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Areas of research in the Goodarzi Laboratory include investigating genetic factors in polycystic ovary syndrome, particularly genes involved in adrenal androgen excess and response to metformin therapy, investigating the role of energy-related and diabetes-related genes in insulin clearance, and searching for genetic factors affecting the insulin system and subclinical atherosclerosis in Hispanic and other populations. In addition, research is ongoing in the phenotyping of insulin resistance by physiologic infusion studies, and in a pharmacogenetic study of the metabolic effects of statin therapy. Our lab is also participating in large-scale consortia for elucidating genes regulating insulin clearance, insulin resistance and diabetes.
Genetic Basis of Insulin Clearance
The Goodarzi Laboratory was the first to report that processes whereby insulin is removed from the circulation are highly determined by genetic factors.
We found that the heritability of insulin clearance in Hispanics exceeds the heritabilities of fasting insulin, insulin resistance and insulin secretion. This work was used to establish an independent line of NIH-funded research to search for insulin clearance genes in Hispanics, a group at high risk for diabetes. The Goodarzi Lab identified regions on chromosomes 15 and 20 that harbor genes for insulin clearance in two independent Hispanic cohorts. To directly interrogate the relevance of insulin clearance inheritance to diabetes, obesity, and cardiovascular disease, the laboratory used the MetaboChip to find that several of ~50 genes previously identified as diabetes, fasting glucose and fasting insulin susceptibility loci were found to modulate insulin clearance.
The GUARDIAN (Genetics Underlying Diabetes in Hispanics) consortium's first paper described the genetic architecture of insulin clearance and its genetic and environmental correlations with insulin sensitivity, insulin secretion and adiposity. These genetic studies may improve our understanding of how the body clears insulin, leading to improved prevention and therapy of diabetes, as well as of other hyperinsulinemic disorders, such as polycystic ovary syndrome. (Obesity 2014;22(4):1157-1164. Diabetologia 2013;56(6):1282-1290. Diabetologia 2012;55(8):2183-2192. Diabetes 2005;54(4):1222-1227.)
Physiologic Significance of Insulin Clearance
The Goodarzi Laboratory found that fasting insulin, used by many as a surrogate for insulin resistance, is actually more highly influenced by insulin clearance. This critical result has major implications for large-scale epidemiologic studies that rely on fasting insulin. We found that insulin clearance is positively correlated with insulin sensitivity and negatively correlated with insulin secretion and adiposity. Differences in insulin clearance by race/ethnicity (lower in African Americans and Hispanics compared with non-Hispanic whites) were largely explained by differences in adiposity, insulin sensitivity and insulin secretion. Our lab discovered that low insulin clearance is a predictor of incident diabetes that developed over five years of follow-up in Hispanic and AfricanAmerican families (Insulin Resistance Atherosclerosis (IRAS) Family Study), highlighting the crucial need to better understand this trait. In the multiethnic IRAS cohort, we found that higher plasminogen activator-1 levels independently predicted the progressive decline of insulin clearance over time. Identification of metabolic traits that influence insulin clearance complements our search for genetic traits that influence insulin clearance. (Diabetes Obes Metab. 2013;15(5):441-447. Diabetologia 2013;56(1):112-120. Diabetes Care 2013;36(1):101-103. Diabetes Care 2013;36(4):901-907. Am J Physiol Endocrinol Metab. 2011;301(2):E402-408.)
Genetic Studies of Physiologically Measured Glucose Homeostasis Traits
Genome-wide association studies (GWAS) in Type 2 diabetes have revealed many loci that influence beta cell function but few that influence insulin sensitivity, in part because insulin sensitivity has not been precisely phenotyped in large cohorts. The Goodarzi Lab participated in the first large-scale GWAS for insulin resistance measured by physiologic studies (e.g., euglycemic clamp). We lead Cedars-Sinai participation in the Genetics Underlying Diabetes in Hispanics (GUARDIAN) study consortium that has assembled six cohorts (totaling >4,000 Hispanic subjects) for a GWAS of insulin clearance and insulin resistance. GUARDIAN recently contributed to the discovery of a novel gene for insulin sensitivity, NAT2. (Diabetes 2015;64(5):1853-1866. J Clin Invest. 2015;125(4):1739-1751. Diabetologia 2009;52(7):1326-1333. Diabetes 2004;53(1):214-220.)
Participation in International Genetic Epidemiologic Consortia
Since 2013, within the Type 2 Diabetes-Glycemia Working Group of the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Consortium, Mark Goodarzi, MD, PhD, has led an international effort focusing on genotyping exomes to identify protein-altering genetic variants that affect fasting glucose and insulin levels.
Under his leadership, the consortium assembled data from more than 60,000 individuals from over 20 cohorts. Meta-analysis combining data from all participating cohorts identified a naturally occurring mutation, an alanine (Ala) to threonine (Thr) change at amino acid position 316, in the glucagon-like peptide-1 receptor (GLP1R) that regulates fasting glucose, with the Thr allele associated with reduced glucose levels. In additional analyses in over 16,000 cases of Type 2 diabetes and 81,000 controls, the Thr allele was found to lower the risk of Type 2 diabetes by 14 percent. In a subset of subjects who had undergone oral glucose tolerance testing, the Thr allele was found to be associated with increased two-hour glucose and decreased acute insulin secretion. Goodarzi and his colleagues hypothesize that the Thr allele may result in glucagon-like peptide-1 (GLP-1) receptors with increased basal activity but reduced response to GLP-1, which may explain the observed associations. In silico models of receptors with the Thr allele documented a significant effect on the conformation of the receptor within the cell membrane, providing powerful support that it may impact GLP-1 receptor function.
GLP-1 receptor is the target of anti-diabetic agents such as exenatide and liraglutide (analogs of the incretin GLP-1, an insulin secretion-stimulating hormone that is released by the gut into the circulation upon food intake). The association of variation in GLP1R with fasting glucose and Type 2 diabetes represents the third instance wherein genetic epidemiology identified a gene that codes for a direct drug target in Type 2 diabetes, the other examples being KCNJ11 (codes for the target of sulfonylureas) and PPARG (codes for the target of thiazolidinediones). In these examples, the drug preceded the genetic discovery. Today, there are over 130 loci for Type 2 diabetes, fasting glucose and fasting insulin. Given that three of these codes for targets of potent anti-hyperglycemic agents, these genetic discoveries represent an extremely promising source of potential targets for future diabetes therapies.
This work, recently published in Nature Communications (Nat Commun. 2015;6:5897), sheds important light on the genetic role of the incretin system in the inheritance of Type 2 diabetes. The American Diabetes Association invited Goodarzi to present these results at a symposium at their 74th Scientific Sessions. CHARGE recognized his contributions by formally appointing him as co-convener of the Type 2 Diabetes-Glycemia Working Group, as well as selecting him to receive the 2014 CHARGE Golden Tiger Award for Working Group Leadership.
Susceptibility Loci for PCOS Are Shared Around the Globe
The first published GWAS in polycystic ovary syndrome (PCOS) was conducted in Chinese subjects and identified variants at DENND1A, THADA, and LHCGR; a second GWAS in Chinese subjects added eight additional loci. In a multicenter European-origin PCOS case/control cohort, the Goodarzi Lab found that many of the same DENND1A and THADA variants that affect PCOS risk in Chinese subjects also do so in Europeans. We also examined several of the additional loci in the form of a genetic risk score, finding further evidence of shared risk alleles. This suggests that PCOS risk genes are universal across human populations, consistent with the notion that PCOS is an ancient disorder. Robust identification of PCOS susceptibility genes is anticipated to lead to new modalities of managing this common condition, which affects 7 percent of young women and puts them at risk for diabetes. We contributed to the replication phase of one of the first GWAS for PCOS conducted in European origin individuals. (Nature Communications. In press. J Clin Endocrinol Metab. 2015;100(1):E182-186. J Med Genet 2012;49(2):90-95. Fertil Steril 2011;95(5):1544-1548.)
Epigenetic and Glycemic Effects of Developmental Androgen Exposure
The Goodarzi Lab is exploring a novel paradigm: whether epigenetic changes (e.g., DNA methylation) play a role in PCOS; our initial data in a monkey model of PCOS was published in PLOS ONE. These monkeys develop PCOS after in utero exposure to elevated androgens. To explore the mechanism of this prenatal reprogramming, we have developed a new model wherein we expose zebrafish embryos to testosterone; as adults these fish exhibit elevated glucose responses to meal challenge as well as global genomic hypomethylation. An exciting result is that this glucose intolerance and altered DNA methylation was transmitted to the next generation of fish that was not exposed to androgens. These data will serve as preliminary data for an NIH grant submission to further study the transgenerational consequences of androgen exposure during development. (Mol Endocrinol. 2014;28(8):1329-1336. PLOS ONE 2011;6(11):e27286. Fertil Steril 2010;94(2):781-783.)