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Applied Pathophysiology > Type 1 & Type 2 Diabetes > Flashcards

Type 1 & Type 2 Diabetes Flashcards

1
Q

What are the 2 metabolic pathways?

A

1) Anabolic pathways:
* synthesis of large molecules from small molecules (e.g. protein and glycogen synthesis)
* require energy (ATP)

2) Catabolic pathways:
* break down of large molecules to small molecules
* release energy (ATP) e.g. respiratory chain; oxidative
phosphorylation

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2
Q

Anabolic hormones:

A

build fuel stores (insulin, growth
hormone)

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3
Q

Catabolic hormones:

A

break down fuel stores (glucagon, cortisol, epinephrine)

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4
Q

Glucose is the circulating form.

What is the storage form & major storage site?

A

glycogen

liver

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5
Q

Fatty acids are the circulating form.

What is the storage form & major storage site?

A

triglycerides

adipose tissue

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6
Q

Amino acids are the circulating form.

What is the storage form & major storage site?

A

proteins

muscle

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7
Q

What is the absorptive (fed) state?

A

period after meal that food is digested (4-5 h)

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8
Q

What is the Post-absorptive (fasting) state?

A

inter-digestive period that begins 5-6 h after meal

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9
Q

What is the short and long fasting states states of Post-absorptive (fasting state)?

A

Short fasting:
Gluconeogenesis - The formation of glucose from non-hexose precursors

Long fasting:
- go to fatty acid ketones
- blood & liver

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10
Q

Plasma glucose is tightly regulated by hormones:

A
  • insulin, glucagon, epinephrine: fast acting (minutes)
  • cortisol, growth hormone: long acting (hours)
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11
Q

Normal plasma glucose:

A

3.9-8.3 mM (70-150 mg/dl)

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12
Q

What is interesting about the brain?

A
  • DEPENDENT on GLUCOSE as a PRIMARY energy
    source (capable of using ketones e.g. fasting)
  • can NOT synthesize glucose
  • can NOT store glycogen
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13
Q

What is the #1 tissue affected when blood glucose is reduced?

A

BRAIN (b/c dependent on glucose as primary energy)

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14
Q

What is the endocrine pancreas and what is each islet?

A
  • Endocrine pancreas:
  • 1-3% of total weight
  • 0.5-1 x 106 islets
  • Each islet:
  • 50-500 μm diameter
  • 2000-4000 cells
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15
Q

β-cells (∼70%):

A

insulin, amylin

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16
Q

α-cells (∼25%):

A

glucagon

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17
Q

δ-cells (∼5%):

A

somatostatin

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18
Q

PP cells:

A

Pancreatic polypeptide

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19
Q

What is Somatostatin?

A
  • found in islets (also hypothalamus, gut, stomach)
  • released in response to nutrients (e.g. glucose)
  • inhibitory actions on many tissues
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20
Q

What is Islet amyloid polypeptide (IAPP; amylin)?

A
  • co-secreted with insulin
  • inhibits gastric emptying
  • decreases appetite
  • forms islet amyloid deposits in T2D
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21
Q

What is Pancreatic polypeptide?

A
  • vagal activation stimulates its secretion
  • physiological role unclear - likely inhibits pancreatic
    exocrine secretion
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22
Q

Islets are ____ ______

A

heavily vascularized

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23
Q

Blood flow within the islet is from ___-cells to ___-cells

A

β
α

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24
Q

Islets innervation:

A

Both sympathetic and parasympathetic fibers

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25
Q

What is the structure of insulin?

A

● insulin is a 6 kDa peptide

● consists of 2 chains:
A-chain → 21 amino acids
B-chain → 30 amino acids

● A-chain and B-chain are linked by DISULFIDE BONDS

● Basic structure is highly conserved in most species e.g. beef → 2 aa pork → 1 aa

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26
Q

What is the synthesis process of insulin?

A

(synthesized in the:) rough endoplasmic reticulum
↓
Proinsulin
↓
proinsulin (9 kDa)
↓
Golgi apparatus
↓
insulin granules
↓
insulin and C-peptide

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27
Q

Proinsulin has __% of the bioactivity of insulin

A

<5&

(is much less - therefore not as effective as mature insulin)

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28
Q

What is the C-peptide?

A

involved in proinsulin processing

  • secreted in equimolar amounts with insulin
  • marker of insulin secretion from β-cells in diabetic patients
  • biological action is not clear
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29
Q

How is insulin secretion regulated?

A

(B-cell)

stimulated by:
- nutrients (GLUCOSE, AA’s, ketones)
- GI hormones (released after meal - GIP, GLP-1)
- islet hormones (glucagon)
- increase PNS

inhibited by:
- somatostatin
- increase SNS
- prolonged glucose + FFA (toxic can lead to destruction)

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30
Q

As [glucose] increases, insulin secretion ___

A

increases

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31
Q

What is the cellular mechanism of insulin secretion?

A

glucose –(glucose transporter)–> glucose –(glucokinase)–> G-6-P –> increase ATP –(inhibit)–> ATP-dependent K+ channel –> membrane depol. –(stimulate)–> voltage-gated Ca2+ channel –(stimulate)–> increase Ca2+ –(insulin vesicles)–> insulin

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32
Q

Insulin receptor is a _____ composed of two α- and β-subunits and acts as an ____ (tyrosine kinase)

A

glycoprotein

enzyme

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33
Q

Insulin has __ _____ _____proteins

A

NO plasma carrier

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34
Q

Insulin has NO plasma carrier proteins

Therefore, it has ____ plasma half-life (___ min)

A

SHORT

3-5 min

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35
Q

∼___% of insulin is removed during ___ pass through ___

A

~50%

1st

liver

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36
Q

Describe the biological effects of insulin

A

↓ Insulin, causes ↓ glucose

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37
Q

What are the major target tissues for insulin?

A
  • skeletal muscle
  • adipose tissue
  • liver
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38
Q

Insulin ___ glucose uptake in ____ and ____ ____ by regulating glucose transporter (GLUT_)

A

↑

muscle and adipose tissue

4

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39
Q

Glucose transporter in LIVER (GLUT _) is ___ regulated by insulin

A

2

NOT

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40
Q

What is the most important hormone in ↑plasma glucose?

A

glucagon

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41
Q

What is glucagon?

A
  • Glucagon is a single chain polypeptide (29 amino acids)
  • Molecular weight: ∼ 3.5 kDa (small peptide)

α cells –> proglucagon –prohormone convertase 2 –> glucagon

42
Q

What happens when glucagon attaches to the glucagon receptor?

A

G-protein activates Adenylate cyclase –> ATP–>cAMP –> cAMP-dependent protein kinase A –> biological effects

43
Q

What is the regulation of glucagon secretion?

A

Stimulated by:
- nutrients (decrease glucose, AA’s)
- hormones: GIP
- increase PNS, increase SNS

Inhibited by:
- nutrients (increase glucose, FA’s)
- hormones (somatostatin, GLP-1)

44
Q

What is the role of glucagon in glucose regulation?

A
  • Glucagon OPPOSES the metabolic actions of insulin
  • The major site of action: LIVER
  • Important metabolic effects of glucagon in the liver:
  • Carbohydrates
  • Fat
  • Protein
45
Q

What is the regulation of blood glucose by insulin & glucagon?

A
  • Insulin ↓ plasma glucose by promoting glucose UPTAKE & its STORAGE
  • Glucagon ↑ plasma glucose by increasing liver GLUCOSE OUTPUT
46
Q

Glucocorticoids – Cortisol (hormone in regulation of carbohydrate metabolism)

A
  • counter-regulatory to insulin action
  • contributes to maintenance of plasma glucose levels during FASTING
  • mechanism: increase hepatic GLUCONEOGENESIS (counteracts insulin)
47
Q

Catecholamines – Epinephrine (hormone in regulation of carbohydrate metabolism)

A
  • mobilizes glucose stores
  • decreases glucose uptake by liver
  • inhibits insulin production
48
Q

Glucagon-like peptide-1 (GLP-1) (hormone in regulation of carbohydrate metabolism)

A
  • an incretin hormone released by small intestine
  • stimulates insulin release from β-cells
  • promotes β-cell proliferation
  • suppresses glucagon release
  • slows gastric emptying and glucose absorption
  • stimulate satiety centre
49
Q

Growth hormone (hormone in regulation of carbohydrate metabolism)

A
  • antagonizes insulin effect
  • inhibits insulin action
  • decreases glucose uptake
50
Q

Primary β-cells occasionally ____.

A

replicate

51
Q

In a normal person there is a ____ BALANCE between
β-cell replication and β-cell death.

A

TIGHT

52
Q

Any factor that INCREASES the RATE of β-cell DEATH will cause ______.

A

diabetes

53
Q

What is Diabetes Mellitus?

A

Diabetes is a chronic metabolic disorder characterized by hyperglycemia resulting from IMPAIRED INSULIN SECRETION and/or ACTION.

  • Diabetes = “siphon” or “running through”
  • Mellitus = sweet
54
Q

What is the MOST common endocrine disorder?

A

diabetes mellitus

55
Q

What is the prevalence of diabetes?

A
  • ~463 million people suffer from diabetes in the world
  • Over 2 million Canadians have diabetes
  • Currently, 1 in 3 Canadians has diabetes or prediabetes
  • Diabetes contributes to death of >40,000 Canadians per year
  • Financial burden of diabetes and its complications is about $3.6 billion/year in Canada
56
Q

What is the mechanism of hyperglycemia in diabetes?

A
  • Absolute (T1D) or relative (T2D) insulin deficiency

1) Increase in hepatic glucose output

2) Decrease in glucose uptake

57
Q

Type 1 diabetes:

A
  • juvenile onset, ketosis-prone diabetes
  • previously named INSULIN-DEPENDENT diabetes mellitus
    (IDDM)
  • usually occurs <30 years
  • incidence: ~1:250
  • 10% of diabetic cases
  • due to AUTOIMMUNE destruction of β-cells
  • involves both GENES and ENVIRONMENTAL factors
58
Q

T1D is an autoimmune disease:

A
  • T lymphocyte infiltration of islet (INSULITIS)
  • Several circulating islet cell ANTIBODIES (ICAs) against β-cell proteins (e.g. insulin, GAD) are produced
  • Associated with other autoimmune diseases (e.g. Hashimoto’s thyroiditis)
59
Q

T1D has an environmental component:

A
  • Viruses associated with T1D (e.g. coxsackie virus B4, mumps, rubella)
  • Diet associated with T1D (e.g. infants fed cow milk)
60
Q

T1D has genetic component:

A
  • Many GENETIC loci associated with T1D were identified
  • Close association with major histocompatibility complex (MHC) class II
  • MHC genes encode human leukocyte antigens (HLAs) => presentation of antigens to the immune system
  • HLA-DR or HLA-DQ alleles can predispose or protect e.g. HLA-DR4 => ~10X increase risk
61
Q

What are possible triggers of autoimmunity in T1D?

A
  • Molecular mimicry:
    Immune system by mistake attacks β-cell proteins
    that share structural similarity with foreign antigen.
  • Bystander activation:
    Islet inflammation stimulates activation of β-cell
    specific T cells (e.g. viral infections)
  • beta-cell apoptosis:
  • environmental trigger of β-cell death (e.g. virus) - phagocytosed by antigen presenting cells (APCs) - present β-cell antigens to immune system
  • initiate immune response
62
Q

Role of T cells in β-cell destruction in T1D:

A
  • Both CD4+ (helper) and CD8+ (cytotoxic) T cells are involved
  • T cells that recognize β-cell antigens (e.g. GAD, insulin) are
    found in islets during T1D
  • β-cell specific CD8+ cytotoxic T cells are the major cell type contributing to β-cell death in T1D
63
Q

Type 2 diabetes:

A
  • Adult-onset, ketosis-RESISTANT diabetes
  • Previously called non-insulin-dependent diabetes
    (NIDDM)
  • Typically patients are >45 years
  • Increasing in children (associated with obesity)
  • Incidence: 1 in 20
  • 90-95% of diabetic cases
  • Symptoms can be absent or minimal (SLOW ONSET)
  • Patients are usually OVERWEIGHT (70-80%)
64
Q

Genetic and environmental factors both contribute to pathogenesis of T2D:

A
  • Genetic component:
  • about 100% concordance in monozygotic twins
  • frequent in certain ethnic groups
  • Environmental component:
  • associated with sedentary life style and high fat
65
Q

Multiple genes are involved in pathogenesis of T2D:

A

Rare single gene mutations:
- insulin receptor
- mitochondrial DNA
- proinsulin
- prohormone convertase 1
- leptin
- PPAR (peroxisome proliferator-activated receptor)

  • Mature onset diabetes of the young (MODY), autosomal dominant, early onset T2D
66
Q

T2D is associated with defects in…

A

BOTH insulin action (↑insulin resistance) and insulin secretion

67
Q

Early diabetes:

A

“impaired glucose tolerance (IGT)”
* abnormal OGTT but normal fasting glucose
* treated with diet and exercise

68
Q

Overt, but mild, diabetes:

A
  • moderate fasting hyperglycemia (∼7 mM)
  • insulin resistance present
  • insulin secretion present but insufficient
  • treat with exercise, diet, oral hypoglycemic drugs
69
Q

Advanced diabetes:

A
  • severe fasting hyperglycemia (>9 mM)
  • insulin secretion greatly impaired (β-cell failure)
  • patients often require insulin therapy
70
Q

What are possible causes of progressive B-cell failure in T2D?

A
  • Glucolipotoxicity:
    Prolonged exposure to high levels of glucose and free fatty acids is toxic to β-cells
  • β-cell exhaustion:
    Islet β-cells become “exhausted” in the presence of increasing insulin resistance and hyperglycemia.
  • Islet amyloid deposits:
    Toxic amyloid deposits formed by aggregation of islet amyloid polypeptide (IAPP; amylin) are found in most patients with T2D
  • Islet inflammation:
    Growing evidence suggests that islet inflammation plays a key role in pathogenesis of T2D
71
Q

In healthy individuals ∼50% of total daily insulin is secreted during ___ periods, which suppresses lipolysis, proteolysis, and glycogenolysis.

A

BASAL

72
Q

The remainder of insulin secretion is postprandial. Insulin is released from islet β-cells in a ______ manner in response to ______ arterial _____ concentration.

A

biphasic

increased

glucose

73
Q

1st phase consists of a ____ spike lasting ∼10 min followed by 2nd phase, which reaches _____ at 2–3 hrs.

A

brief

plateau

74
Q

In response to a meal, there is a _____ release of pre- formed insulin stored in β-cell granules.

A

RAPID

75
Q

This “first phase” of insulin release ____ peripheral use of prandial nutrients, inhibits hepatic glucose production, thereby limits postprandial glucose increase.

A

promotes

76
Q

The first-phase insulin secretion BEGINS WITHIN 2 ____ of nutrient ingestion and continues for 10 to 15 minutes.

A

minutes

77
Q

The second phase of prandial insulin secretion follows, and is sustained until ______ is restored.

A

normoglycemia

78
Q

It is widely believed that _____ first and second phase insulin release are ____ in patients with T2D.

A

BOTH

impaired

79
Q

Evidence suggests that impaired insulin release in T2D occurs:

A
  • at early stages of diabetes
  • precedes insulin resistance
  • represent primary genetic risk factor predisposing
    to T2D
80
Q

The number of islet resident _____ is ELEVATED in pancreatic islets from patients with T2D

A

macrophages

81
Q

Chronic inflammation in T2D:

A

● Islet amyloid formation is a pathologic characteristic of patients in T2D.

● Islet amyloid is formed by aggregation of the β-cell hormone islet amyloid polypeptide (IAPP) or amylin.

● Amyloid formation contributes to islet inflammation in patients with T2D.

82
Q

_____ formation contributes to islet inflammation in patients with T2D.

A

amyloid

83
Q

What is the proposed role for Fas receptor in β-cell death in T2D?

A
  • Normal β-cells do not express cell death Fas receptor at detectable levels.
  • β-cells normally do express Fas ligand.
  • Expression of Fas receptor is up-regulated in β-cells in conditions that cause β-cell stress such as exposure to cytokines or elevated glucose.
84
Q

Progressive LOSS of pancreatic __-cells is the major problem in both T1D and T2D although the underlying mechanisms are different.

A

β

85
Q

β-cell apoptotic factors in T1D and T2D:

A
  1. high glucose
  2. high FFAs
  3. cytokines
  4. islet amyloid (only T2D)
  5. damage of exocrine pancreas
86
Q

What is the main risk factor for T2D (slide 71 has all)

A

overweight or obesity (ABDOMINAL obesity)

(**increase risk if you have this over someone else)

87
Q

What is the diagnosis of diabetes?

A
  • Fasting plasma glucose (FPG) ≥7.0 mmol/L Fasting: no caloric intake for at least 8 hours
  • A1C ≥6.5% (in adults)
  • 2 h plasma glucose (PG) in a 75 g OGTT ≥11.1 mmol/L
    OGTT: oral glucose tolerance test
  • Random PG ≥11.1 mmol/L
    Random: any time of the day, without regard to the interval since the last meal
88
Q

In the ABSENCE of symptomatic HYPERGLYCEMIA, if a SINGLE LAB TEST result is in the diabetes range, a _____ confirmatory lab test (FPG, A1C, 2hPG in a 75 g OGTT) MUST be done on another day.

A

repeat

*need 2 measurements on 2 diff. days for confirmation of diabetes

89
Q

What are the acute complications of diabetes?

A
  • glucosuria: glucose appears in urine
  • polyuria: frequent urination
  • polydipsia: excessive thirst
  • polyphagia: excessive food intake
  • ketoacidosis

↓insulin→↑lipolysis→↑fatty acids→liver→ketones

90
Q

What are chronic complications of diabetes?

A
  • Neuropathy:
  • loss of sensation due to damage of
    nerve fibers (e.g. heat, cold, pain)
  • high blood glucose changes the metabolism of nerve cells
  • reduced blood flow
  • Nephropathy:
  • has a slow onset
  • may result in severe kidney failure
    • patients may need dialysis or kidney transplant
  • Cardiovascular disease: - atherosclerosis
  • high blood pressure
  • myocardial infarction
  • Retinopathy: damage of retina
  • Cataract: damage of lens
  • Both may cause BLINDNESS
91
Q

Treatment strategies for T1D:

A

Insulin therapy
* patients with T1D need exogenous insulin
* insulin can not be administered orally
* insulin preparations:
porcine, bovine & **recombinant human insulin
* inhaled powder insulin

92
Q

Who discovered insulin?

A

Drs Banting & Best (took out dog’s pancreas - became diabetic)

a kid with T1D was underweight and then a year later with insulin therapy gained weight b/c insulin is a growth factor as well

93
Q

What is an advantage & disadvantage of Islet transplantation in T1D?

A
  • Advantage: provides an ENDOgenous source of insulin
  • Disadvantage: requires life-time immunosuppressive therapy
94
Q

What are the treatment strategies for T2D?

A
  • START with DIET modifications and exercise for weight loss (weight loss+ regular exercise:↓risk of progression).
  • If not effective, treat with oral anti-hyperglycemic agents (e.g. metformin).
  • If blood glucose is not controlled by oral agents, insulin therapy is needed.
  • Individualize therapy choice based on characteristics of the patient and the agent.
  • Choose initial therapy based on blood glucose level.
  • Reach target within 3-6 months of diagnosis.
95
Q

What is Gestational diabetes?

A
  • It develops during pregnancy
  • Typically occurs in week 24 - 28 of gestation
  • Higher risk of developing T2D in future
  • Physiological state of insulin resistance requiring higher
    insulin levels during pregnancy
  • Placental hormones provoke ↑blood glucose which can affect
    growth and welfare of baby
  • Most cases are asymptomatic
  • Resolves after pregnancy
96
Q

What are complications of gestational diabetes for the mother?

A
  • high blood pressure
  • pre-eclampsia (a serious complication of pregnancy
    that can threaten lives of both mother and baby)
  • major symptoms:
  • hypertension
  • proteinuria (protein in urine) - edema of hands and feet
  • risk of future gestational diabetes or T2D
97
Q

What are complications of gestational diabetes for the baby?

A
  • excessive birth weight (macrosomia)
  • early (preterm) birth and respiratory distress syndrome
  • low blood glucose (hypoglycemia)
  • seizures (due to severe episodes of hypoglycemia)
  • risk of T2D later in life
98
Q

Insulin excess is characterized by _______

A

HYPOglycemia (↓blood glucose levels)

99
Q

What are common causes & major symptoms of hyperinsulinemia?

A
  • Common causes:
  • high dose of insulin
  • β-cell tumors
  • Major symptoms:
  • depressed brain function
  • unconsciousness
  • death
100
Q

What is the Dawn Effect?

A
  • RISE in the BLOOD GLUCOSE in early morning caused by counter-regulatory hormones.
  • Leads to ELEVATED FASTING blood glucose (FBG) in T1D and T2D patients.
  • Results in body needing MORE INSULIN in early morning.
  • Detected by SELF-MONITORING blood glucose (SMBG) at EARLY morning (2-3 am).

Applied Pathophysiology (34 decks)

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