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ORIGINAL RESEARCH ARTICLE

Ultrastructure of Islet Microcirculation, Pericytes and the Islet Exocrine Interface in the HIP Rat Model of Diabetes

Melvin R. Hayden^*,,,1, Poorna R. Karuparthi^*,, Javad Habibi^*,,,||, Guido Lastra^*,,,||, Kamlesh Patel^*, Chetan Wasekar^*,, Camila Margarita Manrique^*,,,||, Ugur Ozerdem^¶, Sameer Stas^*,, and James R. Sowers^*,,,,||

^* Department of Internal Medicine, Department of Endocrinology Diabetes and Metabolism, Diabetes and Cardiovascular Research Center, Department of Physiology and Pharmacology, University of Missouri School of Medicine, Columbia, Missouri 65212; ^|| Harry S. Truman VA Medical Center, Columbia, Missouri 65201; and ^¶ La Jolla Institute for Molecular Medicine, San Diego, California 92121

To whom requests for reprints should be addressed at ¹ Department of Internal Medicine, Endocrinology Diabetes and Metabolism, Diabetes and Cardiovascular Disease Research Group, University of Missouri School of Medicine Columbia, Missouri, Health Sciences Center, MA410, DC043.00, Columbia, MO 65212. E-mail: mrh29{at}usmo.com

Context: The transgenic human islet amyloid polypeptide (HIP) rat model of type 2 diabetes mellitus (T2DM) parallels the functional and structural changes in human islets with T2DM. Objective: The transmission electron microscope (TEM) was utilized to observe the ultrastructural changes in islet microcirculation. Methods: Pancreatic tissue from male Sprague Dawley rats (2, 4, 8, 14 months) were used as controls (SDC) and compared to the 2-, 4-, 8- and 14-month-old HIP rat models. Results: The 2-month-old HIP model demonstrated no islet or microcirculation remodeling changes when compared to the SDC models. The 4-month-old HIP model demonstrated significant pericapillary amyloid deposition and diminution of pericyte foot processes as compared to the SDC models. The 8-month-old model demonstrated extensive islet amyloid deposition associated with pericyte and β-cell apoptosis when compared with SDC. The 14-month-old HIP model demonstrated a marked reduction of β-cells and intra-islet capillaries with near complete replacement of islets by amyloidoses. Increased cellularity in the region of the islet exocrine interface was noted in the 4- to 14-month-old HIP models as compared to SDC. In contrast to intra-islet capillary rarefaction there was noticeable angiogenesis in the islet exocrine interface. Pericytes seemed to be closely associated with collagenosis, intra-islet adipogenesis and angiogenesis in the islet exocrine interface. Conclusion: The above novel findings regarding the microcirculation and pericytes could assist researchers and clinicians in a better morphological understanding of T2DM and lead to new strategies for prevention and treatment of T2DM.

Key Words: amylin • angiogenesis • apoptosis • beta cell • islet amyloid • islet fibrosis • exocrine pancreas