Diabetes Mellitus and Disorders of Glucose Homeostasis

1
Diabetes Mellitus and Disorders of Glucose
Homeostasis

• Rosens Chapter 124
• December 21, 2006
• Presented by Dr. DIsa-Smith
• Prepared by Michael Savino, DO (PGY-2)

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Normal Physiology

• Normal glucose range 60-150 mg/dL
• Normal plasma glucose levels are critical to
  survival, because glucose is main fuel for CNS
• CNS does not synthesize glucose and only stores a
  few minutes supply of glucose.
• Brief hypoglycemia can cause profound brain
  dysfunction
• Prolonged severe hypoglycemia can cause cellular
  death

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Glucose

• Derived from 3 sources
• 1. intestinal absorption
• 2. glycogenolysis glycogen breakdown
• 3. gluconeogenesis glucose formed from
  precursors such as lactate, pyruvate, amino
  acids, glycerol
• After glucose ingestion, plasma levels rise and
  endogenous production is suppressed.

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Insulin

• b cells of the pancreas detect elevated glucose
  levels triggering release of insulin into the
  hepatic portal circulation
• Major anabolic hormone in diabetic disorder
• Stimulates glucose uptake, storage, and use by
  other insulin-sensitive tissues (fat, muscle)
• Half-life of insulin is about 3-10 minutes
• Metabolized through the liver and kidney

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Liver and Kidney

• Liver and kidney contain glucose-6-phosphatase
  enzyme necessary for the release of glucose into
  the circulation
• The liver is the sole source of endogenous
  glucose production in normal conditions
• The kidney undergoes gluconeogenesis under
  prolonged starvation

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• Hepatocytes do not require insulin for glucose
  transport across cell membrane
• But, insulin augments hepatocyte glucose uptake
  and storage for energy
• Insulin inhibits hepatic gluconeogenesis and
  glycogenolysis

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Muscle cells

• Can store and use glucose via glycolysis
• In muscle glucose ? pyruvate
• Pyruvate ? lactate or alanine ? transported to
  liver ? precursor for gluconeogenesis
• Fasting conditions
• i glucose uptake use fatty acids as energy,
  mobilize amino acids to liver for energy.

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Counterregulatory hormones

• Glucagon
• The major catabolic agent that increases blood
  glucose
• a cells of pancreas
• Released in response to hypoglycemia, stress,
  trauma, infection, starvation.
• Decreases glycoloysis, increases gluconeogenesis
• Increases ketone production in liver
• Epinephrine h hepatic glucose production and
  limits glucose use through a and b adrenergic
  mechanisms
• acts directly glycogenolysis, gluconeogenesis
• Norepinephrine similar to epinephrine
• Growth hormone and cortisol initially i
  glucose, but long-term h glucose

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Types of Diabetes

• Type 1 Diabetes Mellitus
• Type 2 Diabetes Mellitus
• Gestational Diabetes
• Impaired Glucose Tolerance

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Type 1 DM

• Failure to produce insulin. Tendency to ketosis
• Parenteral insulin required to sustain life
• Autoimmune destruction of Beta cells of pancreas
• Strong association with HLA

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Type 1 DM

• Typical patient is lean, younger than 40, prone
  to ketosis.
• Plasma insulin levels are low or absent.
• Glucagon levels are high, but suppressible with
  insulin
• Symptoms of polydipsia, polyuria, polyphagia, and
  wt. loss develop rapidly
• Complications incl DKA, retinopathy,
  nephropathy, neuropathy, foot ulcers, severe
  infections

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Type 2 DM

• Typical patient is middle aged or older,
  overweight, normal to high insulin levels.
• Impaired insulin function related to poor insulin
  production, failure of insulin to reach the site
  of action, or failure of end organ response to
  insulin
• Symptoms begin more gradually than in Type 1

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Type 2 DM - Subgroups

• Most are obese, but 20 are not
• Nonobese Type 2 patients present more like Type 1
• Young persons with mature-onset diabetes

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Type 2 DM

• Symptoms come on gradually
• Diagnosis usually made by elevated blood glucose
  on routine lab work
• Blood glucose levels controlled by diet, oral
  hypoglycemics, or insulin.
• Decompensation usually leads to hyperosmolar
  nonketotic coma rather than ketosis.

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Gestational Diabetes

• Characterized by abnormal oral glucose tolerance
  test (OGTT).
• During pregnancy
• Reverts to normal in postpartum period or remains
  abnormal
• Clinical pathogenesis similar to Type 2
• Clinical presentation usually nonketotic
  hyperglycemia during pregnancy

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Impaired glucose toleranceImpaired Fasting
Glucose

• Plasma glucose levels between normal and diabetic
  and who are at increased risk for development of
  diabetes
• Pathogenesis related to insulin resistance
• Presentations nonketotic hyperglycemia, insulin
  resistance, hyperinsulinism, often obesity
• Less complications than diabetes

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Diagnostic Strategies

• Diagnosis made by
• Random plasma glucose gt 200 mg/dL
• or Fasting glucose gt 140 mg/dL
• or 2 hr postload OGTT
• HbA1c high glucose binds to Hb b chain.
  Half-life of RBCs allows index of glucose for
  prior 6-8 weeks (normal 4-6)
• Glucose dipstick tests use glucose oxidase
• Ketone dipstick tests use nitroprusside rxn.

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Dipstick Blood Glucose (Accucheck)

• Generally more accurate than urine dip
• Hematocrits lt30 or gt55 cause unduly high or low
  readings, respectively

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Hypoglycemia

• Common problem in Type 1 diabetics
• 9 120 episodes per 100 patient-years
• Severe hypoglycemia associated with blood sugar
  below 40-50 mg/dL and impaired cognitive function
• Hypoglycemia unawareness a dangerous
  complication of Type 1. Pts become unarousable
  without warning
• Somogyi phenomenon

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Hypoglycemia - symptoms

• Blood glucose level below 40-50 mg/dL
• Rate at which glucose decreases, age, gender,
  overall health, and previous hypoglycemic
  reactions all contribute to symptom severity
• S/Sx caused by excessive epinephrine secretion
  and CNS dysfunction
• Sweating
• Nervousness, tremor
• Tachycardia
• Bizarre behavior, confusion
• Seizures
• Coma

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Hypoglycemia - treatment

• 1. Suspect hypoglycemia
• Check serum glucose if strong suspicion treat
  before results available
• 2. Correct serum glucose
• If awake, cooperative PO intake
• If unable to take PO 25-75 g glucose as D50W
  (1-3 amps) IV
• Children 0.5-1 g/kg glucose as D25W IV
• Neonates 0.5-1 g/kg glucose as D10W IV
• If unable to get IV access 1-2 mg glucagon IM
  or SC may repeat q20 min
• Glucagon onset of action 10-20 min, peaks at
  30-60 min
• Ineffective in alcohol-induced hypoglycemia b/c
  lack of glycogen

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Hypoglycemia - Management

• ABCs
• Aspiration, seizure precautions
• If ETOH suspected, give thiamine
• D50W should not be used in infants or young
  children because venous sclerosis causes rebound
  hypoglycemia
• Oral hypoglycemics (chlorpropamide) can cause
  prolonged hypoglycemia. Should be admitted for
  observation
• May require constant infusion of D10W

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Hypoglycemia

• Non-diabetic patients
• Most common cause of postprandial hypoglycemia is
  alimentary hyperinsulinism (s/p gastrectomy,
  gastrojejunostomy, vagotomy, pyloroplasty)
• Fasting hypoglycemia inadequate glucose
  production (hormone deficiencies, enzyme and
  substrate defects, severe liver disease)

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HyperglycemiaDiabetic Ketoacidosis

• Syndrome in which insulin deficiency and glucagon
  excess produce
• Hyperglycemia
• Dehydration
• Acidosis
• Electrolyte imbalance
• DKA is typically characterized by
• Hyperglycemia over 300 mg/dL,
• Low bicarbonate (lt15 mEq/L), and
• Acidosis (pH lt7.30) with ketonemia and ketonuria

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Etiology of DKA

• Almost always in Type 1 Diabetics
• Non-compliance with insulin
• Stress (Physical or emotional) despite insulin
  use
• Myocardial infarction
• Infection/ Sepsis
• Gastrointestinal bleeding
• 25 of all episodes of DKA occur in undiagnosed
  patients.

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DKA History and Physical

• Polydipsia, polyuria, polyphagia, visual
  blurring, weakness, wt loss, N/V, abd pain
• May have altered mental status
• Kussmaul respirations
• Odor of acetone (sweet) on breath
• Signs of dehydration
• Tachycardia
• Orthostatic changes

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Pathophysiology DKA

• Markedly elevated glucose levels spill over into
  the urine, drawing water, sodium, potassium,
  magnesium, calcium, phosphorus into the urine.
• This combined with vomiting contribute to
  dehydration experienced in DKA
• Exocrine pancreas dysfunction produces
  malabsorption, further limiting bodys intake of
  fluid and electrolytes.

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Falsely elevated Elyte levels

• 95 of DKA patients
• Na normal or low
• K very low (5-7 mEq/L)
• Mg very low
• Phos very low (3 mEq/L)
• Because of dehydration and acidosis, however,
  these lab values are reported as high!

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Ketosis/Acidosis

• Adipose tissue fails to clear the circulation of
  lipids. Insulin deficiency results in activation
  of hormone-sensitive lipase increasing free fatty
  acid FFA levels. Overload of FFAs on the
  liver oxidizes them to acetoacetate and
  Beta-hydroxybuterate.
• Result is oxidation of FFAs to ketones instead
  of reesterification to triglycerides
• The body while increasing ketone production,
  utilizes less ketones in peripheral tissues
  leading to ketoacidosis.

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Ketoacidosis

• Glucagon levels are 4-5x higher in DKA and is the
  most influential ketogenic hormone.
• Glucagon inhibits malonyl coenzyme A and inhibits
  glycolysis

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• The counterregulatory hormones Epinephrine,
  norepinephrine, cortisol, growth hormone,
  dopamine, and thyroxin enhance ketogenesis
  indirectly by stimulating lipolysis.
• Propranolol and metyrapone can block the effect
  of counterregulatory hormones. They have been
  used to prevent recurrent episodes in known DKA
  patients.

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Acidosis in clinical presentation

• Acidotic patient attempts to increase lung
  ventilation and rid the body of excess acid with
  Kussmauls respiration. Bicarbonate is used up
  in the process.
• Current evidence suggests that acidosis compounds
  the effects of ketosis and hyperosmolality to
  depress mental status directly.

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Pathophysiology of DKA
Adapted from figure 124-1, p. 1963
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Laboratory Tests

• Allow confirmation of diagnosis
• serum and urine glucose (usually greater than
  350, but up to 18 of patients may have
  euglycemic DKA)
• Electrolytes
• ABG/venous pH (w/ K if available)
• Obtain EKG immediately

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Metabolic acidosis

• Metabolic acidosis with elevated anion gap is
  secondary to elevated plasma levels of
  acetoacetate and b-hydroxybutyrate. Also
  contributed by lactate, FFAs, phosphates, volume
  depletion

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Other tests

• CBC w/ differential
• BMP elevated BUN/Cr suggest dehydration.
• Mag, calcium, amylase, ketone, and lactate levels
• U/A rule out infection/renal dz

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Sodium

• Serum sodium value often misleading!
• Sodium is often low in presence of dehydration
  because affected by
• Hyperglycemia
• Hypertriglyceridemia
• Salt-poor fluid intake
• Insensible losses
• Marked hyperglycemia water flows from cells
  into vessels to decrease osmolar gradient,
  causing dilutional hyponatremia
• Correction Na (Gluc 100) 1.6 / 100
• For every increase of 100 mg/dL glucose, the
  serum sodium decreases by 1.6

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Hypertriglyceridemia

• Common in DKA
• Impaired lipoprotein lipase activity and hepatic
  overproduction of VLDL

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Acidosis

• Acidosis and hyperosmolarity by high glucose
  levels shift potassium, magnesium, and
  phosphorous from intracellular to extracellular
  space.
• Dehydration produces hemoconcentration, which
  contributes to normal-high initial serum
  potassium, mag, and phos

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Calculate Correction for potassium

• Correction for the effects of acidosis on serum
  potassium
• Subtract 0.6 mEq/L from lab K for every 0.1
  decrease in pH on ABGs
• Ex if K is reported as 5 mEq/L and the pH is
  6.94, the corrected K 2 mEq/L

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Management of DKA

• Consider intubation in vomiting decompensated
  patient for airway protection
• Once intubated, hyperventilation should be
  maintained to prevent worsening acidosis
• Hypovolemic shock requires aggressive fluid
  resuscitation with 0.9 NSS, rather than pressors
• Consider other causes of shock MI, sepsis
• Diagnosis Hyperglycemia, ketosis, acidosis
• Fluids, electrolytes, insulin therapy begins.

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Summary of treatment for DKA

• Identify DKA glucose, electrolytes, ketones,
  ABG. CBC, U/A, CXR, EKG. Support ABC.
• 1. Rehydrate 1-2 L NSS over 1-3 hours
• Children 20 mL/kg NSS over first hr, then
  follow w/ 0.45 NSS
• 2. Insulin bolus 0.1 U/kg regular IV
• Maintenance 0.1 U/kg/hr regular IV
• Change to D5W/0.45NS when glucose lt300 mg/dL
• 3. Correct electrolytes.
• Na 0.9 NSS and 0.45
• K add 20-40 mEq KCl to each liter. Ensure good
  renal fxn
• Phos usually not necessary to replenish
• Mg 1-2 g MgSO4

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• 4. Correct acidosis add 44-88 mEq/L bicarb to
  1st liter of IV fluids if pH lt 7.0. Correct to a
  pH of 7.1
• Correct underlying precipitant
• Monitor VS, I Os, serum glucose, and
  electrolytes
• Admit to ICU

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Insulin

• Historically, high dosages of insulin were used,
  but resulted in hypoglycemia and hypokalemia
• Now, low-dose insulin therapy with aggressive
  fluid therapy is used, more gradual decrease in
  blood glucose levels, while decreasing risk of
  hypokalemia

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Insulin

• May start with bolus of 10 units regular insulin
• Or infuse regular insulin at a rate of 0.1
  U/kg/hr up to 5-10 U/hr, mixed with IV fluids.
• In children, dosing is 0.1 U/kg. Reduction of
  plasma glucose should be more gradual because of
  greater risk of developing cerebral edema.

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• Half-life of regular insulin is 3 10 minutes.
• Therefore, it should be infused, rather than
  given as repeated boluses.
• When blood glucose has dropped to 250-300 mg/dL,
  then start D5W/0.45 NS to prevent iatrogenic
  hypoglycemia and cerebral edema

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DKA vs. HHNC

• DKA
• Glucose gt350
• Sodium low 130s
• Potassium 4.5-6.0
• Bicarbonate lt 10
• BUN 25-50
• Serum ketones present

• HHNC
• Glucose gt700
• Sodium 140s
• Potassium 5
• Bicarbonate gt 15
• BUN gt 50
• Serum ketones absent

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Hyperglycemic Hyperosmolar Nonketotic Coma

• Acute diabetic decomposition
• Results from severe dehydration that results from
  sustained hyperglycemic diuresis, in which
  patient is unable to drink enough fluids to
  sustain hydration
• Characterized by Hyperglycemia, hyperosmolarity,
  dehydration
• Absence of ketoacidosis is unknown, but FFA
  levels are lower than in DKA, thus less
  substrates to form ketones. Most likely because
  still producing tiny amount of insulin required
  to block ketogenesis

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• More common in elderly with Type 2, but has been
  reported in children with Type 1
• May occur in pts who are not diabetic after
  burns, parenteral hyperalimentation, peritoneal
  dialysis, or hemodialysis
• Clinically signs of dehydration and CNS
  findings predominate
• Most common associated diseases CRI, gm
  pneumonia/sepsis, GI bleeding
• On average, the HHNC patient has 24 or 9L fluid
  fluid deficit

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Treatment of HHNC

• Identify HHNC
• Rehydrate 2-3 L NSS over first few hours.
  Correct ½ fluid deficit in first 8 hours,
  remainder over remaining 24 hrs
• Insulin bolus 0.05-0.1 U/kg regular IV
• Maintenance 0.05-0.1 U/kg/hr regular IV
• Change to D5W/0.45NS when glucose lt300 mg/dL
• . Correct electrolytes.
• Na 0.9 NSS and 0.45
• K add 20-40 mEq KCl to each liter. Ensure good
  renal fxn
• Phos usually not necessary to replenish
• Mg 1-2 g MgSO4

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• 4. Correct acidosis add 44-88 mEq/L bicarbonate
  to 1st liter of IV fluids if pH lt 7.0. Correct
  to a pH of 7.1
• Correct underlying precipitant
• Monitor VS, I Os, serum glucose, and
  electrolytes
• Admit to ICU

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Late complications of DM

• Develop 15-20 yrs after overt hyperglycemia
• Vascular atheroslerosis, thromboembolic
  complications. Probably related to oxidated
  low-density lipoprotein and increased platelet
  activity. CAD, stroke, silent MI, claudication,
  non-healing ulcers, and impotence
• Diabetic nephropathy renal disease is leading
  cause of death and disability in diabetic
  patients.
• Two pathological patterns diffuse and nodular

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• Retinopathy diabetes leading cause of adult
  blindness in US. (11-18 of diabetics)
• Background (simple) retinopathy
• Proliferative retinopathy
• Complaints range from acute blurring of vision to
  sudden unilateral /bilateral blindness. Also may
  have snowflake cataract (vision improves with
  decreasing blood glucose levels)

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• Neuropathy peripheral neuropathy in 15-60.
  Poorly understood
• Diabetic vascular dz effects on vasa nervorum,
  myoinositol, polyol pathway, and protein
  glycosylation may have roles
• Types
• 1. peripheral symmetrical slow, worse at night
• 2. mononeuropathy rapid onset, muscle wasting
• 3. autonomic neuropathy GI, bladder,
  orthostatic hypotension

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The diabetic foot

• Sensory neuropathy, ischemia, infection principle
  contributors to diabetic foot disease. Loss of
  sensation ? pressure necrosis
• Must be Xrayed, no weight bearing, assessed for
  infection
• Mild vs Deep infections managed differently
• Mild gram , oral abiotics, no wt bearing, home
• Deep full-thickness, cellulitis gt 2cm,
  lymphangitis, bone involvement. Polymicrobial
  aerobic gm cocci, gm bacilli, and anaerobes
• Require hospitalization, cultures, IV tx with
  amp-sulbactam, ticarcillin-sulbactam, cefoxitin,
  imipenem, or fluoroquinolone clindamycin.
  Debridement, no wt. bearing

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Infections

• Diabetics at increased risk of extremity
  infections and pyelonephritis
• Tuberculosis, mucocutaneous candidiasis,
  intertrigo, mucormycosis, soft tissue infections,
  nonclostridial gas gangrene, osteomyelitis, and
  malignant otitis externa.

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Cutaneous manifestations

• Dermal hypersensitivity pruritic, red,
  induration at insulin injection sites
• Insulin lipoatrophy
• Insulin lipohypertrophy
• Insulin pumps sensitivity to catheters

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Oral Hypoglycemic Agents

• Sulfonylureas (developed 1940s) mainstay of
  treatment. Increase insulin secretion by binding
  to specific beta cell receptors. Risk of
  hypoglycemia
• Repaglinide similar to sulfonylureas. More
  rapid onset, but less risk of hypoglycemia. OK
  with sulfa allergies.
• Metformin decreases hepatic glucose output.
  Contraindicated in renal insufficiency and
  metabolic acidosis. Withold for 48 hours of
  iodinated contrast media b/c risk of acidosis
• Thiazolidinediones reduce insulin resistance.
  Monitor liver enzymes
• Alpha glucosidase inhibitors delay intestinal
  absorption and prevent complex carb breakdown.
  GI side effects, monitor liver enzymes

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New med on the block

• Byetta (Exetinide) first in a class of encretin
  mimetics.
• mimics the enhancement of glucose-dependent
  insulin secretion
• For Type 2 DM
• Used with metformin and/or sulfonylurea
• Pre-filled injection pen (SQ)
• Dose 5 mcg BID for first 30 days