CARDIOVASCULAR JOURNAL OF AFRICA • Vol 23, No 5, June 2012
286
AFRICA
Conference Report
Novo Nordisk incretin leadership summit, Cape Town
A faculty of top local and international
opinion leaders were unanimous at
the incretin leadership summit hosted
by Novo Nordisk in Cape Town on 5
May 2012. The incretin-based therapies
represent a major advance on what was
previously available for the treatment and
management of type 2 diabetes and are
revolutionising the way the condition is
viewed.
GLP-1 and the beta-cell
Islet cell dysfunction: an under-
lying defect in the pathophysiol-
ogy of type 2 diabetes
Juris Meier, head: Division of Diabetology
and GI Endocrinology, St Josef-Hospital,
Ruhr-Universitat, Bochum, Germany
Over the past 10 to 15 years, there has
been a shift away from the focus on insulin
resistance as the major cause of type 2
diabetes, with increasing recognition of
the role of beta-cell mass and function.
‘We now look at many polymorphisms,
few of which are found in adipose tissue,
bone or the liver. The majority of the
genes associated with type 2 diabetes
are in the pancreas, making it primarily a
pancreatic disease’, said Prof Meier.
On average, patients with type 2
diabetes have 65% less beta-cells than
non-diabetics, a finding that has been
replicated often and in many different
populations, irrespective of whether
the individuals in question were lean or
obese. Prof Meier therefore feels that
there is an important relationship between
beta-cells and glycaemic control and that
a normal beta-cell mass is required for
glucose homeostasis.
Autopsy studies have shown that
those with type 2 diabetes experience
an increased rate of beta-cell apoptosis.
1
‘We have no clear answers yet as
to why this is the case, but there are
many factors associated with it. In
chronic hyperglycaemia, the higher
the glucose concentrations, the higher
the rate of apoptosis, which means that
hyperglycaemia
per se
accelerates the
loss of beta-cells.’
‘Islet amyloid deposits, which are
seldom seen in non-diabetics, are also
a likely cause of the apoptosis; they
are the result of IAPP, a beta-cytotoxic
factor secreted with insulin. Other factors
implicated include high concentrations
of free fatty acids, endoplasmatic
reticulum stress and autoimmune factors.’
He suggested that there might also be
treatment-related factors involved over
and above these endogenous ones.
‘The consequences of all of this include
loss of first-phase insulin secretion, 85%
of which is lost in type 2 diabetes patients.
Loss of insulin pulsatility leads to
peripheral insulin resistance. The clinical
implications thereof are deficits in alpha-
and beta-cell function in the postprandial
context, along with disturbances in
glucagon secretion. The normal glucose-
induced decline in glucagon is almost
absent in type 2 diabetes, leading to
postprandial hyperglycaemia.’
Prof Meier cited an animal study,
which showed a link between the
reduction in insulin secretion, increased
glucagon secretion and beta-cell loss.
2
‘Reduction in beta-cell mass in pigs was
associated with high fasting glucagon
levels, an almost identical picture to that
seen in humans.’
There is an inverse relationship
between insulin and glucagon, with the
former driving down the latter. ‘This
inverse interaction is lost in type 2
diabetes, leading to a failure to suppress
glucagon’, said Prof Meier.
Both insulin resistance and impaired
insulin secretion increase the risk of type
2 diabetes, and the major factor driving
resistance is obesity. Obese individuals
need more than three times as much
insulin to maintain normoglycaemia as
normal-weight individuals. Those with a
body mass index (BMI)
>
30 kg/m
2
have
a 15% greater risk of developing diabetes.
‘But if these are the causes of diabetes,
then all obese individuals should develop
the condition; yet 85% don’t. The
differentiator is that those who don’t
have a healthy pancreas develop diabetes,
which leads to the conclusion that
obesity, insulin resistance and impaired
insulin secretion are important co-factors
increasing diabetes risk, but are not
themselves the underlying causes.’
Turning to the question of whether
loss of beta-cell mass or function is the
key issue, Prof Meier argued that both
are important, as one goes along with the
other. ‘If beta-cells are the key problem
where insulin impairment in diabetes is
concerned, we should be able to restore
normal function by normalising beta-
cell mass and function. We’ve shown
this by transplanting a healthy pancreas
into a previously diabetic patient. After
two years, glucose values were normal,
evidence that healthy beta-cell mass and
function can overcome insulin resistance.’
Summarising, Prof Meier observed
that deficits in beta-cell mass can lead
to stress and impaired function, allied to
disturbances in alpha-cell function and
insulin action. Beta-cell mass and function
are closely related. ‘Restoration of beta-
cell mass can normalise hyperglycaemia’,
he concluded.
Targeting beta cells: the rationale
for GLP-1 use in type 2 diabetes
Wolfgang E Schmidt, chair and professor
of Internal Medicine and director of
the Department of Medicine, St Josef-
Hospital, Ruhr-Universitat, Bochum,
Germany
The UKPDS showed that type 2 diabetes
is associated with a progressive decline
in beta-cells and by the time they are
