There are four types of KPD T2's
.
Ketosis-prone diabetes: dissection of a heterogeneous syndrome using an immunogenetic and beta-cell functional classification, prospective analysis, and clinical outcomes
It is classified by antibodies and pancreatic capacity. This seems obscure but it isn't very hard.Analysis of clinical, phenotypic, and genotypic data derived
from this prospective characterization of multiethnic, heterogeneous,
ketosis-prone diabetic patients indicates the presence of novel
forms of ß-cell dysfunction as well as a classification
scheme to categorize these patients. We propose four groups
based on two important features commonly used to distinguish
type 1 and type 2 diabetes: presence or absence of biological
markers of ß-cell autoimmunity, and presence or complete
absence of ß-cell functional reserve. This is not
meant to be rigid classification, but rather a hypothesis-testing
scheme to differentiate etiologically and clinically distinct
forms of ketosis-prone diabetic syndromes, and thus to uncover
novel forms of ß-cell dysfunction. The distinctive
pathogenetic features and diagnostic implications of the four
Aß groups are discussed individually below.
A+ß- group
Patients in this group, with significantly low ß-cell
functional reserve together with circulating ß-cell
autoantibodies, are likely identical with the well-defined form
of autoimmune type 1 diabetes. They had early onset diabetes
and were generally lean. African-American patients predominated
in this group. The results of the HLA analysis supported the
contention that these patients have typical autoimmune type
1 diabetes. Irrespective of ethnicity, certain HLA allelic variants
are found in high frequency in persons with autoimmune type
1 diabetes (
19,
24,
25,
26,
27,
28,
29,
30,
31). The proportion
of patients with the type 1 diabetes susceptibility HLA alleles
DQB1*02 and DQA*03 was significantly higher in the A+ß-
group than in the three other groups, including the phenotypically
similar A-ß- group. Furthermore, no A+ß-
patients were positive for the protective HLA alleles DRB1*15
and DQB1*0602 (
19,
32,
33,
34,
35,
36). All patients in this
group required multiple daily insulin injections to avoid ketosis
12 months after the episode of DKA, and a significant proportion
had recurrence of DKA during this period despite close monitoring
by the study team.
A-ß- group
Patients in this group are likely to have diverse pathogenic
mechanisms leading to ketosis-prone diabetes, including potentially
novel forms of nonautoimmune ß-cell failure. There
were numerous similarities in clinical characteristics and ß-cell
functional reserve between the A+ß- and A-ß-
groups (Table 2
and Figs. 2–4
). At first glance, the difference
between these two groups appeared to lie solely in their autoantibody
status. However, HLA analysis revealed that there were also
major differences between these two groups in genetic susceptibility
to ß-cell autoimmunity. The frequencies of one class
II allele (DQB1*02), which is strongly associated with autoimmune
type 1 diabetes susceptibility (
24,
29,
32,
37), and of another
(DQA*03), which is in linkage disequilibrium with the strong
susceptibility alleles DQB1*0302 and DQB1*0301, were low in
the A-ß- group compared with the A+ß- group
(Fig. 4
). These features make it likely that the A-ß-
group consists primarily of persons with nonautoimmune mechanisms
of ß-cell injury, rather than persons with autoimmune
type 1 diabetes whose circulating autoantibody levels have declined
over time to undetectable levels (
38). No A+ß- patients
were positive for the protective allele DQB*0602 (
33,
35,
39),
whereas 9% of A-ß- patients possessed this allele.
(There were no statistically significant group differences in
the frequency of DQB*0602, however, probably because of the
small sample sizes as well as the relatively low prevalence
of the DQB*0602 allele in the general population (
40). A-ß-
patients also were more likely to have first-degree relatives
with type 2 diabetes. The current classification scheme of the
Expert Committee on the Diagnosis and Classification of Diabetes
Mellitus (
41) would tend to place patients in the A-ß-
group into the clinical category of idiopathic type 1 diabetes,
a category that begs further definition, as provided by the
criteria presented here.
A+ß+ group
Some patients in this group may represent a variant of what
several reports of European cohorts have termed antibody-positive
type 2 diabetes (
42,
43,
44) or latent autoimmune diabetes of
adults (
45,
46). However, others in the A+ß+ group
likely represent a more aggressive form of late-onset autoimmune
type 1 diabetes than described in these reports. DQB1*02 may
be a marker for the more aggressive subset of A+ß+,
because the six A+ß+ patients with DQB1*02 had higher
mean HbA
1c (8.6 ± 2.5%) than those without DQB1*02 (6.5
± 0.6%) after 12 months of close management (
P = 0.05).
Furthermore, five of the six patients with DQB1*02 still require
insulin treatment to avoid ketosis after 12 months of follow-up,
whereas insulin has been discontinued safely in four of the
five A+ß+ patients who lack this allele (
P = 0.03).
Although analysis of a larger cohort of A+ß+ patients
is needed to confirm this suggestive trend, this combination
of class II HLA and autoantibody markers may represent an important
diagnostic opportunity to identify A+ß+ patients destined
to have a more aggressive course. Because the presence of both
the genetic markers and autoantibodies should precede the onset
of clinical manifestations, it may be possible to identify such
patients before their ß-cells are irreversibly destroyed
(
47).
A-ß+ group
This is the largest group of ketosis-prone patients, comprising
the greatest number with new-onset diabetes. The frequencies
of the autoimmune type 1 diabetes susceptibility HLA alleles
DQB1*02 and DQA*03 are low in this group. A-ß+ patients
appear clinically heterogeneous, with a wide range of BMI (Table
2
). A-ß+ patients have achieved good glycemic control
within 6 months of follow-up, and half have been able to discontinue
insulin treatment.
The causes of severe, acute ß-cell dysfunction leading
to DKA are likely to be diverse in this group. Half the A-ß+
patients have new-onset diabetes, without a notable precipitating
factor for DKA. The mean HbA
1c of this subgroup at presentation
with DKA was 13.9 ± 2.2, indicating a relatively long
period of undetected and untreated hyperglycemia. It is possible
that the cause of acute ß-cell failure in these patients
was glucotoxicity (
48,
49,
50) or lipotoxicity (
51), which reversed
with excellent control of glycemia after the episode of DKA.
The sustained, preserved ß-cell functional reserve
and glycemic improvement in these patients argue against the
likelihood that they have a form of type 1 diabetes with the
poorly defined honeymoon period (
52). In fact, all A-ß+
patients have now been evaluated for more than 1 yr, and one
third for more than 2 yr, and they continue to maintain uniformly
excellent glycemic control (mean HbA
1c 
7.0%) with adequate
fasting levels of C-peptide (
1.25 nmol/liter).
The subset of A-ß+ patients with previously diagnosed
diabetes may comprise patients with long-standing forms of type
2 diabetes with progressive ß-cell failure (
53,
54)
of such causes as ß-cell apoptosis (
55), islet cell
amyloid (
56), or iron infiltration (
57).
Three previous studies have measured islet cell autoantibodies
and ß-cell function in subsets of African-American
patients presenting with DKA (
5,
6,
7). The patients described
in these studies (
e.g. those with "Flatbush diabetes") would
fit into our two ß+ groups. Consistent with our ß+
group data, the mean age at diagnosis of these African-American
cohorts was in the fifth decade, the mean BMI was high, only
a minority had ß-cell autoantibodies, and glycemic
control improved markedly after intensive treatment. These similarities
add support to the concept of the A-ß+ group as manifesting
a distinct form of ketosis-prone diabetes, but our data extend
the expression of this syndrome to patients of Hispanic, Caucasian,
and Asian ethnicity.
HLA genotyping was particularly helpful in distinguishing autoimmune-associated
from probable nonautoimmune-associated forms of ß-cell
dysfunction within the class of patients with low ß-cell
functional reserve (
i.e. in distinguishing the A+ß-
and A-ß- syndromes). In the initial analysis, the
class II alleles selected were those known to be strongly associated
with autoimmune type 1 diabetes in multiple ethnic groups,
e.g.
the positively associated DQB1*02 and DQB1*0302 (
22,
24,
27,
58,
59,
60,
61,
62,
63) and the negatively associated DQB1*0602
(
19,
23,
32,
33,
35,
39). In the pair-wise comparison, there
was a clear difference in the relative frequencies of DQB1*02:
high in the A+ß- group (72%) and low in the A-ß-
group (26%). The frequency of DQB1*0302 showed a trend in the
same direction, but did not attain significance after Bonferroni
adjustment (which may not be necessary, because the association
between this allele and autoimmune type 1 diabetes is well established).
The protective allele DQB1*0602 (
64) was absent in all patients
in the A+ß- group, but present in 9% of A-ß-
patients. DQB1*0602 is a low-frequency allele in the general
population of Caucasian-Americans (5–13%) and African-Americans
(4–15%) (
40), hence a larger sample of patients would
be necessary to have the power to detect group differences in
its frequency. Interestingly, DQA*03, an allele not frequently
reported to be associated
per se with autoimmune type 1 diabetes
susceptibility, also distinguished the A+ß- group
(89%) from the A-ß- group (44%). DQA*03 is known to
be in linkage disequilibrium with the strong susceptibility
alleles DQB1*0302 and DQB1*0301, hence its frequency distribution
is likely to represent a real difference in susceptibility to
autoimmunity between the A+ß- and A-ß- groups.
The absence of features of autoimmune diabetes or HLA-associated
susceptibility to autoimmune diabetes in the A- groups raises
the possibility that they could include persons with genetic
causes of ß-cell dysfunction, such as syndromes of
maturity onset diabetes of youth (MODY) or mitochondrial transfer
RNA mutations. The MODY syndromes are characterized by Mendelian
dominant inheritance due to monogenic mutations (
65). Although
there are at present no reported cases of subjects with documented
MODY gene mutations presenting with ketoacidosis, this is certainly
a possibility. Sixty-four (86%) of the patients in our A- cohort
have a family history of type 2 diabetes, 45 of these with a
potentially dominant mode of transmission. Screening of the
extended pedigrees for linkage to the currently known MODY genes
is ongoing. Diabetes associated with mitochondrial gene mutations
also involves defects in glucose-stimulated insulin secretion
(
66). However, the absence of evidence for maternal transmission
of diabetes and other typical features (
e.g. deafness, neurologic
disorders, cardiac or renal failure) make it unlikely that any
of our patients harbor known mitochondrial gene mutations.
Imagawa
et al. (
67) have described a cohort of lean Japanese
subjects who developed new-onset, fulminant ß-cell
failure of apparently nonautoimmune cause after a relatively
short period of hyperglycemia (HbA
1c < 8%). Our two A- groups
do not appear to include such patients, inasmuch as all of our
A- patients, including those who were of new onset, had significantly
higher HbA
1c levels, a less fulminant course, greater BMI and
higher frequency of first-degree relatives with diabetes. Furthermore,
it is not clear that the Japanese patients were truly nonautoimmune,
because they possessed HLA haplotypes (DRB1, DQA1, DQB1 0405,0303,0401,
or DQB1 0901,0302,0303, or 0802,0401,0302) known to be associated
with autoimmune type 1 diabetes (
68,
69,
70).
The clinical course of the two ß- groups highlights
the critical importance of ß-cell functional reserve
in achieving effective glycemic control. Although both ß-
groups experienced significant (3%) decreases in HbA
1c and marked
declines in the rate of hospital readmissions for DKA as a result
of the study intervention, their chronic glycemic status remained
quite poor. Other factors, such as lack of compliance with insulin
treatment, could also have played a role in this outcome. We
did not systematically record treatment compliance, but it is
well-known that treatment noncompliance is particularly severe
and glycemic control is especially difficult to achieve in type
1 diabetic patients in indigent, minority-ethnic, urban settings
in the United States (
42,
43,
44).
In conclusion, we have used a heterogeneous, multiethnic cohort
to demonstrate that patients presenting with DKA comprise at
least four distinct diabetic syndromes that are separable by
autoantibody status, HLA genotype, and quantitative assessment
of ß-cell function. Novel, nonautoimmune causes resulting
in variable degrees of ß-cell dysfunction are likely
to underlie the A-ß+ and A-ß- syndromes.
Detailed genotypic and phenotypic characterization studies of
patients in these categories are ongoing, in the hope that they
will specify the etiologic bases of the syndromes revealed by
the present analysis. The current data are also of clinical
relevance to the evaluation and prognosis of patients with ketosis-prone
diabetes. ß-Cell functional reserve at the time of
DKA is the strongest indicator of future metabolic control,
but GAD and IA-2 autoantibody status and class II HLA allelotypes
can assist in classifying ketosis-prone patients and improving
prediction of clinical outcomes.
Syndromes of Ketosis-Prone Diabetes Mellitus
http://edrv.endojournals.org/cgi/content/full/29/3/292
Ketosis-prone diabetes (KPD) is a widespread, emerging, heterogeneous
syndrome characterized by patients who present with diabetic
ketoacidosis or unprovoked ketosis but do not necessarily have
the typical phenotype of autoimmune type 1 diabetes. Multiple,
severe forms of β-cell dysfunction appear to underlie the
pathophysiology of KPD. Until recently, the syndrome has lacked
an accurate, clinically relevant and etiologically useful classification
scheme. We have utilized a large, longitudinally followed, heterogeneous,
multiethnic cohort of KPD patients to identify four clinically
and pathophysiologically distinct subgroups that are separable
by the presence or absence of β-cell autoimmunity and the
presence or absence of β-cell functional reserve. The resulting
"Aβ" classification system of KPD has proven to be highly
accurate and predictive of such clinically important outcomes
as glycemic control and insulin dependence, as well as an aid
to biochemical and molecular investigations into novel causes
of β-cell dysfunction
| IV. Classification of KPD |
|---|
To date, attempts to differentiate patients with KPD into clinically
distinct and relevant subgroups have resulted in four different
classification schemes: the ADA classification, a BMI-based
system, a modified ADA classification, and the Aβ system.
The first is contained within the ADA’s most recent classification
of diabetes in general (
15) and has been adopted by investigators
at the University of Texas Southwestern Medical School (Dallas,
TX). All patients who experience DKA are defined as having type
1 diabetes, and among this group those who lack autoantibodies
are referred to as "idiopathic type 1" or "type 1b." Strictly
interpreted, the ADA scheme would define patients with both
type 1a and type 1b diabetes as insulin dependent, because it
does not mention possible reversion to insulin independence
in either category; however, the Dallas group considers patients
with type 1b to behave more like patients with type 2 diabetes,
with some becoming insulin-independent. A second scheme is that
developed by investigators at Emory University (Atlanta, GA)
who separate KPD patients into lean or obese (
9). "Lean KPD"
patients are those with clinical characteristics of type 1 diabetes
with low β-cell function, whereas "obese KPD" patients
are those with clinical characteristics of type 2 diabetes with
some preservation of β-cell function. A modification of
the ADA scheme is used by investigators at the University of
Paris who divide KPD patients into three groups (
20). Patients
with β-cell autoantibodies are classified as type 1a just
as in the ADA scheme, whereas those who lack autoantibodies
are distinguished retroactively, 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 β-cell
function, whereas subjects with KPD-NID have clinical characteristics
of type 2 diabetes with preserved β-cell function for a
prolonged duration.
Our collaborative group at Baylor College of Medicine and the
University of Washington has used a classification system that
distinguishes four KPD subgroups based on the presence or absence
of autoantibodies and the presence or absence of β-cell
functional reserve (Aβ classification) (
1). The four subgroups
are: A+β– (patients with autoantibodies and absent
β-cell function); A+β+ (those with autoantibodies
but preserved β-cell functional reserve); A–β–
(those without autoantibodies but absent β-cell function);
and A–β+ (those without autoantibodies and preserved
β-cell functional reserve). A+β– and A–β–
patients are immunologically and genetically distinct from each
other but share clinical characteristics of type 1 diabetes
with very low β-cell function, whereas A+β+ and A–β+
patients are immunologically and genetically distinct from each
other but share clinical characteristics of type 2 diabetes
with preserved β-cell functional reserve (Fig. 1
and
There will be a test on this later so please read up.
Mike
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IV. Classification of KPD
V. Natural History and...
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