Recent advances in physiological and pathological significance of NAD⁺metabolites: roles of poly(ADP-ribose) and cyclic ADP-ribose in insulin secretion and diabetogenesis

Abstract

Poly(ADP-ribose) synthetase/polymerase (PARP) activation causes NAD + depletion in pancreatic β-cells, which results in necrotic cell death. On the other hand, ADP-ribosyl cyclase/cyclic ADPribose hydrolase (CD38) synthesizes cyclic ADP-ribose from NAD + , which acts as a second messenger, mobilizing intracellular Ca 2+ for insulin secretion in response to glucose in β-cells. PARP also acts as a regenerating gene (Reg) transcription factor to induce β-cell regeneration. This provides the new concept that NAD + metabolism can control the cellular function through gene expression. Clinically, PARP could be one of the most important therapeutic targets; PARP inhibitors prevent cell death, maintain the formation of a second messenger, cyclic ADP-ribose, to achieve cell function, and keep PARP functional as a transcription factor for cell regeneration.Poly(ADP-ribose) synthetase/polymerase: Okamoto model for β-cell damage: Necrosis: Apoptosis:Regenerating geneAbbreviations: CD38, ADP-ribosyl cyclase/cyclic ADP-ribose hydrolase; IL-6, interleukin-6; IP 3 , inositol 1,4,5-trisphosphate; PARP, poly(ADP-ribose) synthetase/polymerase; Reg, regenerating gene.

Cloricromene effect on the enzyme activities of the tryptophan–nicotinic acid pathway in diabetic/hyperlipidemic rabbits

“…This result might be explained also referring to our previous studies conducted on diabetic and hyperlipidemic rabbits (Ragazzi et al, 2002), showing that in these pathological conditions, in comparison to normometabolic controls, the degradation of tryptophan is selectively affected mainly at the level of 3-hydroxyanthranilate 3,4-dioxygenase, which is reduced in kidneys, and at the level of aminocarboxymuconate-semialdehyde decarboxylase whose activity is increased in kidneys and liver. The slight increase of the activity of 3-hydroxyanthranilate 3,4-dioxygenase induced by cloricromene in the liver, observed in this study, both in diabetic/hyperlipidemic rabbits and controls, may suggest a protective event through the activation of the metabolic conversion of tryptophan toward NAD + synthesis, which has been indicated as a pivotal keypoint linked to diabetic condition (Okamoto, 2003). However, the opposite effect induced by cloricromene in the kidneys of control animals may suggest complex enzymatic adjustment within the last steps of the kynurenine pathway.…”

“…Since alterations of tryptophan metabolism have been reported in diabetes and atherosclerosis (Kotake and Tani, 1953;Rosen et al, 1955;Wiseman et al, 1958;Oka and Leppänen, 1963;Ragazzi et al, 2002;Okamoto, 2003), it was thought of interest to investigate any role of cloricromene through the influence on the oxidative metabolism of the amino acid. In diabetic animals the shift of tryptophan metabolism to xanthurenic acid (Kotake and Tani, 1953) and the reduction of kidney 3-hydroxyanthranilate 3,4-dioxygenase activity (Ragazzi et al, 2002) have been observed (Scheme 1), leading to impairment of NAD + synthesis.…”

“…In diabetic animals the shift of tryptophan metabolism to xanthurenic acid (Kotake and Tani, 1953) and the reduction of kidney 3-hydroxyanthranilate 3,4-dioxygenase activity (Ragazzi et al, 2002) have been observed (Scheme 1), leading to impairment of NAD + synthesis. NAD + is synthesized from tryptophan and also from nicotinic acid and nicotinamide, leading to poly(ADP-ribose) and cyclic ADP-ribose (cADPR) by means of the enzymes poly(ADP-ribose) synthetase/ polymerase (indicated as PARP) and ADP-ribosyl cyclase (named CD38) (Okamoto, 2003). These NAD + metabolites and enzymes are crucially involved in the death, regeneration, and functioning of the insulin-producing h-cells of the pancreatic islets of Langerhans Takasawa and Okamoto, 2002;Okamoto, 2003).…”

“…NAD + is synthesized from tryptophan and also from nicotinic acid and nicotinamide, leading to poly(ADP-ribose) and cyclic ADP-ribose (cADPR) by means of the enzymes poly(ADP-ribose) synthetase/ polymerase (indicated as PARP) and ADP-ribosyl cyclase (named CD38) (Okamoto, 2003). These NAD + metabolites and enzymes are crucially involved in the death, regeneration, and functioning of the insulin-producing h-cells of the pancreatic islets of Langerhans Takasawa and Okamoto, 2002;Okamoto, 2003).…”

“…Diabetes is associated with abnormalities of tryptophan metabolism that have been extensively investigated and thoroughly discussed (Kotake and Tani, 1953;Rosen et al, 1955;Wiseman et al, 1958;Oka and Leppänen, 1963;Ragazzi et al, 2002;Okamoto, 2003). Other data indicate that tryptophan metabolism is linked to atherogenesis, mainly focused on the antioxidant role of the amino acid and its metabolites.…”