Endocrine Pharmacology Pancreatic Hormones Diabetes Mellitus Flashcards
What are some insulin preparations, sulfonylureas, biguanides, thiazolidinedones, glucosidase, and hyperglycemic agents
—-Insulin preparations
Lispro
Regular
NPH
Detemir
Glargine
—-Sulfonylureas
Glyburide
—-Biguanides
Metformin
—-Thiazolidinediones
Rosiglitazone
—-Glucosidase inhibitors
Acarbose
—–Hyperglycemic agents
Glucagon
Diazoxide
Where is the pancreas and what are the endocrine islets within it and their functions
Sits between duodenum and spleen, inferior and posterior to the stomach
Endocrine: Islets of langerhans INSULIN COMPONENT
a-cells: secrete glucagon, increases blood glucose by mobilizing glycogen stores
b-cells: secrete insulin, decreases blood glucose by stimulating cellular uptake
s-cells: secrete somatostatin, universal inhibitor of hormone secretion
Exocrine: pancreatic acini digestive enzymes-small intestines.. connected to intestines
what is the cycle of regulation of blood glucose
Food– higher blood glucose–b-cells release insulin which stimulate glucose uptake by peripheral tissues–between meals… lower blood glucose–a cells release glucagon which stimulates glycogen breakdown and gluconeogenesis
State what insulin is, what glucagon is, what glucocorticods are and when the metabolic action for each of these: Glycogen synthesis, glycolysis (energy release), lipogenesis, protein synthesis, glycogenolysis, gluconeogenesis, lipolysis, ketogenesis
Insulin= anabolic
Glucagon=catabolic
Glucocorticods=catabolic
Glycogen synthesis
insulin: ↑
Glucagon: ↓
Glycolysis (energy release)
insulin:↑
Glucagon:↓
Lipogenesis
insulin:↑
Glucagon:↓
Protein synthesis
insulin:↑
Glucagon:↓
Glycogenolysis
insulin:↓
Glucagon:↑
Gluconeogenesis
insulin:↓
Glucagon:↑
Lipolysis
insulin:↓
Glucagon:↑
Ketogenesis (production of ketone bodies)
insulin:↓
Glucagon:↑
What is ketogenesis and ketone bodies and what does it mean for the body and how does insulin play a role
Low blood sugar!
In ketogenesis: body fat breaks down to meet energy needs,
Keto compounds called ketone bodies form (ketone bodies form keto acids)
acidosis
Ketone bodies are: a major fuel in some tissues; they diffuse from the liver mitochondria into the blood which then is transported to peripheral tissues
heart muscle and renal cortex use acetoacetate in preference to glucose in physiological conditions
the brain adapts to acetoacetate in starvation and diabetes
Insulin inhibits ketogenesis; diabetes, low insulin- higher glucose ketogenesis + ketone bodies (acidic)
Insulin; what is it, where is it produced, and what stimulates its release
Peptide hormone with 2 chains linked by disulfide bonds (51 amino acids)
-produced and secreted by b-cells of the islets of langerhans
-release of insulin is stimulated by glucose in the blood; as well as: incretins, glucagon-like peptides
how does glucose stimulate insulin secretion by Beta-cells
- glucose rise after you eat (especially sugary foods), glucose gets taken up by the glucose transporter GLUT4
- Glucose is metabolized to yield ATP
- ATP inhibits ATP-sensitive potassium (Katp) channels causing the membrane depolarization
The depolarization opens V-gated Calcium channels and Ca2+ comes in to trigger release of insulin
GLUT4 + characteristics, tissue
Muscle, adipocytes-dependent on insulin
Defect in GLUT4 associated with major factor in insulin resistance
What channels regulate the release of insulin
REMEMBER: depolarization=more insulin
K-ATP channels
Depolarization gives rise to CA2+
Diazoxide hyperpolarizes
Glyburide depolarizes
Mutations give rise to persistent hyperinsulinemic hypoglycemia of infancy (PHHO)
Anabolic effects of insulin + its main function
To facilitate glucose uptake and promote cell growth (these result in lower blood glucose)
Liver: inhibits glygenolysis, formation of keto acids+gluconeogenesis
Muscle:
increases protein synthesis
increases glucose transport + glycogen synthesis
Adipocytes:
increases glucose transport and triglyceride storage
Insulin signaling
Insulin receptor= tyrosine kinase, when activated it phosphorylates itself and other proteins: IRS (insulin receptor substrates), leads to widespread anabolic and mitogenic effects, regulation of gene expression
activation of PI-3 kinase pathway stimulates translocation of glucose transporters (GLUT4) to the cell surface, an event that is critical for glucose uptake by skeletal muscle and fat
What is the schematic model for glucose-dependent regulation in the a-cell
glucagon: peptide
Glucagon secretion:
-Blood glucose <70 mg/dL
-high levels of circulating AA
-sympathetic and parasympathetic stimulation
-catecholamines
-cholecytokin, gastrin and GIP
Low glucose membrane potential allows for V-gated T and N channels to open for CA and Na to rush in the CA influx makes glucagon release.
High glucose elevates ATP.ADP and blocks KATP channels and blocks glucagon release
what is diabetes mellitus and what is type 1 and type 2
A group of diseases characterized by high blood glucose levels from bodies inability to produce or use insulin
affects 15 million 15% type 1 85% type 2
Type 1: not enough insulin made because ofdestruction of pancreatic b-cells, patients have to take insulin to live
Type two: starts with insulin resistance and then insulin production reduces
Gastational diabetes-high blood glucose, congenital diabetes, other secondary to other diseases, cyctic fibrosis excess GC (referred to as type 3 +4)
What are some things that can happen to unregulated diabetes mellitus
acute=diabetic coma
ketoacidosis: low levels of insulin cause the liver to breakdown fat forming toxic acidic ketone bodies
Hyperosomolarity: excessive glucose in blood draws water from cells causing dehydration
Chronic: microvasual damage, cardiomyopathy, nephropathy, retinopathy, neuropathy, poor wound healing, macrovasual damage- accelerated athroslerosis, heart attack, stroke, dementia, peripheral vascular disease
how is insulin administered and what are the differences in onset and duration
subcutaneous injection
Ultra-short: Insulin lispro: rapid onset within 5-15 minutes, peak after 1-2 hours, duration 4-5 hours
Short: Regular insulin: onset within 30-60 minutes, peak 3 hours, duration 6-8 hours
Intermediate: NPH: onset within 2-5 hours, peak after 4 hours, duration 4-12 hours
Long: Insulin detemir: onset within 1-2 hours, peak after 8-14 hours, duration 18-30 hours
Long: Insulin glargine: onset within 1-1.5 hours, peak after 4-5 hours, duration 11-24 hours
know basics
Insulin lispro vs regular
Insulin lispro: rapid onset
-taken before meal
-mimics normal prandial insulin
-short duration, low risk hypoglycemia
Regular insulin:
slower onset than insulin lispro
-THE ONLY KIND of inulin that can be given intravenously to treat ketoacidosis
Insuling NPT and Detemir vs Insulin Glargine
Insulin NPH: intermediate acting; delayed from combinging insulin with protamine. NPH my be combined with a faster acting insulin for better glucose control
Insuling Detemir is most recently developed lon-lasting insulin
Insulin glargine: Glargine is soluble in acidic solution, but precipitates in more neutral interstitial enviro after subcutaneous injection- forms a crystalline depot of insulin, has slow onset and long duration
you only need to know which is most recent and that these are longer lasting
How is insulin administered and why
subcutaneous injection; it is rapidly degraded in GI, particles too large for transdermal, can be injected using transdermal pump
Inhalation: has to be small enough to pass through alveoli, it was successful to correct levels after eating but not providing basal insulin, removed from market in 2007 bc poor sales and expensive + didn’t fully replace injection
bionic pancreas
Replace fingerstick tests + manual insulin injections for type 1, will adjust insulin every 5 minutes
C-peptide connection; what does it do
Marker for how much glucose has been produced in a longer period of time (2-3 months)..reflects levels of glucose
connecting peptide-31 AA produced with cleavage of proinsulin and stored in equimolar amounts with insulin in secretory granules
-binds to neuronal, endothelial and renal cells to G-protein-coupled recepor
-activates CA2+ leading to increased NA+ K+ ATP and eNOS
what are some complications to insulin therapy
Hypoglycemia: presents as autonomic hyperactivity
-sympathetic: tachycardia, palpitations, sweating, tremors
-para: nausea, hunger
Severe cases: coma, cunvolsion
treatment: sweet drinks, if out: intravenously glucose infusion, honey in buccal pouch
Immunogenicity:
-antibodies against insulin can neutralize insulin
-allergic reactions to contaminations in insulin preparation
Non-insulin treatments for type 2
-stimulate insulin production by pancreatic B cells or increase glucose uptake
-mostly used for type 2 diabetes
-oral administration
-many type 2 diabetics eventually need both insulin and non-insulin treatments
Insulin and secretagogues: sulfonylureas
Sulfonylureas bypass the glucose pathway to directly inhibit KAPT channels and increase insulin by Beta cells
2nd generation: Glyburide:
more potent than tolbutamide, contraindicated in patients with hepatic impairment and renal insufficency
sulfonyluras; how is it administered? how does it work? what is its caveat? what is its side effects
Oral
How it works: inhibit potassium efflux through KATP cannels in pancreatic islet beta cells= depolarization (CA influx, insulin influx)
-stimulates insulin production
Caveat: Katp channels found on other cells, but pancreatic beta cells Katp have the highest affinity for sulfonylureas, so at the right dose it is the safest with little side effects
Side effects: Hypoglycemia (most common), weight gain, Gi disturbances like nausea and vomiting, discontinuation therapy
Meglitinides what is it and whats the onset
drug(Repaglinide); as sulfonylureas they block Katp channels at a different site and increase insulin secretion: more rapid onset, but long-term safety is not determined
Biguanides euglycemic agents: prototype drug and what they do generally + side effects
Prototype: metformin
orally
requires insulin for efficacy
Metformin increases glucose uptake but NO IMPACT on secretion of insulin
Mechanism of action not understood
Generally: decrease risk of cardiovasual disease, can prevent devlopment of diabetes type 2 in obsese middle aged prediabetics
metformin does not lead to weight gain or hypoglycemia
SIDE EFFECTS: gastrointestinal (anorexia, nausea), discontinuation bc diarrhea, lactic acidosis(so can’t used i ppl with renal or hepatic disease, alcoholism, or condition predisposing to tissue anoxia)
Alpha-glucosidase inhibitor what does it do what is the drug associated with it and how is it taken, what does it do, what are side effects
block glucose (sugar) uptake through the GI tract
acarbose: compeitive
oligosaccharide inhibitor of a-glucosidase an enzyme that has to do with absorption of complex starches + sugars from small intestine by breaking it down into simplar sugars
inhibition LEADS to less sugar absorption= so = less postprandial glucose in the blood
ORALLY
SIDE EFFECTS: sugars not absorbed are fermented by bacteria= flatulence + diarrhea
What drug leads to sensitization to insulin in muscle and liver and promotion of glucose uptake and utilization in adipocytes
Thiazolidinediones… also known as glitazones;
rosiglitazone activates peroxisome proliferator-activator receptors PPARy- these are NUCLEAR receptors that regulate transcription of genes w/lipid and glucose metabolism and insulin signal transduction in muscle, adipocytes and hepatocytes… which leads to the questions above
taken: orally
glitazones side effects
bc they act through transciption the on/offset is slow and takes several weeks where as rosiglitazone is rapidly absorbed
Side effects: when combined w/ insulin therapy: hypoglycemia, water retention (edema)
incretin-based therapy: what does it do, what is its peptide like, how often is injection, and what are the side effects
incretins are peptide hormones that stimulate insulin secretion; inhibit glucagon; promotes satiety after meal
Glucagon-like peptide 1=exenatide which must be injected twice daily
Side effects: nausea/vomiting
Incretins are degraded by DPP4 and so inhibitors for DDP4 are effective in treatment ex. Sitagliptin
Glucagon; what and how
its metabolized and inactivated by the liver, kidney in plasma and at its target cells, this results in short half-life (3-6 min)
acts on liver to promote gluconeogenesis and glycogenolysis
acts through activation od adenylyl cyclase, which results in production of cAMP; can mimic effects of beta-adrenergic receptor stimulation
-therapeutic use: mostly hypoglycemia
Diazoxide; info about it
is a thiazide but has no diuretic action
-reduces the release of insulin by opening KAPT channels in the b-cells of pancreatic islets… LEADS TO: hyperpolarization, reduced ca, reduced insulin secretion
Orally; to reduce insulin secretion and increase blood glucose
useful for: hyperinsulinism due to insulinoma (insulin-secreting tumor)
what causes insulin resistance
-decrease in receptor concentration
-decrease in tyrosine kinase activity
-changes in concentration + phosphorylation of IRS-1 + IRS-2 (insulin receptor substrates that transmit intracellular signals in response to insulin)
-decrease PI3-kinase activity
-decrease in glucose transporter (GLUT) translocation
-change in the activity of intracellular enzymes
3 primary storages of glucose
liver, fat tissue, and muscle tissue
MUSCLE AND FAT = insulin-dependent glucose transporters
glucose needs to go in most cells
KAPT and release of insulin
Depolarization- influx of Ca2+, insulin
Diazoxide: activator of KAPT, hyperpolarize, REDUCES Ca2+, inhibit insulin
Glyburide: sulfonylurea drug inhibits KAPT, depolarizes, increases Ca2+, insulin
Mutation in KATP give rise to PUUI
