Insulin, corticosterone and the autonomic nervous system in animal obesities: a viewpoint
Diabetologia
Insulin, corticosterone and the autonomic nervous system in animal obesities: a viewpoint
B. Jeanrenaud 0
0 Laboratoires de Recherches M6taboliques, Faculty of Medicine, University of Geneva , Geneva , Switzerland
The article by Dr. Zawalich is very interesting and his working hypothesis, i.e. that "events at the level of the beta cells are the earliest changes occurring in the prediabetic individual", that "enhanced beta-cell responsiveness, a result of increases in vagal and fuel stimulation of the islets, results in hyperinsulinaemia"; that "chronic or at least long-lasting hyperinsulinaemia is then responsible for changes in target tissue sensitivity to the glucose-regulatory effect of insulin", are very much in keeping with data from our and other basic research laboratories [1-4].
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9 Springer-Verlag1995
The endocrine pancreas. It has been found that the
endocrine pancreas of 17-day-old preobese pups
tested before weaning (i. e. before they become visibly
obese) had a greater insulin output in response to
glucose or arginine than age-matched control animals.
This abnormality was returned to normal by prior
acute administration of atropine. As at.ropine did not
change substrate-induced insulin output of control
pups, these data clearly indicate that an overactive
vagus nerve was responsible for substrate-induced
insulin oversecretion of the preobese group [
5, 6
].
In keeping with this conclusion, a short-acting
electrical stimulation of the cervical vagus nerve
produced an insulin output that was more than 10 times
higher in adult genetically obese fa/fa rats than in
controls [
5
].
Furthermore, a short-acting electrical stimulation
of the vagus nerve carried out immediately before
intravenous glucose administration potentiated
glucose-induced insulin secretion in both adult normal
and genetically obese rats, but to a level that was two
times higher in the obese than in the normal group [
5
].
Finally, isolated perfused pancreases from
genetically obese rats (fa/fa) secreted almost ten times
more insulin in response to arginine than pancreases
from normal rats. Superimposed infusion of atropine
had no effect on arginine-induced insulin secretion
by pancreases from lean rats but decreased that of
obese rats, thereby suggesting the presence of
increased cholinergic activity in pancreases of obese
rats [
5
].
In a model of experimental obesity (ventromedial
hypothalamic lesions, VMH-lesioned rats) the
amount of insulin or glucagon released during
methacholine infusion (a muscarinic agonist) was five and
two times greater, respectively, in isolated
pancreases from experimentally obese rats than in those of
controls, effects that were completely abolished by
the superimposed infusion of atropine, thus
demonstrating the specificity of the methacholine effect on
the cholinergic system [
7
].
When basal insulinaemia was somewhat increased
(by 1.15 fold) in young (21-day-old unweaned)
genetically obese animals, fat accretion was increased and
muscles were not insulin resistant, but insulin
overresponsive [
8
].
Peripheral hormones and metabolism. It has been
shown [
9
] that in adipocytes from 16-day-old
preobese unweaned rats, G L U T 4 m R N A and protein
levels of adipocytes were more than twice those of
controls [
9
]. Although these data were interpreted as
being in agreement with a genotype regulatory effect
on G L U T 4 [
9
], subsequent data reported that basal
insulinaemia was increased in preobese pups of the
same age [
10
]. Furthermore, substrate-induced
insulin output was not measured in these preobese
animals, but was likely to be increased at this phase of
the syndrome, as it was in the 17-day-old preobese
pups mentioned above [
5, 6
].
It is important to emphasise that great efforts have
been made to attempt to detect the earliest
abnormalities of obesity syndromes. One should be aware,
however, that a given alteration cannot always be
accompanied by measurements of the final output
needed to prove the relevance of the alteration in
question. Thus, brown adipose tissue thermogenesis
capacity (as assessed by the binding of guanosine
5'diphosphate to isolated mitochondrial membranes)
was lower, at 2 days of age, in genetically preobese
fa/fa pups compared with their normal littermates
[
11
]. This strongly suggested the early occurrence of
alterations in the central regulation of the autonomic
nervous system, bearing, in this particular case, on
the efferent sympathetic limb innervating the brown
adipose tissue and the energy dissipating
mechanisms thereof. Although not testable, such a defect
could affect the endocrine pancreas, thereby
alleviating the inhibitory effect of the sympathetic nervous
system on insulin output and favouring insulin
oversecretion. At 10 days of age the fa/fa pups showed a
decrease in the P32'000 uncoupling protein m R N A
levels, a protein responsible for the energy
dissipation as heat [
12
]. At this age basal hyperins (...truncated)