Diabetes and obesity are growing health problems in rich and poor countries alike. With this course you will get updated on cutting-edge diabetes and obesity research including biological, genetic and clinical aspects as well as prevention and epidemiology of diabetes and obesity. All lectures are provided by high-profile scientists from one the world's leading universities in diabetes research. This course is part of the EIT Health Campus programme. We hope you will enjoy our course. Best Wishes Jens Juul Holst, Signe Sørensen Torekov and Nicolai Wewer Albrechtsen Department of Biomedical Sciences Novo Nordisk Foundation Center for Basic Metabolic Research Faculty of Health and Medical Sciences University of Copenhagen
Clinical Manifestations of Diabetes and Treatment - Part 3, by Professor Allan Vaag
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Diabetes - a Global Challenge
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Clinical manifestation of Diabetes and Treatment
We hope that you enjoyed the previous modules about glucose regulation and incretin biology though they may seem more advanced compared to the first modules. We hope you stay with us and learn more about Clinical Manifestation of Diabetes and Treatment by Professor Allan Vaag and Treatment of Hyperglycemia by Professor Sten Madsbad.
Rencontrer les enseignants
Jens Juul HolstProfessor, MD, DMSc
Department of Biomedical Sciences & NNF Center for Basic Metabolic Research
Signe Sørensen TorekovAssociate Professor, MSc, PhD
Department of Biomedical Sciences & NNF Center for Basic Metabolic Research
Nicolai Jacob Wewer AlbrechtsenMD, GCSRT, PhD student
Department of Biomedical Sciences & NNF Center for Basic Metabolic Research
[MUSIC]
To understand the paradigm shifting consequences of the
"Thrifty Phenotype Hypothesis" as a conceptual framework to understand
the roots of type two diabetes, some historical background
of our understanding of type two diabetes is needed.
So, research into insulin resistance, type two diabetes and the
metabolic syndrome took off in the 1960s after the first human
plasma insulin assays demonstrated that the majority of cases of
late-onset diabetes could not be explained sufficiently by lack of insulin.
Twin studies from the 80s suggested an almost exclusive role of genetics in
type two diabetes, with nearly 100%
concordance rates among genetically identical monozygotic twins.
The studies of Hales and Barker published in the early
90s, were therefore highly provocative to the diabetes research community,
postulating that not only type two diabetes but also
the key components of the metabolic syndrome representing well-established
cardiovascular disease risk factors, seemed to have at least
parts of their origin in early life.
The notion that factors operating early in life influence these states of
disease was originally devised by the
Norwegian epidemiologist Anders Forsdahl in 1970.
Nevertheless, the undisputable achievement of Hales
and Barker was that in an unselected population sample from Hertfordshire
in the U.K. they provided a direct link between low birth weight
and increased risks of developing type two diabetes, hypertension,
elevated triglycerides, as well as insulin resistance later in life.
Therefore, the paradigm shifting potential of the studies was not
only the idea of a role for fetal programming in itself,
but equally as important, the notion that fetal programming could
represent a significant player in the origin of type two diabetes,
the metabolic syndrome and cardiovascular disease.
Early criticism of the studies of Hales and Barker included the use of
changing definition of markers of growth in
early life and underdevelopment in different studies,
such as birth weight versus ponderal index with respect to exposure,
and different phenotypes such as type two diabetes, the
metabolic syndrome, and insulin resistance with respect to outcome.
So, alongside the diverse beliefs and conceptions regarding the
aetiology of type two diabetes and the metabolic syndrome, there
was a strong polarization of use in the 1980s
and the 1990s concerning the roles of muscle insulin resistance,
defective pancreatic insulin secretion, and elevated hepatic glucose
production in the pathophysiology of type two diabetes.
This debate has now been settled by uniform
agreement that glucose intolerance ranging from the prediabetic states
of impaired fasting and impaired glucose tolerance to overt type two
diabetes constitutes a heterogeneous, dysmetabolic state,
or states involved in the dysfunction of multiple organs,
including liver, muscle, pancreas, adipose tissue, gut, kidney and brain.
And it is of interest that the concept of fetal programming, with its
ideas of organ plasticity which actually
may represent the most plausible hypothesis of a common ground
for the underlying aetiology and molecular mechanisms of type two diabetes.
Thus, the multiple organ functions in type two diabetes, changing with time and age,
and differing in magnitude between type two diabetes patients within and between
societies does require a comprehensive conceptual framework,
such as developmental programming to understand the
clustering of these disease components and risk factors.
Type two diabetes genes have appeared to be more
selective in their influence of organ dysfunctions in
type two diabetes with defective insulin secretion being the most
important affected by the more than 50 known genotypes
involved in the predisposition to type two diabetes.
In contrast, despite their initial hypothesis of fetal programming
of type two diabetes being associated with impaired insulin secretion, Hales
and Barker and their colleagues were the first to document
the association between low birth weight and insulin resistance in humans.
The importance of this finding is underscored by our knowledge that
insulin resistance is a very prominent and early feature of the metabolic syndrome,
and consistently has been associated with fetal programming in humans, regardless
of whether the exposure is low birth weight, prematurity, independent of
low birth weight, gestational diabetes or a twin or zygosity status
that are also known to be associated with an adverse fetal growth.
So, regarding the definition of the metabolic syndrome,
central points in the discussion of its raison d´être over
recent years have been whether it is a real disease entity of clinical relevance.
If insulin resistance is a main common denominator or cause,
if it explains the risk of cardiovascular disease
beyond the contributions of each of the individual components,
and whether the clustering of the proposed components of the metabolic syndrome may
be an artefact when observed from a stringent epidemiological perspective.
What has, however, not been sufficiently emphasized in this debate
is that the thrifty phenotype hypothesis, formulated with great
visionary precision by Hales and Barker represents the most plausible
explanation of the origin of all the components of a metabolic syndrome.
The idea of an adverse fetal environment
rather than genetic determinants defining
origin of type two diabetes and its
associated cardiometabolic risk was supported by twin studies,
that reported lower birth weights among monozygotic twins with type two diabetes,
compared with their genetically identical but non-diabetic co-twins.
Subsequent twin studies have documented both
defective insulin secretion and insulin resistance being
associated with low birth weight in
a complex non-genetic and age dependent manner.
The age dependency may in this context
represent an important issue to explain the highly
age dependent states of type two diabetes,
the metabolic syndrome, as well as cardiovascular disease.
While the concordance estimates from population based twin studies,
questioned the notion of a major genetic component in type two diabetes
being in marked contrast to the earliest studies of twins from the 80s.
Perhaps the most significant lesson from twin
studies was the finding that zygosity and
thus twin status may influence insulin secretion
and insulin action in its own right.
The extent to which twins develop type two diabetes in a differential
age dependent manner compared with singletons is currently the unresolved,
but even the finding in, at least one study, that twins have
a risk of type two diabetes that is similar to a singleton
with a lower birth weight, is consistent with the notion that twins
may differ from singletons with respect to risk of type two diabetes.
Thus, the thrifty phenotype hypothesis has challenged the
role of the classical twin model in the assessment
of genetic versus non-genetic risk of metabolic and
cardiovascular diseases, emphasizing the enormous impact of the hypothesis.
Despite low birth weight being a crude marker of
an adverse intrauterine environment, it has with remarkable consistency, been
associated with risk of type two diabetes, as well
as impaired insulin secretion and insulin resistance in multiple studies,
including population based epidemiological studies.
In addition, studies of the identified genetic type two diabetes marker
have confirmed the notion that the association is predominantly non-genetic.
Thus, only two out of the known 50 type two
diabetes genes are associated with a slightly lower birth weight.
While prematurity is associated with risk of type two diabetes
independently of birth weight, studies of third trimester fetal growth rate,
pointed to what effects prior to or after third trimester
being the most important periods during development, relevant
to programming of components of the metabolic syndrome.
Animal studies have provided substantial proof of concept for
associations of global, as well as distinct protein
undernutrition during pregnancy with glucose intolerance and physiological and
metabolic defects relevant to type two diabetes in the offspring.
Importantly, compared to studies of low birth weight in humans and protein
undernourished rats in utero identified strikingly similar changes
in the expression of key insulin signalling proteins
of the glucose and of the glucose transporter
GLUT4 protein in both skeletal muscle and adipose tissue.
Epigenetics is defined as changing gene functions that are not
due to changes in the sequence of the nucleotides of the genome.
The increasing awareness of a prime role
of epigenetics including DNA methylations and histone modifications
as well as a prime role of regulatory
small noncoding, microRNAs have provided ideas and novel
tools to look for the mechanisms that underlie developing
programming on multiple organ functions in type two diabetes.
These technologies are forecasting groundbreaking
discoveries within the years to come.
Already, prominent examples of recent discoveries in the area
include transcriptional regulation by promoter DNA methylation,
as well as histone modifications of the pancreatic
proliferation and transcription factor Pdx1 by fetal undernutrition
as well as the discovery of increased expression of the
microRNA-483-3p in subcutaneous adipose tissue from humans with
a low birth weight as well as from
rats that were undernourished by protein in utero.
This may confer an increased risk
of lipotoxicity with subsequently, as explained,
has detrimental effects on multiple organ functions in type two diabetes,
probably by regulating a factor involved in the development of
adipose tissue cells, called the growth and differentiation factor three.
Recent studies from our group have suggested that
the key epigenetic abnormalities in developmental programming
of type two diabetes could be hidden in the most immature stem cells in the body.
Stem cells are responsible for the constant renewal
of cells in many tissues including the adipose tissue.
And recent studies have suggested that the turn over rates of cells in subcutaneous
adipose tissue is quantitatively much faster than previously anticipated,
and that the normal functioning stem cells are
required to maintain normal functions of the adipose tissue.
In a study of immature stem cells obtained from
the subcutaneous tissue of low birth weight subjects, we
actually did found several indications of a disproportional
immaturity compared with healthy subjects born with normal birth weights.
And these abnormalities included a impaired release
of the key appetite regulating hormone leptin.
The impaired release of leptin in these cells was associated with a reduced leptin
gene expression, as well as increased leptin gene DNA methylation.
So these abnormalities may be associated with reduced tissue expandability,
and subsequently, as explained, lipo- toxicity, in other tissues.
Furthermore, the impaired leptin release may contribute to increased risk of
adiposity due to reduced appetite suppression, in response to overeating.
Finally, the idea and proof of concept of an immature stem
cell function in low birth weight subjects may suggest that a
more general immature stem cell function in multiple organs may actually
explain the multiple organ dysfunction in itself in type two diabetes.
This is a present hypothetical scenario that we are studying.
Biopsies obtained from the subcutaneous adipose tissue
from different humans with a different risk of
developing type two diabetes, are further processed
in the laboratory to isolate the stem cells.
The stem cells are subsequently stored in a
freezer to be ready for use in later experiments.
Stem cells kept in a freezer can be growth
in in vitro cultures by adding different differentiation factors,
and the cells with different degrees of maturity can subsequently be studied
functionally, morphologically, as well as with respect to epigenetic changes.
The extent to which the global epidemic of diabetes
may be driven by a mismatch between being born with a low birth weight
and the fast propagation of over-nutrition and physical
inactivity seen over recent years in developing countries,
needs to be determined in order to provide
a focus for efforts to prevent metabolic diseases.
Gestational diabetes, also called GDM, may be considered an early manifestation of
type two diabetes that is unmasked by pregnancy-induced insulin resistance.
And studies in both animals and humans have indicated that exposure to an adverse
fetal environment is a significant risk factor for GDM in its own right.
Besides compelling evidence of inter-generational
transmission of type two diabetes and
the metabolic syndrome via low birth weight as well as gestational diabetes,
recognition of this has provided support
for universal screening for gestational diabetes,
and for pregnancy itself, being a window of opportunity to
prevent type two diabetes in both the mother and the child.
The relevance and importance of earlier and more
effective prevention of type two diabetes is underscored by
the modest effects of early detection by screening for
type two diabetes in the general population on mortality
as well as the absence of any
significant effect of intensive, as opposed to conventional
glucose control, as mentioned, on cardiovascular disease
mortality in patients with overt type two diabetes.
Therefore, to understand the full potential of the thrifty phenotype hypothesis
as a platform to implement primary prevention of type two diabetes,
there is an urgent need to determine the extent to which developmental
programming influences type two diabetes
in different manners, in different populations,
as well as to understand the long-term effects of distinct exposures during
pregnancy and the molecular mechanisms involved.
Today, prevention of type two diabetes is achievable through lifestyle
interventions combining healthy diet with increased physical activity.
However, the most effective lifestyle intervention
programs only postpone the onset of type two
diabetes, defined by hypoglycemia, for an average of around two years.
There is, therefore a need for more
effective and sustainable prevention strategies for disease,
and interventions among pregnant women provide another potential to prevent
type two diabetes in a more sustainable manner in the next generations.
As for the pharmacological treatment of type two diabetes today, many different
treatment modalities have now become
available to reduce the plasma glucose level.
Our current treatment modalities include metformin to increase insulin
action, insulin secretagogues such as
sulfonylureas to increase insulin secretion,
DPP-4 inhibitors increasing GLP-1 levels,
glitazones to increase adipose tissue expandability,
SGLT2 inhibitors to increase excretion of glucose in the urine,
and acarbose to reduce the absorption
of carbohydrates from the gastrointestinal channel.
GLP-1 agonists have also become available
to increase insulin secretion as well as to reduce appetite in
different types of a patient with type two diabetes.
Finally, we also have different types of insulin available to compensate for
the reduced indigenous insulin secretion in patients with type two diabetes.
And right now, extremely much research is ongoing to understand
the optimal use of these different drugs in type two diabetes
and further details regarding this topic is
beyond the scope of the current lecture.
However, it needs to be emphasized that
none of the mentioned drugs have been shown
to reduce the risk of diabetes complications,
beyond their potential to reduce plasma glucose levels.
Metformin, being the oldest class of all
glucose lowering drugs, has been suggested in some
studies to reduce the risk of cardiovascular
disease beyond its effect on glucose in itself.
However, this has been questioned in recent meta-analyses.
Furthermore, GLP-1 agonist does reduce weight and blood pressure,
which is very promising in type two diabetes treatment.
And may, therefore, represent the class of drugs that in the future may
prevent diabetes complications beyond their capability to reduce glucose.
However, this has not yet been conclusively proven.
So, altogether, there is an increase or increasing need
for society to invest in research in type two diabetes in order
for us to be able to prevent and to treat the extremely
common disease in a cost-effective manner in the future.
[MUSIC]
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