Diabetes Part II: Slides 5‐10
The complications of diabetes can be broken down into acute and chronic complications. Acute
complications include hypoglycemia, hyerglycemic states of diabetic ketoacidosis ,and hyperperosmolar
nonketotic syndrome. The chronic complications can be further broken down to the microvascular
complications of retinopathy, neurpathy, and nephropathy. And mascrovascular complications of
cerebrovascular disease, peripheral vascular disease (PVD), and coronary artery disease (CAD). Triggers
are underlying etiology of acute complications often include concurrent illness and factors related to the
management of plasma glucose levels including noncompliant with diets or pharmacology therapy or
side effects of pharmacological therapy. Chronic hyperglycemia and the resulted metabolic events have
been associated with the underlying etiology of chronic complications of diabetes. Hyperglycemia affects
cells that do not effectively reduce the transport of glucose into the cell in a hyperglycaemic state. This
results in an intracellular hyperglycemia. Examples of cells that are vulnerable to chronic hyperglycemia
include: capillary endothelial cells in the retina, mesangial cells in the renal, glomerulus, and neurons,
and schwann cells in the peripheral nerves. There are several theories that are well documented and
described the metabolic mechanisms that are associated with the tissue damaging effects of chronic
hyperglycemia and the resulted diabetic complications that will be described later.
Let’s start by looking at the acute diabetic complications. First we will begin by reviewing some content
from the first diabetes module:
1) What is the normal plasma glucose level? This question is not as straight forward as it may first
seem. Plasma glucose varies based on last meal. That being said the homeostatic mechanisms
of the body generally maintain glucose levels less than <6mmol/L
2) What source of energy does the brain rely on solely? The answer is glucose
‐ Take a minute to think about what may be some of the clinical manifestations of hypoglycaemia,
considering that the brain relies solely on glucose as a source of energy
Hypoglycemia is defined by: development of neurologic/autonomic and/or neuroglycopenic symptoms.
Activation of the sympathetic nervous system results in the neurogenic or autonomic symtoms of
trembling, palpitations, sweating, anxiety, hunger, nausea, and tingling. Abrupt cessation of glucose
delivery to the brain results in neuroglycopenic symptoms of difficulty concentrating, confusion,
weaknes, drowsiness, vision changes, difficulty speaking, headache and dizziness. Symptoms are variable
among individuals especially in children and the elderly. However are usually consistent for each person.
Secondly, below than normal blood glucose levels, generally hypoglycaemia occurs when blood glucose
are between 2.5‐ 3.3mmol/L. In diabetic patients treated with insulin or an insulin secretagogue blood
glucose levels <4mmol/L are consisted hypoglycaemia. Lastly, symptoms respond to the administration of a carbohydrate. Hypoglycaemia may be caused by exogenous, indogenous or functional mechanisms.
In diabetic patients the exogenous mechanism of drug induced hypoglycaemia is most common. The
negative social and emotional impact may make patients reluctant to intensify pharmacological therapy.
Furthermore, there are short and long term risks of hypoglycaemia. Short term risks are safety related.
For example it would be unsafe if an individual experienced hypoglycaemia while driving or operating
machinery. Prolonged coma can be associated with transient neurological symptoms like paresis,
convulsions and encephalopathy. Long term risks of severe hypoglycaemia are mild intellectual
impairment, and very rarely permanent neurologic sequelae like hemiparesis, and pontine dysfunction.
Severity of hypoglycaemia is divided into mild, moderate and severe. Mild hypoglycaemia results in
autonomic symptoms and individuals are able to self treat. Moderate hypoglycaemia results in
autonomic and neuroglycopenic symptoms and individuals are able to self‐treat. Severe hypoglycaemia:
individuals are unable to self treat, they require assistance, and they may be unconscious. Blood glucose
is usually <2.8mmol/L in these cases
The cause of hypoglycaemia in diabetes is twofold. First relative excess of insulin in the blood,which can
be the result of too much exogenous insulin or when insulin secretagogues like sulfonylureas are used.
Hypoglycemia is more common in type 1 diabetes and occurs in more than 90% of type 1 diabetics and
often limits the management of the disease. Hypoglycemia can also occur in type two diabetics,
particularly in those taking insulin secretagogues or using exogenous insulin. The cause of hypoglycaemia
can also be linked to deficits in glucose counterregulation. This second point is particulary important in
type one diabetes specifically glucagon and epinephrine release during hypoglycaemia become
defective. Which blunts the otherwise autonomic symptoms associated with mild or moderate
hypoglycaemia and puts these patients at greater risk if developing severe hypoglycaemia. Some risk
factors for hypoglycaemia include: exercise, alcohol, older age, renal dysfunction, and infection, error in
insulin dose, medication changes, cognitive dysfunction, and mental health issues. Specific risk factors
for severe hypoglycaemia in type one diabetics include; prior episode of severe hypoglycaemia, current
low haemoglobin of A1C (<6%), hypoglycaemia awareness, long duration of diabetes, autonomic
neuropathy, low economic status, adolescents, presechool children who are unable to detect or treat
hypoglcemia on their own. The pathophysiology of hypoglycaemia is triggered by the relative excess of
insuklin, causng a decrease in blood sugar. A decrease in the endogenous insulin secretion is the first line
of defence against hypoglycaemia. This is critical in patients who have residual insulin secretion.
Normally beta cells suppress insulin secretion at plasma glucose levels of about 4.6 mmol/L.
Hypoglycemia activates the sympathetic nervous system via the hypothalamus which results in the
stimulation of the adrenal gland to release counterregulatory hormones. You should now be thinking
about the stress response specifically the hypothalamic pituitary adrenal axis. The role of the liver in
sympathoadrenal response to hypoglycaemia is twofold. First the portal vein may play a role in sensing
hypoglycaemia and activating the counterregulatory response. Secondly as you already know, glucagon
stimulates glycogenolysis and glyconeogenis in the liver. Counterregulartory hormones include
norepinephine, epinephrine, growth hormone and cortisol cause an increase in glucose production, and
decrease glucose uptake in periphery specifically adipose and muscle tissues. Now you should take the time to link the effects of each of these hormones to the autonomic symptoms of hypoglycaemia.
Neuroglycopenic symptoms occur due to an abrupt cessation of glucose delivery into the brain
Treatmen tof mild to moderate hypoglycaemia in a conscious person is giving them 15g of carbohydrate.
This will increase their blood glucose levels by 2.1 mmol/L within 20mins. The treatment of severe
hypoglycaemia in a conscious person is giving them 20g of carbohydrate. This will increase their blood
glucose levels by 3.6mmol/L in 45minutes. In both cases patients should re‐test blood glucose within
15minutes and retreat with another 15 or 20g of carbohydrate if their blood glucose remains less than
4.0 mmol/L. Treatment in unconscious individuals with severe hypoglycaemia in ages greater or equal to
5 yrs include; 1mg of glucagon given via subcutaneous or intramuscular route or IV glucose 10‐25g
which equals 20‐50cc D50W over 1‐3 minutes. Examples of 15g of carbohydrates includes 15g of glucose
in the form of glucose tablets, 2 tea spoons or 3 packets of table sugar dissolved in water, 175mL of juice
or regular soft drink, 6 lifesavers or 1 tablespoon of honey. Monosaccharides like glucose are preferred
as they are absorbed directly into the bloodstream. Some clinical pearls to remember from the first
diabetes module are that if a patient is taking alpha glucosidase inhibitor dextrose not sucrose should be
used to treat hypoglycaemia. Secondly glucagon would be ineffective in patients with whose glycogen
stores are depleted. Glucagon will not be as effective in individuals whom have consumed more than 2
standard alcoholic drinks within the previous few hours or those who have advanced liver disease
Hyperglcemic emergencies are life threatening associated with significant morbidity and even mortality.
The two hyperglycaemic conditions associated with diabetes are diabetic ketoacidosis or DKA and
hyperglycaemic hyperosmolar nonketotic syndrome or HHNKS. The features of each of these conditions
can overlap however there are some distinct differences; both conditions arise from either a relative or
absolute insulin deficiency. And some form of trigger that causes an increase in counterreulatory
hormones and result in hyperglycemia. Osmotic diuresis and extra cellular fluid volume depletion or
hypovolemia, more impressive with HHNKS. An acid base imbalance specifically metabolic acidosis due
to ketoacidosis is less likely to occur in HHNKS, but always present in DKA. Electrolyte imbalances occurs
due to the metabolic acidosis and osmotic diuresis . The most serious electrolyte imbalance is hypo and
hypercalemia due to the associated risk for cardiac arrhythmias. Adverse neurological sequelae including
cerebral edema , coma, and death are reported in both conditions.
Let’s look at the pathophysiology a hypoglycemic condition in diabetes, first there is an insulin
deficiencies and some precipitating factor that increases counter regulatory hormones including
glucagon. Glucagon directly stimulates Glycogenolysis in the liver. Counter regulatory hormones include glucagon cause decrease glucose uptake in peripheral tissues. Protein breaks down to provide amino
acids to the liver for Gluconeogenesis. Adipose tissue also breaks down to form glycerol for
Gluconeogenesis. If ther is a relative insulin deficiency and free fatty acids to form ketones in the liver in
the case of absolute insulin deficiencies. Specific ketones formed are called beta‐hydroxybutyric and
acido acidic acids which results in metabolic acidosis. The result of glycogenolysis and gluconeogenesis is
hyperglycemia. Hyperglycemia causes osmotic diuresis and large losses in electrolytes in the urine. Tota l
body water deficit in adults is usually about 5‐7L/DKA and 7‐12 L in HHNKS which represents a loss of 10‐
15% of body weight. If left untreated circulatory failure and size hyper osmolality and metabolic acidosis
can cause CNS depression and if untreated coma. As you can visually appreciate whether the
hyperglycemia condition is classified as DKA/HHNKS depends mostly upon whether or not there is a
relative or absolute insulin deficiency.
Let’s briefly compare DKA and HHNKS, remember that DKA affects Type 1 diabetics and HHNKS affects
Type 2 diabetic, DKA is more common and estimates that between 5000 and 10000 patients are
admitted in hospital in Canada every year because of DKA. HHNKS is less common and is estimated that
between 500 and 1000 patients are admitted to hospital in Canada every year because of HHNKS.
Mortality is lower in DKA ranging from 4‐10% and even reported than 320. In DKA metabolic acidosis is present with a pH
<7.3 and associated decreased bicarbonate .Bicarbonate level are USUALLY less than 15 mml /L. In
HHNKS pH is usually normal. Since is ketone production in DKA the presence of acetone breath which is
describe as fruity odour is usually notice at time of presentation. Also Kussmaul‐Kein respiration due to
metabolic acidosis can also be present especially with severe metabolic acidosis. This clinically features
are not present in HHNKS.DKA AND HHNKS are complex hyperglycemic disorders that have overlapping
features and some distinctive differences. Your previous knowledge in fluids and electrolytes to address
some of the other manifestations to this disorder also part of this required reading for this module your
port pathophysiology text book describe some specific clinical manifestations for both DKA and HHNKS.
You should be able to relate these clinical manifestations to the pathophysiology. For example
hypotension and tachycardia maybe present in either DKA or HHNKS due to extracellular fluid volume
Management of DKA/HHNKS Pathophysiology Slide 13
Key principals in Management of DKA/HHNKS involve the following: fluid rehydration to restore normal
extracellular volume of tissue perfusion, correction of hyperglycemia by addressing absolute or relative
insulin deficiencies, resolution of ketoacidosis, usually occur with insulin therapy and fluid rehydration,
for severe acidosis sodium bicarbonate maybe used in the adult population it is not used as often in
pediatric, monitor and correct electrolytes specifically potassium, diagnostic and treatment of coexisting
illness, which may have been a precipitating factor, monitor for and prevent complications specifically
adverse neurological sequel like cerebral edema, this is a very simplified summary of Management of
DKA/HHNKS. There are specifically clinically algorithms to manage DKA in both adult and children. The
next 2 slides show the algorithm found in Canadian Diabetic Association 2008 Guidelines to manage DKA
in adult and children. It is not necessary to memorize either of algorithms but as you go through it you
should be able to make sense and provide rational for each step. Another important point I want to
make is that Potassium is added to maintenance fluid even the Potassium level are not abnormally low.
This is because with metabolic acidosis began to correct potassium shift s back into the cell. Since is
there already overall a depletion of potassium due to potassium having moved out of the cell during
metabolic acidosis and loss of potassium via osmotic diuresis is imperative to anticipate this to avoid life
threatening arrhythmia. Lastly a sudden change in extra cellular fluid osmolality can occur if
hypoglycemia is corrected to quickly which can result in cerebral edema. This is particularly important in
pediatrics. Cerebral edema is more common in DKA and in children. It can be deadly or having
devastating neurological consequences.
Management of DKA Adults
This is algorithm to manage the DKA in Adults
Management of DKA PEDIATRICS
This is algorithm to manage the DKA in children. Remember it is not necessary to memorize either
algorithm entirely; however you should be able to provide rational for each of the interventions.
Chronic /Long –Term Complications
Slide 16 Chronic and more long term complications of diabetes can cause disease in several bodies systems as
illustrates in this figure. The Canadian Diabetes Association states that 10% of all acute care of hospitals
admission are related to diabetes or its complications. I want to highlight some staggering statistics
about diabetic complications, it is fortunate that diabetic care and management which include health
teaching can prevent or delay all set of complications. 2 landmark studies, one called the diabetic control
and complications trial which flip to type I diabetes and U.K prospective diabetic studies which flip to
type II diabetes found that intensivediabetic treatment can reduce the incidence of complications. 80%
of people with diabetes will die of heart attack or strock.50% of diabetics have chronic kidney disease
and chronic kidney disease with diabetes is the leading cause of kidney failure in Canada. Blindness
cause by diabetes is the most common cause of diabetes in people age 65 and younger. Neuropathy can
cause minor injuries to go unnoticed which if untreated can lead to infection and gangrene.7 out of 10
no traumatic limb amputation is due to diabetes, infection as a chronic complication will not be
discussed in detail in this presentation. Pleaseefer to page 1032 of your Porth pathophysiology for
further information. I have highlighted only some of the more common complications although other are
not really all that in common. For example rectal dysfunction for the first clinical sign of diabetes and up
to 12% of male with diabetes; for the second part of the modules I want to go through these
complications in a bit more details breaking them down in micro vascular and macro vascular disease.
Please use your re