The focus of my research is development of novel clinical assays for application to the problems of diabetes mellitus. The worldwide epidemic of type 2 diabetes mellitus and the devastating consequences of its pathologic sequelae make this disease one of the most important priorities to today's clinicians and biomedical researchers. Our understanding of the pathophysiology and pathogenic mechanisms of this disease has advanced to a point where the field is ideally poised for translation of these discoveries into clinical solutions for disease prevention and optimal clinical management. Type 2 diabetes mellitus is a disease which develops gradually, starting with a pre-diabetic state characterized by compensated insulin resistance and only mildly elevated blood glucose values, progressing over years to pancreatic islet cell failure, insufficient insulin production, and loss of glucose control. The loss of glycemic control and chronically elevated blood glucose concentrations causes toxic effects on multiple tissues, most notably on the vasculature, and results in the kidney, retinal, neuronal, and vascular pathologies commonly associated with long term uncontrolled diabetes. Although these sequelae are devastating, patients with established diabetes mellitus can dramatically delay the onset of these sequelae with aggressive blood glucose control, achieved through diet, exercise, and medications. To achieve blood glucose control, however, patients and their physicians have to be aware of their disease as early as possible. Thereafter, once a person has developed overt diabetes requiring oral hypoglycemic medications and insulin for blood glucose control, their greatest challenge is maintaining optimal daily blood glucose concentrations, avoiding by hyper- and hypo-glycemic excursions.
From this basic review we can see that the most opportune targets for medical intervention are (1) prevention of diabetes mellitus in people at risk, (2) early detection and therapeutic intervention in people just developing diabetes mellitus, and (3) accurate methods for monitoring glycemic control in people with established diabetes mellitus, so that they and their physicians can adjust their treatments appropriately. My research seeks to discover novel clinical assays that address all three of these targets:
1. Prevention of diabetes mellitus is the "holy grail" of my laboratory's research ambitions. It has been shown that insulin resistant people at risk of developing type 2 diabetes mellitus may be able to prevent progression to overt hyperglycemia using diet, exercise, or prophylactic treatment with oral hypoglycemic agents such as metformin. For these preventive strategies to be applied clinically, however, physicians will need to be able to confidently predict that their patient will likely develop this disease. Our growing understanding of diabetes disease progression has opened an opportunity for the discovery of biomarkers that may be able to reliably predict future pancreatic islet failure. My lab is engaged in an ongoing search for these markers using a proteomic/mass spectroscopic approach.
2. Diabetes mellitus is currently diagnosed using fasting plasma glucose measurements. Although this is currently the most accurate method for positive prediction of this disease, the intra-individual variability of daily glucose values compromises the sensitivity and reliability of this approach. Glycated hemoglobin (Hb A1c) is a blood marker of long-term blood glucose concentrations, and there is growing data that suggests that assays for hemoglobin A1c may be more accurate and reliable for this purpose. I am working on specific analytical improvements in the methods for measuring Hb A1c that will increase the superiority of this blood test, making it more clearly preferable to fasting plasma glucose measurement for primary diagnosis of diabetes mellitus. These improvements in the clinical accuracy of diagnostic methods will enable earlier detection (and thus earlier intervention) and more reliable diagnosis.
3. My past research has largely focused on elucidating the functions of the serum protein adiponectin. Adiponectin was discovered by my thesis advisor Philipp Scherer, and in his lab we produced some of the first studies demonstrating the metabolic activities of this "adipokine." Adiponectin is a large multimeric protein secreted from adipocytes; serum concentrations of this protein are paradoxically suppressed in obese states, and we have demonstrated that adiponectin has important insulin sensitizing properties. The low adiponectin serum concentrations found in patients with obesity, metabolic syndrome, polycystic ovarian disease, and in pregnancy are thought to play a causal role in the insulin resistance and propensity to type 2 diabetes mellitus found in persons with these risk factors. As a result of these and other observations, adiponectin has been proposed to be a potentially clinically useful biomarker for prediction of future development of type 2 diabetes mellitus, prediction of cardiovascular risk, and prediction of response to oral hypoglycemic agents. Adiponectin circulates in several large multimeric forms, and several studies have shown that it may be the largest of these forms that mediates the insulin sensitizing activity of adiponectin. Accordingly, studies have suggested that serum levels of this high molecular weight component are, in fact, more important than total adiponectin concentrations, and represent a superior clinical biomarker. Developing high throughput clinical assays specific to this high molecular weight form is challenging, however. The last active project in my laboratory is development of a novel clinical assay for both total and high molecular weight adiponectin serum complexes using atypical high-throughput analytical techniques.