Genetics,
Nutrition and Diabetes
Diabetes
Mellitus is a metabolic problem of carbohydrate, lipid and
protein.
We
need to remember our 'real' history of body shape, food
types and intake and activities of daily living. Our genes
developed for hard work and lean food, but now foods with
fat, salty and sweet tastes appeal and have overtaken the
traditional roughage, carbohydrates, low energy dense foods
and vegetables. Combined with our sedentary lifestyles,
it is no wonder lifestyle diseases like obesity and diabetes
are developing so quickly.
Risk
factors for child onset Type 2 Diabetes
There
are many risk factors, including obesity and increased body
mass, family history, belonging to an ethnic minority, puberty
(diagnosis commonly occurs here), female gender and any
features of syndrome X metabolic syndrome. The common link
between these risk factors is insulin resistance. Both insulin
resistance and beta cell failure are present in diabetes.
What
is diabetes?
Diabetes
is an umbrella term to cover a group of metabolic disorders
characterised by elevated blood glucose levels. It is usually
a product of behaviour - for example overeating and leading
a sedentary lifestyle. The onset of diabetes may also be
due to new environmental pressures which unmask ex-survival
genes, for example the genes that load fat stores become
active. These may interact with various abnormal genes,
environmental and endogenous toxins of pancreatic beta-cells
and cause insulin resistance and lack of insulin secretion.
This can lead to hyperglycaemia, dyslipidaemia and dysproteinaemia.
The
classification of DMTI includes being insulin dependent,
with autoimmune damage to pancreatic islet cells and strong
heredity. For DMTII, it normally occurs in mid-older age,
and is not insulin dependent. Maturity Onset Diabetes in
the Young (MODY) is strongly genetic. Insulin resistance
and secretion failure may or may not occur together in all
diabetes.
The
causes of DMTII are largely genetics, environmental factors,
particulary our Western lifestyle of excess fat, highly
refine foods and low fibre, inactivity, obesity and dietary
toxins with low protective fruits and vegetables. When combined,
these act on our survival genes resulting in obesity, and
then with impaired fasting glucose or glucose intolerance,
DMTII can develop.
Insulin
Resistance
Genes,
lifestyle and diet problems lead to insulin resistance.
With normal beta-cell function in the pancreas, these problems
would be compensated by hyperinsulinaemia to return to a
state of normoglycaemia. The insulin output is increased
to compensate for insulin resistance in the tissue - generally
liver, skeletal muscle, adipose tissue - and the glucose
tolerance remains within the normal range.
However,
with abnormal beta-cell function, a relative state of insulin
deficiency occurs because the amount of insulin secretion
is insufficient to compensate for insulin resistance, which
leads to hyperglycaemia and DMTII.
Progression
to Diabetes
The
initiating factors for diabetes are all genetic abnormalities
in the following genes: insulin resistance genes, insulin
secretion genes, beta-cell capacity genes and obesity genes.
The
progression factors include obesity, beta-cell toxins, diet
and environmental toxins, activity level and age.
The
simplified process is:
- Decreased
insulin and glucose sensitivity
- Increased
insulin secretion
- Glucose
desensitisation of beta-cells
- Failing
insulin secretion
- DMTII
Insulin
is important as it helps glucose disposal into cells, inhibits
hepatic gluconeogenesis and inhibits free fatty acid release
from fat cells.
Insulin
secretion problems are mainly found with DMTI. The opposite
is found with DMTII - excess insulin is secreted as the
end skeletal muscle, organ or tissue fails to sense insulin
or act on the signal - so more is sent out to help uptake
the circulating glucose. Eventually this wears out the pancreatic
beta-cells which have been producing and secreting the insulin,
and they fail. In non-diabetics this on its own is not normally
enough to trigger DM.
Endothelial
cells may become insulin resistant because of low blood
flow and hypertension. The liver may also develop insulin
resistance as there is persistent hepatic glucose production
despite hyperglycaemia, and this causes the liver to release
free fatty acids. The liver and fat cells trigger insulin
resistance in the abdominally obese, and combined with metabolic
syndrome results in further hyperglycaemia and dyslipidaemia.
Mechanisms
of Insulin Resistance
There
may be intracellular accumulation of acyl CoA and triglycerides.
There may be a role of secretion from the adipose tissue
to increase peptides which may combine with free fatty acids
and triglycerides to trigger insulin resistance at the cells
and low glucose transport. It is possible there may be a
change in the insulin signalling cascade, or an increase
in acyl CoA may alter gene expression.
Insulin
signalling is heavily affected by genetic background. It
affects the insulin secretion by the beta-cells, and insulin
signalling in the central nervous system is responsible
for regulation of energy disposal, fuel metabolism and reproduction.
Insulin
resistance occurs frequently in the muscle. If lean and
healthy, fat oxidation is inhibited by insulin. In obesity
and DMTII, skeletal muscle is metabolically inflexible to
allow transitions between fasting and insulin-stimulated
fatty acid and glucose utilisation. This means that in obesity
and DMTII, there is increased low-density lean tissue -
fat laden skeletal muscle.
Fat
excess kills cells - if there is an influx of fatty acids
that exceeds their oxidative requirements, the unoxidised
surplus enters the pathways of non-oxidative metabolism
and triglyceride content rises. Non-oxidative products may
cause dysfunction and death of cells.
Leptin
may protect non-adipocyte cells from fat overload - this
is a peptide secreted by fat and low levels increase hunger.
It also affects reproduction.
Hyperglycaemia
The
toxicity of hyperglycaemia is important in diabetes. The
retina, kidney, nerves and capillaries fail from glucose
damage. Glycated products cause oxidative stress and protein
changes.
The
Glycaemic Index is useful to categorise foods into groups
that cause high or low glucose spikes once eaten. Hyperglycaemia
is more likely after carbohydrate loads - highly cooked
and refined foods are the worst. Protein and fats eaten
with carbohydrates reduce the GI of the food, but you have
to be sensible about the type of fats used. There is much
controversy over whether the GI is useful and valid, and
whether energy density is more important. Generally high
fruit and vegetables and low processed carbohydrates or
traditional foods have a low GI.
Gene
Hypothesis
The
high prevalence of obesity and NIDDM in certain population
groups suggests it may result from a 'thrifty genotype'
- and that it is a real metabolic disease, not just as a
result of gluttony. In DMTII, prediabetic phenotypes may
be inherited for insulin secretion, insulin action and regulation
of insulin signalling; and genome-wide scans of related
families is possible to pinpoint the genetic differences
to healthy people. At least 7 genetic defects are known.
Many
biochemical systems are affected by DMTI, including peptide
hormones, steroid hormones, vitamins and co-factors, trace
elements, coagulation markers and energy management.
With
DMTII, there are macrovascular changes, including causing
insulin resistance or hyperinsulinaemia, hypertension and
hormone changes, atherosclerosis, coronary heart disease,
limb circulation problems leading to gangrene. Most diabetics
die from myocardial infarction or cerebrovascular accident.
Microvascular
damage includes hyperglycaemia due to insulin resistance
and secretion reduction, retina problems leading to blindness,
kidney failure, brain problems, and nerve problems resulting
in skin ulcers, bowel dysfunction and gangrene.
System
alterations of DMTII include steroid hormones and peptides,
blood vessel lining damage which can lead to arteriosclerosis
and deep vein thrombosis, immune depression leading to infections
and chronic inflammation (this is a strong marker for CVD),
and the disease is worse in women.
Health
risks involved with metabolic syndrome include high cholesterol,
blood pressure, gout, homocysteine, increased likelihood
of developing DMTII, heart disease, stroke polycystic ovarian
syndrome, where insulin resistance at the ovary interferes
with vitamin d.
The
definition of metabolic syndrome requires three of the following:
waist circumference of at least 102cm in men or 88cm in
women, serum triglycerides at least 150mg/dL, low HDL, high
blood pressure and high serum glucose.
Oxidants
The
increased free radical production under hyperglycaemic conditions
may originate from mitochondrial respiration. Excess free
radicals cause oxidative stress, leading to tissue dysfunction
and damage. Glucose autoxidation depletes antioxidant stores,
and this is made worse by hyperglycaemia causing glycated
proteins and glycation of protective albumin. This leads
to depletion or glycation of HDL and excess production of
superoxide which triggers further free radical production.
Advanced Glycosylation Endproducts (AGE) are also food derived
and these are triggers for diabetes. It is important to
be eating antioxidant rich foods and use appropriate antioxidant
supplements such as carotenoids, a-tocopherol, vitamin c,
folate, b6 and b12 to protect against oxidative damage.
Alpha-tocopherol
prevents AGE forming in LDL.
Vitamin
C prevents damage from glucose autoxidation and glycation
of proteins, and protects the beta-cells in the pancreas.
Copper
levels are highest in diabetics with microvascular problems.
This would explain their higher zinc excretion levels and
lower plasma zinc. They also have low magnesium and increased
urinary levels of magnesium.
PPAR's
- Peroxisome Proliferator Activated Receptors
These
are a subfamily of the nuclear receptor family, and are
ligand dependent (fatty acids and their derivatives). They
play a central role in sensing nutrient levels and modulating
their metabolism, energy metabolism and cell proliferation.
They may also affect inflammation and blood vessel formation.
There
are numerous links between PPAR's and obesity. Synthetic
agonists for PPAR's are used to lessen abnormalities in
lipid and glucose metabolism. Many abnormalities occur in
parallel with obesity including dyslipidemia, insulin resistance,
DMTII and hypercholesterolemia.
Diabesity
or Diobesity?
Which
order does the disease manifest? 80-90% of DMTII are overweight
or obese. 75% of DMTII is attributable to obesity. Weight
gain precedes this - diabetes reflects the effect of obesity.
Insulin levels are raised in overweight people, and waist
circumference is proportional to insulin levels. A regression
of diabetes can be achieved with weight loss. Metabolic
syndrome leads to impaired glucose tolerance which leads
to diabetes. Visceral adiposity (fat storage) is most strongly
related to skeletal muscle insulin resistance. Fat loss
and physical activity will remedy this problem and reduce
metabolic inflexibility.
Polycystic
Ovarian Syndrome
Obesity,
PCOS and later diabetes often co-exist. It produces high
androgens in women. PCOS and obesity are insulin resistant
states and often present in teenagers. The endocrine manifestation
triggers infertility, menstrual disturbances and excess
hair growth.
Diabetes
and Pregnancy
Stress
in the inutero environment causes the development of a phenotype
known as the 'thrifty gene'. This is to aid the development
of the fetus that has been set up to start off badly in
life as a result of whatever the inuterine stress was (eg
poor nutrition). These babies are more likely to develop
obesity and diabetes as a result of their metabolism adjusting
accordingly to store all incoming fuel instead of burning
it. Small babies are more likely to become insulin resistant
and hypertensive later in life and are at risk of CVD. Possible
causes for this include adrenocorticoid effects, less elastic
in the arteries, low growth hormone, genomic imprinting
and non-permanent DNA modifications.
Gestational
diabetes is closely related to DMTII, and the combination
of insulin resistance and impaired insulin secretion is
important in its pathogenesis. High birth weight is associated
with obesity, and it is probable that the fetal exposure
to the mother's diabetes gives a risk for diabetes above
any genetically transmitted susceptibility.
Summary
The
benefits of a 10% weight loss include significantly reducing
mortality, diabetes, blood pressure, lipid and angina, and
increasing HDL.
Diabetes
Type 2 is a problem growing with obesity causing huge morbidity,
mortality and economic burdens. It is spreading to most
areas of the world. Insulin resistant genes have been caused
by an interplay of environmental, obesity and unmasking
survival genes factors. Once insulin resistance occurs,
multiple systems and organ changes or failures vastly increase
the risk of CVD and other diseases. The failure of systems
such as oxidative stress management, coagulation, cytokines
and inflammation activation, and multiple hormonal systems
are damaged or disrupted. Macro and micronutrients are dealt
with abnormally, and if we alter our convenience lifestyle
and return to a more traditional wholefood diet and lifestyle,
the problem would reduce. Nutrient, genetic and drug treatment
is required to manage the micro and macrovascular diseases
of DMTII.
Summarised
from Anne-Thea McGill lecture, University of Auckland Medical
School , October 2003
|
