Amelioration of Diabetes Mellitus in Partially Depancreatized Rats by Poly(ADP-ribose) Synthetase Inhibitors: Evidence of Islet B-Cell Regeneration

Abstract

SUMMARYNinety percent depancreatized rats received daily intraperitoneal injection of 0.5 g/kg nicotinamide and 0.05 g/kg 3-aminobenzamide, potent inhibitors of islet poly(ADP-ribose) synthetase. One to three months after the partial pancreatectomy, urinary and plasma glucose levels in nicotinamide-and 3-aminobenzamide-treated rats were markedly lower than those in saline-treated control rats. Morphologic examination of the remaining pancreata revealed that islets in the poly(ADP-ribose) synthetase inhibitor-treated rats were markedly enlarged and consisted largely of B-cells. These results suggest that poly(ADP-ribose) synthetase inhibitors induce islet B-cell regeneration, thereby preventing or improving diabetes mellitus in partially depancreatized rats. DIABETES 33:401-404, April 1984. R emoval of the insulin-producing pancreatic Bcells from an animal induces a syndrome that features many of the acute metabolic derangements of diabetes as they are known in man. Mering and Minkowski 1 in 1890 were the first to produce this form of diabetes by surgically removing the pancreata of dogs. Alloxan in 1943 2 and streptozotocin in 1963 3 were found to be highly selective B-cytotoxins and thereafter have been widely used to produce diabetes in experimental animals. Recently, Okamoto and his colleagues 4 " 10 have clarified that alloxan and streptozotocin cause DNA strand breaks in pancreatic B-cells to stimulate nuclear poly(ADP-ribose) syn4hetase, thereby depleting the intracellular nicotinamide-adenine dinucleotide (NAD) level and inhibiting B-cell functions including proinsulin synthesis. We also reported that alloxan- and streptozotocin-induced diabetes can be prevented by inhibiting poly(ADP-ribose) synthetase of B-cells. 8" 10 In this article we show that poly(ADP-ribose) synthetase inhibitors prevent experimental diabetes caused by surgically removing the pancreata of rats. Morphologic evidence indicates that regeneration or proliferation of the pancreatic B-cells occurs in the poly(ADP-ribose) synthetase inhibitor-treated rats. MATERIALS AND METHODSMale Wistar rats weighing 180-200 g were 90% depancreatized according to the technique described by Foglia 11 and maintained on standard rat chow. From 7 days before the partial pancreatectomy, nicotinamide, at a dose of 0.5 g/kg body wt in 2 ml saline, and 3-aminobenzamide • HCI, at a dose of 0.05 g/kg body wt in 2 ml saline, were injected intraperitoneally into each group of five rats every day. Nicotinamide and 3-aminobenzamide are inhibitors of pancreatic B-cell poly(ADP-ribose) synthetase; the inhibitory ability of the latter is about 10-fold as potent as that of the former. 9 The injection was continued until the ninetieth postoperative day. Five control rats received saline daily before and after the partial pancreatectomy. The residual pancreatic tissue, referred to as the remaining pancreas, was removed 3 mo after the partial pancreatectomy and fixed in Bouin's solution. Hydrated 5-|xm sections of paraffin-embedded pancreatic tissues were stained for insul...

Enhancement of Cell Viability in Cryopreserved Rat Vascular Grafts by Administration of Regenerating Gene <i>(Reg)</i> Inducers

“…4, 5). A similar dosage of nicotinamide has been found to actually induce Reg expression and islet regeneration in 90% depancreatized rats [7, 8]. We also found no significant change in intragraft IL-6 mRNA levels between cryopreserved allografts with and without nicotinamide treatment, 9 days after transplantation (fig.…”

“…It has been reported that administration of nicotinamide, an inhibitor of poly(ADP-ribose) synthetase, to 90% depancreatized rats induced regeneration of pancreatic islets [7]. During screening of the regenerating islet-derived complementary DNA (cDNA) library, a novel gene was found and named the ‘regenerating gene’ (Reg) [8].…”

Ductular Cell Proliferation in Islet Cell Neogenesis Induced by Incomplete Ligation of the Pancreatic Duct in Dogs

“…12 The regeneration of islets was also induced by nicotinamide in rats with 90% pancreatectomy. 13,14 The other mechanism of islet regeneration relates to the differentiation from pancreatic precursor cells and the promotion of tissue formation. Several studies have revealed evidence supporting duct cells as a possible source.…”

The role of Islet Neogenesis-Associated Protein (INGAP) in islet neogenesis

“…For example, subtotal pancreatectomy followed by administration of poly(ADPribose) polymerase inhibitors was demonstrated to promote endocrine regeneration, presumably either via the proliferation of remaining islet cells or the de novo formation of islet cells from non-endocrine precursors (islet neogenesis) [56]. Screening of a regenerating rat islet cDNA library identified a novel protein, termed Reg (now known as RegI), as being highly upregulated [42].…”