ORIGINAL INVESTIGATION

Diabetic Ketoacidosis in Type 1 and Type 2

Diabetes Mellitus
Clinical and Biochemical Differences
Christopher A. Newton, MD; Philip Raskin, MD

Background: Diabetic ketoacidosis (DKA), once thought
to typify type 1 diabetes mellitus, has been reported to
affect individuals with type 2 diabetes mellitus. An analy-
sis and overview of the different clinical and biochemi-
cal characteristics of DKA that might be predicted be-
tween patients with type 1 and type 2 diabetes is needed.
Methods: We reviewed 176 admissions of patients with
moderate-to-severe DKA. Patients were classified as hav-
ing type 1 or type 2 diabetes based on treatment history
and/or autoantibody status. Groups were compared for
differences in symptoms, precipitants, vital statistics, bio-
chemical profiles at presentation, and response to therapy.
Results: Of 138 patients admitted for moderate-to-
severe DKA, 30 had type 2 diabetes. A greater propor-
tion of the type 2 diabetes group was Latino American
or African American (P⬍.001). Thirty-five admissions
(19.9%) were for newly diagnosed diabetes. A total of 85%
of all admissions involved discontinuation of medica-
tion use, 69.2% in the type 2 group. Infections were pres-
ent in 21.6% of the type 1 and 48.4% of the type 2 dia-
betes admissions. A total of 21% of patients with type 1
diabetes and 70% with type 2 diabetes had a body mass
index greater than 27. Although the type 1 diabetes group
was more acidotic (arterial pH, 7.21±0.12 vs 7.27±0.08;
P⬍.001), type 2 diabetes patients required longer treat-
ment periods (36.0±11.6 vs 28.9±8.9 hours, P=.01) to
achieve ketone-free urine. Complications from therapy
were uncommon.
Conclusions: A significant proportion of DKA occurs
in patients with type 2 diabetes. The time-tested therapy
for DKA of intravenous insulin with concomitant glu-
cose as the plasma level decreases, sufficient fluid and
electrolyte replacement, and attention to associated prob-
lems remains the standard of care, irrespective of the type
of diabetes.
Arch Intern Med. 2004;164:1925-1931

From The University Diabetes
Treatment Center, Parkland
Memorial Hospital, and
Department of Internal
Medicine, University of Texas
Southwestern Medical Center at
Dallas. Dr Newton is now with
the Department of Internal
Medicine, The Brody School of
Medicine at East Carolina
University, Greenville, NC. The
authors have no relevant
financial interest in this article.
A
N EPISODE OF DIABETIC KE-
toacidosis (DKA) was once
considered a hallmark fea-
ture that would differen-
tiate individuals with type
1 diabetes mellitus from those with type
2 diabetes mellitus. This is a concept that
has been perpetuated by such statements
as “patients with NIDDM [non–insulin-
dependent diabetes mellitus] are [not] ke-
tosis prone”1 and “many individuals with
type 2 DM [diabetes mellitus] (previ-
ously NIDDM) do not require insulin
therapy to prevent ketoacidosis.”2 The
clinical and biochemical characteristics of
DKA have been previously well de-
scribed; however, most patients included
in these reports probably had type 1 dia-
betes mellitus.3-5 More recently, there have
been multiple reports of DKA occurring
in patients with type 2 diabetes melli-
tus.6-8 Additionally, patients with idio-
pathic type 1 diabetes, also referred to as
type 1B, type 1.5, or Flatbush diabetes, will
present with DKA but have few other fea-
tures associated with classic autoim-
mune type 1 diabetes.9-12
Recent epidemiologic studies13 esti-
mate that hospitalizations for DKA have
increased during the past 2 decades. Part
of this increased frequency of admissions
may be related to the increased preva-
lence of type 2 diabetes. With the
changes in the frequency of DKA and the
increased incidence of DKA in patients
with type 2 diabetes mellitus, the ques-
tion may be posed of whether there has
been any change in the clinical or labora-
tory characteristics of the patients with
DKA who present to the emergency de-
partment. In this study, we present the
clinical and biochemical characteristics
of patients with type 2 diabetes com-
pared with type 1 diabetes admitted with
DKA to The University Diabetes Treat-
ment Center at Parkland Memorial Hos-
pital, Dallas, Tex, as well as their re-
sponse to our treatment protocol.

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 pared to the subgroup of patients with type 1 diabetes. Pa-
1. Discontinue all subcutaneous insulin use. tients were assigned to the type 2 diabetes group if they were
2. Measure blood glucose levels every hour. previously diagnosed as having diabetes and at some time in
Measure urine ketones after each void or every 4 hours. their disease, other than a time consistent with the “honey-
3. Give D5%W intravenously using an infusion pump. moon period,” were managed with diet and exercise alone or
4. Make insulin solution using regular insulin to a concentration of 0.5 U/mL. with oral hypoglycemic agents or were noncompliant with their
Give “piggyback” using an infusion pump into the D5%W infusion. insulin regimen for more than 3 weeks preceding admission.
5. Based on the hourly blood glucose determination, change each of the 2 Patients with newly diagnosed diabetes were assigned to the
infusions according to the following schedule:
type 2 group if they tested negative for autoimmune antibody
or if they had phenotypic features of type 2 diabetes (such as
Blood Glucose, Insulin Infusion D5%W,
mg/dL mL/h
obesity, acanthosis nigricans, or a family history of type 2 dia-
U/h mL/h
betes) and were noted to have a stressful event (eg, infection)
≤70∗ 0.5 1.0 250 that precipitated the episode of DKA. Based on recent evi-
71-100 1.0 2.0 225 dence that indicates similar biochemical profiles and physical
101-150 2.0 4.0 200 characteristics, patients with idiopathic type 1 diabetes (type
151-200 3.0 6.0 175 1B) were included in the type 2 diabetes subgroup for pur-
201-250 4.0 8.0 150 poses of analysis.15 Further analyses were performed compar-
251-300 6.0 12.0 100 ing patients diagnosed as having diabetes on admission for DKA
301-350 8.0 16.0 50 with those with a known history of diabetes. Additionally, pa-
351-400 10.0 20.0 0 tients with multiple admissions were compared with the group
401-450 12.0 24.0 0 of patients with only 1 admission during the year.
451-500 15.0 30.0 0
>500 20.0 40.0 0
∗Give 20 mL of D50%W IVP and repeat CBG in 15 minutes.
RESULTS

A total of 138 patients accounted for the 176 admis-

The insulin infusion algorithm used for the management of diabetic
ketoacidosis. To convert blood glucose to millimoles per liter, multiply by
0.0555. D5%W indicates dextrose 5% in water; D50%W, dextrose 50% in
water; IVP, intravenous push; CBG, capillary blood glucose.
METHODS
Of the 679 admissions to the Parkland Memorial Hospital Uni-
versity Diabetes Treatment Center between January and De-
cember 2001, 176 admissions by 138 patients were for moderate-
to-severe DKA. The diagnosis of moderate-to-severe DKA was
made in the emergency department by the presence of 3 labo-
ratory findings: a plasma glucose level of 250 mg/dL or higher
(ⱖ13.9 mmol/L); a serum bicarbonate level of 15 mEq/L or
lower, an arterial blood pH of 7.30 or lower, or a venous blood
pH of 7.25 or lower; and moderate or large urinary ketones.14
Patients were treated by residents of the University of Texas
Southwestern Medical Center under the supervision of an en-
docrinology fellow and an attending from the Division of En-
docrinology. Intravenous insulin was administered according
to the treatment algorithm shown in the Figure. This proto-
col was begun as soon as possible after initial evaluation in the
emergency department. Additional hydration and electrolyte
replacement were left to the discretion of the treating physi-
cians, although following the American Diabetes Association
practice guidelines was encouraged.14 The insulin infusion was
discontinued 2 hours after the administration of subcutane-
ous insulin once patients had resolution of their metabolic sta-
tus, including a ketone-free urine sample, and were able to tol-
erate oral feedings.
These DKA admissions were reviewed retrospectively and
data collected on patient demographics, presenting symp-
toms, precipitating causes of DKA, vital signs, biochemical pro-
files at presentation to the emergency department, amount of
intravenous fluid administered, amount of insulin adminis-
tered, duration of insulin infusion, time from presentation to
resolution of urine ketones, insulin dose at discharge, and length
of hospitalization.
Comparisons between the groups were performed using
the t test, Mann-Whitney rank sums tests, and the ␹2 test as
appropriate. Unless otherwise indicated, all data are ex-
pressed as mean ± SD. Patients with type 2 diabetes were com-
sions to Parkland Memorial Hospital’s University Dia-
betes Treatment Center for moderate-to-severe DKA.
Eighty (58%) of the patients were male, 24 (17%) of the
patients were white, 65 (47%) were African American,
48 (35%) were Latino (mostly Mexican or Mexican Ameri-
can), and 1 patient (1%) was Native American. The pa-
tients were between the ages of 15 and 66 years (mean
age, 35.0±12.1 years). A total of 18.2% of the patients
had a history of polysubstance abuse. A summary of the
patient demographics for the subgroups analyzed is pre-
sented in Table 1. Differences between groups are noted
for age and diabetes duration only.
Symptoms documented to be present at the time of
presentation are summarized in Table 2. The duration
of the symptoms, when they were reported to be pres-
ent, is also shown. Although 42% of the patients admit-
ted to weight loss, only 78% of these patients were able
to quantify the amount of loss, which was reported to
average 13.0 kg over 3 months.
A plausible explanation for the development of DKA
was identified in 90.3% of admissions. Thirty-six pa-
tients were newly diagnosed as having diabetes. Eighty-
five percent of the admissions by patients with a known
history of diabetes followed a period of discontinuation
of medical therapies during the days preceding presen-
tation. Discontinuation of medication use, mostly insu-
lin, was implicated in 90.2% of the admissions by the 16
patients with more than 1 admission during the year. Five
of these patients had a history of polysubstance abuse.
Infections were identified in 38% of all the patients and
included urinary tract infections, upper respiratory tract
infections, pneumonia, cellulitis, and cutaneous ab-
scesses. These infections were present in 22% of the pa-
tients with type 1 diabetes and 48% of patients with type
2 diabetes. Pancreatitis was also present in 10% of the
admissions. Since patients with an acute myocardial in-
farction were admitted to the cardiac care service rather
than the University Diabetes Treatment Center, none of
the patients in this study had a myocardial infarction as

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 Table 1. Demographics for Subgroups of Patients Classified by Type and Previous Diagnosis of Diabetes

Previously Diagnosed Previously Diagnosed Newly Diagnosed Newly Diagnosed

Variable Type 1 DM Type 2 DM Type 1 DM Type 2 DM
No. of patients 78 25 30 5
Age, mean ± SD, y 32.5 ± 11.2 41.0 ± 12.5* 38.2 ± 13.3* 42.5 ± 3.3
Sex, No. (%)
Male 44 (56) 15 (60) 18 (60) 3 (60)
Female 34 (44) 10 (40) 12 (40) 2 (40)
Ethnicity, No. (%)
Non-Hispanic white 18 (23.1) 3 (12) 3 (10) 0
African American 36 (46.1) 12 (48) 12 (40) 5 (100)
Latino American 24 (30.8) 9 (36) 15 (50) 0
Other 0 1 (4) 0 0
Duration of diabetes, mean ± SD, y 12.7 ± 10.0 5.6 ± 4.4† NA NA

Abbreviations: DM, diabetes mellitus; NA, not applicable.

*P⬍.05 for comparison vs previously diagnosed type 1 DM group.
†P⬍.001 for comparison vs previously diagnosed type 1 DM group.

Table 2. Frequency and Duration of Symptoms Reported Table 3. Frequency of Laboratory Data Findings
by Patients Admitted With Moderate-to-Severe at the Time of Presentation
Diabetic Ketoacidosis
Frequency, %
Frequency, Percentage Symptom Duration,
Symptom of Admissions Mean ± SD, d Component Reference Range Low Normal High

Polyuria 75.2 22.3 ± 33.6 Glucose 65-110 mg/dL 0 0 100

Polydipsia 74.4 23.1 ± 33.9 (3.6-6.1 mmol/L)
Polyphagia 33.1 26.3 ± 34.2 Arterial pH 7.35-7.45 100.0 0 0
Weight loss 42.1 89.9 ± 97.7 Bicarbonate 22-31 mEq/L 100.0 0 0
Nausea 83.4 3.2 ± 3.1 Sodium 135-145 mEq/L 77.0 21.8 1.2
Vomiting 78.5 3.1 ± 3.1 Potassium 3.6-5.0 mEq/L 4.6 58.6 36.8
Abdominal pain 51.2 3.4 ± 3.3 Chloride 98-109 mEq/L 66.1 31.0 2.9
Blood urea 7-21 mg/dL 3.5 60.2 36.3
nitrogen (2.5-7.5 mmol/L)
Creatinine 0.6-1.2 mg/dL 1.2 57.3 41.5
a precipitant for the development of DKA. Similarly, sur- (53.0-106.1 µmol/L)
Calcium 8.4-10.2 mg/dL 12.4 68.2 19.4
gical stress was not an observed cause for the develop- (2.1-2.5 mmol/L)
ment of DKA, since all of the patients in this study pre- Magnesium 1.4-1.8 mEq/L 10.0 67.5 22.5
sented to the emergency department presumably from (0.7-0.9 mmol/L)
home. Phosphate 2.4-4.5 mg/dL 8.8 54.1 37.1
On presentation to the emergency department, pa- (0.8-1.5 mmol/L)
tients were tachycardic, with an average heart rate of Amylase 29-108 U/L 23.6 59.9 16.5
Lipase 7-59 U/L 11.6 58.9 29.5
117 ± 19/min and had a slightly elevated systolic/ White blood 4.1-10.9 ⫻ 103/µL 0 44.3 55.7
diastolic blood pressure of 135 ± 23/85 ± 15 mm Hg. By cell count
the time of discharge from the hospital, the patients had Neutrophils 45%-74% 0.6 35.1 64.3
normalization of the heart rate to 83 ± 9/min and nor- Lymphocytes 16%-45% 64.9 34.5 0.6
malization of systolic/diastolic blood pressure to 113±16/ Monocytes 4%-10% 22.8 69.0 8.2
73±10 mm Hg. Patients weighed 69.6 ± 18.3 kg (range,
43.1-147.2 kg; median, 65.3 kg) at the time of admis-
sion to the hospital, having received an average of 3.7±1.5
L of intravenous fluid in the emergency department. Their Table 3 provides a summary of the distribution of
weight increased by an additional 2.7±3.2 kg during the laboratory values for the patients at the time of presen-
hospitalization. Patients newly diagnosed as having dia- tation with DKA. Patients had a hemoglobin A1c level of
betes weighed more than those with a known history of 13.0%±2.5%. Patients with a clinical diagnosis of pan-
diabetes (81.4± 22.7 kg vs 67.3 ± 16.5 kg, P = .02). Based creatitis at the time of admission accounted for 57% of
on weight at the time of discharge from the hospital, 25% the patients with elevated amylase levels and 42% of the
of the patients had a body mass index (a measure of weight patients with elevated lipase levels. Compared with those
in kilograms divided by the square of height in meters) patients with normal or low potassium levels, the pa-
greater than 27. Using their admission weights and re- tients with hyperkalemia at the time of presentation had
ported amount of weight lost, 21% of patients with type correspondingly more severe acidosis. They also had
1 diabetes and 70% of patients with type 2 diabetes had higher plasma glucose levels, lower serum sodium lev-
a body mass index greater than 27 before the onset of els, lower chloride levels, and higher calcium, magne-
symptoms of uncontrolled diabetes. sium, and phosphate levels. Their blood urea nitrogen

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 Table 4. Laboratory Findings in Patients Grouped According to Type of Diabetes
and Whether Admission Was for Newly Diagnosed Diabetes

Previously Diagnosed Previously Diagnosed Newly Diagnosed Newly Diagnosed Foster and Umpierrez
Variable Type 1 DM Type 2 DM Type 1 DM Type 2 DM McGarry3 et al16
No. of 115 26 30 5 88 126
admissions
Glucose, mg/dL 529.2 ± 212.4 (29.4 ± 11.8) 480.3 ± 159.8 (26.7 ± 8.9) 461.4 ± 192.3 (25.6 ± 10.7) 396.6 ± 191.1 (22.0 ± 10.6) 475 (26.4) 628 (34.9)
(mmol/L)
Arterial pH 7.21 ± 0.12 7.27 ± 0.08* 7.19 ± 0.14 7.28 ± 0.03† NA 7.16
Bicarbonate, 10.1 ± 5.1 10.2 ± 4.1 9.8 ± 5.0 12.0 ± 4.6 ⬍10 9
mEq/L
Sodium, mEq/L 131.6 ± 5.0 129.5 ± 5.4 132.5 ± 5.8 130.6 ± 4.6 132 133
Potassium, 5.1 ± 0.9 4.5 ± 0.9* 4.4 ± 0.6* 4.8 ± 0.5 4.8 5.3
mEq/L
Chloride, mEq/L 94.4 ± 8.1 93.1 ± 8.0 97.9 ± 6.3‡ 94.4 ± 6.9 NA 92
Blood urea 22.8 ± 13.3 (8.1 ± 4.7) 19.7 ± 12.5 (7.0 ± 4.5) 17.6 ± 12.3‡ (6.3 ± 4.4) 13.8 ± 4.8 (4.9 ± 1.7) 25 (8.9) 27 (9.6)
nitrogen,
mg/dL
(mmol/L)
Creatinine, 1.5 ± 0.9 (132.6 ± 79.6) 1.2 ± 0.7 (106.1 ± 61.9) 1.2 ± 0.5‡ (106.1 ± 44.2) 1.2 ± 0.3 (106.1 ± 26.5) NA NA
mg/dL
(µmol/L)
Calcium, mg/dL 9.5 ± 0.9 (2.4 ± 0.2) 9.4 ± 0.9 (2.3 ± 0.2) 9.2 ± 1.0 (2.3 ± 0.2) 8.9 ± 0.7 (2.2 ± 0.2) NA NA
(mmol/L)
Magnesium, 1.7 ± 0.3 (0.9 ± 0.1) 1.7 ± 0.3 (0.8 ± 0.2) 1.7 ± 0.3 (0.8 ± 0.2) 1.5 ± 0.4 (0.7 ± 0.2) NA NA
mEq/L
(mmol/L)
Phosphate, 5.0 ± 2.3 (1.6 ± 0.7) 4.0 ± 2.7 (1.3 ± 0.9) 3.9 ± 2.0‡ (1.3 ± 0.6) 2.9 ± 1.3 (0.9 ± 0.4) NA NA
mg/dL
(mmol/L)
White blood 13.0 ± 6.3 13.3 ± 6.8 14.1 ± 7.3 10.0 ± 1.3†§ NA NA
cells,
⫻103/µL
Neutrophils, % 77.6 ± 10.7 73.2 ± 10.8 74.0 ± 13.5 71.3 ± 12.9 NA NA
Lymphocytes, % 14.4 ± 9.3 14.0 ± 10.1 14.9 ± 11.4 21.5 ± 10.8 NA NA
Monocytes, % 6.0 ± 3.1 6.7 ± 2.9 6.7 ± 2.7 6.0 ± 3.4 NA NA

Abbreviations: DM, diabetes mellitus; NA, not applicable.

*P⬍.01 vs previously diagnosed type 1 DM.
†P⬍.01 vs newly diagnosed type 1 DM.
‡P⬍.05 vs previously diagnosed type 1 DM.
§P⬍.05 vs previously diagnosed type 2 DM.

and creatinine levels were both elevated, but the ratio was
similar between the 2 groups.
Patients were classified as having type 2 diabetes,
either type 2 diabetes or idiopathic type 1 diabetes, in
17.6% of the admissions. A greater percentage of these
patients were of African American or Latino American
ethnicity than the group of patients with type 1 diabetes
(P⬍.001 by ␹2 test). Infections accounted for 15 of the
31 admissions for the 30 patients in this group. Patients
previously diagnosed as having type 2 diabetes were found
to be noncompliant with their diabetes therapy in 69.2%
of the admissions. No significant differences were ob-
served in the frequency of symptom complaints in this
group compared with the type 1 diabetes group. This
group of patients weighed more than the patients with
type 1 diabetes (85.4±25.2 kg vs 66.1±14.4 kg, P=.002).
Other vital signs were not significantly different be-
tween the groups.
Laboratory data for the various subgroups ana-
lyzed are shown in Table 4. The laboratory data from 2
other reviews are also included in Table 4 for compari-
son. The cholesterol levels were similar in all groups ex-
cept for the high-density lipoprotein cholesterol levels,
which was lower in patients with a history of type 2 dia-
betes than in those with type 1 diabetes (34.3±13.6 mg/dL
[0.9±0.4 mmol/L] vs 46.4±14.2 mg/dL [1.2±0.4 mmol/
L], respectively, P⬍.001) and in those who were newly
diagnosed as having classic type 1 diabetes (34.2±10.7
mg/dL [0.9±0.3 mmol/L], P⬍.001). No differences were
observed in liver function test results.
The insulin-glucose infusion algorithm shown in the
Figure was used in most admissions. Overall, patients had
cleared their urine ketones at an average of 31.7±11.1
hours after presenting to the emergency department and
21.5±10.5 hours after being initiated on an insulin in-
fusion protocol. They received 9.5 ± 3.5 L of intrave-
nous fluid during that time. Patients continued with the
intravenous insulin infusions for a total of 36.3 ± 28.4
hours and received a total of 200.3±130.1 U of insulin
from this infusion and a total of 13.8±7.9 L of fluid. Com-
pared with patients with a known history of type 1 dia-
betes, who required 28.9±8.9 hours from the time of pre-
sentation to the emergency department and 152±47 U
of insulin to achieve a negative urine ketone status, pa-
tients with newly diagnosed type 1 diabetes and those
with type 2 diabetes required both longer periods

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(39.8±13.3 hours, P= .01; and 36.0 ± 11.6 hours, P =.04;
respectively) and more insulin (283 ± 156 U, P =.01; and
175±69 U, P=.23; respectively) to achieve a negative urine
ketone status. The patients with a known history of type
1 diabetes and those with type 2 diabetes achieved a nega-
tive urine ketone status at similar times following initia-
tion of the intravenous insulin infusion protocol (19.1±8.4
and 23.1±11.6 hours, respectively, P=.22). Patients newly
diagnosed as having type 1 diabetes required 31.7±13.3
hours (P=.005) to achieve negative urine ketones after
initiating the intravenous insulin protocol.
With regard to complications associated with treat-
ment of DKA, 4 patients had a blood glucose level of less
than 70 mg/dL (⬍3.9 mmol/L) at some point during the
insulin infusion. Three of these episodes occurred after
the patient received a subcutaneous injection of insulin
in anticipation of discontinuing the intravenous insulin
infusion but failed to tolerate the associated meal, attest-
ing to the adequacy of the insulin-glucose infusion.
None of the episodes of hypoglycemia were reported to
be clinically significant. Patients received an average of
255 ± 213mM of potassium during their hospitaliza-
tions; however, since a specific protocol for potassium
management was not provided to the treating physi-
cians, the frequency of patients developing hypokale-
mia could not be appropriately assessed. Of note though,
8% of the patients did not receive any potassium supple-
mentation. None of the patients developed cerebral edema,
and there were no deaths. One patient developed a deep
venous thrombosis during his hospitalization. Another
patient was diagnosed as having adult respiratory dis-
tress syndrome within a few hours of presentation to the
emergency department.
Patients remained hospitalized for an average of
4.5±3.3 days, consistent with the national average length
of stay for DKA of 4.5 days.13 Patients with known type
1 diabetes were discharged home on an average daily in-
sulin dose of 1.02 ± 0.25 U/kg per day or 69 ± 22 U/d of
insulin. Patients with type 2 diabetes received 1.10±0.38
U/kg daily or 92 ± 39 U/d (P = .03 vs group with type 1
diabetes). Patients with newly diagnosed type 1 diabe-
tes were discharged on a protocol of 89 ± 36 U/d or
1.22±0.31 U/kg per day. Patients who used insulin be-
fore the admission for DKA were taking significantly less
insulin preceding the admission compared with their dis-
charge dose (62 ± 23 U vs 72 ± 28 U, P = .002).
COMMENT
Our results help illustrate the variability of clinical char-
acteristics of patients who present with DKA and point
out the fact that patients with type 2 diabetes also de-
velop ketoacidosis. Even when restricting the popula-
tion to those patients with moderate or severe DKA, the
patients have a variety of clinical and biochemical find-
ings as shown in Table 3. We found that some of the vari-
ability relates to the precipitating factors for DKA in that
patients with newly diagnosed diabetes have different bio-
chemical findings compared with patients with a known
history of diabetes as shown in Table 4. Additionally, we
found that patients with type 2 diabetes have a different
biochemical presentation of DKA, with less severe aci-
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dosis and a tendency for normal initial serum potas-
sium levels, than patients with classic autoimmune type
1 diabetes.
It has been reported that up to 25% of cases of DKA
do not have an identified precipitating event.17,18 Fre-
quently identified precipitating factors include intercur-
rent illnesses such as infections or myocardial infarc-
tion, omission of or inadequate insulin therapy, and/or
newly diagnosed diabetes.17-19 Psychological issues and
noncompliance are also known to be important factors,
especially in patients with repeated episodes of DKA as
we have also found.17,19 Infections are reported to ac-
count for nearly 30% to 40% of DKA and may be the most
frequent precipitant of DKA in white populations.16,18,19
Omission of insulin has been shown to be the most com-
mon precipitating factor in urban African American popu-
lations.16,20 We have found similar results in our popu-
lation, which includes a large proportion of both African
Americans and Latino Americans, with more than 85%
of the admissions being at least partially attributable to
noncompliance with medical therapy. In our series, 32%
of patients who had omitted their medications were found
to also have an infection that often led the patient to dis-
continue use of their insulin. Part of the explanation for
this behavior may be a fear of hypoglycemia if they are
unable to eat well combined with a lack of understand-
ing by the patient on sick day management of their dia-
betes.21 Specific reasons for discontinuation of medical
therapy among the patients in this study were not able
to be identified in the medical records. It is imperative
to remember that the finding of a plausible explanation
for the development of DKA, such as the omission of in-
sulin, does not preclude the existence of another pre-
cipitating factor, such as infection.
The clinical picture of DKA typically involves poly-
uria, polydipsia, weight loss, weakness, air hunger with
Kussmaul respirations, vomiting, and abdominal pain.
Dehydration is almost always present in DKA but is less
pronounced than in the hyperglycemic hyperosmolar syn-
drome. The symptoms of polyuria, polydipsia, polypha-
gia, and weight loss relate more to hyperglycemia than
ketoacidosis. Although nonspecific, the symptoms of nau-
sea, emesis, and abdominal pain are related to the pres-
ence of ketonemia. It is clear from the duration of symp-
toms listed in Table 2 that symptoms of osmotic diuresis
(eg, polydipsia and polyuria) do not bring people to medi-
cal attention, but nausea, vomiting, and abdominal pain
do. Unfortunately, the classic symptoms of DKA may
not always be apparent.19 The percentages of symptoms
with which the patients presented in our study may be
an underestimate given that the data were collected ret-
rospectively and thus required that the health care team
asked about the symptom and recorded it in the medi-
cal record.
The laboratory data for our patients presented in
Tables 3 and 4 are consistent with results that would be
predicted for DKA. The biochemistry of DKA is in part
explained by the pathogenesis of this state. DKA occurs
in the setting of absolute or relative insulin deficiency
combined with increased levels of counterregulatory hor-
mones, such as glucagon, catecholamines, cortisol, and
growth hormone. Insufficient insulin and elevated coun-
WWW.ARCHINTERNMED.COM
terregulatory hormones contribute to the hyperglyce-
mia through glycogenolysis, gluconeogenesis, and de-
creased peripheral use of glucose. Volume depletion is
probably the principal factor that results in the marked
hyperglycemia seen in DKA. The metabolic acidosis that
develops in DKA is primarily the result of accumulation
of the metabolic acids, acetoacetic acid and ␤-hydroxy-
butyric acid, in the plasma. These ketoacids develop as
a consequence of the lipolysis and proteolysis that oc-
cur when elevated glucagon-insulin ratios cause in-
creased hepatic levels of carnitine and decreased malonyl–
coenzyme A concentrations.3
Other electrolyte abnormalities seem to develop as
a secondary effect of the hyperglycemia and metabolic
acidosis. The glycosuria that is present leads to at least
mild dehydration and an associated increase in blood urea
nitrogen levels, as well as a mild increase in serum cre-
atinine levels. Although serum sodium levels might be
expected to be increased in a dehydrated state, the os-
motic effect of glucose draws water into the extracellu-
lar space and tends to reduce the sodium concentration.
Potassium levels will tend to be high because of the physi-
ologic compensation of the metabolic acidosis and the
hyperosmolarity and insulin deficiency present, al-
though it is known that total body stores of potassium
are depleted in DKA.19,22 It is therefore surprising to find
that nearly 8% of the patients in this review did not re-
quire potassium supplementation during treatment of
their DKA. Although phosphate is severely depleted be-
cause of glycosuria, the plasma values will vary because
of transmembrane shifts in the ion distribution caused
by metabolic acidosis and insulin deficiency. A stress-
induced leukemoid response is responsible for elevated
leukocyte counts.
A little more than one fourth of the patients had
newly diagnosed diabetes, accounting for approxi-
mately 20% of the admissions. Consistent with other re-
ports, newly diagnosed diabetes presenting with DKA was
diagnosed in a substantial number of overweight pa-
tients, a condition frequently associated with type 2 dia-
betes.6,16 Our results suggest that patients with newly di-
agnosed type 1 diabetes have a more normal electrolyte
profile than patients who have a known history of dia-
betes despite similar degrees of acidosis. This is a bit sur-
prising, since they had similar glucose levels, pH levels,
apparent ketonuria, and duration of symptoms. It is
known that the severity of ketoacidosis is decreased when
counterregulatory hormone levels are low.17 Further-
more, it would be expected that patients with newly di-
agnosed diabetes would have a more intact counterregu-
latory hormone system than patients with a prolonged
duration of diabetes.23 As such, we might predict that the
newly diagnosed diabetes would be associated with higher
glucagon and epinephrine levels, which would ulti-
mately induce a greater degree of ketogenesis and a more
severe picture of DKA. Hyperkalemia would be ex-
pected in both groups of individuals, since the insulin
deficiency is present in both, but would be predicted to
be greater in the more acidotic group. Since the groups
had similar pH levels, the potassium and phosphate lev-
els would be predicted to be similar if this were a major
contributing factor. Therefore, the normokalemia in the
(REPRINTED) ARCH INTERN MED/ VOL 164, SEP 27, 2004
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©2004 American Medical Association. All rights reserved.
newly diagnosed group suggests that another process, pos-
sibly related to the osmolarity, may be involved.
The newly diagnosed group did not have markedly
increased blood urea nitrogen levels and only very mildly
increased creatinine levels, possibly explained by the
known interference of acetoacetate with the assay,18 which
might suggest that they are not as dehydrated as the pa-
tients with a known history of diabetes. The new diag-
nosis group required more than 4 L of additional fluid
and more than 12 additional hours of treatment with the
insulin-glucose infusion to achieve a ketone-negative sta-
tus, as well as 10 L of additional fluid during the hospi-
talization compared with the previously diagnosed group.
However, the patients who also had pancreatitis ac-
counted for most of this increased fluid requirement. A
trend toward increased fluid requirements remained when
the patients with pancreatitis were excluded from the
analysis (data not shown). Some of the normalcy of the
laboratory results in the new diagnosis group could be
related to fluid intake and maintenance of urine output
before presentation to the emergency department; how-
ever, this cannot be verified given the retrospective na-
ture of our study. The status of the counterregulatory hor-
mones may or may not be useful in understanding the
observed differences between these groups; however, since
these hormones are generally not of practical value in the
clinical management of DKA, this study cannot address
this possibility.
Patients with type 2 diabetes can develop more than
mild ketosis and may experience moderate-to-severe DKA.
It has been said that these patients require a precipitat-
ing stressor; however, consistent with other reports, we
found that 29% of the patients did not have a precipi-
tant other than noncompliance with their medical
therapy.8 The tendency for the patients with type 2 dia-
betes who develop DKA being Latino or African Ameri-
can compared with white may only be a reflection of the
demographics of the overall patient population at Parkland
Memorial Hospital. However, the possibility of a true eth-
nic variation in patients with type 2 diabetes who are prone
to develop DKA, possibly from a genetic predisposition,
cannot be excluded. In contrast to other reports that com-
pared DKA in type 1 and type 2 diabetes, we found a dif-
ference in the serum electrolyte concentrations and other
biochemical levels of these 2 groups.8 Some of the dif-
ferences we observed may be secondary to differences in
counterregulation and basal insulin levels in these groups.
Our patients with type 1 diabetes had had their disease
for a duration of 12.7 years, which is likely long enough
to place the patients at a time long after the “honey-
moon period” and at a time when they are likely to have
absolute insulin deficiency. The patients with type 2 dia-
betes had a disease duration of 5.6 years and thus would
be expected to still have residual ␤-cell activity.24 Al-
though the type 2 diabetes group had insufficient insu-
lin to prevent DKA, it is theoretically possible that they
had enough insulin to modulate the disease process. In
support of this idea is the finding of lower potassium lev-
els in this group, which as noted herein are dependent
on insulin presence or absence. The less severe acidosis
suggests a lower level of ketoacids; however, this was not
detected in this study. Although we did not observe dif-
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ferences in the degree of ketonuria between the sub-
groups studied, we acknowledge that our method of mea-
suring ketoacids by semiquantitative urine testing fails
to identify the ketoacid that is most prevalent in DKA
and that a difference in ␤-hydroxybutyric acid levels could
exist, although this has not been studied.
The importance of recognizing DKA in a patient with
type 2 diabetes is illustrated by the time it took for these
patients to achieve a negative urine ketone status. Once
patients with either type 1 or type 2 diabetes were treated
by the intravenous insulin infusion protocol, the dura-
tion of treatment required to achieve a negative urine ke-
tone status was similar between the 2 groups. Patients
with type 2 diabetes, however, required more time from
initial presentation to the emergency department to
achieve negative urine ketones. Some of this delay may
be the result of a failure to suspect DKA in the “atypical
patient.”
Our results also show that the insulin-glucose in-
fusion algorithm outlined in the Figure can be used safely
in the management of patients who present with DKA
irrespective of the type of diabetes. Complications that
have been reported with management of DKA were in-
frequent in our population in part because of the age of
our patients but also because of the inclusion of a vari-
able glucose infusion algorithm in the treatment proto-
col. Resolution of the acidosis caused by the presence of
ketoacids is often used as a marker of resolution of DKA.
Reports that serum 3-␤-hydroxybutyric acid levels are
elevated in patients with type 2 diabetes who have nor-
mal fasting blood glucose levels raise concerns about their
utility in DKA management in patients with type 2 dia-
betes.25,26 Our use of urine ketone testing does not pro-
vide direct evidence of ␤-hydroxybutyric acid levels, but
since acetoacetic acid levels remain elevated longer27 and
since urine levels may be positive even after resolution
of serum levels of acetoacetate, the resolution of keton-
uria would imply adequate resolution of ketonemia.
Through our continuation of the insulin-glucose infu-
sion protocol until the urine was ketone free, we have
shown successful use of ketonuria as a marker of reso-
lution of DKA in both type 1 and type 2 diabetes. Fi-
nally, given our results of the successful, almost unevent-
ful management of DKA, we have shown that in adults
the modern management of DKA with essentially no com-
plications of treatment consists of effective intravenous
insulin therapy with concomitant glucose administra-
tion when plasma glucose levels decrease below 300
mg/dL (16.7 mmol/L), sufficient volume and electrolyte
replacement, and careful attention to identification and
management of associated problems, such as acute pan-
creatitis and infection.
Accepted for publication October 31, 2003.
We acknowledge the nursing and support staff of The
University Diabetes Treatment Center at Parkland Memo-
rial Hospital for their dedicated commitment and care of the
patients with diabetes admitted to this service.
Correspondence: Philip Raskin, MD, Department of In-
ternal Medicine, University of Texas Southwestern Medi-
(REPRINTED) ARCH INTERN MED/ VOL 164, SEP 27, 2004
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©2004 American Medical Association. All rights reserved.
cal Center at Dallas, 5323 Harry Hines Blvd, G5.238, Dal-
las, TX 75390-8858 (Philip.Raskin@UTSouthwestern.edu).
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