Diabetes Care

Volume 22 Supplement 2
Improving Prognosis in Type 1 Diabetes
Proceedings from an Official Satellite Symposium
of the 16th International Diabetes Federation Congress

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Nicotinamide in Type 1 Diabetes

Mechanism of action revisited

Hubert Kolb, PHD
Volker Burkart, PHD

Treatment with high doses of nicotinamide (niacinamide, vitamin B3) prevents or delays insulin-deficient diabetes in several animal models of type 1 diabetes and protects islet cells against cytotoxic actions in vitro. In recent-onset type 1 diabetes, nicotinamide administration improves -cell function, without significantly decreased insulin requirements. This review discusses the possible mechanism of action of nicotinamide in vivo. It is proposed that the key target of nicotinamide is the poly(ADP-ribose)polymerase (PARP), and to a lesser extent (mono)ADP-ribosyl transferases (ADPRTs). Suppression of PARP activity by nicotinamide not only decreases consumption of NAD+, the substrate of PARP, but also has major regulatory effects on gene expression, as shown for the major histocompatibility complex class II gene. In addition, PARP activity controls early steps of apoptosis. The possible suppression of ADPRTs by nicotinamide would also affect CD38, a membrane-bound external ADP-ribosyl transferase with potent immunoregulatory properties. Taken together, it is proposed that high doses of nicotinamide primarily affect ADP-ribosylation reactions in -cells as well as in immune cells and the endothelium. As a consequence, cell death pathways and gene expression patterns are modified, leading to improved -cell survival and an altered immunoregulatory balance.

Diabetes Care 22 (Suppl. 2):B16–B20, 1999

The B vitamin nicotinamide is presently being tried in several large studies of preventing type 1 diabetes (13). These trials and previous pilot studies (46) are based on reports of an antidiabetic effect of high-dose nicotinamide in animals.

At first, nicotinamide was successfully used to inhibit or mitigate the diabetogenic action of the -cell toxins alloxan and streptozotocin (7,8). This prompted Yamada et al. (9) to try high-dose nicotinamide for the prevention of autoimmune diabetes in NOD mice. As they reported in 1982 (9), prophylactic treatment with nicotinamide suppressed the development of diabetes and reduced the insulitis grade. These findings were confirmed by other groups (10,11), but it appeared that treatment with nicotinamide delayed rather than completely prevented disease development (10). In their seminal study, Yamada et al. (9) also observed reversal of overt diabetes when treatment with nicotinamide was begun at diagnosis of hyperglycemia. This latter finding could not be confirmed in our own studies (A. Faust, H.K., unpublished observations).

Several groups also tried nicotinamide in the BB rat model of human type 1 diabetes (1215). The majority of these studies did not observe a significant effect of nicotinamide on disease development. However, all BB rat studies documented a trend toward diabetes suppression in the nicotinamide group compared with the control group. Therefore, it is probable that the descriptive statistics performed on the BB rat studies would come up with a 35–45% suppression of diabetes incidence in this animal model due to nicotinamide treatment within the observation period reported.

Taken together, the observations in NOD mice and the BB rat indicate that nicotinamide has a differential protective effect against the development of diabetes in the two animal models. At present, there is no experimental evidence to explain this discrepancy. However, it may be speculated that the pathophysiological processes involved in immune-mediated islet cell destruction in the two rodent strains include phases that differ in their sensitivity to nicotinamide.

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NICOTINAMIDE IN TYPE 1 DIABETES— The available evidence clearly indicates that treatment with high-dose nicotinamide exerts some protective effect on -cell function in humans. In a recent study, we analyzed all published trials of nicotinamide in recent-onset type 1 diabetes, i.e., treatment started within weeks of diagnosis (16). Of these, 10 randomized and controlled trials were eligible for meta-analysis. As shown in Table 1, combined analysis of a total of 158 nicotinamide-treated and 129 control patients revealed significantly better preservation of basal C-peptide secretion in the nicotinamide-receiving cohort after 1 year. Subanalysis of the five placebo-controlled trials gave the same result (16). Despite this outcome, the effects were not substantial enough to improve clinical parameters of nicotinamide-treated individuals within the study period of 12 months.

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Figure 1—Chemical structure of nicotinamide.

NICOTINAMIDE: PHARMACOLOGY— Nicotinamide (niacinamide, vitamin B3) is a water-soluble amide of nicotinic acid (Fig. 1). Several different pharmacological actions have been reported for nicotinamide, and contrasting views have been expressed as to which of these properties contribute or account for the protective effect of nicotinamide on the -cell.

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Figure 2—Concentration dependency of nicotinamide's pharmacological actions. The expected peak levels in vivo after high-dose nicotinamide administration are 0.3–1 mmol/l.

It is important to note that some of the actions of nicotinamide require high concentrations that may not be reached in vivo. As roughly sketched in Fig. 2, nicotinamide already acts as a precursor of NAD+at low concentrations. Nicotinamide is able to scavenge oxygen radicals, although it is not a potent antioxidant. However, it does not scavenge nitric oxide (NO), in contrast to some lipophilic antioxidants, such as vitamin E (17,18). This property probably becomes relevant at concentrations close to 1 mmol/l or above. Because its carbamoyl group is attached to an aromatic ring, nicotinamide is a specific inhibitor of ADP-ribosyl transferases. The 50% inhibition concentration of nicotinamide for poly(ADP-ribose)polymerase (PARP) is ~0.1 mmol/l (19,20). The ability of nicotinamide to inhibit (mono)ADP-ribosyl transferases (ADPRT) is much lower and requires a concentration 110 times higher than IC50 (19). Concentrations of >10 mmol/l are required for nicotinamide to interfere with the transcription of a small number of genes, including inducible nitric oxide synthase (21). At concentrations of >25 mmol/l, a more general inhibition of gene expression and protein synthesis was observed (22).

Although this list of nicotinamide actions is far from complete, it has led to controversial views on how nicotinamide might work. A simple solution is to consider the concentration dependency of the various pharmacological actions and to relate this to plasma levels of nicotinamide obtained in humans. Studies of nicotinamide levels in the plasma of probands receiving high doses of nicotinamide, similar to those applied in type 1 diabetes prevention studies, reported peak levels around 0.3–1.1 mmol/l (23,24). This renders the actions of nicotinamide that are seen only at or above millimolar concentrations less probable as being responsible for the antidiabetic effect of nicotinamide in vivo.

PARP AS TARGET OF NICOTINAMIDE IN MICE— We tested the hypothesis that PARP is the key target of nicotinamide in vivo by analyzing mice with an inactivated PARP gene. PARP is a nuclear enzyme that is activated by DNA strand breaks and allows for a rapid response to DNA damage, such as that induced during the cells' normal life cycle or occurring after chemical, physical, or inflammatory insults (25,26). The sudden induction of widespread DNA damage leads to a rapid, excessive activation of the enzyme; in certain sensitive cells, this results in a critical reduction of the cytoplasmatic pool of NAD+ that serves as a substrate for PARP to synthesize large polymers consisting of ADP subunits (25).

We used the animal model of streptozotocin (STZ)-induced diabetes to determine whether PARP is the target of the antidiabetic action of nicotinamide. Treatment of mice with STZ causes selective -cell death and diabetes (27,28). Cellular insults caused by STZ resemble those seen after exposure of -cells to mediators of islet inflammation, such as activated macrophages or endothelial cells, cytokines, oxygen radicals, or NO (2931). -cell death includes both necrosis and apoptosis pathways during which activation of PARP is observed. The administration of a single high dose of STZ is a means for targeting a toxic attack involving NO and other radicals (3032) to the pancreatic -cells of experimental animals.

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Figure 3—Effects of STZ administration on blood glucose levels. At day 0, groups of five to eight animals received a single intraperitoneal injection of STZ (160 mg/kg body wt) or a corresponding volume of sodium citrate buffer alone as sham treatment (control). The intraperitoneal administration of nicotinamide (NA) (500 mg/kg body wt) was performed 6 h before the STZ injection or the sham treatment. The data show means ± SD of blood glucose concentrations. *P< 0.01. Adapted from Burkart V, Wang ZQ, Radons J, Heller B, Herceg Z, Stingl L, Wagner EF, Kolb H, submitted for publication.

Treatment of 129SV mice with a single high dose of STZ (160 mg/kg) caused the development of acute hyperglycemia within 3 days (Fig. 3). Diabetes development was almost completely suppressed when mice received 500 mg/kg of nicotinamide 6 h prior to STZ (Fig. 3). When the same experiment was repeated with a 129SV mouse line that completely lacks PARP enzyme activity (PARP–/–) as a consequence of PARP gene disruption (33), STZ administration failed to induce hyperglycemia (Fig. 3). Even at a dose of 240 mg/kg body weight, STZ was unable to affect the normal blood glucose level of PARP–/– mice (data not shown). Further follow-up of the animals up to 5 days confirmed stable high blood glucose level in PARP+/+ mice and continuous normoglycemia in PARP–/– mice (data not shown). Histological analysis revealed a significant preservation of the percentage of the insulin-positive area within islets and of the amount of insulin extractable from total pancreas in STZ-treated PARP–/– mice compared with PARP+/+ mice (V. Burkart, Z.-Q. Wang, J. Radons, B. Heller, Z. Herceg, L. Stingl, E.F. Wagner, H.K., unpublished observations).

Taken together, these data demonstrate a key role of PARP in -cell death in vivo. Mice with a disrupted PARP gene appeared to be completely resistant against the diabetogenic actions of STZ. Hence, the antidiabetic actions of nicotinamide in the STZ model are explained by its property to inhibit PARP. Considering that nicotinamide also interferes with diabetes development in NOD mice, it seems probable that the same mechanism applies.

TARGETS OF NICOTINAMIDE ACTION IN HUMANS— Nicotinamide has been used at doses 10–200 times above the recommended vitamin allowance to treat a variety of different conditions, including skin diseases, neurological disorders, and type 1 diabetes. In the course of these studies, several pharmacological effects have been observed. These biochemical actions clearly differ from that of nicotinic acid, i.e., a negligible portion of nicotinamide is metabolized to nicotinic acid, mostly due to bacterial activity, such as in the oral flora (34).

An important property of nicotinamide is the enhancement of radiation damage of tumors at similar plasma concentrations as in mice (35). Initially, it was thought that the sensitization of tumor cells toward radio- or chemotherapy by nicotinamide was due to the inhibition of DNA repair, which enhanced DNA damage in treated tumor cells (3638). More recently, it became evident that the main mechanism involved is the reduction of hypoxia in tumors by increasing the proportion of tumor that is well oxygenated, i.e., by improving microvascular blood flow (3943). This finding may be related to the downregulation of adhesion molecules (ICAM-1 and HLA-DR) on activated human endothelial cells in the presence of nicotinamide (44).

An anti-inflammatory action of nicotinamide has been reported that especially affects neutrophil chemotaxis (45), as also seen in a mouse arthritis model (46).

Another target of nicotinamide action in humans is insulin homeostasis. It has been reported that nicotinamide dosing increases insulin resistance in individuals with subclinical islet autoimmunity (47), whereas no such effects were seen in normal probands (48,49). Our own experience with long-term nicotinamide administration to individuals at risk of type 1 diabetes suggests a depressive effect of nicotinamide on the first-phase insulin response to intravenous glucose (50).

In conclusion, nicotinamide seems to target different cells in humans, such as tumor cells, the microvasculature, or -cells. We regard it as probable that in the different tissues the mechanism of nicotinamide action is the same. Taking this thought further, the primary candidate molecule for interaction with nicotinamide is the family of ADP-ribosylating enzymes. Among these, PARP is inhibited most avidly by nicotinamide, followed by ADP-ribosyl transferases. Based on our studies of PARP knockout mice, described above, we therefore assume that much of the pharmacological effects of nicotinamide are due to the partial suppression of PARP activity, with a possible contribution of the lesser suppression of ADPRTs.

Indeed, the modulatory effect of nicotinamide on major histocompatibility complex (MHC) class II expression probably is due to the interaction with PARP. When PARP activity was modulated by transfection with PARP-expressing plasmids, again modulation of MHC class II expression was noted (51,52). This clearly demonstrates that PARP activity modulates gene expression, besides facilitating DNA repair.

Another important function of PARP is the regulation of apoptosis. An early step of the pathway leading to programmed cell death is the cleavage of PARP by the cysteine protease apopain (CPP32) (53). Inhibition of PARP cleavage is associated with protection from apoptosis (53,54). Pharmacological inhibition of PARP may mimic functional consequences of PARP cleavage. Indeed, administration of the nicotinamide-related PARP inhibitor 3-aminobenzamide was reported to enhance thymocyte apoptosis in mice (55). In conclusion, inhibition of PARP may not only affect gene expression but also modulate apoptosis induction.

An additional pharmacological action of nicotinamide via inhibition of ADPRTs cannot be excluded, although there is only low affinity interaction with this subfamily of ADP-ribose synthesizing enzymes (19,29). Of particular interest is the possible interaction of nicotinamide with glycosylphosphatidyl-inositol–anchored ADP-ribosyl transferases. These enzymes occur on the outer membrane of lymphocytes. The best known is CD38 (56,57), which was recently found to exert ADP-ribosyl cyclase and cADP-ribosyl hydrolase activities (58). Antibodies to CD38 potentiate many biological activities of lymphocytes, in particular promoting B-cell proliferation. The latter may result in a Th2 bias, an immunoregulatory state preventing destructive insulitis (59). In this context, it is of interest that murine CD38 is closely related to the RT6 antigen of rat T-cells, for which a diabetes protective function has been demonstrated in BB rats (60).

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Figure 4 —Possible mechanism of pharmacological actions of nicotinamide in humans. The inhibition of PARP, and to a lesser extent of ADPRT, is proposed to affect functions of -cells, immune cells, and other cell types, such as the endothelium.

As summarized in Fig. 4, the inhibition of ADP-ribosyl-transferring enzymes by nicotinamide modulates cell function and affects cell survival at several levels. These effects are not specific for -cells but may also occur in other cell types, such as leukocytes or endothelial cells.

OUTLOOK— Taken together, modulation of ADP-ribosylation probably represents a promising approach of cellular protection and immunoregulation. Whether the weak and nonselective inhibitor nicotinamide is the appropriate compound to test for the therapeutic potential of this approach presently cannot be judged.

The German multicenter trial of nicotinamide in individuals at risk of type 1 diabetes (DENIS) was terminated in 1997 because no major reduction of diabetes risk was observed in the nicotinamide versus placebo group (2,50). However, this trial had focused on individuals with high diabetes risk and assumed rapid disease progression, i.e., islet cell antibody positive siblings (3–12 years of age) of patients with type 1 diabetes. Further information will come from an ongoing international trial of nicotinamide (ENDIT). The latter trial also includes islet cell antibody positive relatives at lower risk and will be able to detect much smaller effects of treatment on diabetes risk reduction (3).

Acknowledgments— This work was supported by the Deutsche Forschungsgemeinschaft (H.K.), the Bundesminister für Gesundheit, and the Minister für Wissenschaft und Forschung des Landes Nordrhein-Westfalen.

1. Elliott RB, Pilcher CC, Ferguson DM, Stewart AW: A population based strategy to prevent insulin-dependent diabetes using nicotinamide. J Pediatr Endocrinol Metabol 9:501–509, 1996

2. Lampeter EF: Intervention with nicotinamide in pre-type 1 diabetes: the Deutsche Nicotinamid Interventionsstudie—DENIS. Diabete Metab 19:105–109, 1993

3. Gale EAM, Bingley PJ: Can we prevent IDDM? Diabetes Care 17:339–344, 1994

4. Elliott RB, Chase HP: Prevention or delay of type 1 (insulin-dependent) diabetes mellitus in children using nicotinamide. Diabetologia 34:362–365, 1991

5. Herskowitz RD, Jackson RA, Soeldner JS, Eisenbarth GS: Pilot trial to prevent type 1 diabetes: progression to overt IDDM despite oral nicotinamide. J Autoimmun 2:733–737, 1989

6. Manna R, Migliore A, Martin LS, Ferrara E, Ponte E, Marietti G, Scuderi F, Cristiano G, Ghirlanda G, Gambassi G: Nicotinamide treatment in subjects at high risk of developing IDDM improves insulin secretion. Br J Clin Pract 46:177–179, 1992

7. Lazarow A: Protection against alloxan diabetes. Anat Rec 97:353, 1947

8. Lazarow A, Liambies L, Tausch AJ: Protection against diabetes with nicotinamide. J Lab Clin Med 36:249–258, 1950

9. Yamada K, Nonaka K, Hanafusa T, Miyazaki A, Toyoshima H, Tarui S: Preventive and therapeutic effects of large-dose nicotinamide injections on diabetes associated with insulitis. Diabetes 31:749–753, 1982

10. Elliott RB, Pilcher CC, Stewart A, Ferguson D, McGregor MA: The use of nicotinamide in the prevention of type 1 diabetes. Ann NY Acad Sci U S A 696:333–343, 1993

11. Yamamoto K, Miyagawa J, Itoh N, Nakajima H, Waguri M, Shimada T, Yasuda K, Kono N, Namba M, Kuwajima M, Hanafusa T, Matsuzawa Y: Differentiation of -cells from ductal cells and acceleration of this process by nicotinamide: ultrastructural study on the non-obese diabetic (NOD) mouse with overt diabetes. Biomed Res Tokyo 18:171–178, 1997

12. Kolb H, Schmidt M, Kiesel U: Immunomodulatory drugs in type 1 diabetes. In Immunotherapy of Type 1 Diabetes and Selected Autoimmune Disorders. Eisenbarth GS, Ed. Boca Raton, FL, CRC Press, 1989, p. 111–122

13. Sarri Y, Mendola J, Ferrer J, Gomis R: Preventive effects of nicotinamide administration on spontaneous diabetes of BB rats. Med Sci Res 17:987–988, 1989

14. Hermitte L, Vialettes B, Atlef N, Payan MJ, Doll N, Scheimann A, Vague P: High dose nicotinamide fails to prevent diabetes in BB rats. Autoimmunity 5:79–86, 1989

15. Pan JQ, Chan EK, Cheta D, Schranz V, Charles MA: The effect of nicotinamide and glimepiride on diabetes prevention in BB rats. Life Sci 57:1525–1532, 1995

16. Pozzilli P, Browne PD, Kolb H: Meta-analysis of nicotinamide treatment in patients with recent-onset IDDM: the nicotinamide trialists. Diabetes Care 19:1357–1363, 1996

17. Andersen HU, Jorgensen KH, Egeberg J, Mandrup-Poulsen T, Nerup J: Nicotinamide prevents interleukin-1 effects on accumulated insulin release and nitric oxide production in rat islets of Langerhans. Diabetes 43:770–777, 1994

18. Burkart V, Gross-Eick A, Bellmann K, Radons J, Kolb H: Suppression of nitric oxide toxicity in islet cells by alpha-tocopherol. FEBS Lett 364:259–263, 1995

19. Rankin PW, Jacobson EL, Benjamin RC, Moss J, Jacobson MK: Quantitative studies of inhibitors of ADP-ribosylation in vitro and in vivo. J Biol Chem 264:4312–4317, 1989

20. Banasik M, Komura H, Shimoyama M, Ueda K: Specific inhibitors of poly(ADP-ribose)synthetase and mono(ADP-ribosyl)transferase. J Biol Chem 267:1569– 1575, 1992

21. Pellatdeceunynck C, Wietzerbin J, Drapier JC: Nicotinamide inhibits nitric oxide synthase mRNA induction in activated macrophages. Biochem J 297:53–58, 1994

22. Hauschildt S, Scheipers P, Bessler WG: Inhibitors of poly(ADP-ribose)polymerase suppress lipopolysaccharide-induced nitrite formation in macrophages. Biochem Biophys Res Commun 179:865–871, 1991

23. Petley A, Macklin B, Renwick AG, Wilkin TJ: The pharmacokinetics of nicotinamide in humans and rodents. Diabetes 44:152–155, 1995

24. Stratford MRL, Rojas A, Hall DW, Dennis MF, Dische S, Joiner MC, Hodgkiss RJ: Pharmacokinetics of nicotinamide and its effect on blood pressure, pulse and body temperature in normal human volunteers. Radiother Oncol 25:37–42, 1992

25. Satoh MS, Lindahl T: Role of poly(ADP-ribose)formation in DNA repair. Nature 356:356–358, 1992

26. DeMurcia G, Schreiber V, Molinete M, Saulier B, Poch O, Masson M, Niedergang C, Menissier DeMurcia J: Structure and function of poly(ADP-ribose)polymerase. Mol Cell Biochem 138:15–24, 1994

27. Rakieten N, Rakieten ML, Nadkarni MV: Studies on the diabetogenic action of streptozotocin (NSC-37917). Cancer Chemother Rep 29:91–98, 1963

28. Like AA, Rossini AA: Streptozotocin-induced pancreatic insulitis: new model of diabetes mellitus. Science 193:415–417, 1976

29. Rasschaert J, Eizirik DL, Malaisse WJ: Long term in vitro effects of streptozotocin, interleukin-1, and high glucose concentration on the activity of mitochondrial dehydrogenases and the secretion of insulin in pancreatic islets. Endocrinol 130:3522–3528, 1992

30. Kolb H, Kröncke K-D: Lessons from the low dose streptozocin model in mice. Diabetes Rev 1:116–126, 1993

31. Kröncke K-D, Fehsel K, Sommer A, Rodriguez M-L, Kolb-Bachofen V: Nitric oxide generation during cellular metabolization of the diabetogenic N-methyl-N-nitroso-urea streptozotocin contributes to islet cell DNA damage. Biol Chem Hoppe-Seyler 376:179–185, 1995

32. Turk J, Corbett JA, Ramanadham S, Bohrer A, McDaniel L: Biochemical evidence for nitric oxide formation from streptozotocin in isolated pancreatic islets. Biochem Biophys Res Commun 197:1458–1464, 1993

33. Wang Z-Q, Auer B, Stingl L, Berghammer H, Haidacher D, Schwaiger M, Wagner EF: Mice lacking ADPRT and poly(ADP-ribosyl)ation develop normally but are susceptible to skin disease. Genes Dev 9:509–520, 1995

34. Stratford MR, Dennis MF, Hoskin P, Phillips H, Hodgkiss RJ, Rojas A: Nicotinamide pharmacokinetics in humans: effect of gastric acid inhibition, comparison of rectal vs oral administration and the use of saliva for drug monitoring. Br J Cancer 74:16–21, 1996

35. Horsman MR, Hoyer M, Honess DJ, Dennis IF, Overgaard J: Nicotinamide pharmacokinetics in humans and mice: a comparative assessment and the implications for radiotherapy. Radiother Oncol 27:131–139, 1993

36. Riklis E, Kol R, Marko R: Trends and developments in radioprotection: the effect of nicotinamide on DNA repair. Int J Radiat Biol 57:699–708, 1990

37. Chen G, Zeller WJ: Multiple effects of 3-aminobenzamide on DNA damage induced by cisplatin (DDP) in DDP-sensitive and DDP-resistant rat ovarian tumor cell lines. Cancer Lett 67:27–33, 1992

38. Olsson AR, Sheng Y, Pero RW, Chaplin DJ, Horsman MR: DNA damage and repair in tumour and non-tumour tissues of mice induced by nicotinamide. Br J Cancer 74:368–373, 1996

39. Horsman MR: Nicotinamide and other benzamide analogs as agents for overcoming hypoxic cell radiation resistance in tumors: a review. Acta Oncologica 34:571–587, 1995

40. Thomas CD, Prade M, Guichard M: Tumour oxygenation, radiosensitivity, and necrosis before and/or after nicotinamide, carbogen and perflubron emulsion administration. Int J Rad Biol 67:597–605, 1995

41. Price MJ, Li LT, Tward JD, Bublik I, McBride WH, Lavey RS: Effect of nicotinamide and pentoxifylline on normal tissue and FSa tumor oxygenation. Acta Oncologica 34:391–395, 1995

42. Hirst DG, Kennovin GD, Tozer GM, Prise VE, Flitney EW: The modification of blood flow in tumours and their supplying arteries by nicotinamide. Acta Oncologica 34:397–400, 1995

43. Peters CE, Chaplin DJ, Hirst DG: Nicotinamide reduces tumour interstitial fluid pressure in a dose-dependent manner. Br J Radiol 70:160–167, 1997

44. Hiromatsu Y, Sato M, Yamada K, Nonaka K: Inhibitory effects of nicotinamide on recombinant human interferon-gamma-induced intercellular adhesion molecule-1 (ICAM-1) and HLA-DR antigen expression on cultured human endothelial cells. Immunology Lett 31:35–40, 1991

45. Berk MA, Lorinez AL: The treatment of bullous pemphigoid with tetracycline and niacinamide. Arch Dermatol 122:670–674, 1986

46. Miesel M, Kurpisz M, Kröger H: Modulation of inflammatory arthritis by inhibition of poly(ADP-ribose)polymerase. Inflammation 19:379–387, 1995

47. Greenbaum CJ, Kahn SE, Palmer JP: Nicotinamide's effects on glucose metabolism in subjects at risk for IDDM. Diabetes 45:1631–1634, 1996

48. Paul TL, Hramiak IM, Mahon JL, Freeman D, Atkinson P, Finegood DT, Dupre J: Nicotinamide and insulin sensitivity (Letter). Diabetologia 36:369, 1993

49. Bingley PJ, Caldas G, Bonfanti R, Gale EA: Nicotinamide and insulin secretion in normal subjects. Diabetologia 36:675–677, 1993

50. Lampeter EF, Klinghammer A, Scherbaum WA, Heinze E, Haastert B, Giani G, Kolb H, the DENIS Group: The Deutsche Nicotinamide Intervention Study: an attempt to prevent type 1 diabetes. Diabetes 47:980–984, 1998

51. Nomura I, Kurashige T, Taniguchi T: Inhibitory effect of interferon-gamma-dependent induction of major histocompatibility complex class II antigen by expressing exogenous poly(ADP-ribose)synthetase gene. Biochem Biophys Res Commun 175:685–689, 1991

52. Tomoda T, Kurashige K, Taniguchi T: Inhibition of interferon-gamma-induced and phorbol ester-induced HLA-DR and interleukin-1 production by the expression of a transfected poly(ADP-ribose)synthetase gene in human leukemia THP-1 cells. Biochim Biophys Acta 1135:79–83, 1992

53. Nicholson DW, Ali A, Thornberry NA, Vaillancourt JP, Ding CK, Gallant M, Gareau Y, Griffin PR, Labelle M, Lazebnik YA, Munday NA, Raju SM, Smulson ME, Yamin T-T, Yu VL, Miller DK: Identification and inhibition of the ICE/CED-3 protease necessary for mammalian apoptosis. Nature 376:37–43, 1995

54. Dimmeler S, Haendeler J, Nehls M, Zeiher AM: Suppression of apoptosis by nitric oxide via induction of interleukin-1-converting enzyme (ICE)-like and cysteine protease protein (CPP)-32-like proteases. J Exp Med 185:601–607, 1997

55. Hoshino J, Koeppel C, Westhauer E: 3-aminobenzamide enhances dexamethasone-mediated mouse thymocyte depletion in vivo: implication for a role of poly ADP-ribosylation in the negative selection of immature thymocytes. Biochim Biophys Acta 1201:516–522, 1994

56. Lund F, Solvason N, Grimaldi JC, Parkhouse RME, Howard M: Murine CD38: an immunoregulatory ectoenzyme. Immunol Today 16:469–473, 1995

57. Wang J, Nemoto E, Dennert G: Regulation of cytotoxic T cell functions by GPI-anchored ecto-ADP-ribosyltransferase. Adv Exp Med Biol 419:191–201, 1997

58. Yasue T, Nishizumi N, Aizawa S, Yamamoto T, Miyake K, Mizoguchi C, Uehara S, Kikuchi Y, Takatsu K: A critical role of lyn and fyn for B cell responses to CD38 ligation to interleukin 5. Proc Natl Acad Sci U S A 94:10307–10312, 1997

59. Kolb H: Benign versus destructive insulitis. Diabetes Metab Rev 13:139–146, 1997

60. Waite DJ, Appel MC, Handler ES, Mordes JP, Rossini AA, Greiner DL: Ontogeny and immunohistochemical localization of thymus-dependent and thymus-independent RT6+ cells in the rat. Am J Pathol 148:2043–2056, 1996

From the Diabetes Research Institute at the University of Düsseldorf, Düsseldorf, Germany.

Address correspondence and reprint requests to Hubert Kolb, Diabetes Research Institute, Auf'm Hennekamp 65, D-40225 Düsseldorf, Germany. E-mail: kolb@dfi.uni-duesseldorf.de.

Received for publication 27 May 1998 and accepted in revised form 6 November 1998.

Abbreviations: ADPRT, (mono)ADP-ribosyl transferase; MHC, major histocompatibility complex; PARP, poly(ADP-ribose)polymerase; STZ, streptozotocin.

This article is based on a presentation at a satellite symposium of the 16th International Diabetes Federation Congress. The symposium and the publication of this article were made possible by educational grants from Hoechst Marion Roussel AG.

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