Diabetes Research Group
Research Highlights
- Elucidation of the
development of the primate pancreas (1996) which identified major differences
from previous reports and which subsequently was supported by later reports
from other groups
- Identification of pancreatic
endocrine cells containing more than one peptide (1997) illustrating incompletely
differentiated endocrine cells in the pancreas with possible potential for
contribution to insulin demand and leading to regeneration studies.
- Successful regeneration
of the primate pancreas (1998) and elucidation of the early signal transduction
pathway, and the expression of a previously undocumented protein related
to regeneration (2001).
- Findings that even
controlled amounts of a high-fat diet have a rapid deleterious effect on
most of the parameters associated with the development of type II diabetes
and, that after seven months of a high-fat diet, fasting proinsulin-insulin
levels also start increasing (early diagnostic for type II diabetes). Not
every monkey exhibited the same combination of effects but the highest weight
increases were in the two monkeys most compromised by the diet. Despite
all of these changes, fasting plasma glucose levels remained within the
normal range although HbA1C levels (a longer term measure of glucose over
a period of the previous ±6 weeks) steadily increased after 19-21
months.
Heart
research highlights include
- In the study on the
elucidation of the mechanism(s) whereby exposure of the heart to repeated
short episodes of ischaemia-reperfusion (the phenomenon of preconditioning)
elicits protection against necrosis and apoptosis during a subsequent long
period of myocardial ischaemia, the following has occurred:
- Two experimental
models have been established namely (i) the isolated perfused working
rat heart, which can be protected by exposure to 1 x 5 or 3 x 5 min
ischaemia, and (ii) the isolated adult myocytes, which can be preconditioned
by exposure to 10 min hypoxia and 20 min reoxygenation.
- Careful characterization
of events during a multicycle preconditioning protocol showed cyclic
changes in the tissue cyclic nucleotides, cAMP and cGMP, which were
suggestive of
 -adrenergic
stimulation and nitric oxide as triggers of protection.
- -adrenergic
stimulation during the preconditioning protocol acts as trigger since -receptor blockade abolishes
preconditioning-induced protection; on the other hand, protection can
be elicited experimentally by -adrenergic
stimulation (isoproterenol or forskolin) before ischaemia. Similarly,
a role for NO as a trigger could be demonstrated by use of NO donors
(e.g. SNAP or SNP), which mimics preconditioning, whereas inhibition
of NO generation (by L-NAME) abolishes protection.
- Evaluation of further
downstream events revealed activation of two stress kinases, viz p38
MAPK and JNK. Activation of p38 MAPK occurs via both a1- and b-adrenergic
receptors. Although p38 MAPK does not act as a trigger in the preconditioning
process, it has been shown that ischaemic preconditioning attenuates
p38 MAPK activation during sustained ischaemia. Subsequent experiments
with anisomycin (a p38 MAPK activator) and SB203580 (an inhibitor of
p38 MAPK) confirmed that preconditioning-induced cardio protection is
induced by attenuation of p38 MAPK activation.
- The finding that
attenuation or inhibition of the stress kinases leads to myocardial
protection against ischaemia may lead to the development of new drugs
for the treatment of ischaemic heart disease. This approach could also
be applied to improve the post-operative recovery of patients after
coronary artery bypass graft surgery.
- Protection of the
ischaemic myocardium
- Melatonin, a hormone
secreted by the pituitary gland and a potent scavenger of free radicals,
effectively protects the myocardium against ischaemia-reperfusion injury.
- Sevoflurane, a
volatile anaesthetic, significantly improves post-cardioplegic functional
recovery via the KATP channels: glibenclamide, a sarcolemmal
KATP channel blocker, prevents sevoflurane-induced protection.
- Cardiomyopathy in
type II diabetes mellitus
- Two different rat
models of type II diabetes mellitus were established in our laboratory
in order to study early myocardial alterations, which may lead to cardiomyopathy.
By evaluating contractility in papillary muscles we found attenuated
force development in both models as early as six weeks, becoming significant
at 20 weeks. This was accompanied by (i) altered regulation through
a1-adrenergic signalling, (ii) altered insulin signalling leading to
attenuated glucose uptake, (iii) attenuated expression and translocation
of Glut 4 and (iv) altered activation of protein kinase B (PKB).
- Exercising obese
diabetic animals on the other hand, was able to correct the state of
activation of PKB, to improve glucose uptake and to induce Glut 4 expression.
These studies also indicated that -adrenergic
stimulation of the heart has the ability to, via unknown signalling,
intersect with insulin signalling, resulting in activation of PKB and
increased glucose uptake, both in a manner dependent on PI-3-kinase.
- The phosphatase
inhibitor vanadate, in combination with insulin, was found to significantly
improve glucose uptake in the obesity-related diabetic myocardium compared
to control animals, showing promise to be utilized clinically.
Other
information
If you
want to prevent developing type II diabetes, eat a low fat diet and exercise
regularly.
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