Diabetes

Question 1

Type 1 vs Type 2 DM?

Answer 1

• Type I Diabetes
  
  • Cells that produce insulin are destroyed
  • Results in insulin dependence
  • Commonly detected before 30
• Type 2 Diabetes (9x more common compared to type 1)
  
  • Blood glucose levels rise due to
    
    • 1) Lack of insulin production
    • 2) Cells resistant to insulin action
  • Strongly a/w obesity
  • 40% Americans are pre-diabetic.
  • Commonly detected after 40
  • Eventually leads to β-cell failure, resulting in insulin dependence

Question 2

What is gestational diabetes?

Answer 2

• 3-5% of pregant women in US develop gestational daibetes (diabetes during pregnancy)
• typically resolves after baby born
• higher likelihood of developing T2DM later in life

Question 3

How is insulin produced and released?

Answer 3

• Peptide hormone produced in pancreas by β cells –> islets of Langerhans
• β cells have channels in their plasma membrane that serve as glucose detectors
• β cells secrete insulin in response to a rising level of circulating glucose
• GLUT 2 receptors (insulin independent), allow glucose to flow into beta cells by concentraiton gradient.
• Glucose with glucokinase–> glucose 6 phosphate which is oxidized–> Increase ATP
• Increase ATP causes K channels to close, allowing K to stay inside cell, causing depolarization
• Depolarization allows Ca channels to open, Ca enters cell tirggering release of insulin
• Insulin is released as proinsulin, cleavage of C chain makes active form

Question 4

What is proinsulin?

Answer 4

• insulin is released as proinsulin - precursor molecule
• Insulin is a small protein consisting of a chain of 21 amino acids linked by two disulfide (s-s) bridges to a b chain of 30 amino acids
• Cleavage of C chain creates active form of insulin

Question 5

Insulin MOA?

Answer 5

• Insulin binds to plasma membrane receptors initiating an intracellular cascade of enzymatic events (Phosphorylation of tyrosine residues–> phosphorylate many other enzymes and activate them)
• • Glucose diffusion into cells (after GLUT2 placed on membrane)
    
    • Glucose storage mode (glycogen synthetase)
      
      • puts cell in anabolic state
    • Uptake of amino acids, phosphate, potassium & magnesium
    • Protein synthesis & inhibition of proteolysis
      
      • puts cell in anabolic state
    • ↑fatty acid and triglyceride synthesis ;↓lipolysis
    • Regulate DNA/gene expression via insulin regulatory elements
• All tissues express insuiln. higher % on liver, muscle, adipose tissue (neurons do not need insulin for gluocse upatke)

Question 6

What is endogenous insulin physiology?

Answer 6

• Portal circulation receives basal rate of 1 U per hour
  
  • always have basal insuline going in body
  • goal of long acting insulin is to imitate this
• With meals this rate of insulin secretion increases 5-10X
• 40 U is average daily requirement
• “Units” is a term used to quantify potency (i.e. ability to decrease serum BS)
• ANS does influence insulin secretion
  
  • Alpha↓
  • Beta & PSNS ↑
    
    • even though alpha decreases insulin secretion, Beta 2 is more dominant
    • if lots of epi circulating, increase insulin release overall

Question 7

Who needs insulin therapy?

Answer 7

• Type I diabetes patients
  
  • Insulin dependent
  • Body produces no insulin
• Type 2 diabetes patients
  
  • Do not always produce enough insulin
• Treatment via subcutaneous injection or intravenous injection for acute/peri-op control
  
  • periods on incrase glucose load (infection, stress, surgery).
  • epi stimulates glucose release, T2DM can’t respond as well and may need insuin in periop period.

Question 8

What was the insulin drug evolution?

Answer 8

• Stage 1 Insulin was extracted from the glands of cows and pigs. (1920s)
  
  • different AA in beef insulin vs human, can recognize beef insulin as foreign and cause immune reaction
• Stage 2 Convert pig insulin into human insulin by removing the one amino acid that distinguishes them and replacing it with the human version.
• Stage 3 - Insert the human insulin gene into E. coli and culture the recombinant E.coli to produce insulin (trade name = Humulin®). Yeast is also used to produce insulin(trade name =Novolin®) (’87).
  
  • this eliminiated the AA acid diff
• Recombinant DNA technology has also made it possible to manufacture slightly-modified forms of human insulin that work faster (Humalog® and NovoLog®) or slower (Lantus®) than regular human insulin.
  
  • alter AA to make ultra-rapid acting insulin
  • decreases the likelihood for the ultra rapid insulin to aggregate (like normal insuline)
  • this allows the ultra rapid insulin to work quickly

Question 9

What are the types of insulin?

Answer 9

Ultrarapid-Acting- 15 min onset, prevents aggregation of insulin and allows it to work faster. Given immediately before meal

• Lispro (Humalog)
• Aspart (Novolog)
• Glulisine (Apidra)

Short-Acting- has zinc ion that helps with stability of molecule. Given around meals as well

• Regular (Humulin R, Novolin R)

Intermediate-Acting (given in anticipation of meal) 6-8 hours later

• NPH (Humulin N, Novolin N) (NPH- Neutroal Protamine Hagedorn)
  
  • increase risk of immune response from protamine if people take NPH insulin and given huge amoung of proatmine (ie after CPB).
    
    • increase risk for anaphylaxis reaction with protamine

Long-Acting- (provides baseline insuline over time, avoiding peak)

• Glargine (Lantus) - no peak
• Detemir (Levemir)
• Ultralente

Question 10

Why is it important to know SQ insulin peaks, DOA?

Answer 10

NEED TO KNOW SQ PEAKS.

• If patient takes personal insulin SQ, need to know when patient can be at increased risk for hypoglycemia and check BG
• Anesthesia masks s/s of hypoglycemia, including sz. If patient severely hypoglycemic during sx, they possible won’t wake up after sx

Question 11

Insulin administration considerations?

Answer 11

• Parenteral only - SQ most common
• Inhaled - discontinued Jan 2008 now available again
• Rapid-acting convenient - can be injected minutes before a meal
• Mixtures containing Regular/NPH or Rapid/NPH
  
  • If injected before breakfast, R covers breakfast, NPH covers lunch
  • If injected before dinner, R covers dinner, NPH covers night
• Long-acting - mimics basal insulin secretion
  
  • Can give rapid-acting to cover each meal
• Compatibilities: do not mix glargine (long acting) with any others

Question 12

Pharmacokinetics of IV Regular Insulin?

Answer 12

• E1/2t IV bolus dose of insulin 5-10 minutes
  
  • IV insulin doesn’t aggregate like SQ insulin can
• Insulin tightly binds to receptors and therefore has a duration of action much longer than clearance would predict (30-60 minutes)
  
  • intracellular events last much longer
• Proteolytic enzyme metabolizes insulin in the liver and kidneys
  
  • normal physiology releases much more insulin than we actually need because so much is metabolized in liver
• Only the U-100 (100units/ml) formulation should be used IV.
  
  • An U-500 preparation is available for insulin resistant patients but should never be given IV

Question 13

RAPID acting example, SQ onset, peak, duration, usage?

Answer 13

Lispro

• Onset 10-15 min
• Peak 30 min- 1 hours
• Duration 3-5 hours
• Usage- meals or acute hypglycemia

Question 14

Short acting example, SQ onset, peak, duration and usage?

Answer 14

REGULAR

• Onset 30-60 min
• Peak 1-5 hours
• Duraiton 5-8 hours (up to 10 hours)
• Usage- meals or acute hyperglycemia

Question 15

Intermediate acting example, onsetm, peak, duration, usage?

Answer 15

NPH

• Onset- 1-2 hours
• Peak 6-10 hours
• duration 16-20 hours
• Usage- provide basal insuiln, overnight

Question 16

Long acting example, SQ Onset, peak, duration, usage?

Answer 16

Glargine

• Onset 2-6 hours
• Peak- no peak
• Duration 24 hours
• USAGE- BASAL INSULIN, OVERNIGHT

Question 17

Ultra long acting example, SQ Onset, peak, duration, usage?

Answer 17

Degludec

• Onset 2 hours
• peak no peak
• duraiton > 40 hours
• usage- provide basal insulin, overnight

Question 18

Insulin adverse reactions? Contraindication/?

Answer 18

• Adverse Effects
  
  • injection site rxns, lipodystrophy at injection site, protamine allergy, weight gain
• Major danger is hypoglycemia resulting from absence of adequate carbohydrate intake
  
  • Symptoms: diaphoresis, tachycardia, hypertension (epi response attempts to raise BS), CNS agitation, seizures, coma
• Contraindication: hypoglycemia

Question 19

Administration of home insulin?

Answer 19

• Requires ability of patient to draw up correct dosage and inject insulin
• More convenient delivery methods
  
  • Insulin Pens
  • Jet injectors (needleless, high pressure air mechanism)
  • Insulin Pumps- typically d/c for sx . each hospital has it’s own policies/procedures around how these are handled around periop period

Question 20

Drug interaction with insulin?

Answer 20

• ACTH, glucagon, and estrogens oppose the hypoglycemic effects of insulin- working against lowering BG levels because these increase BG
• Epinephrine decreases release of insulin and stimulates mobilization of glucose (glycogenolysis)
  
  • Amount of glucose released with epinephrine is much more significant than the amount of insulin released with epi stimulation so BG goes sky high
• DOA prolonged by tetracycline, chloramphenicol, salicylates
• MOAIs can increase hypoglycemic effects

Question 21

Insulin concentration? What is decrease of BG with admin 1 unit of insulin in Type 1 DM? T2DM?

Answer 21

• Highly Concentrated
  
  • 100units/ml most common
  • Use specialized insulin syringe to reduce risk of error

Dosing Regimen Varies Considerably (in literature, among practitioners and institutions)

• Type I DM – assume 1 u insulin will ↓ BS by 40-50 mg/dL
• Type II DM – assume 1 u insulin will ↓BS by 30-40 mg/dL
• Individual sensitivity to insulin is highly variable
  
  • in one patient you may see 1 u changing BS by 50 mg/dL
  • in another you may see 1 u changing BS by 10mg/dL

Question 22

Debate b/w tight & non tight control BG?

Answer 22

• Tight control of blood glucose levels reduces the risk of chronic complications in Type I diabetics.
• Normalizing blood glucose in the diabetic patient may affect surgical morbidity and mortality.
  
  • Increased wound healing
  • Decreased infection
  • Decreased osmotic diuresis
  • Decreased incidence of Diabetic Ketoacidosis
• However….hypoglycemia is a dreaded complication of tight control as it can cause permanent neurological damage and signs and symptoms are masked by anesthesia
  
  • Tight control is labor intensive
  • Requires adequate BS monitoring capability (q 30minutes)

Question 23

One techqniue for nontight management of diabetic periop?

Answer 23

• Obtain fasting blood sugar AM of surgery
• 2nd IV- infusion of D5W @ 100-125 cc/hour
• 30-50% of normal am intermediate insulin SQ
• Continue glucose throughout surgery and 1st IV for fluid replacement as required
• Check BS q 1-2 hours-adjust D5/W
• If BS >200-250 administer IV regular insulin on sliding scale basis
• 1 unit of regular insulin can be expected to decrease blood sugar 30-50 mg/dL

Question 24

One techqniue for tight BG contorl periop?

Answer 24

• Fasting BS, Start infusion of D5W on a pump at 100-150 cc/h and maintain throughout surgery
• A second IV is started for normal fluid replacement
• Infusion of 50 u of regular insulin in 250cc NS is piggybacked (0.2 u/ml).
• Insulin (units/hr) = last plasma glucose÷150
  
  • (divide by 100 if patient obese, has an infection,or is on corticosteroids)
  • Example: Last plasma glucose = 300mg/dl so 2 units/hour infusion
• Check potassium levels frequently and add 20 mEq to each liter of glucose infusate

Question 25

Dose of insulin to treat hyperkalemia?

Answer 25

10 u reg IV 25g of glucose 1amp of 50% dextrose solution over 5 minutes

Question 26

Treatment of hypoglycemia?

Answer 26

• Patient should wear Medic Alert bracelet
• If conscious: give fast acting oral sugar
• If under anesthesia/impaired: 25-50 ml of 50% dextrose solution

Question 27

Which oral antidiabetic meds can cause hypoglycemia?

Answer 27

• Sulfonylureas
• Meglitinides
• GLP-1 mimetics/gliptins (DPP-4 inhibitors)
• Amylin

however, any oral antidiabetic can have increased risk of hypoglycemia when any oral antidiabetic meds are given together

Question 28

MOA Sulfonylureas? Effectiveness?

Answer 28

Primary MOA: Stimulate release of insulin from pancreatic beta cells

• Binds to ATP sensitive potassium channels in the cell membrane resulting in depolarization, Ca2+ influx and insulin release
• “tricks” beta cells to think insulin is needed

Secondary Mechanisms of Action

• Enhance beta cell sensitivity to glucose
• Enhance tissue sensitivity to insulin
• Normalize increased hepatic glucose production primarily responsible for fasting hyperglycemia in Type 2 DM
• Reduce FBG 60-70 mg/dL
• Reduce Hgb A1c up to 2%

Question 29

Examples of sulfonylureas?

Answer 29

1st generation

• Tolbutamide (Orinase) DOA 6-12 hrs
• Chlorpropamide (Diabinese) DOA 36 -72 hrs

2nd generation

• Glipizide (Glucotrol) DOA 12- 24 hrs
• Glyburide (Micronase, Diabeta) DOA 18-24 hrs
• Glimepiride (Amaryl)

1st generation more drug interactions & SE than 2nd

2nd generation 100x more potent than 1st but not more effective

• 20% people started with sulfonylurea are not successfuly treated. 20% initially have sucess and then fail

Question 30

Metabolism Sulfonylureas? Protein binding? Adverse effects?

Answer 30

• 90-98% protein bound (albumin)
• All metabolized hepatically - some active metabolites; avoid in hepatic disease
• If renal impairment, use glipizide or tolbutamide - completely metabolized to inactive or weakly active products

Most common Adverse Effects

• GI - nausea, fullness, heartburn, cholestasis, altered LFTs; appetite stimulant – may exacerbate obesity
• GU – ADH like effect Na and H2O retention
• Derm - pruritis, rash
• Hypoglycemia
  
  • Hold 24-48 hrs pre-op- but pay attneiton to ones mentioned earlier with longer half life
    
    • ​Chlorpropamide (36-72 hours DOA)
    • glyburide (18-24 hours DOA)

Question 31

MOA Biguanides? Example?

Answer 31

Metformin (Glucophage)

• MOA
  
  • Decreases hepatic and renal glucose production (decreased gluconeogenesis and glycogenolysis)
    
    • bind to mitochondria
  • Enhances insulin receptor binding
  • Increases glucose utilization and decreases insulin resistance
  • Requires the presence of insulin for effect.
    
    • no impact on amount of insulin released

Question 32

Excretion/clinical effects of Metformin (Biguanide)

Answer 32

• Pharmacokinetics
  
  • Excreted unchanged by kidneys
• Clinical effects
  
  • Decreases FPG 60 mg/dL
  • Additive effect with sulfonylureas

Question 33

Benefits, s/e, contraindications with Biguanides (Metofrmin)

Answer 33

• Benefits
  
  • No weight gain or modest weight loss
  • May increase HDL, decrease LDL & TGs
  • Hypoglycemia rare when used alone
• Adverse effects
  
  • GI distress - diarrhea, metallic taste, nausea
  • Lactic acidosis- metformin molecule bind to mitochondrial membrane. this decreases release ATP nad increases AMP and glucose will be metabolized anaerobically. Increase pyruvate–> increase lactate
    
    • ​stop metformin 48 hours before surgery!!
  • Rash
• Contraindications
  
  • Women with ESRD serum Cr > 1.4 mg/dL
  • Men with ESRD serum Cr > 1.5 mg/dL
  • Hepatic dysfunction- can’t clear lactate
  • CHF, Shock, hypoxic pulmonary disease- decrease lactate metablism/elimination and increased risk lactic acidosis

Question 34

Examples/MOA of Thiazolidinediones (TZDs)?

Answer 34

Pioglitazone (Actos)

Rosiglitazone (Avandia)

MOA

• Improves insulin sensitivity/decreases insulin resistance (particularly in skeletal muscle and adipose tissue)
  
  • Work on PPR gamma to turn on insulin response genes
  • enhancing insulin action at target sites (works at sensitivity)
• Reduces hepatic glucose production
• Requires the presence of insulin for effect

Question 35

Clinical effect, pk, other effects of thiazolidinediones?

Answer 35

• Clinical effect
  
  • Decreases FPG up to 50 mg/dL
  • Decreases Hgb A1c 1-2%
• Pharmacokinetics
  
  • PO
  • Hepatic metabolism
• Other effects
  
  • Resumption of ovulation in premenopausal women who were experiencing anovulation from insulin resistance (PCOS)

Question 36

A/E Thiazolidinediones?

Answer 36

• Common/major adverse effects
  
  • Edema
  • Weight gain
  • Hepatotoxicity - monitor LFTs, counsel pts about symptoms of jaundice
• Black Box Warnings
  
  • CHF
    
    • Can cause or exacerbate
    • Not rec for patients with symptomatic CHF
  • MI (rosiglitazone only) - mixed data

Question 37

MOA Alpha glucosidase inhibitors? Examples?

Answer 37

Acarbose (Precose)

Miglitol (Glyset)

MOA

• Competitively and reversibly antagonizes enzymes in the intestinal brush border responsible for digesting complex carbohydrates- prevents glucose from being absorbed
• Delays glucose absorption
• Lowers post-prandial hyperglycemia

Question 38

Clinical effect, PK, s/e alpha glucosidase inhibitors?

Answer 38

• Clinical effect
  
  • Only decreases FBG 25-30mg/dL
  • Decreases PPG 60-70 mg/dL
  • Decreases Hgb A1c 0.7-0.9%
• Pharmacokinetics
  
  • Not absorbed after oral administration
  • Excreted in stool
• Adverse Effects
  
  • GI - abdominal pain/distension, diarrhea, flatulence

Question 39

Admin of alpha-glucosidase inhibitors?

Answer 39

• Take with FIRST BITE of meal
• Caution in patients with history of IBD, colonic ulceration, intestinal obstruction that can worsen with gas formation

Question 40

MOA Meglitinides? Drug examples?

Answer 40

Repaglinide (Prandin)

Nateglinide (Starlix)

MOA

• Stimulates insulin secretion from pancreatic beta cells
• Quick onset and peak effect (1 hr)
• Short duration of action (4 hrs) with a concentrated effect around meal-time glucose
• Reduces post-prandial hyperglycemia
  
  • similar to sulfonylureas but these have shorter peaks/DOA and are better for postprandial BG control
  • shorter time for when patient is at r/f hypoglycemia periop

Question 41

Dosing and A/E meglitinides?

Answer 41

• Dosing - PO
  
  • Dose 15-30 minutes before meals
  • Skip a meal, skip a dose
  • Add a meal, add a dose
• AE
  
  • Similar to sulfonylureas
  • Hypoglycemia
  • GI - n/v/c/d, heartburn
  • Headache

Question 42

MOA Sodium-glucose Co transporter 2 (SGLT-2) inhibitors? Examples?

Answer 42

ex- Canagliflozin (10-13 hr. half life/effect ~24 hours), dapagliflozin, empagliflozin

• SGLT-2 - high capacity, low affinity transporter S1 segment proximal tubule
  
  • 90% of glucose reabsorption in the kidney
• Inhibitors decrease glucose reabsorption in the kidney increasing excretion of glucose in the urine
• Improved blood glucose concentrations and weight loss
• Approved for Type II DM, clinical trial evaluating use in DM Type I

Question 43

SGLT-2 Inhibitor s/e, interactions?

Answer 43

• Adverse effects:
  
  • UTI, genital fungal infections (women)
  • increased urination (osmotic diuresis/hypovolemia) ,
  • postural hypotension (may be more prone to interoperative hemodynamic instability)
  • hyperkalemia- issue in someone taking ACE/ARB or renal disease.
  • by themselves, unlikely to cause hypoglycemia
• Rare severe AE:
  
  • ​euglycemic diabetic ketoacidosis- BG <300, but all other issues with lactic acidosis. look for polydipsia, tachycardia, epigastric pain/HA/AMS or other s/s A/B is off.. Glucose in urine increases mobilization FFA and increase lipolysis, predisposes pt to ketogenesis
    
    • ​Triggersn- fasting, illness, reduced insulin doses
  • urosepsis
  • pyleonephritiis
  • higher incidence of amputation.
• Interactions: diuretics (enhanced diuresis), rifampin, phenytoin, and phenobarbital (enhanced metabolism)
• *Hold 24 hours prior to surgery in the fasting patient- DUE TO RISK OF EUGLYEMIC DKA

Question 44

MOA Bromocriptine? s/e

Answer 44

Dopamine agonist

• Bromocriptine: FDA approved “as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes”
  
  • don’t know why this happens. It was noted dopamine antagonists had worsened BG, pt on dopamine agonists had improved BG control
• improves glycemic control (HgbA1C ) and glucose tolerance in obese type 2 diabetic patients
• Not associated with hypoglycemia
• Side effects: nausea, visual and auditory hallucinations, hypotension, dyskinesia, pleuropulmonary fibrosis (pleural effusion), and erythromelalgia(red, tender extremities), ALT/AST elevations

Question 45

GLP-1 Agonists and MImetics MOA? examples?

CLinical effect? AE?

Answer 45

• Inhibit DPP-4 (dipeptidyl peptidase) an enzyme that inactivates incretin hormones (GLP-1)- Incretin hormones metabolic hormones that stimulate decrease BG level. Inhibiting enzyme that breaks incretin hormones down, have higher [incretin] and work to decrease BG
  
  • Enhances glucose-dependent insulin secretion
  • Reduces glucagon secretion
  • Exhibits other anti-hyperglycemic actions once released from the gut including decreased appetite and slowing gastric emptying
• EX- Sitagliptan (Januvia) (E1/2t 12 hours)
• Modestly reduces post-prandial and fasting blood sugar
• 3rd line drug
• AE: comparable to placebo, rare fatal pancreatitis & anaphylaxis reported.
  
  • INCREASED RISK HYPOGLYCEMIA

Question 46

MOA Exenatide (Byetta)? A/E?

Answer 46

• Synthetic GLP-1 analog that mimics GLP-1 (an incretin)
  
  • ​enhanced incuslin secretion, less glucagon, increase peripheral responsiveness to insuline
  • Nearly identical effects as Gliptins
  • Adjunct to metformin or sulfonylureas No weight gain
• Adverse Effects
  
  • GI side effects (N&V)
  • Some patients develop antibodies against drug
  • Pancreatitis (potentially fatal)
  • Renal failure 1:13,000 (transplant required)
  • Hypersensitivity
  • Delayed gastric emptying (abx and oral contraceptives 1 hour before exanatide)

Question 47

Amylin MOA, A/E, Interactions?

Answer 47

• Synthetic analog of amylin (a pancreatic hormone released with insulin) that decreases gastric emptying, decreases glucagon secretion, and increases sensation of satiety
  
  • Reduces post-prandial blood glucose
  • Peak 20 minutes after injection, 49 min ½ life
    
    • Metabolized in the kidneys NOT the liver
• Used to enhance insulin effects in both type I and type II DM pts who fail to attain acceptable control with insulin
• Adverse Effect: High risk for hypoglycemia, nausea, injection site reactions
• Interactions: Decreased absorption of drugs (ABX, oral contraceptives 1 hr before or 2 hrs after injection)

Question 48

Combo products?

Answer 48

• Glucovance (Glyburide and Metformin)
• Avandamet (Rosiglitazone and Metformin)
• Avandaryl (Glimepiride and Rosiglitazone)
• Duetact (Glimepiride and Pioglitazone)
• Metaglip (Glipizide and Metformin)
• Janumet (Sitagliptin and Metformin)
• In general, combination therapy with drugs that affect different molecular targets and that have different MOA has the adcantage of improving glycemic control by lowering the dose and adverse effects of each individual drug.