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THE ENDOCRINE SYSTEM

DIABETIC ACIDOSIS

A 21-year-old brother of a person with insulin-dependent diabetes mellitus experienced


increased urination and thirst for 6 weeks, along with a 15-lb weight loss, despite a normal
appetite. Fearing that these symptoms meant he also had developed diabetes mellitus, he did
not seek medical attention promptly. However, when he developed nausea and vomiting for
48 hours, followed by a stuporous state, his college roommate insisted on taking him to the
emergency room. There, he was found to be semi coherent, and his mucous membranes and
skin were dry. Blood pressure was 84/52 and pulse rate was 120beats/min. He was breathing
deeply at a rate of 30 respirations per minute. The remainder of the examination was within
normal limits. A urine sample contained a glucose concentration of 5% and tested strongly
positive for acetoacetic acid. Plasma glucose was 800 mg/dl. Sodium was 132mEq/L,
bicarbonate was 5mEq/L, chloride was 104mEq/L, and potassium was 5.8mEq/L. Blood pH was
7.1, PCO2 was 17 mmHg, and PO2 was 95 mmHg. Blood urea nitrogen was 28 mg/dl, and
plasma creatinine was 1.4 mg/dl. On treatment with insulin, intravenous fluids, and potassium,
the patient’s clinical and biochemical status was restored to normal in 24 hours.

1. What is the cause of this patient’s very high plasma glucose level?

2. What are the mechanisms that elevated plasma glucose?

3. Glucose production and release by the liver in part reflect the balance between glycolysis
(glucose to pyruvate) and gluconeogenesis (pyruvate to glucose). What control points
regulate the rates of bidirectional flow between glucose and pyruvate, and how are they
affected by the relevant hormones?

4. What has replaced bicarbonate in the patient’s plasma, and by what mechanisms?
5. Why is the patient breathing rapidly, and why is the blood pH low?
6. Why is the blood pressure low and the pulse rate high?
7. What levels of free fatty acid and triglycerides might you expect in plasma?

8. What levels of amino acids might you expect in plasma?


9. What other hormone levels would be increased in plasma?
10. What contributed to this patient’s weight loss?
11. What caused his thirst and increased appetite?
12. What other constituents of the urine would be present in excessive quantities, especially
when one considers that he had no food intake for 48 hours?
13. What effect would insulin treatment have on his plasma bicarbonate, pH, potassium, and
phosphate levels?

[ANSWER]

1. The primary cause is insulin deficiency resulting from destruction of the beta cells of the
pancreatic islets. Secondarily, loss of insulin leads to disinhibition of glucagon secretion by
the alpha cells of the islets, and thereby causes glucagon excess. The clinical
consequences of insulin deficiency and glucagon excess create a state of "stress," which
additionally stimulates cortisol secretion, growth hormone secretion, and epinephrine and

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norepinephrine release. This complete hormonal setting of insulin deficiency arrayed
against increases of glucagon, cortisol, growth hormone, and catecholamines generates
hyperglycemia.

2. Hepatic glucose production and release are elevated, initially because of exaggerated
glycogen breakdown (low insulin, high glucagon, high epinephrine) and subsequently
because of increased rates of gluconeogenesis (high glucagon, cortisol, catecholamines,
low insulin). The efficiency of glucose uptake by both muscle and adipose tissue is
diminished because of impaired glucose transport and intracellular blocks in glucose
metabolism (low insulin, high cortisol, high epinephrine). The high plasma glucose level is
required to maintain normal rates of intracellular glucose utilization. Finally, as
dehydration occurs, plasma glucose rises still further because of a reduction in glomerular
filtration rate.

3. The bidirectional flow between glucose and phosphoenolpyruvate is determined by the


bidirectional flow between fructose-6-phosphate and fructose-l,6-biphosphate. These two
phosphates in turn are modulated by the level of fructose-2,6-biphosphate. A low ratio of
insulin to glucagon decreases the level of fructose-2,6-biphosphate, which increases flow
toward fructose-6-phosphate and gluconeogenesis by activating fructose-l,6-
biphosphatase and inhibiting 6-phosphofructokinase. Flow from phosphoenolpyruvate to
pyruvate (glycolysis) is determined by the activity of pyruvate kinase, which is diminished
by insulin deficiency. Flow from pyruvate to phosphoenolpyruvate (gluconeogenesis) is
determined by pyruvate carboxylase and phosphoenolpyruvate carboxykinase, which are
increased by high cortisol and glucagon levels and low insulin levels. In brief, the
hormonally induced alterations in this patient at key control points favor gluconeogenesis
over glycolysis and glucose production over its utilization.

4. Deficiency of insulin plus excess of catecholamines, glucagon, growth hormone, and


cortisol generates unrestrained lipolysis of adipose tissue triglycerides. The increased flow
of free fatty acids to the liver greatly exceeds that organ's oxidative capacity. Large
quantities of four carbon ketoacids are formed (beta hydroxybutyrate and acetoacetate)
and released by the liver. These acids have pK values well below 6.1 and require buffering
by sodium bicarbonate This reaction produces the sodium salts of the keto acids and
carbonic acid. The latter dissociates to carbon dioxide and water.

5. Excess production of CO2 stimulates central chemoreceptors and peripheral


chemoreceptors by increasing extracellular hydrogen ion concentrations. This increases
the rate of ventilation. However, the resultant fall in the PaCO 2 produced by this patient's
maximum respiratory effort failed to compensate for the marked reduction in plasma
bicarbonate. According to the Henderson-Hasselbach equation, an increase in blood
hydrogen ion concentration occurs, that is, a fall in pH.

6. For 6 weeks, high plasma glucose levels created a filtered load of glucose that exceeded
the tubular maximum for renal tubular glucose reabsorption. The glucose that escaped
reabsorption caused an osmotic diuresis. This, along with the lessened oral intake of water
and the gastrointestinal losses from vomiting, resulted in severe dehydration and
hypovolemia that lowered the blood pressure. In turn, decreased baroreceptor firing
caused a reflex tachycardia.

7. Plasma free fatty acids will be high because of increased lipolysis. Plasma triglycerides will
be high because of increased production of very low density lipoprotein from the increased
free fatty acid load to the liver. This elevation of triglycerides will be aggravated by
decreased clearance of very low density lipoprotein from plasma because of loss of
adipose tissue lipoprotein lipase activity when insulin is deficient.

8. Plasma branch chain amino acids will be high because of increased muscle proteolysis in
the absence of insulin and because of elevated cortisol levels. The high amino acid flow to
the liver sustains accelerated rates of gluconeogenesis.

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9. Plasma aldosterone will be high, stimulated by the renin-angiotensin system, which is
activated by the patient's hypovolemia. Plasma antidiuretic hormones (ADH) will be high,
mostly stimulated by a high plasma osmolality from glucose and secondarily by
hypovolemia.

10. There are three components to the patient's weight loss: (a) extracellular fluid losses from
osmotic diuresis and vomiting; (b) loss of adipose mass because insulin deficiency leads to
increased lipolysis and decreased reesterification of free fatty acids by glycerol phosphate;
and (c) loss of lean body mass because insulin deficiency accelerates proteolysis and
diminishes protein synthesis. In addition, somatomedin levels fall, further decreasing
protein synthesis.

11. High plasma osmolality plus hypovolemia stimulates thirst. Appetite increases in response
to wasting large quantities of calories as glucose in the urine.

12. Urea nitrogen excretion will be elevated, reflecting high rates of amino acid use for
gluconeogenesis instead of for protein synthesis. Ammonia excretion will be elevated as a
means of buffering excess hydrogen ion generated by the presence of strong ketoacids in
the tubular urine. Potassium phosphate and magnesium excretion will be increased
because these intracellular electrolytes are released when glycogen and protein stores
diminish.

13. Restoration of insulin will inhibit lipolysis and reduce production of the strong ketoacids.
This will result in an increase in plasma bicarbonate and pH. Plasma potassium will fall for
several reasons: (a) insulin directly stimulates potassium uptake by cells; (b) as insulin
diminishes ketoacid levels and extracellular fluid acidosis, potassium will move from
extracellular fluid to intracellular fluid in exchange for hydrogen ion released from
intracellular buffers; and (c) as insulin decreases plasma glucose, water will move from
extracellular space to the intracellular space, and potassium will be carried along by
solvent drag. Plasma phosphate will fall because insulin stimulates cellular uptake of
phosphate as glucose transport is increased and phosphorylated glucose intermediates
are formed.

Increased urination
Nausea and vomiting
Stupor
Semi coherence
Skin and mucous membrane dryness
Low blood pressure (84/52), high pulse rate (120beats/min)
Deep and rapid breathing (30 respirations per minute)
Urine contained a glucose concentration of 5% and positive for acetoacetic acid