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Drug Action II > Block 3: Diabetes Physiology > Flashcards

Block 3: Diabetes Physiology Flashcards

1
Q

Describe the structure of glucose?

A
  1. Monosac
  2. Hexose
  3. Pyranose ring
  4. C6H12O6
  5. Utilized in glycolysis pathway for energy
  6. Fasting: 70-100 mg/dL
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2
Q

How is carb reg affected by diabetes?

A

Type 1: Complete loss of pancreatic insulin
Type 2: High/low insulin, poor tissue utilization

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3
Q

What is the “common pathway” for metabolic fuels?

A

Acetyl-Coa

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4
Q

What are the types of pancreatic islet cells?

A
  1. Insulin b-cells (70-80%)
  2. Glucagon a-cells (5-10%)
  3. Somatostatin delta-cells (3-5%)
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5
Q

What are the characteristics of endocrine hormone signalling?

A
  1. Chemical regulators of cellular function
  2. Synthesized by endocrine glands
  3. Hormones act of target cell initiating a response important for physiology
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6
Q

Describe the production of insulin?

A
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7
Q

Describe how insulin is structured/processed?

A

Insulin chain folds on itself by disulfide bonds, C-Petide is cleaved from structure while A and B insulin chains remain intact

Both Insulin and the ‘C-Peptide’ are released from the granule
* C-peptide (last longer in the body) is a marker if insulin is being made

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8
Q

What is the difference between basal and bolus insulin?

A

Basal: steady, low level of insulin produced throughout the day and night
Bolus: Higher amounts of insulin that are produced when blood glucose is increased, peaks after food intake

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9
Q

Describe the control of pancreatic hormones?

A

Glucose: ↑ B-cell insulin (primary)
Catecholamines: ↓ insulin and ↑ a-cell glucagon
A-adrenergic: ↓ insulin (dominant tone)
B-adrenergic: ↑ glucagon (dominant)

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10
Q

Describe the insulin feedback system?

A
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11
Q

Describe how insulin is released from beta-cells?

A
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12
Q

Describe the binding of insulin to receptor? Slide 20

A

Activation of cytoplasmic tyrosine kinase initiates insulin singal transduction at the b-subunit of the insulin receptor

  1. Insulin bonds to a-subunit of the cell surface receptor
  2. Insulin binding activates tyrosine kinases on cytoplasmic side, autophosphorylating the receptor
  3. The activated TK receptor phosphorylates the ‘Insulin Receptor Substrate-1’ (IRS-1)
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13
Q

Describe the activation of insulin receptors?

A

Primary action of insulin in muscle and fat for reducing plasma glucose levels

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14
Q

What are the the glucose “facilitated” transporters

A

GLUT 1: Most abundant in brain and kidneys
GLUT 2: Glucose sensor, low affinity in b cells and liver
GLUT 3
GLUT 4: Insulin stimulated glucose uptake in the muscle and adipose

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15
Q

How does SGLT mediate glucose reabsorption?

A
  1. Na/K ATPase creates an “energy” gradient with Na+
  2. Allows glucose to be absorbed against concentration gradient using sodium influx in 2:1 (secondary active transport)
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16
Q

Describe the importance of SGLT?

A

SGLT1 is in the straight section of the proximal tubule (S3)
SGLT2 is in the convoluted section of the proximal tubule (S1).

90% of glucose absorption in the kidney is mediated by SGLT2

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17
Q

Compare the the differences between SGLT1 and 2?

A
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18
Q

What kind of hormone is insulin?

A

Anabolic hormone by increasing energy storage:
Insulin increases fuel storage (↑ anabolism)
Insulin decreases breakdown of fuel (↓ catabolism)

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19
Q

What pathway is affected by insulin?

A
  1. Glucose metabolism
  2. Glycolytic pathway
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20
Q

When does glucocon levels dominate over insulin? How?

A

Fasting state metabolism
1. ↑ Glycogenolysis
2. ↑ Gluconeogenesis
3. ↑ Ketones for lipolysis

All used in ↑ plasma glucose for brain and peripheral tissues

↓ Insulin provides precursors for glucagon activation

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21
Q

Where does glucagon primarily act?

A

Liver: glucagon acts to prevent hypoglycemia by increasing plasma glucose and break down fuel stores

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22
Q

What kind of hormone is glucagon?

A

Catabolic: increase utilization of fuel storage

Increased lipolysis: B2 and 3
Decreased glycogenesis: a1, B2
Increased glycogenolysis and gluconeogenesis

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23
Q

Why are counter-regulatory hormones so important in a diabetic patient?

A

They provide synergistic effects

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24
Q

What are the counter-reg hormones?

A
  1. Glucagon
  2. Cortisol
  3. Epinephrine
  4. Growth hormone
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25
Q

What happens during the fed-state?

A

Increased insulin:
1. Increase glucose uptake in muscle and fat
2. Increase fat storage
3. Increase glycogenesis in liver
4. Blocks and prevents actions of glucagon

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26
Q

What is the function of postpranial plasma glucose? How is this affected in diabetics?

A
  1. Rate of carbohydrate digestion
  2. Gastrointestinal hormones
  3. Plasma insulin levels
  4. Muscle uptake and utilization of glucose

Earliest abnormality seen in diabetes in postprandial hyerglycemia
* Glucose intolerance or IGT

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27
Q

What is IGT?

A
  1. Impaired ability to handle dietary carbs
  2. Rise in plasma glucose that occurs after eating carb is greater than normal

Considered an intermediate state between normal glucose and pre-diabetes/diabetes

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28
Q

What is a marker for insulin resistance?

A

Glucose disposal rate decreases as IGT and T2DM progresses even at identical plasma insulin levels

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29
Q

What are the metabolic markers of impaired fasting glucose?

A

Blood glucose levels are elevated in the fasting state (>100) but not high enough to be classified as diabetes (>126).

Also an intermediate state

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30
Q

Why is pre-diabetes significant?

A

Cardiovascular risks equivalent to having diabetes

Increases risk of developing diabetes

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31
Q

What occurs during the fasting state?

A

Decreased insulin, increased glucagon:
1. Increase glycogenolysis
2. Increases gluconeogenesis
3. Increases free FA and ketogenesis
4. Increase proteolysis

All effect occur in order to feed the brain

Diabetic metabolic decompensation is similar to the fasting state

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32
Q

What are the characterisitcs of DM?

A
  1. Metabolic disorder characterized by hyperglycemia
  2. Defects in fat, carbs, and proteins
  3. Defects in pancreatic insulin production, insulin sensitivity in the tissues or both
  4. Progressive disorders resulting in long term chronic complications
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33
Q

What the types of DM?

A

T1, T2, gestational, mature onset diabetes in the young (MODY)

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34
Q

What are the characterisitcs of Type 1 DM?

A

b-cell destruction leading to absolute insulin def
1. Idiopathic
2. Genetic predisposition
3. Autoimmune
4. Ketoacidosis

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35
Q

What are the chracterisitcs of T2DM?

A

Insulin resistance with possible insulin secretory defect (obseity is a main cause)

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36
Q

What is gestational diabetes?

A

Impaired glucose tolerance during pregnancy is a marker of predisposition for type-2 diabetes

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37
Q

What is T3CDM?

A
  1. Pancreotogenic DM
  2. Loss of b-cell function leading to insulin def

Caused by:
1. Pancreatitis
2. Pancrease removal
3. CF
4. Hemachromatosis

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38
Q

What are the presentation of T1DM?

A
  1. Low or diminished C-peptide (severe or complete insulin def)
  2. Ketoacidosis
  3. Signs of dehydration
  4. Onset of sx bay be rapid

Precipitating or presenting events (three-polys):
2. Polyuria
3. Polydipsia
4. Polyphagia

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39
Q

What is the difference between T1 and T2?

A
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40
Q

What are the causes of T1DM?

A
  1. Genetic predisposition (HLA-linked genes and other genetic loci_
  2. Environmental insult (Viral infection and/or damage of beta cells)
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41
Q

What are the diabetic HLA polymorphisms?

A

DR3 and DR4

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42
Q

Antigens from extracellular proteins are derived from what peptides?

A

MHC class II

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43
Q

Describe the events of b-cell destruction?

A
  1. Foreign antigens binds with MHC complexes (both 1 and 2) are transported to cell surface of b-cel
  2. T-helper cell receptor recognizes this complex (CD4 and 8) which sensitives the T cells and activates macrophages
  3. CD8+ T cells are activated by interleukin-2 (IL2) and differentiate into cytotoxic T-cells.
  4. Macrophages, activated by interferon (IFN- and IFN-), & tumor necrosis factor
    (TNF-) act to destroy the pancreatic b-cells.
  5. Beta cells can also be damaged by perforin released from CD8+ cytotoxic T cells
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44
Q

Describe the developments of T1DM?

A
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45
Q

What causes hyperglycemia?

A
  1. Under-utilization of glucose
  2. Over-production of glucose
46
Q

What are the effects of insulin deficiency?

47
Q

When would you start to see a glucose spill?

A

Serum glucose of 180-200 mg/dL

Elimination in urine (100g) due to glucose osmotic diuretic properties (5L of water)

48
Q

What are the characteristics of diabetic ketoacidosis?

A
  1. Commonly in T1DM
  2. Decrease in insulin and increase in glucagon
  3. Maximal gluconeogenesis (increased production) with impaired utilization
  4. Activation of the ketogenic process and development of a metabolic acidosis
49
Q

What is ketogenesis?

A

High glucagon/insulin ratio:

Increased liberation of FFAs due to the loss of the inhibiotry action of insulin on the hormone sensitive lipase

50
Q

Describe how keton bodies form?

A
  1. Increased liberation of free fatty acids (FFAs) due to the loss of the inhibitory action of insulin
  2. (Carnitine Palmitoyltransferase-1 (CPT-1)) activation that allows long chain FFAs to reach beta-oxidative enzymes in mitochondria where ketone production occurs
  3. This results in ketogenesis and high circulating levels of b-hydroxybutyrate, acetoacetate (both weak organic acids) and acetone (fruity breath

Transport to Mitochondria and Activation of CPT-1

51
Q

What are the clinical presentations of ketosis?

A
  1. Anorexia
  2. Polydipsia
  3. Polyuria
  4. Stupor, coma
  5. Abdominal pain
  6. Kussmaul breathing (acetone/fruity breath)
  7. Dehrydration/volume depletion
  8. Hyperglycemia (>300 and pH <7.3)
  9. Potassium may be normal or elevated, but is misleading due to large total body potassium deficit (diuresis and increased ADH)
    * Hypokalemia: cardiac arrhythmias and arrest
    * Hyperkalemia: cardiac arrest
52
Q

What are the RF of T2DM?

A
  1. Age
  2. Obesity
  3. PA
  4. Family hx
  5. Pace
  6. Pre-diabetes (impared fasting glucose and glucose tolerance)
  7. Gestational diabetes
  8. Metabolic Syndrome
53
Q

What is the age of T2DM risk groups?

A

Greater than 40 YO

However, fastest growing age group is teens and YA

54
Q

What are the genetic components of T2DM?

A

Increased incidence in first degree relatives with Type 2 diabetes

High risk groups include: Aboriginal, Maltese, Native Americans, Polynesian, African Americans.

55
Q

What are the characterisitcs of T2DM risk groups?

A

Obesity: common risk factor
* Adiposity: BMI
* Overwieght: 25-30, Obese >30

Waist circumference: men >102, women >88
Past hx of gestational diabetes

56
Q

What is the number one risk factor for T2DM?

57
Q

Diabetes is the leading cause of:

A
  1. Renal failure
  2. New cases of blindness
  3. Nontraumatic amputations
58
Q

How many people have Prediabetes in the US?

A

96 million

59
Q

What are the presentations of T2DM?

A
  1. Gradual and insidious
  2. Triple poly
  3. Hyperglycemia
  4. Hyperosmotic Hyperglycemic nonketotic State (HHS)

Long-term
1. Retinopathy
2. Renal dysfunction
3. Nephropathy
4. Neuropathy

60
Q

Describe the MOA of T2DM?

61
Q

Describe IGT and IFG in relation to T2?

A

IGT is an impaired ability to appropriately manage dietary carbohydrates:
* The rise in plasma glucose after eating carbohydrates is greater than normal.

IFG is a consistently elevated fasting blood glucose level

Both are indicators of resistance and intermediate state

Early diagnosis leads to beter CV outcomes

62
Q

What are the presentation of insulin resistance in T2?

A

Greater than normal amounts of insulin are required to produce a normal biological response:
* Muscle/fat: impaired glucose uptake
* Liver: Impaired glycogenesis, increased glucose production
* Pancreas: compensated with hyperinsulemia and elevated C-peptide

63
Q

What is secondary b-cell failur?

A

Hyperinsulemia -> b-cell failure -> Worsening hyperglycemia and secondary failure of oral secretagogues, such as sulfonylureas.

Exhaustion of cells

64
Q

What are the secondary events of long term T2?

A
  1. Delay in secretion
  2. Loss of B-cell response to glucose
  3. Glucagon excess
  4. Amylin
  5. Reduced circulating levels of incretin (GIP/GLP1)
  6. Absolute decrease in amount of insulin secreted
    * Loss or burn out of insulin secreting b-cells (exhaustion)
65
Q

What is gestational DM?

A

Any degree of glucose intolerance with onset or first recognition during pregnancy

66
Q

What are the risk factors of GDM?

A
  1. Family with T2DM
  2. African American, Native American, Asian, Hispanic, or Pacific Islander
  3. 25 YO or older
  4. Overweight
67
Q

What are the consequences of gestational diabetes?

A

Offspring:
1. Macrosomic baby (difficult delivery)
2. Neonatal hypoglycemia

Long term on offspring:
1. Increased risk of obestiy
2. Increased risk of diabetes as an adult

68
Q

What are the acute metabolic complications of diabetes?

A
  1. Hypoglycemia coma (iatrogenic)
  2. Diabetic ketoacidosis (DKA, primarily type 1)
  3. Hyperosmolar non-ketotic coma (HHS, primary type 2)
69
Q

What do you do if your unsure if patient is hyperglycemic or hypoglycemia?

A

When in doubt treat as if hypoglycemic

Never give an unconscious patient insulin

70
Q

Why is hypoglycemia dangerous?

A

An acute, life threatenign problem for diabetic practicing tight glucose control

<50mg/dL: Cognitive dysfunction
<30mg/dL: induce coma
Severe: 15 mg/dL
Death if not treated

71
Q

What are sx of hypoglycemia?

A
  1. Confusion
  2. Coma
  3. Weakness/HA
  4. Lassitude
  5. Morning HA
  6. Tremor
  7. Shakiness
72
Q

What are the acute conditions of hyperglycemia?

A
  1. Diabetic Ketoacidosis (DKA) (T1)
  2. Hyperosmolar Hyperglycemic State (HHS) (T2)
  3. Morning hyperglycemia (fasting): dawn phenomenon, somogyi effect
73
Q

What are the presentation of Diabetic ketoacidosis?

A

Can be observed in type-2 diabetics under stress and patients taking SGLT-2 inhibitors

74
Q

What are the presentation of Hyperosmolar Hyperglycemic Nonketotic State?

A
  1. Hyperosmolar Hyperglycemic State (HHS)
  2. Hyperosmolar Hyperglycemic Nonketotic State

Extreme hyperglycemia over time

75
Q

What are the complications of DKA, HHS Tx?

A
  1. Cerebral edema
  2. Hyperkalemia
  3. Hypokalemia
  4. Infection
  5. Hypoglycemia
76
Q

What are the morning hyperglycemia types?

A

Dawn phenomenon
Somogyi Effect

77
Q

What is dawn phenomenon?

A

Bedtime glucose levels are normal -> see normal or elevated glucose levels during the middle of the night (around 3 AM) -> but then see hyperglycemia in the morning

Increase basal insulin dose

78
Q

What is Somogyi effect?

A

rebound hyperglycemia

Bedtime glucose levels are normal -> see low glucose levels during the middle of the night (around 3 AM) -> but then see hyperglycemia in the morning

Too much “basal” insulin at night
Rebound hyperglycemia due to ↑ in counter regulatory hormones and ↑ hepatic glucose production

79
Q

Poor glycemic control and hyperglycemia leads to?

A

Primary cause of many long term complications related to diabetes

80
Q

Factors that increase risk of diabetic complications?

A
  1. Inactive
  2. Overweight
  3. Poor blood sugar control
  4. Uncontrolled bp
  5. High cholesterol
  6. Smoking
81
Q

What are the outcomes of glycosylation of proteins?

A

Dysfunctional and reactive proteins

82
Q

What are the examples of glycosylated proteins?

A
  1. Glycosylated Hb (HbA1C)
  2. Basement membrane collagen (glomerulus, capillaries)
  3. Glycosylated myeline and neuronal proteins
83
Q

How is a glycosylated protein formed?

A

Advance glycosylated end-products (AGEs) are slow irreversible chemical rearrangements of glycosylated protein that can cross-link proteins, altering the function permanently

84
Q

Describe the polyol pathway?

A
  1. Activated by excessive glucose
  2. Aldose reductase converts glucose to D-sorbitol
  3. Sorbitol is converted to D-fructose
  4. D-sorbitol and D-fructose are non-diffusable sugars
86
Q

What are the microvascular complications of diabetes?

A
  1. Retinopathy
  2. Nephropathy
  3. Autonomic and sensory neuropathy
87
Q

Diabetic retinopathy is the leading cause of what?

88
Q

What underlies microvascular complications of diabetes?

A

Vascular microangiopathy

89
Q

What are the stages of retinopathy?

A
  1. Non-proliferative/background
  2. Pre-proliferative
  3. Proliferative
90
Q

What is non-proliferative retinopathy?

A
  1. Opthalmoscope is used
  2. Retinal microaneurysms (2 yr onset)
  3. Blot hemorrages and macular edema
  4. Hard exudates
91
Q

What is pre-proliferative retinopathy?

A

Lesions related to ischemia
1. Cotton wool spots
2. Intraretinal microvascular abnormalities are the earliest signs of neovascularivation

92
Q

What is proliferative retinopathy?

A

Photocoagulation may reduce the level of Vascular Endothelial Growth Factor (VEGF) elaborated by the peripheral, poorly perfused retina

Leads to vitreous hemorrhage and retinal detachment

93
Q

What is the treatment for proliferative retinopathy?

A

Laser phocoagulation reduces the risk of severe visual loss by 50%

95
Q

How is the polyol pathway affect the diabetic retinopathy?

A
  1. Prolonged activation leads to pericyte death from osmotic damages
  2. New blood vessels bud in areas of pericyte deterioration -> neovascularization and proliferative retinopathy
96
Q

What is the difference between autonomic and peripheral sx of diabetic neuropathy?

A

Autonomic: urinary incontinence, gastric stasis, othrostatic hypotension
Peripheral: Development of foot ulcers and lower extremity amputations

97
Q

What causes foot ulcers and amputations in diabetic patients?

A

Microvascular disease (poor perfusion) and secondary neuropathy (poor sensation)

99
Q

How is the stomach affected by autonomic neuropathy?

A

Gastroparesis: delayed emptying of the stomach

100
Q

Mortality from all causes in ESRD patients ____ higher than in those without renal dysfunction

A

20X to 40X

101
Q

Hyperglycemia in diabetic nephropathy is caused by?

A

Glomerular and tubule basement membrane glycosylation and thickening

102
Q

What are the lab presentations of diabetic nephropathy?

A
  1. Proteinuria
  2. Microalbuminuria (excretion of 30–300 mg/day)

20X higher risk of developing nephropathy than in normoalbuminuric patients

103
Q

Describe the overall complications of diabetes?

A

Eye damage
Kidney disease
Nerve damage
Foot damage

Leads to

Infections
Slow wound healing
Gum disease
Erectile dysfunction

104
Q

What are the macrovascular diseases of diabetes?

A
  1. Hypertension
  2. DLD
  3. Vascular inflammation
  4. Thrombolic risk
  5. Atherosclerosis

Heart disease is the main determinant of life expectancy in diabetic patients

105
Q

What disease state is the leading cause of premature death in diabetics?

A

Coronary heart disease

106
Q

What are the characteristics of atherogenic DLD?

A
  1. Elevated TG
  2. Reduced HDL
  3. Normal to elevated LDL
    * Increased oxidation of LDL
    * Oxidized LDL
107
Q

What is metabolic syndrome?

A

A complex interrelationship of metabolic abnormalities related to insulin resistance associated withan increased risk of coronary artery disease

108
Q

How do you minimize cardiovascular risk factors?

A
  1. Control HTN
  2. Statins for at risk patients
  3. Aspirin 81 mg daily
109
Q

What is the best way to reduce long term diabetic complications?

A

Glycemic control

110
Q

What is the clinical trial that studied T1D?

A

The Diabetes Control and Complications Trial (DCCT)

111
Q

What is the clinical trial that studied T2D?

A

UK Prospective Diabetes Study (UKPDS)

Drug Action II (28 decks)

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