Saturday Morning Research Review – October 22, 2016

Recent studies of glucose control and autoimmunity in pets

by Adam Burrack, PhD

Last fall I profiled diabetic guide dogs, which have been gaining favor among people with type 1 diabetes (T1D) who live alone and/or are concerned about severe hypoglycemic episodes. Today I will describe several more recent reports detailing the development of diabetes in pets and treatment options. It has been known for some time that dogs and cats could develop diabetes. One ‘controversy’ in veterinary pathology circles is whether these cases of diabetes are autoimmune in nature or whether these cases reflect insulin resistance and is thereby a type 2 diabetes-like clinical manifestation.

A recent report from researchers at the University of Minnesota presents convincing evidence that pet dogs can develop autoimmune diabetes. The Modiano lab demonstrated both B cell responses – by autoantibodies against beta cell proteins targeted in human T1D – and by T cell responses – by cytokine production in response to insulin-derived peptides. This lab’s focus is treating cancer is pet dog populations, but for this study they switched to the other side of the immunology field, autoimmunity. Autoantibody testing was shipped out to the Barbara Davis Center in Denver for standard human-grade clinical tests. The current standard in basic and clinical immunology for demonstrating “antigen-specific” T cell responses is called an ELISPOT test. Essentially, cells from the test subject are incubated with peptides that could be targeted, in this paper peptides derived from the insulin molecule. In these experiments, T cells from diabetic dogs produced the effector cytokine IFN-gamma in response to insulin peptides. This is direct experimental confirmation that animals can develop autoimmune diabetes. An important future direction in this research is determining the role of genetics (most dogs are in-bred to a degree, which may place some breeds at higher-risk) and environment (diversity of gut microbiome, which is an area of very active research in human T1D). The authors make the case in this primary research paper that the observation of dog T1D makes the ethical test for using dogs in clinical trials of insulin-specific tolerance induction. There is no model of autoimmune diabetes using non-human primates (regardless of NIH limitations on non-human primate research), so spontaneous diabetes in dogs may represent the only option besides NOD mice for non-human clinical trials in attempts to re-establish immune system tolerance to insulin.

As with human diabetes, therapies for canine diabetes are sought which “relieve some of the stress” on remaining beta cells in the pancreas, and which limit the over-exuberant production of glucagon by alpha cells in the relative absence of insulin. A recent paper in PlosOne characterizes a treatment which may accomplish both of these goals. Fibroblast growth factor 21 (FGF21) has a hormone-like (or endocrine-like) function: it promotes glucose uptake by fat cells but not by other cells. Treating diabetic dogs with recombinant (synthetically produced) FGF21 promoted glucose uptake and decreased glucagon production in diabetic dogs (and streptozotocin-induced diabetic mice). As such, the authors suggest that treatment with synthetic FGF21 may “ameliorate hyperglycemia and promote beta cell survival” in diabetic animals.

Lastly, as an attempt to improve insulin sensitivity in pre-diabetic dogs, researchers treated with exenatide – a glucagon-like peptide 1 agonist. Exenatide is FDA-approved to treat human patients with type 2 diabetes, so the motivation for this study was to test whether this treatment also enhanced insulin sensitivity in pre-diabetic dogs (which has the potential to delay diabetes onset). It did, which is encouraging and suggests that this treatment would be useful applied to diabetic canine (or feline, using a weight-based dosing strategy) populations.

In summary, animals can develop autoimmune diabetes, and treatments which enhance insulin sensitivity in humans also enhance insulin sensitivity in diabetic animals. This is good news, both for owners of diabetic animals (who would benefit from treatment with these pharmalogic agents) and for pharmaceutical companies (who would sell them the treatments). Presumably, other insulin sensitizing agents and SGLT2 inhibitors, would have beneficial effects for diabetic animals. This is good news for owners of diabetic pets!


Posted in Immunology, Research Review.