Session: Imaging of Metabolism & Metabolic Diseases, Thursday, May 12, 2016 Title: Molecular & Cellular Imaging of Diabetes Anna Moore, Ph.D. E-mail: amoore@helix.mgh.harvard.edu

Highlights

· Diabetes mellitus is hallmarked by high levels of blood glucose caused by lack of insulin production and/or insulin resistance

· The development of strategies for the noninvasive assessment of molecular events associated with this disease constitutes an important healthcare priority

· Molecular imaging can provide answers to many of the questions related to diabetes and offers the unprecedented potential to unravel the complex natural history of the disease and to permit diagnosis at the earliest causative stages.

Targeted audience: This presentation is intended for graduate students, postdoctoral scientists, and physicians (radiologists) who are either new to the field of Molecular and Cellular Imaging of Diabetes or wish to be updated on the current state-of-the-art in its applications to various human pathologies.

Summary of the presentation:

Diabetes mellitus is hallmarked by high levels of blood glucose caused by lack of insulin production, insulin resistance in peripheral tissues, or both (1) and represents a worldwide health problem. Studies show that approximately 280 million people or 6.4% of the world population suffer from this disease. These numbers could increase to 438 million by 2030 (2; 3) causing diabetes-related healthcare costs to rise up to 40% of the total healthcare budget in high incidence countries. In addition, diabetes increases a risk for cardiovascular disease, and is the leading cause of kidney failure, lower limb amputations, and adult onset blindness. Normally, insulin is secreted by the beta cells in the pancreatic islets of Langerhans in response to a rise in blood glucose levels (for example after a meal) and serves as a signal for glucose uptake and assimilation by peripheral tissues. As diabetes develops, however, the body loses the capacity for insulin production/assimilation, resulting in elevated blood glucose (hyperglycemia).

Type 1 diabetes (T1D), also known as “ juvenile” or “insulin dependent” diabetes, is an autoimmune disease in which CD4+ and CD8+ T cells infiltrate the islets of Langerhans, resulting in beta cell destruction, leaving patients dependent upon exogenous insulin for survival (4). It accounts for an estimated 5% to 10% of diabetic Americans. Type 2 diabetes is known as adult-onset or noninsulin-dependent diabetes (NIDDM), and is a chronic condition that affects the way human body metabolizes glucose. With type 2 diabetes, human body either resists the effects of insulin — a hormone that regulates the uptake of glucose into the cells — or doesn't produce enough insulin to maintain a normal glucose level.

Considering the remarkable toll diabetes is having in terms of human life, it becomes clear that the development of strategies for the noninvasive assessment of molecular events associated with this disease constitutes an important healthcare priority. The ability to image the pathology on that scale would be instrumental in understanding the time course of the disease, identifying the key initiating events, and possibly designing novel therapeutic approaches and monitoring their efficacy.

Molecular imaging, a rapidly emerging biomedical research discipline, has a high potential to provide insights into when, why, and how diabetes occurs, as well as to devise new ways to treat the disease. Imaging is one of the most valuable tools for diabetes research and clinical management since it could provide real time non-invasive data of various biological parameters and their functions as they relate to diabetes progression and treatment.

Accomplishing the goal of molecular imaging in diabetes, however, presents a tremendous challenge. The underlying reasons extend both from the unique structure and distribution of pancreatic islets and the metabolic complexity of the disease. With respect to the first challenge, pancreatic islets are small organ-like entities (about 100 microns in diameter) dispersed throughout the pancreas at a low density and comprising only about 1.7% of the pancreatic volume (5). The islet itself is a complex structure, consisting of insulin-producing beta cells, which constitute approximately 50% of the islet, glucagon-secreting alpha cells (15-20%), delta cells involved in somatostatin production (3-10%), and cells, which release pancreatic polypeptide (1%). Hormone production and secretion by all of these cells is a tightly regulated dynamic process driven by the need to respond to ever-changing energy demands and influenced by metabolic and environmental factors continually throughout the life of an organism. In diabetes, this delicate functional balance is disrupted. Identifying the key cellular events, which define the pathology of diabetes and become manifest at early enough stages of the disease to allow intervention, is a demanding process critical for the success of imaging.

The main event that defines diabetes progression is the development of hyperglycemia. Therefore, the study of diabetes has focused mainly on the insulin-secreting pancreatic beta cell, since beta-cell failure has been implicated as a central event in the progression to hyperglycemia. Considering the central role of the beta cell, strategies for cellular imaging of diabetes would focus on the detection of beta cells via a variety of markers. Various strategies have been proposed for detection of beta cells and for estimation of a functional beta cell mass. Magnetic resonance imaging has been applied for detection of beta cells using their intrinsic insulin/zinc secreting properties (6-8). Other investigators focused on utilizing manganese as a reporter for beta cell mass (9-11). Finally, targeting of beta cell surface markers has been utilized in combination with MRI (12-16).

Autoimmune destruction of beta cells is primarily a T-cell-mediated process. It is postulated that a loss of more than 90% of the beta cells takes place before insulin production is no longer sufficient to regulate blood glucose levels, resulting in hyperglycemia. Importantly, this initial stage of insulitis begins a long time before the manifestation of overt symptoms, persists for many years, and progressively decreases after diabetes onset, as beta-cell mass declines (17; 18). Therefore, the early detection and continuous monitoring of immune cell infiltration of the pancreas in real-time would represent a significant step towards identifying the initial insult leading to beta-cell destruction and permit effective curative and not just palliative intervention. Potential strategies for imaging immune cell infiltration in diabetes include antigen-specific (19; 20) and non-specific (21; 22) targeting of infiltrating cells using iron oxide based nanoparticles.

The progression of inflammation in diabetes is associated with changes in pancreatic islet vasculature and subsequent vasculature dysfunction. At sites of inflammation, blood vessels become “leaky” and allow large molecules to extravasate through the walls of the damaged vessel into the surrounding tissue. Vascular leakage was utilized for delivering imaging agents to the islets and showed promise for further development of image-guided therapies (23; 24).

Islet transplantation has emerged as one of the most promising new treatments for diabetes. Successful monitoring of the stability and functionality of the graft would also permit us to test the effectiveness of various immunosuppressive regimens, as well as islet delivery strategies and ultimately assist the further optimization of the islet transplantation procedure. Towards this goal several pre-clinical studies showed the potential of labeling pancreatic islets for subsequent monitoring after transplantation (25-33). First clinical studies showed the potential of this method (34; 35).

Clearly, molecular imaging can provide answers to many of the questions related to diabetes. It offers the unprecedented potential to unravel the complex natural history of the disease and to permit diagnosis at the earliest causative stages, characterized by the first signs of metabolic or molecular disturbance. Furthermore, by combining the global anatomical/physiologic scale of currently available in vivo imaging modalities with the detailed molecular/cellular scale of biochemistry and cell and molecular biology, molecular imaging allows the noninvasive real-time monitoring of diabetes progression as well as response to therapy non-invasively and in authentic physiologic environments.