Endocrine Pharmacology Pancreatic Hormones Diabetes Mellitus

Question 1

What are some insulin preparations, sulfonylureas, biguanides, thiazolidinedones, glucosidase, and hyperglycemic agents

Answer 1

—-Insulin preparations
Lispro
Regular
NPH
Detemir
Glargine
—-Sulfonylureas
Glyburide
—-Biguanides
Metformin
—-Thiazolidinediones
Rosiglitazone
—-Glucosidase inhibitors
Acarbose
—–Hyperglycemic agents
Glucagon
Diazoxide

Question 2

Where is the pancreas and what are the endocrine islets within it and their functions

Answer 2

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

Question 3

what is the cycle of regulation of blood glucose

Answer 3

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

Question 4

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

Answer 4

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:↑

Question 5

What is ketogenesis and ketone bodies and what does it mean for the body and how does insulin play a role

Answer 5

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)

Question 6

Insulin; what is it, where is it produced, and what stimulates its release

Answer 6

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

Question 7

how does glucose stimulate insulin secretion by Beta-cells

Answer 7

1. glucose rise after you eat (especially sugary foods), glucose gets taken up by the glucose transporter GLUT4
2. Glucose is metabolized to yield ATP
3. 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

Question 8

GLUT4 + characteristics, tissue

Answer 8

Muscle, adipocytes-dependent on insulin

Defect in GLUT4 associated with major factor in insulin resistance

Question 9

What channels regulate the release of insulin

Answer 9

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)

Question 10

Anabolic effects of insulin + its main function

Answer 10

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

Question 11

Insulin signaling

Answer 11

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

Question 12

What is the schematic model for glucose-dependent regulation in the a-cell

Answer 12

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

Question 13

what is diabetes mellitus and what is type 1 and type 2

Answer 13

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)

Question 14

What are some things that can happen to unregulated diabetes mellitus

Answer 14

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

Question 15

how is insulin administered and what are the differences in onset and duration

Answer 15

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

Question 16

Insulin lispro vs regular

Answer 16

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

Question 17

Insuling NPT and Detemir vs Insulin Glargine

Answer 17

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

Question 18

How is insulin administered and why

Answer 18

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

Question 19

bionic pancreas

Answer 19

Replace fingerstick tests + manual insulin injections for type 1, will adjust insulin every 5 minutes

Question 20

C-peptide connection; what does it do

Answer 20

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

Question 20

what are some complications to insulin therapy

Answer 20

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

Question 21

Non-insulin treatments for type 2

Answer 21

-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

Question 22

Insulin and secretagogues: sulfonylureas

Answer 22

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

Question 23

sulfonyluras; how is it administered? how does it work? what is its caveat? what is its side effects

Answer 23

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

Question 24

Meglitinides what is it and whats the onset

Answer 24

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

Question 25

Biguanides euglycemic agents: prototype drug and what they do generally + side effects

Answer 25

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)

Question 26

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

Answer 26

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

Question 27

What drug leads to sensitization to insulin in muscle and liver and promotion of glucose uptake and utilization in adipocytes

Answer 27

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

Question 28

glitazones side effects

Answer 28

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)

Question 29

incretin-based therapy: what does it do, what is its peptide like, how often is injection, and what are the side effects

Answer 29

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

Question 30

Glucagon; what and how

Answer 30

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

Question 31

Diazoxide; info about it

Answer 31

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)

Question 32

what causes insulin resistance

Answer 32

-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

Question 33

3 primary storages of glucose

Answer 33

liver, fat tissue, and muscle tissue

MUSCLE AND FAT = insulin-dependent glucose transporters

glucose needs to go in most cells

Question 34

KAPT and release of insulin

Answer 34

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