Pathophysiology: Diabetes Mellitus Part 1
Prevalence of Diabetes
The prevalence of diagnosed diabetes has increased by 4% in 2006/07.
Type 2 DM accounts for over 80% of diabetes. Type 1 DM accounts for 10%. The rest of
the 10% is made up of gestational diabetes and others.
2 million Canadians have been diagnosed with diabetes. But more then 9 million live
with diabetes or prediabetes.
Personal costs of diabetes: reduced quality of life, increased risk of heart disease,
blindness, amputation and erectile dysfunction. 80% of people with diabetes die because
of a heart disease or stroke.
Type 1 diabetics life expectancy may be shortened by 15 years, Type 2 diabetics life
expectancy may be shortened by 510 years.
The financial burden is 23 times higher then a non diabetic. Cost ranging from 10
Etiology Type 1 DM
There are 2 types: Autoimmune Type 1A and Idiopathic Type 1B.
Autoimmune type 1A = 90/95% of Type 1 DM cases
there is an autoimmune mediated specific loss of beta cells in the pancreatic
Type 1 diabetes includes cases of diabetes that are primarily that are the result of
beta cell destruction which leads to absolute insulin deficiency and is prone to
• This is believed to be a result of geneticenvironment interaction
• When looking at genetic susceptibility to type 1A is the inherited major
histocompatibility complex genes on chromosome 6 which encode for human
leukocyte antigen HLADQ and HLADR. HLADR3 and HLADR4 is
associated with an increased risk of type 1A that is 2040 times higher than
general population. Some specific human leukocyte antigens are thought to
decrease the risk of developing type 1diabetes including HLADR2.
• There is also an insulin gene which regulates beta cell replication and function on
there are many polymorphisms of multiple genes that have been found to
influence the risk of type 1A diabetes
there is likely a polygenic inheritance of type 1 diabetes meaning that susceptible
individuals have more then one genetic polymorphism.
1013% individuals with newly diagnosed type1 diabetes have a 1 degree
relative with type 1 diabetes
• Autoantibodies specific to beta cell destruction include: insulin antibodies, islet
cell autoantibodies, antibodies directed at other islet anutoantigens like: glutamic
acid decarboxylaseGAD and tyrosin phosphatase 1A2
• Environmental factors interact with genes
Certain chemicals such as Alloxanm Strptozotocin and Vacor. And some drugs
such as Pentamidine have been associated with type 1 diabetes. Nutritional intake of bovine milk and high levels of nitrosamines has also been
linked to type 1 diabetes.
viruses have also been linked to type 1 D. 40% of people with congenital rubella
infection develop Type 1 D later. Persistent cytomegalovirus infection appear
relevant in some type 1 D cases. While mumps and coxsackievirus have small
effect on the development of type 1 D.
• Seasonal distribution
more new cases reported in fall and winter in the northern hemisphere
There are 10% of type 2 diabetics who appear to have immune mediated destruction of
beta cells who fall into type 1A diabetes. This population is called the latent autoimmune
disease in adults LADA.
TYPE 1 Diabetes is diagnosed in childhood majority of the time. Peaks at 12 year of age
and rare before 9 months of age.
Idiopathic Type 1B Diabetes
• Also known as nonimmune type 1 diabetes
• Idiopathic type 1B accounts for <10% of those with type 1 diabetes
• There is a strong genetic component to the development of Type 1 B diabetes
• Most people affected are African or Asian decent
• Affected people have varying degrees or insulin deficiency that can come and go
which leads to episodic ketoacidosis
Etiology Type 2 DM
• Type 2 diabetes is a hetergenous condition characterized by hyperglycemia,
insulin resistance and relative impairment in insulin secretion
• Type 2 D may range from: Predominant insulin resistance with relative insulin
deficiency to predominant secretory defect with insulin resistance
• The etiology of type 2 D is thought to involve an environmentgenetic interaction.
1525% of 1 degree relatives of people with type 2 D will develop either
impaired glucose tolerance or diabetes.
There is a 2 to 4 fold increased risk of type 2 D associated with a + family
• Variants of genes has been identified that increase the risk of type 2 D.
Genetic defects of beta cell function, genetic defects in insulin synthesis,
secretion and action
Genes that encode proteins for pancreatic development, amyloid deposition in
beta cells, cellular insulin resistance impaired regulation of gluconeogenesis
• Risk factors of Type 2 D: age, obesity, hypertension, physical inactivity and
High risk of developing type 2 D and associated cardiovascular complications
with metabolic syndrome
• Type 2 DM occurs mostly in adults, but there is increased prevalence in children
as childhood obesity rate climb
Canadian aboriginal children are particularly affected Etiology GDM and Other
• Gestational D is defined as any degree of glucose intolerance with onset or 1 t
recognition during pregnancy
Pregestational D refers to pregnancy in persons with preexisting diabetes
the exact etiology of glucose intolerance in GD is unknown but a combination of
insulin resistance and impaired insulin secretion are most definitely contributing
• Risk factors: older age, family history, history of glucose intolerance, obesity,
membership in certain ethnic or racial groups, history of poor obstetric outcomes
and infant weighing greater than 9 pounds
• Diagnosis is made based on gestational diabetes screen which is a 50g glucose
load followed by a plasma glucose level 1 hour later
Diagnosed of gestational diabetes is made based on different lab values than for
non pregnant individuals
Type 2 diabetes accounts for 80% and type 1 510% in US, CAN, EU
• Specific genetically defined forms of diabetes include genetic defects of beta cell
function and genetic defects in insulin action.
One specific grouping of genetically defined form of diabetes is maturity onset
diabetes of the young also known as MODY. These individuals present at a
young age have mild disease due to beta cell dysfunction with some insulin
production and inherit the disease via autosomal dominant transmission. There is
normal insulin sensitivity in individuals with MODY.
There have been 6 different genetic abnormalities identified that are responsible
for betacell function impairment. MODY type 2 and 3 account for 65 and 15 %
of the cases.
• Diabetes associated with the exocrine pancreas or endocrinopathies.
Endocrinopathies like Cushing syndrome or acromegaly results in diabetogenic
effects due to excess hormone levels
• Diabetes induced by infections, drug or chemicals
there are also specific genetic syndromes sometimes associated with diabetes like
Down syndrome and umcommon forms of immunemediated diabetes like stiff
• Glucose is a 6 carbon molecule, its efficient at breaking down fuel into co2 and
h2o when metabolized in the presence of oxygen.
• Brain and nervous system rely only on glucose for fuel
other tissues and organ systems can use other sources of non carbohydrate fuel:
like fatty acids and ketones
the brain is not able to synthesize glucose or store more than a few minutes worth
of glucose supply. Therefore a continues supply of glucose from the circulation is
required o maintain normal cerebral function. • Fasting blood glucose is tightly regulated between 4.45.0 mmol/L in nondiabetic
• Insulin is secreted by beta cells in the pancreas in response to rising blood glucose
• After a meal is ingested, approx. 2/3 of glucose is stored in the liver as glycogen
• The liver releases glucose by breaking down glycogen in a process called
glycogenolysis to maintain normogylcemia between meals
• Once the liver and skeletal muscles are saturated with glycogen, additional
glucose is converted into fatty acids by the liver and then stored as triglycerides in
• The liver also synthesizes glucose from non carbohydrate sources such as amino
acids, glycerol, and lactic acid in a process called gluconeogenesis
• Proteins are essential for the formation of all body structures including genes,
enzymes, contractile structure in muscle, matrix of bone and hemoglobin of red
• Amino acids are the building blocks of proteins
• There is limited capacity for the storage of excess amino acids. Most stored amino
acids are contained in body proteins
• Amino acids not needed for protein synthesis are converted to fatty acids, ketones
or glucose and then stored or used as metabolic fuel
• Amino acids are broken down from proteins and used as a major substrate for
gluconeogenesis when metabolic needs exceed food intake
• Fat is the most efficient form of fuel yielding 9kal/g of stored energy compared
with 4kal/g yielded by stored carbohydrates and proteins
• Approx. 3035% calories obtained from fat in a normal Canadian diet. 55%
obtained by carbohydrates and 15% from proteins
• Many carbs consumed in diet are converted to triglycerides and stored in adipose
• Triglycerides are composed of 3 fatty acids linked by a glycerol molecule
• Lipase which is an enzyme that breaks down triglycerides into its 4 components
when fat is required for fuel
• Glycerol is then used in the glycolytic pathway and can be used with glucose to
produce energy or to produce glucose
• Fatty acids are transported to tissues and can be used interchangeably with
glucose for energy in all body cells besides brain, nervous system and red blood
• Liver converts left over fatty acids into ketones and releases them into the
• When large amounts of ketones are released into the blood stream it causes
KETOACIDOSIS Putting it all together
• Glucose is a necessary and efficient fuel used in our body
brain requires a constant supply of glucose from the circulation to maintain
normal cerebral function.
after a meal is consumed the pancreas releases insulin in response to increasing
plasma glucose. This allows the glucose to enter cells and be used,
• Glucose that is not needed will go to the liver and be stored as glycogen.
glucose is converted back to glucose between meals to maintain normoglyemia
in a process called glycogenolysis
• When the liver and skeletal muscle are saturated with glycogen additional glucose
is converted into fatty acids by liver and then stored as triglycerides in adipose
• Many carbohydrates consumed are converted to triglycerides and stored in
almost all body cells can use fatty acids as an energy source and fuel storage
• Amino acids are the building blocks of proteins
proteins are essential for the formation of all body structures
proteins are broken down into amino acids for gluconeogenesis when metabolic
needs exceed carbohydrate availability
• Glucose is stored in skeletal muscle as glycogen
• Pancreas is responsible for the hormonal control of blood glucose
its located behind the stomach, between the spleen and duodenum
its made up of 2 components: endocrine pancreas and exocrine pancreas
the exocrine pancreas produces digestive juices which are secreted into the
the endocrine component of the pancreas makes up 12% of the pancreas volume
and secretes hormones that regulate most of the carbohydrate metabolism in the
• The acini cells make up the exocrine pancreas
before these cells secrete digestive juices into the duodenum via the pancreatic
the endocrine pancreas is made up of the islets of Langerhans
the pancreatic islets are made up of beta cells that secrete insulin and amylin
alpha cells that secrete glucagon and delta cells that secrete somatostatin
Insulin – secreted beta cells
Glucagon – secreted by alpha cells
Somatostatin – secreted by delta cells
Amylin – secreted beta cells
Endocrine Pancreas Hormones
• Only hormone to have direct affect on lowering blood glucose levels its important to understand the effects of insulin as insulin resistance in type 2
diabetes is one of the main patho features
• In its active form of insulin is composed of 2 polypeptides chains, A chain and B
chain. Active insulin is formed from proinsulin which is composed of active
insulin and a biological inactive connecting peptide.
• Insulin is released from beta cells in response to blood glucose. Blood glucose
enters the beta cell by means of glucose transporter. It is metabolized to form
adenosine triphosphate or ATP through phosphorylation by an enzyme called
glucokinase. ATP is needed to close the K+ channels and depolarize the cell.
• Once the beta cell is depolarized the Ca+ channels can open and insulin is
secreted. Causing insulin secretion is decreased when blood glucose levels are
lower and increased sten blood glucose levels are higher. Insulin response is
biphasic with the 1 release of insulin peaking 35 min post food ingestion and
returning to baseline within 23 hours. During the 1 phase, stored preformed
insulin is secreted. The 2 phase begins around 2 min and continues to increase
slowly for at least 60 min or until stimulus ceases. The insulin released in the 2 nd
phase is newly synthesized insulin
• Insulin has 3 main actions:
Promotes uptake of glucose by target cells and increases glycogen synthesis
Prevents fat and glycogen breakdown
Inhibits gluconeogenesis and increases protein synthesis
Structure of Proinsulin
• A and B chain are joined by the connecting peptide
the cleaving of the connecting peptide results in proinsulin being converted to
insulin. Both active insulin and inactive insulin C peptide chain are packaged
into secretory granules and released from the beta cell at the same time
it is possible to measure serum Cpeptide to assess beta cell function and the
need for insulin therapy
Action of Insulin on Cells
• As plasma glucose increases insulin is secreted by the beta cells and enters the
portal circulation. Once in the liver 50% is used or degraded.
the ½ life is approx. 15 min once released in the circulation
to initiate the effect on target tissue insulin binds to the membrane receptor
the membrane receptor is composed of 2 subunits the alpha unit that extends
outside of the cell membrane where insulin binds and the smaller beta subunit that
is predominately inside the cell membrane.
The beta subunit contains kinase enzyme that activates with insulin binding. The
kinase enzyme results in autophosphorylation of the beta subunit which in turn
activates some enzymes and inactivates others.
this causes the desired intracellular effect of insulin on glucose, fat, and protein
metabolism as well cell growth.
specifically insulin receptor substrates 14 causes glucose transport fatty acid
synthesis, glycogen synthesis, cell growth and survival and amino acid/
electrolyte transport. cell membrane are almost impermeable to glucose and therefore require a special
carrier called a glucose transporter to move glucose from the blood into the cell.
There is a family of glucose transporters:
Glucose transporter 4 or GLUT4 is the insulin dependent glucose transporter for
skeletal muscle and adipose tissue. It is stimulated by insulin to move from its
inactive site to the cell membrane where it facilitates glucose entry.
GLUT2 is the major transporter for glucose into beta and liver cells.
GLUT1 is present in all tissues and does not require the actions of insulin. Its
important in the transport of glucose into cells of the nervous system. All of the
glucose transporters move glucose across the cell membrane at a faster rate then
would occur with diffusion alone.
mitogen activated protein kinase signaling cascade promotes cell growth and
differentiation as well as gene expression.
• Its released at the same time as insulin by beta cells
it regulates blood sugar by delaying nutrient uptake through inhibition of gastric
emptying and suppressing glucagon secretion after meals
over it has antihyperglycemic and satiety effects
• Glucagon is a polypeptide molecule produced by the alpha cells and works
opposite to insulin. Like insulin it travels to the liver via the portal circulation. It
exerts its main function in the liver. Glucagon maintains blood sugar levels
between meals by
initiating glycogenolysis in the liver
increasing transport of AA into liver and stimulating gluconeogenesis
When there are high levels of glucagon, glucagon activates adipose cell lipase
making fatty acids available for use as an alterative source of energy.
Glucagon can also have an inotropic effect, enhance bile secretion and inhibit
gastric acid secretion at high levels
• Somatostatin is released by delta cells in the endocrine pancreas. Food ingestion
stimulate somatostatin secretion.
Main activities of somatostatin are to decrease GI activity + inhibit release of
this causes extended time for food to be absorbed and extends the use of
absorbed nutrients by tissue.
Counter Regulatory Hormones
They counteract the storage functions of insulin in regulating the blood glucose levels
during periods of fasting, exercise and stress. So these are situations that either limit
glucose intake or deplete glucose stores.
• Epinephrine is a catecholamines released by the adrenal medulla when stimulated
by the sympathetic nervous system. It is more so active in the stress response. it causes transient hyperglycemia by promoting gluconeogenesis and
glycogenolysis in the liver and inhibits glycogen formation as well as increasing
the breakdown of muscle glycogen stores
it also inhibits insulin release from beta cells which decreases glucose uptake in
muscles and other organs, preserving glucose for the brain.
Glucose released by the muscle glycogen is not released into the blood however
the mobilization of these stores for muscle use conserves blood glucose for use by
other tissues that rely almost solely on glucose for energy like the brain and
Epinephrine stimulates lipolysis by freeing triglycerides and fatty acids from
adipose tissue, also inhibits the degradation of circulating cholesterol to bile acids.
• Growth hormone increases protein synthesis in all cells of the body stimulates
lipolysis and antagonizes thee effects of insulin
Also decreases cellular uptake and use of glucose. Acromegaly is a disease
characterized by hypersecretion of growth hormone can result in glucose
intolerance or the development of DM.
For those with D an increase in GH which occurs in periods of stress and growth
for children can lead to the whole spectrum of metabolic abnormalities associated
with poor regulation even though insulin treatment may be optimized
• Glucocorticoids (cortisol) are synthesized in the adrenal cortex. Refers to steroid
hormones that have direct effect on carbohydrate metabolism
one of the main effects of cortisol is to stimulate gluconeogenesis
they also moderately decrease the use of glucose by tissues
almost any type of stress causes the release of corticotropin releasing hormone
from the hypothalamus, which stimulates the anterior pituitary gland to release
adrenocorticotrophic hormone (ACTH) which then signals the adrenal gland to
increase secretion of cortisol
outside of the liver, glucocorticoids stimulate protein catabolism and inhibit
amino acid uptake and protein synthesis.
Increased cortisol complicates diabetes
• Glucagon is a counterregulatory hormone
• CDA defines DM
a metabolic disorder characterized by the presence of hyperglycemia due to
defective insulin secretion, defective insulin action or both. The chronic
hyperglycemia of diabetes is associated with significant long –term sequelae,
particularly damage, dysfunction and failure of various organs – especially the
kidneys, nerves, eyes, heart and blood vessels”
• Dysglycemia is a qualitative term used to describe blood glucose that is abnormal
without defining a threshold. The adoption of this term reflects uncertainty about
optimal blood glucose ranges and the current understanding that cardiovascular
risk and mortality risk exist in people with even slightly elevated blood glucose
levels Pathophysiology Type 1 DM
• Type 1 D is a catabolic disorder characterized by
absolute lack of insulin
breakdown of fats and proteins for energy instead of carbohydrates
It is because of the absolute lack of insulin what makes type 1 D people prone to
The destruction of beta cells is 2 fold
a) 1 there is lymphocyte and macrophage infiltration of islets which results in
indlammation or insulitis and islet beta cell death
b) 2 there is production of autoantibodies against islet cells, insulin, glutamic
acid decarboxylase (GAD) and other cytoplasmic proteins. Glutamic acid
decarboxylase is an enzyme in beta cells that is involved in glucagon synthesis
1. Genetic Predispostion and Environmental factors
2. Causes autoantigens to form on insulin producing beta cells and circulate in the
blood stream and lymphatics
3. Processing and presentation of autoantigen by antigen presenting cells as the
autoantigens circulate through the body
4. T helper 1 lymphocytes are activated when circulating autoantigens are ingested
by antigenpresenting cells
5. T helper 1 lymphocytes secrete interferon which activates macrophages and
stimulates the releases of inflammatory cytokines cause beta cell destruction and
6. Activation of T helper 1 lymphocytes also secrete interleukin 2 which activates
beta cell autoantigen specific T lymphocytes. This leads to the destruction of beta
with decreased insulin secretion.
7. Activation of T helper 2 lymphocytes causes the secretion of interleukin 4 which
stimulates B lymphocytes to proliferate and produce antibodies. These
autoantibodies contribute to the destruction of beta cells and decreased insulin
Therefore there is dysfunction in both humoral and cell mediated immunity. (ch 17
T regulatory cells usually act to inhibit the immune response. There have been
mutations affecting these cell noted in a rare form of diabete