Multiplex diabetic families may be caused by mutations in genes of hepatocyte nuclear factors (maturity-onset diabetes of the young [MODY]1, -3, and -5), glucokinase (MODY2), insulin promoter factor-1 (MODY4), NeuroD1 (MODY6), mitochondrion ND1 and tRNALeu(UUR), and some other unknown genetic mutations. Recent studies showed that mutations of MODY are not common causes of diabetes in Chinese diabetic families (1–3), indicating that there may be other causes and mechanisms involved. Latent autoimmune diabetes in adults (LADA) shares some similar clinical phenotypes with MODY and is common in phenotypic type 2 diabetes (10–25%) (4). This study was conducted to investigate the distribution of GAD antibody (GADA) in multiplex diabetic pedigrees from the ChengDu area of China.

A total of 140 family members of 18 families were recruited. In our previous study, most members had been screened for variants in mitochondrion ND1 and tRNALeu(UUR) and had been proved to be without deficiencies in these genes (5). Among them, 42 subjects in four families had been further screened in the hepatic nuclear factor-1α gene and had been found to have no suspected variant (T.C., Y.R., H.Y., X.Z., H.T., X. Cao, unpublished observations). Each family had three or more diabetic individuals in at least two generations, and most probands were diagnosed as diabetic between ages 23 and 40 years. The probands had a mean ± SD BMI of 24.4 ± 3.1 kg/m2. Only one (5.6%) had hypertension, and seven (38.9%) met the International Diabetes Federation diagnosis criteria of metabolic syndrome (6). The mean (range) age of whole family members was 42.8 ± 18.1 years (2–83), and mean BMI was 23.6 ± 3.4 kg/m2. Eighteen subjects (12.9%) had hypertension, and 30 (21.4%) met diagnosis criteria of metabolic syndrome. Another 50 unrelated healthy subjects were recruited as normal controls. All subjects underwent an oral glucose tolerance test and insulin release tests after 8 h of fasting. GADAs were measured with a radioimmunoassay kit (Beijing North Institute of Biological Technology). Categorical variables were compared by χ2 tests. Continuous variables were evaluated by Student’s t tests.

There were 59 diabetic patients, 20 pre-diabetic subjects (including 10 with impaired glucose tolerance, 6 with impaired fasting glucose, and 4 with both impaired glucose tolerance and impaired fasting glucose), and 61 subjects with normal glucose tolerance (NGT) in the 18 families. GADA presented in 38 of 140 family members (27.1%), a percentage higher than that of the normal control group (6%); P = 0.002. Further analysis showed that 21 of 59 (35.6%) diabetic patients were positive for GADA, as were 4 of 20 (20%) pre-diabetic patients, 13 of 61 NGT subjects (21.3%), and 3 of 50 normal control subjects (6.0%). The difference was significant (P = 0.002). When compared between groups, diabetic patients had a higher prevalence of GADA than found in the normal control group (P = 0.000) and showed a tendency of higher prevalence of GADA compared with pre-diabetic and NGT subjects, though the difference was not significant. Pre-diabetic and NGT patients also showed a high GADA-positive rate compared with the normal control group, while no significant difference was found (Table 1).

There were 17 newly diagnosed and 42 previously diagnosed diabetic patients. The prevalence of GADA was 5 of 17 (29.4%) in newly diagnosed and 16 of 42 (38.1%) in previously diagnosed patients. No significant difference was found (P > 0.05).

Of the 59 diabetic patients, 21 were GADA positive and 38 GADA negative. No difference was found between these two subgroups in age of onset (50.9 ± 13.0 vs. 50.0 ± 12.1 years), BMI (23.4 ± 2.5 vs. 23.8 ± 2.9 kg/m2), rate of metabolic syndrome (38.1 vs. 32.4%), or course of diabetes (4.1 ± 5.5 vs. 5.8 ± 7.3 years).

Published studies showed that GADA-positive frequencies in newly diagnosed phenotypic type 2 diabetic patients were 10% in UK Prospective Diabetes Study 25 (7) and 7.1% in a study of a Chinese population (8). Our study found that GADA was present in 36.1% of diabetic patients in our nonmitochondrion ND1 and tRNALeu(UUR) gene variant–predisposed pedigrees, a rate higher than that in the above studies (P < 0.000). GADA was one established serological marker indicating autoimmune damage to islet cells. GADA combined with type 2 diabetic phenotype could lead to the diagnosis of LADA (4). Thus, more than one-third of diabetic patients in our diabetic families could be LADA patients, which is more common than the rate observed in sporadic phenotypic type 2 diabetic patients. Whether genetic or environmental factors caused this gathering phenomenon remains to be established.

In addition, our study found that GADA-positive and -negative subjects in diabetic families did not show a difference in age of onset, diabetes course, BMI, or metabolic syndrome rate. This may be due to our limited case number or, as described by Juneja et al., because only antibodies, mainly islet cell antibody and GADA, identify LADA, while age and BMI do not (9).

In summary, we have shown a high frequency of GADA in 18 non–insulin dependent diabetic pedigrees, which suggests that LADA is common in these special populations and that autoinmmune β-cell destruction might be another etiology in apparently gene deficient–predisposed diabetic pedigrees. It is necessary to detect GADA in patients with a multiplex diabetes family history to provide better diagnosis and treatment.

Table 1—

Frequencies of GADA in subgroups of diabetic pedigrees and normal control subjects

Diabetic pedigrees
Normal control subjectsP*
DiabetesPre-diabetesNGT
n 59 20 61 50  
GADA 35.6 (21)† 20.0 (4) 21.3 (13) 6.0 (3) 0.003 
Diabetic pedigrees
Normal control subjectsP*
DiabetesPre-diabetesNGT
n 59 20 61 50  
GADA 35.6 (21)† 20.0 (4) 21.3 (13) 6.0 (3) 0.003 

Data are % (n) unless otherwise indicated.

*

P = 0.003, compared among the four groups;

†

P = 0.000, compared with the normal control group.

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This study was supported by a grant for Scientific Research from the Ministry of Education, Beijing, China (20030610073).

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Published ahead of print at http://care.diabetesjournals.org on 18 September 2007. DOI: 10.2337/dc07-0954.

A table elsewhere in this issue shows conventional and Système International (SI) units and conversion factors for many substances.

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2007