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2016 Endocrine > Test 2 Diabetes Pathophysiology part 1 > Flashcards

Test 2 Diabetes Pathophysiology part 1 Flashcards

1
Q

Beta and Alpha cells are in the

A

Pancreas

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2
Q

Beta cells release

A

Beta cells release insulin that increases uptake of glucose from the blood and into the cells.

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3
Q

Alpha cells release

A

Alpha cells release glucagon that increases output of glucose from the cells into the blood.

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4
Q

The carbohydrates in food are broken down into

A

a simple sugar called glucose.

Glucose gets absorbed from your digestive system into your blood stream causing an increase in blood sugar levels.

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5
Q

How does glucose move through the body?

A

Your circulatory system then carries the glucose to muscle cells throughout your body where it is used to generate energy.

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6
Q

What is insulin?

A

Insulin is a small protein hormone produced by your pancreas.

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7
Q

What does insulin do?

A
  • As the concentration of glucose in your blood stream rises your pancreas senses this increase and is stimulated to release insulin into the bloodstream.
  • The newly-released insulin plays a key role in regulating the concentration of glucose in your blood a process known as glucose homeostasis.
  • The insulin that is now released in your bloodstream binds to the extracellular domain of receptor proteins found on the surface of liver muscle and fat cells. This binding triggers the auto phosphorylation of the intracellular domains which in turn phosphorylate a specific substrate signaling protein.
  • This protein then phosphorylates other downhill signaling proteins leading to an amplification of the signal at each step.
  • This overall signaling process is known as a signal transduction cascade. One important consequence of this signal cascade is the movement of glucose transport proteins called glutes towards the cell surface.
  • As these storage vesicles fuse with the cell membrane the number of glutes present on the surface of the cells increase allowing the glucose to enter the cell.
  • As a result the glucose concentration in the blood stream decreases.
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8
Q

What happens once glucose enters the cell?

A

The glucose is now inside the cell where it can be metabolized to generate the energy in the form of ATP that is needed in all of your cells.

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9
Q

What is Diabetes Mellitus

A

• Disease resulting in hyperglycemia (if you don’t have hyperglycemia, you don’t have diabetes)

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10
Q

Factors that cause Diabetes Mellitus

A

• Could be due to:

  • Decreased insulin secretion/efficacy
  • Decreased glucose utilization/storage (rare mutation…and wouldn’t be able to live because they continually release glucose due to inability to store it)
  • Increased glucose production
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11
Q

Consequences Diabetes Mellitus may have on health

A
  • Health Consequences
    • High association with Renal disease (most serious)
    • Nerve damage to peripheral or eyes(most serious)
    • Amputation (impaired wound healing…can’t feel it, impaired blood flow to feet…can lead to infection)
    • Blindness (#1 cause of adult blindness)
    • Cardiovascular (trifecta → DM + high lipids + high blood pressure = poor prognosis)
    • Cancer (the unchecked glucose feeds the cancer cells)
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12
Q

How we get glucose

A
  • Carbohydrates
    • Sucrose, fructose, glucose, lactose, starch
    • (you eat to bring glucose in…gets broken from polysaccharides to mono via digestion)
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13
Q

Carbohydrate Digestion

A
  • Digestion of carbs (breakdown from poly to mono via digestion)
    • Mechanical—Chewing in mouth
    • Chemical
      • Mouth (a-amylase in saliva)
      • Small intestine (a-amylase, hydrolases, glucosidases)
    • Simple sugars get absorbed into the portal vein→liver (collects excess glucose and stores it as glycogen)

• Simple sugars are usually not found alone before being broken down (usually seen as disaccharide or polysaccharides)

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14
Q

Are Carbs the Enemy?

A
  • Necessary for energy (especially the brain)
    • The brain can also work on ketone bodies in case of emergency
    • Does not have the ability to break glycogen into glucose
  • Satiety
  • Protein glycosylation
    • Both good and bad
    • Excessive glycosylation is extremely bad – peripheral neuropathy, retinopathy
  • Microflora and bowel health
    • Need sugars to function and survive
  • Post-exercise recovery
    • helps with muscle repair
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15
Q

Q: Which of the following factors would not influence blood glucose response to a food?

a. Complexity of carb
b. Fiber content
c. Fat content
d. Preservative content
e. Liquid vs solid

A

d. Preservative content

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16
Q

Glycemic Index (GI)

A
  • Measure of the ability of the food to raise blood glucose
    • Simple carbs have high GI, but high fat foods like nuts have low GI
    • Area under the blood glucose response curve
    • 50 g carbohydrate portion of test food
    • % response compared to a standard food (everything is relative)
  • Low GI = decreased postprandial blood glucose and less insulin release/need
    • Less insulin released
    • Fat and fiber will slow digestion and absorption – won’t spike glucose and insulin as quickly
    • Insulin spike may lead to insulin resistance (hypothesized)
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17
Q

Carbohydrate/Glucose Homeostasis

A
  • Excess glucose gets stored for use later
    • Glucose is stored as glycogen or fat
    • helps keep a level blood glucose
  • Insulin
    • Synthesized in pancreas (islet cells – b-cells)
    • Released in response to increasing blood glucose levels to lower blood glucose levels
      • As blood glucose spikes, insulin will begin getting released
  • Glucagon
    • Synthesized in pancreas (islet cells – a-cells)
    • Prevents hypoglycemia
    • Peptide that kicks in and raises blood glucose levels
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18
Q

Gluconeogenesis

A

Formation of glucose not from glycogen

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19
Q

Glycogenolysis

A

Formation of glucose from glycogen

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20
Q

Glycolysis

A

Breakdown of glucose for energy

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21
Q

Glycogenesis

A

Formation of glycogen

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22
Q

Lipolysis

A

Breakdown of fat

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23
Q

Lipogenesis

A

Formation of fat

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24
Q

Insulin Response

A
  • Stimulated when glucose rises
    • Fasting
      • Pulsatile pattern even when fasting! (small pulsatile release throughout day even when fasting probably has to do with glucagon)
      • Can be induced by glucagon
  • Meals
    • Concentration dependent increase in response to rising glucose
    • Immediate spike, remains elevated for hours (after a big meal)
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25
Q

Insulin Actions in liver

A
  • In the liver, insulin causes:
  • Energy storage
    • **INCREASES Glycogen synthesis-increase in glucose stores
    • Increases Lipogenesis-makes more fat stores
    • Increases Protein formation-store energy as protein
    • **DECREASES Gluconeogenesis-making of glucose from non-sugars (peptides)
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26
Q

Insulin Actions in muscle

A
  • In the muscle, insulin causes:
    • Decreased Gluconeogenesis (formation of glucose not from glycogen)
    • ­Increased Glucose utilization (glycolysis-breakdown of glucose for energy)
    • **­Increased Uptake of glucose
    • ­ Increased Amino acid uptake (protein synthesis)

Muscles use glucose for energy. When glucose is high, insulin allows glucose to be taken into the muscles, where it is utilized by glycolysis for energy, allowing protien synthesis to increase, and the need for glucose formation by gluconeogenesis decreases

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27
Q

Insulin actions in adipose tissue

A
  • ­In adipose (fat) tissues, insulin causes:
    • Increased Storage of fats – increase in lipogenesis (fat formation)
    • **­Increased uptake of glucose by adipocytes (fat cells) – pull glucose out of circulation and into fat cells
28
Q

_________ concentrations of insulin inhibit gluconeogenesis in liver.

_________ concentrations of insulin are required to increase muscle uptake of glucose.

A

Lower, Higher (there is a difference in affinity of the receptors)

If low pulses of insulin (such as during fasting) increased muscle uptake of glucose, the muscles would take up glucose and the person would become hypoglycemic frequently (it would go against the homeostasis of glucose).

If they don’t have the slow pulses of low concentrations of insulin, then gluconeogenesis (Formation of glucose not from glycogen) in liver isn’t inhibited and their glucose increases without food. The low pulses of insulin inhibit gluconeogenesis until t is actually needed-produces ketone bodies. Increase insulin levels to inhibit gluconeogenesis over night (in diabetic patients) – keeps over night blood glucose levels low.

29
Q

Pancreas (Islets of Langerhans)

A
  • ~1 ­­­­­­­­­­­­million islets
  • Contains alpha, beta, and delta cells
  • Well vascularized, innervated by sympathetic and parasympathetic neurons
    • Adrenergic alpha 2 agonists decrease insulin release
    • Beta 2 agonists and vagal activity increase insulin release
      • Fight or flight situation
30
Q

Beta-cells

A

Vast majority of the cells in Islets

  • Produce insulin and amylin from pro-peptide
  • Insulin and C-peptide are stored and co-released together
31
Q

Alpha-cells

A

Fewer cells in Islets

• Regulate glucagon secretion and hepatic glucose output

32
Q

Delta-cells

A

• Secrete somatostatin

33
Q

Insulin

A
  • Proinsulin (a pro-peptide) is cleaved to form C-peptide and the A- and B-chains of insulin (dipeptide that contains three disulfide bonds)
  • C-peptide (a byproduct of insulin production) is released with insulin
    • C-peptide is a Good indicator of insulin release (and beta-cell health) since it is more slowly eliminated than insulin
      • Lots of C-peptide = beta cells are working
    • Not as easily degraded as insulin (has a longer half-life)
34
Q

Insulin Release

A

Glucose is the primary regulator of insulin release (other things can affect release as well)

  1. As glucose in blood rises, GLUT1 (in humans) transfers glucose into the beta-cells by facilitated diffusion.
  2. Once the glucose is inside, glucokinase phosphorylates glucose to glucose-6-phosphate. Once it is phosphorylated, it is trapped in the cell.
  3. The phosphorylated Glucose-6-phosphate uses glycolytic pathways to increase levels of ATP in the beta cell.
  4. The increase in ATP: ADP ratio inhibits an ATP sensitive potassium channel, causing an increase of potassium in the cell.
  5. The potassium increase leads to depolarization of the membrane which activates Ca voltage sensitive Ca channels, and causes Ca to flood into the cell.
  6. The influx of Ca in the cell leads to exocytosis of vesicles containing insulin granules due to the vesicles move to and bind the membrane where they dump their insulin contents into the blood.
  7. Also insulin secretion occurs via incretins (acting through G-protein coupled receptors, which increase cAMP causing the vesicle dumping of insulin into circulation)
35
Q

Sulfonylureas and insulin release from beta cells

A

Sulfonylureas bind to the site on ATP and block ATP-dependent K+ channel → membrane depolarization →insulin release

Beta-cell Insulin Release

  • Sulfonylurea receptor (SUR)
  • Blockade of SUR keeps K+ channel closed
36
Q

Insulin Release: The Incretin Effect

A
  • Insulin response to oral glucose load is greater than i.v. glucose load
    • Due to Incretins
    • Hospital patient may be receiving IV glucose
  • Incretins
    • Gut-derived hormones responsible–produced in response to food which increase insulin release independent of rise in glucose
      • They include GLP-1 and GIP
        • Glucagon-like peptide 1 (GLP-1) –cleaved from the same propeptide as glucagon
        • Glucose-dependent insulinotropic polypeptide (GIP)
    • Gut-derived hormone release is somewhat proportional to food intake and nutrient load → large meal = more incretin release
    • helps with satiety (less hungry feeling)
  • Type 2 diabetics have impaired incretin effect (release) as well as impaired insulin release (due to less incretin response) → not helping the situation
37
Q

Insulin Receptor

A
  • On tissues throughout the body (liver, muscle, fat, etc)
  • Insulin binds to receptor on cell membrane (2 a-parts and 2 b-parts)
  • Receptor tyrosines phosphorylate
  • Cascades activated (2nd messenger/intracellular)
  • PIP3 and Akt involved in translocating intracellular GLUT 4 to cell membrane and embed them there
    • More efficiently get glucose from circulation into the cells (goes from 1 glucose transport receptor to 4)
    • The more you exercise, the more GLUT 4 you always have present on the cell membrane – better management of glucose
  • Glucose transported into cells of muscle/fat/etc, removing it out of blood
  • Glycogenesis (Formation of glycogen) and/or glycolysis (Breakdown of glucose for energy)
38
Q

Liver stimulation by insulin

A
  • Insulin Stimulates:
    • Liver Glycogen Synthesis & Glycolysis (liver and muscle are major storage of glycogen)
      • Insulin activates hexokinase which phosphorylates glucose and forms glucose 6 phosphate
        • Phosphorylated glucose is trapped in hepatocytes
        • must be made into glycogen or go through glycolysis
      • Insulin activates enzymes in glycogen synthesis
        • phosphofructokinase and glycogen synthase
      • Up to 5% or so build-up of glycogen (at some point, around 5%, liver has all the glycogen it can make and transfers glycogen production to fatty acid production)
        • Then glucose is transferred to fatty acid production
        • Fatty acids exported from liver as lipoproteins
        • Lipoproteins broken down into free fatty acids (TG synthesis)
39
Q

Insulin and fat

A

Insulin Is “Fat-sparing”

  • Encourages most cells to preferentially use glucose over fats
  • Inhibits lipolysis (breakdown of fat) in adipose by inhibiting lipase
  • Insulin increases lipogenesis
40
Q

Other Insulin Effects

A
  • Anabolic
    • Stimulates uptake of amino acids into cells
    • Increase protein production
41
Q

Amylin

A
  • Produced in beta cells
  • Co-released with insulin (in the vesicles with insulin and c-peptide)
  • Slows gastric emptying & decreases speed of glucose absorption
    • Lowers Glycemic Index
  • Suppresses glucagon output from alpha-cells
  • Increases satiety
    • Eat less and feel more full
  • Also impaired in Type 1 DM
42
Q

Glucagon

A
  • Increases blood glucose
  • 29 amino acid peptide
  • Synthesized as proglucagon (also a pro-peptide)
    • Cleaved into glucagon in the alpha cells of pancreatic islets
  • Proglucagon is also found in gut
    • Cleaved into glucagon-like peptides (NOT glucagon)
43
Q

Glucagon Physiological Effects

A
  • Major target organ is the liver
  • Stimulates glycogenolysis (breakdown of glycogen to create glucose)
  • Activates gluconeogenesis (non-hexose formation of glucose)
  • Inhibits glycogen synthase (important for glycogen synthesis)
  • Mild promotion of insulin secretion
    • We need insulin to get glucose into the cells→allows GLUT4 transporters get to membrane to so the tissue to take up the glucose for use in glycolysis
    • Type 1 diabetics are cellularly starving even though they have an abundance of glucose in the blood→insulin is not responding appropriately
44
Q

Regulation of Glucagon

A
  • Secreted in response to:
    • Low blood glucose (hypoglycemia)
    • Increased blood levels of amino acids (to eliminate them via gluconeogenesis)
    • Exercise
  • Secretion is inhibited by:
    • high blood glucose,
    • insulin
    • amylin
    • somatostatin
45
Q

The release of glucose, glucagon and insulin

A
  • In fasting:
    • Glucose preferentially goes to brain and heart (which gets steady amounts in fasting & post pradial)
    • alpha cell glucagon and adipose fatty acids go to liver to increase glucose available
    • insulin is low and pulsatile to allow glucose intake by cells
  • Post prandial:
    • Glucose is higher and more gets delivered to muscle and liver (steady amounts still going to brain & heart)
    • Glucagon release is lower and fatty acids from adipose decrease
    • Insulin release increases
46
Q

Classification of Diabetes Mellitus

A
  • Pathogenesis-based
    • type 1 or type 2
  • NOT by age such as juvenile-onset, adult-onset
    • Juvenile’s are now getting type 2 more frequently.
    • Adults can also get type 1.
  • NOT by therapeutic approach such as insulin-dependent, insulin-independent
    • advanced type 2 are sometimes treated with insulin (not insulin-independent)
47
Q

Type 1 Diabetes Mellitus

A
  • Insulin production is completely (or nearly completely) absent
  • Insulin therapy is required
    • they are sensitive to insulin, but they don’t have/make any
  • Usually < 30 y.o. at onset (often school-aged children)
  • Usually autoimmune (not sure what causes it): body attacks the beta-cells in the pancreas → destroys production of insulin
  • 5-10% all diabetics (very small proportion of diabetic population)
  • How they treat their diabetes for the rest of their life will affect their life expectancy and quality of life
  • Greatest complications due to inabilities to always/forever control glucose levels
48
Q

Type 2 Diabetes Mellitus

A
  • Insulin present, but not effective
  • Can reverse with diet, weight loss, exercise (more glut 4 receptors on muscle and liver),
    • it doesn’t take much in many people to reverse
  • Insulin may be used (but isn’t necessarily required)
  • Used to be adult onset, now kids too
  • Incidence increasing
  • Insulin is typically not used in T2DM that is recently diagnosed (more commonly used in advanced T2DM)
  • More obese → more likely you are to suffer from T2DM (not all obese people have T2DM, and not all people with T2DM are overweight)
  • 90% T2DM
49
Q

Other Types of Diabetes Mellitus

A
  • Gestational – test at the end of 2nd trimester
    • May reverse after birth (but sig. increased risk of developing type 2 within 10-20 years)
    • Insulin may be helpful
  • Cystic fibrosis (islet destruction) – leads to diabetic state
  • Cushing’s syndrome – excess cortisol- glucocorticoid production may lead to a diabetic state
50
Q

What would a lack of insulin mean (physiologically)?

A
  • Blood glucose would be high
  • Cellular metabolism would be low
51
Q

Type 1 DM Physiology

A
  • Essentially no insulin
    • No insulin means the cells that need glucose can’t get it causing fat and every other resource to be utilized for fuel
  • When initially presenting, appearance is usually very thin
  • As beta cells die off, they go into hyperglycemic state
  • “Honeymoon” period
    • by giving beta cells a bit of insulin, they get a break and start to come back a little bit to producing insulin
    • possible after initiation of insulin therapy
    • determining dosage of insulin plus unpredictable insulin production may cause hypoglycemia for a period of time.
    • Eventually beta cells level out their production, and hypoglycemia is not as frequent.
  • Before insulin was developed, T1DM was a death sentence (cellular starving)
52
Q

Q: Why is amylin secretion decreased in Type 1 DM?

A

Loss of beta-cells

53
Q

Q: T/F: If you are obese, you will eventually develop type 2 DM

A

False

54
Q

Risk Factors for Type 2 DM

A
  • Family history
  • Obesity
  • Low/no exercise
  • Ethnicity (African Americans, Latino, Native Americans, Asian Americans, Pacific Islanders)
  • Hypertension, high TGs
55
Q

Type 2 DM Physiology

A
  • Decreased sensitivity of beta-cell to glucose
    • beta-cell may not sense there is a glucose increase
    • Are often hyperinsulinemic (have an over-production of insulin)
  • Decreased mass of beta-cells (death due to hyperglycemia?)
    • in advanced disease
    • not how they first present
  • Insulin resistance
    • high levels of insulin, but receptors do not respond – most likely
56
Q

Insulin Resistance

A
  • Primary Mechanism we see
    • Liver
      • gluconeogenesis causes glucose production despite hyperglycemia (insulin is not suppressing gluconeogenesis, glucagon not inhibited)
    • Muscle
      • Decreased ability to take up glucose
    • Adipocytes
    • Decreased ability to take up glucose
    • Lipase enzyme isn’t inhibited, leading to increased plasma FFA (free fatty acids)
57
Q

Diabetic Ketoacidosis Pathophysiology

A
  • Usually seen in T1DM
  • Fatty acids are being broken down to form ketones in the body from fat breakdown
  • Insulin absence and glucagon (or catecholamine or cortisol) excess
  • Excessive gluconeogenesis, glycogenolysis and ketone body formation
58
Q

Diabetic Ketoacidosis Symptoms

A
  • Type 1 DM develop this
    • Many Type 1 Diabetics are in DKA when they find out they have diabetes
  • Symptoms:
    • Nausea/vomiting
    • Increased thirst/polyuria
    • Abdominal pain
    • Shortness of breath (acetone/fruity breath)
    • Tachycardia
    • Dehydration/hypotension
    • Lethargy, cerebral edema, coma, seizures
    • Can very quickly become fatal
59
Q

Major issues with DKA

A
  • Dehydration/volume depletion
    • Causing thirst, but volume is very low
      • High blood sugar is adding to problem
      • High osmolality of blood
      • Electrolyte imbalance (K+ in blood is high)
  • Acidosis
    • Increased ketone production
  • Lack of glucose utilization (especially brain)
  • Tx: Address dehydration – rehydrate them
    • Rehydration fixes osmolality in blood thinning out all concentrations including ketones and glucose levels
60
Q

Hyperosmolar hyperglycemic syndrome

A
  • Version of DKA usually seen in type 2 DM
    • Ketone production less of an issue
    • Dehydration is still a major issue
    • Blood glucose levels at presentation may actually be higher than DKA patients
      • Don’t have as much of a problem with ketone/acidosis production, therefore they can handle much higher glucose levels
  • Still at risk for electrolyte imbalance
  • Tx: Address dehydration – rehydrate to bring down blood glucose level
61
Q

Diabetic Complications: hyperglycemia

A
  • Hyperglycemia results in glycosylation
    • Glycosylation is a measure longer-term control of blood glucose
      • Reversible glycosylation of proteins correlated with blood glucose levels
      • HbA1C - long term picture of compliance
62
Q

Advanced Glycosylation End Products

A
  • Intracellular
    • High glucose in cells glycosylates proteins in the cells
    • Altered protein function, increase reactive oxygen species, increase endothelial permeability
  • Extracellular
    • Cause cell injury and damage
  • Stimulate oxidative damage
  • Resistant to normal degradation (hard to get rid of – avoid production because once they are produced they can cause damage to nerves and vasculature)
63
Q

Diabetic Complications: Vascular

A
  • Vascular
    • Microvascular (retinopathy, neuropathy, nephropathy)
      • High correlation to glucose control
    • Macrovascular (heart disease, peripheral vascular disease, cerebrovascular disease)
      • Low correlation to glucose control
      • having DM puts the patient at risk of macrovascular complications
      • regardless of control, they are still at increased risk
  • Infections – especially in areas that have very poor vasculature (hands and feet)
    • very hard to heal→ amputation
  • Metabolic Syndrome
64
Q

Microvascular Complications

A
  • Chronic hyperglycemia is to blame
    • Excessive protein glycosylation
    • Increased oxidative stress
65
Q

Macrovascular Complications

A
  • Not correlated well with degree of hyperglycemia
  • Endothelial dysfunction
  • Dyslipidemia
  • Eventually leads to development of atherosclerotic lesion
66
Q

Metabolic Syndrome

A
  • Cluster of conditions
    • Hyperinsulinemia, hypertension, abdominal/visceral obesity, dyslipidemia, hypercoagulability
  • Poor prognosis without change – much shorter life span, decreased quality of life
  • Patient needs to make life changes and be put on medication
67
Q

What is needed to get the glucose from the blood into the muscles

A

In order to get that glucose that’s in your bloodstream into your muscle cells you need to have insulin present to trigger that uptake event

2016 Endocrine (19 decks)

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