APPP 08 and 13: Pancreas Flashcards

1
Q

If diabetes is poorly treated, what are some of the serious consequences?

A
  • renal failure
  • blindness
  • heart attack
  • stroke
  • end-limb amputation
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2
Q

Diabetes Prevalence Statistics

A
  • 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
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3
Q

What is insulin?

A

a hormone secreted from the islets of langerhans scattered throughout the pacreas

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4
Q

What are the 4 major cell types within the islets?

A
  • beta-cells
  • ?
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5
Q

What do beta-cells do?

A

(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

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6
Q

What does glucose do?

A
  • 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
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7
Q

Can amino acids trigger insulin secretion?

A

yes

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8
Q

Can fatty acids trigger insulin secretion?

A

yes

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9
Q

How do sulfonylureas (ie. tolbutamide, glyburide) affect insulin secretion?

A
  • block K+ channels by a direction action on a site located at or near the channel (sulfonylurea urea receptor or SUR)
  • increase insulin secretion
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10
Q

How does glucagon-like peptide 1 (GLP-1) affect insulin secretion?

A

enhances secretion

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11
Q

How do catecholamines affect insulin secretion?

A

inhibits secretion

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12
Q

How does insulin action get initiated?

A
  • 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
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13
Q

What type of disorder is diabetes considered to be?

A

a metabolic disorder (carbohydrate, protein, fat)

  • characterized by hyperglycemia and hyperlipidemia
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14
Q

What are the clinical manifestations of diabetes?

A

(the 3 P’s)

  • polyuria
  • polydypsia
  • polyphagia
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15
Q

What does insulin do?

A

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
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16
Q

What is required for insulin to work?

A

cells must have enough receptors

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17
Q

Glucose Regulation

How does insulin regulate glucose?

A
  • 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
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18
Q

Glucose Regulation

What is responsible for glucose uptake?

A
  • skeletal muscle is responsible for 80-85%
  • adipocytes are responsible for 4-5%
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19
Q

Glucose Regulation

Describe glucose’s fate after entry into the cell?

A
  • oxidative breakdown to produce energy
  • conversion to glycogen for storage in the liver and muscle
  • conversion to fats for storage in adipocytes
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20
Q

How does insulin regulate lipids?

A

can lower plasma triglyceride and fatty acid levels by multiple mechanisms:

  • increase in glucose transport, which is then esterified to triglyceride
  • inhibition of lipolysis
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21
Q

How does insulin regulate protein?

A
  • increases the uptake of amino acids into many tissues (muscle, liver, adipose)
  • stimulates protein synthesis
  • inhibits protein degradation
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22
Q

What are the net effects of insulin? (4)

A
  • decrease blood glucose
  • decrease triglycerides and cholesterol
  • decrease blood free fatty acids
  • decrease blood amino acids
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23
Q

What are the 3 key functions of insulin?

A
  • 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)

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24
Q

What is diabetes mellitus?

A

a metabolic disorder characterized by the presence of hyperglycemia due to defective insulin secretion and/or defective insulin action (ie. increased resistance to insulin)

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25
Q

What is the primary manifestation of diabetes mellitus?

A

hyperglycemia (and other disturbances in fat and protein metabolism) can arise from various causes, with later manifestations like cardiovascular, neurological, ocular, and renal complications

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26
Q

What is type I diabetes?

A

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
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27
Q

What are people with type I diabetes prone to?

A

ketoacidosis

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28
Q

Is type I diabetes genetic or environmental?

A
  • has genetic component
  • environmental factors have also been suggested to initiate the autoimmune response – viruses (congenital rubella, Coxsackievirus B), cow’s milk, chemical toxins
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29
Q

What do type I diabetics depend on?

A

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
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30
Q

Describe patients at presentation of type I diabetes.

A
  • usually a rapid presentation of the disease with thirst, polyuria, weight loss, blurred vision, lethargy, and dizziness
  • usually thin and ketotic
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31
Q

What is type II diabetes?

A

consequence of tissues (like skeletal muscle, adipose tissue, and liver) not responding to insulin

  • around 90% of diagnosed cases
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32
Q

What are the 2 key factors that lead to type II diabetes?

A
  • 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)

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33
Q

What is insulin resistance?

A

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
34
Q

What are the two phases of insulin secretion?

A
  • early rapid phase
  • late prolonged phase
35
Q

How does type II diabetes affect insulin secretion?

A

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)

36
Q

What happens as insulin resistance develops?

A

beta-cells of the pancreas attempt to compensate by producing more insulin

37
Q

What happens following the onset of beta-cell dysfunction?

A

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
38
Q

What factors are associated with increased insulin resistance?

A
  • lack of exercise (sedentary lifestyle)
  • genetic factors
  • central obesity
39
Q

What factors are correlated with decreased beta-cell function?

A
  • increased free fatty acid levels
  • genetic factors
40
Q

What is glucose toxicity?

A

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
41
Q

What is the treatment for type II diabetes?

A
  • physical activity and weight control
  • oral medications
  • insulin injections may be required
42
Q

Describe the onset of type II diabetes.

A

onset may be slow without any obvious signs or symptoms, therefore diagnosis may be delayed until complications begin to surface

43
Q

What is gestational diabetes?

A

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)
44
Q

What is secondary diabetes?

A

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
45
Q

What do assessments of diabetic symptoms include?

A
  • 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
46
Q

When is diabetes detected?

A

when a high level of glucose is detected in the blood

47
Q

What are the 4 laboratory tests for diabetes?

A
  • fasting plasma glucose (FPG)
  • casual blood glucose
  • glycated hemoglobin levels (HbA1c)
  • oral glucose tolerance test (OGTT)
48
Q

What is the fasting plasma glucose (FPG) test?

A

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
49
Q

What is the casual blood glucose test?

A

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
50
Q

What is the glycated hemoglobin levels (HbA1c) test?

A

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
51
Q

What is the oral glucose tolerance test (OGTT)?

A

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
52
Q

What does the diagnosis of diabetes require? (4)

A

(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)

53
Q

What is pre-diabetes?

A

when blood glucose is higher than the normal range, but not high enough to be diagnosed as diabetes

54
Q

How would laboratory testing indicate pre-diabetes?

A

(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%
55
Q

Type I vs. Type II Diabetes

Percentage of Diabetics

A
  • type I: 10%
  • type II: 90%
56
Q

Type I vs. Type II Diabetes

Age

A
  • type I: < 30 – common in youth
  • type II: > 20 – frequent in adults
57
Q

Type I vs. Type II Diabetes

Onset

A
  • type I: sudden
  • type II: gradual
58
Q

Type I vs. Type II Diabetes

Nutritional Status

A
  • type I: undernourished (usually thin)
  • type II: majority are overweight
59
Q

Type I vs. Type II Diabetes

Ketosis

A
  • type I: prone – unless diet, insulin coordinated
  • type II: resistant
60
Q

Type I vs. Type II Diabetes

Insulin

A
  • type I: required 100%
  • type II: < 30% required
61
Q

Type I vs. Type II Diabetes

Diet

A
  • type I: mandatory
  • type II: controls 30-50% of cases
62
Q

Type I vs. Type II Diabetes

Beta-cells

A
  • type I: none – complete islet cell loss
  • type II: varies
63
Q

Type I vs. Type II Diabetes

Islet Cell Abs

A
  • type I: yes
  • type II: no
64
Q

Type I vs. Type II Diabetes

Family History

A
  • type I: positive in 10%
  • type II: positive in 30%
65
Q

Type I vs. Type II Diabetes

Identical Twins

A
  • type I: 50% concordance
  • type II: 60-80% concordance
66
Q

What are ketones

A

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
67
Q

What are the early manifestations of type I diabetes? (9)

A
  • 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)
68
Q

What are the early manifestations of type I diabetes? (3)

A
  • fatigue
  • impotence
  • perhaps type I symptoms
69
Q

What are the late manifestations of type I and II diabetes? (5)

A
  • ocular (retinopathy)
  • renal (proteinuria)
  • atherosclerotic arterial disease
  • neuropathy
  • hypertension
70
Q

Late Manifestations of Type I and II Diabetes

Ocular (Retinopathy)

A
  • 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
71
Q

Late Manifestations of Type I and II Diabetes

Renal (Proteinuria)

A
  • serum proteins in the urine exceed 500 mg in 24 hours
  • diabetes is the most common cause of end-stage renal failure
72
Q

Late Manifestations of Type I and II Diabetes

Atherosclerotic Arterial Disease

A
  • cardiovascular disease is a major cause of morbidity and mortality with diabetes
  • risk of coronary artery disease (CAD) and stroke is increased 2-4x
73
Q

Late Manifestations of Type I and II Diabetes

Neuropathy

A

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

74
Q

Late Manifestations of Type I and II Diabetes

Hypertension

A

consequence of an increase in peripheral vascular resistance

75
Q

Key Points to Remember

What is the normal function of insulin? (2)

A
  • take glucose from the blood and put it into skeletal muscle and adipose tissue
  • prevent glucose output from the liver
76
Q

Key Points to Remember

What is the difference between type I and II diabetes?

A
  • type I: pancreas does not produce insulin
  • type II: either due to insulin resistance and/or impaired beta-cell function
77
Q

Key Points to Remember

What is diabetes mellitus?

A

common metabolic disorder characterized by high blood glucose levels and alterations in the metabolism of fats, proteins, and glucose

78
Q

Key Points to Remember

What are the current Canadian diagnostic criteria for diabetes?

A

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%
79
Q

Key Points to Remember

What is diabetes mellitus associated with chronically?

A

with many end-organ complications

  • retinopathy
  • neuropathy
  • nephropathy
  • cardiovascular disease
80
Q

Key Points to Remember

What is the role of the pharmacist in regards to diabetes?

A
  • 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