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Centre National de la Recherche Scientifique Unité de Recherches Associée 1461 - Université Paris V, Hôpital Necker, 75015 Paris, France
Address all correspondence and requests for reprints to: Françoise Homo-Delarche, Centre National de la Recherche Scientifique Unité de Recherches Associeé 1461, Hôpital Necker, 161, rue de Sèvres, 75743 Paris Cedex 15, France. E-mail: dardenne{at}infobiogen.fr
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Abstract |
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 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
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Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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The conflicting data cited above could reflect the fact that the observations may involve different steps in the progression of the prediabetic stage. For example, in our investigation on stress effects in 2-month-old prediabetic NOD mice, we observed that, 2 h after saline injection, plasma insulin concentrations were significantly higher in NOD than in age-matched C57BL/6 females (28). Moreover, we also showed an unexpected recovery of insulin secretion during immobilization stress, only in 2-month-old NOD females, compared with age-matched C57BL/6 females and NOD and C57BL/6 males, in which insulin reduction was, as normally described, sustained throughout the stress period (29). These findings indicated that insulin production was far from being impaired at the prediabetic stage in NOD females, despite the progression of insulitis, and these results even suggest the existence of some ß-cell hyperactivity (30). We therefore examined various parameters of glucose homeostasis (glycemia, insulinemia, and pancreatic insulin content) under basal conditions in both sexes of 4-, 6-, and 8-week-old fed NOD mice, compared with sex- and age-matched fed C57BL/6 mice, taken as controls. We also assessed glucose tolerance in fasting 8-week-old NOD females and males, compared with sex- and age-matched fasting C57BL/6 mice. Finally, to demonstrate a possible relationship between the progression of insulitis and the appearance of ß-cell hyperactivity, we investigated glucose tolerance in younger NOD mice, which exhibited various degrees of insulitis.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Experimental protocol under basal conditions and for glucose
tolerance test
For glucose tolerance determinations, overnight-fasted mice were
injected ip with glucose (Assistance Publique, Paris, France),
dissolved in 0.9% NaCl, at doses varying from 1–6 g/kg (19, 20, 22, 25, 26). For basal and glucose tolerance test determinations, all
experiments started at 0900 h. In all cases, unanesthetized
animals were bled in less than 2 min by retroorbital puncture. As
previously shown, this technique avoids stress-induced metabolic
changes, at least during the sampling time (29). In this study, mean
values (± SEM, n = 6 mice per age group) of blood
corticosterone concentrations were 39 ± 5, 51 ± 8, 20
± 3, and 24 ± 3 ng/ml in 4- to 8-week-old NOD females, C57BL/6
females, NOD males, and C57BL/6 males, respectively, with the higher
values observed in females reflecting the expected sexual dimorphism
(29, 35, 36). In each series of experiments, different groups of
animals were bled at different times to avoid the hyperglycemic effect
of repeated orbital puncture (29). Blood samples were kept on ice and
centrifuged at 13,000 x g for 2 min at 4 C and were
stored at -20 C. Pancreata were rapidly removed, weighed, and
homogenized in 15 ml cold acid ethanol extraction medium [1.5%
(vol/vol) 1 N HCl in 75% ethanol]. After addition of another 10 ml
extraction medium, the homogenates were centrifuged (800 x
g for 15 min, 4 C), and the supernatants were left standing
overnight at 4 C. The pH of the supernatants was adjusted to 8.5 with
ammonium hydroxide and, after centrifugation (800 x g
for 15 min, 4 C), 5 ml of each supernatant were stored at -20 C until
assayed.
Glucose and insulin determinations
Glucose concentrations were measured using the glucose-oxidase
method (Biotrol glucose enzymatic color, Biotrol, Paris, France).
Insulin concentrations were determined using a standard RIA kit
(SB-INSULIN CT, CIS BioInternational, Gif-sur-Yvette, France).
Statistical analyses
All data are means ± SEM. The differences
between mean values of glucose and insulin were evaluated by means of a
two-, three-, or four-P-factor ANOVA. Post hoc
analysis, using the Newman-Keuls test, was done when the main effect
and interaction were significant (P < 0.05), as
assessed by ANOVA.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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(upper panel)
shows body weight curves for both sexes of NOD and C57BL/6 mice at 4,
6, and 8 weeks of age. ANOVA revealed, among other effects and
interactions, that strain, sex, and age affected body weight
(P < 10-6 for each factor). Indeed, for
both sexes at all ages investigated, NOD mice weighed significantly
more than C57BL/6 mice (P < 0.00005 in all cases, by
post hoc analyses). Moreover, for both strains, body weights
of females were significantly lower than those of males at each age
evaluated (P < 0.00005 by post hoc
analyses), except 4-week-old C57BL/6 mice. Finally, body weight
increased significantly as a function of age for both sexes of NOD and
C57BL/6 mice, and this effect was significant at each age studied
(P values from 0.02 to < 0.0005 by post hoc
analyses).
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(middle
panel). ANOVA indicated, among others, that strain, sex, and age
affected pancreas weight (P < 10-6). For
both sexes, at each age investigated, pancreas weights were
significantly higher for NOD than C57BL/6 mice (P <
0.00002 in all cases, by post hoc analyses), except for
6-week-old females (P = 0.02). Pancreas weights were
generally lower for females than males, with the effect being
significant in 6-and 8-week-old NOD and C57BL/6 mice (P
values from 0.002 to < 0.00002 by post hoc analyses).
Pancreas weights also increased as a function of age, and this effect
was seen for all groups of mice between 4 and 6 weeks and 6 and 8 weeks
of age (P values from 0.02–0.00002 by post hoc
analyses for all groups), except C57BL/6 females between 6 and 8 weeks
of age. It should be mentioned that body and pancreas weights were
systematically greater in NOD than in sex- and age-matched C57BL/6
mice. However, when the pancreas weight was normalized to body weight
(Fig. 1, lower panel), there was no statistically
significant difference between both strains.
Blood nonfasting glucose and insulin concentrations are shown for both
sexes of NOD and C57BL/6 mice, as a function of age, in Fig. 2 (upper panel). ANOVA
revealed, among the various effects, that strain, sex, and age affected
glycemia (P < 10-6 in all cases). First,
at 6 and 8 weeks of age, in both females and males, glycemia values
were significantly lower in NOD than in C57BL/6 mice (P
values from 0.002–0.0003 by post hoc analyses). Second, in
NOD mice, glycemia values were statistically significantly lower for
females than males at 4 and 6 weeks of age (P = 0.003
and P = 0.00003, respectively, by post hoc
analyses) but not at 8 weeks of age. In C57BL/6 mice, glycemia values
were statistically lower for females than males at 6 and 8 weeks of age
(P = 0.00002 and P = 0.04,
respectively, by post hoc analyses) but not at 4 weeks of
age. Third, while no significant effect of age was observed for females
of both strains, it could be noted that, for males of both strains,
glucose concentrations increased from 4–6 weeks of age (with the
effect being significant only for C57BL/6 males, P =
0.00003 by post hoc analyses) and then decreased
significantly from 6–8 weeks of age (P = 0.00001 and
P = 0.002 for NOD and C57BL/6 males, respectively, by
post hoc analyses).
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, lower panel),
ANOVA indicated, among others, that strain and age affected its
concentrations (P < 10-5 in both cases).
First, in females at the three ages investigated, basal blood insulin
values were significantly higher in NOD than in C57BL/6 mice
(P values from 0.001–0.00001 by post hoc
analyses). For males, the same pattern was observed between the two
strains, but it reached statistical significance only at 6 weeks of age
(P = 0.00003 by post hoc analyses). Second,
although at each age studied, there was no significant difference
concerning basal blood insulin concentration values between C57BL/6
females and males, these values were significantly higher in NOD males
than females at 6 weeks of age, and the opposite was found at 8 weeks
of age (P = 0.0002 and P = 0.01,
respectively, by post hoc analyses). Third, though there was
no significant effect of age on blood insulin values in females of both
strains, by contrast, these values peaked at 6 weeks of age in males,
with the effect being statistically significant only for NOD males
(P = 0.00002 when comparing 6-week-old to 4- or
8-week-old animals).
Pancreatic insulin contents are shown in Fig. 3. When expressed in nmol/pancreas
(upper panel), ANOVA revealed that strain (P
< 10-6), sex (P = 0.005), and age
(P < 10-6) affected pancreatic insulin
content. Pancreatic insulin contents expressed in nmol/pancreas were
significantly higher in NOD than in C57BL/6 females at 4 and 6 weeks of
age (P = 0.009 and P = 0.01,
respectively, by post hoc analyses) and in 6-week-old NOD
males than in C57BL/6 males (P = 0.007 by post
hoc analyses). A sex effect was only observed for 8-week-old
C57BL/6 mice; females exhibited significantly higher pancreatic insulin
contents (nmol/pancreas) than males (P = 0.01 by
post hoc analyses). Pancreatic insulin content also
increased as a function of age, with the effect being significant from
4–6 weeks of age for NOD females, C57BL/6 females, and NOD males
(P = 0.03, P = 0.03, and
P = 0.01, respectively, by post hoc
analyses) and from 6–8 weeks of age for C57BL/6 females
(P = 0.008 by post hoc analyses). When
expressed in pmol/mg of pancreas (Fig. 3, lower panel),
ANOVA indicated that sex (P = 0.01) and age
(P = 0.00002) influenced insulin pancreatic contents.
Among NOD mice, females seemed to have higher insulin contents (pmol/mg
of pancreas) than males at 4 and 6 weeks of age, but the effect was
significant only at 6 weeks of age (P = 0.04 by
post hoc analyses). For 4-week-old C57BL/6 mice, the
opposite was found, with males showing higher insulin contents than
females (P = 0.0002 by post hoc analyses).
However, this effect disappeared rapidly, so that 6- and 8-week-old
C57BL/6 females tended to exhibit higher insulin contents than males.
Indeed, the C57BL/6 male insulin content, expressed in pmol/mg of
pancreas, dropped sharply between 4 and 6 weeks of age
(P = 0.0001 by post hoc analyses). Finally,
4-week-old C57BL/6 males had higher insulin contents (pmol/mg of
pancreas) than age-matched NOD males (P = 0.0002 by
post hoc analyses).
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. Basal fasting glucose values (time
zero) were 3.8 ± 0.5, 4.2 ± 0.5, 4 ± 0.5, and
4.3 ± 0.5 mmol/liter (means ± SEM, 18
mice/group) in NOD females, NOD males, C57BL/6 females, and C57BL/6
males, respectively. No significant differences were observed among the
various groups. The effect of glucose, given at the single dose of 1
g/kg, was studied on blood glucose concentrations 5, 10, 30, 60, and 90
min after injection (Fig. 4, upper panel). ANOVA revealed
that strain, sex, and time affected blood glucose concentrations
(P < 10-5 for each factor). Moreover,
there were strain x sex (P = 0.01), strain
x time, and sex x time interactions (P <
10-6 in both cases). Indeed, for a given sex, the
glucose-response pattern differed between the two strains: peak plasma
glucose values were reached faster, at 5 min in NOD mice vs.
10 min in C57BL/6 mice. Ten minutes after glucose injection, glucose
values were significantly higher in both sexes of C57BL/6 than in
sex-matched NOD mice (P = 0.00003 and P
= 0.00001 for females and males, respectively, by post hoc
analyses). Moreover, in each strain, glucose concentrations returned
less rapidly to basal values in males than females. This slower return
to basal glucose levels in males was more pronounced in C57BL/6 mice
(P values varying from 0.0001–0.04 at 30, 60, and 90 min,
by post hoc analyses), whereas in NOD mice, the effect was
only significant at 30 min (P = 0.01 by post
hoc analyses).
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The effects of various glucose doses (from 1–6 g/kg) on blood
glucose and insulin concentrations in each strain were analyzed at 8
weeks of age, 5 and 10 min after injection being the respective time
points of maximal responses in fasting NOD and C57BL/6 mice (Fig. 5). Saline was injected as the control.
ANOVA indicated that strain, sex, and treatment influenced blood
glucose concentrations (P < 10-6,
P = 0.01, and P < 10-6,
respectively) (Fig. 5, upper panel). Moreover, there was a
strain x treatment interaction (P <
10-6). Indeed, blood glucose concentrations increased
gradually in both sexes of both strains, with increasing doses of
glucose (P values varying from 0.004–10-5 in
each group, by post hoc analyses), and the effect was less
pronounced in NOD than in C57BL/6 mice (P = 0.0001 and
P = 0.00002 for females at 4 and 6 g/kg glucose,
respectively; and P = 0.04, P = 0.0007,
and P = 0.00002 for males at 2, 4, and 6 g/kg glucose,
respectively, by post hoc analyses).
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, lower panel), ANOVA indicated that
strain, sex, and treatment affected its concentrations
(P = 0.0003, P = 0.004, and
P < 10-6, respectively). Moreover,
there were strain x sex and strain x treatment
interactions (P = 10-6 and
P = 0.009, respectively). The observation that the sex
effect differed according to the strain considered should be
emphasized: for NOD mice, glucose administration led always to higher
insulin concentrations in females than in males, with the effect being
significant at 1 and 6 g/kg of glucose (P = 0.0003 and
P = 0.05, respectively, by post hoc
analyses). In C57BL/6 mice, the opposite effect seemed to be found, but
it never reached statistical significance.
The effect of varying glucose concentrations on blood glucose and
insulin concentrations in both sexes of 4-, 6-, and 8-week-old
fasting NOD mice was also analyzed (Fig. 6). We previously demonstrated that
4-week-old NOD mice exhibit no insulitis, whereas 10–20% and 30–40%
of the islets show signs of insulitis at 6 and 8 weeks of age,
respectively (37, 38). ANOVA revealed that age and treatment affected
blood glucose concentrations both individually and together
(P < 10-6 in all cases) (Fig. 6, upper panel). Indeed, increases in glucose concentrations
with increasing glucose doses were less marked at 4 than at 6 and 8
weeks of age in both sexes, with the effect being significant at all
glucose doses (P values ranging from 0.02–0.00001 by
post hoc analyses).
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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With regard to basal insulinemia in nonfasting animals, a marked strain
difference was observed; this effect was particularly striking, at all
ages, for females, with NOD mice having higher insulin levels than sex-
and age-matched C57BL/6 mice. Therefore, at the prediabetic stage, the
high NOD mouse basal insulinemia may be responsible for the low
glycemia. It should be emphasized that blood insulin levels are
extremely sensitive to environmental and experimental conditions.
Therefore, extreme care in animal housing and bleeding (as assessed by
corticosterone determinations) is needed to avoid the
2-adrenergic inhibitory effect of catecholamines on
insulin secretion (29, 37). Our in vivo data, showing high
basal insulin secretion in fed NOD mice, confirm data obtained in
vitro using isolated islets from various mouse strains (38).
Kinetic studies, after glucose loading, demonstrated that in both sexes
of NOD mice, insulin levels peaked earlier than in sex-matched C57BL/6
mice. Moreover, prediabetic 8-week-old NOD females secreted,
surprisingly, approximately twice as much insulin as NOD males in
response to glucose (1 g/kg) loading, an effect that has been confirmed
in dose-response studies and which differs from that observed in
C57BL/6 mice. Indeed, in normal rodents, circulating insulin
concentrations, under basal conditions and/or response to glucose, have
generally been reported to be higher in males than in females, because
of the presence of androgens, which induce a state of insulin
resistance (28, 29, 39, 40, 41). However, it should be emphasized here that
androgens may act on the progression of type I diabetes in a complex
manner, by exerting both deleterious effects (via their antiinsulin
action) and beneficial, immunosuppressive effects (42). Finally, in
males of both strains, in parallel to what has been observed for
glycemia, blood basal insulin concentrations peaked at 6 weeks of age.
Moreover, the insulin response to glucose loading was enhanced at 6
(compared with 8) weeks of age in NOD females and also in NOD males,
when considering the highest glucose dose administered. This effect can
be linked to the hormonal changes that occur during the pubertal
period. It is well known that insulin resistance occurs during puberty
in normal and diabetic children of both sexes (43, 44, 45). Adrenal
androgens, such as DHEA-s, and GH may be factors responsible for the
decline in insulin sensitivity (44).
The finding of ß-cell hyperactivity, particularly in prediabetic NOD females, corroborates that of concomitant ß-cell hyperplasia (46). The cause of ß-cell hyperplasia in early prediabetes in NOD mice is unknown. In rat models of IDDM induced by partial pancreatectomy, various compensatory mechanisms are involved, including increases of ß-cell sensitivity and activity, ß-cell hyperplasia, and islet regeneration (47, 48, 49, 50, 51). Hypertrophy and regeneration of some islets of Langerhans is a normal feature of recent-onset human IDDM (52, 53). However, ß-cell loss does not seem to be responsible for the ß-cell hyperactivity observed at the various ages investigated here, because: 1) ß-cell loss is considered to be a late phenomenon in NOD mice (54, 55); and 2) pancreatic insulin contents (nmol/pancreas) were not lower. It should be emphasized that the decrease in pancreatic insulin content, which is observed when expressing the results in pmol/mg of pancreas, is linked to the striking growth of the exocrine pancreas after birth (56, 57). It is also interesting to note that, in NOD females, whereas significant hyperinsulinemia was observed under basal nonfasting conditions as early as 4 weeks of age, an increased response to glucose loading was only observed as of 6 weeks of age. The above observations should be interpreted in light of the following data: 1) A primary (genetic) ß-cell abnormality, taking into account the role of the insulin gene, and especially the variable number tandem repeat region in human IDDM (58, 59, 60), cannot be excluded. 2) The NOD female ß-cell hyperactivity in response to glucose loading seems to follow the appearance of insulitis, because it is not observed in 4-week olds, in which less than 1% of the islets exhibit insulitis (33). This ß-cell hyperactivity, therefore, may be linked to the production of cytokines, for example IL-1 (which, at low doses, is known to stimulate insulin secretion but is inhibitory at high doses) (61, 62, 63). In keeping with this mode of action, specific IL-1 receptors are located in the islets of Langerhans in prediabetic NOD mice (64). 3) In addition to androgens, estrogens are able to modulate glucose homeostasis. In rodents, estradiol treatment can induce hypoglycemia, raise plasma insulin (and sometimes, pancreatic insulin contents), increase the ß-cell response to glucose in vivo, and induce ß-cell hyperplasia (65, 66, 67). Furthermore, the adrenal glands seemed to be essential for the expression of these estradiol effects on ß-cells (67), and this observation is consistent with the particular sensitivity of the NOD mouse hypothalamo-pituitary-adrenal axis (28). It is possible to suggest that, in NOD females, estrogens and glucocorticoids may synergize with the stimulatory effect of cytokines on ß-cell hyperactivity.
As mentioned here, sex steroids exert multiple and complex effects at various levels of glucose homeostasis in normal animals. We showed previously that castration increases the incidence of the disease in NOD males, though having no effect in NOD females, results which were mainly interpreted in terms of immunosuppressive effects of androgens (31). However, because orchidectomy is also known to induce islet hypertrophy and increased insulin response to hyperglycemia, even in normal animals (68), it remains to be determined whether the effects of hormonal modulation on islet characteristics and glucose homeostasis play a direct role in the pathogenesis of the disease in NOD mice.
In conclusion, the notion of transient hyperactivity of some islets of Langerhans may be crucial in the context of the role of the target organ in the development of the disease (30). Indeed, the expression of autoantigen(s) in the islet of Langerhans is required in NOD mice for activation of T cells and diabetes transfer (69). Moreover, studies in humans and rodents suggest that prophylactic insulin treatment slows the progression of the disease, partly by inducing ß-cell rest (30, 70, 71, 72, 73). Hyperactive islets are known to express elevated levels of cell adhesion ligands, MHC molecules, and autoantigens, which may heighten the sensitivity of ß-cells to the cytotoxic effects of cytokines and precipitate diabetes onset (30, 74, 75). In this context, it is worth noting that the NOD-scid/scid mouse, which lacks functional lymphocytes and exhibits neither insulitis nor diabetes, is also characterized by the presence of mega-islets and dendritic/macrophage infiltration (46) and the same parameters of glucose homeostasis as those described here for the young prediabetic NOD mouse, i.e. low basal glycemia and high insulinemia in the nonfasting state (76). These results suggest that an early abnormality at the level of the islet of Langerhans may play a role in the pathogenesis of type I diabetes, but the presence of functional lymphocytes is necessary for progression toward true insulitis and overt diabetes. The clinical and immunological importance of this finding and its pathophysiological mechanism(s) remain to be resolved (77).
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Acknowledgments |
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Footnotes |
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Received June 20, 1997.
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| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
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) and C57BL/6 (
) mice. Values are means ±
SEM (n = 12 mice/age group). Strain,
sex, and age affected body and pancreas weights (P
< 10-6 in all cases, by ANOVA).
0.0003 by post hoc
analyses). Note a significant sexual dimorphism in insulin
concentrations, at 5 min in NOD mice, with females exhibiting higher
values than males (P < 10-5 by
post hoc analyses).
