Nadeau, Kristen Jane
Impact of Metformin on Organ-Specific Insulin Sensitivity and Cardiovascular Function in Youth with Type 1 Diabetes
General Research Subject: Both Type 1 And Type 2 Diabetes
Focus: Complications\ Macrovascular-Atherosclerotic CVD and Human Diabetes, Insulin Action\Insulin Resistance, Pediatrics\Type 1
Type of Grant: Career Development
Project Start Date: July 1, 2011
Project End Date: June 30, 2016
Diabetes causes early cardiovascular disease (CVD) and death, despite careful control of blood sugar and other heart-related risks. Diabetes increasing in youth, predicting earlier diabetes complications. Our long-term goal is to prevent diabetes-associated illness and early death by understanding their early origins. Poor insulin action (insulin resistance, IR) contributes strongly to CVD in type 2 diabetes (T2D), but the cause of CVD in type 1 diabetes (T1D) is less clear. We discovered poor cardiovascular and exercise function and IR in pediatric type 1 diabetes (T1D). Why IR occurs in T1D children and how it affects future CVD are unclear.
Hypothesis: IR occurs for different reasons in youth with T1D compared to T2D, yet damages the cardiovascular system in both groups.
Aim1a: To understand where in the body IR occurs in youth with T1D and T2D by measuring insulin action in liver, muscle and fat.
Aim1b: To determine the unique cardiovascular problems in T1D and T2D youth and whether high glucose or IR cause these problems.
Hypothesis: Metformin, a common pediatric T2D medication, will improve IR, cardiovascular, muscle and exercise function in T1D youth.
Aim2: To determine the effects of metformin on IR, cardiovascular, muscle and exercise problems in T1D youth.
This study will measure liver, muscle and fat IR with sophisticated insulin clamps; energy use, heart and blood vessel function with painless imaging methods ideal for children. This important information will guide how IR and CVD could be prevented in people with diabetes and a possible new T1D treatment approach.
What area of diabetes research does your project cover? What role will this particular project play in preventing, treating and/or curing diabetes?
Cardiovascular disease (CVD) is the leading cause of death in Type 1 diabetes (T1D) and Type 2 diabetes (T2D) and shortens lifespan relative to people without diabetes, despite our best treatments. Traditional CVD risk factors (cholesterol, blood pressure, and smoking) cannot explain this high rate of CVD in diabetes. Waiting until adulthood to treat CVD complications of diabetes is too late, as many changes may still be reversible in youth, but not in adulthood. In particular, T1D has been defined historically as solely a lack of insulin, leading to a research focus on helping the pancreas make more insulin or improving insulin delivery methods. However, a lack of insulin may not be the only problem. In obesity and T2D, CVD is closely related to poor response to insulin or (insulin resistance, IR), yet very little is known about IR in T1D. We determined that normal weight T1D children are as IR as obese youth. Early IR may greatly increase the risk of CVD and kidney disease. Thus, one goal is to identify why IR happens in T1D youth and how it differs from T2D youth, and how IR vs. high blood sugars in T1D and T2D youth relates to early development of CVD and kidney disease.
IR is associated with many factors, including obesity, puberty, poor fitness, excess fat in muscle, liver and the abdomen, abnormal glucose storage (glycogen) and abnormal mitochondrial energy production (ATP). Other factors may include glucose levels and kidney function. Our group is skilled at painless magnetic resonance imaging (MRI) techniques of the liver, abdomen and muscle that can measure fat, glycogen and ATP. We are also skilled in state of the art heart imaging during exercise, measuring the ability of blood vessels to dilate and vessel stiffness, fitness with stationary bicycle tests, blood lipid profiles, and gold standard measures of IR. These tests are safe and well tolerated in youth with diabetes. We will also use these techniques in order to understand more about why IR happens in T1D and T2D youth, its effects on the cardiovascular system and kidney, and targets for treatment. By increasing the understanding of IR in pediatric T1D and T2D, we hope to help prevent CVD, kidney disease and early death in people with diabetes.
If a person with diabetes were to ask you how your project will help them in the future, how would you respond?
Cardiovascular disease (CVD) significantly shortens lifespan in diabetes despite our best treatments. Common causes of CVD (cholesterol, blood pressure, and smoking) do not explain this high CVD rate. Thus, we need new approaches to preventing CVD in diabetes. In obesity and type 2 diabetes (T2D) in adults, CVD closely relates to how well insulin works in the body (insulin resistance, IR). We lack information about the early origins of CVD in youth, and how it is related to IR We determined recently that normal weight youth with T1D are unexpectedly as IR as obese youth. Surprisingly, our studies also suggest that T1D youth lack many of the findings present in other populations with IR (high triglycerides, low HDL, high muscle fat). Therefore, we believe IR occurs in T1D and T2D for different reasons. It is unknown whether other typical components of IR (excess liver and abdominal fat, abnormal muscle and liver glucose storage [glycogen], and abnormal mitochondrial energy production) are present in T1D youth. We need to learn what components of IR are present in TID youth and why, how they differ from T2D, and how they are related to CVD, in order to design therapies to improve IR. Shared abnormalities may respond to established T2D therapies, while areas unique to T1D will require innovative therapies.
Our initial data also suggest exercise, blood vessel and heart muscle dysfunction in T1D and T2D youth. Such early abnormalities may greatly increase the risk of early CVD over the lifetime. Therefore, we wish to determine whether these defects are more related to IR or high blood sugars, and determine whether improving IR with metformin, a drug currently only used in T2D is the way to improve these defects in T1D as well. Such information will help us understand how to better prevent CVD, the leading killer in diabetes, and could lead to large changes in the way we treat patients with T1D.
We are also currently developing a sensitive biomarker of kidney dysfunction included in the protocol that could be used to detect early kidney disease in youth with diabetes, allowing earlier treatment. In addition, abnormal lipid profiles, detected by more sensitive assays than currently used clinically, predicted coronary calcium deposits in T1D adults and thus we will apply these more sensitive lipid studies to T1D and T2D youth, to test them as an early biomarker of T1D and T2D patients likely to develop CVD. Finally, this project will also help to improve the pediatric research methods at a large pediatric diabetes center and support a new pediatric endocrinologist and multidisciplinary collaborative teams, all committed to improving the length and quality of life people with diabetes.
Why is it important for you, personally, to become involved in diabetes research? What role will this award play in your research efforts?
I chose Pediatric Endocrinology due to my Native American heritage, as T2D disproportionately affects Native American and other historically disadvantaged groups, and I continue to strive to better serve this population. My research is focused on reducing long-term complications of pediatric-onset diabetes. I wish to better understand the cause(s) of insulin resistance (IR) in pediatric T1D and T2D and find treatment targets for interventions to improve IR, ultimately to reduce diabetes complications. Through my just-completed NIH K23 project, I produced extensive IR and exercise data, and preliminary cardiovascular (CVD) data on a cohort of children with obesity, T1D and T2D, compared to well-matched controls.
To continue as an independent investigator and expert in noninvasive techniques ideal for studying pediatric IR and CVD, I require continued protected time for research and funding. In order to be competitive for an RO1 or ADA research grant, I need additional data on the non-invasive imaging techniques, the more sophisticated cardiovascular evaluations, vascular imaging, and measurements of hepatic and adipose IR. I also require preliminary data on the effects of improving IR in youth with T1D on the CVD abnormalities we have identified in youth, to inform future RO1 or ADA research award-level intervention studies. The ADA Career Development award will ensure my continued success by providing continued longitudinal protected research time at this critical juncture in my career and obtain the data, equipment and continued publications required for larger independent grants, and a long-term strategic plan. This support would allow me to continue a career in academics and clinical translational diabetes research, and to be a mentor to future diabetes researchers.
In what direction do you see the future of diabetes research going?
We expect that insulin resistance (IR) will play a large role in the cardiovascular (CVD) and kidney complications of T1D as well as T2D. This will require treatments beyond insulin to improve IR in T1D, such as oral medications to improve IR, currently not a focus of T1D clinical care. In addition, with the current obesity and inactivity epidemics in today's youth, we expect that CVD and other diabetes complications may begin to worsen again, despite improved insulin delivery devices and glucose monitors. This will require more focus on improving IR, diet and exercise, and interventions aimed at youth, an age where prevention is still possible and lifestyle habits are being established. We anticipate that improving blood sugars will partly, but not completely improve IR, heart, blood vessel and kidney function in T1D. Thus, we will need more emphasis on the non-glucose portions of diabetes care. In addition, learning which abnormalities are more related to IR and which are related to high blood sugar will help target appropriate therapies.
We expect the cause of IR will differ in youth with T1D vs. T2D.
This will require unique approaches aimed at improving IR in T1D. It is
likely that mitochondrial function will be abnormal in both T1D and
T2D, and area in need of further research. We expect that heart and
blood vessel function will be abnormal in both T1D and T2D youth, but
the types of abnormalities will differ. Early screening markers of
complications, such as novel non-invasive makers of kidney function and
vascular function will allow early detection and targeted prevention.
In addition, more subtle abnormalities in cholesterol may help explain
the paradox of normal or better than normal lipid levels in T1D, yet
higher CVD rates. By better understanding the causes of IR and CVD early
on in T1D, we hope to identify future targets, such as the muscle, for
therapies to improve IR in youth with T1D. Finally, being able to
identify which group of diabetes patients are likely to have early
complications will help identify those in most need of intervention.
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