Molecular & Cellular Imaging of Diabetes
Anna Moore

Synopsis

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.

Summary of presentation

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.

Acknowledgements

No acknowledgement found.

References

1. Lin M, Lubag A, McGuire MJ, Seliounine SY, Tsyganov EN, Antich PP, Sherry AD, Brown KC, Sun X: Advances in molecular imaging of pancreatic beta cells. Front Biosci 2008;13:4558-4575

2. Shah A, Mital D: Molecular imaging for diagnosis and management of diabetes - a review. Int J Medical Engin Inform 2012;4:325-342

3. Shaw JE, Sicree RA, Zimmet PZ: Global estimates of the prevalence of diabetes for 2010 and 2030. Diabetes Res Clin Pract 2010;87:4-14

4. Church EJ: Imaging diabetes. Radiol Technol 2009;80:340-360

5. Butler AE, Janson J, Bonner-Weir S, Ritzel R, Rizza RA, Butler PC: Beta-cell deficit and increased beta-cell apoptosis in humans with type 2 diabetes. Diabetes 2003;52:102-110

6. De Leon-Rodriguez L, Lubag AJ, Jr., Sherry AD: Imaging free zinc levels in vivo - what can be learned? Inorganica Chim Acta 2012;393:12-23

7. Esqueda AC, Lopez JA, Andreu-de-Riquer G, Alvarado-Monzon JC, Ratnakar J, Lubag AJ, Sherry AD, De Leon-Rodriguez LM: A new gadolinium-based MRI zinc sensor. J Am Chem Soc 2009;131:11387-11391

8. Lubag AJ, De Leon-Rodriguez LM, Burgess SC, Sherry AD: Noninvasive MRI of beta-cell function using a Zn2+-responsive contrast agent. Proc Nat Acad Sci U S A 2011;108:18400-18405

9. Antkowiak PF, Stevens BK, Nunemaker CS, McDuffie M, Epstein FH: Manganese-enhanced magnetic resonance imaging detects declining pancreatic beta-cell mass in a cyclophosphamide-accelerated mouse model of type 1 diabetes. Diabetes 2013;62:44-48

10. Antkowiak PF, Tersey SA, Carter JD, Vandsburger MH, Nadler JL, Epstein FH, Mirmira RG: Noninvasive assessment of pancreatic beta-cell function in vivo with manganese-enhanced magnetic resonance imaging. Am J Physiol Endocrinoly Metabol 2009;296:E573-578

11. Antkowiak PF, Vandsburger MH, Epstein FH: Quantitative pancreatic beta cell MRI using manganese-enhanced Look-Locker imaging and two-site water exchange analysis. Magn Reson Med 2012;67:1730-1739

12. Kavishwar A, Medarova Z, Moore A: Unique sphingomyelin patches are targets of a beta-cell-specific antibody. J Lipid Res 2011;52:1660-1671

13. Kavishwar A, Moore A: Sphingomyelin patches on pancreatic beta-cells are indicative of insulin secretory capacity. J Histochem Cytochem 2013;61:910-919

14. Zhang B, Yang B, Zhai C, Jiang B, Wu Y: The role of exendin-4-conjugated superparamagnetic iron oxide nanoparticles in beta-cell-targeted MRI. Biomaterials 2013;34:5843-5852

15. Wang P, Yoo B, Yang J, Zhang X, Ross A, Pantazopoulos P, Dai G, Moore A: GLP-1R-targeting magnetic nanoparticles for pancreatic islet imaging. Diabetes 2014;63:1465-1474

16. Vinet L, Lamprianou S, Babic A, Lange N, Thorel F, Herrera PL, Montet X, Meda P: Targeting GLP-1 receptors for repeated magnetic resonance imaging differentiates graded losses of pancreatic beta cells in mice. Diabetologia 2015;58:304-312

17. Gepts W: Pathologic anatomy of the pancreas in juvenile diabetes mellitus. Diabetes 1965;14:619-633

18. Bottazzo GF, Dean BM, McNally JM, MacKay EH, Swift PG, Gamble DR: In situ characterization of autoimmune phenomena and expression of HLA molecules in the pancreas in diabetic insulitis. N Engl J Med 1985;313:353-360

19. Moore A, Grimm J, Han B, Santamaria P: Tracking the recruitment of diabetogenic CD8+ T cells to the pancreas in real time. Diabetes 2004;53:1459-1466

20. Medarova Z, Tsai E, Evgenov N, Santamaria P, Moore A: In vivo imaging of a diabetogenic CD8+ T cell response during type 1 diabetes progression. Magn Reson Med 2008;59:712-720

21. Gaglia J, Guimaraes A, Harisinghani M, Turvey S, Jackson R, Benoist C, Mathis D, Weissleder R: Noninvasive imaging of pancreatic islet inflammation in type 1A diabetes patients. J Clin Invest 2011;121:442-445

22. Gaglia J, Harisinghani M, Aganj I, Wojtkiewicz G, Hedgire S, Benoist C, Mathis D, Weissleder R: Noninvasive mapping of pancreatic inflammation in recent-onset type-1 diabetes patients. Proc Natl Acad Sci U S A 2015;112:2139-2144

23. Medarova Z, Castillo G, Dai G, Bolotin E, Bogdanov AJ, Moore A: Noninvasive magnetic resonance imaging of microvascular changes in Type 1 Diabetes. Diabetes 2007;56:2677-2682

24. Medarova Z, Greiner DL, Ifediba M, Dai G, Bolotin E, Castillo G, Bogdanov A, Kumar M, Moore A: Imaging the pancreatic vasculature in diabetes models. Diabetes Metab Res Rev 2011;27:767-772

25. Barnett BP, Arepally A, Karmarkar PV, Qian D, Gilson WD, Walczak P, Howland V, Lawler L, Lauzon C, Stuber M, Kraitchman DL, Bulte JW: Magnetic resonance-guided, real-time targeted delivery and imaging of magnetocapsules immunoprotecting pancreatic islet cells. Nat Med 2007;13:986-991

26. Barnett BP, Arepally A, Stuber M, Arifin DR, Kraitchman DL, Bulte JW: Synthesis of magnetic resonance-, X-ray- and ultrasound-visible alginate microcapsules for immunoisolation and noninvasive imaging of cellular therapeutics. Nat Prot 2011;6:1142-1151

27. Barnett BP, Ruiz-Cabello J, Hota P, Liddell R, Walczak P, Howland V, Chacko VP, Kraitchman DL, Arepally A, Bulte JW: Fluorocapsules for improved function, immunoprotection, and visualization of cellular therapeutics with MR, US, and CT imaging. Radiology 2011;258:182-191

28. Medarova Z, Evgenov NV, Dai G, Bonner-Weir S, Moore A: In vivo multimodal imaging of transplanted pancreatic islets. Nat Prot 2006;1:429-435

29. Evgenov N, Medarova Z, Dai G, Bonner-Weir S, Moore A: In vivo imaging of islet transplantation. Nat Med 2006;12:144-148

30. Evgenov N, Medarova Z, Pratt J, Pantazopoulos P, Leyting S, Bonner-Weir S, Moore A: In vivo imaging of immune rejection in transplanted pancreatic islets. Diabetes 2006;55:2419-2428

31. Evgenov N, Pratt J, Pantazopoulos P, Moore A: Effects of glucose toxicity and islet purity on in vivo MR imaging of transplanted pancreatic islets. Transplantation 2008;85:1091-1098

32. Wang P, Schuetz C, Ross A, Dai G, Markmann JF, Moore A: Immune rejection after pancreatic islet cell transplantation: in vivo dual contrast-enhanced MR imaging in a mouse model. Radiology 2013;266:822-830

33. Wang P, Schuetz C, Vallabhajosyula P, Medarova Z, Tena A, Wei L, Yamada K, Deng S, Markmann JF, Sachs DH, Moore A: Monitoring of Allogeneic Islet Grafts in Nonhuman Primates Using MRI. Transplantation 2015;99:1574-1581

34. Toso C, Vallee JP, Morel P, Ris F, Demuylder-Mischler S, Lepetit-Coiffe M, Marangon N, Saudek F, James Shapiro AM, Bosco D, Berney T: Clinical magnetic resonance imaging of pancreatic islet grafts after iron nanoparticle labeling. Am J Transplant 2008;8:701-706

35. Saudek F, Jirak D, Girman P, Herynek V, Dezortova M, Kriz J, Peregrin J, Berkova Z, Zacharovova K, Hajek M: Magnetic resonance imaging of pancreatic islets transplanted into the liver in humans. Transplantation 2010;90:1602-1606



Proc. Intl. Soc. Mag. Reson. Med. 24 (2016)