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VOLUME 9 NUMBER 2 • JUNE 2012
81
SA JOURNAL OF DIABETES & VASCULAR DISEASE
CONFERENCE REPORT
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 underlying
defect in the pathophysiology 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 con-
centrations of free fatty acids, endoplasmatic
Novo Nordisk incretin leadership summit, Cape Town
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 diagnosed,
most patients will already have lost 50% of
their beta-cells. Prof Schmidt underscored
that stopping that decline is a challenge,
but that glucagon-like peptide 1 (GLP-1), an
incretin whose role in diabetes is increasingly
being recognised, could help to achieve
some currently unmet treatment goals.
The so-called ‘incretin effect’ is severely
impaired in type 2 diabetes patients, which
suggests that if the ‘something missing’
is reconstituted, the condition could be
positively impacted on.
‘The progressive loss of beta-cells starts
early in the disease process, during the pre-
clinical phase’, he said. ‘Even those who
have only impaired fasting glucose levels
experience beta-cell loss, and this loss is the
basis for the deterioration in glucose control
seen in so many studies. Different drugs
have differing effects on beta-cell apoptosis.
Incretin therapy nowgives us the opportunity
to intervene by targeting an aspect of islet cell
dysfunction that other drugs don’t, namely
the alpha-cell dysfunction/hyperactivity that
causes hyperglucagonaemia.’
GLP-1 and 2 were discovered in 1983
and the former’s role in stimulating insulin
secretion was identified in 1985. ‘It’s a player
in the pathophysiology of diabetes as well as
a promising candidate for therapy’, observed
Prof Schmidt. ‘It normalises glucose levels in
poorly controlled type 2 diabetes without
inducing hyperglucagonaemia. Beta-cells are