Professional Interests

Keiichi Kodama MD, PhD is Senior Research Associate at Division of Systems Medicine in the Pediatric Department at Stanford University School of Medicine. Dr. Kodama's research interests focus on integrating genomics (bioinformatics) to identify diagnostics biomarkers, disease mechanisms and therapeutical drugs for diabetes and other polygenic diseases.


Journal Articles

  • Anti-CD44 Antibody Treatment Lowers Hyperglycemia and Improves Insulin Resistance, Adipose Inflammation, and Hepatic Steatosis in Diet-Induced Obese Mice. Diabetes Kodama, K., Toda, K., Morinaga, S., Yamada, S., Butte, A. J. 2014


    Type 2 diabetes (T2D) is a metabolic disease affecting >370 million people worldwide. It is characterized by obesity-induced insulin resistance, and growing evidence has indicated that this causative link between obesity and insulin resistance is associated with visceral adipose tissue inflammation. However, using anti-inflammatory drugs to treat insulin resistance and T2D is not a common practice. We recently applied a bioinformatics methodology to open public data, and found that CD44 plays critical role in the development of adipose tissue inflammation and insulin resistance. In this report, we examined the role of CD44 in T2D by administering daily injections of anti-CD44 monoclonal antibody in a high-fat diet (HFD) mouse model. Four weeks of therapy with CD44 mAb suppressed visceral adipose tissue inflammation compared to controls and reduced fasting blood glucose levels, weight gain, liver steatosis, and insulin resistance to levels comparable to or better than the drugs metformin and pioglitazone. These findings suggest that CD44 mAb may be useful as a prototype drug for therapy of T2D by breaking the links between obesity and insulin resistance.

    View details for DOI 10.2337/db14-0149

    View details for PubMedID 25294945

  • Ethnic Differences in the Relationship Between Insulin Sensitivity and Insulin Response A systematic review and meta-analysis DIABETES CARE Kodama, K., Tojjar, D., Yamada, S., Toda, k., Patel, C. J., Butte, A. J. 2013; 36 (6): 1789-1796


    OBJECTIVE Human blood glucose levels have likely evolved toward their current point of stability over hundreds of thousands of years. The robust population stability of this trait is called canalization. It has been represented by a hyperbolic function of two variables: insulin sensitivity and insulin response. Environmental changes due to global migration may have pushed some human subpopulations to different points of stability. We hypothesized that there may be ethnic differences in the optimal states in the relationship between insulin sensitivity and insulin response. RESEARCH DESIGN AND METHODS We identified studies that measured the insulin sensitivity index (SI) and acute insulin response to glucose (AIRg) in three major ethnic groups: Africans, Caucasians, and East Asians. We identified 74 study cohorts comprising 3,813 individuals (19 African cohorts, 31 Caucasian, and 24 East Asian). We calculated the hyperbolic relationship using the mean values of SI and AIRg in the healthy cohorts with normal glucose tolerance. RESULTS We found that Caucasian subpopulations were located around the middle point of the hyperbola, while African and East Asian subpopulations are located around unstable extreme points, where a small change in one variable is associated with a large nonlinear change in the other variable. CONCLUSIONS Our findings suggest that the genetic background of Africans and East Asians makes them more and differentially susceptible to diabetes than Caucasians. This ethnic stratification could be implicated in the different natural courses of diabetes onset.

    View details for DOI 10.2337/dc12-1235

    View details for Web of Science ID 000321472600056

    View details for PubMedID 23704681

  • Expression-based genome-wide association study links the receptor CD44 in adipose tissue with type 2 diabetes PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA Kodama, K., Horikoshi, M., Toda, k., Yamada, S., Hara, K., Irie, J., Sirota, M., Morgan, A. A., Chen, R., Ohtsu, H., Maeda, S., Kadowaki, T., Butte, A. J. 2012; 109 (18): 7049-7054


    Type 2 diabetes (T2D) is a complex, polygenic disease affecting nearly 300 million people worldwide. T2D is primarily characterized by insulin resistance, and growing evidence has indicated the causative link between adipose tissue inflammation and the development of insulin resistance. Genetic association studies have successfully revealed a number of important genes consistently associated with T2D to date. However, these robust T2D-associated genes do not fully elucidate the mechanisms underlying the development and progression of the disease. Here, we report an alternative approach, gene expression-based genome-wide association study (eGWAS): searching for genes repeatedly implicated in functional microarray experiments (often publicly available). We performed an eGWAS across 130 independent experiments (totally 1,175 T2D case-control microarrays) to find additional genes implicated in the molecular pathogenesis of T2D and identified the immune-cell receptor CD44 as our top candidate (P = 8.5 × 10(-20)). We found CD44 deficiency in a diabetic mouse model ameliorates insulin resistance and adipose tissue inflammation and also found that anti-CD44 antibody treatment decreases blood glucose levels and adipose tissue macrophage accumulation in a high-fat, diet-fed mouse model. Further, in humans, we observed CD44 is expressed in inflammatory cells in obese adipose tissue and discovered serum CD44 levels were positively correlated with insulin resistance and glycemic control. CD44 likely plays a causative role in the development of adipose tissue inflammation and insulin resistance in rodents and humans. Genes repeatedly implicated in publicly available experimental data may have unique functionally important roles in T2D and other complex diseases.

    View details for DOI 10.1073/pnas.1114513109

    View details for Web of Science ID 000303602100060

    View details for PubMedID 22499789

  • Tissue- and age-specific changes in gene expression during disease induction and progression in NOD mice CLINICAL IMMUNOLOGY Kodama, K., Butte, A. J., Creusot, R. J., Su, L., Sheng, D., Hartnett, M., Iwai, H., Soares, L. R., Fathman, C. G. 2008; 129 (2): 195-201


    Whole genome oligo-microarrays were used to characterize age-dependent and tissue-specific changes in gene expression in pancreatic lymph nodes, spleen, and peripheral blood cells, obtained from up to 8 individual NOD mice at 6 different time points (1.5 to 20 weeks of age), compared to NOD.B10 tissue controls. "Milestone Genes" are genes whose expression was significantly changed (approximately 3 fold) as the result of splicing or changes in transcript level. Milestone Genes were identified among genes within type one diabetes (T1D) susceptibility regions (Idd). Milestone Genes showing uniform patterns of changes in expression at various time points were identified, but the patterns of distribution and kinetics of expression were unique to each tissue. Potential T1D candidate genes were identified among Milestone Genes within Idd regions and/or hierarchical clusters. These studies identified tissue- and age-specific changes in gene expression that may play an important role in the inductive or destructive events of T1D.

    View details for DOI 10.1016/j.clim.2008.07.028

    View details for Web of Science ID 000260553600003

    View details for PubMedID 18801706

  • Systematic identification of interaction effects between genome- and environment-wide associations in type 2 diabetes mellitus HUMAN GENETICS Patel, C. J., Chen, R., Kodama, K., Ioannidis, J. P., Butte, A. J. 2013; 132 (5): 495-508


    Diseases such as type 2 diabetes (T2D) result from environmental and genetic factors, and risk varies considerably in the population. T2D-related genetic loci discovered to date explain only a small portion of the T2D heritability. Some heritability may be due to gene-environment interactions. However, documenting these interactions has been difficult due to low availability of concurrent genetic and environmental measures, selection bias, and challenges in controlling for multiple hypothesis testing. Through genome-wide association studies (GWAS), investigators have identified over 90 single nucleotide polymorphisms (SNPs) associated to T2D. Using a method analogous to GWAS [environment-wide association study (EWAS)], we found five environmental factors associated with the disease. By focusing on risk factors that emerge from GWAS and EWAS, it is possible to overcome difficulties in uncovering gene-environment interactions. Using data from the National Health and Nutrition Examination Survey (NHANES), we screened 18 SNPs and 5 serum-based environmental factors for interaction in association to T2D. We controlled for multiple hypotheses using false discovery rate (FDR) and Bonferroni correction and found four interactions with FDR <20 %. The interaction between rs13266634 (SLC30A8) and trans-?-carotene withstood Bonferroni correction (corrected p = 0.006, FDR <1.5 %). The per-risk-allele effect sizes in subjects with low levels of trans-?-carotene were 40 % greater than the marginal effect size [odds ratio (OR) 1.8, 95 % CI 1.3-2.6]. We hypothesize that impaired function driven by rs13266634 increases T2D risk when combined with serum levels of nutrients. Unbiased consideration of environmental and genetic factors may help identify larger and more relevant effect sizes for disease associations.

    View details for DOI 10.1007/s00439-012-1258-z

    View details for Web of Science ID 000317691100002

    View details for PubMedID 23334806

  • Amyloid formation results in recurrence of hyperglycaemia following transplantation of human IAPP transgenic mouse islets DIABETOLOGIA Udayasankar, J., Kodama, K., Hull, R. L., Zraika, S., Aston-Mourney, K., Subramanian, S. L., Tong, J., Faulenbach, M. V., Vidal, J., Kahn, S. E. 2009; 52 (1): 145-153


    Islet transplantation is a potential cure for diabetes; however, rates of graft failure remain high. The aim of the present study was to determine whether amyloid deposition is associated with reduced beta cell volume in islet grafts and the recurrence of hyperglycaemia following islet transplantation.We transplanted a streptozotocin-induced mouse model of diabetes with 100 islets from human IAPP (which encodes islet amyloid polypeptide) transgenic mice that have the propensity to form islet amyloid (n = 8-12) or from non-transgenic mice that do not develop amyloid (n = 6-10) in sets of studies that lasted 1 or 6 weeks.Plasma glucose levels before and for 1 week after transplantation were similar in mice that received transgenic or non-transgenic islets, and at that time amyloid was detected in all transgenic grafts and, as expected, in none of the non-transgenic grafts. However, over the 6 weeks following transplantation, plasma glucose levels increased in transgenic but remained stable in non-transgenic islet graft recipients (p < 0.05). At 6 weeks, amyloid was present in 92% of the transgenic grafts and in none of the non-transgenic grafts. Beta cell volume was reduced by 30% (p < 0.05), beta cell apoptosis was twofold higher (p < 0.05), and beta cell replication was reduced by 50% (p < 0.001) in transgenic vs non-transgenic grafts. In summary, amyloid deposition in islet grafts occurs prior to the recurrence of hyperglycaemia and its accumulation over time is associated with beta cell loss.Islet amyloid formation may explain, in part, the non-immune loss of beta cells and recurrence of hyperglycaemia following clinical islet transplantation.

    View details for DOI 10.1007/s00125-008-1185-7

    View details for Web of Science ID 000261375400020

    View details for PubMedID 19002432

  • Tissue-targeted therapy of autoimmune diabetes using dendritic cells transduced to express IL-4 in NOD mice CLINICAL IMMUNOLOGY Creusot, R. J., Yaghoubi, S. S., Kodama, K., Dang, D. N., Dang, V. H., Breckpot, K., Thielemans, K., Gambhir, S. S., Fathman, C. G. 2008; 127 (2): 176-187


    A deficit in IL-4 production has been previously reported in both diabetic human patients and non-obese diabetic (NOD) mice. In addition, re-introducing IL-4 into NOD mice systemically, or as a transgene, led to a beneficial outcome in most studies. Here, we show that prediabetic, 12-week old female NOD mice have a deficit in IL-4 expression in the pancreatic lymph nodes (PLN) compared to age-matched diabetes-resistant NOD.B10 mice. By bioluminescence imaging, we demonstrated that the PLN was preferentially targeted by bone marrow-derived dendritic cells (DCs) following intravenous (IV) administration. Following IV injection of DCs transduced to express IL-4 (DC/IL-4) into 12-week old NOD mice, it was possible to significantly delay or prevent the onset of hyperglycemia. We then focused on the PLN to monitor, by microarray analysis, changes in gene expression induced by DC/IL-4 and observed a rapid normalization of the expression of many genes, that were otherwise under-expressed compared to NOD.B10 PLN. The protective effect of DC/IL-4 required both MHC and IL-4 expression by the DCs. Thus, adoptive cellular therapy, using DCs modified to express IL-4, offers an effective, tissue-targeted cellular therapy to prevent diabetes in NOD mice at an advanced stage of pre-diabetes, and may offer a safe approach to consider for treatment of high risk human pre-diabetic patients.

    View details for DOI 10.1016/j.clim.2007.12.009

    View details for Web of Science ID 000255231100010

    View details for PubMedID 18337172

  • FitSNPs: highly differentially expressed genes are more likely to have variants associated with disease GENOME BIOLOGY Chen, R., Morgan, A. A., Dudley, J., Deshpande, T., Li, L., Kodama, K., Chiang, A. P., Butte, A. J. 2008; 9 (12)


    Candidate single nucleotide polymorphisms (SNPs) from genome-wide association studies (GWASs) were often selected for validation based on their functional annotation, which was inadequate and biased. We propose to use the more than 200,000 microarray studies in the Gene Expression Omnibus to systematically prioritize candidate SNPs from GWASs.We analyzed all human microarray studies from the Gene Expression Omnibus, and calculated the observed frequency of differential expression, which we called differential expression ratio, for every human gene. Analysis conducted in a comprehensive list of curated disease genes revealed a positive association between differential expression ratio values and the likelihood of harboring disease-associated variants. By considering highly differentially expressed genes, we were able to rediscover disease genes with 79% specificity and 37% sensitivity. We successfully distinguished true disease genes from false positives in multiple GWASs for multiple diseases. We then derived a list of functionally interpolating SNPs (fitSNPs) to analyze the top seven loci of Wellcome Trust Case Control Consortium type 1 diabetes mellitus GWASs, rediscovered all type 1 diabetes mellitus genes, and predicted a novel gene (KIAA1109) for an unexplained locus 4q27. We suggest that fitSNPs would work equally well for both Mendelian and complex diseases (being more effective for cancer) and proposed candidate genes to sequence for their association with 597 syndromes with unknown molecular basis.Our study demonstrates that highly differentially expressed genes are more likely to harbor disease-associated DNA variants. FitSNPs can serve as an effective tool to systematically prioritize candidate SNPs from GWASs.

    View details for DOI 10.1186/gb-2008-9-12-r170

    View details for Web of Science ID 000263074100009

    View details for PubMedID 19061490

  • Gestational diabetes mellitus increases the risk of cardiovascular disease in women with a family history of type 2 diabetes DIABETES CARE Carr, D. B., Heckbert, S. R., Utzschneher, K. M., Boyko, E. J., Hull, R. L., Fujimoto, W. Y., Tong, J., Kahn, S. E., Wallace, T. M., Kodama, K., Shofer, J. B. 2006; 29 (9): 2078-2083


    We sought to determine whether a history of gestational diabetes mellitus (GDM) further increases the risk of cardiovascular disease (CVD) in parous women with first-degree relatives with type 2 diabetes.Women with (n = 332) and without (n = 663) a history of GDM were compared regarding 1) the revised National Cholesterol Education Program Adult Treatment Panel III metabolic syndrome criteria, 2) the prevalence of type 2 diabetes, and 3) self-reported CVD.Women with prior GDM were younger (48.6 +/- 0.7 vs. 52.4 +/- 0.6 years [means +/- SE];P < 0.001) and less likely to be postmenopausal (48.3 vs. 57.9%; P < 0.005). Although both groups were obese (BMI 34.4 +/- 1.2 vs. 33.7 +/- 0.6 kg/m(2)), women with prior GDM were more likely to have metabolic syndrome (86.6 vs. 73.5%; P < 0.001) and type 2 diabetes (93.4 vs. 63.3%; P < 0.001). Moreover, they had a higher prevalence of CVD (15.5 vs. 12.4%; adjusted odds ratio 1.85 [95% CI 1.21-2.82];P = 0.005) that occurred at a younger age (45.5 +/- 2.2 vs. 52.5 +/- 1.9 years;P = 0.02) and was independent of metabolic syndrome (1.74 [1.10-2.76]; P = 0.02) and type 2 diabetes (1.56 [1.002-2.43];P < 0.05).Among women with a family history of type 2 diabetes, those with prior GDM were even more likely to not only have CVD risk factors, including metabolic syndrome and type 2 diabetes, but also to have experienced CVD events, which occurred at a younger age. Thus, women with both a family history of type 2 diabetes and personal history of GDM may be especially suitable for early interventions aimed at preventing or reducing their risk of CVD and diabetes.

    View details for DOI 10.2337/dc05-2482

    View details for Web of Science ID 000240456800014

    View details for PubMedID 16936156

  • Genetic background determines the extent of islet amyloid formation in human islet amyloid polypeptide transgenic mice AMERICAN JOURNAL OF PHYSIOLOGY-ENDOCRINOLOGY AND METABOLISM Hull, R. L., Watts, M. R., Kodama, K., Shen, Z. P., Utzschneider, K. M., Carr, D. B., Vidal, J., Kahn, S. E. 2005; 289 (4): E703-E709


    Genetic background is important in determining susceptibility to metabolic abnormalities such as insulin resistance and beta-cell dysfunction. Islet amyloid is associated with reduced beta-cell mass and function and develops in the majority of our C57BL/6J x DBA/2J (F(1)) male human islet amyloid polypeptide (hIAPP) transgenic mice after 1 yr of increased fat feeding. To determine the relative contribution of each parental strain, C57BL/6J (BL6) and DBA/2J (DBA2), to islet amyloid formation, we studied male hIAPP mice on each background strain (BL6, n = 13; and DBA2 n = 11) and C57BL/6J x DBA/2J F(1) mice (n = 17) on a 9% (wt/wt) fat diet for 1 yr. At the end of 12 mo, islet amyloid deposition was quantified from thioflavin S-stained pancreas sections. The majority of mice in all groups developed islet amyloid (BL6: 91%, F(1): 76%, DBA2: 100%). However, the prevalence (%amyloid-positive islets; BL6: 14 +/- 3%, F(1): 44 +/- 8%, DBA2: 49 +/- 9%, P < 0.05) and severity (%islet area occupied by amyloid; BL6: 0.03 +/- 0.01%, F(1): 9.2 +/- 2.9%, DBA2: 5.7 +/- 2.3%, p < or = 0.01) were significantly lower in BL6 than F(1) and DBA2 mice. Increased islet amyloid severity was negatively correlated with insulin-positive area per islet, in F(1) (r(2) = 0.75, P < 0.001) and DBA2 (r(2) = 0.87, P < 0.001) mice but not BL6 mice (r(2) = 0.07). In summary, the extent of islet amyloid formation in hIAPP transgenic mice is determined by background strain, with mice expressing DBA/2J genes (F(1) and DBA2 mice) being more susceptible to amyloid deposition that replaces beta-cell mass. These findings underscore the importance of genetic and environmental factors in studying metabolic disease.

    View details for DOI 10.1152/ajpendo.00471.2004

    View details for Web of Science ID 000231737800024

    View details for PubMedID 15899941

  • Long-term treatment with rosiglitazone and metformin reduces the extent of, but does not prevent, islet antyloid deposition in mice expressing the gene for human islet antyloid polypeptide DIABETES Hull, R. L., Shen, Z. P., Watts, M. R., Kodama, K., Carr, D. B., Utzschneider, K. M., Zraika, S., Wang, F., Kahn, S. E. 2005; 54 (7): 2235-2244


    Islet amyloid deposition in type 2 diabetes is associated with reduced beta-cell mass. Therefore, interventions aimed at reducing islet amyloid formation may help preserve beta-cell mass in type 2 diabetes. Rosiglitazone and metformin act by different mechanisms to improve insulin sensitivity and thereby reduce beta-cell secretory demand, resulting in decreased release of insulin and islet amyloid polypeptide (IAPP), the unique constituent of islet amyloid deposits. We hypothesized that this reduced beta-cell secretory demand would lead to reduced islet amyloid formation. Human IAPP (hIAPP) transgenic mice, a model of islet amyloid, were treated for 12 months with rosiglitazone (1.5, n = 19), metformin (1, n = 18), or control (n = 17). At the end of the study, islet amyloid prevalence (percent islets containing amyloid) and severity (percent islet area occupied by amyloid), islet mass, beta-cell mass, and insulin release were determined. Islet amyloid prevalence (44 +/- 8, 13 +/- 4, and 11 +/- 3% for control, metformin-, and rosiglitazone-treated mice, respectively) and severity (9.2 +/- 3.0, 0.22 +/- 0.11, and 0.10 +/- 0.05% for control, metformin-, and rosiglitazone-treated mice, respectively) were markedly reduced with both rosiglitazone (P < 0.001 for both measures) and metformin treatment (P < 0.001 for both measures). Both treatments were associated with reduced insulin release assessed as the acute insulin response to intravenous glucose (2,189 +/- 857, 621 +/- 256, and 14 +/- 158 pmol/l for control, metformin-, and rosiglitazone-treated mice, respectively; P < 0.05 for metformin vs. control and P < 0.005 for rosiglitazone vs. control), consistent with reduced secretory demand. Similarly, islet mass (33.4 +/- 7.0, 16.6 +/- 3.6, and 12.2 +/- 2.1 mg for control, metformin-, and rosiglitazone-treated mice, respectively) was not different with metformin treatment (P = 0.06 vs. control) but was significantly lower with rosiglitazone treatment (P < 0.05 vs. control). When the decreased islet mass was accounted for, the islet amyloid-related decrease in beta-cell mass (percent beta-cell mass/islet mass) was ameliorated in both rosiglitazone- and metformin-treated animals (57.9 +/- 3.1, 64.7 +/- 1.4, and 66.1 +/- 1.6% for control, metformin-, and rosiglitazone-treated mice, respectively; P < 0.05 for metformin or rosiglitazone vs. control). In summary, rosiglitazone and metformin protect beta-cells from the deleterious effects of islet amyloid, and this effect may contribute to the ability of these treatments to alleviate the progressive loss of beta-cell mass and function in type 2 diabetes.

    View details for Web of Science ID 000230164000040

    View details for PubMedID 15983227

  • Dietary-fat-induced obesity in mice results in beta cell hyperplasia but not increased insulin release: evidence for specificity of impaired beta cell adaptation DIABETOLOGIA Hull, R., Kodama, K., Utzschneider, K., Carr, D. B., Prigeon, R. L., Kahn, S. E. 2005; 48 (7): 1350-1358


    Increased dietary fat intake is associated with obesity and insulin resistance, but studies have shown that the subsequent increase in insulin release is not appropriate for this obesity-induced insulin resistance. We therefore sought to determine whether the impaired beta cell adaptation is due to inadequate expansion of the beta cell population or to a lack of an adaptive increase in insulin release.Male mice were fed diets containing increasing amounts of fat (15, 30 or 45% of energy intake) for 1 year, after which islet morphology and secretory function were assessed.Increased dietary fat intake was associated with a progressive increase in body weight (p<0.001). Fractional beta cell area (total beta cell area/section area) was increased with increasing dietary fat (1.36+/-0.39, 2.46+/-0.40 and 4.93+/-1.05%, p<0.001), due to beta cell hyperplasia, and was positively and highly correlated with body weight (r2=0.68, p<0.005). In contrast, insulin release following i.p. glucose did not increase with increasing dietary fat (118+/-32, 108+/-47 and 488+/-200 pmol/l per mmol/l, p=0.07) and did not correlate with body weight (r2=0.11). When this response was examined relative to fractional beta cell area (insulin release/fractional beta cell area), it did not increase but rather tended to decrease with increasing dietary fat (157+/-55, 43+/-13 and 97+/-53 [pmol/l per mmol/l]/%, p=0.06) and did not correlate with body weight (r2=0.02).Long-term fat feeding is associated with an increase in the beta cell population but an inadequate functional adaptation. Thus, a functional rather than a morphological abnormality appears to underlie dietary-fat-induced beta cell dysfunction.

    View details for DOI 10.1007/s00125-005-1772-9

    View details for Web of Science ID 000230651500018

    View details for PubMedID 15937671

  • A reduced-fat diet and aerobic exercise in Japanese Americans with impaired glucose tolerance decreases intra-abdominal fat and improves insulin sensitivity but not beta-cell function DIABETES Carr, D. B., Utzschneider, K. M., Boyko, E. J., Asberry, P. J., Hull, R. L., Kodama, K., Callahan, H. S., Matthys, C. C., Leonetti, D. L., Schwartz, R. S., Kahn, S. E., Fujimoto, W. Y. 2005; 54 (2): 340-347


    Lifestyle modification reduces the risk of developing type 2 diabetes and may have its effect through improving insulin sensitivity, beta-cell function, or both. To determine whether diet and exercise improve insulin sensitivity and/or beta-cell function and to evaluate these effects over time, we quantified insulin sensitivity and the acute insulin response to glucose (AIRg) in 62 Japanese Americans (age 56.5 +/- 1.3 years; mean +/- SE) with impaired glucose tolerance (IGT) who were randomized to the American Heart Association (AHA) Step 2 diet plus endurance exercise (n = 30) versus the AHA Step 1 diet plus stretching (n = 32) for 24 months. beta-Cell function (disposition index [DI]) was calculated as S(i) x AIRg, where S(i) is the insulin sensitivity index. The incremental area under the curve for glucose (incAUCg) was calculated from a 75-g oral glucose tolerance test. Intra-abdominal fat (IAF) and subcutaneous fat (SCF) areas were measured by computed tomography. At 24 months, the Step 2/endurance group had lower weight (63.1 +/- 2.4 vs. 71.3 +/- 2.9 kg; P = 0.004) and IAF (75.0 +/- 7.9 vs. 112.7 +/- 10.4 cm(2); P = 0.03) and SCF (196.5 +/- 18.0 vs. 227.7 +/- 19.9 cm(2); P < 0.001) areas, greater S(i) (4.7 +/- 0.5 vs. 3.3 +/- 0.3 x 10(-5) min . pmol(-1) . l(-1); P = 0.01), and a trend toward lower AIRg (294.9 +/- 50.0 vs. 305.4 +/- 30.0 pmol/l; P = 0.06) and incAUCg (8,217.3 +/- 350.7 vs. 8,902.0 +/- 367.2 mg . dl(-1) . 2 h(-1); P = 0.08) compared with the Step 1/stretching group after adjusting for baseline values. There was no difference in the DI (P = 0.7) between the groups. S(i) was associated with changes in weight (r = -0.426, P = 0.001) and IAF (r = -0.395, P = 0.003) and SCF (r = -0.341, P = 0.01) areas. Thus, the lifestyle modifications decreased weight and central adiposity and improved insulin sensitivity in Japanese Americans with IGT. However, such changes did not improve beta-cell function, suggesting that this degree of lifestyle modifications may be limited in preventing type 2 diabetes over the long term.

    View details for Web of Science ID 000226613400006

    View details for PubMedID 15677490

  • Impact of intra-abdominal fat and age on insulin sensitivity and beta-cell function DIABETES Utzschneider, K. M., Carr, D. B., Hull, R. L., Kodama, K., Shofer, J. B., Retzlaff, B. M., KNOPP, R. H., Kahn, S. E. 2004; 53 (11): 2867-2872


    The prevalence of glucose intolerance and type 2 diabetes increases with age. To determine whether the hyperbolic relationship between insulin sensitivity and the insulin response is affected by age and whether the decline in beta-cell function with age is related to increases in intra-abdominal fat or age per se, we studied 220 healthy subjects with fasting glucose <6.1 mmol/l (89 men and 131 women, aged 26-75 years, BMI 18.7-40.4 kg/m(2)). The insulin sensitivity index (S(i)) and the acute insulin response to glucose (AIRg) were determined, and from these beta-cell function was estimated as the disposition index (S(i) x AIRg). Intra-abdominal fat and subcutaneous fat areas were quantified by computed tomography. S(i) (5.40 +/- 0.5 vs. 7.86 +/- 0.7 x10(-5) min(-1)/[pmol/l]), P < 0.01) was decreased and intra-abdominal fat (117 +/- 10 vs. 81 +/- 9 cm(2), P < 0.05) was increased in the oldest (age 60-75 years) versus the youngest (age 26-44 years) quartile. The hyperbolic relationship between S(i) and AIRg was present independent of age; thus, beta-cell function measured as the disposition index (1,412 +/- 120 vs. 2,125 +/- 150 x10(-5) min(-1), P < 0.01) was lower in the oldest versus the youngest quartile. In multiple regression, intra-abdominal fat (r = -0.470, P < 0.001) but not age was associated with S(i), but both intra-abdominal fat (r = -0.198, P = 0.003) and age (r = -0.131, P = 0.05) were correlated with the disposition index. These data suggest that although intra-abdominal fat is a strong determinant of insulin sensitivity and beta-cell function, age has an independent effect on beta-cell function that may contribute to the increased prevalence of type 2 diabetes in older populations.

    View details for Web of Science ID 000224826000016

    View details for PubMedID 15504967

  • Insulin-like growth factor-1 (IGF-1)-derived peptide protects against diabetes in NOD mice AUTOIMMUNITY Kodama, K., Shimada, A., Funae, O., Morimoto, J., Irie, J., Shigihara, T., Oikawa, Y., Tokui, M., Watanabe, K., Saruta, T. 2004; 37 (6-7): 481-487


    Spontaneous diabetes in non-obese diabetic (NOD) mice results from beta-cell destruction by autoreactive T lymphocytes. Here, we report the significance of insulin-like growth factor-1 (IGF-1) peptide as a tool for the prevention of type 1 diabetes. Female NOD mice were immunized with a subcutaneous injection of IGF-1, glutamic acid decarboxylase (GAD), insulin or IGF-1-derived peptides (residues 8-23, 24-41 or 50-70) in incomplete Freund's adjuvant (IFA) or with IFA only as the control group at 4 weeks of age, and observed up to 36-37 weeks of age. Diabetes onset was significantly suppressed and delayed in the IGF-1 group as compared to the GAD, insulin and control groups (p<0.05), and it was significantly suppressed and delayed in the (50-70)IGF-1 group as compared to the (8-23)IGF-1 and control groups (p<0.02). Although the degree of insulitis in all treated mice was not significantly different, a significant number of IL-4-producing cells in response to IGF-1 peptides were detected in (50-70)IGF-1-treated mice in intracellular cytokine assay. In conclusion, IGF-1 peptide 50-70 immunizations of NOD mice suppressed and delayed diabetes onset, probably through amplification of the Th2-type response. It was suggested that IGF-1 peptide 50-70 immunization can be used as a tool for prevention of type 1 diabetes.

    View details for DOI 10.1080/08930400001909

    View details for Web of Science ID 000226384200008

    View details for PubMedID 15621575

  • GAD-reactive T cells were mainly detected in autoimmune-related type 1 diabetic patients with HLA DR9 IMMUNOLOGY OF DIABETES III Itoh, A., Shimada, A., Kodama, K., Moritmoto, J., Suzuki, R., Oikawa, Y., Irie, J., Nakagawa, Y., Shigihara, T., Kanazawa, Y., Okubo, Y., Motohashi, Y., Maruyama, T., Saruta, T. 2004; 1037: 33-40


    Type 1 diabetes mellitus (T1DM) is considered to be a T cell-mediated disease, and many reports suggest that some HLA types, especially HLA DR4 and DR9, convey susceptibility to T1DM in Japanese. We investigated the association between T cell reactivity against GAD and HLA types in "islet-associated autoantibody-positive" T1DM in Japanese. Blood samples were obtained from 36 "autoantibody-positive" type 1 diabetic patients with HLA DR4 or DR9 and 23 type 2 diabetic patients with HLA DR4 or DR9 as controls. They were divided into three groups, DR4/9, DR4/X, and DR9/X groups. In each HLA type group, GAD-reactive IFN-gamma-producing CD4(+) cells were assessed by means of intracellular cytokine staining for flow cytometry. Type 1 diabetic patients with HLA DR9/X had significantly higher numbers of GAD-reactive IFN-gamma-producing CD4(+) cells as compared to type 1 diabetic patients with DR4/X or DR4/9 (P < 0.05) and all type 2 diabetic patients. There was no significant difference in the number of GAD-reactive IFN-gamma-producing CD4(+) cells between type 1 diabetic and type 2 diabetic patients belonging to the DR4/X and DR4/9 groups. There was an association between T cell reactivity against GAD and HLA DR9 in Japanese type 1 diabetes.

    View details for DOI 10.1196/annals.1337.006

    View details for Web of Science ID 000227728900006

    View details for PubMedID 15699491

  • Assessment of beta cell mass and oxidative peritoneal exudate cells in murine type 1 diabetes using adoptive transfer system AUTOIMMUNITY Yamada, S., Irie, J., Shimada, A., Kodama, K., Morimoto, J., Suzuki, R., Oikawa, Y., Saruta, T. 2003; 36 (2): 63-70


    Because it is controversial how the beta cell mass is reduced during the disease process in type 1 diabetes, we transferred splenocytes from Non-obese diabetic (NOD) to NOD-scid mice and evaluated the relation between the status of the pancreas in donors and the time taken to transfer diabetes to the recipients. We also evaluated the usefulness of assessment of the proportion of oxidative peritoneal exudate cells (PEC) as a novel marker of disease activity in this system. We examined the proportion of oxidative PEC, pancreatic insulin content and pancreatic histology in 16-18-week-old female NOD mice (donors), and transferred their splenocytes into 5-week-old female NOD-scid mice (recipients). After the onset of diabetes in NOD-scid recipients, we assessed the relation between insulin content (or severity of insulitis) of NOD donors and the time taken to transfer diabetes to NOD-scid recipients. The insulin content of "diabetes-prone" donors whose disease status was considered to be just before the onset of diabetes ("malignant" donors) was the same as that of diabetic mice, whereas the insulin content of "diabetes-prone" donors excluding "malignant" donors ("benign" donors) was the same as that of "non-diabetes-prone" donors. Because its proportion of oxidative PEC was inversely correlated with the severity of insulitis, we then evaluated the relation between the proportion of oxidative PEC and the time taken to transfer diabetes. "Malignant" donors had less proportion of oxidative PEC (< 10%), as compared to "benign" and "non-diabetes-prone" donors. These results suggest that a marked reduction of beta cell mass occurs at the very late prediabetic stage, and assessment of the proportion of oxidative PEC is useful to evaluate disease activity in type 1 diabetes.

    View details for DOI 10.1080/0891693031000079266

    View details for Web of Science ID 000182081800002

    View details for PubMedID 12820687

  • T-cell function in anti-GAD65(+) diabetes with residual beta-cell function JOURNAL OF AUTOIMMUNITY Suzuki, R., Shimada, A., Maruyama, T., Funae, O., Morimoto, J., Kodama, K., Oikawa, Y., Kasuga, A., Matsubara, K., Saruta, T., Narumi, S. 2003; 20 (1): 83-90


    We have recently reported that in patients with anti-glutamic acid decarboxylase (GAD) 65(+)diabetes with residual beta-cell function, most with a 'high-titer' (>10U/ml) required insulin within 5 years, whereas most with a 'low-titer' (1.3-9.9U/ml) did not need insulin for over 15-20 years after the onset. We therefore examined T-cell function to evaluate the difference between the high-titer and low-titer groups. Interleukin (IL)-10 production upon polyclonal activation was significantly lower in the high-titer group than in the low-titer group. The serum level of interferon-inducible protein-10 (IP-10) was higher in the high-titer than the low-titer group. Although GAD65-reactive CD4(+)cells in the periphery were detected in both groups, a significant positive correlation between serum IP-10 level and the number of GAD65-reactive CD4(+)cells was observed only in the high-titer group. Therefore, it has been speculated that the co-existence of GAD65-reactive IFN-gamma-producing CD4(+)cells and a high serum IP-10 level may be important for rapid disease progression as seen in the high-titer group. Based upon these results, T-cell function is considered to be different between the high-titer and low-titer groups in anti-GAD65(+)diabetes with residual beta-cell function, supporting our previous findings regarding the clinical outcome of insulin-dependence in the two groups.

    View details for DOI 10.1016/S0896-8411(02)00093-8

    View details for Web of Science ID 000181293800008

    View details for PubMedID 12604315

  • Relationship between beta cell mass of NOD donors and diabetes development of NOD-scid recipients in adoptive transfer system IMMUNOLOGY OF DIABETES II: PATHOGENESIS FROM MOUSE TO MAN Yamada, S., Shimada, A., Kodama, K., Morimotb, J., Suzuki, R., Oikawa, Y., Irie, J., Saruta, T. 2003; 1005: 211-214


    There is controversy about the way the beta cell mass is reduced in type 1 diabetes. One view is that a gradual fall in beta cell mass begins soon after the onset of insulitis. Another view is that a sudden wave of beta cell destruction occurs just before the onset of diabetes. To clarify how the beta cell mass is reduced, we performed adoptive transfer experiments and examined the relationship between the pancreatic status of NOD donors and the time taken to transfer diabetes into NOD-scid recipients.We killed 18-week-old female NOD mice (n = 20), removed their spleen, and transferred splenocytes into 5-week-old female NOD-scid mice (n = 60). The relationship between the pancreatic status of donors and the time taken to transfer diabetes into recipients was assessed. As pancreatic status, we measured insulin content and severity of insulitis.There was no linear correlation between the pancreatic status of donors and the time taken to transfer diabetes into recipients. NOD donors who needed 7 or more weeks to transfer diabetes in NOD-scid recipients had similar levels of insulin content or severity of insulitis as those of NOD donors who could not transfer diabetes. On the other hand, NOD donors who needed 6 or less weeks to transfer diabetes in recipients had similar levels of insulin content or severity of insulitis as those of diabetic NOD mice.According to our observations, beta cell mass seems to be preserved until just before the onset of diabetes and decreased dramatically within a few weeks.

    View details for DOI 10.1196/annals.1288.028

    View details for Web of Science ID 000187496100027

    View details for PubMedID 14679061

  • Detection of GAD-reactive CD4+ cells in so-called "type 1B" diabetes IMMUNOLOGY OF DIABETES II: PATHOGENESIS FROM MOUSE TO MAN Shimada, A., Kodama, K., Morimoto, J., Oikawa, Y., Irie, J., Nakagawa, Y., Matsubara, K., Maruyama, T., Saruta, T. 2003; 1005: 378-386


    Although the majority of type 1 diabetes is considered to be type 1A, some patients with type 1 diabetes have no islet-associated autoantibody in their serum. This type of type 1 diabetes has usually been diagnosed as type 1B on the basis of islet-associated autoantibody-negativity. In this study, we tried to demonstrate the existence of islet-associated antigen-specific T cells in type 1 diabetes without islet-associated autoantibody.Peripheral blood samples were obtained from 110 Japanese diabetic patients, including 15 type 2 diabetic patients. Measurement of islet-associated antigen-specific cytokine response was performed by intracellular cytokine staining for flow cytometry.The number of GAD-reactive IFN-gamma-producing CD4+ cells in 50,000 CD4+ cells in diabetics with type 1B (113.6 +/- 34.6, median 45), type 1A (132.4 +/- 33.3, median 25), and LADA (154.4 +/- 44.1, median 20) was higher than that in type 2 diabetics (0.3 +/- 0.3, median 0) and control subjects (3.8 +/- 2.4, median 0). When the normal upper limit of the number of GAD-reactive CD4+ cells was set at the mean + 3SD of values in control subjects, at least half (52.4%) of the so-called "type 1B" patients were positive for GAD-reactive IFN-gamma-producing CD4+ cells, a significantly larger proportion than that in type 2 diabetics (0%; p < 0.001).Assessment of T cell reactivity against islet-associated antigen may contribute to the diagnosis of "autoimmune-related" type 1 diabetes.

    View details for DOI 10.1196/annals.1288.063

    View details for Web of Science ID 000187496100062

    View details for PubMedID 14679096

  • A case of fulminant type 1 diabetes with strong evidence of autoimmunity DIABETES CARE Shimada, A., Oikawa, Y., Shigihara, T., Senda, T., Kodama, K. 2002; 25 (8): 1482-1483

    View details for Web of Science ID 000185504100039

    View details for PubMedID 12145259

  • T-cell-mediated autoimmunity may be involved in fulminant type 1 diabetes DIABETES CARE Shimada, A., Morimoto, J., Kodama, K., Oikawa, Y., Irie, J., Nakagawa, Y., Narumi, S., Saruta, T. 2002; 25 (3): 635-636

    View details for Web of Science ID 000174168500046

    View details for PubMedID 11874969

  • Elevated serum IP-10 levels observed in type 1 diabetes DIABETES CARE Shimada, A., Morimoto, J., Kodama, K., Suzuki, R., Oikawa, Y., Funae, O., Kasuga, A., Saruta, T., Narumi, S. 2001; 24 (3): 510-515


    Although most patients with type 1 diabetes are considered to have T-cell-mediated autoimmune disease, a method of measuring of pancreatic beta-cell-specific T-cell function in cases of type 1 diabetes has yet to be established. Here, we focused on interferon-inducible protein-10 (IP-10), a chemokine that promotes the migration of activated T-helper 1 (Th1) cells and measured serum IP-10 levels in patients with human type 1 diabetes, which is regarded as a Th1-mediated disease.Serum samples were obtained from diabetic patients, and the levels of autoantibodies (GAD and insulinoma-associated protein-2 [IA-2]) and IP-10 were measured. Diabetic patients positive for either or both of the autoantibodies were classified as Ab+ type 1, and those negative for both were classified as Ab type 1. To evaluate islet antigen-specific responses, peripheral blood from patients stimulated with or without GAD was used, and intracellular cytokine staining for flowcytometry was performed.The Ab+ and Ab- type 1 groups both showed a significantly higher serum IP-10 level than the healthy subjects (P < 0.001 and P < 0.05, respectively), and the IP-10 level in the recent-onset Ab+ subgroup was significantly higher than that in the established (longstanding) Ab+ subgroup (P < 0.002). Furthermore, there was a significant positive correlation between the serum IP-10 level and the number of GAD-reactive gamma-interferon-producing CD4+ cells in the Ab+ type 1 group (P < 0.007).Our findings demonstrate that measurement of serum IP-10 concentrations is useful in patients with type 1 diabetes.

    View details for Web of Science ID 000167271200018

    View details for PubMedID 11289477

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