Type 2 Diabetes Part 1 Flashcards
Pathology of Obesity-Related T2D
name 5 locations that are related to obesity progression and the effects
- Skeletal Muscle Insulin Resistance
- Pancreas: Hyperinsulinemia, Hyperglucagonemia
- Liver: Increased Hepatic Glucose Production & Triacylglycerol Secretion
- Brain: Increased appetite
- Adipocytes: Increased Adiposity & Inflammation
Control blood sugar levels < 7%, macrovascular is not controlled well
Pathology of Obesity-Related T2D
describe Skeletal Muscle Insulin Resistance
- First develop skeletal muscle insulin resistance
- Skeletal muscles take up a lot of glucose by action of insulin, but it is not taking in glucose
- islet beta cells work harder to secrete more insulin so it can get in
- Beta cell dysfunction first or skeletal muscle first?
Pathology of Obesity-Related T2D
describe Hyperinsulinemia, Hyperglucagonemia
- beta cells work harder to secrete more insulin
- alpha cells also secrete more glucagon to increase glucose in blood
- leads to alpha and beta cell dysfunction
Pathology of Obesity-Related T2D
describe Increased Hepatic Glucose Production & Triacylglycerol Secretion
- glucagon acts on liver to make glucose through gluconeogenesis
- elevated production contributing to high blood sugar levels
Pathology of Obesity-Related T2D
describe Increased appetite
- Insulin is satiety factor - tells hypothalamus you are full
- Impaired satiety
- increase appetite contributing to obesity
Pathology of Obesity-Related T2D
describe Increased Adiposity & Inflammation
- adipose builds
- chronic low grade info that leads to release of cytokines that can cause insulin resistance
- Lipid starts to build up, circulating lipids increased,
- excess storage of fat that leads negative effect on insulin signaling and sensitivity
what is T2D initially characterized by?
what may happen as the disease progresses?
– Initially characterized by insulin resistance, hyperinsulinemia and hyperglycemia
➢Hyperglycemia also due to excessive hepatic glucose
production (hyperglucagonemia)
– As disease progresses, beta-cell dysfunction and/or
destruction may take place (due to stress)
➢Insulin therapy is beneficial at this stage
➢Insulin secretagogues may no longer be as effective
what are the targets for glucose-lowering in T2D? (2 general)
- overcome insulin resistance
- insulin independent methods of glucose-lowering
what 2 ways can be used to overcome insulin resistance?
– Increase insulin secretion
➢Insulin secretatagogues*
➢Incretin-based therapies
– Increase insulin sensitivity
➢Thiazolidinediones*
➢Metformin?*
what 3 ways can be used to as insulin-independent methods of glucose-lowering?
– Decrease hepatic glucose production
➢Metformin*
– Increase glucose excretion
➢Sodium-glucose cotransporter-2 inhibitors
– Prevent dietary glucose absorption
➢α-glucosidase inhibitors*
Secretagogues - sulfonylureas
Types of sulfonylureas? what is their difference
1st Generation Sulfonylureas
– Tolbutamide, Chlorpropamide, Acetohexamide
- 2nd Generation Sulfonylureas
- Glyburide [or glibenclamide] (Diabeta®, generics)
- Glipizide (Glucotrol®)
- Glimepiride (Amaryl®) [some references suggest this is a 3rd gen]
– 2nd gen More potent, have a shorter half-life, fewer side effects
- needs less strength to exert the same effect
Secretagogues - sulfonylureas
MOA?
what is the normal pathway?
what about sulfonylureas?
receptors?
- Agents bind to and inhibit KATP channels
- May also reduce hepatic clearance of insulin
• GLUT 2 is the transporter for glucose in beta cell
(not insulin sensitive, always present)
• Metabolized leading to formation of ATP which closes KATP channels which prevents K+ efflux and induces depolarization
• K+ stays in the cell, Ca2+ flows in to induce response to tell insulin granules to release insulin
Sulfonylureases bypass the process:
• Sulfonylureas bind the sulfonylurea receptor/subunit of the KATP channel
• Inhibition of KATP channels prevents K+ efflux and induces depolarization
• Activates Ca2+ channels and subsequent Ca2+ influx, leading to exocytosis of insulin from insulin granules
Chronic use - beta cell dysfunction as there is only so much insulin
Secretagogues - sulfonylureas
AE? (4)
• Lower risk of drug-drug interactions with 2nd generation agents (more selective
- Can cause hypoglycemia
– Glyburide, chlorpropamide, and glipizide are most
likely for prolonged risk
- Chlorpropamide: most, long duration of action and half life, it should be avoided in seniors - Hyponatremia (chlorpropamide): secondary action on vasopressin
- Weight gain: insulin is anabolic hormone
- Cardiovascular complications?
– Interference with ischemic preconditioning (Activation of KATP channels in the heart induces preconditioning)
Secretagogues - Non-sulfonylurea (meglitinide
analogues)
Name 2
what are they derived from?
– Derivatives of benzoic acid or
phenylalanine
• Repaglinide (GlucoNorm®)
• Nateglinide (Starlix®)
Secretagogues - Non-sulfonylurea (meglitinide
analogues)
MOA?
same as sulf
– Bind to a different site of the KATP channel
– More selective for the beta cell KATP channel than the cardiac KATP channel
– Rapid onset and short duration of action due to more
rapidly dissociating from the receptor (although still
have risk of hypoglycemia, severity and frequency of
hypoglycemia is lower)
α-Glucosidase Inhibitors
name 3
how potent compared to other diabetic drugs?
what are they?
– Acarbose
– Miglitol
– Voglibose
- Least potent of diabetic drugs
- Substrates for alpha-1,4- glucosidase which are enzymes that break down sugars into glucose (disaccharides)
α-Glucosidase Inhibitors
MOA?
– Competitive inhibitor of intestinal αglucosidase, an enzyme responsible for breakdown of disaccharides (e.g. sucrose, maltose)
– Delays and decreases absorption of monosaccharides
– Reduces postprandial glucose rise
Extra:
- Amylase breaks straches into maltose
- enterocytes have microvilli where the a-glucosidase is present and hydrolyzes saccharide bond, release glucose into absorption
- Acarbose nitrogen protects from hydrolyzing the bond, competitive inhibitor, delay abs of carbs into blood stream
α-Glucosidase Inhibitors
AE?
when to take it?
what to do with hypoglycemic episode?
– Take with meal (first bite of food)
– Does not cause hypoglycemia (Not related to insulin)
– Significant GI complications (flatulence, carbs not digested so bacteria does it)
– Hypoglycemic episodes require glucose
Cannot use table sugar if hypoglycemic person on a-glucosidase inhibitors MUST take free glucose
Thiazolidinediones
Name 3
what are they?
Rosiglitazone (Avandia®), Pioglitazone (Actos®) & Troglitazone (Rezulin®) (original)
Agonists of peroxisome-proliferator-activated receptor
gamma (PPARγ, nuclear receptor highly expressed in
adipose tissue)
insulin sensitizers
Thiazolidinediones
MOA
how long does it take?
increase insulin sensitivity
– Agonists of PPARγ
– Promote uptake & storage of fatty acids into adipose
tissue (prevents excess fat from being stored in other
organs)
– Improves muscle insulin sensitivity
– Takes 6-12 weeks to reach full effect
- Increases differentiation of maturation of adipocytes which will store more fat and away from other organs
- Excess fat in muscle and liver causing hepatic and insulin resistance
- putting fat where it should be
- Takes 2-3 months to work
- Lipid is used as fuel source for energy
- Type 2 diab - Elevated lipid is always delivered to muscle, has more fat stored in organ
- Lower circulating lipid levels, decreased delivery to muscle, when it use the excess fat stored, it dissipates over time and doesn’t get replenished
- Insulin sensitivity is restored and can cause glucose to enter muscle, decrease gluconeogenesis
Thiazolidinediones
AE (3)
– Fluid retention (can aggravate pre-existing heart failure)
– Cardiovascular (… and now cancer) complications limiting use of rosiglitazone and pioglitazone
- rosi disproved for cardio
– Weight gain - fat into adipocytes
CV death is number 1 death cause for T2D ppl, so drugs must undergo CV outcome studies
Metformin (Glucophage®, Generics)
drug class?
what line of therapy?
- Drug Class: biguanides
* First line therapy for type 2 diabetes
Metformin (Glucophage®, Generics)
MOA?
– Exact mechanism remains unknown
– Most common beliefs…
• MOA related to adenosine 5’monophosphateactivated protein kinase (AMPK), a major cellular regulator of energy metabolism
• Inhibits glucagon signaling in the liver
• *Decreases glucose production in the liver (hepatic
gluconeogenesis) - MOST LIKELY
• Promotes glucose uptake by skeletal muscle?
Metformin (Glucophage®, Generics)
describe pathway of AMPK
AMPK inhibits acetyl CoA carboxylase (ACC) to reduce hepatic lipid content
- AMPK inhibits ACC
- ACC synthesizes malonyl CoA which inhibits fat oxidation
- Low ACC - increases fat oxidation in liver, lowers hepatic lipid accumulation
- inhibit glucagon signaling prevents activating hepatic gluconeogenesis
- Decreased hepatic glucose production and subsequent blood glucose levels
