Jon Levine (WNPRC), Charles Roberts (ONPRC), and Suzette Tardif (SNPRC)

Type 2 diabetes and its complications such as cardiovascular disease, largely driven by obesity, now represent the major noncommunicable disease burden worldwide. While a number of basic mechanisms of insulin action and aspects of weight regulation and metabolic control have been elucidated in rodent systems, the nonhuman primate represents a crucial pre-clinical model with important similarities to human endocrine physiology that facilitate translation of experimental findings to the clinic.

Specific examples of nonhuman primate physiology that reflect the human situation that are not characteristic of rodent models are enumerated below.

1. Pancreatic islet structure in macaque and human islets involves a lower proportion of beta cells and extensive intermingling of cell types (1,2,3). In contrast, rodent islets are composed of mostly beta cells that form a central core surrounded by a thin layer of non-beta cells. Thus, interactions between insulin- and glucagon-producing cells are much more pronounced in primate islets.

2. Primate islet vasculature is significantly less dense that rodent (4) and is separated from the endocrine compartment by a double basement membrane, representing an extension of the vascular endothelial basement membrane into the islet interior subtending the parenchymal islet basement membrane. In rodents, there is a single internal parenchymal basement membrane, suggesting that the mechanics of endocrine communication may differ (5,6). The type and location of innervation of rodent and human islets also differs, in that endocrine cells in mouse islets exhibit direct autonomic innervation by sympathetic and parasympathetic fibers, while, in human islets, autonomic sympathetic fibers act on vascular cells to exert indirect effects on islet function through control of blood flow (7,8).

3. Glucose-stimulated insulin secretion in human and primate islets differs from rodents, in that they exhibit higher basal insulin secretion and lower glucose-stimulated insulin secretion than mouse islets (9).

4. The ability of beta cells to proliferate also differs between rodents and humans, in that, during pregnancy, expansion of beta cell mass is robust in rodents but modest in humans (10), and in vitro proliferation is also possible in rodent beta cells but not human (11).

5. With respect to peripheral insulin action, the majority (70-90%) of insulin-stimulated glucose uptake occurs in skeletal muscle in humans (12,13), while, in mice, insulin-mediated control of blood glucose is primarily due to the liver (14,15).

Nonhuman primate models of type-2 diabetes have been developed at the Oregon and Southwest NPRCs in cynomolgus, rhesus, and Japanese macaques as well as baboons, typically generated through diet-induced obesity. These models have been the basis of a large number of NIH and foundation-funded studies on molecular mechanisms of insulin resistance and type-2 diabetes, and have also been accessed by a number of industry entities for pre-clinical evaluation of the mechanism of action of new therapeutic agents through sponsored research agreements and strategic partnerships. Models of gestational diabetes have also been produced at the Oregon NPRC by maternal high-fat feeding before and during gestation, and these have provided valuable information on the adverse effects of overnutrition on offspring that are independent of maternal obesity. The relatively recent development of metabolic biomarkers, including insulin, for common marmosets has led to the development of this small New World monkey as a model of obesity and diabetes at the Wisconsin NPRC and Southwest NPRC. Clear advantages of this model in terms of size and lifespan have encouraged the initiation of studies focused on nutrition and obesity. Marmosets are an emerging model for pediatric obesity, displaying routine features common to human pediatric obesity, such as higher early growth rates, altered rates of fat versus lean mass gain, and increased risk of early life insulin resistance (16, 17).

Although classical autoimmune type-1 diabetes does not occur in nonhuman primates, an experimental model can be generated, as in rodents, with the beta cell toxin streptozotocin. This model has been used to investigate aspects of islet transplantation, which is pertinent to treatment of type-1 diabetes but also advanced type 2 diabetes, in which beta cell loss has progressed to result in an insulin deficiency equivalent to that seen in type 1 diabetes. New techniques, such as Designer Receptors Exclusively Activated by Designer Drugs (DREADD) technology, provide opportunities for a more directed model of type-1 diabetes that will comprise an important complement to the current dietary models of type-2 diabetes.

References cited

1. Brissova M, Fowler MJ, Nicholson WE, Chu A, Hirshberg B, Harlan DM, Powers AC. Assessment of human pancreatic islet architecture and composition by laser scanning confocal microscopy. J Histochem Cytochem. 2005;53(9):1087-97.

2. Cabrera O, Berman DM, Kenyon NS, Ricordi C, Berggren PO, Caicedo A. The unique cytoarchitecture of human pancreatic islets has implications for islet cell function. Proc Natl Acad Sci U S A. 2006;103(7):2334-9.

3. Bosco D, Armanet M, Morel P, Niclauss N, Sgroi A, Muller YD, Giovannoni L, Parnaud G, Berney T. Unique arrangement of alpha- and beta-cells in human islets of Langerhans. Diabetes. 2010;59(5):1202-10.

4. Brissova M, Shostak A, Fligner CL, Revetta FL, Washington MK, Powers AC, Hull RL. Human Islets Have Fewer Blood Vessels than Mouse Islets and the Density of Islet Vascular Structures Is Increased in Type 2 Diabetes. J Histochem Cytochem. 2015;63(8):637-45.

5. Virtanen I, Banerjee M, Palgi J, Korsgren O, Lukinius A, Thornell LE, Kikkawa Y, Sekiguchi K, Hukkanen M, Konttinen YT, Otonkoski T. Blood vessels of human islets of Langerhans are surrounded by a double basement membrane. Diabetologia. 2008;51(7):1181-91.

6. Otonkoski T, Banerjee M, Korsgren O, Thornell LE, Virtanen I. Unique basement membrane structure of human pancreatic islets: implications for beta-cell growth and differentiation. Diabetes Obes Metab. 2008;10 Suppl 4:119-27.

7. Molina J, Rodriguez-Diaz R, Fachado A, Jacques-Silva MC, Berggren PO, Caicedo A. Control of insulin secretion by cholinergic signaling in the human pancreatic islet. Diabetes. 2014;63(8):2714-26.

8. Rodriguez-Diaz R, Abdulreda MH, Formoso AL, Gans I, Ricordi C, Berggren PO, Caicedo A. Innervation patterns of autonomic axons in the human endocrine pancreas. Cell Metab. 2011;14(1):45-54.

9. Dai C, Brissova M, Hang Y, Thompson C, Poffenberger G, Shostak A, Chen Z, Stein R, Powers AC. Islet-enriched gene expression and glucose-induced insulin secretion in human and mouse islets. Diabetologia. 2012;55(3):707-18.

10. Shepherd PR, Kahn BB. Glucose transporters and insulin action--implications for insulin resistance and diabetes mellitus. N Engl J Med. 1999;341(4):248-57.

11. Postic C, Dentin R, Girard J. Role of the liver in the control of carbohydrate and lipid homeostasis. Diabetes Metab. 2004;30(5):398-408.

12. Butler AE, Cao-Minh L, Galasso R, Rizza RA, Corradin A, Cobelli C, Butler PC. Adaptive changes in pancreatic beta cell fractional area and beta cell turnover in human pregnancy. Diabetologia. 2010;53(10):2167-76.

13. Genevay M, Pontes H, Meda P. Beta cell adaptation in pregnancy: a major difference between humans and rodents? Diabetologia. 2010;53(10):2089-92.

14. Michael MD, Kulkarni RN, Postic C, Previs SF, Shulman GI, Magnuson MA, Kahn CR. Loss of insulin signaling in hepatocytes leads to severe insulin resistance and progressive hepatic dysfunction. Mol Cell. 2000;6(1):87-97.

15. Bruning JC, Michael MD, Winnay JN, Hayashi T, Horsch D, Accili D, Goodyear LJ, Kahn CR. A muscle-specific insulin receptor knockout exhibits features of the metabolic syndrome of NIDDM without altering glucose tolerance. Mol Cell. 1998;2(5):559-69.

16. Power ML, Ross CN, SchulkinJ, Tardif SD The development of obesity begins at an early age in captive common marmosets (Callithrix jacchus). Am J Primatol 2012 Mar; 74:261-269. PMCID: PMC3767183

17. Power ML, Ross CN, Schulkin J, Ziegler TE, Tardif SD Metabolic consequences of early onset of obesity in common marmoset monkeys. Obesity 2013 21:E592-E598. PMCID: PMC3855166

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