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Departments of Physiology (O.C., S.C., K.I., M.V., S.G.M.), Obstetrics and Gynecology (S.G.M.), and Medicine (M.V.), University of Toronto, Toronto, Ontario, Canada M5S 1A8
Address all correspondence and requests for reprints to: Dr. Stephen G Matthews, 1 King’s College Circle, Medical Sciences Building, Room 3240, University of Toronto, Toronto, Ontario, Canada M5S 1A8. E-mail: stephen.matthews{at}utoronto.ca
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Abstract |
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Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Hyperactivation of the HPA axis of patients with diabetes mellitus has been reported previously, especially when poor glycemic control and ketoacidosis are present (3, 4, 5). Both type 1 and type 2 diabetic patients have been characterized with elevated circulating cortisol levels along with increased 24-h urinary free cortisol levels (6). Moreover, diabetic patients have been shown to have disrupted circadian patterns of cortisol secretion, with elevated cortisol levels, during the trough and normal or slightly elevated values during peak secretion (3, 7). Studies have revealed that increases in HPA activity in diabetic patients may be attributable to altered control of ACTH release from corticotrophs, as well as direct actions of CRH at the adrenal gland to release cortisol independently of pituitary ACTH release (8, 9). In addition, both type 1 and type 2 diabetic patients exhibit greater incidences of nonsuppression of pituitary-adrenal activity, after glucocorticoid administration, compared with nondiabetic individuals (10). This study suggests that hyperactivation of the HPA axis in diabetic patients may be attributable, in part, to decreased glucocorticoid-negative feedback sensitivity. However, the precise mechanism remains to be determined. Molecular regulation of the HPA axis has not been studied in humans.
Increases in plasma glucocorticoid levels are beneficial, during times of stress, to aid in the mobilization of glucose stores from the liver and FFA from adipocytes, as well as to suppress further activity of the HPA axis. However, chronic exposure to elevated glucocorticoid levels is harmful (11, 12, 13, 14). Glucocorticoids inhibit glucose uptake in adipocytes and fibroblasts, decrease local cerebral glucose utilization, and inhibit glucose uptake in hippocampal neurons in vitro. Prolonged exposure of hippocampal neurons to elevated glucocorticoid levels can lead to neurodegeneration or suppressed neurogenesis in the hippocampus, particularly in CA3 pyramidal neurons (15). This may have important implications in neuropathologies associated with diabetes, especially in the areas of learning and memory and cognitive dysfunction (16).
The purpose of this study was to examine alterations in central regulation of the HPA axis during the early stages of streptozotocin (STZ)-induced diabetes, and to examine mechanisms involved in normalization of HPA activity with insulin therapy. We hypothesize that central regulation of the HPA axis differs among normal, diabetic, and insulin-treated diabetic rats.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Experimental design
Three groups of rats were used: 1) normal controls (n = 6);
2) untreated diabetic (n = 6); and 3) insulin-treated diabetic
(n = 6) rats. On d 0, diabetes was induced with a single injection
of STZ (65 mg/kg; Sigma, St. Louis, MO) in sterile saline,
through the penile vein, under light ketamine (100 mg/kg BW, ip;
MTC Pharmaceuticals, Cambridge, Ontario, Canada), acepromazine (1 mg/kg
BW, ip; Wyeth-Ayerst Laboratories, Inc., Montréal,
Québec, Canada), xylazine (1 mg/kg BW, ip; Bayer Corp., Etobicoke, Ontario, Canada) cocktail anesthesia. Control
animals received an injection of sterile saline under similar
conditions. To correct the diabetes (defined as blood glucose >15
mM), a subgroup of diabetic rats was treated ip
with Linplant (
2.5 U insulin/d, ip; LinShin Canada, Inc., Toronto, Ontario, Canada), a sustained release bovine
insulin preparation, 4 d after the induction of diabetes. The
implant was conducted under light ketamine/acepromazine/xylazine
anesthesia using aseptic techniques and remained in place for 4 d.
The rationale and technical aspects of the insulin implant have been
detailed previously (17). Blood glucose was monitored
twice daily in all groups, using a blood glucose meter (Glucometer
Elite 3909; Bayer Corp.), to ensure that fasting
normoglycemia was maintained in control and insulin-treated animals and
that adequate hyperglycemia (>15 mM) was
achieved in diabetic rats. Insulin-treated animals that demonstrated
hypoglycemic episodes were excluded from the study. To maintain parity
with glucose turnover studies performed in fasted animals in our
laboratory, the rats were fasted for 24 h before being killed
(18). In our experience and others (19, 20),
an acute overnight fast does not significantly influence basal
corticosterone levels (basal corticosterone in nonfasted rats; normal
controls, 295.2 ± 63.9; and STZ-diabetic rats, 521.1 ± 75.6
nM). These values were not significantly
different from those of the fasted rats (see Fig. 1D
). Because diabetic rats are
hyperphagic, we therefore hypothesize that after a 24-h fast, the
diabetic rats will be more comparable with normal fasted rats than a
comparison between fed normal controls and fed diabetic rats. During
the fasting period, insulin-treated animals received a 5% sucrose
solution, in place of their regular drinking water, to prevent
hypoglycemia and to maintain normal blood glucose levels
(21). Eight days after the initial injection of saline or
STZ, the rats were killed, between 1000 h and 1100 h, by
decapitation. Trunk blood samples were taken from each animal; and
plasma samples were separated, aliquoted into storage tubes, and stored
at -20 C (or at -80 C for catecholamine determination). The brain and
pituitary gland were quickly removed under sterile conditions, frozen
on dry ice, and stored at -80 C until processing for in
situ hybridization.
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The method of in situ hybridization has been described in
detail, previously (23). Briefly, 45 mer
antisense CRH (bases 536–580) (24), POMC (bases 572–616)
(24), MR (bases 2942–2986) (25), and GR
(bases 1321–1365) (26) oligonucleotide probes,
synthesized by Dalton Chemical Laboratories Inc. (Toronto, Ontario,
Canada), were labeled using terminal deoxynucleotidyltransferase
(Pharmacia Biotech, Baie d’Urfé, Québec,
Canada) and [35S]-deoxyadenosine
5'-(
-thio)triphosphate (1300 Ci/mmol, NEN Life Science Products, Du Pont Canada, Mississauga, Ontario, Canada) to a
specific activity of 1.0 x 109 cpm/µg.
Labeled probe in hybridization buffer (180 µl) was applied to each
slide at a concentration of 1.0 x 106
cpm/µl. Slides were incubated overnight in a moist chamber at 42.5 C.
After washing in 1x SSC (20 min at room temperature), 1x SSC (35 min
at 55 C), the slides were rinsed twice with 1x SSC and with 0.1x SSC
at room temperature, then dehydrated in 70% and 95% ethanol (1 min
each), air dried, and exposed to autoradiographic film (Biomax;
Eastman Kodak Co., Rochester, NY). The films were
developed using standard procedures (exposure time: CRH, 21 d;
POMC, 2 h; MR, 14 d; and GR, 35 d).
Plasma hormone and catecholamine determination
Plasma insulin was measured using a modified version of
the insulin RIA by Herbert et al. (27). Plasma
ACTH (DiaSorin, Inc., Stillwater, MN), corticosterone
(ICN Pharmaceuticals, Inc., Orangeburg, NY), and glucagon
(Diagnostic Products, Los Angeles, CA) concentrations were
determined using commercially available RIA kits. Epinephrine and
norepinephrine levels were determined using the simultaneous
single-isotope derivative radioenzymatic assay technique described
previously (28).
Data analysis
For in situ hybridization, brain sections were
processed simultaneously for each probe to allow for direct comparisons
between the three treatment groups. Six to eight sections were selected
from each animal for each region to be analyzed by in situ
hybridization. The sections were exposed, together with
14C-standards (American Radiochemical, St.
Louis, MO) to ensure analysis in the linear region of the
autoradiographic film. The relative optical density (ROD) of the signal
on autoradiographic film was quantified, after subtraction of
background values, using a computerized image analysis system
(Imaging Research, Inc., St. Catherines, Ontario, Canada).
Hormone data are presented as mean ± SEM,
and in situ hybridization data are expressed as ROD
(mean ± SEM). Statistical analysis was by
ANOVA, using the Statistical Analysis System package for personal
computers (SAS Institute, Inc., Cary, NC), with
P < 0.05 set as the criterion for statistical
significance.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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). Although
insulin treatment normalized fasting blood glucose levels in diabetic
animals (Fig. 1A), postprandial glucose levels were still almost two
times greater than normal (normal controls, 6.0 ± 0.2;
STZ-diabetic rats, 21.8 ±0.7; and insulin-treated diabetic rats,
9.8 ± 2.0 mM). Plasma insulin concentrations were
similar between normal and diabetic rats (Fig. 1B). Insulin treatment
of diabetic rats resulted in plasma insulin concentrations that were
elevated almost 10-fold, compared with control and untreated diabetic
rats, though levels remained within normal postprandial values
(29). Plasma ACTH and corticosterone concentrations were
significantly (P < 0.05) higher in diabetic (compared
with control and insulin-treated diabetic) animals (Fig. 1, C and D).
There were no significant differences in plasma ACTH and corticosterone
levels between control and insulin-treated diabetic animals. Basal
plasma glucagon concentrations were significantly lower
(P < 0.05) in insulin-treated diabetic animals,
compared with control and STZ-diabetic animals (Table 1). Plasma epinephrine concentrations
were significantly (P < 0.05) lower in STZ-diabetic
animals and higher in insulin-treated diabetic animals, compared with
normal controls (Table 1). Plasma norepinephrine levels were similar in
all three groups (Table 1).
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).
Hypothalamic and pituitary neuropeptide expression
CRH mRNA was expressed in the hypothalamic paraventricular nucleus
(PVN). The highest levels of CRH mRNA expression were localized in the
medial parvocellular region of the PVN. After 8 d of moderate
diabetes, CRH mRNA levels were significantly (P <
0.05) higher in diabetic animals, compared with controls (Fig. 2A). Insulin treatment further increased
CRH mRNA levels in diabetic animals (P < 0.05).
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).
There were no differences in POMC mRNA levels among the three treatment
groups.
Corticosteroid receptor expression
MR mRNA expression was almost exclusively localized to
limbic structures in the rat brain. The highest expression of MR mRNA
was in the dentate gyrus and CA1/2 and CA3 fields of the hippocampus
(Fig. 3). Compared with control animals,
diabetic rats had significantly increased MR mRNA content throughout
all fields of the hippocampus (CA1/2, CA3, and CA4) and in the dentate
gyrus (P < 0.05). In insulin-treated diabetic animals,
limbic MR mRNA levels remained elevated above control values
(P < 0.05) and were similar to those observed in
untreated diabetic animals (Fig. 3).
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). GR mRNA was also present in the PVN,
the ventromedial hypothalamic nuclei, the arcuate nucleus (Fig.
4B), and the pars distalis (Fig. 4C). No significant differences in GR
mRNA expression were detected between control and diabetic animals in
any of these regions. However, insulin-treatment resulted in
significantly increased (P < 0.05) GR mRNA expression
in the PVN and the pars distalis in diabetic animals, compared with
normal controls.
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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In this study, significantly higher circulating plasma concentrations of both ACTH and corticosterone were observed in diabetic rats in the morning. Together, the endocrine data confirms hyperactivation of the HPA axis at the level of the pituitary and adrenal cortex under conditions of uncontrolled diabetes mellitus. More significantly, normalization of plasma insulin and glycemia, with ip insulin treatment, restored basal ACTH and corticosterone concentrations to control levels.
In our experience, 65 mg/kg STZ in Sprague Dawley rats results in diabetes with normal fasting basal insulin values (39, 40). The dose of STZ that we used was very small, and STZ is considered to be highly specific for ß-cells. In the literature, there is no evidence of toxic side effects of STZ on components of the HPA axis. Although these rats have normal fasting insulin levels, they are incapable of increasing insulin secretion in response to high glucose levels and thus have markedly elevated blood glucose levels in the fed state (41). The purpose of our insulin treatment studies was to treat diabetic rats with Linplants ip to mimic peripheral insulin concentrations that are seen in normal rats during the fed state (29). In contrast to the fluctuations in daily insulin concentrations seen in normal rats, the insulin-treated rats have insulin levels characteristic of the fed state during both fasting and feeding. In our present experiments with diabetes, glucose control was moderate in insulin-treated rats. Fasting blood glucose was normal; but in the fed state, it was still almost two times higher, in spite of the postprandial insulin levels. Despite this, insulin-treatment normalized plasma ACTH and corticosterone concentrations in diabetic animals, indicating that the increase in HPA activity in uncontrolled diabetes may be attributable, in part, to chronic hyperglycemia and/or hypoinsulinemia.
Whereas glucagon secretion is usually increased in cases of poorly controlled diabetes, mild or moderate diabetes results in normal or only moderately elevated glucagon levels (42). Thus, the moderate diabetes achieved in our studies may not have been sufficient to significantly elevate basal glucagon secretion. The decrease in basal glucagon secretion seen in the insulin-treated group was presumably caused by the direct suppressive actions of exogenous insulin on glucagon secretion (43).
With respect to basal catecholamine concentrations, STZ-diabetes resulted in significantly decreased plasma epinephrine levels. Munck and Kvetnansky (44, 45) have demonstrated that suppression of sympathetic nervous system activity may be the result of chronic exposure to glucocorticoids. Insulin treatment significantly raised basal epinephrine levels in our diabetic animals, suggesting that the decline in epinephrine levels may have been a direct effect of hypoinsulinemia on the adrenal medulla and/or prolonged exposure to elevated glucocorticoid levels. Unchanged insulin values during the fed and fasted state could be the cause of elevated epinephrine levels during insulin treatment (46). Further studies are required to determine the causal factor. Our data indicate that basal secretion of norepinephrine is unaffected in the early stages of STZ-diabetes. It is of interest to note that alterations in HPA function and epinephrine secretion seem to precede those of glucagon and norepinephrine secretion.
We observed increased levels of CRH mRNA in the medial parvocellular region of the PVN of STZ-diabetic rats. Insulin treatment did not restore these levels to normal. This latter observation is somewhat surprising, because plasma ACTH and corticosterone concentrations were normalized with insulin treatment. In contrast to our data, studies by Schwartz et al. (38, 47) have shown that STZ-diabetes results in decreased CRH mRNA in the PVN. It was suggested that the decrease in CRH mRNA expression was attributable to glucocorticoid-mediated suppression. Differences in CRH mRNA expression, observed between these and the present study, may be attributable to differences in plasma insulin concentrations. In the present study, plasma insulin levels were similar between control and diabetic animals, whereas in the previous studies, they were much higher in controls than in diabetic animals. These studies (38, 47), along with the present one, have shown that insulin has a stimulatory effect on hypothalamic CRH mRNA expression in the PVN. In the present study, whereas normal animals exhibited low plasma insulin levels and relatively lower hypothalamic CRH mRNA levels, the insulin-treated diabetic animals exhibited constant fed-state insulin concentrations and high levels of hypothalamic CRH mRNA. As a result, it may be that CRH mRNA levels are modified directly by physiological fluctuations in plasma insulin concentrations and, as such, we feel that the high CRH mRNA levels that we observed in diabetic animals with consistently lower plasma insulin levels are reflective of the diabetic state rather than fasting per se. The increased CRH mRNA expression observed in our diabetic animals correlates with the increase in plasma ACTH and corticosterone concentrations. This would suggest that increased hypothalamic drive is, in part, responsible for hyperactivation of the diabetic HPA axis. However, one cannot rule out the possibility that other systems involved in ACTH secretion are also activated in diabetes. The fact that insulin treatment failed to normalize hypothalamic CRH mRNA levels suggests that insulin corrects pituitary-adrenal function at a level below the hypothalamus and that factors other than insulin may play a role in increasing CRH expression in diabetes.
Despite the increases in plasma ACTH concentrations in diabetic rats, there was no corresponding change in POMC mRNA levels in the pars distalis. This can be explained by the fact that POMC and ACTH are stored in high quantities in corticotropes (48, 49). With such an abundant reservoir of the ACTH precursor, the increase in CRH activity, though increasing ACTH secretion, may not produce any changes in POMC mRNA levels in the pituitaries of diabetic rats over the 8-d time course of these studies.
In the present study, we saw a marked increase in MR mRNA expression throughout all fields of the hippocampus and the dentate gyrus of uncontrolled diabetic animals. Because hippocampal MRs have been shown to tonically inhibit HPA activity through a number of direct and indirect connections between limbic structures and the hypothalamic PVN (50, 51), an increase in MR would indicate increased inhibitory tone. Interestingly, our data indicate that there is an increase in central drive to the HPA axis that works to overcome the tonic inhibition resulting from increased MR activation in untreated diabetic animals. Furthermore, insulin-treatment, which normalized plasma ACTH and corticosterone concentrations, did not normalize hippocampal MR mRNA expression. We postulate that the increase in hippocampal MR mRNA expression in STZ-diabetes is caused by factors other than insulin or hyperglycemia.
No significant differences in GR mRNA expression were observed between control and diabetic animals. With an increase in the amount of circulating glucocorticoids, it was expected that there might be a down-regulation of GR mRNA in STZ-diabetic animals. However, this did not occur in our model. Insulin treatment in diabetic animals resulted in significantly increased GR mRNA expression in the PVN and pars distalis. This occurred in the presence of reduced pituitary-adrenal activity and increased hypothalamic CRH mRNA levels. It is possible that an increase in GR mRNA levels, and presumably active GR in the pars distalis, acts to increase glucocorticoid feedback at the corticotroph, and in doing so, reduces subsequent pituitary-adrenal activity (52, 53, 54). The simultaneous increase in GR mRNA and CRH mRNA in the PVN of insulin-treated diabetic animals is more difficult to reconcile and warrants further investigation. Taken together, our data indicates that, in early diabetes, normalization of pituitary-adrenal activity with insulin therapy primarily involves the suppressive action of glucocorticoids on ACTH secretion at the level of the pars distalis.
In conclusion, we have demonstrated that not only does diabetes up-regulate HPA activity, but it seems that the changes in epinephrine and HPA function precede changes in glucagon and norepinephrine secretion that are characteristic of chronic diabetes. We suggest that, in uncontrolled diabetes, there is an increase in central HPA drive that overrides the potential inhibitory influences of increased glucocorticoid feedback from elevated hippocampal MR mRNA expression. Although central drive remains with insulin treatment, we hypothesize that normalization of pituitary-adrenal activity involves suppression of ACTH secretion via increased GR mRNA expression in the pars distalis. This could be related to the fact that continuous insulin administration, without oscillation related to feeding, did not normalize glucose in the fed state. This observation could have relevance to human type 1 diabetes, which is characterized by peripheral hyperinsulinemia, and incomplete control of plasma glucose oscillation related to fasting and feeding periods. These changes in HPA activity may prove to have profound consequences on a diabetic individual’s ability to respond to environmental and physiological stressors.
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Acknowledgments |
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Footnotes |
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Abbreviations: HPA, Hypothalamo-pituitary-adrenocortical; PVN, paraventricular nucleus; ROD, relative optical density; STZ, streptozotocin.
Received April 12, 2001.
Accepted for publication July 18, 2001.
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, P < 0.05 vs. normal
controls.
,
P < 0.05 vs. normal controls.