Physiology of Type 1 Diabetes

Question 1

What are the stages in the development of Type 1 Diabetes Mellitus?

Answer 1

1. Genetic susceptibility (multigenic)
2. Hypothetical triggering event (some environmental factor)
3. 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
4. Gradual loss of pancreatic insulin reserve (decrease in functioning beta cell mass)
5. 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
6. 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

Question 2

Describe Type 1 Diabetes.

Answer 2

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

Question 3

Describe hormonal control of lipolysis by hormone sensitive lipase

Answer 3

An intracellular enzyme that leads to lipolysis and release of glycerol and free fatty acids (FFA) from adipose tissue

Question 4

Describe hormonal control of lipolysis by insulin

Answer 4

Insulin suppresses release of FFA from adipose tissue by inhibiting hormone sensitive lipase

Question 5

Describe hormonal control of lipolysis by epinephrine

Answer 5

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

Question 6

Describe hormonal control of lipolysis by lipoprotein lipase (LPL)

Answer 6

LPL is the enzyme that allows plasma lipoproteins to deposit their triglycerides into adipose tissue for storage

LPL activity is enhanced by insulin

Question 7

How does insulin promote triglyceride storage?

Answer 7

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

Question 8

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.

Question 9

Diagram the pathways involved in generation of ketone bodies in the liver and their catabolism by extrahepatic tissues.

Question 10

What are the consequences of lipolysis and delivery of free fatty acids (FFA) to the liver?

Answer 10

1. Enhanced FFA oxidation
2. Production of ketone bodies
3. Stimulation of gluconeogenesis
4. Enhanced synthesis of Very Low Density Lipoproteins (VLDL)

Question 11

Describe the changes in plasma glucose and ketone body concentrations in a patient with type 1 DM after stopping insulin.

Answer 11

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

Question 12

Describe the downstream effects of insulin deficiency (low insulin to glucagon ratio)

Question 13

What are the classic symptoms of diabetes?

Answer 13

The ‘polys’

1. Polyuria
2. Polydipsia
3. Polyphagia
4. Weight loss

Question 14

What is diabetic ketoacidosis?

Answer 14

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

Question 15

What are the signs and symptoms in patients with diabetic ketoacidosis?

Answer 15

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

Question 16

How can the kidneys help to correct the acidosis?

Answer 16

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+

Question 17

Why do the patients with diabetic ketoacidosis become dehydrated and what are the clinical manifestations of dehydration?

Answer 17

Osmotic diuresis

Manifestations: decreased blood pressure, tachycardia, vasoconstriction (cool skin), decreased skin turgor, dry mucous membranes

Likely to have orthostatic hypotension

Question 18

How can lab tests help confirm a suspicion of dehydration?

Answer 18

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)

Question 19

What is the clinical correlation between the BUN to creatinine ratio?

Answer 19

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)

Question 20

How do you calculate osmolality and why is this relevante to patients with DKA?

Answer 20

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)

Question 21

What is the therapy for DKA?

Answer 21

1. Rehydration - via IV infusion of electrolyte solutions
2. Correction of electrolyte imablance - osmotic diuresis causes urine loss of important electrolytes
3. Reversal of insulin deficiency - admin insulin IV, dose-regulated drip
4. Search for underlying medical illness that may have precipitated DKA

Question 22

Why is rehydration a good therapy for DKA?

Answer 22

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

Question 23

Why is the correcting of electrolyte imbalance an important therapy for DKA and how does that relate to potassium levels?

Answer 23

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

Question 24

Why is it important to make sure the patient has adequate urine output before administering supplemental potassium for DKA?

Answer 24

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

Question 25

Why is the correcting of electrolyte imbalance an important therapy for DKA and how does that relate to sodium levels?

Answer 25

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

Question 26

How can exogenous insulin treatment for DKA cause hypokalemia?

Answer 26

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

Question 27

Why might a physician administer sodium bicarbonate to a patient with DKA? What are the potential complications of this?

Answer 27

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

Question 28

What is the most common precipitating factor of DKA?

Answer 28

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

Question 29

How does hemoglobin A1c relate to plasma glucose levels?

Answer 29

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

Question 30

What is nonenzymatic glycation of proteins?

Answer 30

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)

Question 31

What is HbA1c?

Answer 31

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

Question 32

What are the macrovascular complications of diabetes mellitus?

Answer 32

accelerated coronary, cerebrovascular, and peripheral vascular disease 'premature aging' atherosclerosis blocks arteries supplying the heart, brain, and extremities

Question 33

What are the microvascular complications of diabetes mellitus?

Answer 33

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

Question 34

What are some complications of diabetes mellitus?

Answer 34

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'

Question 35

What is distal symmetrical polyneuropathy and where would it show?

Answer 35

stocking-glove distribution Polyneuropathy - sensory impairment involving pain, touch, position, temperature, and vibration

Question 36

What are the goals of treatment of diabetes?

Answer 36

Alleviate symptoms (the polys) Prevent chronic complications

Question 37

Why do patients with diabetes develop complications?

Answer 37

1. Glycation modifies proteins 2. Intracellular sorbitol 3. Oxidative stress and formation of free radicals 4. Inflammation

Question 38

How does glycation modifying proteins cause complications for diabetics?

Answer 38

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

Question 39

How does intracellular sorbitol cause complications for diabetics?

Answer 39

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

Question 40

How does oxidative stress and formation of free radicals cause complications for diabetics?

Answer 40

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

Question 41

How does inflammation cause complications for diabetics?

Answer 41

Elevated glucose may increased production of pro-inflammatory cytokines (interleukin 1beta, TNFalpha), which affect the kidneys, cardiovascular system, retina, and/or nervous system