Structural and Functional Abnormalities in the Islets Isolated From Type 2 Diabetic Subjects Shaoping Deng, 1 Marko Vatamaniuk, 2,3 Xiaolun Huang, 1 Nicolai Doliba, 2,3 Moh-Moh Lian, 1 Adam Frank, 1 Ergun Velidedeoglu, 1 Niraj M. Desai, 1 Brigitte Koeberlein, 1 Bryan Wolf, 4 Clyde F. Barker, 1 Ali Naji, 1 Franz M. Matschinsky, 2,3 and James F. Markmann 1 Type 2 diabetic subjects manifest both disordered insu- lin action and abnormalities in their pancreatic islet cells. Whether the latter represents a primary defect or is a consequence of the former is unknown. To examine the -cell mass and function of islets from type 2 diabetic patients directly, we isolated islets from pan- creata of type 2 diabetic cadaveric donors (n  14) and compared them with islets from normal donors (n  14) matched for age, BMI, and cold ischemia time. The total recovered islet mass from type 2 diabetic pancreata was signiﬁcantly less than that from nondiabetic control subjects (256,260 islet equivalents [2,588 IEq/g pan- creas] versus 597,569 islet equivalents [6,037 IEq/g pancreas]). Type 2 diabetic islets were also noted to be smaller on average, and histologically, islets from dia- betic patients contained a higher proportion of gluca- gon-producing -cells. In vitro study of islet function from diabetic patients revealed an abnormal glucose- stimulated insulin release response in perifusion as- says. In addition, in comparison with normal islets, an equivalent number of type 2 diabetic islets failed to reverse hyperglycemia when transplanted to immunode- ﬁcient diabetic mice. These results provide direct evi- dence for abnormalities in the islets of type 2 diabetic patients that may contribute to the pathogenesis of the disease. Diabetes 53:624 – 632, 2004 N early 150 million individuals are afﬂicted with type 2 diabetes worldwide, and this number is expected to double within 25 years (1). Al- though the magnitude of the health care prob- lem posed by this disorder is well recognized (2,3), the pathogenesis of the disease remains enigmatic. Current evidence suggests a complex interplay of unknown genet- ic-, environmental-, and lifestyle-related factors (4 – 8). Resistance to insulin action often accompanying obesity and ineffective compensation by pancreatic islets to main- tain normoglycemia are the most striking manifestations (9 –13). Abnormalities of insulin secretion have been demon- strated in type 2 diabetic patients and may reﬂect the inability of the -cell to adapt in the context of peripheral resistance (14 –16). Hyperglycemia itself has been impli- cated to be toxic to -cells, thus a self-reinforcing cycle of glucose intolerance and progressive -cell injury could contribute to the progression of the disease (17–20). Structural changes in the islets of type 2 diabetic subjects have been described including the deposition of amyloid within the islets (21). In addition, some but not all inves- tigators have reported a reduction in -cell mass at au- topsy (22–23). Given the fact that islet mass may normally increase with body mass (24) and that hyperinsulinism may be an early compensatory mechanism for insulin resistance, it might have been predicted that the islet mass in type 2 diabetic subjects would be increased, at least early in the course of the disease. Few studies have directly examined the islet mass, composition, or function of islets isolated from patients with type 2 diabetes (25). Since diabetes is so prevalent in the general population and is a risk factor for chronic vascular complications such as heart disease and stroke, which frequently lead to brain death and the potential for organ donor candidacy, it is not surprising that a signiﬁcant number of cadaveric donors carry the diagnosis of type 2 diabetes (26). We thus took advantage of the availability of cadaveric organ donors with type 2 diabetes to conduct a systematic comparison of pancreatic islets isolated from type 2 dia- betic subjects with those from normal donors. We used standardized techniques to isolate islets from diabetic and control pancreata and to examine the islet morphology, composition, and total mass recovered. Isolated islet func- tion was evaluated both by an in vitro perifusion assay to provide dynamic detail of the glucose-stimulated insulin release response as well as by islet transplantation to immunodeﬁcient murine hosts to asses the potency of their function in vivo. Our results suggest both anatomic and functional abnormalities in the islets of type 2 diabetic subjects that could lead to impaired insulin secretion. RESEARCH DESIGN AND METHODS Human pancreata. Human pancreata were obtained through the local organ procurement organization. Donors who were previously diagnosed with type 2 diabetes were designated as type 2 diabetic donors. Control donors who had no diabetes history were considered normal donors. The islet preparations studied were from 14 consecutive diabetic and 14 normal control subjects. From the 1 Department of Surgery, Harrison Department of Surgical Research, Hospital of the University of Pennsylvania, Philadelphia, Pennsylvania; the 2 Department of Biochemistry and Biophysics, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania; the 3 Penn Diabetes Center, Hospital of the University of Pennsylvania, Philadelphia, Pennsylvania; and the 4 Department of Pathology, The Children’s Hospital of Philadelphia, Philadelphia, Pennsylvania. Address correspondence and reprint requests to James F. Markmann, MD, PhD, Department of Surgery, Hospital of the University of Pennsylvania, 4th ﬂoor Silverstein, 3400 Spruce St., Philadelphia, PA 19104. E-mail: james. markmann@uphs.upenn.edu. Received for publication 27 May 2003 and accepted in revised form 16 December 2003. GSIR, glucose-stimulated insulin release; RIA, radioimmunoassay. © 2004 by the American Diabetes Association. 624 DIABETES, VOL. 53, MARCH 2004