CASE PRESENTATION #3: HYPERGLYCEMIA AND HYPERKETONEMIA

PATIENT PRESENTATION: A 40 year-old woman was brought to the hospital in a

disoriented and confused state.
FOCUSED HISTORY: As noted on her medical alert bracelet, the patient has had type 1
diabetes mellitus (T1D) for the last 24 years. Her husband reports that this is her first medical
emergency in 2 years.

PERTINENT TEST RESULTS: Rapid, bedside tests were strongly positive for glucose and
acetoacetate, and negative for protein. Results on blood test performed by the clinical
laboratory are shown below:

Microscopic examination of her urine revealed a urinary tract infection (UTI).

DIAGNOSIS: The patient is in diabetic ketoacidosis that is precipitated by a UTI. [Note:

Diabetes increases the risk for infections such as UTIs.]

IMMEDIATE TREATMENT:
 The patient was rehydrated with normal saline given intravenously.
 She was also given insulin intravenously.
 Blood glucose, ketone bodies and electrolytes were measured periodically.
 The patient was started on an antibiotic for her UTI.

LONG-TERM TREATMENT:
 Diabetes increases the risk for macrovascular complications (coronary artery disease
and stroke)
  Microvascular complications (retinopathy and neuropathy).
 Ongoing monitoring for these complications will be continued.

NUTRITION:
 Monitoring total intake of carbohydrate is primary in blood glucose control.
Carbohydrate should come from whole grains, vegetables, legumes, and fruits.
 Low-fat dairy products and nuts and fish rich in omega-3 fatty acids are encouraged.
Intake of saturated and trans fats should be minimized.

PROGNOSIS:
 Diabetes is the sixth leading cause of mortality by disease in the United States.
 Individuals with diabetes have a reduced life expectancy relative to those without the
disorder.

DIABETES MELLITUS TYPE 1:

 Type 1 DM is the result of

interactions of genetic,
environmental, and
immunologic factors that
ultimately lead to the
destruction of the
pancreatic beta cells and
insulin deficiency.
 Beta cell mass then begins to
decrease, and insulin
secretion progressively
declines, although normal
glucose tolerance is
maintained.
 Features of diabetes do not
become evident until a
majority of beta cells are
destroyed (70–80%). At this
point, residual functional
beta cells exist but are
insufficient in number to
maintain glucose tolerance.
 The events that trigger the
transition from glucose intolerance to frank diabetes are often associated with
increased insulin requirements, as might occur during infections or puberty.

DIABETIC KETOACIDOSIS: Diabetic ketoacidosis (DKA) is an acute, severe disorder

directly related to diabetes. DKA was formerly considered a hallmark of type 1 DM, but also
occurs in individuals who lack immunologic features of type 1 DM.
CLINICAL FEATURES:

 The symptoms and physical signs of DKA usually develop over 24 h.

 DKA may be the initial symptom complex that leads to a diagnosis of type 1 DM, but
more frequently, it occurs in individuals with established diabetes.
 Nausea and vomiting are often prominent, and their presence in an individual with
diabetes warrants laboratory evaluation for DKA.
 Abdominal pain may be severe and can resemble acute pancreatitis or ruptured
viscus.
 Hyperglycemia leads to glucosuria (occurs when blood glucose = >180mg/dL),
volume depletion, and tachycardia.
 Hypotension can occur because of volume depletion in combination with peripheral
vasodilatation.
 The low pH indicated a severe acidosis due to greatly increased production of
acetoacetic acid and β-hydroxybutyric acid.
 Calculation of the anion gap (Na+ – [Cl- + HCO3-]) is useful in a number of
metabolic situations. In this case it is elevated because of the presence of excess
ketoacids in the blood.
 Kussmaul respirations and a fruity odor on the patient’s breath (secondary to
metabolic acidosis and increased acetone) are classic signs of the disorder.
 The elevated values of urea (BUN) indicated some renal impairment (due to
diminished renal perfusion because of low blood volume secondary to dehydration),
dehydration, and increased degradation of protein.
 A high plasma level of potassium is often found in DKA owing to a lowered uptake
of potassium by cells in the absence of insulin.
 The increased osmolality of plasma due to hyperglycemia also contributes to the
development of coma in DKA.
 Signs of infection, which may precipitate DKA, should be sought on physical
examination, even in the absence of fever.

PATHOPHYSIOLOGY:

 DKA is often precipitated by increased insulin requirements in patient with DM

Type 1, as occurs during a concurrent illness (infection). Failure to augment insulin
therapy often compounds the problem. Complete omission or inadequate
administration of insulin by the patient or health care team (in a hospitalized patient
with type 1 DM) may precipitate DKA.

 Individuals with DKA have a greater frequency and severity of infection such as UTI.
The reasons for this include incompletely defined abnormalities in cell-mediated
immunity and phagocyte function associated with hyperglycemia, as well as
diminished vascularization. Hyperglycemia aids the colonization and growth of a
variety of organisms (Candida and other fungal species).

 DKA results from relative or absolute insulin deficiency combined with

counterregulatory hormone excess (glucagon, catecholamines, cortisol, and
growth hormone). Both insulin deficiency and glucagon excess, in particular, are
necessary for DKA to develop.
 The decreased ratio of insulin to glucagon promotes gluconeogenesis,
glycogenolysis, and ketone body formation in the liver, as well as increases in
substrate delivery from fat and muscle (free fatty acids, amino acids) to the liver.

 The combination of insulin deficiency and hyperglycemia reduces the hepatic level of
Fructose-2,6-bisphosphate, which alters the activity of Phosphofructokinase
(glycolysis) and Fructose-1,6-bisphosphatase (gluconeogenesis).

 Glucagon excess decreases the activity of pyruvate kinase, whereas insulin deficiency
increases the activity of phosphoenolpyruvate carboxykinase (gluconeogenesis).
These changes shift the handling of pyruvate toward glucose synthesis and away from
glycolysis.

 The increased levels of glucagon and catecholamines in the face of low insulin levels
promote glycogenolysis.

 Insulin deficiency also reduces levels of the GLUT4 glucose transporter, which
impairs glucose uptake into skeletal muscle and fat and reduces intracellular glucose
metabolism.

 Ketosis results from a marked increase in free fatty acid release from adipocytes,
with a resulting shift toward ketone body synthesis in the liver. Reduced insulin
levels, in combination with elevations in catecholamines and growth hormone,
increase lipolysis and the release of free fatty acids.

 Normally, these free fatty acids are converted to triglycerides or very-low-density

lipoprotein (VLDL) in the liver. However, in DKA, hyperglucagonemia alters hepatic
metabolism to favor ketone body formation, through activation of the enzyme
Carnitine Palmitoyltransferase I (CPT-I). This enzyme is crucial for regulating
fatty acid transport into the mitochondria, where beta oxidation and conversion to
ketone bodies occur.

 At physiologic pH, ketone bodies exist as ketoacids, which are neutralized by

bicarbonate. As bicarbonate (HCO3) stores are depleted, metabolic acidosis ensues.
Kussmaul respirations (compensatory respiratory alkalosis) and a fruity odor on the
patient’s breath (secondary to metabolic acidosis and increased acetone) are classic
signs of the disorder.

 Increased lactic acid production also contributes to the acidosis. The increased free
fatty acids increase triglyceride and VLDL production. VLDL clearance is also
reduced because the activity of insulin-sensitive lipoprotein lipase in muscle and fat
is decreased. Hypertriglyceridemia may be severe enough to cause pancreatitis.

 The very high levels of blood glucose (sometimes as high as 8 to 10 times normal in
severe untreated diabetes) can cause severe cell dehydration throughout the body.
This dehydration occurs partly because glucose does not diffuse easily through the
pores of the cell membrane, and the increased osmotic pressure in the extracellular
fluids causes osmotic transfer of water out of the cells.
  In addition to the direct cellular dehydrating effect of excessive glucose, the loss of
glucose in the urine causes osmotic diuresis—that is, the osmotic effect of glucose in
the renal tubules greatly decreases tubular reabsorption of fluid. The overall effect is
massive loss of fluid in the urine, causing dehydration of the extracellular fluid, which
in turn causes compensatory dehydration of the intracellular fluid. Thus, polyuria
(excessive urine excretion), intracellular and extracellular dehydration, and increased
thirst are classic symptoms of diabetes: polyuria (increased urination), polydipsia
(increased thirst), and polyphagia (increased hunger).

 Hypotension can occur because of volume depletion in combination with peripheral

vasodilatation.

 Summary of some mechanisms involved in the causation of the Ketoacidosis of type 1

Diabetes Mellitus

Sources:
 Harper’s Illustrated Biochemistry
 Harrison’s Principles of Internal Medicine
 Guyton and Hall Textbook of Medical Physiology

Prepared by SGD Group 3

 Apiong, Arsee
 Bautista, Chedee
 Buenavista, Averil
 Datumolok, Hazziem
 Hinacay, Ric
 Jaralve, Kent
 Manaros, Rohanimah
 Oliveros, Chandee
 Taal, Meera Lou
 Villegas, Marie Grace
 Diabetes Mellitus Type 1

Produce increased
Infection (UTI) Genetic, environmental &
levels of
immunologic factors
adrenaline/cortisol

Antagonistic Insulin deficiency Glucagon excess

effect to Insulin

Decreased activity
Promotes
of Pyruvate kinase
Glycogenolysis Glucose excess in blood
circulation
Promotes
Increases (Hyperglycemia) = 414
Glycogenolysis
substrate mg/dL (high)
delivery from
fat & muscle
(FFA & AA) to Polyuria, Polydipsia, Dehydration
Promotes Inhibits the liver Polyphagia
Gluconeogenesis Glycolysis
s Promotes Increased lipolysis
ketone body Volume depletion in
Proteolysis combination with Hypotension
formation on
Decrease level the liver Marked increase peripheral vasodilation
of Fructose 2, in release of FFA
Increased
6
ammonia Reduces levels
bisphosphate Activation of CPT I
of GLUT 4
glucose
Increased
Increased transporter
excretion of Beta-oxidation of
BUN = activation of fatty acids
8 mmol/L Fructose 1, 6 Impairs glucose
bisphosphate Increased levels of Increased production
(high) uptake into
Ketogenesis 3-hydroxybutyrate: of acetone – faintly
cardiac &
350 mg/dl (high) fruity odor of breath
skeletal muscle
& adipose Compensation:
tissue Neutralization by
Inhibits
HCO3
PFK 1
Reduces
intracellular Compensation HCO3 levels of 12
glucose cannot equate mmol/L (low)
metabolism ketogenesis

Metabolic pH: 7.1 (acidic)

Decreased
Acidosis compensation:
activity of
(Ketoacidosis) Respiratory alkalosis
Sodium-
(Kussmaul’s Respiration)
Potassium
pump

Increased K: 5.3
mmol/L

Increased Cl:
103 mmol/L

Decreased Na:
136 mmol/L