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
Metformin (Glucophage®, Generics)
AE?
– Does not cause hypoglycemia, insulin sparing
– Weight neutral or no weight gain
- Weight loss GDF 15 increase secretion (grwoth diff factor)
– GI symptoms most common side effect
– *Lactic acidosis? (more for phenformin), build up of lactate due to it being renal excreted so ppl with renal failure should not use it
– Vitamin B12 absorption??? (take calcium supplements)
what drugs bind and inhibit KATP channels?
Insulin secretagogues
sulfonylureas
and meglitinide analogues
what drugs prevent breakdown of disaccharides to
monosaccharides (e.g. glucose)
α-glucosidase inhibitors prevent postprandial
rises in blood glucose levels
what drugs are PPARy agonists?
Thiazolidinediones
increase fat storage in adipose tissue and reduce fat
storage in muscle and liver, thereby improving
insulin sensitivity
what drugs reduce hepatic glucose production
Metformin is the first-line therapy for type 2
diabetes
