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59 Cards in this Set
- Front
- Back
What cells synthesize insulin?
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Beta cells of pancreatic islets secrete insulin as preproinsulin
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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) |
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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.
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True.
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IGF structure is homologous to:
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proinsulin
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IGFs are produced in many tissues and regulates ?
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growth rather than metabolism
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Islet of Langerhans is composed of what four types of cells and what hormone is synthesized by each?
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Beta - insulin; primary glucose sensor
Alpha - glucagon Delta - somatostatin PP or F - pancreatic polypeptide |
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Insulin release is stimulated by:
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*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 |
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Step-by-Step process of insulin regulation by glucose within the pancreas
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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 |
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Degradation of insulin
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*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 |
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If you eat a whole bag of potato chips for dinner, what will happen assuming you are healthy?
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Insulin production and release will increase
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What does insulin do?
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*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 |
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Regulation of glucose transport into muscle and adipose tissue
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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 |
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Hexokinase families
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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 |
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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 |
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Diabetes mellitus is a group of syndromes characterized by:
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hyperglycemia; altered metabolism of lipids, carbohydrates, and proteins; increased risk of complications from vascular disease
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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 |
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What factors contribute to diabetes or can cause diabetes?
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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) |
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Risk factors for DM
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*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) |
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Type 1 DM and genetic factors
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*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 |
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How does insulin lower glucose concentration in the blood?
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by inhibiting hepatic glucose producation and stimulating uptake and metabolism of glucose by muscle and adipose tissue
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the effects of insulin are opposed by:
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glucagon (elevated in untreated patients) opposes insulin effects by stimulating glycogenolysis and gluconeogenesis in liver
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Metabolism of insulin (how it affects protein, lipids, amino acids, etc)
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*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 |
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Ketonemia in diabetes
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*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 |
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vascular changes in diabetes
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* 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 |
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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 |
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Insulin therapy: what type it's used for? how adminstered? Brand of insulin?
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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 |
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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 |
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Indications of insulin therapy
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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 |
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Goal of insulin therapy
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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 |
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Factors affecting insulin absorption
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*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 |
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What is most rapid insulin absorption site?
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abdomen, followed by arm, buttock, and thigh
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Which produces a more rapid onset of action for insulin absorption: IM or SubQ injection?
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IM is more rapid
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What is continuous subQ insulin infusion (CSII)? What are some possible problems with it?
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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 |
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Adverse reactions of insulin therapy
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*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 |
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Treatment of Ketoacidosis
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*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 |
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Types of sulfonylureas (name 1st and 2nd generation)
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1st generation: tolbutamide, acetohexamide, tolazamide, chlorpropamide
2nd generation: glyburide (Micronase), glipizide (Glucotrol), glimepiride (Amaryl) |
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MOA of sulfonylureas
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cause hypoglycemia by stimulating insulin release from pancreatic beta cells
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ADME of sulfonylureas
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*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) |
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Which generation of sulfonylureas are more potent?
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2nd generation drugs are 100 time more potent
* half-life 3-5hours * duration 12-24 hours (can be given once daily) |
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Adverse reactions of sulfonylureas
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*infrequent
*Severe: coma due to hypoglycemic reactions * nausea, vomiting, cholestatic jaundice, agranulocytosis, aplastic and hemolytic anemias, generalized hypersensitivity reactions, dermatological reactions *may induce hyponatremia |
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Sulfonylureas: indication, contraindications
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Indication: hyperglycemia in type 2 DM patients
Contraindications: Type 1 DM, pregnancy, lactation, significant hepatic or renal insufficiency * Continued dietary restrictions are essential |
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Initial daily dose for glyburide, glipizide, and glimepiride
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Glyburide: 2.5-5mg
Glipizide: 5mg QD Glimepiride: 0.5mg QD |
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Repaglinide (Prandin) - class; MOA; side effect; contraindication
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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 |
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Nateglinide (Starlix) - derived from?; MOA; therapeutic effect; dosing
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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 |
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Metformin (Glucophage): class; Binding; Excretion; dose
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Class: biguanide
Binding: does not bind to plasma proteins Excretion: excreted unchanged in urine Dose: 2.5g QD, taken in 3 div doses |
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Metformin (Glucophage) MOAs
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*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) |
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Name 2 thiazolidinediones
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rosiglitazone (Avandia) and pioglitazone (Actos)
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Thiazolidinediones MOA
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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 |
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Thiazolidinediones: dose, side effects, contraindications, and metabolism
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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 |
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What is the best way to avoid diabetes?
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Exercise!
2 and 1/2 hours of exercise per weak lowers incidence by 80% |
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For a pt who is recently diagnosed with Type 2 diabetes, the best drug to start with is?
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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 |
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alpha-Glucosidase Inhibitors: Types and MOA
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*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 |
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Where is glucagon synthesized and by what premolecule?
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Produced in pancreatic alpha cells and synthesized by preproglucagon
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Glucagon secretion is regulated and inhibited by what?
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Regulated by: dietary glucose, insulin, amino acids, and fatty acids
Inhibited by: somatostatin, free fatty acids, and ketones |
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Is glucagon increased or decreased in poorly controlled diabetic patients?
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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 |
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Glucagon MOA
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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 |
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Glucagon is used to treat:
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sever hypoglycemia
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What does Glucagon-like peptide 1 do?
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*augments glucose-dependent insulin secretion
*reduces glucagon secretion, slows gastric empyting, and decreases appetite |
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Name 2 drugs that are GLP-1 receptor agonsists
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exendin-4 (Byetta) and sitagliptin (Januvia)
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