DM Pathophysiology

Question 1

Diabetes

Answer 1

• Chronic, metabolic disorder of fat, carb, and protein metabolism
• Hyperglycemia arising from defects in insulin secretion, action, or both

Question 2

Type I DM

Answer 2

• B-cell destruction
• Absolute insulin deficiency
• 5-10% of DM cases

Question 3

Type II DM

Answer 3

• Insulin resistance _ relative insulin deficiency

- 90-95% of all DM cases

Question 4

DM I Pathophysiology

Answer 4

Autoimmune cells
destruction of B-cells

Four Features of Disease Progression:

1. Pre-clinical period: presence of immune markers
2. Hyperglycemia after 80-90% of B-cells are destroyed due to deficiency of insulin and amylin
3. Honeymoon phase - transient remission
4. Established disease

Question 5

T1DM Autoimmune Markers

Answer 5

• Type I diabetes: immune mediated in >95% of cases
• Idiopathic in less than 5%
• GAD65 (70-90%), IAA, ICA512, ZnT8

Question 6

Insulin Cleavage

Answer 6

• Synthesized as preproinsulin
• Cleaved to proinsulin
• Proinsulin split into insulin and C peptide

Question 7

T2DM Pathophysiologu

Answer 7

• Progressive, heterogeneous disorder with ongoing B-cell failure
• Relative insulin deficiency
• Range from severe insulin resistance, minimal insulin secretory defects, primary defect in insulin secretion
• Majority of patients have glycemic control that deteriorates with time
• Metabolic disorder

Question 8

T2DM Development

Answer 8

• Healthy individuals: insulin secretion by pancreatic islet allows for normal glucose disposal into insulin-sensitive tissues
• Prediabetes: genetic predisposition, over-nutrition, and physical inactivity reduce the response to insulin-stimulated glucose uptake that is compensated for by increasing insulin production
• Type 2 DM: insulin secretion no longer compensates for increased peripheral insulin demand

Question 9

T2DM Progression

Answer 9

• Insulin Resistance
• Increased insulin production
• Death/burnout of beta cells
• Reduced or absent insulin

Question 10

T2DM: Insulin Resistance

Answer 10

• Body cells become less responsive to the insulin we make

- Usually takes a long time to develop (years to decades)

Question 11

T2DM Beta Cell Burnout

Answer 11

• By the time of T2DM diagnosis, more than 80% of B-cells may be gone
• Progression doesn’t always occur

Question 12

Hyperglycemia - Ominous Octet

Answer 12

1. Decreased insulin secretion
2. Increased glucagon secretion
3. Increased HGP
4. Neurotransmitter dysfunction
5. Decreased glucose uptake
6. Increased glucose reabsorption
7. Increased lipolysis
8. Decreased incretin effect

Question 13

Egregious Eleven: B-Cell destruction Effects

Answer 13

1. Pancreatic B-Cells
2. Incretin Effect
3. Alpha-cell defect
   4-6. Adipose, Muscle, Liver
4. Brain
5. Colon/Biome
6. Immune Dysregulation/inflammation
7. Stomach/Small Intestine
8. Kidneys: SGLT2

Question 14

Pancreatic B-Cells Dysfunction

Answer 14

• Insulin resistant organs: liver, muscle, adipose tissue (increased lipid exposure can lead to B-cell dysfunction)
• Other organs: brain, colon, immune system

Question 15

Incretin Effect

Answer 15

• Resistance to the action of glucose-dependent insulinotrophic polypeptide also called gastric inhibitory polypeptide (GIP)
• B-cell resistance to the stimulatory effect of GIP on insulin secretion
• Deficiency of GLP-1: resistance to stimulatory effect of GLP-1 on insulin secretion

Question 16

Alpha-cell Defect

Answer 16

-Increased glucagon

Question 17

Adipose, Muscle Liver

Answer 17

• Insulin promotes fuel storage (anabolism) in these tissues
• Also prevents the breakdown of release of fuel that have already been stored (catabolism)
• Insulin resistance and inflammation lead to production/release of FFAs and insulin resistance-provoking proinflammatory cytokines in the adipose cells

Question 18

Brain Effects

Answer 18

• May experience insulin resistance like other organs
• Increased appetite due to decreased GLP-1/GIP
• Decreased morning dopamine surge
• Increased sympathetic tone

Question 19

Colon/Biome

Answer 19

• Gut microbiome role in digestion: strengthens immune system, prevents infection
• Antibiotic use may increase risk of T2DM: kill “good” bacteria allowing for “bad” bacteria to dominate GI tract, alters nutrient absorption/metabolism
• Associated insulin resistance

Question 20

Stomach/Small Intestine

Answer 20

• Amylin production decreased as a result of B-cell dysfunction: amylin co-secreted with insulin from B-cell
• Effects of decreased amylin: accelerated gastric emptying, increased glucose absorption in small intestine, corresponding increases in postprandial glucose levels

Question 21

Kidneys Effects

Answer 21

• As blood glucose increases, the kidney begins to reabsorb the glucose so it will not go into urine
• Up-regulates SGLT-2 protein in kidney to further hyperglycemia

Question 22

Complexities of Diabetes

Answer 22

• Increased insulin resistance
• Increased hepatic glucose production
• B-cell failure or destruction
• Abnormalities in incretin action
• Enhanced renal SGLT2 activity
• Abnormalities of glucagon physiology