Pathophysiology of ketoacidosis in Type 2

Pathophysiology
Original article
Oxford, UK
Diabetic
DME
Blackwell
0742-3071
22 Article
Medicineof ketoacidosis
Publishing, Ltd.
2005 in Type 2 diabetes P. Linfoot et al.

diabetes mellitus
P. Linfoot, C. Bergstrom and E. Ipp

Abstract
Department of Medicine, Los Angeles Biomedical Aims Despite an increasing number of reports of ketoacidosis in populations
Research Institute at Harbor-UCLA Medical Center, with Type 2 diabetes mellitus, the pathophysiology of the ketoacidosis in these
Torrance, CA, USA
patients is unclear. We therefore tested the roles of three possible mechanisms:
Accepted 19 December 2005 elevated stress hormones, increased free fatty acids (FFA), and suppressed insulin
secretion.
Methods Forty-six patients who presented to the Emergency Department with
decompensated diabetes (serum glucose > 22.2 mmol /l and /or ketoacid concen-
trations ≥ 5 mmol /l), had blood sampled prior to insulin therapy. Three groups
of subjects were studied: ketosis-prone Type 2 diabetes (KPDM2, n = 13) with
ketoacidosis, non-ketosis-prone subjects with Type 2 diabetes (DM2, n = 15),
and ketotic Type 1 diabetes (n = 18).
Results All three groups had similar mean plasma glucose concentrations. The
degree of ketoacidosis (plasma ketoacids, bicarbonate and anion gap) in Type 1
and 2 subjects was similar. Mean levels of counterregulatory hormones (glucagon,
growth hormone, cortisol, epinephrine, norepinephrine), and FFA were not sig-
nificantly different in DM2 and KPDM2 patients. In contrast, plasma C-peptide
concentrations were approximately three-fold lower in KPDM2 vs. non-ketotic
DM2 subjects (P = 0.0001). Type 1 ketotic subjects had significantly higher
growth hormone (P = 0.024) and FFA (P < 0.002) and lower glucagon levels
(P < 0.02) than DM2.
Conclusions At the time of hospital presentation, the predominant mechanism
for ketosis in KPDM2 is likely to be greater insulinopenia.
Diabet. Med. 22, 1414–1419 (2005)
Keywords C-peptide, insulin, ketoacidosis, Type 2 diabetes
Abbreviations BMI, body mass index; FFA, free fatty acid; ICA, islet cell
antibody; KPDM2, ketosis-prone Type 2 diabetes; OHA, oral hypoglycaemic agent

findings that characterize the state of ketoacidosis: availability

Introduction
Ketoacidosis is a key clinical feature of Type 1 diabetes. The
mechanisms have been extensively studied and are known to
be a result of the severe insulin deficiency that underlies this
disease. Two other factors complete a triad of pathophysiological
Correspondence to: Eli Ipp MD, Harbor-UCLA Medical Center, 1000 W. Carson
Street, Box 16, Torrance, CA 90509-2910, USA. E-mail: ipp@labiomed.org
of substrate (free fatty acids) and a ketogenic set of the liver
that is dependent in large part upon elevation of circulating
counterregulatory hormones [1–3]. However, it has become
evident that ketoacidosis is no longer seen exclusively in Type 1
diabetes. A similar syndrome in Type 2 diabetes has now
been reported in numerous populations. Winter [4] first
described ketoacidosis in an inherited form of adolescent-onset
Type 2 diabetes in African-Americans. In many of these
patients, insulin was discontinued later and their course

1414 © 2005 Diabetes UK. Diabetic Medicine, 22, 1414–1419


was otherwise fairly typical Type 2 diabetes. Banerji [5] also
described ketoacidosis in black patients at onset or during the
course of Type 2 diabetes. Since then, this phenomenon has
been described in other ethnic groups by centres in the USA
[6–10] and world-wide [11– 16].
The pathogenic mechanisms identified in Type 1 diabetes
have not been tested during ketoacidosis in Type 2 diabetes,
although subjects studied after resolution of ketoacidosis are
reported to be relatively insulin deficient [5,6,17]. An addi-
tional explanation commonly provided for ketoacidosis in
Type 2 diabetes is increased severity of concomitant illnesses,
with stress-induced elevation of counterregulatory hormones
proposed as a contributory factor [18]. We therefore set out to
evaluate the pathogenic triad in subjects with Type 2 diabetes
and ketoacidosis. We tested whether counterregulatory
hormone and/ or free fatty acid concentrations are higher in
patients at initial presentation with ketoacidosis in Type 2
diabetes, compared with Type 2 patients and decompen-
sated diabetes who were not ketotic. In addition, we evaluated
insulin secretion during ketoacidosis in all subjects. Our
results suggest that the pathophysiology of ketoacidosis
in Type 2 diabetes is associated primarily with severe insulin
deficiency.
Materials and methods
Enrolment criteria
Any patient with serum glucose > 22.2 mmol / l and / or serum
ketones ≥ 1+ was eligible for enrolment. Subjects gave a complete
history and underwent full physical examination, and were
questioned about the time of their last meal and last use of
alcohol. Clinical ketoacidosis for screening purposes was defined
by the presence of a metabolic acidosis with anion gap > 16
mEq/l and serum ketones > 2+, measured semiquantitatively
using the nitroprusside method. Ketosis was subsequently
confirmed biochemically using quantitative radioenzymatic
assays. Ketoacidosis was considered to be present if total
serum ketones (acetoacetate and β-hydroxybutyrate) exceeded
5.0 mmol /l.
Patients groups
A non-consecutive, convenience sample was obtained of
patients who presented to the Harbor-UCLA Medical Center
Emergency Department with acutely decompensated diabetes
mellitus. We studied three groups of subjects. The primary
study group consisted of patients with ketoacidosis who
appeared to have Type 2 diabetes (ketosis-prone Type 2 diabetes,
KPDM2). There were two control groups. The primary control
group consisted of subjects with typical Type 2 diabetes who
presented to hospital with decompensated diabetes, but who
did not develop ketosis (DM2). Comparison between the two
groups of Type 2 diabetes allowed us to test which of the patho-
physiological triad—insulin deficiency, increased free fatty
acids (FFA) and / or counterregulatory excess— could account for
ketoacidosis. A second control group with ketoacidosis and
© 2005 Diabetes UK. Diabetic Medicine, 22, 1414–1419
Original article 1415
Type 1 diabetes was also included in order to provide addition-
al comparative data in patients with a classical clinical presen-
tation. However, we did not study patients with decompensated
Type 1 diabetes any further after screening if they were not
ketotic on biochemical analysis.
Subjects were placed into the Type 2 diabetic group if they
were islet antibody negative and in addition were treated with
diet or oral hypoglycaemic agent (OHA) therapy prior to pres-
entation. If diabetes was previously undiagnosed, subjects were
classified as Type 2 if they met three criteria: islet cell antibody
(ICA) negative, late-onset diabetes (age of onset ≥ 40 years or
> 35 years in Hispanics) and / or were overweight [body mass
index (BMI) > 27 kg / m2]. Where possible, measurement of
glucagon-stimulated C-peptide secretion at least 3 months after
presentation, or evidence for the absence of insulin dependency
(i.e. treatment with diet or OHAs) were obtained. Subjects were
classified as Type 1 diabetes only if they fitted typical clinical
criteria of leanness, young age of onset of diabetes and insulin
use since diagnosis. This resulted in a group consistent with the
Type 1 phenotype, with mean age of onset 26.0 ± 2.3 years and
BMI 21.5 ± 0.7 kg / m2, respectively (Table 1). Antibodies were
not measured in this group.
The total patient population consisted of 30 men and 18
women. Ages at the time of presentation ranged from 21 to
90 years. Prior informed consent was obtained in the Emergen-
cy Department from all patients who participated in this study,
which was approved by the institution’s human subjects review
committee. All patients had routine admission laboratory
studies and were managed by the admitting medicine service in
an intensive care unit setting.
Procedures
Prior to starting insulin infusion (usually after initiation of fluid
therapy), blood was sampled for estimation of C-peptide, glu-
cagon, cortisol, growth hormone, epinephrine, norepinephrine,
acetoacetate, β-hydroxybutyrate, lactate, pyruvate, and FFAs.
Where possible, ketotic subjects had a glucagon stimulation test
to assess β-cell secretory function after at least 3 months of out-
patient treatment. Following an overnight fast, 1 mg of glucagon
was injected intravenously. A plasma C-peptide concentration
> 0.6 nmol/l at 6 min post injection was defined as a Type 2
response [9,19].
Analytical methods
C-peptide, glucagon, cortisol, and growth hormone were meas-
ured by radioimmunoassay as previously described [20,21].
Epinephrine and norepinephrine were measured by radioenzy-
matic assays as described [20]. Acetoacetate, β-hydroxybutyrate,
lactate, and pyruvate were measured by enzymatic assays also
previously described [22]. FFAs were measured using the color-
imetric method of Falholt [23]. ICAs and insulin autoantibodies
were measured as described by Neufeld [24].
Statistical analyses were carried out using the Statview
program. ANOVA or χ2 analysis was used depending on whether
continuous or categorical data were used; post hoc analyses
were performed using Fisher’s PLSD test. Data are presented as
mean ± SEM, unless otherwise indicated.
 1416 Pathophysiology of ketoacidosis in Type 2 diabetes • P. Linfoot et al.

Table 1 Clinical characteristics of study subjects

Age Prior Age of Duration BMI

DM type (years) therapy onset (years) (years) (kg/m2) Precipitant

Type 2 non-ketotic
1 52 None 52 0 33.2 None found
2 77 OHA 60 17 44.1 None found
3 52 OHA 36 16 25.2 Cellulitis
4 38 None 38 0 36.6 None found
5 62 OHA 58 4 25.4 UTI
5 39 None 39 0 34.2 None found
7 44 OHA 41 3 27.3 Non-compliance
8 60 None 60 0 22.6 Pneumonia
9 90 OHA 89 1 — Pneumonia
10 62 OHA 47 15 32.0 Non-compliance
11 41 None 41 0 32.4 None found
12 73 OHA — — — Urosepsis
13 71 Diet 50 21 22.3 Obstructive uropathy
14 53 None 53 0 46.0 Pyelonephritis
15 40 OHA 40 2 — Foot ulcer, non-compliance
Mean ± SEM 57 ± 4.1 50 ± 3.7 5.5 ± 2.1 31.8 ± 2.2
(N = 15)
Type 2 ketotic
16 36 None 36 0 — Sepsis (died)
17 38 None 38 0 32.7 None found
18 42 OHA 41 1 23.0 Cholecystitis
19 50 None 50 0 20.1 None found
20 21 OHA 21 0.25 32.1 Non-compliance
21 23 OHA 22 1 — Exudative pharyngitis
22 42 Insulin 38 4 24.4 Non-compliance
23 53 None 53 0 40.4 Buttock abscess
24 36 OHA 35 1 24.8 Non-compliance
25 48 OHA 45 3 22.0 Non-compliance
26 58 Insulin 48 10 24.8 Non-compliance
27 68 Diet 63 5 25.4 Cellulitis
28 25 None 25 0 43.1 None found
Mean ± SEM 41 ± 3.9a 39 ± 3.4b 1.9 ± 0.8 28.4 ± 2.3
(N = 13)
Type 1 ketotic
Mean ± SEM 35 ± 2.3c None or 26 ± 2.3d,e 9.3 ± 2.0f 21.5 ± 0.7g,h
(n = 18) insulin

a
P = 0.0036 and bP < 0.0247 vs. Type 2 non-ketotic. cP = 0.0247, eP < 0.0001 and gP < 0.0001 vs. Type 2 non-ketotic. dP < 0.0001, fP = 0.0076 and
h
P = 0.0061 vs. Type 2 ketotic.
BMI, Body mass index; OHA, oral hypoglycaemic agent; UTI, urinary tract infection.

as an out-patient. All of the remaining nine KPDM2 subjects

Results
Classification of patients
Of 48 patients entered into the study, the data from 46 were
analysed (Table 1). Two subjects first classified as non-ketotic
Type 2 diabetes were found to be ICA+, placing them in the
non-ketotic Type 1 category, and were excluded. ICAs were
measured in all non-ketotic Type 2 and nine of 13 ketotic Type
2 subjects. The four subjects in whom ICAs were not obtained
were retained in the KPDM2 group because they were success-
fully managed subsequently with an OHA or, if they continued
to be treated with insulin, were found to maintain adequate
C-peptide secretory response to glucagon after several months
tested were ICA–. All subsequent statistical comparisons were
made between the following three groups: KPDM2, n = 13;
DM2, n = 15; Type 1 ketotic, n = 18.
Clinical and demographic features
For the most part, the clinical characteristics of KPDM2
subjects were similar to those without ketosis (Table 1). Only
the mean age of onset of diabetes was significantly lower in the
ketotic subjects (P = 0.0247), though not as low as in the Type 1
group (P = 0.0001). Duration of diabetes and the BMI were not
significantly different between the two Type 2 groups, though BMI
was higher in both than in the Type 1 group (P < 0.0065).

© 2005 Diabetes UK. Diabetic Medicine, 22, 1414–1419

 Original article 1417

Precipitating causes of metabolic decompensation were sim-
ilar in the two Type 2 groups (Table 1; note that more than one
cause was assigned to some subjects). The most common pre-
cipitant was infection in 7/ 15 of DM2 patients and 5 /13 of the
KPDM2 patients. Six patients had newly diagnosed diabetes in
the DM2 group and five in the KPDM2 group. In five DM2
and four KPDM2 subjects, no precipitating event could be
found—in both groups, in most of these this was the first pres-
entation of diabetes. Non-compliance with medication may
have been a factor in the decompensated diabetes of two DM2
subjects and five of the KPDM2 subjects.
The demographic characteristics of the three groups were
not similar. The Type 1 and DM2 patients were roughly evenly
distributed between men and women; Type 1 ketotic (7 F/11
M) and DM2 (8 F /7 M). However, KPDM2 subjects were pre-
dominantly males (2 F/11 M). Type 1 diabetes occurred more
often in caucasians (10 C/ 5 AA/ 3 H), DM2 in Hispanics (8 H /
4 AA /3 C) and KPDM2 in African-American and Hispanic
subjects (6 AA / 5 H/ 2 C).
Metabolic and hormonal features
The biochemical characteristics of the three groups are shown
in Table 2. All three groups had a similar degree of hypergly-
caemia. The two ketotic groups had a similar decrease in plasma
bicarbonate and comparable anion gap acidosis. pH in the
KPDM2 was less than in the DM2 group, but not as low as in
the Type 1 ketotic group. Levels of total plasma ketoacids were
elevated in both ketotic groups, and not significantly different
Table 2 Metabolic characteristics of subjects upon presentation to
emergency room
from each other (Table 2). Ketoacids were predominantly
in the form of β-hydroxybutyrate (acetoacetate not shown).
Lactate (Table 2) and pyruvate (not shown) were similarly,
mildly elevated in all three groups.
Mean concentrations of counterregulatory hormones and
FFA (Table 3) were not significantly different in KPDM2
and DM2, respectively. Epinephrine (661 ± 317 vs. 437 ± 164
pmol/ l), norepinephrine (7482 ± 1442 vs. 4716 ± 1093 pmol / l),
cortisol (772 ± 193 vs. 634 ± 110 nmol / l) and growth hormone
(84 ± 42 vs. 60 ± 19 pmol/ l) were elevated, but not significantly,
in the KPDM2 group. Plasma glucagon concentrations were
lower in the KPDM2 group (118 ± 15 vs. 200 ± 60 pmol/ l),
but also not significantly different from DM2. FFA levels upon
presentation were also not significantly different (673 ± 85 vs.
410 ± 42 µEq/ l, respectively). Type 1 ketotic patients showed
some differences from the other two groups. Growth hormone
concentrations were higher in Type 1 DM than in either of the
Type 2 groups (P = 0.0135 vs. DM2, P = 0.0240 vs. KPDM2).
In Type 1 patients, FFA concentrations (972 ± 190) were also
significantly higher ( P = 0.0017), and glucagon (74 ± 15),
significantly lower (P = 0.0189) than in the DM2 group; the
ketotic Type 1 and 2 subjects were not different.
Plasma C-peptide concentrations at the time of presentation
are shown in Table 3. Type 1 ketotic patients had the lowest
level of endogenous insulin secretion (0.118 ± 0.07 nmol/ l).
KPDM2 patients had intermediate (0.463 ± 0.08 nmol/ l) and
DM2 patients the highest C-peptide concentrations (1.245 ±
0.184 nmol/ l). Mean C-peptide concentrations in KPDM2
subjects were almost three times less than in DM2 patients. Both
ketotic groups had mean C-peptide levels that were significantly
different from the non-ketotic DM2 group (P = 0.0001).

Type 2 Type 2 Type 1 Discussion

DM type ketotic non-ketotic ketotic
The pathophysiology of ketoacidosis has been well described
Glucose (mmol/l) 31.2 ± 4.1 33.2 ± 4.1 31.3 ± 2.3 in Type 1 diabetes [1 – 3]. However, there is little information
Bicarbonate (mEq/l) 17 ± 0.8 22 ± 1.4 19.4 ± 1.5 on the pathophysiology of this metabolic state in Type 2
Anion gap (mEq/l) 16 ± 1.4 14.1 ± 1.5 19.9 ± 1.8 diabetes. This study provides a broad biochemical and hormonal
pH 7.30 ± 0.02 7.36 ± 0.04 7.22 ± 0.03
profile of ketoacidosis in patients with Type 2 diabetes, includ-
Total ketones (mmol/l) 9.0 ± 1.1 2.3 ± 0.4 11.8 ± 1.4
Lactate (mmol/l) 1.7 ± 0.4 1.4 ± 0.3 1.8 ± 0.3 ing FFAs, lactate, pyruvate and counterregulatory hormones
at presentation, and differs from previous studies of Type 2
Mean ± standard error of mean. ketoacidosis in a number of ways. First, previous studies of the

Table 3 Hormonal and free fatty acid (FFA)

values during presentation with ketoacidosis Type 2 Type 2 Type 1
ketotic non-ketotic ketotic

Epinephrine (pmol/l) 661 ± 317 437 ± 164 531 ± 208

Norepinephrine (pmol/l) 7482 ± 1442 4716 ± 1093 7454 ± 2134
Cortisol (nmol /l) 772 ± 193 634 ± 110 966 ± 193
Growth hormone (pmol/l) 84 ± 42 60 ± 19 567 ± 205a,b
Glucagon (pmol /l) 118 ± 15 200 ± 60 74 ± 15b
FFA (µEq/l) 673 ± 85 410 ± 42 972 ± 190c
C-peptide (nmol/l) 0.463 ± 0.08c 1.245 ± 0.184 0.118 ± 0.07c

Mean ± standard error of mean.

a
P = 0.024 vs. Type 2 ketotic. bP < 0.02 vs. Type 2 non-ketotic. cP < 0.002 vs. Type 2 non-ketotic.

© 2005 Diabetes UK. Diabetic Medicine, 22, 1414–1419

 1418 Pathophysiology of ketoacidosis in Type 2 diabetes • P. Linfoot et al.
pathogenesis of ketoacidosis in Type 2 diabetes reported
C-peptide only [6,17]. Second, those studies were carried out
after ketoacidosis had cleared [6,17]. Third, earlier compara-
tive studies of metabolic and hormonal pathogenesis such as
this did not distinguish between Type 1 and Type 2 DM; a
ketoacidosis group was compared with the hyperosmolar non-
ketotic state [2,25]. Thus, specific data on the pathogenesis of
Type 2 ketoacidosis are lacking, and the paucity of data in this
area of investigation was acknowledged in a recent technical
review [2].
Comparison of our two groups with Type 2 diabetes reveals
that despite similar degrees of deterioration in glucose control,
ketotic patients displayed a clear-cut ketoacidosis distinct from
non-ketotic control subjects, and similar to Type 1 patients
recruited in the same period. Because both Type 2 groups were
otherwise comparable with respect to their clinical presenta-
tion, we were able to evaluate the respective contribution of
the major mechanisms for ketoacidosis. The primary patho-
physiological triad tested include (i) an excess of circulating
counterregulatory hormones; (ii) increased delivery of the pri-
mary substrate for ketogenesis, i.e. FFAs; and (iii) diminished
insulin secretion [1–3]. This study demonstrates that, of these
three factors, diminished insulin secretion (measured as
C-peptide) during ketoacidosis best differentiates between the
two groups with Type 2 diabetes. Mean C-peptide levels were
three-fold lower in the KPDM2 group. In contrast, plasma
concentrations of the counterregulatory hormones and FFAs
were not significantly different in the two groups with Type 2
diabetes. This suggests that increased substrate availability
or hormonal stress do not explain increased ketogenesis in
Type 2 diabetes. However, it should be noted that the relatively
small size of the groups studied precludes a definitive statement
with respect to FFA and some (e.g. norepinephrine) but not
other (e.g. glucagon) counterregulatory hormones. Of note,
KPDM2 was associated with growth hormone levels similar to
DM2 patients, not the much higher concentrations seen in
Type 1 ketoacidosis (Table 3). This suggests that high growth
hormone levels seen in Type 1 ketoacidosis [25] may be
enhanced by younger age or lower BMI, rather than ketoaci-
dosis per se [25]. In this study, C-peptide concentrations in the
KPDM2 subjects were not significantly different from those in
Type 1 diabetic patients.
Diminished insulin secretion is clearly the initial event in
ketoacidosis of Type 1 diabetes and thus is a logical mecha-
nism for the syndrome seen in KPDM2. This is consistent with
other studies that measured insulin or C-peptide long after res-
olution of ketoacidosis [5]. The cause of severe insulinopenia
in Type 2 patients with ketoacidosis remains uncertain. In
many patients, insulin can be discontinued at a later date (e.g.
[5,15,16]), suggesting that severe insulin deficiency seen dur-
ing ketoacidosis later resolves in some cases. We therefore con-
sidered some of the possible transient causes of insulinopenia
in this clinical setting: (i) glucotoxicity impairs β-cell function
[26, 27]; yet ketotic and non-ketotic Type 2 subjects had
similar levels of hyperglycaemia at presentation [and HbA1c was
found to be similar in another group of similar patients that we
have since studied (J. Canales, personal communication)]; (ii)
hypokalaemia can impair insulin secretion [28]; however,
potassium levels were similar in ketotic and non-ketotic
subjects; (iii) prolonged fasting increases the rate of ketosis in
Type 1 subjects [29] and may decrease insulin secretion, but
the number of subjects who had fasted for longer than 12 h did
not differ between the two groups (data not shown).
Other factors that may have contributed to ketosis were
considered. No evidence for increased stress [18] was found;
both Type 2 groups were similar with respect to: (i) precipitat-
ing causes (Table 1), (ii) degree of elevation of counterregula-
tory hormones and (iii) severity of illness, evaluated indirectly
by measurement of serum osmolality and a blood urea nitrogen /
creatinine ratio (data not shown). Alcohol may cause ketoaci-
dosis, but does not explain insulinopenia [30]. Nor was there
a difference in the number of subjects reporting recent use of
alcohol in the Type 2 groups. Half of the KPDM2 subjects
denied prior use of alcohol at any time. Thus, although other
environmental factors cannot be ruled out, it is possible that
the insulinopenia observed in the KPDM2 subjects has a
unique constitutional or genetic basis.
Limitations of this study include the fact that we sampled at
only one time point in the evolution of ketoacidosis in these
patients. Prior to entry into the study, counterregulatory hor-
mone and FFA concentrations may have been different from those
observed, particularly if one takes into account the known
pulsatility of many counterregulatory hormones [20]. Also,
classification of patients as Type 1 or Type 2 diabetes is imper-
fect; in an attempt to deal with this problem, Maldonado et al.
[9] suggested that patients with ketoacidosis be classified into
four groups, based upon the presence or absence of autoanti-
bodies and / or evidence of residual insulin secretion subsequent
to the episode of ketoacidosis. We recognize that some among
the four subjects in the Type 2 group with ketoacidosis in whom
autoantibodies were not obtained could theoretically fall into
the Maldonado A+β+ group (antibody+; insulin secretion+),
and therefore technically have Type 1 diabetes. Since even
in that study [9] this was a relatively rare occurrence (10% of
patients with ketoacidosis), it is unlikely that subjects of this
type would be of significant number in our KPDM2 group.
In summary, we evaluated the metabolic pathophysiology
during ketoacidosis in patients with Type 2 diabetes. Our find-
ings indicate that β-cell dysfunction manifesting as severe insulin
insufficiency is the most likely proximate cause for ketoacidosis
in this setting.
Competing interests
None declared.
Acknowledgements
We are indebted to Dr Noel Maclaren who performed the ICA
measurements. We acknowledge the expert assistance of the
© 2005 Diabetes UK. Diabetic Medicine, 22, 1414–1419

nursing and laboratory staff of the GCRC at Harbor-UCLA
Medical Center and we thank the subjects who agreed to
participate. These studies were supported in part by a grant
from the NIH to the GCRC at Harbor-UCLA Medical.
Center (MO1-RR00425).
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