APPP 08 and 13: Pancreas Flashcards
If diabetes is poorly treated, what are some of the serious consequences?
- renal failure
- blindness
- heart attack
- stroke
- end-limb amputation
Diabetes Prevalence Statistics
- global: around 463 million, projected to grow to 700 million by 2045
- Canada: over 11 million people with diabetes or pre-diabetes
- 75% of people with diabetes require hospitalization due to complications
What is insulin?
a hormone secreted from the islets of langerhans scattered throughout the pacreas
What are the 4 major cell types within the islets?
- beta-cells
- ?
What do beta-cells do?
(60-80% of all islets)
produce insulin and principally function as ‘fuel-sensors capable of adapting the rate of insulin secretion to variations in plasma levels of glucose
What does glucose do?
- most important controller of insulin secretion – increases the ATP/ADP ratio, closing the K+ channel, eliciting depolarization of the membrane, facilitating Ca2+ entry, and causing exocytosis of secretory granules containing insulin
- an initiator or primary stimuli able to increase insulin secretion in the absence of any other stimulatory agent
Can amino acids trigger insulin secretion?
yes
Can fatty acids trigger insulin secretion?
yes
How do sulfonylureas (ie. tolbutamide, glyburide) affect insulin secretion?
- block K+ channels by a direction action on a site located at or near the channel (sulfonylurea urea receptor or SUR)
- increase insulin secretion
How does glucagon-like peptide 1 (GLP-1) affect insulin secretion?
enhances secretion
How do catecholamines affect insulin secretion?
inhibits secretion
How does insulin action get initiated?
- synthesis in beta cells of the pancreas as proinsulin
- C-peptide (31 amino acid peptide that bridges the insulin A and B chains in the proinsulin molecule) is split off
- active form of the hormone consists of 51 amino acids in 2 chains – A chain with 21 amino acids, and B chain with 30 amino acids (both A and B chains are linked by disulfide bonds)
- (like all peptide hormones) insulin initiates its action by binding to a receptor on the cell surface, which leads to the generation of molecular signals that facilitate insulin action
What type of disorder is diabetes considered to be?
a metabolic disorder (carbohydrate, protein, fat)
- characterized by hyperglycemia and hyperlipidemia
What are the clinical manifestations of diabetes?
(the 3 P’s)
- polyuria
- polydypsia
- polyphagia
What does insulin do?
the principal messenger that facilitates the buildup of energy reservoirs (energy conserving hormone)
- promotes glycogen synthesis in the liver
- promotes muscle and lipid formation in adipocytes
- initiates amino acid uptake and protein synthesis in most cells
What is required for insulin to work?
cells must have enough receptors
Glucose Regulation
How does insulin regulate glucose?
- lowers plasma glucose levels by stimulating glucose uptake with the help of the glucose transporter GLUT4 in muscle and adipose tissue
- suppresses hepatic production of glucose
Glucose Regulation
What is responsible for glucose uptake?
- skeletal muscle is responsible for 80-85%
- adipocytes are responsible for 4-5%
Glucose Regulation
Describe glucose’s fate after entry into the cell?
- oxidative breakdown to produce energy
- conversion to glycogen for storage in the liver and muscle
- conversion to fats for storage in adipocytes
How does insulin regulate lipids?
can lower plasma triglyceride and fatty acid levels by multiple mechanisms:
- increase in glucose transport, which is then esterified to triglyceride
- inhibition of lipolysis
How does insulin regulate protein?
- increases the uptake of amino acids into many tissues (muscle, liver, adipose)
- stimulates protein synthesis
- inhibits protein degradation
What are the net effects of insulin? (4)
- decrease blood glucose
- decrease triglycerides and cholesterol
- decrease blood free fatty acids
- decrease blood amino acids
What are the 3 key functions of insulin?
- help blood sugar enter the body’s cells
- moderate the breakdown of the body’s reserves of carbohydrates, proteins, and fats
- inhibit glucose production in the liver
(by ‘putting the brakes’ on these processes, insulin keeps the body from becoming overloaded with breakdown products and/or glucose)
What is diabetes mellitus?
a metabolic disorder characterized by the presence of hyperglycemia due to defective insulin secretion and/or defective insulin action (ie. increased resistance to insulin)
What is the primary manifestation of diabetes mellitus?
hyperglycemia (and other disturbances in fat and protein metabolism) can arise from various causes, with later manifestations like cardiovascular, neurological, ocular, and renal complications
What is type I diabetes?
consequence of an inability of the pancreas to produce insulin – absolute insulin deficiency
- around 10% of diagnosed cases of diabetes
- associated with deficient insulin secretion due to autoimmune pancreatic beta-cell destruction
What are people with type I diabetes prone to?
ketoacidosis
Is type I diabetes genetic or environmental?
- has genetic component
- environmental factors have also been suggested to initiate the autoimmune response – viruses (congenital rubella, Coxsackievirus B), cow’s milk, chemical toxins
What do type I diabetics depend on?
externally supplied insulin
- administered in the form of daily injections (syringes and needles, injection pens, or insulin pumps)
- most monitor their blood glucose at frequent intervals and adjust their insulin to the amount they plan to eat and exercise
Describe patients at presentation of type I diabetes.
- usually a rapid presentation of the disease with thirst, polyuria, weight loss, blurred vision, lethargy, and dizziness
- usually thin and ketotic
What is type II diabetes?
consequence of tissues (like skeletal muscle, adipose tissue, and liver) not responding to insulin
- around 90% of diagnosed cases
What are the 2 key factors that lead to type II diabetes?
- abnormalities in insulin action – body’s cells are unable to respond normally to insulin (ie. insulin resistance due to defects in insulin structure, insulin receptor, and glucose transporters)
- deficiency in insulin secretion – pancreas cannot secrete enough insulin in response to high blood glucose
(many diabetic patients demonstrate both insulin resistance and a deficiency in insulin secretion)
What is insulin resistance?
condition in which the cells of various body tissues fail to respond efficiently to the physiological effects of insulin (including those on glucose, lipid, and protein metabolism)
- key factor in the pathogenesis of type II diabetes
- generally present prior to the onset of type II diabetes
- ie. muscle tissue fails to increase its uptake of blood glucose, and hepatic production of glucose is not inhibited, as it normally would be by insulin
What are the two phases of insulin secretion?
- early rapid phase
- late prolonged phase
How does type II diabetes affect insulin secretion?
usually results in the loss of first phase insulin release, and has been linked to beta-cell loss (related to prolonged exposure of beta-cells to high glucose, fatty acids, pro-inflammatory cytokines like TNF-α and islet amyloid deposits)
What happens as insulin resistance develops?
beta-cells of the pancreas attempt to compensate by producing more insulin
What happens following the onset of beta-cell dysfunction?
pancreas is no longer able to compensate for insulin resistance by relative hypersecretion of insulin
- as a result, control of blood glucose worsens, leading to impaired glucose tolerance, increased fasting and post-prandial glucose levels, and then type II diabetes
What factors are associated with increased insulin resistance?
- lack of exercise (sedentary lifestyle)
- genetic factors
- central obesity
What factors are correlated with decreased beta-cell function?
- increased free fatty acid levels
- genetic factors
What is glucose toxicity?
decrease in insulin secretion and an increase in insulin resistance due to chronic hyperglycemia
- hyperglycemia itself worsens the insulin resistance and beta-cell function
- therefore physical activity and weight control are often part of therapy
What is the treatment for type II diabetes?
- physical activity and weight control
- oral medications
- insulin injections may be required
Describe the onset of type II diabetes.
onset may be slow without any obvious signs or symptoms, therefore diagnosis may be delayed until complications begin to surface
What is gestational diabetes?
glucose intolerance during pregnancy
- in 2-4% of pregnancies in North America
- blood sugar returns to normal after delivery
- but these women face a lifelong risk of developing type II diabetes (20-50% chance in the next 5-10 years)
What is secondary diabetes?
diabetes associated with certain conditions or syndromes
- hyperglycemia occurring in relation to other disease states (ie. pancreatic disorders like carcinoma of the pancreas) and drug (glucocorticoids) induced conditions
What do assessments of diabetic symptoms include?
- polyuria (frequent urination)
- polydypsia (excessive thirst)
- polyphagia (excessive hunger)
- weight loss
- fatigue
- changes in vision
- slow-healing cuts or infections
- persistent itching of the skin
- ketoacidosis
- hyperlipidemia
- hyperglycemia
When is diabetes detected?
when a high level of glucose is detected in the blood
What are the 4 laboratory tests for diabetes?
- fasting plasma glucose (FPG)
- casual blood glucose
- glycated hemoglobin levels (HbA1c)
- oral glucose tolerance test (OGTT)
What is the fasting plasma glucose (FPG) test?
mainly reflects hepatic gluconeogenesis and basal metabolic needs
- normal range between 3.8 and 6.1 mmol/L
- levels between 6.1 and 6.0 mmol/L are considered ‘impaired fasting glucose’
- levels ≥ 7.0 mmol/L is indicative of diabetes
- fasting – no caloric intake for at least 8 hours
What is the casual blood glucose test?
reflects dietary intake and should be monitored as it significantly contributes to the overall daily glycemic profile
- normal is < 7.8 mmol/L
- casual – any time of day, without regard to the interval since the last meal
What is the glycated hemoglobin levels (HbA1c) test?
blood test based on RBC (lifespan of around 120 days) – measures amount of glucose that binds to hemoglobin (aka the % of hemoglobin coated with sugar)
- hemoglobin is irreversibly glycated throughout the life of a RBC
- non-enzymatic reaction that depends upon blood glucose concentrations
- 1% change reflects 1.4-1.9 mM change in mean blood glucose
- follow every 3-4 months (lifespan of RBC)
- may indicate compliance/adherence to treatment regimen
- normal is 4-6%
- recommended target for glycemic control is HbA1c ≤ 6% (if safely achievable) or 6.5%
- Diabetes Canada is now recommending an A1c ≥ 6.5% as a new diagnostic criteria for T2D in adults
- does not require fasting
- not affected by short-term lifestyle changes
What is the oral glucose tolerance test (OGTT)?
measures the body’s ability to breakdown carbohydrates
- overnight fast of 8-15 hours, but can drink water
- standard dose of 75 g of glucose is given as a drink, then blood is drawn at 1 and 2 hours post-ingestion to measure blood glucose
- 2-hour sample of blood glucose ≥ 11.1 mmol/L is a diagnosis for diabetes
What does the diagnosis of diabetes require? (4)
(one of the following)
- symptoms of diabetes + random (casual) blood glucose ≤ 11.1 mmol/L
- fasting plasma glucose (FPG) ≥ 7.0 mmol/L
- plasma glucose value in the 2-hour sample of an oral glucose tolerance test (OGTT with 75 g of glucose) ≥ 11.1 mmol/L
- A1c ≥ 6.5%
(note: a confirmatory test must be done on another day)
What is pre-diabetes?
when blood glucose is higher than the normal range, but not high enough to be diagnosed as diabetes
How would laboratory testing indicate pre-diabetes?
(one of the following)
- impaired fasting glucose – FPG between 6.1-6.0 mmol/L
- impaired glucose tolerance – 2-hour glucose is between 7.8-11.0 mmol/L after a 75 g OGTT
- A1c between 6.0-6.4%
Type I vs. Type II Diabetes
Percentage of Diabetics
- type I: 10%
- type II: 90%
Type I vs. Type II Diabetes
Age
- type I: < 30 – common in youth
- type II: > 20 – frequent in adults
Type I vs. Type II Diabetes
Onset
- type I: sudden
- type II: gradual
Type I vs. Type II Diabetes
Nutritional Status
- type I: undernourished (usually thin)
- type II: majority are overweight
Type I vs. Type II Diabetes
Ketosis
- type I: prone – unless diet, insulin coordinated
- type II: resistant
Type I vs. Type II Diabetes
Insulin
- type I: required 100%
- type II: < 30% required
Type I vs. Type II Diabetes
Diet
- type I: mandatory
- type II: controls 30-50% of cases
Type I vs. Type II Diabetes
Beta-cells
- type I: none – complete islet cell loss
- type II: varies
Type I vs. Type II Diabetes
Islet Cell Abs
- type I: yes
- type II: no
Type I vs. Type II Diabetes
Family History
- type I: positive in 10%
- type II: positive in 30%
Type I vs. Type II Diabetes
Identical Twins
- type I: 50% concordance
- type II: 60-80% concordance
What are ketones
water soluble byproducts produced when fatty acids are broken down in the liver for energy
- can be used by extra hepatic tissues (heart and brain) as an energy source
- their excess production results in ketoacidosis, and a tell-tale smell of acetone on the breath
What are the early manifestations of type I diabetes? (9)
- fatigue
- weight loss
- polyuria, nocturia
- thirst (polydypsia)
- increased appetite (polyphagia)
- pruritis (itching)
- impotence (erectile dysfunction)
- infections (ie. urinary tract, oral, and vulvovaginal candidiasis)
- ketoacidosis (metabolic acidosis)
What are the early manifestations of type I diabetes? (3)
- fatigue
- impotence
- perhaps type I symptoms
What are the late manifestations of type I and II diabetes? (5)
- ocular (retinopathy)
- renal (proteinuria)
- atherosclerotic arterial disease
- neuropathy
- hypertension
Late Manifestations of Type I and II Diabetes
Ocular (Retinopathy)
- most common microvascular complication of diabetes
- leading cause of adult blindness in North America
- small hemorrhages, microvascular leakage and edema, formation of new blood vessels with eventual visual loss
- cataracts and glaucoma are significantly more frequent, especially over age 65
Late Manifestations of Type I and II Diabetes
Renal (Proteinuria)
- serum proteins in the urine exceed 500 mg in 24 hours
- diabetes is the most common cause of end-stage renal failure
Late Manifestations of Type I and II Diabetes
Atherosclerotic Arterial Disease
- cardiovascular disease is a major cause of morbidity and mortality with diabetes
- risk of coronary artery disease (CAD) and stroke is increased 2-4x
Late Manifestations of Type I and II Diabetes
Neuropathy
peripheral nerve dysfunction
- starts with distal extremities such as the foot – loss of sensation to touch, vibration, or temperature)
- may lead to ulceration or gangrene if proper care or attention is not provided
other forms of neuropathy include autonomic neuropathy, leading to erectile dysfunction
Late Manifestations of Type I and II Diabetes
Hypertension
consequence of an increase in peripheral vascular resistance
Key Points to Remember
What is the normal function of insulin? (2)
- take glucose from the blood and put it into skeletal muscle and adipose tissue
- prevent glucose output from the liver
Key Points to Remember
What is the difference between type I and II diabetes?
- type I: pancreas does not produce insulin
- type II: either due to insulin resistance and/or impaired beta-cell function
Key Points to Remember
What is diabetes mellitus?
common metabolic disorder characterized by high blood glucose levels and alterations in the metabolism of fats, proteins, and glucose
Key Points to Remember
What are the current Canadian diagnostic criteria for diabetes?
any of the following:
- casual blood glucose ≥ 11.1 mmol/L (with symptoms)
- FPG ≥ 7.0 mmol/L
- 2-hour glucose level after a 75 g OGTT ≥ 11.1 mmol/L
- A1c > 6.5%
Key Points to Remember
What is diabetes mellitus associated with chronically?
with many end-organ complications
- retinopathy
- neuropathy
- nephropathy
- cardiovascular disease
Key Points to Remember
What is the role of the pharmacist in regards to diabetes?
- counsel the patient – diabetes is a chronic complication associated with both acute and chronic complications
- treatment of diabetes will include both lifestyle modifications and medications
