Thyroid function, glycemic control, and diabetic nephropathy in patients with type 2 diabetes over 24 months: prospective observational study.

BACKGROUND: The higher prevalence of thyroid dysfunction in type 1 diabetes patients has been well established, whereas it is a matter of debate whether that is also observed in type 2 diabetes patients. This study was conducted to reveal whether higher prevalence of thyroid dysfunction is observed in patients with type 2 diabetes. METHODS: We examined thyroid functions and thyroid autoantibodies in 200 patients with type 2 diabetes and 225 controls, with 24 months follow up for those with type 2 diabetes. RESULTS: Serum free triiodothyronine (fT3) levels and fT3/free thyroxine (fT4) ratio were significantly lower, while fT4 levels were significantly higher in patients with type 2 diabetes. The number of patients with thyroid dysfunction or patients positive for thyroid autoantibodies were not different between the two groups. The fT3/fT4 ratio was positively and negatively correlated with serum c-peptide and HbA1c levels, respectively, suggesting that the difference can be attributable to insulin resistance and diabetic control. In the follow-up observation, we found no significant correlation between basal thyrotropin (TSH), fT3, fT4 or fT3/fT4 ratio with the amounts of changes of HbA1c levels at 12 or 24 months after the basal measurements. There was a negative relationship between TSH levels and eGFR at baseline measurements, but TSH levels did not seem to predict future decline of eGFR levels. No relationship was observed between urine albumin/ g‧cre levels and thyroid function. CONCLUSION: Thyroid dysfunction and thyroid autoantibodies were not different in prevalence between patients with type 2 diabetes and controls, although in patients with type 2 diabetes, the fT3/fT4 ratio was decreased. Basal thyroid function did not predict future diabetes control or renal function within 24 months of follow-up.

Bilateral atrophy of the extensor digitorum brevis muscle might be a useful sign for diagnosing diabetic polyneuropathy in Japanese men who do not sit in the traditional "seiza" style.

AIMS/INTRODUCTION: As the extensor digitorum brevis muscle is a small muscle in the most distal part of the legs, its atrophy (EDBA) might reflect symmetric polyneuropathy (SPN). We aimed to clarify the EDBA-related factors and the usefulness of bilateral EDBA detection for diagnosing SPN, especially diabetic SPN (DSPN). MATERIALS AND METHODS: In 1,893 participants from the Japanese general population (investigation I) and 133 established diabetes patients (investigation II), relationships between EDBA and various factors including the traditional sitting style called "seiza'" (kneeling and sitting on one's heels) were investigated. Analyses were carried out by univariate and multivariate analysis, and SPN or DSPN was diagnosed by the criteria of "Probable DSPN" of the Toronto Consensus. The validity of EDBA detection for diagnosing SPN/DSPN was also evaluated. RESULTS: Investigation I: EDBA was more prevalent in women than men (44% vs 20%). Significant EDBA-related factors were aging and seiza habit regardless of sex. Male-specific EDBA-related factors were SPN and known diabetes. In men without seiza habit, EDBA was significantly associated with SPN regardless of diabetes, so EDBA seemed to be a useful sign for diagnosing SPN/DSPN. Investigation II: In men, DSPN was more prevalent in the EDBA group than the non-EDBA group (71% vs 33%). Sensitivity, specificity, positive predictive value and kappa coefficient of EDBA detection for diagnosing DSPN were 44, 87, 67% and 0.323, showing fair agreement. CONCLUSIONS: EDBA detection might be a useful method to screen for distal symmetric polyneuropathy, such as DSPN in men, although the exclusion of individuals with seiza habit is necessary to improve accuracy.

Early detection of euglycemic ketoacidosis during thoracic surgery associated with empagliflozin in a patient with type 2 diabetes: A case report.

We report the first case of intraoperatively detected euglycemic diabetic ketoacidosis (DKA) associated with sodium-glucose cotransporter 2 inhibitors during thoracic surgery. A 59-year-old man had a 12-year history of type 2 diabetes mellitus treated with insulin and empagliflozin. The patient developed bacterial empyema and was initiated with antibiotics at a local hospital. Owing to the persistence of his symptoms, he was transferred to our hospital after the medication of empagliflozin the day before surgery. After overnight fasting, the patient underwent thoracoscopic debridement and intrathoracic lavage surgery. During this surgery, he was noted to have euglycemic ketosis and acidosis, and diagnosed as euglycemic DKA. Immediately after the consultation in our department, the patient underwent treatment for DKA. He awoke from anesthesia normally and showed no symptoms of DKA. DKA gradually resolved over the next 24 h. Early identification and management are critical for rapid recovery from perioperative euglycemic DKA associated with sodium-glucose cotransporter 2 inhibitors, especially during thoracic surgery.

Neonatal diabetes caused by the heterozygous Pro1198Leu mutation in the ABCC8 gene in a male infant: 6-year clinical course.

Neonatal diabetes is a rare disease, often caused by a monogenic abnormality. A male infant patient developed diabetic ketoacidosis at 2 months-of-age due to the heterozygous ABCC8 gene mutation (p.Pro1198Leu). After genetic diagnosis, insulin therapy was successfully transitioned to oral sulfonylurea therapy. For >6 years, oral sulfonylurea therapy has been safe and effective, and the required amount of sulfonylureas has progressively decreased. The mutation was transmitted in an autosomal-dominant fashion across three generations of his family, but the severity of diabetes varied among members from neonatal diabetes to mild diabetes. One family member had normal glucose tolerance despite having the mutation. This case presentation could help in the understanding of neonatal diabetes caused by the ABCC8 gene mutation.

Identification of a compound heterozygous inactivating ABCC8 gene mutation responsible for young-onset diabetes with exome sequencing.

Activating mutations in the ABCC8 gene cause diabetes and inactivating mutations usually cause hyperinsulinemic hypoglycemia in infancy. Patients with hypoglycemia in infancy due to a heterozygous inactivating mutation have been reported to occasionally progress to diabetes later in life. We explored the gene responsible for diabetes in two brothers, who were suspected to have diabetes at 15 and 18 years-of-age, respectively, with whole exome sequencing, and identified a compound heterozygous ABCC8 gene mutation (p.Arg168Cys and p.Arg1421Cys). Although their father and mother were heterozygous carriers of the p.Arg168Cys and the p.Arg1421Cys mutation, respectively, neither parent had diabetes. These mutations have been reported to be responsible for hypoglycemia in infancy and function as an inactivating mutation. Our results suggest that the inactivating ABCC8 gene mutation is also important in the etiology of diabetes.

Clinical polyneuropathy does not increase with prediabetes or metabolic syndrome in the Japanese general population.

AIMS/INTRODUCTION: The prevalence of clinical polyneuropathies (ClinPNs) or nerve conduction abnormality (NCA) in the groups stratified by glucose tolerance, individual components of metabolic syndrome (metabolic syndrome [MetS] components: hypertension, dyslipidemia, obesity) and MetS defined by the International Diabetes Federation consensus was investigated in the Japanese general population. Factors associated with ClinPN and NCA were also identified. MATERIALS AND METHODS: A total of 625 examinees of regional medical checkup programs were recruited to this cross-sectional study. ClinPNs were diagnosed by the Toronto Consensus. NCA was judged by at least one bilateral abnormality of sural nerve action potential amplitude or conduction velocity measured by a point-of-care nerve conduction device (DPNCheck). Clinical factors associated with ClinPNs or NCA were examined by multiple logistic regression analysis. Deteriorating factors of sural nerve action potential amplitude or conduction velocity values were also investigated in participants without diabetes (n = 550). RESULTS: As for glucose tolerance, ClinPNs or NCA significantly increased only in known diabetes patients compared with other groups. There was no difference between prediabetes and the normal group. The prevalence of ClinPNs and NCA was not significantly related to MetS or MetS' components, except for frequent NCA in obesity. The factors significantly associated with both NCA and ClinPNs were smoking and known diabetes. In non-diabetic participants, aging, tall height and hypertension were significant deteriorating factors of nerve conduction functions. CONCLUSIONS: In Japan, ClinPNs and NCA were increased in known diabetes patients, but did not increase in participants with prediabetes, MetS and MetS' components. Smoking and known diabetes were factors significantly associated with ClinPNs or NCA. Hypertension might be a modifiable deteriorating factor of nerve function.

Identification of a variant associated with early-onset diabetes in the intron of the insulin gene with exome sequencing.

Whole-exome sequencing is a new technology. We used it to explore the gene responsible for early-onset diabetes as a result of impaired insulin secretion in a family. In the INS gene, we identified the heterozygous c.188-31G>A mutation in the proband - a 43-year-old woman. The mutation was also identified in her two daughters with diabetes, but not in her son or her parents, all of whom did not have diabetes. The substitution was located 31 bp proximal to exon 3 in intron 2. It was predicted to create an ectopic splice site leading to inserting 29 nucleotides of intron 2 as an exonic sequence in the transcript. The mutation has been reported in White families, and the present case is the first report in an Asian person. The present results would help in understanding the role of the mutation in developing diabetes.

Fulminant Type 1 Diabetes Mellitus Accompanied by Positive Conversion of Anti-insulin Antibody after the Administration of Anti-CTLA-4 Antibody Following the Discontinuation of Anti-PD-1 Antibody.

An 80-year-old woman with malignant melanoma received 20 cycles of anti-programmed death 1 (PD-1) antibody (nivolumab) treatment and showed normal glucose tolerance. Three weeks after switching to anti-cytotoxic T-lymphocyte associated antigen 4 (CTLA-4) antibody (ipilimumab), her plasma glucose level was elevated to 639 mg/dL, her HbA1c was 7.7%, and her fastening serum C-peptide immunoreactivity was undetectable. Anti-glutamic acid decarboxylase and insulinoma-associated protein-2 antibodies were negative. She was diagnosed with fulminant type 1 diabetes mellitus (F1DM). Remarkably, her anti-insulin antibody was positively converted, and her Sialylated Carbohydrate Antigen, Krebs von den Lungen-6 levels increased after ipilimumab therapy. She possessed F1DM-susceptible Human Leukocyte Antigen-DR4. A fluorescence activated cell sorting analysis showed an altered T-cell population. This case of F1DM highlights specific mechanisms underlying pancreatic beta cell immunity.

Difference in normal limit values of nerve conduction parameters between Westerners and Japanese people might need to be considered when diagnosing diabetic polyneuropathy using a Point-of-Care Sural Nerve Conduction Device (NC-stat®/DPNCheck™).

AIM/INTRODUCTION: Studies on a novel point-of-care device for nerve conduction study called DPNCheck have been limited to Westerners. We aimed to clarify Japanese normal limits of nerve action potential amplitude (Amp) and conduction velocity by DPNCheck (investigation I), and the validity of DPNCheck to identify diabetic symmetric sensorimotor polyneuropathy (DSPN; investigation II). MATERIALS AND METHODS: For investigation I, 463 non-neuropathic Japanese participants underwent DPNCheck examinations. Regression formulas calculating the normal limits of Amp and conduction velocity (Japanese regression formulas [JRF]) were determined by quantile regression and then compared with regression formulas of individuals from the USA (USRF). For investigation II, in 92 Japanese diabetes patients, 'probable DSPN' was diagnosed and nerve conduction abnormalities (NCA1: one or more abnormalities, and NCA2: two abnormalities in Amp and conduction velocity) were determined. Validity of NCAs to identify 'probable DSPN' was evaluated by determining sensitivity, specificity, reproducibility (kappa-coefficient) and the area under the curve of receiver operating characteristic curves. RESULTS: For investigation I, JRF was different from USRF, and normal limits by JRF were higher than that of USRF. The prevalence of Amp abnormality calculated by JRF was significantly higher than that of USRF. For investigation II, the sensitivity, specificity and reproducibility of NCA1 and NCA2 judged from JRF were 85%, 86% and 0.57, and 43%, 100% and 0.56, respectively. These values of JRF were higher than those of USRF. The area under the curve of JRF (0.89) was larger than USRF (0.82). CONCLUSIONS: A significant difference in the normal limits of nerve conduction parameters by DPNCheck between Japanese and USA individuals was suggested. Validity to identify DSPN of NCAs might improve by changing the judgment criteria from USRF to JRF.

Resistance to Thyroid Hormone Complicated with Type 2 Diabetes and Cardiomyopathy in a Patient with a TRß Mutation.

Resistance to thyroid hormone (RTH) is a genetic disorder characterized by reduced tissue responsiveness to thyroid hormone. We herein describe a 60-year old man who presented with the clinical features of cardiomyopathy, diabetes mellitus and elevated thyroid hormones with unsuppressed thyroid stimulating hormone. A genetic analysis of thyroid hormone receptor (TR) revealed a missense mutation (A268D) in the TRß gene. Clinical manifestations of RTH may be variable due to different tissue distributions of TR subtypes and different actions of mutant receptors. The current case demonstrates that patients with a TRß mutation may have impaired his glucose metabolism and a reduced cardiac function, although patients appear clinically euthyroid.

Clinical and functional characterization of the Pro1198Leu ABCC8 gene mutation associated with permanent neonatal diabetes mellitus.

AIMS/INTRODUCTION: The adenosine triphosphate (ATP)-sensitive potassium (KATP) channel is a key component of insulin secretion in pancreatic ß-cells. Activating mutations in ABCC8 encoding for the sulfonylurea receptor subunit of the KATP channel have been associated with the development of neonatal diabetes mellitus (NDM). The aim was to investigate clinical and functional characterization of the Pro1198Leu ABCC8 gene mutation associated with permanent NDM (PNDM). MATERIALS AND METHODS: The coding regions and conserved splice sites of KCNJ11,ABCC8 and INS were screened for mutations in a 12-year-old girl diagnosed with PNDM. The functional property of the mutant channel identified was examined with patch-clamp experiments in COS-1 cells. We also investigated the difference of effectiveness between two groups of oral sulfonylureas in vitro and in the patient. RESULTS: We identified a heterozygous missense mutation (c.3593 C>T, Pro1198Leu) in ABCC8. The mutated residue (P1198) is located within a putative binding site of sulfonylureas, such as tolbutamide or gliclazide. In patch-clamp experiments, the mutant channel was less ATP sensitive than the wild type. Furthermore, the sensitivity to tolbutamide was also reduced in the mutant channel. In addition to the tolbutamide/gliclazide binding site, glibenclamide is thought to also bind to another site. Glibenclamide was more effective than other sulfonylureas in vitro and in the patient. The treatment of the patient was finally able to be switched from insulin injection to oral glibenclamide. CONCLUSIONS: We identified the Pro1198Leu ABCC8 mutation in a PNDM patient, and clarified the functional and clinical characterization. The present findings provide new information for understanding PNDM.

A case of liver abscess caused by Edwardsiella tarda.

Edwardsiella tarda, a member of the Enterobacteriaceae family, is found in freshwater and marine environments. Extraintestinal infections of Edwardsiella tarda have been rarely reported. We describe a 70-year-old Japanese woman suffering from autoimmune hemolytic anemia, with liver abscess caused by Edwardsiella tarda. She had a history of cholecystectomy for gallbladder stone 10 years prior to this admission. She was successfully treated with percutaneous transhepatic abscess aspiration and meropenem. This is the first report of liver abscess caused by Edwardsiella tarda in Japan.

Numbness and paresthesia in bilateral toes and soles, and disproportional sweating restricted to face and trunk are suitable symptoms useful for the diagnosis of diabetic symmetric polyneuropathy.

UNLABELLED: Aims/Introduction: In order to diagnose diabetic symmetric polyneuropathy (DSPN) more simply and accurately, we identified symptoms that correlated with neurological functions and existed more frequently in diabetic than non-diabetic subjects. MATERIALS AND METHODS: The relationships between 10 symptoms (numbness or paresthesia in toe and sole, numbness in hand, pain in foot or hand, coldness in legs, painful leg cramp, dizziness on standing, sweating restricted to face/trunk and frequent constipation/diarrhea) and clinical background, defined as DSPN and cardiovascular autonomic neuropathy (CAN) by the criteria proposed in the statement of the American Diabetes Association, and seven quantitative nerve function data were evaluated in 593 diabetic patients in Wakayama Medical University Hospital (WMUH). Furthermore, the prevalence of various symptoms was examined by three questionnaires: a WMUH survey (999 diabetic outpatients), a Nationwide survey (1524 male diabetic outpatients under a primary-care physician) and a Control survey (501 non-diabetic subjects). RESULTS: Bilateral 'numbness in toe and sole', 'paresthesia in toe and sole', 'pain in foot' and 'sweating restricted to face/trunk' were significantly associated with diabetes duration, retinopathy, probable and confirmed DSPN, possible and advanced CAN, and all or six nerve functions. Questionnaire surveys clarified that symptoms that are not rare (>15%) and more frequent in diabetic than non-diabetic subjects were bilateral 'numbness in toe and sole', 'paresthesia in toe and sole', 'coldness in legs', 'dizziness on standing' and 'sweating restricted to face/trunk'. CONCLUSIONS: Therefore, bilateral 'numbness in toe and sole', 'paresthesia in toe and sole' and 'sweating restricted to face/trunk' are suitable symptoms useful for the diagnosis of DSPN. (J Diabetes Invest, doi: 10.1111/j.2040-1124.2011.00124.x, 2011).

Pro198Leu missense polymorphism of the glutathione peroxidase 1 gene might be a common genetic predisposition of distal symmetric polyneuropathy and macrovascular disease in Japanese type 2 diabetic patients.

UNLABELLED: Aims/Introduction: We have previously reported that the Pro198Leu missense polymorphism in the glutathione peroxidase 1 (GPx-1) gene was associated with frequent macrovascular disease (MVD). Our goal was to examine whether the GPx-1 genotype is associated with diabetic neuropathy. MATERIALS AND METHODS: We determined the GPx-1 genotype in 173 Japanese type 2 diabetic patients who received medical interviews, physical examinations, nerve conduction studies, quantitative vibratory perception (QVP), head-up tilt and heart rate variability tests by polymerase chain reaction-restriction fragment-length polymorphism. Diabetic sensorimotor distal symmetric polyneuropathy (DSPN) and diabetic autonomic neuropathy (DAN) were evaluated separately. DSPN and DAN were defined by two or more abnormalities of neuropathic leg symptoms, diminished Achilles tendon reflexes or impaired QVP in toes, and two autonomic dysfunctions, respectively. The association of the GPx-1 genotype with DSPN, DAN, MVD and other clinical manifestations was analyzed. RESULTS: The prevalence of DSPN, impaired QVP and painful leg cramps in patients having a genotype with Pro/Leu at the codon 198 (Pro/Leu type) was significantly higher than those with Pro/Pro type. As a result of multivariate analyses that contained the GPx-1 genotype as an independent variable, the Pro/Leu type was extracted as a significant risk factor of DSPN, QVP impairment and MVD. The statistical significance did not disappear, even after proteinuria, retinopathy and a history of MVD were introduced as independent variables. In contrast, the GPx-1 genotype was not associated with DAN. CONCLUSIONS: The Pro198Leu missense polymorphism of the GPx-1 gene might have a common genetic predisposition to DSPN and MVD. (J Diabetes Invest, doi: 10.1111/j.2040-1124.2011.00127.x, 2011).

SUMO4 Met55Val polymorphism is associated with coronary heart disease in Japanese type 2 diabetes individuals.

The Met55Val polymorphism in the small ubiquitin-like modifier 4 (SUMO4) gene has been associated with susceptibility not only to type 1 diabetes, but also to type 2 diabetes and diabetic nephropathy. We tried to confirm the association with susceptibility to type 2 diabetes and to investigate its role in diabetic vascular complications. The polymorphism was genotyped in two independent Japanese samples (Wakayama and Tokyo) by the TaqMan method. Susceptibility to type 2 diabetes and prevalence of diabetic vascular complications (coronary heart disease, cerebral infarction, retinopathy, and nephropathy) were evaluated by case-control study and multivariate logistic regression analysis, respectively. There were no significant differences in the frequency of alleles or genotypes between patients and controls. The Val allele, however, was associated with higher prevalence of coronary heart disease in patients in both groups (Wakayama, n=423, odds ratio, 1.64; 95% confidence interval, 1.02-2.64; P=0.041; Tokyo, n=451, odds ratio, 1.58; 95% CI, 1.07-2.34; P=0.021, in an additive model, respectively). No significant associations were observed with other diabetic vascular complications. Although association of the polymorphism with susceptibility to type 2 diabetes or nephropathy was not replicated, an association of the polymorphism with risk of coronary heart disease in type 2 diabetes is suggested.

Tumor-induced hypophosphatemic osteomalacia diagnosed by the combinatory procedures of magnetic resonance imaging and venous sampling for FGF23.

This report describes a 37-year-old man with tumor-induced osteomalacia (TIO). The patient had hypophosphatemia and elevated fibroblast growth factor 23 (FGF23) in the peripheral blood. Magnetic resonance imaging detected an abnormal mass in the left greater trochanter. Venous sampling revealed a significantly higher level of FGF23 in the left common iliac vein (proximal to the tumor), verifying that the tumor is responsible for TIO. The serum level of FGF23 decreased and symptoms improved after removal of the tumor. The combined diagnostic procedures of MRI and venous sampling for FGF23 effectively detected the tumor responsible for TIO.

Cardio-ankle vascular index measures arterial wall stiffness independent of blood pressure.

Although brachial-ankle pulse wave velocity (baPWV) is a non-invasive method of detecting arteriosclerosis, it is affected by changes in blood pressure (BP). Cardio-ankle vascular index (CAVI) is a new method for estimating arteriosclerosis, and it has been reported to be less influenced by BP. We investigated the influence of BP changes on CAVI and the correlation of CAVI to clinical factors and carotid arteriosclerosis. CAVI and baPWV in 35 non-diabetic and 33 diabetic subjects were measured in increased BP (after stair climbing) and rested BP (after 10min of rest). Intima-media thickness (IMT) of carotid arteries was measured by ultrasoundsonography. We achieved the following results: CAVI did not show a significant change with a change in BP in both non-diabetic and diabetic subjects. On the contrary, baPWV was significantly influenced by BP changes. Carotid artery IMT had a significant positive correlation with CAVI and baPWV. Multiple regression analysis revealed that significant risk factors of high baPWV were age and systolic BP. On the contrary, significant risk factors of high CAVI were age and hemoglobin A1c, while systolic BP was not relevant. Our findings suggest that CAVI is independent of BP and useful as an indicator of early arteriosclerosis in diabetic subjects.

Polymorphisms in the IDE-KIF11-HHEX gene locus are reproducibly associated with type 2 diabetes in a Japanese population.

CONTEXT: A genome-wide association study in the French population has detected that novel single-nucleotide polymorphisms (SNPs) in the IDE-KIF11-HHEX gene locus and the SLC30A8 gene locus are associated with susceptibility to type 2 diabetes. OBJECTIVE: We investigated whether SNPs in these loci were associated with type 2 diabetes in Japanese. DESIGN: Two SNPs, rs7923837 and rs1111875, in the IDE-KIF11-HHEX gene locus and one SNP, rs13266634, in the SLC30A8 gene locus were genotyped in Japanese type 2 diabetic patients (n = 405) and in nondiabetic control subjects (n = 340) using the TaqMan genotyping assay system. RESULTS: The G allele of rs7923837 was associated with type 2 diabetes [odds ratio 1.66, 95% confidence interval (CI) 1.28-2.15; P = 0.00014], following the same tendency as in the French population of the previous report. Heterozygous and homozygous carriers of the risk allele had odds ratios of 1.57 (95% CI 1.15-2.16; P = 0.0050) and 3.16 (95% CI 1.40-7.16; P = 0.0038) relative to noncarriers. Although the G allele was a major allele (66.5%) in the French population, it was a minor allele (23.8%) in Japanese. The G allele of rs1111875 was also associated with type 2 diabetes (odds ratio 1.42, 95% CI 1.13-1.78; P = 0.0024). Heterozygous and homozygous carriers of the risk allele had odds ratios of 1.31 (95% CI 0.97-1.77; P = 0.0810) and 2.40 (95% CI 1.34-4.32; P = 0.0028) relative to noncarriers. A significant association with type 2 diabetes was not observed for rs13266634. CONCLUSIONS: Polymorphisms in the IDE-KIF11-HHEX gene locus are associated with susceptibility to type 2 diabetes across the boundary of race.

Ferulic acid prevents pathological and functional abnormalities of the kidney in Otsuka Long-Evans Tokushima Fatty diabetic rats.

We investigated the preventive effects of ferulic acid (FA) and alpha-tocopherol (AT) on the progression of diabetic nephropathy. Otsuka Long-Evans Tokushima Fatty (OLETF) and Long-Evans Tokushima Otsuka (LETO) rats were used as type 2 diabetes and non-diabetes models, respectively. Two-thirds of the OLETF rats were fed 0.2% FA-containing or 0.5% AT-containing chow. Diabetic nephropathy was assessed based on urinary protein excretion and pathological changes which were scored based on the percentages of extracellular matrix area in the glomerular area. Furthermore, renal messenger RNA (mRNA) expression of intercellular adhesion molecule-1 (ICAM-1), cyclooxygenase-2 (COX-2) and transforming growth factor-beta1 (TGF-beta1) was quantified by real-time polymerase chain reaction. After 12 weeks of FA- or AT-supplementation, urinary protein in untreated-OLETF group was significantly higher than that in LETO group, thus FA-supplementation significantly decreased urinary protein excretion. Pathological scores in FA-supplemented group were significantly lower than those in untreated OLETF group. Supplementation with either FA or AT significantly prevented the elevation of TGF-beta1 mRNA expression caused by diabetes. Treatment with neither FA nor AT had a significant effect on COX-2 or ICAM-1 mRNA expressions. We have demonstrated the preventative effects of FA on diabetic nephropathy via suppression of TGF-beta1 upregulation, furthermore FA may be more potent than AT.