Review Flashcards
describe the pathway where ketone bodies are made
During prolonged starvation/fasting there is low blood sugar and brain needs to use ketone bodies for feul
- body mobilizes fat from adipose tissue for energy goes to liver and turns into ketone bodies for use in brain
- T1 diabetic ketone bodies acidic and can cause toxicity
- insulin is needed to shut off ketogenesis
where is endogenous insulin stored?
which organs are responsible for removing insulin and what ratio? (2)
• Stored within granules in β-cells of pancreas
• Half-life of circulating insulin is 3-5 minutes
• Two organs are responsible for removing
insulin from the circulation
– Liver (~60%)
– Kidney (35-40%)
ratio is reversed in diabetics
what are the sources of exogenous insulin?
what are the two types?
• Available as an OTC drug
• Usual solution strength is 100 units/mL
• Principal source is recombinant DNA (rDNA)
technology from human proinsulin gene, grow in vector
– Eli Lily uses E coli to make their human insulin (Humulin)
– Novo Nordisk uses yeast to make their human
insulin (NovoLog)
• Animal insulin (bovine & porcine) available
only through the special access program
- people may have adverse rxns to animal insulin
what is regular insulin?
duration of action?
– Recombinant DNA technology from the human
proinsulin gene (significantly reduced antigenicity)
– Short acting insulin (administer ~30 min before
having a meal)
– Clear solution
what is Neutral Protamine Hagedorn (NPH or N)?
– Produced by adding protamine to regular insulin
– Reduces the absorption rate from an injection site
resulting in an intermediate duration of action
– Highest variability of absorption (25-50%)
– Cloudy solution
- Endogenous proteases in body eat protamine, leading to a slower release of insulin in body
- used with regular insulin
- Mimic basal release of insulin - search for a better one
Rapid Acting Formulations (mimic meal-time
insulin) (3)
– Aspart (NovoRapid® - Novo Nordisk) – Glulisine (Apidra® - Sanofi Aventis) – Lispro (Humalog® - Lilly) ➢Duration of action ~4-5 hrs ➢Lowest variability of absorption (5%)
more costly
Long Acting Formulations (mimic basal insulin) (3)
– Glargine (Lantus® - Sanofi Aventis)
– Detemir (Levemir® - Novo Nordisk)
– Degludec (Tresiba® - Novo Nordisk – Approved
Sept 2015)
Once daily insulin
Preferred long acting insulin
NPH - variable in a patient and also variable for diff patients
what are unique properties of insulin glargine?
- what does added arginine do?
long acting insulin
2 arginine residues are added
– Two positive charges added to carboxyl terminus of B chain
– Isoelectric point shifts
– Molecules are less water soluble at the isoelectric point, therefore, glargine will precipitate out at physiologic pH so it is slowly absorbed
– This also means the pharmaceutical preparation for glargine is an acidic solution
When insulin glargine is injected into subcutaneous tissue, which is at physiologic pH, the acidic solution is neutralized. Microprecipitates of insulin glargine are formed, from which small amounts of insulin are released throughout a 24-hour period, resulting in a relatively stable level of insulin throughout the day
what are unique properties of insulin glargine?
- what does glycine do?
Glycine molecule (A chain)
Asn on 21 becomes Glycine
– Asparagine is degraded in acidic solution
– Replacement produces a more stable molecule
glargine once daily
Insulin Action/Pharmacology
what is the receptor type?
where does it act on?
what are the main actions/end goals?
what type of hormones is it and what does it mean?
• Free insulin binds to insulin receptors
– Intrinsic receptor tyrosine kinase activity
– Primarily the muscle, adipose tissue, and liver
– Promotes glucose uptake, glucose metabolism, and
energy storage in muscle
– Reduces endogenous glucose production by the liver
– Anabolic hormone
▪ Glycogen storage in liver
▪ Fat storage in adipose tissue
▪ Protein synthesis in muscle
Insulin Action/Pharmacology
- How does it lead to glycogen synthesis
– a lot of glycogen is stored as fuel source during fasting
- Inhibition of GSK3 prevents GSK3- mediated inhibition of GS
- Akt phosphorylates and inhibits GSK3
- GSK3 phosphorylates glycogen synthase (GS) to
prevent synthesis of glycogen/storage of glycogen
- Akt prevents this phosphorylation
- Now GS is active and stores glucose as glycogen
Insulin Action/Pharmacology
- How does it lead to stopping gluconeogenesis?
– Inhibition of FoxO1 reduces the transcription of numerous genes of gluconeogenesis (liver)
- Tells liver to stop making glucose - increases expression of genes used to make glucose from aa and lactate (during fasting) to make normal blood sugar levels
- Akt phosphorylates Fox01 (transc factor) and kicks it out of nucleus - can no longer turn on transcription
- Cannot make glucose
Insulin Action/Pharmacology
- How does it lead to protein synthesis?
– Activation of mTOR modifies numerous signaling molecules that turn on protein synthesis (muscle
– mTOR which is a master regulator of protein synthesis to turn on synth
Insulin Action/Pharmacology
- How does it shut of ketogenesis and reduce lipolysis? (2)
– Activation of Akt leads to increased phosphodiesterase 3B activity, which degrades cAMP,
and reduces lipolysis (adipose tissue)
- decreases mobilization of fat from tissue
– Reductions in lipolysis reduce circulating free fatty acid delivery to the liver, thereby reducing rates of ketone body production
– Insulin activates acetyl CoA carboxylase (ACC) in the liver, which produces malonyl CoA
• Inhibits fatty acid oxidation
• Promotes fatty acid biosynthesis
- In order to make ketone body, liver oxidizes fat to ketone body
- Reduces rate of oxidation of fat which DOES make it to the liver
– This collectively leads to an inhibition of ketogenesis
AE of insulin
hypocglycemia
– Localized lipodystrophy is either a loss or
hypertrophy of fatty tissue at the site of injection
▪ More common with animal source insulin
- Rotate injection sites to minimize this site
– Insulin allergy is rare resulting from localized
histamine release
▪ Likely caused by non-insulin components of solution
- IgE is the main one that can cause allergy
- Too much IgG = resistance to insulin
– Insulin resistance is very rare, caused by
development of anti-insulin antibodies in circulation
– Weight gain due to it being an anabolic hormone
Glucagon Action/Pharmacology
how does it affect hepatic glucose output?
Glucagon & Hepatic Glucose Output
– Glucagon activation of the glucagon receptor GPCR is linked to activation of Gs proteins and activation of AC, increasing cAMP levels & activating PKA
– Activates glycogen phosphorylase to mobilize liver glycogen stores for increases hepatic glucose output to maintain normoglycemia
• Glucagon pens (1 mg) can be injected intramuscularly or subcutaneously
– In hypoglycemic individuals that go unconscious, may restore consciousness within 15 min to allow sugar ingestion
- diabetics should carry pen for emergency
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
*1. 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
* 3. 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)
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)
Sodium Glucose Cotransporter 2 (SGLT2) Inhibitors
Name 4 (ending)
Canagliflozin (Invokana®),
Dapagliflozin (Forxiga®),
Empagliflozin (Jardiance®),
Ertugliflozin (Steglatro®)
newest therapy for type 2 diabetes
Sodium Glucose Cotransporter 2 (SGLT2) Inhibitors
MOA?
– Inhibit SGLT2 (SGLT2 inhibitors induces glucosuria, gluc excretion)
• Our kidneys filter 160-180 grams of glucose/day
• The vast majority of this glucose (up to 99%) is
reabsorbed by the kidneys (proximal tubule)
• Hyperglycemia increases both the amount of filtered
glucose and reabsorbed glucose by the kidneys
• SGLT2 is the primary mediator of glucose reabsorption
Sodium Glucose Cotransporter 2 (SGLT2) Inhibitors
what advantages does it have? (4)
▪ Does not cause hypoglycemia (glucose independent)
▪ Can be prescribed with other therapies for diabetes
▪ Are effective at all stages of type 2 diabetes
▪ Have beneficial effects on the cardiovascular system
- Almost every SGLT inhibitor shows benefits for CV functions
- Empagliflozin (Jardiance®)shows best outcomes for CV, may be a heart disease drug
Sodium Glucose Cotransporter 2 (SGLT2) Inhibitors
what disadvantages does it have? (4)
Sodium Glucose Cotransporter 2 (SGLT2) Inhibitors
what disadvantages does it have? (4)
▪ *Increases genital and urinary tract infections
-increasing glucose in urine - conducive of bacterial growth
▪ May increase hepatic glucose production (via increasing glucagon secretion?)
- SGLT2 in alpha cells in islets increases glucagon sec
▪ *May increase ketoacidosis
- can be due to increased fat oxidation with glucagon
- ketone bodies may lead to increased CV benefits with increased signaling pathways
▪ *Increased risk of amputation (only seen with
canagliflozin)
what are the pleiotropic effects of GLP-1 receptor agonism on glycemia?
5 locations
pancreas
- increase insulin (PRIMARY) and decrease glucagon secretion
liver
- dec glucagon reduce hepatic glucose production, decrease blood sugar levels
intestine
- GLP-1 is expressed in intestine, delay gastric emptying, delay absorption of sugar from eating
brain
- Lower food intake, reductions in appetite
- approved for obesity
adipose tissue
- decreased adiposity with low appetite
which drug shows some SGLT1 inhibitory action
• SGLT2 is expressed in the following tissues – Kidney – Islet α-cells • SGLT1 is expressed in the following tissues – Kidney – Heart – Small intestine ➢May delay intestinal glucose absorption ➢May enhance incretin hormone secretion - may be beneficial to inhibit SGLT1
- canagliflozin shows some SGLT1 inhibitory action
Incretin-Based Therapies - GLP-1 Receptor Agonists
MOA?
4 main actions
• promotes glucose stimulated insulin secretion
➢ Ability to enhance glucose-stimulated insulin secretion is glucose dependent, being more potent at higher plasma glucose levels
(low risk for hypoglycemia)
• inhibits glucagon secretion, which reduces hepatic
glucose production in patients with diabetes
• inhibits gastric emptying
➢ Delays appearance of nutrients (e.g. glucose) into the circulation
• inhibits appetite
➢ Leads to reductions in body weight and adiposity
Incretin-Based Therapies - GLP-1 Receptor Agonists
name 6 GLP-1 analogs that are resistant to DPP-4
what is their dosage form?
➢Exenatide (Byetta®) [T1/2 ~ 2 hours]
❖Synthetic version of the Gila monster salivary hormone, exendin-4
- DPP-4 can’t access
➢Liraglutide (Victoza®) [T1/2 ~ 12 hours]
❖Acylated GLP-1 analog that noncovalently binds to
albumin
- alanine still there but bind to albumin so DPP-4 can’t access
➢Albiglutide (Tanzeum®) [T1/2 ~ 4-7 days]
❖GLP-1 dimer fused to albumin
➢Lixisenatide (Lyxumia®) [T1/2 ~ 2.5 hours]
❖Structurally related to exendin-4
➢Semaglutide (Ozempic®) [T1/2 ~ 1 week]
❖Longer-acting alternative to liraglutide
• Proteins, therefore must be injected
➢ Can lead to formation of neutralizing antibodies
(exenatide)
- oral recently approved
