INTRODUCTION: Insulin resistance in latent autoimmune diabetes in adults (LADA) patients is controversial. The aim of this study was to evaluate insulin resistance and its related factors (metabolic syndrome parameters) among subjects with LADA and glutamic acid decarboxylase antibodies (GADA) negative diabetes, as well as the impact of these factors on insulin resistance.
MATERIALS AND METHODS: GADA levels were investigated in 1140 diabetic patients aged between 30 and 70 years. Insulin resistance and metabolic syndrome parameters were assessed in LADA and GAD-negative diabetic patients by general linear model. In addition, the impact of metabolic syndrome factors on insulin resistance was assessed in LADA and glutamic acid decarboxylase (GAD)-negative diabetic patients.
RESULTS: LADA was diagnosed in 33 subjects from 1140 Malaysian diabetic patients (prevalence = 2.9%). The results showed that LADA patients had higher insulin resistance and high density lipoprotein cholesterol (HDLc) (P = 0.003 and 0.00017 respectively) and lower body mass index (BMI) (P = 0.007) compared to GAD-negative diabetic patients. The HDLc was associated with decreased insulin resistance in LADA patients (P = 0.041), whereas HbA1c, triacylglycerides (TG) and waist were associated with increased insulin resistance in GAD-negative diabetic patients (P = 3.6×10⁻¹², 1.01×10⁻⁵ and 0.004 respectively). HbA1c was highly associated with decreasing β-cell function in both LADA (P = 0.009) and GAD-negative diabetic subjects (P = 2.2×10⁻²⁸).
CONCLUSION: Insulin resistance is significantly higher in LADA than GAD-negative diabetic Malaysian subjects.
In this paper, the islet autoimmunity status and relation to clinical characteristics, beta cell function and cardio-metabolic risk factors in young-onset Asian diabetic patients are evaluated at baseline. The study population consisted of 912 patients (from China, India, Malaysia and Singapore) with age 12-40 years and diabetes duration <12 months. Autoantibodies to glutamic acid decarboxylase (GADA) and tyrosine phosphatase (IA-2A), beta cell function and cardio-metabolic risk parameters were assessed. Among our young patient cohort, 105 (11.5%) patients were GADA and/or IA-2A positives (Ab +ve). Ab +ve patients were younger, leaner, had more severe hyperglycaemia and lower beta cell function. The frequency of metabolic syndrome was significantly lower in Ab +ve patients (27%) compared to Ab -ve patients (54%). However, a substantial proportion of patients in both groups of patients had atherogenic dyslipidaemia, hypertension and albuminuria (micro or macro). In our study cohort, only one in 10 Asian youth with new-onset diabetes had evidence of islet autoimmunity. At least 60% of Ab +ve and 50% of Ab -ve patients demonstrated classical features of type 1 and type 2 diabetes respectively. Regardless of autoimmunity status, the cardio-metabolic risk factors, in particular atherogenic dyslipidaemia, hypertension and albuminuria were common in our patients with young-onset diabetes.
This study determined the prevalence and significance of autoantibodies to GAD65 (GAD Ab), insulin (IAA), tyrosine-like phosphatase (IA2) and islet-cell (ICA) in a group of 213 young Malaysian Type 1 diabetics, diagnosed before the age of 40 years. Venous blood was taken at fasting, and at 6 minutes post-glucagon (1 mg i.v.). IAA was detected in 47.4%, GAD Ab in 33.8%, IA2 in 8.9% and ICA in 1.4% of the subjects. When based on post-glucagon C-peptide level of 600 pmol/L, 172 (80.7%) patients had inadequate pancreatic reserve, while the remainder 41(19.3%) showed normal response. The autoantibodies, either alone or in combination, were detectable in both groups of patients; higher prevalence in those with poor or no beta-cell function (73.3% versus 46.3%, p = 0.0001). Although the prevalence of GAD Ab was highest in newly diagnosed patients (< 5 years), unlike IA2 and ICA, the marker remained detectable in 24-25% of those patients with long-standing disease. Nineteen patients could probably belong to the "latent autoimmune diabetes in adults (LADA)" subset, where pancreatic reserve was adequate but patients had detectable autoantibodies and insulin-requiring. On the other hand, 68 of the 213 patients (32%) were seronegative, but presented with near or total beta-cell destruction. Thus, as has also been suggested by others, there is indeed etiological differences between the Asian and the Caucasian Type 1 diabetics, and, there is also the possibility that other, but unknown autoantigens are involved in causing the pancreatic damage.
This study determined the prevalence of glutamic acid decarboxylase antibodies (GAD Ab) in a group of 926 young Malaysian diabetics of three ethnic groups, Malay, Chinese, and Indian. Patients were clinically diagnosed to be Type 1 or Type 2 before the age of 40 years. The overall GAD Ab positivity was 17.4% (161/926), significantly higher in the Type 1 than the Type 2 diabetics (35.5%, 116/329 vs. 7.5%, 45/597, P=0.0001). Compared to GAD Ab negative patients, seropositive diabetics were diagnosed at younger age (21.2+/-0.9 vs. 27.4+/-0.3 y, P=0.0001), had lower fasting (289+/-27.4 vs. 640+/-17.6 pmol/l, P=0.0001) and post-glucagon C-peptide levels (527+/-51.8 vs. 1030+/-28.9 pmol/l, P=0.0001). There were no racial differences in the prevalence of GAD Ab; of the total Type 1, 30.8, 36.4, and 39.4% were Malay, Chinese, and Indian diabetics, respectively and of the total Type 2, 8.8, 8.2, and 4.4% were Malay, Chinese, and Indian diabetics respectively. There was a curvilinear relationship between GAD Ab and the post-glucagon C-peptide levels, suggesting that GAD Ab do play a role in the beta-cells destruction and could be an important immune marker for the LADA group. This study reconfirmed previous reports that the autoimmune mechanisms in the Type 1 Asian diabetics are indeed different from the Caucasians, and further investigations should be carried out to explain the differences.
BACKGROUND: Circulating antibodies to glutamic acid decarboxylase (GADab) and tyrosine phosphatase-like molecule IA-2 (IA-2ab) are major indicators for auto-immune destruction of pancreatic islet cells. They identify a majority of Caucasians with type 1 diabetes and approximately 50% of Asians, providing evidence of an idiopathic aetiology in the latter. The present study investigated these autoantibodies in a mixed ethnic group.
METHODS: Hospital clinic patients with clinically defined type 1 (n = 93) and type 2 (n = 300) diabetes and representing Singapore's major ethnic groups--Chinese, Indians and Malays--were studied. GADab and IA-2ab frequencies, and association of autoimmunity status with clinical and biochemical profiles were analysed.
RESULTS: Radio-immunoprecipitation assays detected either or both antibodies (seropositivity) in 41.9% of subjects with type 1 diabetes. GADab was detected in 36.6% and IA-2ab in 23.7% of type 1 diabetics. Prevalence of IA-2ab showed a reduction in frequency with disease duration (P = 0.026). In clinical type 2 diabetics, seropositivity was 10.0% with higher frequency in Malays (17.5%) than Chinese (9.7%) and Indians (4.5%). Multivariate analysis revealed that low fasting C-peptide was associated with seropositivity (odds ratio (OR) = 0.15; 95% confidence interval (CI) = 0.04-0.58). A significant relationship (OR = 13.5; 95% CI = 5.0-36.7) between insulin requirement and duration (>5 years) was also revealed. In patients with type 2 diabetes there was a trend of gradual progression to insulin dependency. However, there was considerable variation in body mass index between ethnic subgroups of type 2 diabetics, particularly for Chinese (mean (SD) = 26.0 (4.7)) and Malays (mean (SD) = 29.2 (5.9); P < 0.001).
CONCLUSIONS: Presence of both antibodies in our mixed ethnic group of type 1 diabetes patients was much lower than in Caucasians. Significant numbers of patients were seronegative for antibodies. Influences due to ethnicity and adiposity would require further investigations.