Q J Med 2001; 94: 39-43
© 2001 Association of Physicians
Ethnic differences in C-peptide levels and anti-GAD antibodies in South African patients with diabetic ketoacidosis
From the Department of Internal Medicine, University of Pretoria, South Africa, and 1 Julius Centre of General Practice and Patient-Oriented Research, Utrecht University, Netherlands
Received 1 May 2000 and in revised form 2 November 2000
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Summary |
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To determine differences between Black and White South Africans with diabetic ketoacidosis (DKA) and between Black patients on insulin vs. those on oral agents presenting with DKA, post stabilization fasting C-peptide levels and anti-glutamic acid decarboxylase (GAD) antibodies were measured together with serum glucose, acid base and urine ketones on admission. Of 60 patients with diabetic ketoacidosis (DKA) (76 admissions), the 43 Black patients had a higher BMI (23.1 vs. 20.0 kg/m2, p=0.05) than did the 17 White patients, were more often newly diagnosed (37% vs. 1%, p=0.03), and a greater proportion of Black patients had fasting C-peptide levels >0.3 nmol/l (28% (10/36) vs. 0%, p=0.03). Of these 10 Black patients, eight were anti-GAD-negative. Thirteen Black patients (33%) were anti-GAD-positive vs. 10 (67%) White patients (p=0.03). There was no statistically significant difference in anti-GAD positivity between Black patients on oral agents or those on insulin. Most patients (5/7) admitted on oral agents had negative C-peptide levels after stabilization. Our results suggest that in patients presenting with DKA, a quarter of Black South Africans have C-peptide levels regarded as being indicative of type 2 DM and are less frequently anti-GAD-antibody-positive than are White South Africans.
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Introduction |
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Diabetic ketoacidosis (DKA) and hyperosmolar non-ketotic coma (HONKC) represent a spectrum of hyperglycaemic emergencies. Traditionally ketoacidosis has been understood to signify insulin deficiency due to beta-cell destruction. Recently a number of studies have demonstrated that DKA also occurs in subjects with type 2 diabetes mellitus in the USA and also in South Africa.1–4
African-Americans with type 2 diabetes followed up after DKA have insulin resistance. They are often obese and have diminished insulin sensitivity that improves over time to levels similar to those seen in obese non-diabetic individuals.1,2
These African-Americans with type 2 diabetes are notably anti-GAD-antibody-negative.2 Anti-GAD antibodies10–13 predict type 1 diabetes before clinical onset, predict the need for insulin 1–2 years after diagnosis, and are raised in type 2 patients with secondary failure on oral drugs.
Black South African type 25 diabetic subjects differ from their African-American counterparts in that they are more likely to develop depletion of beta-cell function. Black South African subjects categorized as type 2 presenting with DKA may thus not have the relatively good insulin reserve shown in African-American patients, but are more likely to be insulin-deficient at time of presentation, or present a late-onset form of auto-immune diabetes (LADA).
The objective of our study was to examine whether the presentation of DKA differed between Black and White South Africans and to compare antibody status and pancreas reserve in these groups, as well as between Black insulin users and those on oral agents at the time of admission.
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Methods |
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Patients recruited in sequential fashion at the Pretoria Academic Hospital Internal Medicine wards were included in the study. Approval for the study was obtained from the University of Pretoria Ethics and Research committee, and informed consent was obtained from all participants. From December 1996 to November 1997, all cases presenting with DKA according to strict criteria were prospectively collected. Criteria for DKA were serum glucose >13 mmol/l, serum pH <7.3 and urine ketones >1+.
On admission, blood glucose and acid-base measurements were taken. All samples were analysed as soon as possible as part of the management of hyperglycaemic emergencies. Patients were managed according to standard guidelines.
Fasting C-peptide measurement was done once the patient had been off intravenous therapy for 24 to 48 h (RIA, Incstar). Two control runs were done, with all values falling within the designated range (0.29–0.69 nmol/l in the first control and 1.0–2.0 nmol/l in the second). The lowest range of measurement was 0.03 nmol/l, and subjects were classified into two groups using a cut-off value for fasting C-peptide level of 0.3 nmol/l, below which an individual was considered insulinopaenic.5 Glutamic acid decarboxylase antibodies (anti-GAD antibodies) were measured. (Diaplets, Boehringer Mannheim). During the study period, a test run was done twice and was valid in both instances (values being within the specified 660±330 ng/ml range). Anti-GAD concentration <32 ng/ml was considered negative, 32–50 ng/ml intermediate, and >50 ng/ml positive. Body mass index and waist:hip ratio were determined by trained dieticians. Body mass index was calculated as weight in kg per height (m) squared. The waist circumference was measured as the point midway between the iliac crest and the lower rib margin. The hips were measured over the maximal protuberance of the buttocks.
Data was analysed on Statistica. Groups were compared with t tests or Mann-Whitney U tests as appropriate. Proportions were compared using Pearson's 
2 statistic or Fisher's exact test. Two-tailed p values <0.05 were regarded as significant.
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Results |
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There were 76 documented admissions for DKA in 43 Black and 17 White patients. Only first DKA admissions were used in this evaluation (n=60). In Table 1
, the characteristics and comparisons of Black with White patients are given. There were 16 new-onset Black patients, compared with one White patient. Three Black patients were uncertain as to prior diagnosis and treatment. Duration of diabetes was not known accurately by most patients, and thus was not evaluated. The Black patients as a group had higher BMI (mean±SD 23.1±5.4) compared to the white subjects (20.0±2.8) (p=0.05).
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Thirteen Black patients (33%) were anti-GAD-positive vs. 10 (67%) White patients (p=0.03). More Black patients (10, 28%) had C-peptide levels >0.3 nmol/l than did White patients (none) (p=0.03). Of these 10 Black patients, nine were female, five were newly-diagnosed, one was on insulin, two were on oral agents, and two patients were unsure as to whether they had received insulin preceding this admission. Eight (8/10) of these Black patients with positive C-peptide responses were anti-GAD-negative.
A number of patients were on oral agents at the time of presentation. To investigate whether they now had beta-cell failure or represented LADA, we compared insulin users with oral agent users in the Black group (because all White patients were presumably type 1). Patients using insulin were younger than those using oral agents (p=0.03). The difference in BMI (21.2±4.4 vs. 23.6±5.3) was not statistically significant (p=0.32); neither was the waist:hip ratio (0.87±0.15 in insulin users vs. 0.99±0.14 in oral users) (p=0.14). Twenty-nine percent (2/7) of the oral users had C-peptide levels >0.3 nmol/l compared with 8% (1/12) of those on insulin, a non-significant trend (p=0.52). Of all the Black patients who were anti-GAD-negative, 35% had positive C-peptide responses.
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Discussion |
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Our study suggests that approximately a quarter of Black patients presenting with DKA do so with a relatively good beta-cell reserve, as indicated by a fasting C-peptide >0.3 nmol/l. This probably indicates that they have type 2 rather than type 1 diabetes mellitus. Of the 10 such patients in our study, five were newly diagnosed. The large proportion of Black patients (37%) with newly diagnosed diabetes might reflect inadequate availability of primary health care services and presumed delayed diagnosis of diabetes. Type of therapy used at time of admission does not seem to discern adequately between those with or without adequate beta-cell reserve. Unfortunately most of these patients do not follow-up at the Academic Hospital Diabetes Clinic, so that evaluation of insulin requirement after a period of time was not possible. The comparison of those on insulin with those on oral agents is also limited by the small sample size. The BMIs of patients with adequate C-peptide responses or who are on oral agents at the time of presentation are relatively low, probably indicating progressive beta cell failure. Zouvanis et al.4 in a study from Johannesburg, South Africa, found that 55.2% of Black patients presenting with DKA at Hilbrow Hospital were type 2 diabetic patients.
DKA in patients with type 2 diabetes mellitus have been described in different population groups, but have been studied best in obese African-Americans. In the studies by Banerji2 and Umpierrez,1 these obese patients had a better beta-cell reserve than did lean patients with DKA, but worse than obese subjects presenting with hyperglycaemia only. Umpierrez1 also demonstrated that insulin sensitivity improves with time and approaches that of non-diabetic obese controls. Most of these patients are insulin-resistant and can be put on oral agents during the year following DKA. The cause of DKA in these patients is ascribed to a temporal insulin deficiency in the presence of insulin resistance.
Recently Umpierrez et al.6 investigated lean and obese patients presenting with DKA with regard to immunopathogenetic mechanisms and insulin secretion indices. Their results indicated that most obese African-Americans with DKA have type 2 diabetes characterized by higher insulin secretion, absence of auto-immune markers and a lack of HLA genetic association (there were no significant differences in HLA distribution between obese hyperglycaemic subjects, lean subjects with DKA and obese subjects with DKA).
Approximately half of African-American patients with type 2 diabetes mellitus are found to be insulin-sensitive, and half insulin-resistant.7 It is said however8 that the majority of Black South Africans demonstrate progressive beta-cell failure akin to the insulin-sensitive group of Black Americans. It is therefore unlikely that the Black South Africans in our and Zouvanis's studies share a similar mechanism with the insulin-resistant black Americans who present with DKA. Even though Black South Africans are said to have more advanced beta-cell failure than Black Americans, in our study a significant number of Black patients developed DKA despite reasonable beta-cell reserve, suggesting that other mechanisms must be responsible for the increased susceptibility to ketogenesis.
‘Phasic type 1 diabetes mellitus’9 has been described in the Caribbean, Asian and Africa. This is a form of malnutrition-related diabetes causing phases of insulin dependence. However, these young adults are typically insulin-resistant as well as ketosis-resistant. This type of diabetes is therefore also unlikely to explain the presence of DKA in Black South Africans with Type 2 diabetes.
Anti-GAD antibodies have been studied repeatedly in population samples during the last number of years.10–13 They predict insulin requirement even before the clinical onset of diabetes. They also predict insulin requirement in type 2 diabetes mellitus. Moreover, they have also been used to characterize a subset of diabetic patients with so called latent-onset auto-immune diabetes mellitus in adults (LADA). These patients, who present initially as type 2 diabetics, need insulin within the ensuing 2–3 years. Patients who are anti-GAD-antibody-positive have a more rapid decline in beta-cell function. Panz and others14 have recently investigated the presence of anti-GAD antibodies in different groups of Black South Africans with diabetes. They found 44% (44/100) of those with type 1 diabetes were anti-GAD-positive compared to 2.5% (2/80) of subjects with type 2 diabetes.
In the study of Banerji,2 the patients with so called flat-bush diabetes were all anti-GAD-negative. In our study, we found that 8/10 Black patients with fasting C-peptide levels >0.3 nmol/l were anti-GAD-negative.
Why the susceptibility for DKA occurs mainly in Black and Hispanic type 2 patients and infrequently in White patients is debatable. Is there a plausible mechanism by which, at a given level of insulinopaenia, Black subjects are more susceptible to ketogenesis than White subjects? In South African obese subjects without diabetes there appears to be lower C-peptide and insulin response to both oral glucose and tolbutamide-glucagon stimulation in Black compared to White subjects.15 Van der Merwe et al.16 investigated lactate and glycerol release from the subcutaneous adipose tissue of obese urban women from South Africa. The Black women had less visceral fat (matched for BMI) and were more insulinopaenic than their White counterparts. However following an oral glucose load, microdialysis of adipose tissue measured higher levels of lactate and glycerol in the post-absorptive state in the Black women, indicating higher lipolytic rates. Given hyperglycaemia with insulinopaenia under stressful conditions, it is feasible that Black women have brisker lipolysis with ensuing ketogenesis than their White counterparts.
In conclusion, our study demonstrates that a significant proportion of Black diabetics presenting with DKA are females (9/10) with a fair beta-cell reserve and who are negative for anti-GAD antibodies. This small study failed to show statistically significant differences in fasting C-peptide levels and anti-GAD antibody levels between Black diabetic patients on oral agents and those on insulin, but there was a trend toward higher C-peptide levels in those on oral agents.
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Acknowledgments |
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The authors thank Ingrid Bornman, Annetjie van der Merwe and Heidi Fickl from the Departments of Chemical Pathology and Immunology for the C-peptide and anti-GAD analyses.
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Notes |
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Address correspondence to Professor P. Rheeder, Medihelp Chair in Clinical Epidemiology, University of Pretoria, PO Box 667, Pretoria 0001, South Africa. e-mail: prheeder{at}medic.up.ac.za
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References |
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