Geffner Laboratory

Research Topics

  • Metabolic disturbances associated with HIV infection and/or its treatment.

  • Cardiovascular disease risk factors in adrenal hyperplasia. 

  • Obesity and diminished pituitary function in the setting of underdeveloped optic nerves.  

Research Overview

The research of Mitchell Geffner, MD, is clinical/translational in nature and focuses on metabolic abnormalities associated with overweight and excess body fat. Key areas of study include simple obesity and type 2 diabetes, HIV infection, adrenal hyperplasia and diminished pituitary function in the setting of underdeveloped optic nerves. Research studies involve improving understanding of the basis by which these disorders lead to abnormal metabolism as well as to unfavorable long-term cardiovascular health. Finally, improved prevention strategies and treatment approaches are also being investigated.

  • Description of baseline clinical and demographic characteristics of the largest group of adolescents and youth with recent-onset type 2 diabetes studied to date as part of a national multi-center study (TODAY = Treatment Options for type 2 Diabetes in Adolescents and Youth).

  • Determination of the best treatment modality (metformin, metformin + rosiglitazone, or metformin + intensive lifestyle) to maintain glycemic control in youth with type 2 diabetes in the TODAY Trial.

  • Assessment of body fat distribution in perinatally HIV-infected and HIV-exposed but uninfected children from the Pediatric HIV/AIDS Cohort Study (PHACS) in the era of highly active anti-retroviral therapy.

  • Analysis of factors associated with insulin resistance among children and adolescents perinatally-infected with HIV-1 in the Pediatric HIV/AIDS Cohort Study (PHACS). 

  • Characterization of metabolic abnormalities and viral replication associated with biomarkers of vascular dysfunction in HIV-infected children.

  • Assessment of the relationship of biochemical and radiological assessments quantifying intima media thickness and hepatic and visceral fat in adolescents with congenital adrenal hyperplasia (CAH).

  • Assessment of brown and white fat compartments in youth with obesity, Type 2 diabetes, and hypo- and hyperthyroidism.

  • Description of presenting metabolic features and long-term effects of growth hormone treatment of children with optic nerve hypoplasia/septo-optic dysplasia.

  • Correlation of serum prolactin concentrations in relation to hypopituitarism and obesity in children with optic nerve hypoplasia.

  • Determination of the specific role of brown adipose tissue (BAT) in metabolism and obesity.

Research Accomplishments

Leading-edge diagnostic testing and technology

New diagnostic technologies being applied to my clinical research include measurement of carotid intima medial thickness (IMT) by Doppler ultrasound; visceral subcutaneous, and hepatic fat by computerized tomography; and brown and white fat by magnetic resonance imaging. 

Major Accomplishments

  • Being one of the largest enrolling sites in the national multi-center TODAY trial and determining that dual drug therapy rather than either monotherapy alone or monotherapy + lifestyle intervention appears to be the most efficacious treatment approach for youth with Type 2 diabetes.
     
  • Serving as national endocrinology consultant to the multi-center PHACs study evaluating:  (1) the long-term safety of fetal and neonatal exposure to prophylactic anti-retroviral chemotherapy, as recommended by current U.S. PHS guidelines, and (2) the effects of perinatally-acquired HIV infection in adolescents.
     
  • Serving as endocrinology consultant to the PHACS sub-study:  (1) comparing mitochondrial function of HIV-infected to HIV-negative children currently enrolled in PHACS, (2) assessing clinical characteristics that are associated with mitochondrial dysfunction among HIV-infected children, and (3) determining whether mtDNA copies per cell, mtRNA transcripts, and/or mitochondrial oxidative stress are associated with insulin resistance.

Research Goals

  • To retain our original Type 2 diabetes cohort from the TODAY trial in the observational TODAY2 trial to better characterize the long-term natural history of the disease when diagnosed in childhood.

  • To continue longitudinal studies of endocrinological, metabolic, and mitochondrial disturbances in:  (1) adolescents with perinatally acquired HIV infection and (2) to quantify the effects of intrauterine exposure to anti-retroviral therapy on growth and mitochondrial disorders in non-HIV-infected offspring.

  • To complete studies of cardiovascular disease (CVD) risk factors in patients with adrenal hyperplasia using state-of-the-art radiological methods, including assessment of IMT and fat deposition in various compartments, as well as incorporate new MRI methodology to study brown and white fat percentages in various clinical disorders.     

  • Pioneering research and other innovations. Based on the results of the TODAY trial, determination of optimal treatment for youth with Type 2 diabetes likely consists of multiple medications taken simultaneously in conjunction with lifestyle change.

Key Findings 

  • Youth with T2DM are demographically and clinically diverse, and have a high prevalence of co-morbidities, with 66% having additional cardiovascular risk factors associated with “metabolic syndrome.” There are ethnic/racial differences in baseline characteristics and co-morbidities. The outcomes and response to interventions in this group of patients warrant careful study and long-term follow-up in TODAY2. Geffner_Lab_TODAY_Study.jpg

  • In the TODAY treatment comparison trial in youth with Type 2 diabetes, we showed that metformin therapy alone was not an effective treatment for many of these youth. In fact, metformin had a much higher failure rate in study participants than has been reported in studies of adults with Type 2 diabetes treated with metformin alone. A combination of two diabetes drugs, metformin and rosiglitazone, was more effective in treating youth with recent-onset Type 2 diabetes than metformin alone. Adding an intensive lifestyle intervention to metformin provided no more benefit than did metformin therapy alone. Type 2 diabetes appears to be a more aggressive disease in youth than in adults and progresses more rapidly.

  • In HIV-infected adolescents participating in the national PHACS study, we observed a 15.2% prevalence of insulin resistance that was more closely linked to obesity than to any other variable.  This finding mirrors the high prevalence of obesity-mediated insulin resistance currently seen in American youth. However, observed associations with CD4 count and use of protease inhibitors may indicate some effect of HIV and/or its treatment. 

Current Funding

For roll-over studies of our original TODAY cohort into the long-term TODAY2 observational trial, we rely significantly on NIH support. Additional annual funding is also derived from the California Newborn Screening Program and various pharmaceutical companies for a combination of investigator-initiated trials, company-sponsored clinical trials and company-sponsored registries.

  1. Pediatric HIV/AIDS Cohort Study (PHACS)
    To prospectively examine:  (1) the long-term safety (regrowth and metabolism) of fetal and neonatal exposure to prophylactic anti-retroviral chemotherapy, as recommended by current U.S. PHS guidelines and (2) the metabolic and endocrine effects of perinatally acquired HIV infection in adolescents.
     
  2. Mitochondrial Determinants of Metabolic Disease in HIV-Infected Children
    To compare mitochondrial function of HIV-infected to HIV-negative children currently enrolled in PHACS and to determine clinical characteristics that are associated with mitochondrial dysfunction among HIV-infected children and to determine whether mtDNA copies per cell, mtRNA transcripts, and mitochondrial oxidative stress are associated with insulin resistance. 
     
  3. Pharmacodynamics of C-Type Natriuretic Peptide During Growth Hormone Treatment in Children: A Potential Biomarker of Efficacy  
    To determine how blood levels of the hormone, C-type natriuretic peptide (CNP), change in children being treated with growth hormone.
     
  4. Endocrine Dysfunction and Growth Hormone Deficiency in Children with Optic  Nerve Hypoplasia 
    (1) To determine the prevalence and types of endocrinopathies in children with ONH and correlate endocrine outcome with radiographic, ocular, and developmental findings in children with ONH; (2) to examine effects of GH treatment on growth and obesity in children with ONH, GH deficiency, and either subnormal or normal growth compared to children with ONH that are not GH-deficient; (3) to compare growth outcomes between children with isolated GH deficiency and those with multiple hormone deficiencies; and (4) to examine the effect of GH on serum lipid levels in children with ONH.
  5. The Answer Program
    To study the long-term efficacy and safety of GH usage in patients treated with Norditropin®.

  6. Increlex™ (mecasermin [rDNA origin] injection) Growth Forum Database – IGFD Registry:  A Patient Registry for Monitoring Long-Term Safety and Efficacy of Increlex™
    To study the long-term efficacy and safety of rhIGF-I usage in patients treated with Increlex®.

  7. Statistics Center for Pediatrics Type 2 Diabetes Therapy (STOPP-T2D)
    To study the efficacy and safety of medical and lifestyle treatments for children and adolescents with type 2 diabetes.

  8. STOPP-T2D Treatment Year 10 – TODAY2 Phase1
    Observational immediately following TODAY. This study is only open to former TODAY study subjects.

  9. Newborn Screening Endocrine
    To provide diagnosis, treatment and outcome data for endocrine patients identified through the California Newborn Screening Program (NBSP).

  10. A Four-Year Open-Label Multi-Center Randomized Two-Arm Study of Genotropin in Idiopathic Short Stature Patients:  Comparing An Individualized, Target-Driven Treatment Regimen to Standard Dosing of Genotropin
    To compare a standard dose or a higher individualized dose of GH (Genotropin) in the treatment of prepubertal children with idiopathic short stature over 4 years.

  11. Effect of early growth hormone treatment on long-term growth and skeletal maturation in girls with Turner syndrome
    To test the hypothesis that infants and toddlers with Turner syndrome who initiate recombinant human growth hormone (rhGH; Humatrope®) between 9 months and 4 years of age will have significantly better final adult heights than those who start GH later.

  12. Risk of Cardiovascular Disease in Obese Latino Children and Adolescents with Congenital Adrenal Hyperplasia (KL2 Award to Mimi Kim, MD)
    To determine the risk of CVD in the Latino population of patients with CAH. The short-term objective is to identify obese patients with CAH at risk for development of CVD, with an emphasis on carotid intima-media thickness (IMT) measurements by ultrasound (a marker of subclinical atherosclerosis) as it relates to one or more CVD risk factors.  The long-term objective would be to see how these factors relate to the possible future development of coronary artery disease, which could significantly impact the strategies of care and long-term health of individuals with CAH.

  13. Kids N Fitness Junior:  Efficacy of a Weight Management Program on Children Ages 3 to 7 and Their Families
    The goal of this proposed project is to adapt our evidence-based Kids N Fitness© weight management intervention program to target younger children (ages 3 to 7 years) and their parents, creating the spin-off program, Kids N Fitness Junior.