Transcript Liposcience- NMR LipoProfile

Diabetes Mellitus and Disorders
of Glucose Homeostasis
Rosen’s Chapter 124
December 21, 2006
Presented by: Dr. D’Isa-Smith
Prepared by: Michael Savino, DO (PGY-2)
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
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.
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
Liver and Kidney
• Liver and kidney contain glucose-6phosphatase – 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
• 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
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.
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
Types of Diabetes
• Type 1 Diabetes Mellitus
• Type 2 Diabetes Mellitus
• Gestational Diabetes
• Impaired Glucose Tolerance
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
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
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
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
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.
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
Impaired glucose tolerance
Impaired 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
Diagnostic Strategies
Diagnosis made by:
• Random plasma glucose > 200 mg/dL
• or Fasting glucose > 140 mg/dL
• or 2 hr postload OGTT
• HbA1c – high glucose binds to Hb b chain. Halflife of RBC’s allows index of [glucose] for prior
6-8 weeks (normal 4-6%)
• Glucose dipstick tests use glucose oxidase
• Ketone dipstick tests use nitroprusside rxn.
Dipstick Blood Glucose
(Accucheck)
• Generally more accurate than urine dip
• Hematocrits <30% or >55% cause
unduly high or low readings,
respectively
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
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:
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•
Sweating
Nervousness, tremor
Tachycardia
Bizarre behavior, confusion
Seizures
Coma
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
Hypoglycemia - Management
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•
ABC’s
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
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)
Hyperglycemia:
Diabetic 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 (<15 mEq/L), and
• Acidosis (pH <7.30) with ketonemia and
ketonuria
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.
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
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 body’s intake
of fluid and electrolytes.
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!
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 FFA’s on
the liver oxidizes them to acetoacetate and
Beta-hydroxybuterate.
• Result is oxidation of FFA’s to ketones
instead of reesterification to triglycerides
• The body while increasing ketone production,
utilizes less ketones in peripheral tissues
leading to ketoacidosis.
Ketoacidosis
• Glucagon levels are 4-5x higher in DKA
and is the most influential ketogenic
hormone.
• Glucagon inhibits malonyl coenzyme A
and inhibits glycolysis
• 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.
Acidosis in clinical presentation
• Acidotic patient attempts to increase lung
ventilation and rid the body of excess acid
with Kussmaul’s 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.
Pathophysiology of DKA
Increased
lipolysis
Decreased
glucose
uptake
Increased FFA
Hyperglycemia
Increased BUN/
Amino acids
Increased
ketogenesis
Glycosuria
Increased
Gluconeogenesis
Ketonuria
Acidosis
Osmotic diuresis
Electrolyte Loss
Volume
depletion
Adapted from figure 124-1, p. 1963
Increased
proteolysis
Hyperglycemia
Osmotic
diuresis
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
Metabolic acidosis
• Metabolic acidosis with elevated anion
gap is secondary to elevated plasma
levels of acetoacetate and bhydroxybutyrate. Also contributed by
lactate, FFA’s, phosphates, volume
depletion
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
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
Hypertriglyceridemia
• Common in DKA
• Impaired lipoprotein lipase activity and
hepatic overproduction of VLDL
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
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 ABG’s
• Ex: if K+ is reported as 5 mEq/L and the
pH is 6.94, the corrected K+ = 2 mEq/L
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.
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/0.45%NS when glucose <300 mg/dL
• 3. Correct electrolytes.
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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
• 4. Correct acidosis – add 44-88 mEq/L
bicarb to 1st liter of IV fluids if pH < 7.0.
Correct to a pH of 7.1
• Correct underlying precipitant
• Monitor VS, I & O’s, serum glucose, and
electrolytes
• Admit to ICU
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
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.
• 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
DKA vs. HHNC
DKA
• Glucose >350
• Sodium ~ low 130s
• Potassium ~ 4.5-6.0
• Bicarbonate < 10
• BUN ~25-50
• Serum ketones
present
HHNC
• Glucose >700
• Sodium ~ 140s
• Potassium ~ 5
• Bicarbonate > 15
• BUN > 50
• Serum ketones
absent
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
• 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
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/0.45%NS when glucose <300 mg/dL
• . Correct electrolytes.
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•
•
•
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
• 4. Correct acidosis – add 44-88 mEq/L
bicarbonate to 1st liter of IV fluids if pH
< 7.0. Correct to a pH of 7.1
• Correct underlying precipitant
• Monitor VS, I & O’s, serum glucose, and
electrolytes
• Admit to ICU
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
• 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)
• Neuropathy – peripheral neuropathy in 1560%. 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
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 > 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
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.
Cutaneous manifestations
• Dermal hypersensitivity – pruritic, red,
induration at insulin injection sites
• Insulin lipoatrophy
• Insulin lipohypertrophy
• Insulin pumps – sensitivity to catheters
Oral Hypoglycemic Agents
• Sulfonylureas (developed 1940’s) – 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
New med on the block
• Byetta (Exetinide) – first in a class of encretin
mimetics.
• “mimics” the enhancement of glucosedependent 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