Molecular scanning of interleukin-21 gene and genetic susceptibility to type 1 diabetes.

A recent study in the nonobese diabetic (NOD) mouse demonstrated the involvement of interleukin (IL)-21 in the pathogenesis of type 1 diabetes. A strong susceptibility locus, Idd3, has also been mapped to the interval containing the murine gene for IL-21 (Il21), making Il21 and the human orthologue IL21 a functional and positional candidate gene for type 1 diabetes. To investigate the contribution of the human genes for IL-21 and its receptor (IL-21R) to susceptibility to type 1 diabetes, we re-sequenced IL21 to identify novel sequence variants, searched for informative variants of IL21R, and studied the association of these variants with the disease. Two polymorphisms, a single nucleotide polymorphism (SNP) and a mononucleotide repeat polymorphism, were identified for IL21, and an allele of the mononucleotide repeat polymorphism was positively associated with the disease. Two novel microsatellite polymorphisms of IL21R were identified, one of which was associated with the disease. Scoring of individuals according to the status of these alleles showed a significant trend for high scores for susceptibility in diabetes patients, suggesting the contribution of IL21 and IL21R to disease susceptibility in an additive manner. These data suggest a contribution of IL21 and IL21R to genetic susceptibility to type 1 diabetes and possible involvement of IL-21 and its receptor system in the disease pathogenesis.

Renoprotective effect of N-type Ca channel blockade in diabetic nephropathy.

OBJECTIVE: This study aimed to investigate the renoprotective effect on diabetic nephropathy of a novel class of Ca(2+) channel blocker, cilnidipine, that inhibits both L-type and N-type Ca(2+) channels; a conventional L-type Ca(2+) channel blocker was substituted with cilnidipine in type 2 diabetic patients with albuminuria. METHODS: Urinary albumin index (UAI), serum creatinine, and blood pressure were measured in 38 outpatients with type 2 diabetes receiving amlodipine, an L-type Ca(2+) channel blocker, in addition to an angiotensin I converting enzyme inhibitor and/or an angiotensin type 1 receptor blocker. Amlodipine was then substituted with cilnidipine, and the same parameters were measured after 3 months. RESULTS: Although blood pressure was not significantly changed after substitution with cilnidipine, log-transformed UAI was significantly decreased (P=.004) with a mean reduction of 28% [95% confidence interval (CI)=11-42]. Serum creatinine was significantly (P=.04) increased (from 0.82+/-0.22 to 0.86+/-0.23 mg/dl). When the subjects were divided into two groups according to the change in serum creatinine, UAI change was significant only in those with an increase in serum creatinine, who exhibited a mean reduction of UAI of 39% (95% CI=16-56, P=.005), but not in those without an increase in serum creatinine, whose mean reduction of UAI was 18% (95% CI=-12 to 40, P=.2). CONCLUSIONS: In patients with diabetic nephropathy, blocking N-type Ca(2+) channels with a new class of Ca(2+) channel blocker resulted in a significant reduction in albuminuria, suggesting a renoprotective effect of N-type Ca(2+) channel blockade, even when combined with renin-angiotensin inhibition.

Asian-specific HLA haplotypes reveal heterogeneity of the contribution of HLA-DR and -DQ haplotypes to susceptibility to type 1 diabetes.

To assess the effect of Asian-specific HLA haplotypes on susceptibility to type 1 diabetes, we investigated the association of genotypic combinations of DRB1-DQB1 haplotypes with susceptibility to type 1 diabetes. We studied 132 Japanese patients with type 1 diabetes and 157 control subjects, along with 67 Korean patients and 109 control subjects. DRB1*0405-DQB1*0401 and DRB1*0901-DQB1*0303 were confirmed to be two major susceptible HLA haplotypes in the Japanese population. The frequencies of heterozygotes and homozygotes with DRB1*0405-DQB1*0401 were similarly higher in patients than in control subjects (homozygotes, 5.3% vs. 3.8%; heterozygotes, 48.5% vs. 26.1%). In contrast, homozygotes, but not heterozygotes, with DRB1*0901-DQB1*0303 were more frequent in patients with type 1 diabetes than in control subjects (homozygotes, 12.9% vs. 0.6%; heterozygotes, 22.0% vs. 24.8%). A similar tendency was also observed in the Korean population. In multiple logistic regression analysis, DRB1*0405-DQB1*0401 fitted a dominant model and DRB1*0901-DQB1*0303 fitted a recessive model. These data, which indicate that the contribution of HLA haplotypes to the genetic susceptibility to type 1 diabetes differs depending on the genotypic combination of HLA haplotypes, suggest the importance of extensive analysis of genotypes in studies on HLA and disease association in general.

Combination of half doses of angiotensin type 1 receptor antagonist and angiotensin-converting enzyme inhibitor in diabetic nephropathy.

BACKGROUND: To investigate the renoprotective effect of combination therapy with an angiotensin I converting enzyme inhibitor and an angiotensin type I receptor blocker (ARB) on diabetic kidney disease, half doses of each monotherapy were given to type 2 diabetic patients with albuminuria. METHODS: Urinary albumin index (UAI) and blood pressure (BP) were measured in a total of 27 outpatients with type 2 diabetes mellitus receiving 10 mg imidapril or 8 mg candesartan per day. Either agent was then substituted with a combination of 5 mg imidapril and 4 mg candesartan. After 3 months of combination therapy, UAI and BP were measured. Changes in the parameters were assessed by paired t test. RESULTS: Although BP was not significantly different prior to and at the end of combination therapy, log-transformed UAI was significantly reduced (P = 0.003) from an initial UAI (mean log-transformed UAI +/- SD) of 79.4 (27.4-231)mg/g Cre to 52.5 (17.1-161)mg/g Cre at the end of combination therapy. The reduction was not associated with the initial UAI, initial BP, decrease in BP, pretreatment medication or other concomitant antihypertensive agents. CONCLUSIONS: In patients with type 2 diabetes and nephropathy, dual blockade of the renin system with an angiotensin-converting enzyme inhibitor and angiotensin receptor blocker significantly reduces albuminuria and, thus, may be renoprotective even when the doses of the agents are reduced by one half.

Functional polymorphism in Z-DNA-forming motif of promoter of SLC11A1 gene and type 1 diabetes in Japanese subjects: association study and meta-analysis.

The association of the polymorphism of the Z-DNA-forming repeats in the promoter region of SLC11A1 (solute carrier family 11 member 1), formerly designated NRAMP1 (natural resistance associated macrophage protein 1), with type 1 diabetes was studied in a total of 244 Japanese subjects. Three alleles were detected in Japanese subjects. In diabetic patients, allele 2 was less frequent and allele 3 was more frequent, albeit not significantly, than in control subjects. Allele 2 was significantly ( P < .024) less frequent whereas allele 3 was more, albeit not significantly, frequent in the younger onset group than in the control subjects. In patients with a susceptible HLA allele, DRB1*0405 or DRB1*0901 , the frequency of allele 2 was significantly ( P < .013) lower and that of allele 3 tended to be higher than that in patients without either DRB1*0405 or DRB1*0901 . The protective effect of allele 2 against type 1 diabetes and other autoimmune diseases was confirmed by meta-analysis (summary odds ratio, 0.71, 95% confidence interval, 0.53-0.96). Because allele 2 was shown to be associated with low expression of SLC11A1 and protection against another autoimmune disease, rheumatoid arthritis, the negative association of allele 2 with autoimmune type 1 diabetes in the present study suggests that a less active immune system in subjects with allele 2 may protect individuals from autoimmune diseases.

Improvement of liver function parameters in patients with type 2 diabetes treated with thiazolidinediones.

To increase our understanding of the effect of thiazolidinediones, a new class of antidiabetic drugs, on liver function as well as glycemic control, we investigated liver function before, during, and after treatment with troglitazone and pioglitazone. A total of 32 patients with type 2 diabetes were studied. Glycemic control and liver function were measured before, during, and after 4 to 12 weeks of treatment with troglitazone or pioglitazone. Glycemic control was assessed by fasting levels of plasma glucose, hemoglobin A 1c , and serum insulin, and liver function was assessed by asparatate aminotransferase (AST), alanine aminotransferase (ALT), and gamma -glutamyl transpeptidase ( gamma-GTP). Homeostasis model assessment for insulin resistance was used as an index of insulin resistance. During treatment with troglitazone, fasting plasma glucose and hemoglobin A 1c levels and homeostasis model assessment for insulin resistance were significantly decreased. Serum AST, ALT, and gamma-GTP levels were significantly decreased during treatment (AST, -17.4%; ALT, -27.2%; gamma-GTP, -47.9%) and returned to pretreatment levels after 4 weeks of withdrawal of the drug. A similar tendency was observed during treatment with pioglitazone (AST, -4.7%; ALT, -16.4%; gamma-GTP, -30.8%). These data suggest that, in contrast to the deterioration of liver function reported in a small subset of patients treated with troglitazone, treatment with thiazolidinediones was associated with a decrease in serum transaminases in most patients. The improvement in liver function parameters known to be associated with fatty liver in the present study, together with an improvement in fatty liver reported for another class of insulin sensitizers, biguanides, suggests that thiazolidinediones may have a beneficial effect on fatty liver.

A common polymorphism of uncoupling protein 2 gene is associated with hypertension.

OBJECTIVES: The genes responsible for obesity are also candidate genes for obesity-related conditions, such as hypertension and type 2 diabetes. A functional polymorphism in the uncoupling protein 2 (UCP2) promoter has been reported to be associated with obesity in Caucasians. To clarify the contribution of this polymorphism to obesity and related conditions, we studied the association of the -866 G/A polymorphism of the UCP2 gene with obesity, hypertension and type 2 diabetes mellitus. METHODS: A total of 632 unrelated Japanese subjects were studied: 342 type 2 diabetic patients (among them, 158 patients complicated with hypertension), 156 hypertensive patients without diabetes mellitus and 134 control subjects. The -866 G/A polymorphism of UCP2 was determined by polymerase chain reaction (PCR)-restriction fragment length polymorphism (RFLP). RESULTS: The frequency of the minor A allele was significantly higher in Japanese than in Caucasians (48.9 versus 37.2%, P=0.01). In contrast to the significant association with obesity in Caucasians, the polymorphism was not associated with obesity in Japanese. The polymorphism, however, was significantly associated with hypertension in Japanese (frequency of A allele: 51.8% in hypertensives versus 46.6% in normotensives, P<0.05). No significant difference was observed in body mass index (BMI), fasting insulin level or HOMA-R between patients with different genotypes. CONCLUSION: These data indicate that the polymorphism of the UCP2 gene is associated with hypertension, and suggest the possibility of UCP2 as a target molecule for studies on the etiology and treatment of hypertension.

Association of Pro12Ala polymorphism of PPARgamma gene with insulin resistance and related diseases.

To clarify the contribution of the Pro12Ala polymorphism of the peroxisome proliferator-activated receptor gamma (PPARgamma) gene to susceptibility to insulin resistance and related diseases, 505 unrelated Japanese subjects were investigated, including 175 normotensive non-diabetic (NN) subjects, 125 normotensive diabetic (ND) subjects, 102 hypertensive non-diabetic (HN) subjects, and 103 hypertensive diabetic (HD) subjects. Ala phenotype frequency was lowest in patients with both type 2 diabetes and hypertension (3.9% in HD group), followed by patients with either one of these conditions (5.6% in ND group, 7.8% in HN group), and highest in subjects without these conditions (9.7% in NN group). When stratified by hypertensive status, the Ala phenotype was negatively associated with diabetes, giving an odds ratio of 0.53 (95% confidence interval: 0.25-1.09). In contrast, when stratified by diabetic status, the odds ratio of the Ala phenotype for hypertension was 0.75 (95% confidence interval: 0.37-1.54). In non-diabetic hypertensive subjects, glucose and insulin levels during oral glucose tolerance test as well as M-value estimated by glucose-clamp test were not significantly different according to the genotype. The data suggest a contribution of the Pro12Ala polymorphism of PPARgamma to genetic susceptibility to type 2 diabetes mellitus and hypertension, but not to insulin sensitivity in hypertensive subjects.

Common genetic basis between type 1 and type 2 diabetes mellitus indicated by interview-based assessment of family history.

To investigate the intrafamilial clustering of type 1 and type 2 diabetes, an interview-based assessment of family history of diabetes was conducted. Outpatients with either type 1 (n = 23) or type 2 diabetes (n = 124), and non-diabetic subjects (n = 118) received an interview regarding the diabetic status of each of their family members. In patients with type 1 diabetes, 22% (5 out of 23) had a parental history of diabetes, and diabetes in these 5 parents was assessed as type 2 diabetes mellitus. The prevalence of parental diabetes in the type 1 diabetic probands (22%) was significantly higher (P < 0.05) than that in non-diabetic probands (7%, 8 out of 118). In probands with type 2 diabetes, the prevalence of parental diabetes was 39% (48 out of 124), which was significantly higher (P < 0.0005) than that in the non-diabetic probands (7%). In the type 2 diabetic probands, no significant difference was noted in the prevalence between paternal (19%, 23 out of 124) and maternal diabetes (23%, 28 out of 124), suggesting no preferential inheritance of maternal diabetes in this population. The present interview-based assessment of family history of diabetes suggested a common genetic basis between type 1 and type 2 diabetes.