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

Recent NPRC Publications

There are currently 188 publications available for Obesity and Type 2 Diabetes.

2018

Andersen B, Straarup EM, Heppner KM, Takahashi DL, Raffaele V, Dissen GA, Lewandowski K, Bödvarsdottir TB, Raun K, Grove KL, Kievit P
FGF21 decreases body weight without reducing food intake or bone mineral density in high-fat fed obese rhesus macaque monkeys.
Int J Obes (Lond) 2018 Jun; (): .

Andrew MS, Huffman DM, Rodriguez-Ayala E, Williams NN, Peterson RM, Bastarrachea RA
Mesenteric visceral lipectomy using tissue liquefaction technology reverses insulin resistance and causes weight loss in baboons.
Surg Obes Relat Dis 2018 Mar; (): .

Bishop CV, Mishler EC, Takahashi DL, Reiter TE, Bond KR, True CA, Slayden OD, Stouffer RL
Chronic hyperandrogenemia in the presence and absence of a western-style diet impairs ovarian and uterine structure/function in young adult rhesus monkeys.
Hum. Reprod. 2018 Jan; 33(1): 128-139.

Bishop CV, Stouffer RL, Takahashi DL, Mishler EC, Wilcox MC, Slayden OD, True CA
Chronic hyperandrogenemia and western-style diet beginning at puberty reduces fertility and increases metabolic dysfunction during pregnancy in young adult, female macaques.
Hum. Reprod. 2018 Feb; (): .

Chen S, Bastarrachea RA, Shen JS, Laviada-Nagel A, Rodriguez-Ayala E, Nava-Gonzalez EJ, Huang P, DeFronzo RA, Kent JW, Grayburn PA
Ectopic BAT mUCP-1 overexpression in SKM by delivering a BMP7/PRDM16/PGC-1a gene cocktail or single PRMD16 using non-viral UTMD gene therapy.
Gene Ther. 2018 Aug; (): .

More...

Recent News Articles and Reference Materials

November 29, 2018
Researchers Use CRISPR Technology to Identify Altered Genes Causing Obesity

November 27, 2018
Could 'Genetic Editing' Tackle the Problem of Hispanic Childhood Obesity?

November 26, 2018
Texas Biomed Scientists Targeting Factors Involved in Hispanic Childhood Obesity

June 1, 2017
Permanently cutting the daily calories you consume may turn out to have a profound effect on your future life, according to some tantalising scientific studies.

January 17, 2017
Calorie restriction lets monkeys live long and prosper

December 5, 2016
Texas Biomed scientists part of consortium finding new areas of genetic influence for body fat distribution in multiethnic study

November 15, 2016
News Release: Genetic factor found for under diagnosis of type 2 diabetes in Inuit population

November 4, 2016
Experts discover gene variants that protect a lucky few primates against obesity from a high fat diet

October 13, 2016
Preventing child obesity in the next generation

August 5, 2016
Texas Biomed scientist discusses weight gain in America with HealthDay

July 19, 2016
TOPS’ Genome Registry May Hold Answers to Obesity

January 12, 2016
Mom’s weight during pregnancy shapes baby’s health

June 26, 2015
Texas Biomed establishes the TOPS® Nutrition and Obesity Research Center

January 19, 2015
Sex-specific differences in lipid and glucose metabolism

October 12, 2014
Scientists close in on diabetes cure with production of insulin-producing cells

May 2, 2014
There Might Be a Cure for Diabetes. Thank NASA Research

January 27, 2014
Infertility, Diabetes, Obesity and the Mystery of PCOS

May 31, 2013
New Center for Global Diabetes and Cardiometabolic Research at Emory University

February 24, 2011
OHSU Researchers Locates Brain-Based Cause Of Type 2 Diabetes, Possible Method For Reversing Disease

American Diabetes Association resource page: type-2 diabetes

CDC Resource Page: Diabetes

International Diabetes Federation resource page: type-2 diabetes