CASE REPORT
H1N1 Influenza: The Trigger of Diabetic Ketoacidosis in a
Young Woman With Ketosis-Prone Diabetes
Huiwen Tan, MD, Chun Wang, MD and Yerong Yu, MD
Abstract: In this study, the authors report a case of new-onset ketosis-
prone diabetes in a 21-year-old Chinese woman with H1N1 influenza,
who presented with fever, polyuria and loss of appetite for 3 days
before admission. She was hospitalized and diagnosed with acute-onset
diabetic ketoacidosis for the first time. Her diabetes-associated anti-
bodies were negative. Interestingly, she had an unexplained fever and
her white blood cell count was low at admission and remained low for
several days. She was believed to have a viral infection, which was
found to be H1N1 influenza infection. The literature regarding virus
infection and diabetic ketoacidosis is reviewed. The precipitating fac-
tors, symptomatology, pathophysiology and management of ketosis-
prone diabetes are discussed in the current case report.
Key Indexing Terms: Diabetes; Diabetic ketoacidosis; H1N1 influenza;
Precipitate factor; Classification. [Am J Med Sci 2012;343(2):180–183.]
I n April 2009, the first report of H1N1 influenza was pub-
lished.1 An outbreak of H1N1 influenza A virus infection was
detected in Mexico, with subsequent cases observed in many
other countries, including the United States and China.1,2 In-
fection with H1N1 influenza A virus may result in worsening of
chronic medical conditions with a higher risk of severe com-
plications. A relationship between virus infection and diabetic
ketoacidosis (DKA) in patients with ketosis-prone diabetes
mellitus (KPD) has been proposed.3,4 KPD, once described as
atypical diabetes mellitus, idiopathic type 1 diabetes, type 1B
diabetes and Flatbush diabetes,4 –7 is an uncommon subform of
diabetes first described in African American patients and re-
cently in Asian populations, including the Japanese and Chi-
nese.8,9 Patients with KPD often present acutely with DKA
without autoantibodies to islet antigens of classic type 1 dia-
betes, but they demonstrate clinical and metabolic features of
type 2 diabetes.5,8 It has long been assumed that an episode of
DKA is a hallmark of type 1 diabetes mellitus, but it is now
recognized that DKA can occur in type 2 diabetes under
conditions of severe stress or infection and even without any
definite precipitating factors. This syndrome was recently
named ketosis-prone type 2 diabetes or KPD.5 In this study, we
present a case of KPD in a patient precipitated by H1N1
influenza.
CASE REPORT
A 21-year-old Chinese woman presented with fever,
polyuria, polydipsia and loss of appetite for 3 days. On day 2,
From the Division of Endocrinology and Metabolism (H-WT, CW, Y-RY)
and Laboratory of Endocrinology and Metabolism (Y-RY), West China
Hospital of Sichuan University, Chengdu, China; and Division of Endocri-
nology (H-WT), Geronotology and Metabolism, Stanford University School
of Medicine Palo Alto, California.
Submitted April 25, 2011; accepted in revised form September 9, 2011.
Presented at the 71st American Diabetes Association Scientific Session,
June 24 –28, 2011, San Diego, California.
Correspondence: Yerong Yu, MD, Division for Endocrinology and
Metabolism, West China Hospital of Sichuan University, Guoxue Road 37,
Chengdu 610041, China (E-mail: yerongyu@scu.edu.cn).
180 The American Journal of the Medical Sciences • Volume 343, Number 2, February 2012
she visited the clinic of a local general practitioner, where she
was treated for common cold but no specific diagnosis was
made. She was told to drink more water and to take rest. Fever,
weakness and general malaise developed. On the third day,
nausea and vomiting occurred without cough or abdominal
pain, and she visited the No. 2 People Hospital where her blood
glucose was found to be ⬎30 mmol/L. After insulin and fluid
replacement therapy, her blood glucose decreased to 20
mmol/L. The patient still felt weakness and nausea. She was
seen in the emergency department of West China Hospital and
was diagnosed as having severe hyperglycemia and positive
urinary ketone bodies. She had a family history of diabetes and
was overweight. She had no history of drug abuse or heavy
drinking (soft drinks or alcohol).
At admission, her height was 156 cm and weight 62.8
kg. Her body mass index was 25.8 kg/m2 even while clinically
dehydrated. She had lost almost 5 kg in 1 week. Her blood
pressure was 107/65 mmHg and heart rate was 110 bpm.
Respirations were 26 per minute. Physical examination of the
chest and heart revealed no abnormalities, and the abdomen
was soft. Her deep tendon reflex was normal. Neither patho-
logic reflexes nor paralysis was observed. No clinical evidence
of diabetic retinopathy, neuropathy or nephropathy was found.
Laboratory data are shown in Table 1. Plasma glucose at
admission was 18.28 mmol/L (329 mg/dL) and serum potas-
sium was 1.62 mmol/L. Her urine had 4⫹ ketones, and arterial
blood gases showed compensated metabolic acidosis. The ar-
terial pH was 7.2, anion gap was 25 mmol/L and serum
bicarbonate was 7.8 mmol/L. Her serum C peptide was 0.145
nmol/L. Insulin autoantibodies, islet cell antibodies and glu-
tamic acid decarboxylase antibodies were negative. Her chest
x-ray revealed no infiltrate (Figure 1). Abdominal ultrasonog-
raphy showed hepatic adipose infiltration (Figure 2).
On the basis of these findings, we diagnosed and treated
her for new-onset KPD according to the accepted criteria in a
consensus statement from the American Diabetes Association.7
Fluid repletion was initiated with isotonic saline (0.9% sodium
chloride) to correct the fluid deficit. To reduce the serum
glucose concentration, she was given a bolus of 10 IU of
regular insulin intravenously, followed by a continuous intra-
venous infusion of regular insulin at a rate of 0.1 U/kg/hr. She
was subsequently treated with subdermal glargine 6 units
before bedtime and 4 to 8 units of insulin aspart (Novo R)
before each meal: for a total daily insulin dose of 18 to 30 units
under intensive monitoring of plasma glucose. The doses of
insulin were adjusted according to her blood glucose. Except
for fever, the other symptoms subsided within 48 hours, and her
blood glucose level was near-normalized within 72 hours. Her
body temperature, however, increased to 38.6, and urine ke-
tones were still positive. In addition, it was interesting to note
that bacterial culture was negative. The white blood cell count
was 1.59 ⫻ 109 /L. She was suspected of having a viral
infection, and an H1N1 influenza screening was positive, which
as confirmed by the Center for Disease Control and Prevention
 H1N1 Influenza Induces DKA

gradually diminished over the next 2 weeks. She was dis-

TABLE 1. Laboratory date of the patient with KPD charged with advice for periodic follow-up. The patient was
on admission
taken off insulin and remained near-normoglycemic on Met-
Reference value formin 500 mg orally twice a day. Eight weeks after diagnosis
and normal and treatment, the patient maintained good weight control
Subjects Data range (body mass index, 23.9 kg/m2) and near-normoglycemic con-
Blood analysis trol, with fasting plasma glucose less than 7.0 mmol/L and C
RBC (⫻1012/L)
peptide of 0.26 nmol/L after short-term insulin therapy. Her
3.97 3.5–5.5
hemoglobin level had decreased from 12.3% to 6.9% (Table 2).
WBC (⫻109/L) 1.59 4–10
Platelets (⫻109/L) 125 100–300
Hemoglobin (g/L) 102 120–160 DISCUSSION
Arterial blood gas analysis The morbidity and mortality associated with H1N1 virus
pH 7.201 7.35–7.45 infection is relatively low.1,2 However, it still causes severe
Bicarbonate ion (mmol/L) 7.8 22–27 complications such as DKA in patients with diabetes.3 The
Base excess (mmol/L) ⫺22 ⫺2 to ⫹ 3 most common clinical characteristics of the H1N1 influenza
␤-Cell function and autoantibodies pandemic were fever [temperatures of 100°F (37.8°C) or
greater], cough, sore throat or headache; vomiting and diarrhea
Triglyceride (mmol/L) 1.95 0.29–1.83
were also frequent, both of which are unusual features of
Fasting plasma glucose (mmol/L) 9.4 3.9–5.6
seasonal influenza. There were 1.29 million people who re-
Two-hour blood glucose (mmol/L) 21.42 3.9–7.8 ceived the H1N1 influenza vaccine in Sichuan Province after
Fasting C peptide (nmol/L) 0.145 0.48–0.78 the first case of a Chinese student in Chengdu was reported,
Two-hour C peptide (nmol/L) 0.226 1.34–2.50 who had been to the United States for short-term study in
HbA1c (%) 12.3 4.5–6.1 2009.2 In the current case, we found that H1N1 infection was
GADA (U/mL) 0.59 ⬍1.05 the precipitating factor of DKA in a young Chinese woman
IAA (%) 0.94 5 with new-onset diabetic ketosis. To our knowledge, this is the
ICA Negative Negative first report of H1N1 infection in patients with KPD in China.
Urinalysis The prevalence of KPD and the underlying pathogenesis of this
Protein (⫺) Negative
syndrome are unclear.5– 8,10 Results of the current case study
may help illustrate the pathophysiology of KPD.
Blood (⫺) Negative
This case has several unique features. First and foremost,
Glucose (⫹⫹⫹⫹) Negative this individual with KPD is a young overweight woman with
Ketone body (⫹⫹⫹⫹) Negative negative antibodies and preserved ␤-cell function. Insulin-
RBC, red blood cells; WBC, white blood cells; HbA1c, hemoglobin related antibodies, including glutamic acid decarboxylase anti-
A1c; GADA, glutamic acid decarboxylase antibodies; IAA, insulin body, islet cell antibodies and insulin autoantibodies, are hall-
autoantibody; ICA, islet cell antibody. marks of classic type 1 diabetes. Her pancreatic ␤-cell function
was preserved as shown by her fasting C peptide concentration
and oral glucose tolerance test. This differs in some respects
from the classic autoimmune type 1 diabetes or typical type 2
in Chengdu by reverse transcriptase polymerase chain reaction diabetes.4 Recent evidence indicated that most patients with
methodology.9 On the third hospital day, the patient was KPD are obese, middle-aged men with a strong family history
transferred to the Division of Infection of West China Hospital, of type 2 diabetes, but few women have spontaneous diabetic
where she remained on insulin and was treated with the anti- ketosis.10,11 At presentation, patients with KPD showed signif-
viral, Tamiflu (75 mg twice daily). Six days after the initiation icant impaired insulin secretion and action, but intense antidi-
of antiviral medication, the patient recovered uneventfully. Her abetic treatment results in marked improvement in insulin
flu symptoms disappeared, and her white blood cell count sensitivity and pancreatic ␤-cell function, allowing discontin-
returned back within the normal range (white blood cell count, uation of insulin in the follow-up period.8,10 What causes the
4.34 ⫻ 109/L with 68.8% neutrophils). Insulin requirements initial pancreatic ␤-cell insult leading to acute insulin defi-
ciency if there is no auto-immunology evidence in patients with
KPD? Recent studies show that patients with new-onset type 2
diabetes are prone to diabetic ketosis, especially overweight
patients. The increased prevalence of KPD in men indicates
that there may be other causes and mechanisms involved.
Although hormonal factors, including estrogen and testoster-
one, are favorite suspects in search for the underlying patho-
physiology of the male predominance in KPD, body fat distri-
bution and other less recognized factors may play a significant
role in glucose homeostasis and insulin sensitivity changes.
Environmental factors, such as diet and physical activity, and
still largely unknown genetic factors interact to produce the
syndrome.10,11
Second, we observed that our patient with KPD had
fever caused by the H1N1 virus before the onset of DKA. The
most common triggers that cause a patient with diabetes to
FIGURE 1. Chest x-ray of the patient with KPD and H1N1 influenza. develop DKA are infection, followed by noncompliance

© 2012 Lippincott Williams & Wilkins 181

Tan et al
FIGURE 2. B-ultrasound images of the liver and kidney in the patient with KPD and H1N1 influenza.
with therapy such as omission of insulin therapy or inade-
quate insulin therapy. Other possible triggers include stress,
surgery, heart attack and stroke, alcohol or drug abuse and
heavy consumption of soft drinks.4 In the current case, the
precipitating factor for the development of DKA is H1N1
virus infection, which has rarely been reported.2 Most pa-
tients with DKA present with a high leukocyte count. In
ketoacidosis, leukocytosis is attributed to stress, dehydration
and demargination of leukocytes. However, values lower
than 4000 are seldom seen in the absence of virus infection.
In light of this report, we suggest that virus infection should
be kept in mind when patients with KPD have hyperglyce-
mia and fever with neutropenia.
In addition, this case also highlights the fact that not only
bacterial infection but also virus infection [such as human
herpes virus-8 (HHV-8), herpes zoster virus and H1N1] can be
potential triggers of DKA in patients with diabetes,10 –12 al-
though the association between virus infection and KPD has
not been well described in the medical literature.11,12 Investi-
gators in France found a high association between KPD and
HHV-8 infection,12 and produced evidence that this virus was
able to infect human ␤-cells in vitro. In Japan, 3 viruses have
been reported to be the precipitating factor in the development
of fulminate type 1 diabetes.7 These triggers were HHV-6,
herpes simplex virus and Coxsackie B3 virus.6,9 The possibility
of virus infections in the development of KPD is still uncer-
TABLE 2. The change of demographic and laboratory
characteristics of the patient with KPD at onset and during
near-normoglycemic remission
Baseline Follow-up (8 wk)
Weight (kg) 62.78 58.22
BMI (kg/m2) 25.8 23.9
Fasting glucose (mmol/L) 18.28 6.7
HbA1c (%) 12.3 6.9
Fasting C peptide (nmol/L) 0.145 0.26
WBC (⫻109/L) 1.59 4.34a
a
WBC count was detected on 1 day before the discharge.
BMI, body mass index; WBC, white blood cells.
182
tain.12 The association between KPD and H1N1 influenza may
involve many complex and interrelated factors, all of which
require further research and analysis.
CONCLUSIONS
This case exemplifies the fact that DKA can occur not
only in patients with type 1 diabetes but also in type 2 diabetes
during severe infection or stress conditions. The exact type of
KPD is still in dispute.13 It is often difficult to classify patients
with acute-onset diabetic ketosis at the time of diagnosis,
especially those with negative antibodies. Despite major ad-
vances in the understanding of the potential pathogenesis and a
more uniform agreement on the diagnosis of KPD, there is
increasing clinical evidence that indicate that patients with
this syndrome are more likely to have A⫺␤⫹ KPD,14 which is
similar to classic type 2 diabetes, and that some patients can
remain in near-normoglycemic remission without insulin after
intensive glycemic management.
Early diagnosis and prompt treatment, including identi-
fication of comorbid precipitating causes in DKA, are impor-
tant in patients with DKA. Physicians should be prepared to
provide emergency care to patients with KPD to decrease the
risk of increased morbidity and mortality during a severe
influenza pandemic in the future.
ACKNOWLEDGMENTS
We thank our patient and her mother for all their help
and enthusiasm. We also acknowledge our clinical colleagues
in the Division of Endocrinology and Metabolism of West
China Hospital, especially Dr. Hui Huang and Yan Ren, MD,
for their help in organizing various investigations.
We are grateful to Professor Andrew R. Hoffman, Divi-
sion of Endocrinology, Gerontology and Metabolism, Stanford
University School of Medicine, for his support and advice in
manuscript revision.
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