Obesity and Diabetes

Question 1

Blood glucose levels are determined by… (4)

Answer 1

Dietary intake
Tissue uptake
Mobilization
Excretion

Question 2

What molecules does
1. Liver
2. Adipose
store caloric excess as?

Answer 2

1. Glycogen

2. Triglycerides

Question 3

What are the blood glucose values for

1. Post-prandial
2. Mean
3. Fasting

Answer 3

1. ~6.0-8.0 mmol/L
2. ~5.5 mmol/L
3. ~4.5-6.0 mmol/L

Question 4

Glucagon

1. Target
2. Result on target
3. Overall effect
4. Stimuli

Answer 4

1. Hepatocytes (liver)
2. Increase glucose release, increase glucose synthesis, increase glycogen breakdown, decrease glucose storage
3. Raises blood glucose level (promotes glucose mobilization)
4. Low blood glucose (hypoglycemia) - alpha cells secrete it

Question 5

Insulin

1. Targets
2. Results on targets
3. Overall effect
4. Stimuli

Answer 5

1. Liver, fat, skeletal muscle
2. Increase glucose uptake (all), increase glucose storage (l, f), increase glucose utilization (sm), decrease glycogen breakdown (l), decrease glucose synthesis (l)
3. Lowers blood glucose levels (promotes glucose storage and utilization)
4. High blood glucose (hyperglycemia) - beta cells secrete it

Question 6

Insulin protein stucture

Answer 6

Anabolic polypeptide hormone
Secreted exclusively by beta cells of pancreatic islets of Langerhans
Synthesized as a 51 amino acid (proinsulin)
Cleaved by intracellular proteases to generate A and B chain
Linked by 2 disulphide bridges

Question 7

How does Glucose-Stimulated Insulin Secretion work?

Answer 7

1. Glucose enters the pancreatic beta cell via GLUT2 (low affinity transporter, only works when glucose levels are high)
2. Glucose is metabolized, elevating intracellular [ATP]
3. Elevated [ATP] inhibits ATP-sensitive K+ channel
4. Accumulation of K+ inside the cell results in depolarization
5. Voltage gated Ca2+ channel is opened, and Ca2+ flows in
6. increased intracellular Ca2+ results in exocytic secretion of insulin from storage vesicles into the blood

Question 8

Diabetes Mellitus

Answer 8

First noticed as causing rapid weight loss and excessive urination
All characterized by high blood glucose
2 primary causes: inadequate insulin secretion, or impairment of insulin action

Question 9

Type 1 Diabetes

Answer 9

5-10% of all cases
Most commonly arises under 20 years old
Autoimmune destruction of pancreatic beta cells
Reduced or absent insulin secretion
Chronic disease

Question 10

Type 2 Diabetes

Answer 10

90-95% of all cases
Most commonly arises >40 yrs old, but getting younger
Tissue resistance to the biological actions of insulin
Advanced stages associated with insufficient insulin secretion
Chronic disease

Question 11

Gestational diabetes

Answer 11

5-10% of all pregnancies
Tissue resistance to the biological actions of insulin (mother)
Acute disorder that generally resolves shortly after birth

Question 12

Pathophysiology of Type 1 Diabetes

Answer 12

Autoimmune destruction of pancreatic beta cells
Cause not well characterized (multifactorial - genetics, environment, pathogen exposure)
Progressive loss of insulin production and GSIS
Loss of tissue glucose uptake and energy storage
Failure to inhibit glucose production and release from the liver
Chronically elevated blood glucose

Question 13

Acute effects of type 1 diabetes

Answer 13

Excessive urine production
Extreme thirst and hunger
Rapid heartbeat
Nausea, dizziness, confusion
Weakness, shaking, fainting

Question 14

Chronic complications of type 1 diabetes

Answer 14

Extreme weight loss, wasting
Damage to blood vessels of eyes and in extremities
Kidney damage
Peripheral nerve damage
Hyperlipidemia
Hypertension
CV disease

Question 15

Treatment of Type 1 diabetes

Answer 15

Careful control of diet
Insulin replacement
Even with good management of hyperglycemia, there is an elevated risk of chronic complications

Question 16

Pathophysiology of type 2 diabetes

Answer 16

Development of insulin resistance in tissues
At early stages, increases insulin secretion can compensate for moderate insulin resistance
But later on elevated insulin secretion cannot compensate for worsening insulin resistance
Reduced glucose uptake and energy storage
Increased liver glucose synthesis and release
Chronic hyperglycemia
Chronic insulin resistance and hyperglycemia is toxic for pancreatic beta cells

Question 17

What is insulin resistance and what does it result in (5)?

Answer 17

Reduced response of tissues to insulin
Results in:
Decreased activation of membrane glucose transporters by insulin receptor
Decreased glucose uptake
Decreased glucose storage
Increased glucose synthesis
Elevated blood glucose levels

Question 18

Adipokines

Answer 18

Signalling molecules with hormone-like actions
Synthesized and secreted by adipose tissue
Regulate energy metabolism in adipose as well as other tissues
Ex: leptin, adiponectin, TNFalpha, etc

Question 19

Acute effects of type 2 diabetes

Answer 19

Same as type 1
Excessive urine production
Extreme thirst and hunger
Rapid heartbeat
Nausea, dizziness, confusion
Weakness, shaking, fainting

Question 20

Chronic complications of type 2 diabetes

Answer 20

Same as Type 1
Extreme weight loss, wasting
Damage to blood vessels of eyes and in extremities
Kidney damage
Peripheral nerve damage
Hyperlipidemia
Hypertension
CV disease

Question 21

Treatment of Type 2 diabetes

Answer 21

Careful control of diet, exercise, weight loss
Metformin, insulin secretagogues, incretin agents, gliflozins, TZDs, insulin
Even with good management, elevated risk for chronic complications

Question 22

Therapeutic lifestyle changes for diabetes

Answer 22

Increased physical activity
Diet modification
Weight reduction

Question 23

6 pharmacological approaches to diabetes

Answer 23

1. Insulin and insulin analogues
2. Metformin
3. Insulin secretagogues
4. Incretin agents
5. Gliflozins
6. Thiazolidinediones

Question 24

Insulin replacement therapy

Answer 24

Always required for type 1

Not required for all type 2 patients - only when other therapies fail, for severe/advanced cases, used in combo

Question 25

How is insulin administered?

Answer 25

By subcutaneous injection | It is rapidly degraded by proteolytic enzymes in GI tract so cannot be taken orally

Question 26

Rate of absorption determines ... (3)

Answer 26

Onset of action Peak activity Duration of action

Question 27

3 forms of insulin, and the speed they are absorbed and their duration of action

Answer 27

1. Hexamers (slowest at diffusion, slow onset of action, long duration) 2. Dimers (in the middle) 3. Monomers (fastest at diffusion, rapid onset of action, short duration)

Question 28

Natural Insulin 1. Form 2. Onset 3. Peak 4. Duration

Answer 28

1. Hexamers 2. 30 min 3. 2 hours 4. 6-8 hours

Question 29

Insulin Lispro 1. Form 2. Onset 3. Peak 4. Duration

Answer 29

1. Single amino acid change - form dimers 2. 15 mins 3. 30 mins 4. 4 hours

Question 30

Amino acid substitutions affect... (3)

Answer 30

``` Quaternary structure (hexamers vs dimers) Crystallization properties (high vs low) Solubility (low vs high) ```

Question 31

GSIS replacement

Answer 31

Rapid/regular actin insulin Mimics beta cell release of insulin in response to a nutrient load Taken just before a meal

Question 32

Basal replacement

Answer 32

Intermediate/long acting insulin Administered once or twice daily Provides constant insulin levels that are relatively stable for many hours Important to prevent glucose release from liver during fasting state (ex: while sleeping)

Question 33

3 insulin infusion devices

Answer 33

Good: traditional insulin replacement (monitor levels with glucometer, inject insulin) Better: insulin infusion pump (monitor levels with glucometer, pump provides 480 small does of rapid acting insulin per day, plus larger bolus at meals) Best: artificial pancreas (continuous automated monitoring, numerous doses of rapid acting insulin throughout the day)

Question 34

What is the most common/severe adverse effect associated with insulin replacement therapy?

Answer 34

Hypoglycemia Can lead to convulsions and coma Glucose (oral or infusion is the treatment)

Question 35

Common causes of hypoglycemia

Answer 35

Inadequate carbohydrate consumption Unusual physical activity Insulin dose too large

Question 36

Why is weight gain a common adverse effect of insulin replacement therapy?

Answer 36

Insulin is an anabolic hormone and promotes energy storage Increased glycogen synthesis in liver and muscle Increased triglyceride synthesis and storage in adipose tissue Reduced resting metabolic rate

Question 37

Metformin

Answer 37

Drug of first choice for type 2 diabetes Activates AMP-dependent kinase, which is a key regulator of energy metabolism in most cell types Decreases basal and post-prandial blood glucose

Question 38

Adverse effects of metformin

Answer 38

GI irritation Lactic acidosis (reduced liver uptake of lactate for glucose synthesis) Low risk for hypoglycemia

Question 39

Insulin secretagogues

Answer 39

Ex: sulfonylureas, meglitinides Stimulate insulin release from pancreatic beta cells Inhibit ATP-sensitive K+ channels in pancreatic beta cells (stimulates the GSIS pathway without glucose) Uncouples insulin release from blood glucose levels Increased circulating insulin levels can partially/completely compensate for tissue insulin resistance

Question 40

Adverse effects of insulin secretagogues

Answer 40

Similar to insulin replacement therapy Hypoglycemia Weight gain

Question 41

Incretins

Answer 41

Gastrointestinal derived hormones that regulate pancreatic insulin and glucagon release Reduced glucagon release and glucose production Increases insulin release and glucose uptake Short duration of action - only get action with high glucose levels (not basal insulin secretion)

Question 42

Incretin agents: DPP-4 inhibitors

Answer 42

Reduce GLP-1 degradation (so increase their levels) Increases pancreatic GSIS insulin release, and reduced glucagon release Can partially/fully overcome tissue insulin resistance Usually used in combo with metformin and/or secretagogues

Question 43

Adverse effects of DPP-4 inhibitors

Answer 43

GI (nausea, vomiting) Low risk for hypoglycemia Pancreatitis (rare)

Question 44

Incretin agents: Incretin mimetics

Answer 44

Activate pancreatic GLP-1 receptors (agonists) Increase pancreatic GSIS release, reduce glucagon release Can partially/fully overcome tissue insulin resistance Usually used in combo with metformin and/or secretagogues Requires subcutaneous injection

Question 45

Adverse effects of Incretin mimetics

Answer 45

GI (nausea, vomiting) Low risk for hypoglycemia Pancreatitis (rare) Thyroid dysfunction/cancer potential risk

Question 46

Gliflozins

Answer 46

Inhibit renal glucose reabsorption Used in combo with metformin Inhibitors of sodium-glucose transporter linked transporter 2 (SGLT2) Gliflozins block reabsorption and lead to greater urinary glucose excretion

Question 47

Adverse effects of gliflozins

Answer 47

Hypoglycemia Urinary tract infections Dehydration

Question 48

Thiazolidinediones

Answer 48

Improve insulin sensitivity in many tissues PPARy agonists Normalization of adipose tissue function