelial cells (Young et al 2000; Tsimaratos et al 2003), C-peptide has been shown to increase intracellular Ca 2+ , thereby inducing NO production by endothelial NOS (eNOS) and iNOS, causing an NO-dependent vasodilation. In myocardial ischemia-reperfusion, C-peptide has been shown to exert cardioprotective effects through the release of NO (Young et al 2000).…”

“…It has been suggested that C-peptide has effects on angiogenesis (Chakrabarti et al 2004). There are indications that diabetes induces the up-regulation of oncofetal fibronectin in the retina (Khan et al 2004), a substance believed to be involved in angiogenesis and normally not found in mature tissue (Castellani et al 1994; Karelina and Eisen 1998).…”

“…There are indications that diabetes induces the up-regulation of oncofetal fibronectin in the retina (Khan et al 2004), a substance believed to be involved in angiogenesis and normally not found in mature tissue (Castellani et al 1994; Karelina and Eisen 1998). Increased retinal expression of oncofetal fibronectin in diabetic rats is completely prevented by C-peptide treatment (Chakrabarti et al 2004). This normalization of the diabetes-induced up-regulation of oncofetal fibronectin in diabetic retinas, may suggest an important role of C-peptide for the development of microangiopathy.…”

Early transcriptional regulation by C‐peptide in freshly isolated rat proximal tubular cells

“…Hence, when insulin production is impaired as in type 1 diabetes, C‐peptide secretion is also affected. With time, type 1 diabetic patients develop complications including atherosclerosis, nephropathy, retinopathy, and neuropathy 1–5. Administration of exogenous C‐peptide to type 1 diabetic patients has been shown to exert beneficial effects in many tissues affected by microvascular complications 6.…”

Renal and vascular benefits of C-peptide: Molecular mechanisms of C-peptide action

“…When, as in type 1 diabetes and late type 2 diabetes, insulin synthesis is impaired, synthesis of C-peptide is similarly impaired. Exogenous C-peptide has been shown to improve the function of many tissues commonly affected by diabetes complications (Lindstrom et al 1996; Johansson et al 2000; Chakrabarti et al 2004; Sima and Li 2006), a development supported by the fact that pancreatic and islet of Langerhans transplantation, restoring not only insulin secretion, but also secretion of C-peptide, will prevent and even reverse diabetic complications (Fiorina et al 2003a, 2003b, 2005a, 2005b; Lee et al 2006; Venturini et al 2006). Hence, C-peptide deficiency has successively emerged as a possible mechanism for the development of the disproportionate burden of complications affecting insulinopenic diabetes patients.…”