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Division of Endocrinology, Department of Medicine, Baylor College of Medicine (M.M., S.D., D.I., A.R., A.B.); and Endocrine Service, Ben Taub General Hospital (M.M., L.R., A.B.), Houston, Texas 77030; Robert J. Williams Laboratory, Department of Medicine, University of Washington School of Medicine (C.S.H., L.K.G., L.P.H., Å.L.); and Puget Sound Blood Center (L.K.G., D.B.), Seattle, Washington 98195
Address all correspondence and requests for reprints to: Ashok Balasubramanyam, M.D., Division of Endocrinology, BCM 719E, Baylor College of Medicine, One Baylor Plaza, Houston, Texas 77030. E-mail: ashokb{at}bcm.tmc.edu.
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Abstract |
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Introduction |
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TopAbstractIntroductionPatients and MethodsResultsDiscussionReferences |
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We hypothesized that the basis of different ketosis-prone diabetic syndromes resides in variations in two key features associated with classic, autoimmune, type 1 diabetes: presence or absence of markers of ß-cell autoimmunity, and quantitative differences in ß-cell function. We further hypothesized that differences in these two measures would influence clinical outcomes of ketosis-prone diabetic patients, such as long-term glycemic control and requirement for insulin treatment. To address these hypotheses, we have established a comprehensive, prospective program to characterize the subtypes of DKA-prone patients in a large, multiethnic diabetic population, using detailed clinical, serological, biochemical, and genetic measurements. We report the data from 103 such patients, who have been followed closely and assessed repeatedly for 12 months after the index episode of DKA. Our results indicate that there are four distinct forms of ketosis-prone diabetes, with important implications both for identification of novel pathogenic mechanisms of ß-cell dysfunction and for predicting clinical outcomes.
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Patients and Methods |
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TopAbstractIntroductionPatients and MethodsResultsDiscussionReferences |
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The protocol was approved by the Institutional Review Boards for Human Studies of Baylor College of Medicine and the Harris County Hospital District (Houston, TX). Adult patients admitted to the Ben Taub General Hospital with a diagnosis of DKA from July 1, 1999, to January 31, 2001, were invited to participate in the study. Informed consent was obtained from all patients who elected to participate. DKA was defined by the presence of all of the following: anion gap equal to or greater than 15, blood pH less than 7.30; serum bicarbonate concentration equal to or less than 17 mmol/liter; serum glucose concentration greater than 200 mg/dl (>11 mmol/liter); serum ketones equal to or greater than 5.2 mmol/liter, by the Acetest reagent (Bayer Corporation, Pittsburgh, PA) or urine ketones moderate to large (>13.9 mmol/liter), together with the absence of concomitant conditions that might result in anion gap acidosis or ketosis, such as pregnancy, renal insufficiency (other than a mild, reversible prerenal state), lactic acidosis, acute alcohol intoxication, or organic poison ingestion. A family history of diabetes was defined by a reported diagnosis of diabetes in a parent or sibling of the patient.
Clinical outcomes analysis. Patients admitted to Ben Taub General Hospital with DKA during the study period were interviewed within 24 h of admission. Those who met entry criteria and consented to participate underwent a detailed assessment of medical history, physical signs, precipitating causes of DKA, serum and urine biochemistry, anthropometry, and clinical course during the hospitalization. Following a standard inpatient protocol for management of DKA, the study team assumed all subsequent outpatient diabetes management of enrolled patients.
A standard outpatient diabetes management protocol was followed in a clinic dedicated to the study. Patients were 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 2 hospital days. They were instructed to measure capillary blood glucose levels before each meal and at bedtime. Stored blood glucose data were uploaded to a computer database. The first clinic visit was 1 wk after hospital discharge. Subsequent visits were scheduled at 1- to 4-wk intervals. If mean blood glucose values during a 2-wk period attained American Diabetes Association-defined goals for fasting and/or bedtime plasma glucose levels (11), the insulin dose was reduced by 50%, and the patient was reassessed in the clinic 1 wk later. If the mean blood glucose values remained at American Diabetes Association goals at two consecutive clinic visits made 2–4 wk apart, insulin was discontinued, and the patient was monitored closely (by daily telephone contact for at least 1 wk, then less frequently). If blood glucose values increased after cessation of insulin but ketosis did not develop (as measured by plasma acetone concentration), the patient was placed on oral hypoglycemic agents and monitored periodically for hyperglycemia and ketosis. Conversely, if the patient developed ketosis on decreasing insulin dosage, the insulin regimen was intensified, and no further attempts were made to discontinue insulin in such patients. Glycosylated hemoglobin (HbA1c) was measured at baseline and every 3 months.
Autoantibody analysis. Serum was analyzed for the presence of glutamic acid decarboxylase (GAD)65, GAD67, and IA-2 autoantibodies by highly sensitive and specific quantitative radioligand binding assay methods, as reported previously (12, 13), with recent modifications (14). Briefly, 35S-labeled recombinant GAD65, GAD67, and IA-2 proteins were produced by in vitro transcription and translation of the respective cDNA preparations. The radiolabeled antigen was incubated overnight at 4 C with a 1/25th final dilution of serum. Antibody bound to the radiolabeled antigen was separated from free labeled antigen using protein A-Sepharose beads (Zymed, San Francisco, CA) in microtiter plates (14). Bound radioactivity was determined by liquid scintillation counting (1450 Microbeta Liquid Scintillation Counter, Wallac, Turku, Finland). Antibody-positive and -negative samples were included in every assay to correct for interassay variation. The World Health Organization islet cell autoantibody standard (15) was used as the positive standard for GAD65Ab and IA-2Ab. An in-house GAD67Ab-positive serum sample, as verified by immunoprecipitation, was used as the positive standard for GAD67Ab. A randomly selected control serum sample from a healthy volunteer was used as the negative standard.
Autoantibody levels were expressed as a relative index, as described previously (12, 13, 14): index = [counts per minute (cpm) of tested sample - cpm of negative standard]/(cpm of positive standard - cpm of negative standard). The upper limit of the normal range was established for each antibody and for each ethnic group specifically for this study. The upper limit was defined as the value at the 99th percentile of the level measured in each of the following healthy, nondiabetic groups of adult subjects living in Houston: 80 Caucasian-Americans, 104 Hispanic-Americans, and 83 African-Americans. All the control subjects were aged 21–70 yr and were normoglycemic persons identified during screening studies to recruit subjects for an influenza virus vaccine trial (Caucasian-Americans), a weight loss trial (Hispanic-Americans), and a hypertension prevalence study (African-Americans). Patients were classified as antibody positive (A+) if the antibody index for at least one of the measured serum antibodies exceeded the ethnic-specific 99th percentile, or antibody negative (A-) if the index for every antibody was below the 99th percentile.
Human leukocyte antigen (HLA) genotyping. DNA was isolated from peripheral blood leukocytes (16). Comprehensive HLA class II genotyping was performed by an oligoblot method using sequence-specific oligonucleotides, as described earlier (16). The polymorphic second exons of DQA1, DQB1 and DRB1, DRB3, DRB4, and DRB5 were amplified using PCR and labeled by incorporation of digoxigenin-labeled 2'-deoxyuridine 3'-triphosphate (dUTP) during the PCR. Labeled PCR products were hybridized to allele-specific probes selected from the second exon of the various loci described above, which were immobilized on nylon membranes. Positive reactions were visualized by a color precipitation reaction.
Measurement of ß-cell secretory capacity. ß-Cell secretory capacity was assessed in all patients in two ways: 1) fasting plasma C-peptide concentration, measured on three occasions: at the time of initial presentation with DKA (after correction of ketoacidosis), and after 6 months and 12 months close outpatient management; and 2) plasma C-peptide response to glucagon [glucagon stimulation test (GST)], measured at the time of initial presentation with DKA (after correction of ketoacidosis) and after 6 months of follow-up.
The initial measurement of fasting plasma C-peptide concentration was performed as follows. The plasma sample was obtained at 0800 h, at least 6 h after the last sc dose of regular insulin and at least 24 h after cessation of iv insulin, when the patient was nonketotic (acetone-negative in undiluted plasma). The initial GST was performed after an overnight fast, at least 10 h after the last sc dose of NPH or regular insulin. One milligram of glucagon was injected iv, and serum C-peptide concentrations were measured at 0, 5, and 10 min. The repeat measurements were performed in a similar manner, at a time when the patient had stable levels of HbA1c and fasting blood glucose and was following a stable antidiabetic regimen. The tests were performed in the overnight fasting state, at least 10 h after an sc dose of NPH or regular insulin, or (if the patient had discontinued insulin) at least 10 h after a dose of metformin or thiazolidinedione, or 24 h after a dose of sulfonylurea. C-peptide concentrations were determined by highly specific RIA (Human C-Peptide RIA kit, Linco Research Inc., St. Louis, MO).
ß-Cell functional reserve was defined as preserved (ß+) if the peak C-peptide response to glucagon was at least 1.5 ng/dl (0.5 nmol/liter) or fasting C-peptide concentration was at least 1 ng/dl (0.33 nmol/liter). ß-Cell functional reserve was defined as absent (ß-) if the glucagon-stimulated or fasting C-peptide concentrations did not meet these criteria. Receiver operator characteristic analysis of these levels, together with those in 105 type 1 and 145 type 2 diabetic subjects, as well as five normal healthy controls of each relevant ethnic group (Caucasian-American, African-American, and Hispanic-American), were used to determine these cutoff values [area under the curve (AUC) value = 0.97776 for fasting C-peptide, 0.96751 for peak C-peptide response to glucagon, and 0.96089 for C-peptide/glucose ratio]. These cutoff values are very similar to those reported previously to differentiate normal subjects, type 1 diabetic patients, and type 2 diabetic patients (17, 18).
Statistical analysis
Descriptive statistics (means, SD, and SEM) were used to characterize the four groups. Contingency table analysis with likelihood ratio tests were used to assess differences in relative frequencies of categorical variables (gender, ethnicity, family history of diabetes, DKA precipitant, proportion of obese patients, ability to discontinue insulin, presence of antibodies, and category of ß-cell function) among the four patient groups. When this test indicated that there were significant differences between groups, pair-wise comparisons were made to identify those differences. ANOVA was used to assess differences in continuous variables [age, age at diagnosis, years with diabetes, HbA1c on admission, body mass index (BMI), glucose on admission, HbA1c on follow-up, C-peptide levels, and AUC for C-peptide concentrations in the GST]. Pair-wise testing using a post hoc multiple comparison procedure (Tukey-Kramer) was used when the four-group comparison indicated significant group differences.
To quantify the influence of HLA genotype on the types of ketosis-prone diabetes, group comparisons were made for alleles at the DQA1, DQB1, and DRB1 loci that are known to have strong associations, either positive or negative, with autoimmune type 1 diabetes (19, 20, 21, 22, 23).
First, the global null hypothesis of no differences between the relative frequencies of each allele in the patient groups was tested, with a Bonferroni adjustment at each locus. In the case of each allele for which the global null hypothesis was rejected, a priori pair-wise comparisons were made between autoantibody-positive and autoantibody-negative patients within the ß+ and ß- groups.
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Results |
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The mean age of the 103 patients was 39 yr; 56% were males, and the ethnic distribution was 40% Hispanic-American, 44% African-American, 15% Caucasian-American, and 1% Asian-American. There was a prior diagnosis of diabetes in 60% (mean duration, 5.4 yr), whereas 40% were new onset (i.e. no prior diagnosis of diabetes). The mean HbA1c level on admission was 13.7 ± 2.4%.
Aß classification scheme and analysis
Patients were classified into four Aß categorical groups based on the presence or absence of autoantibodies (A+ or A-) and of ß-cell functional reserve (ß+ or ß-). The frequency distribution of the four groups is shown in Fig. 1
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). However, there were significant group differences in mean age at diagnosis of diabetes: 25 ± 17, 26 ± 12, 42 ± 12, and 39 ± 12 yr, respectively, for the A+ß-, A-ß-, A+ß+, and A-ß+ groups (P < 0.0001). The difference in the mean duration of diabetes in the four groups was significant in the reverse direction: 9.1 ± 10.4, 9.8 ± 8.7, 0.9 ± 3.0, and 3.0 ± 4.8 yr, respectively, for group A+ß-, A-ß-, A+ß+, and A-ß+ (P < 0.0001). These differences were also reflected in the distribution of new-onset diabetic patients: 17, 9, 91, and 51%, respectively, for group A+ß-, A-ß-, A+ß+, and A-ß+ (P < 0.0001).
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). After 6 months of closely monitored clinical management by the DKA study team, the proportions of patients who no longer required insulin treatment to prevent ketoacidosis were 0, 0, 45, and 51%, respectively, for the A+ß-, A-ß-, A+ß+, and A-ß+ groups (P < 0.0001). The frequency of recurrent episodes of DKA during the study period in the four groups showed the opposite trend: 39, 30, 9, and 2%, respectively, in the A+ß-, A-ß-, A+ß+, and A-ß+ groups (P < 0.0001).
Ethnic distribution of the four Aß groups.
There was a significant difference in the distribution of ethnic groups across the four Aß groups, largely due to a high frequency of Hispanic-Americans in the A-ß+ group and a high frequency of African-American patients in the A+ß- group (P = 0.02, Table 1).
ß-Cell functional reserve of the four Aß groups.
At the time of admission for DKA, there was a significant difference in the group distribution of mean AUC of plasma C-peptide in response to glucagon stimulation, and this difference persisted after 6 months of outpatient treatment (P < 0.0001; Table 2 and Fig. 2A). Both ß+ groups had significant improvement in ß-cell function after 6 months. Similar differences were seen in mean fasting serum C-peptide levels (Table 2 and Fig. 2B).
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). There were group differences in serum glucose concentration, calculated serum osmolality, and anion gap, and this was due to higher levels of these parameters in the A+ß+ group compared with the other three groups. There were no significant group differences in mean HbA1c concentration at baseline (Table 2 and Fig. 3). Differences in glycemic control between the four groups became evident after 3 months of close follow-up and management by the study team and persisted after 6 months, with mean levels of HbA1c 10.3 ± 1.5, 11.5 ± 1.6, 7.1 ± 1.4, and 7.6 ± 2.1%, respectively, for the A+ß-, A-ß-, A+ß+, and A-ß+ groups (P < 0.0001). The HbA1c levels have remained stable in all patients after 12 months of follow-up (Fig. 3).
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shows the HLA alleles tested and the patient group frequencies evaluated in this manner. The global null hypothesis of no frequency difference was rejected for two alleles: DQA*03 (P = 0.02) and DQB1*02 (P = 0.005). For these two alleles, a priori pair-wise comparisons were made within each ß-cell function class (i.e. A+ß- compared with A-ß-, and A+ß+ compared with A+ß-), and the results are described in the paragraph below.
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Paired comparisons within the ß+ and ß- groups
A+ß- compared with A-ß-.
Aside from autoantibody status, the two ß- groups differed in that A-ß- patients had a significantly lower frequency of the autoimmune type 1 diabetes susceptibility HLA alleles DQB1*02 (P = 0.003) and DQA*03 (P = 0.004) (Fig. 4). A significantly greater proportion of A-ß- patients also had a family history of diabetes compared with the A+ß- group. The two ß- groups were otherwise similar in most demographic, anthropomorphic, biochemical, and glycemic characteristics, both initially and after 6 and 12 months of follow-up.
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). There was also a significantly higher proportion of patients with new-onset diabetes in the A+ß+ group. The two ß+ groups were otherwise similar in most demographic, anthropomorphic, biochemical, and glycemic characteristics (with the exception of higher serum osmolality in the A+ß+ group at the time of DKA), both initially and after 6 and 12 months of follow-up. |
Discussion |
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TopAbstractIntroductionPatients and MethodsResultsDiscussionReferences |
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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 HbA1c (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 HbA1c 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 HbA1c 
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 (HbA1c < 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 HbA1c 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 HbA1c 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.
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Acknowledgments |
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Footnotes |
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Abbreviations: AUC, Area under the curve; BMI, body mass index; DKA, diabetic ketoacidosis; GAD, glutamic acid decarboxylase; GST, glucagon stimulation test; HbA1c, glycosylated hemoglobin; HLA, human leukocyte antigen; MODY, maturity onset diabetes of youth.
Received February 4, 2003.
Accepted July 7, 2003.
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TopAbstractIntroductionPatients and MethodsResultsDiscussionReferences |
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N. Rasouli and S. C. Elbein Improved Glycemic Control in Subjects with Atypical Diabetes Results from Restored Insulin Secretion, But Not Improved Insulin Sensitivity J. Clin. Endocrinol. Metab., December 1, 2004; 89(12): 6331 - 6335. [Abstract] [Full Text] [PDF]
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S. Tanaka, T. Endo, K. Aida, H. Shimura, N. Yokomori, M. Kaneshige, F. Furuya, S. Amemiya, M. Mochizuki, K. Nakanishi, et al. Distinct Diagnostic Criteria of Fulminant Type 1 Diabetes Based on Serum C-Peptide Response and HbA1c Levels at Onset Diabetes Care, August 1, 2004; 27(8): 1936 - 1941. [Abstract] [Full Text] [PDF]
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A. E. Kitabchi Ketosis-Prone Diabetes--A New Subgroup of Patients with Atypical Type 1 and Type 2 Diabetes? J. Clin. Endocrinol. Metab., November 1, 2003; 88(11): 5087 - 5089. [Full Text] [PDF]
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