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59 Cards in this Set

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What cells synthesize insulin?
Beta cells of pancreatic islets secrete insulin as preproinsulin
In solution, insulin exists in what forms?

What form is stored in the granules of Beta cells?
insulin exists as monomer, dimer, or hexamer in soln

Hexamer is stored (much more stable form)
True or False: Because insulin is a well-conserved protein throughout the species, even the insulin taken from C. elegans (a worm) works in humans.
True.
IGF structure is homologous to:
proinsulin
IGFs are produced in many tissues and regulates ?
growth rather than metabolism
Islet of Langerhans is composed of what four types of cells and what hormone is synthesized by each?
Beta - insulin; primary glucose sensor
Alpha - glucagon
Delta - somatostatin
PP or F - pancreatic polypeptide
Insulin release is stimulated by:
*Glucose is primary stimulus
*Most potent GI hormones are gastrointestinal inhibitory peptide and glucagone-like peptide-1
*Gastrin, secretin, cholecystokinin, vasoactive intestinal peptide, gastrin-releasing peptide, and enteroglucagon
Step-by-Step process of insulin regulation by glucose within the pancreas
1) Glucose enters beta cell by facilitated diffusion by GLUT2
2) Glucose is phosphorylated by glucokinase (glucose sensor)
3) Glucose metabolism results in increase in ATP/ADP ratio (more ATP - glycolysis)
4) The increased ATP closes K+ channel leading to accumulation of K+ in cell
5) The positive cell charge causes depolarization to activate Ca++ channel and increase Ca++ influx
6) Ca++ activates phospholipase A2 and C to form IP3 and mobilize more Ca++ from ER
7) Large Ca++ concentration causes release of insulin
Degradation of insulin
*1/2 life = 5-6 min
*Occurs in live, kidney, and muscle
*Proteolytic degradation in liver occurs after internalization of hormone and its recepter complex
If you eat a whole bag of potato chips for dinner, what will happen assuming you are healthy?
Insulin production and release will increase
What does insulin do?
*Insulin is primary hormone controlling uptake, utilization, and storage of cellular nutrients
*Stimulates intracellular utilization and storage of glucose, AAs, and FAs; inhibits catbolic processes, such as breakdown of glycogen, fat, and protein
Regulation of glucose transport into muscle and adipose tissue
1) Stimulation of glucose transport
- stimulated by insulin
2) Glucose enters cells by facilitated diffusion through 1 of 5 glucose transporters (GLUT1 to GLUT5)
3) Glucose converted to G6-P by hexokinase (2 families regualted by insulin)

G6-P can enter 1 of 2 pathways:
a) glycolytic pathway and lead to production of ATP
b) glycogenesis after isomerization to G1-P
Hexokinase families
Hexokinase IV - glucokinase (GLUT2 in liver and pancreatic beta cells)
Hexokinase II (GLUT4 in skeletal and cardiac muscle & adipose tissue)
Liver glucokinase gene is regulated by insulin
Regulation of gene expression
(Insulin receptor binding)
A major action of insulin is regulation of gene transcription.

*Insulin binds to recepter causing dimerization
*Receptor itself has tyrosine kinase activity and phosphorylates Tyr
*IRS proteins (containing SH2 domain) are then phosphorylated to initiate kinase cascade
Diabetes mellitus is a group of syndromes characterized by:
hyperglycemia; altered metabolism of lipids, carbohydrates, and proteins; increased risk of complications from vascular disease
What % of patients in US have Type 1 diabetes and what % have Type 2?

How many people in the world have diabetes?
Type 1: 5-10%
Type 2: 90%

more than 125 million people have diabetes in the world
What factors contribute to diabetes or can cause diabetes?
contributing factors: increasing age, obesity, sedentary lifestyle, and low birth weight

Causing factors: mutations in insulin or other genes
*Maturity-onset diabaetes of youth (MODY), maternally inherited diabetes and deafness (MIDD)
Risk factors for DM
*family history
- identical twins show 70-80% concordance for type 2
- 70% prevalence for type 2 in off-spring of parents with diabetes

*Obesity - more than 20% overweight
- 80-90% of type 2 DM patients are obese

*Certain ethnic groups (Native americans, african americans, hispanics, polynesian islanders)
Type 1 DM and genetic factors
*Type 1 DM is caused by autoimmune disease of pancreatic beta cell
*Presence of high-titer islet-cell bodies and GAD Abs, or ICA combined with insulin autoAbs, confers high risk of type 1 DM in 1st-degree relatives
How does insulin lower glucose concentration in the blood?
by inhibiting hepatic glucose producation and stimulating uptake and metabolism of glucose by muscle and adipose tissue
the effects of insulin are opposed by:
glucagon (elevated in untreated patients) opposes insulin effects by stimulating glycogenolysis and gluconeogenesis in liver
Metabolism of insulin (how it affects protein, lipids, amino acids, etc)
*Insulin inhibits hormone-sensitive lipase in adipose tissue and inhibits hydrolysis of triglycerides
*Insulin counteracts the lipolytic action of catecholamines, cortisol, and growth hormone
* Insulin enhances transcription of lipoprotein lipase which increases level of LDL (hypertriglyceridemia and hypercholesterolemia occur in diabetes)
*Insulin stimulates AA uptake and protein synthesis and inhibits protein degradation
*Insulin decreases circulating concentrations of most AAs
Ketonemia in diabetes
*The liver produces ketone bodies by oxidation of fatty free acids.
- insulin inhibits lipolysis, stimulates fatty-acid synthesis, increasing malonyl CoA, and decrease producation of ketone bodies
- glucagon has the opposite effects

*In diabetes, the insulin deficiency and glucagon excess promote ketogenesis, lead to ketonemia and acidosis
vascular changes in diabetes
* thickening of capillary basement memebrane narrows vessel lumina
-inadequate perfusion of critical regions and organs
- contribute to major complications: premature atherosclerosis, intercapillary glomerulosclerosis, retinopathy, neuropathy, and ulceration and gangrene of extremities
toxic effect of hyperglycemia results from accumulation of:

What is glucose reduced to that contributes to toxicity?
nonenzymatically glycosylated products and osmotically active sugar alcohols in tissues, plus effects of glucose on cellular metabolism

*Glucose is reduced to sorbitol, which contributes to increased osmotic effects and tissue damage
Insulin therapy: what type it's used for? how adminstered? Brand of insulin?
Used for all type 1 and some type 2 DM patients

Administered IV or IM, long-term use is SubQ injection

Human insulin (Humulin, Novolin) is standard form
How are preparations of insulin classified?

What classification are these drugs? Lispro; glargine; NPH
according to duration of action: short, intermediate, long-acting

Lispro - rapid
glargine - slow
NPH - intermediate
Indications of insulin therapy
SubQ injection for:
type 1 DM patients, type 2 DM patients that aren't controlled by diet and/or oral hypoglycemic agents, and patients with postpancreatectomy diabets or gestational diabetes
Goal of insulin therapy
normalization of blood glucose and all aspects of metabolsim
*to achieve a fasting blood glucose concetration between 90-120 mg/dl and a 2-hour postprandial value below 150mg/dl
Factors affecting insulin absorption
*site of injection
*type of insulin
*SubQ blood flow: massage, hot bath, exercise increase absorption
*muscular activity at site of injection
*volume and concentration of insulin
*Depth of injection
What is most rapid insulin absorption site?
abdomen, followed by arm, buttock, and thigh
Which produces a more rapid onset of action for insulin absorption: IM or SubQ injection?
IM is more rapid
What is continuous subQ insulin infusion (CSII)? What are some possible problems with it?
An alternative to several daily injections in intensive insulin therapy. Pumps are used to provide a constant basal infusion at different rates.

*Mechanical problems may cause accidental interruption which causes insulin deficiency and ketoacidosis with high level of K+
*Possibility of SubQ abscesses and cellulitis
Adverse reactions of insulin therapy
*Most common is hypoglycemia
*Sweating, hunger, paresthesias, palpitations, tremo, and anxiety
*difficulty concentrating, confusion, weakness, drowsiness, feeling of warmth,dizziness, blurred vision, and loss of consciousness
*resistance and allergic reactions
Treatment of Ketoacidosis
*IV administration of insulin (0.1 U/kg/hour
*Blood glucose will fall by 10% an hour (acidosis corrected more slowly)
*glucose may be administered along with insulin to prevent hypoglycemia and remove all ketones
Types of sulfonylureas (name 1st and 2nd generation)
1st generation: tolbutamide, acetohexamide, tolazamide, chlorpropamide

2nd generation: glyburide (Micronase), glipizide (Glucotrol), glimepiride (Amaryl)
MOA of sulfonylureas
cause hypoglycemia by stimulating insulin release from pancreatic beta cells
ADME of sulfonylureas
*effectively absorbed from GI tract
*90-99% are bound to proteins in plasma (albumin), least for chlorpropamide and greatest for glyburide
*all metabolized in liver and excreted in urine (pts with liver or kidney problems must be careful in taking these drugs)
Which generation of sulfonylureas are more potent?
2nd generation drugs are 100 time more potent
* half-life 3-5hours
* duration 12-24 hours (can be given once daily)
Adverse reactions of sulfonylureas
*infrequent
*Severe: coma due to hypoglycemic reactions
* nausea, vomiting, cholestatic jaundice, agranulocytosis, aplastic and hemolytic anemias, generalized hypersensitivity reactions, dermatological reactions
*may induce hyponatremia
Sulfonylureas: indication, contraindications
Indication: hyperglycemia in type 2 DM patients

Contraindications: Type 1 DM, pregnancy, lactation, significant hepatic or renal insufficiency

* Continued dietary restrictions are essential
Initial daily dose for glyburide, glipizide, and glimepiride
Glyburide: 2.5-5mg
Glipizide: 5mg QD
Glimepiride: 0.5mg QD
Repaglinide (Prandin) - class; MOA; side effect; contraindication
Prandin = "lunch"

Class: meglitinide
MOA: stimulates insulin release by closing ATP-dependent K+ channels in pancreatic beta cells
Side effect: hypoglycemia
Contraindications: pts with hepatic or renal insufficiency
Nateglinide (Starlix) - derived from?; MOA; therapeutic effect; dosing
Derived from D-phenylalanine
MOA: stimulates insulin secretion by blocking ATP-sensitive K+ channels in pancreatic beta cells
Therapeutic effect: reduces postprandial glycemic elevations in type 2 DM patients
Dosing: taken 1-10 min before a meal at dose of 120mg
Metformin (Glucophage): class; Binding; Excretion; dose
Class: biguanide
Binding: does not bind to plasma proteins
Excretion: excreted unchanged in urine
Dose: 2.5g QD, taken in 3 div doses
Metformin (Glucophage) MOAs
*antihyperglycemic, NOT hypoglycemic

*Reduces glucose levels by:
1) decreasing hepatic glucose production (activate AMPK - kinase)
2) increasing insulin action in muscle and fat (somehow sensitize muscle receptors)
Name 2 thiazolidinediones
rosiglitazone (Avandia) and pioglitazone (Actos)
Thiazolidinediones MOA
They are selective agonists for nuclear peroxisome proliferator-activated receptor gamma (PPARgamma)
* They bind to PPARgamma, which activates insulin-responsive genes that regulate carb and lipid metabolism
- require insulin for their action
- lower insulin resistance in peripheral tissue, may also lower glucose production in liver

**Protect beta cells
Thiazolidinediones: dose, side effects, contraindications, and metabolism
Dose: rosiglitazone (Avandia) 1, 4, 8 mg QD and pioglitazone (Actos) 15, 30, 45mg QD

Side effects: edema, body weight gain, and CHF
Contraindications: pts with active hepatic disease
Metabolism: by the liver cytP450 enzymes
What is the best way to avoid diabetes?
Exercise!
2 and 1/2 hours of exercise per weak lowers incidence by 80%
For a pt who is recently diagnosed with Type 2 diabetes, the best drug to start with is?
Low dose of metformin and TZD

*2 drugs with different MOAs:
- TZD: protect beta cells and sensitize cells greatly
- Metformin: inhibt glucose production by liver and sensitive muscle cells

*Also, TZD lowers the diarrhea side effect of metformin
alpha-Glucosidase Inhibitors: Types and MOA
*acarbose (Prescose) and miglitol (Glyset)
*MOA: reduce intestinal absorption of starch, dextrin, and disaccharides by inhibiting the action of intestinal brush border alpha-glucosidase

*Don't stimulate insulin release and don't cause hypoglycemia
*may be sued as monotherapy in elderly patients or in patients with predominantly postprandial hyperglycemia
Where is glucagon synthesized and by what premolecule?
Produced in pancreatic alpha cells and synthesized by preproglucagon
Glucagon secretion is regulated and inhibited by what?
Regulated by: dietary glucose, insulin, amino acids, and fatty acids

Inhibited by: somatostatin, free fatty acids, and ketones
Is glucagon increased or decreased in poorly controlled diabetic patients?
Increased - exacerbates the hyperglycemia

*In normal individuals, glucagon secretion is increased in hypoglycemia. This defense mechanism is lost in type 1 DM patients with insulin-induced hypoglycemia
Glucagon MOA
Glucagon binds to a GPCR, which activates Gs, which activates adenylyl cyclase to produce more cAMP.
*cAMP activates phosphorylase (rate-limiting enzyme in glycogenolysis) while inactivated glycogen synthase
- THUS enhances glycogenolysis and inhibits glycogen synthesis
Glucagon is used to treat:
sever hypoglycemia
What does Glucagon-like peptide 1 do?
*augments glucose-dependent insulin secretion
*reduces glucagon secretion, slows gastric empyting, and decreases appetite
Name 2 drugs that are GLP-1 receptor agonsists
exendin-4 (Byetta) and sitagliptin (Januvia)