Diabetes:

Recall the effects of insulin. It has a role in the metabolism of carbohydrates, proteins
and lipids as well as a critical function in regulating blood glucose concentration.
Insulin works to lower blood [glucose] by;
- promoting increased facilitated diffusion of glucose into cells of connective tissues
including adipose as well as into resting skeletal muscles and WBC's. It is not
required for glucose transport into brain , kidney, liver or exercising skeletal
muscles.
- inhibiting glycogenolysis ( conversion of glycogen to glucose) in the liver
- inhibiting gluconeogenesis ( conversion of non-carbohydrates to glucose) in the liver
- enhancing glucose utilization in cellular respiration
Insulin influences protein metabolism by;
- promoting increased active transport of amino acids into cells
- promoting protein synthesis in most tissues
Insulin influences lipid metabolism by;
- promoting glucose uptake into adipose tissues
- promoting triglyceride synthesis from glucose in adipose
- inhibition of lypolysis.

The stimuli for insulin secretion from the pancreatic islet of langerhans cells include;
- increased blood [glucose]
- increased blood [amino acid] and [fatty acid]

Increased levels of insulin are necessary for increased growth especially in childhood and
adolescence growth spurts and also for healing ( ie. promotes protein synthesis).
Insulin levels will increase immediately after eating as absorbed nutrients stimulate
increased insulin secretion. Many hormones promote hyperglycemia and so act as
antagonists to insulin in terms of blood [glucose]. These hormones include epinephrine,
glucagon, thyroxine, growth hormone and glucocorticoids and so whenever they are
secreted in increased amounts it promotes increased insulin secretion. Note that Growth
Hormone is an antagonist to insulin in terms of [glucose] but they both work to increase
protein synthesis and thus increase growth ( agonists).
Fever increases the bodies metabolic rate and so also increases the insulin requirement.
Stress will also increase the requirements for insulin and both of the hormones involved –
epinephrine and glucocorticoids work to increase blood [glucose] and so stimulate
increased insulin secretion. The insulin then promotes glucose entry into tissues that need
it to cope with the stressor.
Insulin is a protein so that any that is ingested (eg. orally administered} would be
broken down by gut digestive enzymes before it could serve any purpose. Large proteins
can't be absorbed through the gut anyway.
Diabetes results from;
a. ) an insufficiency in the secretion of insulin by pancreatic islet cells
b.) the decreased effect of insulin on target tissues d/t a deficiency of insulin
receptors on target cell membranes.
There are two main forms of Diabetes;
 TYPE 1 or Insulin Dependent Diabetes Mellitus (or IDDM)
Previously known as juvenile onset diabetes. This form is responsible for about 10% of
cases. It involves an absolute deficiency of insulin secretion. The beta cells of the islets of
Langerhans that normally produce insulin are reduced in mass and little or no insulin is
produced. IDDM generally has an onset before the age of 30, most commonly before the
age of 15, but it can develop in individuals of any age. In many cases the development of
IDDM seems to involve individuals with a genetic predisposition as well as some
exposure to a triggering factor such as a viral infection or exposure to certain chemical
agents. Autoimmune responses are thought to be part of the pathological process.
Individuals with IDDM are more prone to problems with ketoacidosis and because of
the early onset there is greater potential for further complications such as vascular
pathologies, vision loss etc.etc.

TYPE II or Non Insulin Dependent Diabetes Mellitus (or NIDDM)

This form is also known as maturity or late-onset diabetes and it is responsible for
about 80% of diabetes cases. Onset is usually greatest in individuals after age 30
especially after 40. This type of diabetes may involve some reduction in insulin levels
but generally the insulin is available but it has much less effect on target cells. This
resistance to insulin effects may be d/t impairment of receptors, reduction in the # of
receptors , the presence of circulating antagonists to insulin or decreased responsiveness
of beta cells to elevated blood glucose levels.
Predisposing factors to NIDDM include;
- age - incidence rises sharply after age 40 and progressively increases with age
- heredity -A family history seems to play a bigger role with NIDDM than with IDDM
-Body Weight - In about 80% of NIDDM cases the affected individual is obese with
greater frequency for upper body obesity ( apple shapes instead of pears). Loss of weight
often leads to a reduction in symptoms.
- Diet ( ie. high fat, high calorie) , stress and pregnancy may also play predisposing
roles.

Generally with a later onset there are fewer complications and the problems can often be
more effectively controlled through weight loss and diet and lifestyle management such
as increased exercise.

Problems associated with Diabetes

The HHNK or Hyperosmolar Hyperglycemic Non-ketotic state is most common in

association with type II diabetes but it can also be associated with surgery, acute illness
( especially infections), severe stress (eg. MI), acute pancreatitis and use of some oral or
parenteral nutrition solutions. It involves severe hyperglycemia ( > 600 mg/dL) and a
resulting very high osmolarity (>350 mOsm/kg). There are usually no ketones in the
urine and no acidosis because there is still some insulin present to inhibit the catabolism
of fats. The hyperglycemia by exceeding the renal transport capacity for glucose
reabsorption leads to high glucose levels in the filtrate which, in turn, leads to decreased
water reabsorption in the renal tubules leading to dehydration. The dehydration will also
provoke a stress response which will further elevate the blood [glucose]. Furthermore the
hemoconcentration of blood that occurs with dehydration will lead to increased risk of
thrombus formation. There is also a risk of hypovolemic shock.
One of the big problems with HHNK is that it occurs slowly and gradually – it is
insidious because you are largely unaware of any significant symptoms until the problem
is quite severe.

Diabetic Ketoacidosis or DKA is most commonly associated with Type 1 diabetes.

The absolute deficiency of insulin leads to increased levels of lipolysis. Breakdown of
triglycerides to fatty acids and glycerol leads to liver conversion of the fatty acids to
ketones that can be used as energy sources. Ketones, however, act as acids and will lower
the pH – ie. metabolic ketoacidosis. Ketoacidosis is typically initiated by inadequate use
of insulin therapy or by factors that produce stress (eg. physical stress such as strenuous
exercise or emotional stress) which will lead to increased secretion of stress hormones
such as glucocorticoids and catecholamines – which also promote fat catabolism.
The onset of DKA is slower than hypoglycemic shock but it still occurs quite quickly –
usually within 24 hours. The main problems are hyperglycemia, dehydration and
acidosis. Blood glucose levels are greater than 250 mg/dL and so the renal capacity for
glucose reabsorption will be exceeded thus causing glucose to remain in the filtrate and
urine. This raises the osmotic pressure of the filtrate and so less water will be reabsorbed
by the tubules. The result will be polyuria and ultimately dehydration will develop from
this water loss. Typical s/s include polydipsia ( thirst and increased drinking) , warm dry
skin , dry mouth and other mucous membranes and because of the decrease in blood
volume there will be tachycardia, decreased BP and a weak thready pulse. Water loss can
also lead to significant weight loss.
During dehydration there will be a shift of water out of cells into the extracellular
compartment and intracellular potassium will go with it. Potassium blood levels will
stay nearly normal though because of the losses of potassium with vomiting and
increased urine losses so overall there will be potassium depletion occurring. For tissues
– more critically, insulin is needed to transport insulin into cells and so tissues become
hypokalemic.
The other s/s will be the development of metabolic acidosis including nausea, vomiting
and anorexia quite quickly and a gradual depression of neurological function ranging
from lethargy to stupour and eventually to coma. Other common findings include
Kussmauls breathing in compensation and the fruity odour of ketones ( eg. acetone) in
the breath and urine. The initial compensation by increasing the rate and depth of
breathing will lower the blood PCO2 to lower carbonic acid concentration thus balancing
the loss of bicarb that occurs as it is used up by the ketoacid production. Eventually
though the ability to compensate will be exceeded leading to uncompensated acidosis and
a decrease in blood pH – with widespread negative consequences.

The Somogyi Effect – This occurs when an excess dose of insulin leads to
hypoglycemia and this, in turn, leads to a stress response. The glucocorticoids and
catecholamines then lead to hyperglycemia in response. This now may lead to an
additional dose of insulin to lower the blood glucose back down, Clearly this can lead to
a vicious cycle which can be particularly dangerous, especially if it occurs at night when
the effects may not be detected. Ultimately the wide swings must be prevented through
modification of dietary intake and modified insulin use.
There is another phenomenon known as the Dawn Effect that involves episodes of
hyperglycemia and therefore increased insulin requirements in the early morning hours
probably d/t the typically elevated levels of Growth Hormone that occurs at that time. If
this leads to a response that causes the Somogyi effect it can cause quite severe effects.

Long Term Complications of Diabetes Mellitis

Diabetes can cause a wide range of pathological change. The mechanisms are not
absolutely understood but they may involve i.) osmotic changes that result fro
accumulation of sorbitol ( a metabolic byproduct of glucose metabolism d/t elevated
blood glucose levels ii.) structural damage to the basement layers of small blood vessels
possibly d/t the formation of glycoproteins (glucose +protein) or iii.) reduced O2 delivery
to tissues because of altered hemoglobin leading to a greater affinity of hemoglobin to
oxygen so that less is released to tissues.
Some of the most significant blood vessel changes include;
Macroangiopathy – ie. pathological changes to larger vessels and this is primarily in
the form of atherosclerosis of the larger arteries which can lead to reduced blood flow,
increased systemic BP as a result of greater PVR and an increased risk of
thromboembolus formation. These changes can have a wide variety of effects including
increased risk of MI, CHF, CVA's, and very commonly peripheral vascular disease. The
lower limbs are often affected by decreased blood flow quite early in the process and we
see such problems as intermittent claudication ( pain in the legs with increased activity
such as walking, stair climbing etc) as well as the development of ulcers and gangrene.
Microangiopathies are the result of the thickening and hardening of the basement
membranes of capillaries and small arterioles. This can lead to local ischemia and
necrosis of tissues but it can also lead to other changes in the vessels such as
microaneurysms and a variety of other structural distortions. This often has very
significant effects on tissues such as;
-the renal glomeruli in diabetic nephropathy which can ultimately lead to renal failure
- the retina in diabetic retinopathy which can lead to vision loss and blindness since the
part of the retina often most severely affected is the area of the fovea and macula where
there is greatest cone density and thus where the highest acuity vision would arise.

Cataracts are a common complication of diabetes. The elevated blood glucose leads to
an accumulation of sorbitol ( a product of the metabolic pathway for glucose utilization)
which, in turn, alters the osmolarity of the lens and alters the lens proteins leading to a
permanent loss of transparency which leads to vision loss progressing until the only
treatment is surgery to remove the lens and replace it with an artificial one. As stated
earlier, vision loss will also result from diabetic retinopathy in which we see thickened
distorted capillaries and microaneurysms well as the accumulation of soft exudates
known as cotton wool spots on the retinal surface on ophthalmoscopic examination.
These vision losses are also permanent and critical to functions such as reading and other
activities requiring high visual acuity. Diabetes also increases the risk of retinal
detachment that can also lead to vision loss.

Neuropathies are another serious longterm consequenceo of diabetes. Neurons are

highly susceptible to damage d/t ketoacidosis ( and dehydration) and are also greatly
affected by hypoglycemia in insulin reactions. The myelin sheath tends to degenerate
( probably d/t decreases in myoinositol which is necessary for Schwann cell function.The
microangiopathy is also a major contributor to neuropathy d/t ischemic damage.
If the ANS is affected it leads to a decrease in responsiveness to bladder filling and
bladder atony causing incomplete emptying and can lead to a delay in gastric emptying
and interference with peristalsis. Decreased control over vasomotor reflexes can also lead
to problems with dizziness and sexual dysfunction ( eg. erectile dysfunction).
The somatic sensory system can also be affected leading to decreased touch, temperature
and pain sensation which can have serious consequences as a result of unawareness of
accidental injury and infection. Loss of sensation can also have other consequences such
as a reduced sexual response.

Infections are often a much greater risk with diabetes. The insulin deficit leads to
decreased protein synthesis and therefore less effective healing and the elevated blood
glucose concentration tends to support greater microbial growth. Without insulin there is
also decreased entry of glucose into critical WBC's such as neutrophils and macrophages.
Probably the most critical factor leading to reduced immunity though is the reduced
blood flow d/t the macro and microangiopathies so that immune components cannot be
effectively delivered. Some of the common infections include bladder infections (cystitis)
and pyelonephritis ( ureters to kidneys) as well as dental cavities and gum (periodontal)
disease. Candida and other fungal infections in the mouth and vaginal become much
more common. Probably the most common infections occur though in the legs and feet as
a result of accidental injury, the lack of sensory awareness of the injury and poor
subsequent healing d/t decreased protein synthesis and decreased blood flow. As a result
these infections often become quite extensive and in combination with the ischemia can
lead to gangrene involving extensive tissue necrosis. The poor circulation means that the
prognosis is poor and frequently amputation is required to prevent systemic infections.
A wide variety of other diseases are exacerbated as a result of the underlying problems
associated with diabetes. A good example of this is the higher risk of infection and more
severe consequences of infections such as tuberculosis.

Diabetes and Pregnancy

During the first trimester there is often a decrease in food intake with morning sickness
( d/t high HCG levels) as well as increased transfer of glucose and amino acids across the
placenta to the fetus so that overall the insulin requirements do not increase. There may
even be some greater risk of hypoglycemia for these reasons.
For the second half of the pregnancy there is an enormous increase in the growth of
tissues as well as a rise in secretion of GH and placental lactogen which are both insulin
antagonists ( ie. they raise blood [glucose]) and this leads to an increase in insulin
requirements and careful monitoring as the requirements change quite quickly. There is
then also an increased risk of hyperglycemia and ketoacidosis.
Post partum the decreased levels of hPL (placental lactogen) and GH means that the
insulin intake should be reduced in order to prevent hypoglycemia. Some risks associated
with diabetes in pregnancy include;
- increased risk of infection
- increased incidence of pre-eclampsia and eclampsia
- increased risk of caesarian section
- increased risk of post partum hemorrhage
- increased risk of congenital fetal abnormalities. This can include a wide range of
changes since during the critical early embryonic and fetal period organogenesis occurs
and small changes in chemistry can lead to profoundly altered patterns of development .
Elevated ketones, hypoxia and wide fluctuations in [glucose] can play significant roles
esp. regarding nervous tissue development. Neural tube defects such as anencephaly,
microcephaly, hydrocephaly as well as heart defects and renal defects and even GI
abnormalities can develop. Stillbirth , probably as a result of developmental defects, is
also quite common as is the birth of small for gestational age (SGA) babies as a result of
poor uterine/placental circulation that leads to decreased growth in the early stages.
Another common problem, especially as a result of decreased control over blood
glucose in the 2nd half of the pregnancy is fetal macrosomia ( ie. newborn greater than
the 90th percentile). By 10-12 weeks of development the fetal pancreas becomes
competent and produces more insulin in response to the elevated blood glucose that
crosses from the maternal circulation through the placenta to the fetal circulation. The
fetal insulin lowers the blood glucose but it also stimulates much more protein synthesis
and more fetal growth,This larger fetal size can lead to dystocias ( ie. cephalopelvic
disproportion) and lead to difficult forceps delivery or a caesarian section.
Post partum the newborn may now have a problem with hypoglycemia since in utero it
was producing high levels of insulin in response to elevated maternal blood glucose
levels but at birth that source is removed but the baby still has persistent high insulin
levels and no immediate source of glucose at high levels so hypoglycemia can develop
within the first 30-60 minutes.
Infants of mothers with diabetes are also at much greater risk of infant respiratory
distress syndrome (IRDS). Hyperinsulinemia and hyperglycemiamay delay the
maturation of the alveoli and the production of surfactant or the baby may be born
prematurely and not yet be at the stage of adequate surfactant production.