Physiology of Type 1 Diabetes Flashcards
What are the stages in the development of Type 1 Diabetes Mellitus?
- Genetic susceptibility (multigenic)
- Hypothetical triggering event (some environmental factor)
- Active autoimmunity - immune system attacks beta cells
- Anti-islet cell antibodies (to islet cell antigens such as glutamic acid decarboxylase GAD) are detectable as a marker of the autoimmune process - Gradual loss of pancreatic insulin reserve (decrease in functioning beta cell mass)
- glucose rises to meet criteria for diagnosis of DM - usually onset of symptoms is abrupt; development of DKA often precipitated by some stress which abruptly raises insulin needs above limited insulin availability
- ultimately complete beta cell destruction (no insulin or C-peptide detectable); titers of anti-islet cel antibodies may gradually decrease, since the antigen has been destroyed
Describe Type 1 Diabetes.
Absolute insulin deficiency
Dependent on exogenous insulin for life
Prone to ketoacidosis
Recent weight loss
Abrupt onset of symptoms
Usually before age 30, but may occur in the aged
Describe hormonal control of lipolysis by hormone sensitive lipase
An intracellular enzyme that leads to lipolysis and release of glycerol and free fatty acids (FFA) from adipose tissue
Describe hormonal control of lipolysis by insulin
Insulin suppresses release of FFA from adipose tissue by inhibiting hormone sensitive lipase
Describe hormonal control of lipolysis by epinephrine
Epinephrine enhances FFA mobilization by activating hormone sensitive lipase.
other factors also activate hormone sensitive lipase:
- Norepinephrine
- ACTH
- Glucagon
- Growth Hormone
- sympathetic afferents
- caffeine
- theophylline
Describe hormonal control of lipolysis by lipoprotein lipase (LPL)
LPL is the enzyme that allows plasma lipoproteins to deposit their triglycerides into adipose tissue for storage
LPL activity is enhanced by insulin
How does insulin promote triglyceride storage?
Normally, the glycerol released by lipolysis is not ‘reused’ by the adipocyte for reesterification, since lipolysis -> immediate reesterification would constitute a ‘futile cycle’
Instead, insulin-mediated glucose uptake by the adipocyte is necessary for generation of glycerol 3-P, which can be used for FFA esterification and triglyceride storage
Diagram the major inputs to the triglyceride stores of the adipocyte, the continuing lipolysis and reesterification of fatty acids, and the output exclusively as free fatty acids and glycerol.
Diagram the pathways involved in generation of ketone bodies in the liver and their catabolism by extrahepatic tissues.
What are the consequences of lipolysis and delivery of free fatty acids (FFA) to the liver?
- Enhanced FFA oxidation
- Production of ketone bodies
- Stimulation of gluconeogenesis
- Enhanced synthesis of Very Low Density Lipoproteins (VLDL)
Describe the changes in plasma glucose and ketone body concentrations in a patient with type 1 DM after stopping insulin.
plasma glucose is higher overall
beta hydroxybutyrate increases steadily
- direct measurement is becoming available in some labs, but involves blood collection by fingerstick and is more accurate indicator of ketoacidosis
acetoacetate concentration remains relatively constant
- only organic acid measured by clinical tests, but BHB is usually higher (by 2-3fold) so amt of ketone bodies present may be greatly underestimated by testes
- acetone can be exhaled, so it does not accumulate as much as BHB or acetoacetate
*all after insulin treatment
Describe the downstream effects of insulin deficiency (low insulin to glucagon ratio)
What are the classic symptoms of diabetes?
The ‘polys’
- Polyuria
- Polydipsia
- Polyphagia
- Weight loss
What is diabetic ketoacidosis?
Result of insulin deficiency and is typically precipitated by infection or other stress
Stress is accompanied by secretion of counter-regulatory hormones (epinephrine, glucagon, GH, cortisol) -> anti-insulin effects and ‘stress’ hormones raise blood glucose
When blood glucose gets too high, the kidney cannot reabsorb the glucose it filters and glucose is lost in urine; glucose increases the volume of water excreted -> loss of important electrolytes (Na+, K+, phosphate, and magnesium) so may lead to dehydration
State of insulin deficiency -> breakdown of stored triglycerides -> glycerol and free fatty acids; d/t lack of insulin, much larger release of FFAs, which are catabolized to acetyl-CoA in the liver -> ketone bodies
Ketone body production > ketone body utilization, so they accumulate, liberate H+ ions -> bicarbonate buffering system overwhelmed -> pH of blood/body fluid drops -> metabolic acidosis
What are the signs and symptoms in patients with diabetic ketoacidosis?
Polyuria
Polydipsia
Nausea and vomiting: allows loss of some H+
Abdominal pain and distension: caused by impaired gut motility
Weight loss
Fruity (acetone) breath
Kussmaul respiration: rapid, deep respirations/increased ventilations (more CO2 losses)
Dehydration
Cool, dry skin
Low blood pressure
Drowsiness
Coma
How can the kidneys help to correct the acidosis?
if dehydration can be avoided, and adequate renal perfusion maintains the glomerular filtration rate
kidneys can reabsorb filtered bicarbonate and excrete excess H+ (much of the tubular H+ combines with NH3 to form NH4+, which ‘traps’ H+ in the lumen so it can be excreted in the urine)
Renal excretion of H+ can be considered equivalent to ‘creating new’ bicarbonate
An increase in adrenal gland hormone aldosterone can stimulate the kidney to excrete even more H+
Why do the patients with diabetic ketoacidosis become dehydrated and what are the clinical manifestations of dehydration?
Osmotic diuresis
Manifestations: decreased blood pressure, tachycardia, vasoconstriction (cool skin), decreased skin turgor, dry mucous membranes
Likely to have orthostatic hypotension
How can lab tests help confirm a suspicion of dehydration?
In dehydrated patients, blood urea nitrogen (BUN) is elevated and the ratio of BUN to serum creatinine is high (the kidney reabsorbs a substantial amount of filtered BUN while creatinine reabsorption is minimal)
What is the clinical correlation between the BUN to creatinine ratio?
Creatinine clearance is a kidney function test that is used to estimate the glomerular filtration rate (GFR), which can also be estimated from measurement of serum creatinine (as GFR decreases, creatinine clearance decreases and serum creatinine rises)
Blood Urea Nitrogen (BUN) is increased in patients with kidney dysfunction, however BUN is more commonly increased as a result of dehydration
Ratio of BUN to creatinine can be used to differentiate between renal dysufunction (BUN and creatinine are both increased) vs. dehydration (disproportionate increase in BUN relative to serum creatinine since more urea is reabsorbed by kidney tubules in dehydration, while reabsorption of creatinine remains normal)
How do you calculate osmolality and why is this relevante to patients with DKA?
As patients with DKA become gradually more dehydrated, this will be reflected as an increase in plasma osmolality
Osmolality = 2(Na + K) + (BUN/2.8) + (glucose/18)
What is the therapy for DKA?
- Rehydration - via IV infusion of electrolyte solutions
- Correction of electrolyte imablance - osmotic diuresis causes urine loss of important electrolytes
- Reversal of insulin deficiency - admin insulin IV, dose-regulated drip
- Search for underlying medical illness that may have precipitated DKA
Why is rehydration a good therapy for DKA?
As dehydration worsens and blood pressure decreases, kidney perfusion is decreased which limits glomerular filtration, therefore the ability of the kidney to help compensate for metabolic acidosis is impaired
IV large amounts of fluids containing sodium to: raise blood pressure, restore kidney perfusion, and increase glomerular filtration
Why is the correcting of electrolyte imbalance an important therapy for DKA and how does that relate to potassium levels?
Osmotic diuresis causes urine loss of important electrolytes
Potassium important for maintaining a normal resting membrane potential of excitable cells
Hypokalemia can occur because of excess K+ loss from the body, sometimes caused by glucose-induced osmotic diuresis
- in acidosis, cells can act as buffers by taking up H+ ions in exchange for K+ leaving the cells
- patients with DKA have lost K+ through osmotic diuresis, but because K+ shifts out of cells during acidosis, plasma K+ may appear normal
- total K+ loss may be 3-5mEq/kg body weight
Why is it important to make sure the patient has adequate urine output before administering supplemental potassium for DKA?
Hypotension may reduce renal perfusion causing acute kidney injury and oliguria (low urine production) or anuria (no urine production)
Anuric patients cannot excrete potassium. they still have a total body potassium deficiency, but admin of IV potassium might overshoot the normal range and cause dangerous hyperkalemia
Why is the correcting of electrolyte imbalance an important therapy for DKA and how does that relate to sodium levels?
The presence of hyperglycemia causes an osmotic flux of water from intracellular to extracellular space and plasma, which dilutes the concentration sodium creating the appearance of hyponatremia
The greater the plasma glucose, the lower the measured plasma sodium concentration appears
To “correct” measured plasma sodium concentration for diluting effect of hyperglycemia = [Na+] falls by approximately 1.6mEq for ever 100mg/dL increase in glucose above the upper limit of normal fasting glucose (choose 100 to make calc easy)
(blood glucose - 100)/100 * 1.6 + measured plasma sodium conc = actual plasma sodium conc
Consider hyperglycemia is an explanation for hyponatremia if plasma osmolality is high
How can exogenous insulin treatment for DKA cause hypokalemia?
If patients with DKA are treated with insulin, insulin acts to stimulate the Na+/K+ ATPase in muscle and adipose cells, which moves K+ back into these cells, lowering ECF and plasma K+
Insulin stimulates the muscle Na+/K+/Cl- co-transporter (NKCC), which also moves K+ into cells
insulin-mediated transcellular flux of K+ can cause hypokalemia
Insulin can also enhance uptake of phosphate and magnesium ions into insulin-sensitive cells
Why might a physician administer sodium bicarbonate to a patient with DKA? What are the potential complications of this?
Rarely, the patient’s initial pH is so low it is barely compatible with life, so sodium bicarb is admin to acutely raise pH
bicarbonate increases the risk of hypokalemia
- a rise in extracellular pH toward normal stimulates the muscle sodium-hydrogen exchanger (NHE) to transport H+ out of cells and Na+ into cells
- resultant rise in intracellular Na+ stimulates Na+/K+ ATPase, which moves K+ into cells -> hypokalemia
Admin of bicarb also shifts hemoglobin dissassociation curve to the left, making O2 unloading more difficult
What is the most common precipitating factor of DKA?
Infection causes increased secretion of stress hormones (cortisol, growth hormone, epinephrine, and glucagon) that increase blood glucose through anti-insulin (counter-regulatory) effects
More insulin is needed to maintain normoglycemia
How does hemoglobin A1c relate to plasma glucose levels?
the average plasma glucose over a prolonged period of time can be estimated by measuring the extent of glycation of hemoglobin
glucose enters red blood cells via GLUT1 glucose transporters, a process that is not stimulated by insulin; once inside RBCs, glucose can bind irreversibly to hemoglobin (glycation or glycosylation of hemoglobin)
higher amount of glycated hemoglobin in a blood sample reflects a higher average blood glucose during the preceding 2-3months
What is nonenzymatic glycation of proteins?
formation of covalent linkages with glucose
aldehyde function of glucose condenses with amino groups to form a reversible Schiff base or aldimine linkage, which can undergo irreversible Amadori rearrangement to form a more stable ketoamine
the process of protein glycation may lead to the development of some complications of diabetes (if glycation process impairs function of the protein)
What is HbA1c?
structurally identical to hemoglobin A, except the glucose is attached to the NH2 terminus of the beta chain by a ketoamine linkage
glycation of the NH2 terminal valine on a hemoglobin beta chain converts this molecule to HbA1c, which moves more rapidly than hemoglobin A on electrophoresis
The concentration of HbA1c provides an index of the average blood glucose conc over 120d
What are the macrovascular complications of diabetes mellitus?
accelerated coronary, cerebrovascular, and peripheral vascular disease
‘premature aging’
atherosclerosis blocks arteries supplying the heart, brain, and extremities
What are the microvascular complications of diabetes mellitus?
Retinopathy - a disease of the retina that may lead to blindness
Renal disease - abnormal structure and function of the glomerulus causing filtration of large proteins such as albumin -> proteinuria
- may lead to kidney failure
What are some complications of diabetes mellitus?
Increased susceptibility to infections - impaired immune system responses
Foot ulcers - contributing factors include neuropathy, increased susceptibility to infection, and impaired bloodflow
-gangrene may develop and require amputation
Erectile dysfunction - contributing factors are neurologic and vascular
Cataracts - ‘premature aging’
What is distal symmetrical polyneuropathy and where would it show?
stocking-glove distribution
Polyneuropathy - sensory impairment involving pain, touch, position, temperature, and vibration
What are the goals of treatment of diabetes?
Alleviate symptoms (the polys)
Prevent chronic complications
Why do patients with diabetes develop complications?
- Glycation modifies proteins
- Intracellular sorbitol
- Oxidative stress and formation of free radicals
- Inflammation
How does glycation modifying proteins cause complications for diabetics?
When a protein is exposed to a high glucose concentration, incorporation of glucose can occur
glycated proteins may go on to form advanced glycation endproducts (AGEs) or form intermolecular or intramolecular crosslinks
Protein glycation or formation of AGEs and/or cross-links may alter the function of proteins, which may lead to retinopathy, neuropathy, nephropathy, or cardiovascular disease
How does intracellular sorbitol cause complications for diabetics?
As more glucose enters certain cells during hyperglycemia, there is increased flux through the polyol pathway with conversion of glucose to sorbitol by aldose reductase
When sorbitol accumulates, other metabolic derangements may lead to nerve dysfunction (neuropathy), cataract formation, etc
How does oxidative stress and formation of free radicals cause complications for diabetics?
Increased glucose metabolism is associated with reduction of antioxidant mechanisms, increased production of free radicals, and increased lipid peroxidation
These processes can lead to development of certain complications of diabetes
How does inflammation cause complications for diabetics?
Elevated glucose may increased production of pro-inflammatory cytokines (interleukin 1beta, TNFalpha), which affect the kidneys, cardiovascular system, retina, and/or nervous system
