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Endocrinology Vol. 143, No. 7 2491-2495
Copyright © 2002 by The Endocrine Society

INSULIN-GLUCAGON-GI PEPTIDES-DIABETES MELLITUS

Human ß Cells Are Exceedingly Resistant to Streptozotocin in Vivo

Hua Yang and James R. Wright, Jr

Departments of Pathology, Surgery, and Biomedical Engineering, Izaak Walton Killam Health Centre and Dalhousie University, Halifax, Nova Scotia, Canada

Address all correspondence and requests for reprints to: James R. Wright, Jr., M.D., Ph.D., Department of Pathology, Izaak Walton Killam Health Center, 5850 University Avenue, Halifax, Nova Scotia B3H 1V7, Canada. E-mail: . jim.wright{at}iwk.nshealth.ca


   Abstract
Top
 Abstract
Introduction
 Materials and Methods
 Results
 Discussion
 References
 
Streptozotocin (STZ) causes ß cell death in rodents via the mechanism of DNA damage precipitating poly(ADP-ribose) synthetase activation followed by lethal nicotinamide adenine dinucleotide depletion. It is unclear whether humans are susceptible to this mechanism. Islets were isolated from STZ-sensitive (CD1 mice and Lewis rats) and resistant [fish (tilapia)] species and from man and then were transplanted into diabetic nude mice under the kidney capsule. Normoglycemic recipients with normal glucose tolerance tests on d 30 were injected with increasing iv doses of STZ and their plasma glucose levels followed for 5 d; glucose tolerance tests were repeated on nondiabetic mice. Mice were then killed; grafts and native pancreata were examined. Based upon three criteria (i.e. nonfasting plasma glucose levels, glucose tolerance tests, and islet histology), the following observations were made: 1) Recipients of rat islets were resistant to 25 mg/kg but were uniformly diabetic at doses of 50 or 75 mg/kg. 2) Recipients of mouse islets were resistant to 75 mg/kg but were uniformly diabetic at 150 or 200 mg/kg. 3) Recipients of the fish islets were resistant to 300, 400, and 450 mg/kg. 4) Recipients of human islets were resistant to 100, 200, 300, 400, and 450 mg/kg. The results in recipient mice bearing long-term rat, mouse, or fish islet grafts were the same as previously published dose-response data for each donor species. We extrapolate from our results based on human islet grafts in mice that human ß cells are exceedingly resistant to STZ.


   Introduction
Top
 Abstract
 Introduction
Materials and Methods
 Results
 Discussion
 References
 
STREPTOZOTOCIN (STZ) is the prototype for ß cell death via the mechanism of DNA damage precipitating poly(ADP-ribose) synthetase activation followed by lethal nicotinamide adenine dinucleotide (NAD) depletion, a mechanism well documented in rodent islets (1). It is unclear whether human islets are susceptible to this type of damage. The diabetogenic doses of STZ in rodents are well known but for obvious ethical reasons, no one has ever performed a dose response study on human subjects. Therefore, we performed a study in which we determined the susceptibility of human islets to various doses of STZ in a nude mouse islet transplantation model; to validate this model, we also demonstrated that STZ sensitivity in recipients of islet grafts from species known to be highly susceptible (rats), susceptible (mice), and highly resistant (fish) to the diabetogenic effects of STZ maintain the same pattern of STZ sensitivity as the donor species. Ergo, we can extrapolate that our results based on human islet grafts in murine recipients closely reflects STZ sensitivity in man. Our study conclusively demonstrates, using an islet transplant model, that human islets are exceedingly resistant to the diabetogenic effects of STZ in vivo.


   Materials and Methods
Top
 Abstract
 Introduction
 Materials and Methods
Results
 Discussion
 References
 
Islet donors, harvesting, and transplantation
Fish [tilapia (Oreochromis niloticus], Dalhousie Marine Gene Probe Laboratory hatchery, Halifax, Canada), male Lewis rats (Harlan Sprague Dawley, Inc., Indianapolis, IN) and male CD-1 mice (Charles River Laboratories, Inc., Montréal, Canada) were used as animal islet donors.

Fish islets were enzymatically mass harvested and purified (2). Rodent islets were isolated from donor rats or mice using the collagenase-Ficoll method (3, 4), and further purified by hand-picking (5). Both fish and rodent islets were cultured overnight at 37 C, 5% CO2 in CMRL 1066 culture medium with 10% FCS, 100 U/ml penicillin, and 100 µg/ml streptomycin sulfate before transplantation. Cadaveric human islets were provided by the Juvenile Diabetes Foundation International Human Islet Distribution Program at the University of Minnesota (Minneapolis, MN). They were transported to our laboratory in CMRL 1066 culture medium supplemented with 10% horse serum albumin, and immediately transplanted.

Male athymic nude mice weighing approximately 25–30 g (Harlan Sprague Dawley, Inc.) were rendered diabetic by iv injection of 200 mg/kg STZ (Sigma, Oakville, Ontario, Canada). Diabetic mice with at least two successive nonfasting blood glucose measurements over 400 mg/dl (22.2 mmol/liter) were selected as recipients.

Mouse, rat, fish, or human islets were transplanted under the left kidney capsules of STZ-diabetic nude mouse recipients using a method previously described (6, 7). Sufficient islets from each species were transplanted to assure uniform restoration of normoglycemia [i.e. roughly 500 hand-picked rat or mouse islets, all of the islet tissue harvested from 800-1000 g (total body weight) of donor fish (7), and roughly 4000 human islet equivalents]. After transplantation, nonfasting blood glucose levels were monitored three times a week using retro-orbital sampling and a Glucometer Elite (Bayer Corp. Canada, Etobicoke, Ontario, Canada). Normoglycemia was defined as nonfasting blood glucose levels less than 200 mg/dl (11.1 mmol/liter).

Glucose tolerance test (GTT)
On d 30 postislet transplantation, recipient mice bearing islet grafts from different donor sources were subjected to GTTs (8, 9). GTTs were performed as follows. After an overnight fast (18 h), mice were injected ip with 50% dextrose (Abbott Laboratories, Montréal, Canada) at a dose of 4 g/kg body weight. Blood samples were collected at 0, 10, 30, 60, and 120 min postglucose loading. Blood glucose levels were measured as before. Recipient mice that were not overtly diabetic after the STZ injection (see below) were subjected to a second GTT on d 40.

STZ injection
As shown in Table 1Go, on d 35 postislet transplantation (i.e. 5 d after first GTT), recipient mice bearing islet grafts from different donor sources received iv STZ injection at different doses ranging from 25–450 mg/kg body weight. STZ solutions were prepared in citrate buffer and were injected within 2 min of preparation. After STZ injection, recipients’ blood glucose levels and body weights were monitored daily, and the second GTTs were performed 5 d later.


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  		Table 1. STZ dose-response study in nude mouse recipients of Lewis rat, CD1 mouse, tilapia, or human islets

 
Histological studies
After STZ injection, those recipients with blood glucose levels greater than 200 mg/dl (11.1 mmol/liter) were terminated 5 d later. Those recipients that remained normglycemic and were given a second GTT on d 5 post-STZ injection were terminated another 2 d later. Terminated recipient mice were necropsied. Graft-bearing left kidneys and native pancreata were fixed in Bouin’s solution overnight and then postfixed in formalin. Tissues were processed for light microscopy. Paraffin sections of graft-bearing kidneys and native pancreata were stained with hematoxylin and eosin (H&E), aldehyde fuchsin (AF), immunoperoxidase for tilapia insulin (10), or immunoperoxidase for human insulin (DAKO Corp. A564, Santa Barbara, CA) (note that this antiserum cross-reacts well with both rat and mouse insulin).

Studies were performed in accordance with the Canadian Council on Animal Care guidelines and with the approval of the Dalhousie University Committee on Laboratory Animal Care.


   Results
Top
 Abstract
 Introduction
 Materials and Methods
 Results
Discussion
 References
 
The data are summarized in Table 1Go. Based upon three criteria (i.e. nonfasting plasma glucose levels, GTTs, and islet histology results), the follow observations were made: 1) recipients of rat islets were resistant to 25 mg/kg STZ (n = 3) but were uniformly diabetic at doses of either 50 (n = 3) or 75 (n = 3) mg/kg; 2) recipients of CD1 mouse islets were resistant to 75 mg/kg (n = 3) but were uniformly diabetic with doses of either 150 (n = 3) or 200 (n = 2) mg/kg; and 3) recipients of fish islets were uniformly resistant to doses of 225 (n = 1), 300 (n = 3) and 400 (n = 3) mg/kg STZ; however, at a dose of 450 mg/kg (n = 4), all mice were nondiabetic, but one had an abnormal GTT and one died while normoglycemic. Complete autopsies followed by histopathological examination, performed on mice receiving the higher doses, did not show any consistent changes indicative of significant systemic toxicity. Doses higher than 450 mg/kg were not tested in any mice because of the finite solubility of STZ in citrate buffer and the desire to avoid marked hemodilution by injecting excessive volume. The patterns in these three groups of recipients were consistent with the known degree of STZ sensitivity of each of the donor species (see Discussion). The results showed that relative degrees of STZ sensitivity could be accurately determined by performing STZ dose-response curves on islet-bearing recipient nude mice.

As summarized in Table 1Go, recipients of human islets were resistant to 100 (n = 1), 200 (n = 1), 300 (n = 2), 400 (n = 3), and 450 (n = 3) mg/kg (note that one mouse in the high dose group died while normoglycemic); none of these mice became overtly diabetic. Figure 1Go, superimposing the GTT profiles for recipients of human islets before STZ treatment and after STZ treatment at doses of 300 mg/kg iv, 400 mg/kg iv, and 450 mg/kg iv, demonstrates that massive doses of STZ had no apparent effect on GTT profiles. The GTT profiles of all human islet graft-bearing mice were substantially different from those of nondiabetic nude mice, which are glucose intolerant (11).



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  		Figure 1. GTT profiles for recipients of human islets before STZ treatment (each time point represents the mean value from n = 9 mice) and after STZ treatment at doses of 300 mg/kg iv (n = 2 mice), 400 mg/kg iv (n = 3 mice), and 450 mg/kg iv (n = 2 mice). Even at these massive doses, there was no apparent effect on glucose tolerance.

 
Figure 2Go shows the typical appearance of an human islet graft after treatment with a massive dose of STZ; in all instances, the ß cells remained densely granulated when stained for insulin by aldehyde fuchsin or immunoperoxidase.



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  		Figure 2. Histological sections showing human islets transplanted under the renal capsule of a nude mouse killed, while still normoglycemic, 1 wk after receiving 450 mg/kg iv STZ. In both photomicrographs, the upper portion of the photograph is the renal capsule containing an island of adipose tissue, the middle portion is the islet graft under the kidney capsule, and the lower portion is the renal cortex. A, Note the normal appearance of the islets (H&E, x156). B, Aldehyde fuchsin stain shows normally granulated ß cells (x156).

 

   Discussion
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
References
 
STZ, a methylnitrosourea with a 2-substituted glucose, causes ß cell necrosis and insulin-dependent diabetes mellitus in many species (12, 13, 14, 15, 16). The mechanism of action of STZ on rodent ß cells is well known. The glucose moiety allows preferential uptake of STZ into ß cells, probably via the glucose transporter (GLUT)-2 (17, 18). Because STZ is an alkylating agent, it causes DNA strand breaks which then activate poly(ADP-ribose) synthetase, an enzyme that polymerizes the ADP-ribose moiety of NAD to form poly(ADP-ribose); activation of poly(ADP-ribose) synthetase causes a precipitous, lethal depletion of NAD in the ß cells (1). Further aggravating the situation, intracellular metabolism of STZ yields nitric oxide which also precipitates additional DNA strand breaks (19). Within 48 h, severe insulin-dependent diabetes ensues, characterized histologically by massive ß cell necrosis and macrophage infiltration. This is also presumed to be the mechanism by which diabetogenic doses of STZ induce diabetes in other susceptible species. A number of other mammalian species have been reported to be sensitive (12, 13, 14, 15, 16), but rabbits are highly resistant with little metabolic or histologic evidence of ß cell damage at doses of up to 300 mg/kg and with higher doses having severe systemic toxicity (20). The diabetogenic dose of STZ in man is unknown, but there is considerable in vitro (21) and incidental in vivo (22) evidence that human islets are likely to be relatively resistant to STZ.

The results of STZ dose-response curves in recipient nude mice bearing long-term Lewis rat, CD1 mouse, or fish islet grafts parallelled the results of previously published dose-response data for each of the donor species. It is well documented that Lewis rats are highly sensitive to the diabetogenic effects of STZ with near uniform induction of severe diabetes with single iv doses of between 50 and 75 mg/kg (23) and that a single dose of 25 mg/kg will not induce overt diabetes in Lewis rats (24). Mice are also sensitive to STZ but are much less so than rats. We have published a STZ dose-response curve for male CD-1 mice at doses of 0, 60, 80, 100, 120, 140, and 160 mg/kg iv (8), which corresponds well with the current study; single iv injections of STZ at doses below 100 mg/kg did not cause either overt diabetes or GTT abnormalities, and, between 140 and 160 mg/kg, the incidence of overt diabetes reached 100% (8). Histologic sections of pancreatic islets stained for H&E and AF correlated well with the plasma glucose levels in this study (8).

The fish, for reasons that are currently unclear, are exceedingly resistant to STZ-induced ß cell toxicity (25). We have previously shown that doses below 300 mg/kg iv have no effect; doses of 300 and 350 mg/kg iv, although causing marked hepatic toxicity, some renal toxicity and, in some instances, temporary hyperglycemia, did not cause either ß cell necrosis or permanent hyperglycemia; higher doses could not be tested because of systemic toxicity. This is consistent with our current transplant data; however, surprisingly, we found that fish islet graft-bearing mice tolerated even higher doses with little apparent systemic toxicity; at a massive dose of 450 mg/kg iv, no animals became overtly diabetic and only one had an abnormal GTT. Doses higher than 450 mg/kg were not tested.

Because the results of STZ dose-response curves in recipient nude mice bearing long-term Lewis rat, CD1 mouse, or fish islets parallelled the results of previously published dose-response data for each of the donor species, we can extrapolate that our results based on human islet grafts in murine recipients closely reflects STZ sensitivity in man. Because nude mice bearing human islet grafts were resistant to doses up to and including 450 mg/kg iv, we conclude that human ß cells, like fish ß cells, are exceedingly resistant to the diabetogenic effects of STZ in vivo.

One very puzzling finding is that human ß cells appear to be radically more resistant to STZ than those of all other primates that have been studied. For instance, high incidences of insulin-dependent diabetes have been reported in cynomologus monkeys, rhesus monkeys, vervet monkeys, pig-tailed macaques, and baboons at very low doses varying from 30–60 mg/kg iv (16, 26, 27, 28, 29, 30, 31, 32). It is interesting that humans and the other primates appear at opposite extremes of the STZ sensitivity continuum.

Results of a study examining the effectiveness of STZ on fetal ß cells strongly support our tenet that human ß cells are resistant to STZ. Tuch et al. (33) transplanted human fetal pancreas fragments under the renal capsules of pairs of nondiabetic nude mice, allowed the grafts to mature for 3 wk before injecting 275 mg/kg STZ ip to induce diabetes (i.e. destroying the islets in the murine native pancreas) in one of each pair, and then removed the grafts 1 wk, 2–4 wk, or 3 months later and measured insulin content (or compared numbers of ß cells after immunoperoxidase staining) relative to the paired controls. In this study, they found that STZ had "no demonstrable effect on the human fetal B cell" and suggested that these findings supported their original hypothesis that "this agent would not adversely affect the immature B cell, as opposed to its well known effect on the adult B cell." In the light of our present study, an alternative explanation for their data could be that the STZ was ineffective because human ß cells are resistant to STZ rather than because they were immature. However, studies with porcine islets clearly suggest that fetal islets (34, 35) are more resistant to STZ than adult islets (15).

One possible explanation for the marked resistance of human ß cells to STZ could be impaired uptake. De Vos et al. (36) have shown that human ß cells express predominately GLUT-1 instead of GLUT-2. Furthermore, the 100-fold lower levels of GLUT-2 in human vs. rat ß cells is associated with a 10-fold lower uptake of the ß cell toxin alloxan. De Vos et al. (36) have invoked this mechanism to explain the marked resistance of human ß cells to the diabetogenic effects of alloxan, an observation that has been shown in vitro by Eizirik et al. (21) and then confirmed in vivo using an islet transplant model (21, 37). While the lack of STZ uptake by human ß cells (i.e. relative to rodent ß cells) could also provide a logical explanation for STZ’s absence of an effect on human islet grafts, STZ uptake by human ß cells has not been specifically studied. However, the human fetal pancreas data presented by Tuch et al. (33) would seem to suggest that impaired uptake by human vs. rodent ß cells may not be the explanation since they were able to show preferential uptake of STZ into human fetal pancreas transplanted under the renal capsule of nude mice relative to any other nude mouse tissue including liver and kidney (i.e. sites of STZ metabolism) as well as relative to fetal human nonpancreatic tissue transplanted under the renal capsules of nude mice. Interestingly, tissue levels in human fetal pancreas grafts were at least 5-fold higher (per mg of tissue) than in recipient nude mouse native pancreas. Considering that the murine native pancreas is comprised of roughly 1% ß cells and that the fetal human pancreas is comprised of 4–10% ß cells, STZ uptake by human fetal ß cells seems to be roughly equivalent to uptake by mouse ß cells, which possess high levels of GLUT-2.

Because STZ is an alkylating agent which, based upon animal studies, is known to have preferential activity against ß cells, it has generally been considered to be the drug of choice for treatment of patients with malignant insulinomas (22, 38, 39, 40). Our results demonstrating that STZ has no apparent effect on normal human ß cells, along with those of Tuch et al. pertaining to fetal ß cells (33), may explain the poorer than expected efficacy of STZ in the treatment of patients with insulinomas (22, 38, 39, 40). Our results also explain the absence of diabetes as a common sequella of treatment of insulinoma patients with STZ (22, 38). Clinical STZ treatment usually involves repetitive, minuscule doses [note that the antineoplastic doses of STZ used clinically may be up to two orders of magnitude lower than the high doses used in the current study (22)]. Furthermore, even the total cumulative doses of STZ given to cancer patients are very much lower than the single doses used in this study. Considering that many studies have shown that the use of multiple, small doses of STZ is a very poor way to induce diabetes in almost all animal species tested [n.b., the notable exception is the multiple low-dose STZ model of autoimmune diabetes that works in only a few genetically susceptible mouse strains (41)], the absence of diabetogenic side effects in these patients is hardly surprising. Like normal human ß cells (36), insulinoma cells are known to express predominately GLUT-1 rather than GLUT-2 (42).

In addition to the aspects discussed above, the results of our study suggest one possible broader repercussion. STZ is the prototype for ß cell death via the mechanism of DNA damage precipitating poly(ADP-ribose) synthetase activation followed by lethal NAD depletion (1). There are twenty years of compelling evidence for this mechanism of action for STZ in rodent ß cells (43, 44, 45, 46, 47, 48). Okamoto (1) and others have suggested that poly(ADP-ribose) synthetase activation is involved in the pathogenesis of insulin dependent diabetes, regardless of whether ß cell DNA strand breaks are initiated by drugs, environmental insults (e.g. nitrosamines, nitroallenes, etc.), by nonspecific inflammatory mediators involved in the insulitis process (e.g. cytokines, oxygen radicals or nitric oxide), or by other insults. If so, our data suggest that this mechanism may be operative in rodent islets but that there may be a fundamental difference between the mechanism underlying the onset of diabetes in rodents and in man. If such a difference does exist, it calls into question the validity of popular rodent models of spontaneous autoimmune diabetes such as the nonobese diabetic mouse and BB Wistar rat as well as the logic of clinical trials attempting to prevent diabetes with nicotinamide, a potent poly(ADP-ribose) synthetase inhibitor that prevents STZ-induced diabetes in rodents (1) and delays the onset of autoimmune diabetes in nonobese diabetic mice (49). Although this interpretation may be extreme, it highlights the need to determine why human ß cells differ so radically from most other types of mammalian ß cells (i.e. including those of all other primate species that have been studied) relative to their susceptibility to STZ.


   Footnotes
 
Financial support was provided by the Canadian Institutes for Health Research, Izaak Walton Killam Health Center Research Associateship (Yang), Dalhousie University Senior Clinical Research Scholarship (Wright), and the Juvenile Diabetes Foundation International Human Islet Distribution Program.

Abbreviations: GLUT, Glucose transporter; GTT, glucose tolerance test; H&E, hematoxylin and eosin; NAD, nicotinamide adenine dinucleotide; STZ, streptozotocin.

Received December 26, 2001.

Accepted for publication March 19, 2002.


   References
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 References
 

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