Syndromes of ketosis-prone diabetes mellitus

Syndromes of ketosis-prone diabetes mellitus

Authors
Ashok Balasubramanyam, MD
Ramaswami Nalini, MD
Section Editor
David M Nathan, MD
Deputy Editor
Jean E Mulder, MD
Disclosures
All topics are updated as new evidence becomes available and our peer review process is
complete.
Literature review current through: Mar 2013. | This topic last updated: May 3, 2012.

INTRODUCTION — Since the mid-1990s increasing attention has been focused on a

heterogeneous condition characterized by presentation with diabetic ketoacidosis (DKA)
in patients who do not necessarily fit the typical characteristics of autoimmune type 1
diabetes. Earlier reports used the terms "atypical diabetes," "Flatbush diabetes,"
"diabetes type 1B," and "ketosis-prone type 2 diabetes mellitus" to describe subsets of
this condition, and it was noted that in some instances patients presented with DKA as
the first manifestation of diabetes and evolved to insulin-independence [ 1 ]. While
initially these reports suggested that the condition, now termed ketosis-prone diabetes
(KPD), might be limited to persons of non-Caucasian ethnicity, its prevalence appears to
be increasing worldwide [ 2-22 ].

The classification, pathophysiology, natural history, and management of KPD will be

reviewed here. Patients with islet autoantibodies who do not present with ketosis,
including those termed "latent autoimmune diabetes in adults" (LADA), "type 1.5
diabetes" [ 23,24 ], and "slowly progressing type 1 diabetes" [ 25 ] are discussed
elsewhere. (See "Classification of diabetes mellitus and genetic diabetic syndromes" .)

CLASSIFICATION OF KPD — Ketosis prone diabetes (KPD) comprises a group of

atypical diabetes syndromes characterized by severe beta cell dysfunction (manifested
by presentation with DKA or unprovoked ketosis) and a variable clinical course. These
syndromes do not fit the traditional categories of diabetes defined by the American
Diabetes Association (ADA). To date, attempts to differentiate patients with KPD into
clinically distinct subgroups have resulted in four different classification schemes: the
ADA system, a modified ADA system, a BMI-based system, and the Aß system. The goal
of new classification schemes is to enable clinicians to predict which patients with DKA
require temporary insulin treatment versus life-long insulin therapy. They also highlight
subgroups for further genetic and pathogenetic studies.

In a longitudinal study comparing the four classification schemes for accuracy and
predictive value, the Aß system was shown to be the most accurate in predicting long-
term insulin dependence 12 months after the index DKA event, with 99 percent
sensitivity and 96 percent specificity [ 4,26 ].
ADA system — In the ADA classification, type 1 diabetes is characterized by
autoimmune destruction of the pancreatic beta cells, leading to absolute insulin
deficiency. Markers of immune-mediated diabetes include antibodies to glutamic acid
decarboxylase (GAD) and to the tyrosine phosphatase IA-2. Among patients presenting
with DKA (absolute insulin deficiency), those who lack autoantibodies are referred to as
"idiopathic type 1" or "type 1b"; the latter includes patients with the clinical appearance
of type 2 diabetes, with some becoming insulin-independent. (See "Classification of
diabetes mellitus and genetic diabetic syndromes", section on 'Type 1 diabetes' .)

Modified ADA system — A modification of the ADA scheme is utilized by investigators

in France, who divide KPD patients into three groups [ 22 ]. Patients with beta cell
autoantibodies are classified as type 1a just as in the ADA scheme, while those who lack
autoantibodies are distinguished retrospectively, based on long-term insulin dependence,
into "KPD insulin dependent" (KPD-ID) and "KPD non-insulin dependent" (KPD-NID).
Both type 1a and KPD-ID patients have clinical characteristics of type 1 diabetes with
poor beta cell function, while subjects with KPD-NID have clinical characteristics of type
2 diabetes with preserved beta cell function for a prolonged duration.

BMI system — The BMI-based scheme separates KPD patients into lean (BMI
<28 kg/m2, clinically resembling type 1 with low beta cell function) or obese (BMI
≥28 kg/m2, clinically resembling type 2 with preserved beta cell function) [ 11 ].

Aß system — The collaborative group at Baylor College of Medicine and the University
of Washington utilize a classification system (Aß classification) that distinguishes four
KPD subgroups based on the presence or absence of autoantibodies and the presence or
absence of beta cell functional reserve, as measured by a fasting or glucagon -stimulated
C-peptide level [ 3 ]. (See'Beta cell secretory reserve' below.) The four subgroups are
defined as follows:

 A+ß- autoantibodies present, beta cell function absent

 A+ß+ autoantibodies present, beta-cell function present
 A-ß- autoantibodies absent, beta cell function absent
 A-ß+ autoantibodies absent, beta cell function present

A+ß- and A-ß- patients are immunologically and genetically distinct from each other but
share clinical characteristics of type 1 diabetes with decreased beta cell function, and
both subgroups would be termed type 1 diabetes (type 1 and 1b) in the current ADA
classification system. A+ß+ and A-ß+ patients are immunologically and genetically
distinct from each other but share clinical characteristics of type 2 diabetes with
preserved beta cell functional reserve and would be termed type 2 diabetes in the ADA
scheme.

A-ß+ patients comprise the largest KPD subgroup (approximately 50 percent) in

multiethnic cohorts of KPD patients in the United States ( table 1 ). They are also the
patients who most commonly come to the notice of clinicians because they present with
DKA yet have the clinical features and subsequent behavior of type 2 diabetes [ 1,3,27 ].
In the interest of defining and investigating novel syndromes of beta cell dysfunction,
the broader terminology of "ketosis-prone diabetes" with its four subgroups subsumed
under the Aß classification, rather than ketosis-prone type 2 diabetes, is more useful and
it does not presume to define a syndrome a priori.

PATHOPHYSIOLOGY OF KPD SYNDROMES

Autoantibodies present, beta cell function absent or present — There is a
spectrum of beta cell destruction in patients with antibody positive diabetes.
Distinguishing A+ß- from A+ß+ KPD permits investigators to explore different
autoimmune pathways leading to clinically distinct patterns of beta cell loss, such as
different latencies and variable degrees of beta cell destruction.

The later onset and more moderate clinical course (ability to discontinue insulin for over
two years following the index episode of DKA in 50 percent of the patients) of A+ß+ KPD
compared to A+ß- KPD appears to be related in part to epitope-specific antibodies to the
65-kDa isoform of glutamic acid decarboxylase (GAD65). A specific amino-terminal
epitope defined by monoclonal antibody DPD correlated with higher beta cell functional
reserve and was associated with the milder A+ß+ phenotype [ 28 ]. The mechanisms
that result in this autoantibody specificity and give rise to variable beta cell functional
reserve remain to be elucidated.

Autoantibodies and beta cell function absent — A-ß- KPD is characterized by beta
cell failure without evidence of autoimmunity. Some A-ß- KPD patients may possess
untested autoantibodies such as those against the zinc transporter (ZnT8) [ 29 ] or
SOX13 (SRY-related HMG box antigen 13) [ 30 ]. Alternatively, some A-ß- KPD patients
may be misclassified as "A-" because of a decline in autoantibody titers over time. In
one cohort, only 10 percent of patients who were A-ß- had new-onset diabetes when
identified at presentation with DKA; the majority had had insulin-dependent diabetes for
many years previously [ 3 ].

However, a decline in antibody titer is less likely as GAD autoantibodies are reported to
be quite durable [ 31-33 ]. In addition, extensive HLA typing reveals that the frequencies
of major class II alleles associated with susceptibility to autoimmune type 1 diabetes are
not significantly higher in A-ß- KPD patients than in ethnic-matched population controls,
whereas they are significantly higher in A+ß- KPD patients, suggesting significant
differences in the two populations [ 34 ].

The strong family history of diabetes in relatives of A-ß- KPD suggests that there is a
familial trait and that genes required for beta cell development, regeneration, or function
may be involved. Potentially significant variants in the genes TCF1, PAX-4, and PDX-1,
encoding the key beta cell transcription factors hepatocyte nuclear factor-1alpha
(HNF1a), PAX-4, and pancreas-duodenum homeobox-1 (PDX-1), are enriched in A-ß-
KPD patients compared to ethnic-specific population controls; these may contribute to
the A-ß- phenotype [ 35 ].

Autoantibodies absent, beta cell function present — The A-ß+ phenotype is

characterized by partially reversible beta cell dysfunction, which may be due to
metabolic, genetic, or viral etiologies [ 36-38 ]. Increased oxidant stress in the islets
may also contribute to A-ß+ KPD. In one study of West African patients, X-linked
glucose-6-phosphate dehydrogenase (G6PD) deficiency contributed to depressed beta
cell defense against oxidant stress in the face of acute hyperglycemia, but its cause does
not appear to be a genetic mutation [ 39 ].

NATURAL HISTORY OF KPD SYNDROMES — The natural history of KPD after the
initial episode of DKA depends upon the presence of autoantibodies and long-term beta
cell reserve. Long-term beta cell reserve is the key determinant of long-term glycemic
control and insulin dependence [ 40,41 ].
The natural history of KPD is best detailed in large cohorts with longitudinal follow-up
[ 2,10,11,22,34 ]. One of the largest of these cohorts, the Houston cohort, includes 185
multiethnic adults patients admitted with DKA between 1999 and 2001 and followed for
a mean of 5.5 years. The most frequent KPD subgroup was A-ß+ (54 percent), followed
by A-ß-, A+ß-, and A+ß+ accounting for 20, 18, and 8 percent of patients, respectively
[ 34 ].

The A+ß- and A-ß- KPD patients displayed a typical course of complete insulin
dependence and difficulty in attaining and achieving excellent long-term glycemic
control. Although there was no difference in the mean age of the patients admitted with
DKA during study recruitment, there were significant group differences in mean age at
diabetes diagnosis and duration of diabetes ( table 1 ). Compared to patients with the A-
ß+ and A+ß+ phenotypes, patients with the A+ß- and A-ß- phenotypes were diagnosed
at an earlier age (approximately 25 versus 40 years) and had a longer duration of
diabetes (approximately nine versus two years).

The majority of A+ß+ KPD patients had new onset diabetes. Shortly after resolution of
DKA, about 50 percent of patients had adequate beta cell functional reserve and could
discontinue insulin; the others remain insulin dependent ( table 1 ).

Approximately 50 percent of A-ß+ KPD patients had new-onset diabetes and developed
DKA without a clinically evident precipitating factor ("unprovoked" A-ß+ KPD), while the
remainder had had long-standing diabetes prior to presentation with DKA, and developed
ketoacidosis in association with acute illness or noncompliance with antidiabetic
treatment ("provoked" A-ß+ KPD). Unprovoked A-ß+ KPD patients displayed a striking
male predominance (2.6:1, male:female) that is quite distinct from provoked A-ß+ KPD
patients (0.7:1); this gender imbalance has been noted also in patients with the
unprovoked A-ß+ KPD phenotype in other cohorts [ 10,22,42 ].

Longitudinal data suggest other phenotypic differences between the unprovoked and
provoked subgroups of A-ß+ KPD patients. Prospective assessment of 83 unprovoked
and 64 provoked A-ß+ KPD patients revealed that despite equivalent degrees of
hyperglycemia and beta cell functional reserve at initial testing following the index DKA
episode, the two subgroups had different genetic characteristics, natural histories of beta
cell function, and insulin requirements [ 43 ]. Unprovoked A-ß+ KPD was characterized
by reversible beta-cell dysfunction with male predominance and increased frequency of
DQB1*0602, whereas provoked A-ß+ KPD was characterized by progressive loss of beta-
cell reserve and increased frequency of DQB1*0302 and DRB1*04. In this prospective
assessment, unprovoked DKA predicted long-term beta-cell functional reserve, insulin
independence, and glycemic control in KPD patients.

In a smaller cohort study of patients with new-onset unprovoked DKA, beta cell
functional reserve was preserved in a greater proportion of obese compared with lean
patients [ 10,11 ].

In another cohort study with 10-year follow-up, KPD patients with the probable A-ß+
phenotype (unprovoked) initially achieved insulin independence and glycemic control
with oral agents [22 ]. At the end of the follow-up period, 40 percent were still insulin
independent. In those that required insulin, the mean duration until relapse to insulin
dependence was 40 months. Some of these patients experienced relapsing and remitting
ketosis.
MANAGEMENT OF KPD — Clinical management of KPD includes:

 Acute management of DKA

 Outpatient management shortly after resolution of DKA, including classification of
the patient according to KPD subgroup and evaluation of predictive factors
 Long-term management

Initial treatment is the same as for patients with type 1 diabetes and ketoacidosis.
However, the long term outcomes and insulin requirements of these patients are
variable. In the Houston cohort described above, insulin was successfully discontinued
after 12 months of treatment in 50 and 44 percent of patients in the A+ß+ and A-ß+
subgroups, respectively, whereas all patients in the ß- subgroups remained insulin
dependent ( table 1 ). Thus, a subset of patients will require long-term insulin therapy to
prevent recurrent ketoacidosis.

As these patients are heterogeneous and the "type" of diabetes is unclear at

presentation, they should all be maintained on insulin initially. In addition, in some
patients ketoacidosis may result from transient suppression of beta cell function due to
an increased sensitivity to glucose toxicity [ 1 ]. In these patients, insulin therapy is
required until recovery from the effects of glucose toxicity.

Acute management of DKA — All patients who present with DKA should be treated
according to established principles of acute management of the metabolic
decompensation. Standard inpatient hospital protocols requiring aggressive fluid
replacement, continuous insulin therapy, assessment for and treatment of precipitating
factors, monitoring for resolution of hyperglycemia, ketoacidosis and electrolyte
disorders, and transition from intravenous insulin to subcutaneous insulin regimens have
been well-described [ 1 ]. (See "Treatment of diabetic ketoacidosis and hyperosmolar
hyperglycemic state in adults" .)

Inpatient treatment during the episode of DKA should be the same regardless of the
apparent phenotype of the KPD patient, and all KPD patients should be discharged from
the hospital on a regimen that provides 24-hour insulin coverage. Any attempt to
withdraw insulin treatment should be based upon precise classification of the KPD
subgroup and assessment of predictive factors, which should be performed at the first
outpatient visit one to three weeks following hospital discharge.

Evaluation in the first 2 to 10 weeks following resolution of DKA — Assessment

of beta cell secretory reserve and beta cell autoimmunity can be performed one to three
weeks after resolution of ketoacidosis to minimize the acute effects of glucose toxicity or
desensitization on beta cell function. Beta cell secretory reserve (as measured by fasting
plasma C-peptide, C-peptide response to glucagon stimulation, and C-peptide to glucose
ratio) following DKA resolution is the strongest predictor of long-term glycemic control
and insulin dependence [ 40,41,44].

Beta cell secretory reserve — Beta cell function can be assessed by measuring
fasting or glucagon -stimulated C peptide concentrations. These tests are performed
after an overnight fast and at least 10 hours after the last dose of short-acting or
intermediate-acting insulin, metformin , or thiazolidinedione, and at least 24 hours after
a dose of sulfonylurea or long-acting insulin (glargine, detemir) [ 3 ]. The fasting C-
peptide measurement is less expensive and easier to perform.
Patients are classified as "ß-" if the fasting serum C peptide concentration is less than
1 ng/mL (0.33 nmol/L) and the peak serum C peptide response to glucagon (measured
at 5 and 10 minutes after intravenous injection of 1 mg glucagon) is less than
1.5 ng/mL (0.5 nmol/L) [ 3 ]. They are classified as "ß+" if the fasting serum C peptide
concentration is at least 1 ng/mL(0.33 nmol/L) or the peak serum C peptide response to
glucagon is at least 1.5 ng/mL (0.5 nmol/L). Although the cut-points noted above do not
independently predict the potential for successful and safe withdrawal of insulin, a high
ratio (>11) of fasting C-peptide (in nmol/L) to glucose (in mmol/L) at six months
predicts such a course among ß+ patients [ 41 ].

These cutpoints (established using the Linco RIA for human C-peptide) have been shown
to accurately predict beta cell function and glycemic control after one year [ 4,40 ];
however, they have not as yet been standardized across other C-peptide assays.

Beta cell autoimmunity — Although beta cell functional reserve provides most of the
information required to predict the patient's clinical course, careful quantitative
assessment of beta cell autoantibodies is also clinically useful, specifically for patients
with the predominantly "new-onset" A+ß+ KPD phenotype. Patients of this subgroup
follow one of two divergent clinical courses within the first two years of diagnosis;
approximately 50 percent maintain stable beta cell function and remain insulin
independent, while the others convert to ß- status and become insulin dependent. Hence
identification of patients as A+ß+ rather than simply ß+ alerts the clinician to follow
them closely. Furthermore, these are the patients in whom HLA genotyping provides
additional prognostic markers of clinical behavior, as the presence of specific
autoimmune type 1 diabetes susceptibility alleles such as HLA DQB1*02 are associated
with higher risk of progressive beta cell functional loss. (See "Pathogenesis of type 1
diabetes mellitus", section on 'Genetic susceptibility' .)

GAD65 and insulinoma-associated protein 2 (IA-2) autoantibody titers can be measured

in the patients' sera by highly sensitive and specific assays, with care taken to establish
the upper limits of the normal range for the autoantibody levels specifically for each
regional ethnic group [ 3 ]. Patients may be classified as "A+" if the autoantibody index
for either of the autoantibodies exceeds the ethnic-specific 99 th percentile or "A-" if the
indices for both are below the 99 th percentile.

Clinical practice — Long-term management of KPD can be guided rationally by

accurate classification based upon assessment of beta cell functional reserve, beta cell
autoantibodies, and in some instances, HLA allelotyping. Although assessment of these
parameters in all patients presenting with DKA is ideal, cost constraints and assay
availability may be prohibitive in some regions.

For patients with DKA and the typical type 1 diabetes clinical phenotype (young, thin), it
is probably unnecessary to check C-peptide or antibodies. These patients should be
continued on insulin indefinitely.

However, for anyone presenting in an atypical fashion (older, overweight, no

spontaneous weight loss, non-Caucasian ethnicity), measurement of C-peptide and
antibodies (GAD65, IA-2) should be considered for classification of KPD type and for
greater certainty in selecting patients for insulin withdrawal. In regions where such
testing is unavailable, future likelihood of insulin independence in atypically presenting
patients can be assessed by reducing the insulin dose and monitoring serum glucose and
serum or urine ketones. The safety of the latter approach depends upon a patient's
ability to self-monitor and the attentiveness of the provider. (See 'Assessing for insulin
independence' below.)

Glycemic management in the first 2 to 10 weeks following discharge — Because

the "type" of diabetes is unclear at presentation, all patients should be maintained on
insulin initially. Insulin should never be discontinued in patients who are classified as "ß-
", regardless of whether they are A+ or A-, as these patients invariably require insulin to
avoid ketosis. Evidence from the Houston cohort shows that no patient initially classified
as "ß-" by the above protocol has recovered beta cell function sufficiently to warrant a
trial of insulin withdrawal.

Assessing for insulin independence — Future likelihood of insulin independence in

patients who are initially categorized as "ß+" may be assessed as follows. Patients are
placed on twice daily NPH insulin at the time of hospital discharge, with the dose
determined by the mean daily insulin requirement during the previous two hospital days.
Patients with known diabetes may be given insulin at the dose they were receiving
before the onset of DKA. In previously insulin-naive patients, another approach is to
administer multidose insulin at a dose of 0.6 to 0.8units/kg per day, with 50 percent as
regular or rapid-acting insulin (in divided doses before meals) and 50 percent as basal
insulin [ 45,46 ]. Dose can be titrated with frequent glucose monitoring until an optimal
dose is established. The first clinic visit is within two weeks of discharge from the
hospital. (See "Insulin therapy in adults with type 1 diabetes mellitus", section on
'Designing an MDI insulin regimen' .)

If capillary blood glucose values before each meal and at bedtime during a two-week
period attain ADA goals for fasting/pre-prandial (90 to 130 mg/dL [5.0 to
7.2 mmol/L]) andbedtime/peak post-prandial plasma glucose levels
(180 mg/dL [10.0 mmol/L]), the insulin dose is reduced by 50 percent and the patient
reassessed in the clinic one week later. If mean blood glucose values remain at goal for
two consecutive clinic visits, insulin is discontinued and the patient is monitored closely.

Patients are advised to use urine ketone strips or a blood ketone testing meter to check
for significant ketosis if the blood glucose level rises above 200 mg/dL. If blood glucose
values remain at goal, they are instructed to continue with lifestyle modification and are
monitored without pharmacologic therapy.

If blood glucose values increase without development of ketosis, the patients are placed
on oral hypoglycemic agents. In A-ß+ patients, insulin sensitizing agents such
as metformin are recommended, as these patients have the highest frequency of the
metabolic syndrome among KPD groups [ 47 ]. (See "Initial management of blood
glucose in type 2 diabetes mellitus" .) If blood glucose levels do not achieve therapeutic
targets within eight weeks, addition of low doses of a sulfonylurea, thiazolidinedione,
meglitinide or alpha-glucosidase inhibitor should be considered. (See "Management of
persistent hyperglycemia in type 2 diabetes mellitus" .)

Aggressive management of the metabolic syndrome (including weight loss and exercise)
and cardiovascular risks are important in all subgroups of KPD patients. (See "The
metabolic syndrome (insulin resistance syndrome or syndrome X)", section on 'Lifestyle
modification' .)
Conversely, if the patient develops ketosis upon decreasing the insulin dose, the insulin
regimen is intensified and no further attempts are made to discontinue insulin.
(See "Insulin therapy in adults with type 1 diabetes mellitus" .)

The duration of this process of insulin withdrawal is variable and may range from 10 to
14 weeks to longer.

Long-term management — Once the patient has been classified for KPD type,
assessed for predictive factors and begun on an appropriate treatment course, standards
of diabetes management should be followed. Patients should be counseled by a
nutritionist and diabetic educator periodically. Physical activity for at least 150 minutes
per week should be recommended, and weight loss may be advised for all obese
patients. Smoking cessation should be reinforced. Screening and treatment for
microvascular and macrovascular complications of diabetes are advised. (See "Overview
of medical care in adults with diabetes mellitus" .)

Special considerations — As described earlier, A-ß+ KPD patients may be divided into
a new-onset "unprovoked" group (presenting with DKA in the absence of significant
stress) and a previously diagnosed "provoked" group (DKA associated with significant
stress). Patients in the former subgroup have a significantly greater rate of insulin
discontinuation and better long-term glycemic control than the latter.

New onset diabetes, older age at onset of diabetes, and high levels of beta cell functional
reserve (fasting C-peptide to glucose ratio >11) may be used as reliable predictors of
insulin discontinuation in ß+ patients [ 41,44,48,49 ]. In a multivariate model, new
onset diabetes and beta cell functional reserve remained predictive.

The presence of beta cell autoantibodies is a determinant of future beta cell function. In
analyses that do not differentiate the four Aß subgroups, KPD patients with
autoantibodies tend to have lower beta cell function both shortly after the correction of
the acidosis and on long-term follow-up [ 17,22 ]. However, this is not an infallible
criterion, as approximately 50 percent of A+ß+ KPD patients maintain long-term beta
cell functional reserve. Most A+ß+ KPD patients are able to come off insulin therapy
initially, but they require close monitoring for at least two years, since the evolution of
their beta cell function is the least predictable of the KPD groups. HLA typing may play a
useful role in the management of this group of KPD patients, as it may help to identify
those who are likely to experience a more aggressive course or may be candidates for
future immunomodulatory therapy.

SUMMARY AND RECOMMENDATIONS — Ketosis-prone diabetes (KPD) is a

heterogeneous syndrome characterized by the presence of diabetic ketoacidosis in
patients who may lack the typical clinical phenotype of autoimmune type 1 diabetes.
Recognition of KPD coincides with the emergence of the concept that early beta cell
dysfunction is likely to be a primary defect in the pathophysiology of diabetes, regardless
of "type." Although proper epidemiologic surveys remain to be conducted, syndromes of
KPD appear to be increasingly recognized worldwide, especially among urban,
multiethnic populations. They offer challenges to both clinicians and researchers, but
also offer the prospect of revealing novel mechanisms of beta cell dysfunction relevant to
common forms of diabetes.

Classification
  There are four different classification schemes for KPD. The Aß classification
distinguishes four KPD subtypes based upon the presence or absence of
autoantibodies and beta cell functional reserve. This classification most
accurately predicts long-term insulin dependence 12 months after DKA
presentation. (See 'Classification of KPD' above.)

Evaluation and management

 DKA should be treated according to established principles. (See "Treatment of

diabetic ketoacidosis and hyperosmolar hyperglycemic state in adults" .)
 When patients are discharged from the hospital after resolution of DKA, we
recommend initial treatment with insulin, rather than oral agents, regardless of
the apparent phenotype of the KPD patient ( Grade 1B ). (See 'Management of
KPD' above.)
 Assessment of beta cell reserve and beta cell autoimmunity after resolution of
DKA helps predict clinical course and long-term treatment. This assessment is
typically performed one to three weeks after resolution of ketoacidosis.
(See 'Evaluation in the first 2 to 10 weeks following resolution of DKA' above.)

Natural history

 Patients with poor beta cell function (ß-) after resolution of the index DKA event
typically require long-term exogenous insulin therapy, regardless of
autoantibody status. (See 'Glycemic management in the first 2 to 10 weeks
following discharge' above.)
 Patients with beta cell secretory reserve who are antibody negative (A-ß+) are
often able to discontinue insulin, especially if they had unprovoked DKA as the
initial manifestation of diabetes. The duration of the process of insulin
withdrawal is variable and may range from 10 to 14 weeks to longer.
(See 'Assessing for insulin independence' above.)

If after discontinuation of insulin blood glucose values increase without

development of ketosis, treatment with oral or injectable agents to lower blood
glucose is required.

If the patient develops ketosis upon decreasing the insulin dose, insulin should
be intensified. In this setting, we suggest not attempting to withdraw insulin a
second time ( Grade 2C ). (See 'Assessing for insulin independence' above.)
 Patients with preserved beta cell function who have autoantibodies (A+ß+) have
a variable course with some demonstrating progressive beta cell deterioration
and others long-term preservation. This group of individuals requires more
careful monitoring, and these patients may benefit from HLA genotyping to
provide additional prognostic markers of clinical behavior. (See 'Beta cell
autoimmunity' above.)

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