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1.  Association of fasting insulin and C peptide with diabetic retinopathy in Latinos with type 2 diabetes 
Residual insulin secretion provides important protection against the development of diabetic retinopathy in type 1 diabetes. The data to support this in type 2 diabetes are unclear. We therefore tested in type 2 diabetes whether markers of residual beta-cell function are associated with the development of diabetic retinopathy, an important microvascular complication of diabetes.
Prospective, cross-sectional, family-based study.
585 Latino type 2 diabetic participants, ascertained in families via a proband either with known diabetes duration of greater than 10 years and/or with diabetic retinopathy.
Outcome measures
Circulating levels of fasting insulin and C peptide measured and correlated to degree of diabetic retinopathy, assessed by digital fundus photography and graded using the Modified Airlie House Classification and the Early Treatment Diabetic Retinopathy Study scale (range: levels 10–85).
Fasting plasma insulin (β=−0.29; 95% CI −0.38 to −0.20; p<0.0001) and C peptide (β=−0.21; 95% CI −0.30 to −0.13; p<0.0001) concentrations in these diabetic participants were significantly correlated with retinopathy and its degree of severity. This relationship remained significant after adjusting for potential covariates including age, gender, glycosylated hemoglobin, duration of diabetes, blood pressure, and renal function.
These data suggest that residual endogenous insulin secretion is associated with the presence of diabetic retinopathy and its severity in Latinos with familial type 2 diabetes. It remains to be proven whether beta-cell targeted therapies, to maintain beta-cell mass and/or function in addition to glycemic control, will further the goal of preventing diabetic microvascular disease.
PMCID: PMC4212555  PMID: 25452868
Retinopathy; Insulin; C-Peptide
2.  Genome-wide association study in a Chinese population with diabetic retinopathy 
Human Molecular Genetics  2013;22(15):3165-3173.
Diabetic retinopathy (DR) is a leading cause of preventable blindness in adults. To identify genetic contributions in DR, we studied 2071 type 2 diabetics. We first conducted a genome-wide association study of 1007 individuals, comparing 570 subjects with ≥8 years duration without DR (controls) with 437 PDR (cases) in the Chinese discovery cohort. Cases and controls were similar for HbA1c, diabetes duration and body mass index. Association analysis with imputed data identified three novel loci: TBC1D4-COMMD6-UCHL3 (rs9565164, P = 1.3 × 10−7), LRP2-BBS5 (rs1399634, P = 2.0 × 10−6) and ARL4C-SH3BP4 (rs2380261, P = 2.1 × 10−6). Analysis of an independent cohort of 585 Hispanics diabetics with or without DR though did not confirm these signals. These genes are still of particular interest because they are involved in insulin regulation, inflammation, lipid signaling and apoptosis pathways, all of which are possibly involved with DR. Our finding nominates possible novel loci as potential DR susceptibility genes in the Chinese that are independent of the level of HbA1c and duration of diabetes and may provide insight into the pathophysiology of DR.
PMCID: PMC3699066  PMID: 23562823
To describe the uncommon presentation of hyperinsulinism in an 8-year-old boy.
We describe the patient's clinical findings, results from biochemical and imaging studies, surgical approach, and outcome. The discussion encompasses a review of literature that provided the basis for the diagnostic and surgical approach applied to this patient's case.
An obese 8.5-year-old boy initially presented with hypoglycemic seizures after initiation of dietary changes to treat obesity. Biochemical analysis indicated hyperinsulinism. Endoscopic ultrasonography showed no pancreatic lesions suggestive of insulinoma. Genetic studies identified no known mutations in the ABCC8, KCNJ11, GCK, or GLUD1 genes. Selective arterial calcium stimulation and hepatic venous sampling did not document a focal source for hyperinsulinism in the pancreas, and positron emission tomography with 18-fluoro-L-3,4-dihydroxyphenylalanine showed diffusely increased uptake in the pancreas. The patient ultimately required partial pancreatectomy because of continued hypoglycemia while taking diazoxide and octreotide. Intraoperative glucose monitoring directed the extent of surgical resection. A 45% pancreatectomy was performed, which resolved the hypoglycemia but led to impaired glucose tolerance after surgery.
The unusual presentation of hyperinsulinism in childhood required a personalized approach to diagnosis and surgical management using intraoperative glucose monitoring that resulted in a conservative pancreatectomy.
PMCID: PMC3865787  PMID: 22548943
4.  A Genome-Wide Search for Linkage of Estimated Glomerular Filtration Rate (eGFR) in the Family Investigation of Nephropathy and Diabetes (FIND) 
PLoS ONE  2013;8(12):e81888.
Estimated glomerular filtration rate (eGFR), a measure of kidney function, is heritable, suggesting that genes influence renal function. Genes that influence eGFR have been identified through genome-wide association studies. However, family-based linkage approaches may identify loci that explain a larger proportion of the heritability. This study used genome-wide linkage and association scans to identify quantitative trait loci (QTL) that influence eGFR.
Genome-wide linkage and sparse association scans of eGFR were performed in families ascertained by probands with advanced diabetic nephropathy (DN) from the multi-ethnic Family Investigation of Nephropathy and Diabetes (FIND) study. This study included 954 African Americans (AA), 781 American Indians (AI), 614 European Americans (EA) and 1,611 Mexican Americans (MA). A total of 3,960 FIND participants were genotyped for 6,000 single nucleotide polymorphisms (SNPs) using the Illumina Linkage IVb panel. GFR was estimated by the Modification of Diet in Renal Disease (MDRD) formula.
The non-parametric linkage analysis, accounting for the effects of diabetes duration and BMI, identified the strongest evidence for linkage of eGFR on chromosome 20q11 (log of the odds [LOD] = 3.34; P = 4.4×10−5) in MA and chromosome 15q12 (LOD = 2.84; P = 1.5×10−4) in EA. In all subjects, the strongest linkage signal for eGFR was detected on chromosome 10p12 (P = 5.5×10−4) at 44 cM near marker rs1339048. A subsequent association scan in both ancestry-specific groups and the entire population identified several SNPs significantly associated with eGFR across the genome.
The present study describes the localization of QTL influencing eGFR on 20q11 in MA, 15q21 in EA and 10p12 in the combined ethnic groups participating in the FIND study. Identification of causal genes/variants influencing eGFR, within these linkage and association loci, will open new avenues for functional analyses and development of novel diagnostic markers for DN.
PMCID: PMC3866106  PMID: 24358131
5.  Diabetes, Metformin, and Breast Cancer in Postmenopausal Women 
Journal of Clinical Oncology  2012;30(23):2844-2852.
Emerging evidence suggests that metformin may reduce breast cancer incidence, but reports are mixed and few provide information on tumor characteristics. Therefore, we assessed associations among diabetes, metformin use, and breast cancer in postmenopausal women participating in Women's Health Initiative clinical trials.
Patients and Methods
In all, 68,019 postmenopausal women, including 3,401 with diabetes at study entry, were observed over a mean of 11.8 years with 3,273 invasive breast cancers diagnosed. Diabetes incidence status was collected throughout follow-up, with medication information collected at baseline and years 1, 3, 6, and 9. Breast cancers were confirmed by review of central medical records and pathology reports. Cox proportional hazards regression, adjusted for breast cancer risk factors, compared breast cancer incidence in women with diabetes who were metformin users or nonusers with breast cancer incidence in women without diabetes.
Compared with that in women without diabetes, breast cancer incidence in women with diabetes differed by diabetes medication type (P = .04). Women with diabetes receiving medications other than metformin had a slightly higher incidence of breast cancer (hazard ratio [HR], 1.16; 95% CI, 0.93 to 1.45), and women with diabetes who were given metformin had lower breast cancer incidence (HR, 0.75; 95% CI, 0.57 to 0.99). The association was observed for cancers positive for both estrogen receptor and progesterone receptor and those that were negative for human epidermal growth factor receptor 2.
Metformin use in postmenopausal women with diabetes was associated with lower incidence of invasive breast cancer. These results can inform future studies evaluating metformin use in breast cancer management and prevention.
PMCID: PMC3826090  PMID: 22689798
6.  Systemic Soluble TNF Receptors 1 and 2 are Associated with Severity of Diabetic Retinopathy in Hispanics 
Ophthalmology  2012;119(5):1041-1046.
To investigate the associations of serum amyloid A protein (SAA) and soluble tumor necrosis factor receptors 1 and 2 (sTNF-R1 and sTNF-R2) with diabetic retinopathy (DR) in Hispanics.
Prospective, nonrandomized, cross-sectional, family-based observational cohort study.
Four hundred seventy-three Hispanics type II diabetic subjects, in families ascertained via proband with DR.
Levels of SAA, sTNF-R1, and sTNF-R2 were measured with enzyme-linked immunosorbent assay (ELISA). DR was assessed by fundus photography and graded using modified Airlie House classification.
Main Outcome Measures
Levels of SAA, sTNF-R1, and sTNF-R2 to severity of DR with and without covariates.
A direct association of sTNF-R1 (2.37±0.13, 2.15±0.09, 3.09±0.24, 3.25±0.46, 5.02±0.61 ng/ml; p<0.0001) and sTNF-R2 (6.04±0.20, 6.25±0.52, 7.96±0.70, 8.14±1.13, 14.83±1.68 ng/ml; p<0.0001) was found for no DR, mild non-proliferative DR (NPDR), moderate NPDR, severe NPDR, and proliferative DR (PDR), respectively. These associations remained significant after adjusting for age, gender, body mass index, hemoglobin A1c, diabetes duration, systolic blood pressure, and serum creatinine (p<0.0001 for sTNF-R1 and p=0.0004 for sTNF-R2). A similar pattern was observed when we adjusted for urinary albumin-to-creatinine ratio in place of serum creatinine (p=0.005 for sTNF-R1 and p=0.02 for sTNF-R2).
Levels of sTNF-R1 and sTNF-R2 are highly correlated with severity of DR, suggesting that inflammation and insulin resistance may play a critical role in the development of DR. These may be useful biomarkers for DR, aiding in etiologic studies, and possibly in identifying at-risk patients for active intervention.
PMCID: PMC3343221  PMID: 22330960
7.  Genomewide Linkage Scan for Diabetic Renal Failure and Albuminuria: The FIND Study 
American Journal of Nephrology  2011;33(5):381-389.
Diabetic nephropathy (DN) is a leading cause of mortality and morbidity in patients with type 1 and type 2 diabetes. The multicenter FIND consortium aims to identify genes for DN and its associated quantitative traits, e.g. the urine albumin:creatinine ratio (ACR). Herein, the results of whole-genome linkage analysis and a sparse association scan for ACR and a dichotomous DN phenotype are reported in diabetic individuals.
A genomewide scan comprising more than 5,500 autosomal single nucleotide polymorphism markers (average spacing of 0.6 cM) was performed on 1,235 nuclear and extended pedigrees (3,972 diabetic participants) ascertained for DN from African-American (AA), American-Indian (AI), European-American (EA) and Mexican-American (MA) populations.
Strong evidence for linkage to DN was detected on chromosome 6p (p = 8.0 × 10−5, LOD = 3.09) in EA families as well as suggestive evidence for linkage to chromosome 7p in AI families. Regions on chromosomes 3p in AA, 7q in EA, 16q in AA and 22q in MA displayed suggestive evidence of linkage for urine ACR. The linkage peak on chromosome 22q overlaps the MYH9/APOL1 gene region, previously implicated in AA diabetic and nondiabetic nephropathies.
These results strengthen the evidence for previously identified genomic regions and implicate several novel loci potentially involved in the pathogenesis of DN.
PMCID: PMC3078269  PMID: 21454968
Albuminuria; Diabetes mellitus; Renal failure; End-stage renal disease; Linkage; Allelic association
8.  Mexican-American Admixture Mapping Analyses for Diabetic Nephropathy in Type 2 Diabetes Mellitus 
Seminars in nephrology  2010;30(2):141-149.
Diabetic nephropathy is a classic complex trait, whose development in a given individual reflects contributions from multiple genes and whose expression is modulated by environmental factors. Numerous genetic strategies have been used to identify common disease risk loci and genes, including candidate gene analyses, linkage analysis, transmission disequilibrium testing (a family based association test to identify linkage between a genetic marker and a biological trait or disease), and admixture mapping (also referred to as mapping by admixture linkage disequilibrium). Choosing the best genetic strategy to identify susceptibility genes in a disease is dependent on knowing whether the disorder is monogenic (the result of one gene), oligogenic (the result of a few genes), or polygenic (the result of many genes). The likelihood of finding risk loci for a disease with a putative genetic contribution is in part owing to the disease recurrence risk ratio (the risk of expressing the disease phenotype in siblings of the proband divided by the risk observed in the general population), the genotypic risk ratio (the risk of expressing the phenotype if the gene is present divided by the risk if the gene is not present), the number of susceptibility genes, how the susceptibility genes interact, how much of the disease risk is contributed by environmental factors, and the disease penetrance (the likelihood that the phenotype will be expressed if the gene is present).
PMCID: PMC2967569  PMID: 20347643
Admixture mapping; diabetic nephropathy risk loci; Mexican-Americans
9.  Genome-wide linkage scans for type 2 diabetes mellitus in four ethnically diverse populations; significant evidence for linkage on chromosome 4q in African Americans: the Family Investigation of Nephropathy and Diabetes (FIND) Research Group 
Previous studies have shown that, in addition to environmental influences, type 2 diabetes mellitus (T2DM) has a strong genetic component. The goal of the current study is to identify regions of linkage for T2DM in ethnically diverse populations.
Phenotypic and genotypic data were obtained from African American (AA; total number of individuals (N)=1004), American Indian (AI; N=883), European American (EA; N=537), and Mexican American (MA; N=1634) individuals from the Family Investigation of Nephropathy and Diabetes. Nonparametric linkage analysis, using an average of 4,404 SNPs, was performed in relative pairs affected with T2DM in each ethnic group. In addition, family-based tests were performed to detect association with T2DM.
Statistically significant evidence for linkage was observed on chromosomes 4q21.1 (LOD=3.13; genome-wide p=0.04) in AA. In addition, a total of eleven regions showed suggestive evidence for linkage (estimated at LOD>1.71), with the highest LOD scores on chromosomes 12q21.31 (LOD=2.02) and 22q12.3 (LOD=2.38) in AA, 2p11.1 (LOD=2.23) in AI, 6p12.3 (LOD=2.77) in EA, and 13q21.1 (LOD=2.24) in MA. While no region overlapped across all ethnic groups, at least five loci showing LOD>1.71 have been identified in previously published studies.
The results from this study provide evidence for the presence of genes affecting T2DM on chromosomes 4q, 12q, and 22q in AA, 6p in EA, 2p in AI, and 13q in MA. The strong evidence for linkage on chromosome 4q in AA provides important information given the paucity of diabetes genetic studies in this population.
PMCID: PMC2783577  PMID: 19795399
FIND; Type 2 Diabetes; linkage analysis; ethnicity
10.  Heritability of the Severity of Diabetic Retinopathy: The FIND-Eye Study 
Diabetic retinopathy (DR) and diabetic nephropathy (DN) are serious microvascular complications of diabetes mellitus. Correlations between severity of DR and DN and computed heritability estimates for DR were determined in a large, multiethnic sample of diabetic families. The hypothesis was that (1) the severity of DR correlates with the presence and severity of nephropathy in individuals with diabetes mellitus, and (2) the severity of DR is under significant familial influence in members of multiplex diabetic families.
The Family Investigation of Nephropathy and Diabetes (FIND) was designed to evaluate the genetic basis of DN in American Indians, European Americans, African Americans, and Mexican Americans. FIND enrolled probands with advanced DN, along with their diabetic siblings who were concordant and discordant for nephropathy. These diabetic family members were invited to participate in the FIND-Eye study to determine whether inherited factors underlie susceptibility to DR and its severity. FIND-Eye participants underwent eye examinations and had fundus photographs taken. The severity of DR was graded by using the Early Treatment Diabetic Retinopathy Study Classification (ETDRS). Sib–sib correlations were calculated with the SAGE 5.0 program FCOR, to estimate heritability of retinopathy severity.
This report summarizes the results for the first 2368 diabetic subjects from 767 families enrolled in FIND-Eye; nearly 50% were Mexican American, the largest single ethnicity within FIND. The overall prevalence of DR was high; 33.4% had proliferative DR; 7.5%, 22.8%, and 9.5% had severe, moderate, and mild nonproliferative DR, respectively; 26.6% had no DR. The severity of DR was significantly associated with severity of DN, both by phenotypic category and by increasing serum creatinine concentration (χ2 = 658.14, df = 20; P < 0.0001). The sib–sib correlation for DR severity was 0.1358 in the total sample and 0.1224 when limited to the Mexican-American sample. Broad sense heritabilities for DR were 27% overall and 24% in Mexican-American families. The polygenic heritability of liability for proliferative DR approximated 25% in this FIND-Eye sample.
These data confirm that the severity of DR parallels the presence and severity of nephropathy in individuals with diabetes mellitus. The severity of DR in members of multiplex diabetic families appears to have a significant familial connection.
PMCID: PMC2583147  PMID: 18765632

Results 1-10 (10)