We conclude that GADab(+) non-insulin-deficient patients differ from GADab(+) patients with insulin deficiency with respect to clinical characteristics, humoral autoimmunity to other organ-specific autoantibodies, as well as HLA class II genes.

To clarify heterogeneity in Japanese adult-onset type 1 diabetes, we analyzed the HLA-DR and -DQ haplotypes, depending on the clinical phenotype, and compared them with those in childhood-onset type 1 diabetes (CO). The patients in a previously reported Ehime Study were divided into subgroups by the mode of onset of diabetes: 68 acute-onset type 1 diabetic patients (AO) and 28 slowly progressive type 1 diabetic patients (SO). HLA haplotypes were compared with those of 80 CO patients and 190 control subjects. Two major susceptible HLA haplotypes in the Japanese, DRB1*0405-DQB1*0401 (DR4) and DRB1*0901-DQB1*0303 (DR9), were significantly increased in the AO and CO groups, but only DR9 was increased in the SO group. AO subjects had a higher frequency of DR9 than CO subjects. Accordingly, the DR9:DR4 frequency increased with increasing age of onset. Another susceptible haplotype, DRB1*0802-DQB1*0302 (DR8), was involved only in the CO group. Analysis of haplotype combinations revealed that DR4 and DR9 had significant dosage effects on the AO and CO groups (P < 0.0001), but only DR9 had such an effect in the SO group (P < 0.03). These results suggest differences in the contribution of HLA class II haplotypes to susceptibility of type 1 diabetes depending on the clinical phenotype and also indicate that HLA class II haplotypes may be associated with the onset age of type 1 diabetes. Diabetes 53: 2684 -2690, 2004 T ype 1 diabetes is the result of a destruction of pancreatic ␤-cells and leads to complete insulin deficiency (1,2). Although type 1 diabetes is frequently considered to be a childhood disease and is characterized by a rapid progression to insulin dependency, the clinical onset of type 1 diabetes is not confined to children. Epidemiological data suggest that 30 -50% of type 1 diabetic patients may develop clinical signs of diabetes after age 20 years (3,4). Moreover, there is increasing evidence to indicate that type 1 diabetes, especially when developed in adulthood, is clinically and immunologically heterogeneous. Insulin secretion abruptly ceases in fulminant type 1 diabetes (5), whereas pancreatic ␤-cell function can be preserved for over a decade in some patients, a condition that is referred to as slowly progressive insulin-dependent diabetes (6) or latent autoimmune diabetes in adults (LADA) (7). Compared with our extensive knowledge of the epidemiological, clinical, and genetic characteristics of childhood-onset type 1 diabetes, our understanding of adult-onset type 1 diabetes is incomplete.Susceptibility to type 1 diabetes is determined by both environmental and genetic factors. Although multiple genes have been implicated, HLA class II genes, especially the HLA-DR and -DQ genes, are most important and are estimated to account for ϳ50% of the susceptibility to the disease (8). These HLA associations vary depending on geographic and ethnic origin (9). It has been shown that Japanese type 1 diabetic patients have different HLA associations than Caucasian patients. In Caucasian populations, the DRB1*...

Compared to European countries, the USA and Israel, the Japanese cohort of children with diabetes presents the following differences: the incidence is much lower, there is a preponderance of girls and there is (with one exception) no seasonal pattern.

A B S T RThe results indicate that the net glucose release by the kidney in vivo in normal fed rats was 0.75+0.13 mg/dl per min, and that its contribution to blood glucose was 25.9±5.0%. When unilateral nephrectomy was performed, under the same conditions, renal net glucose release was one-half of that in rats with two intact kidneys, which indicates the quantitative accuracy ofthe isotope-dilution method employed in this study.In rats starved for 24 h, the renal net glucose release increased to 0.99+0.08 mg/dl per min. Diabetic rats showed a remarkably higher renal net glucose of 2.28 +0.33 mg/dl per min, which was 360% of the normal level. Treatment of diabetic rats with insulin, restored the renal net glucose release to the normal level. In

Tyrosinemia type II (Richner-Hanhart syndrome, RHS) is a disease of autosomal recessive inheritance characterized by keratitis, palmoplantar hyperkeratosis, mental retardation, and elevated blood tyrosine levels. The disease results from deficiency in hepatic tyrosine aminotransferase (TAT; L-tyrosine:2-oxoglutarate aminotransferase, EC 2.6.1.5), a 454-amino acid protein encoded by a gene with 12 exons. To identify the causative mutations in five TAT alleles cloned from three RHS patients, chimeric genes constructed from normal and mutant TAT alleles were tested in directing TAT activity in a transient expression assay. DNA sequence analysis of the regions identified as nonfunctional revealed six different point mutations. Three RHS alleles have nonsense mutations at codons 57, 223, and 417, respectively. One "complex" RHS allele carries a GI GG splice donor mutation in intron 8 together with a Gly Val substitution at amino acid 362. A new splice acceptor site in intron 2 ofthe fifth RHS allele leads to a shift in reading frame.Tyrosinemia type II, also known as Richner-Hanhart syndrome (RHS), is an inborn error of metabolism due to a block in the transamination reaction converting tyrosine to p-hydroxyphenylpyruvate, a step catalyzed by the hepatic cytosolic enzyme tyrosine aminotransferase (TAT; L-tyrosine:2-oxoglutarate aminotransferase, EC 2.6.1.5). RHS patients suffer from keratitis, palmar and plantar hyperkeratosis, and sometimes mental retardation, accompanied by highly elevated serum and urine levels of tyrosine and its metabolites. The condition improves rapidly on a tyrosine-and phenylalanine-restricted diet (for reviews see refs. 1 and 2).TAT has been extensively studied in rat and mouse, revealing a complex pattern of regulation. Enzyme activity is virtually absent in fetal rat liver and becomes detectable just after birth (3). The TAT gene is under hormonal control by glucocorticoids and cAMP, which increase the basal transcription rate 5-to 10-fold (4, 5), acting via different response elements in the 5' flanking region of the gene (6, 7). Furthermore, the rodent TAT genes are subject to two trans-acting regulators. Basal expression and hormone inducibility of the Tat gene on mouse chromosome 8 are controlled by a positive trans-acting factor, alf, encoded on mouse chromosome 7 (8). Conversely, the tissue-specific extinguisher locus Tse-J on mouse chromosome 11 encodes a product that represses Tat gene transcription in nonliver cells (9).Little is known about the regulation of the human TAT gene. As in rodents, hepatic TAT activity reaches significant levels shortly after birth, although some activity is present in the fetus (10). Induction of human TAT by glucocorticoids and cAMP has been demonstrated in fetal liver organ cultures (11). Moreover, there is evidence for a Tse-1-like factor on human chromosome 17 (9).The human TAT gene extends over 10.9 kilobases (kb) containing 12 exons, and its 3.0-kb mRNA codes for a 454-amino acid protein of 50.4 kDa (12). We previously described an RHS ...