Gene Therapy: A Cure for Canine Diabetes

Beagle dog, from Wikipedia commons

Treatment of Diabetes and Long-term Survival Following Insulin and Glucokinase Gene Therapy

David Callejas, Christopher J. Mann, Eduard Ayuso, Ricardo Lage, Iris Grifoll, Carles Roca, Anna Andaluz, Rafael Ruiz-de Gopegui, Joel Montané, Sergio Muñoz, Tura Ferre, Virginia Haurigot, Shangzhen Zhou, Jesús Ruberte, Federico Mingozzi, Katherine A. High, Felix Garcia, and Fatima Bosch

Diabetes (Published online before print) February 1, 2013, doi:10.2337/db12-1113

In both man and dogs, diabetes is a chronic disease for which there is no cure. Almost all diabetic dogs need insulin replacement therapy to survive, but glycemic control is never perfect (1-3). Therefore, long-term complications of diabetes (e.g., cataracts) disease are frequently observed (4-6). In addition, burden of our traditional treatment methods takes a toll on the owners of diabetic pets and results in a proportion of pets being euthanized instead of being treated (7). If pet owners do decide to treat their diabetic pets, they commonly report a significant treatment burden, with a number of negative effects on various aspects of the pet’s and owner’s lifestyle (7,8).

Gene therapy for diabetes
Obviously, a less arduous treatment option for controlling diabetes mellitus in dogs would be welcomed.  Gene therapy has the potential to provide this alternative method of treatment for animals as well as for humans. Simplistically, in gene therapy, particular strings of DNA are "inserted" into cells such that the machinery of the cell takes the DNA, transcribes it into RNA, and then makes the protein that is encoded in the new DNA. This technique allows us to force cells to make proteins that they might not otherwise make, and in the last decade it has started to see success in small trials to treat a number of diseases.

As it turns out, however, designing and targeting a string of DNA at a cell is not easy (8,9). Currently, most investigators use what is called viral vectors to get the DNA inside cells— basically, this involves taking a virus that contains the DNA we want to insert, and infect cells with the virus. The virus enters the cell, where it can integrate its DNA segment into the chromosomes of the host cell (8).

For diabetes, experimental gene therapy has generally involved injection of protein-coding genes into skeletal muscle or the liver. This exploits these tissues' intrinsic ability to read such genes and subsequently constitutively produce the corresponding protein, which is then secreted into the general circulation by virtue of the extensive vascularization of peripheral muscles (10-14).

Study reporting successful gene therapy for canine diabetes
To date, most gene therapy has involved studies in diabetic mice. As reported by Callejas et al. in the  journal Diabetes (15), these researchers from the Center of Animal Biotechnology and Gene Therapy, Universitat Autonoma de Barcelona, Spain, used gene therapy to treat and "cure" 5 Beagle dogs with insulin-deficient diabetes.

This same research group had already tested this type of therapy on mice (10), but the excellent results obtained for the first time with large animals lays the foundation for the clinical translation of this gene therapy approach to veterinary medicine and eventually for diabetic human patients.

The diabetic state in these dogs had been induced by injection of a mixture of streptozotocin and alloxan, both of which are toxic to beta cells (16). After becoming diabetic, the dogs were treated with one of the following:

1. Insulin glargine, administered twice daily
2. Intramuscular injection of the glucokinase gene alone 
3. Intramuscular injection of the insulin gene alone
4. Intramuscular injection of both the insulin and glucokinase genes. 

Not surprisingly, without treatment, the dogs were markedly hyperglycemic. The dogs on twice daily insulin were better controlled but remained hyperglycemic.

To test both the insulin and glucose kinase vectors together, the researchers injected 5 dogs with one or two doses of the viral vectors. These dogs quickly regained normoglycemia, and even the higher doses were tolerated well; none of the dog had any side effects. Unlike the dogs given insulin alone, the dogs given both genes together responded much better to an oral glucose tolerance test, spiking slightly up to between 200 and 300 mg/dL, but stayed well below the levels seen with the diabetic dogs.

The dogs gained weight, had lower serum fructosamine levels, and experienced long-term remission of the diabetes without secondary complications. Therapy that included only the insulin gene or the glucose kinase gene but not both did not result in the same level of success.

Click here to see a video of the treated dogs in diabetic remission.

My Bottom Line:

Since the 1922 breakthrough discovery of Banting and Best (17), who corrected hyperglycemia in dogs using pancreatic extracts, exogenous insulin administration has been the mainstay of diabetes therapy (1-3). Alternative therapies have been studied, but thus far only a handful of approaches, mainly involving allo- or xeno-transplantation of pancreatic islets, have reached clinical application (18).

The authors of this landmark study (15) took a different approach: instead of trying to transplant or manufacture beta cells that respond to glucose and produce insulin, they used dual gene therapy to develop a “glucose sensor” in skeletal muscle that permitted long-term, normoglycemia in this canine model of diabetes.

The gene therapy used in these dogs consisted of a single session of intramuscular injections to introduce gene therapy vectors, with two ultimate objectives: to express the insulin gene, on the one hand, and that of glucokinase, on the other. Glucokinase is an enzyme that regulates the uptake of glucose from the blood (19). When both insulin and glucokinase genes act simultaneously, they function together as a glucose sensor to automatically regulate the uptake of glucose from the blood, thus reducing hyperglycemia (20).

The results of this study look very promising indeed. The dogs in the study, once treated, experienced long-term normoglycemia, both in the fasting or fed state, with no need for exogenous insulin therapy. There were no episodes of hypoglycemia, even after the dogs were exercised. In addition, all dogs regained lost body weight and developed no secondary complications 4 years after treatment.

Hopefully, this study will provide the basis for the initiation of clinical studies in dogs (and cats?) with naturally-occurring diabetes. Such veterinary clinical trials should also help investigators in preparing for the use of this approach in humans patients with diabetes.  

References:

1. Davison LJ, Herrtage ME, Catchpole B. Study of 253 dogs in the United Kingdom with diabetes mellitus. Vet Rec 2005;156:467-471.
2. Nelson RW. Canine diabetes mellitus In: Ettinger SJ, Feldman EC, eds. Textbook of Veterinary Internal Medicine: Diseases of the Dog and Cat. Seventh ed. St. Louis: Saunders Elsevier, 2010;1449-1474.
3. Davison LJ. Canine diabetes mellitus In: Mooney CT, Peterson ME, eds. BSAVA Manual of Canine and Feline Endocrinology. Fourth ed. Quedgeley, Gloucester: British Small Animal Veterinary Association, 2012;116-132.
4. Munana KR. Long-term complications of diabetes mellitus, Part I: Retinopathy, nephropathy, neuropathy. Vet Clin North Am Small Anim Pract 1995;25:715-730. 
5. Basher AW, Roberts SM. Ocular manifestations of diabetes mellitus: diabetic cataracts in dogs. Vet Clin North Am Small Anim Pract 1995;25:661-676. 
6. Beam S, Correa MT, Davidson MG. A retrospective-cohort study on the development of cataracts in dogs with diabetes mellitus: 200 cases. Vet Ophthalmol 1999;2:169-172. 
7. Niessen SJ, Powney S, Guitian J, et al. Evaluation of a quality-of-life tool for dogs with diabetes mellitus. J Vet Intern Med 2012;26:953-961. 
8. Bertolaso M, Olsson J, Picardi A, et al. Gene therapy and enhancement for diabetes (and other diseases): the multiplicity of considerations. Diabetes Metab Res Rev 2010;26:520-524. 
9. Alenzi FQ, Lotfy M, Tamimi WG, et al. Review: Stem cells and gene therapy. Lab Hematol 2010;16:53-73. 
10. Mas A, Montane J, Anguela XM, et al. Reversal of type 1 diabetes by engineering a glucose sensor in skeletal muscle. Diabetes 2006;55:1546-1553.  
11. Wong MS, Hawthorne WJ, Manolios N. Gene therapy in diabetes. Self Nonself 2010;1:165-175. 
12. Bagley J, Paez-Cortez J, Tian C, et al. Gene therapy in type 1 diabetes. Crit Rev Immunol 2008;28:301-324. 
13. Niessen SJ, Fernandez-Fuente M, Mahmoud A, et al. Novel diabetes mellitus treatment: mature canine insulin production by canine striated muscle through gene therapy. Domest Anim Endocrinol 2012;43:16-25. 
14. Ren B, O'Brien BA, Byrne MR, et al. Long-term reversal of diabetes in non-obese diabetic mice by liver-directed gene therapy. J Gene Med 2013;15:28-41. 
15. Callejas D, Mann CJ, Ayuso E, et al. Treatment of diabetes and long-term survival following insulin and glucokinase gene therapy. Diabetes 2013 (in press). 
16. Anderson HR, Stitt AW, Gardiner TA, et al. Induction of alloxan/streptozotocin diabetes in dogs: a revised experimental technique. Lab Anim 1993;27:281-285. 
17. Banting FG, Best CH, Collip JB, et al. Pancreatic extracts in the treatment of diabetes mellitus. Can Med Assoc J 1922;12:141-146. 
18. Robertson RP. Islet transplantation a decade later and strategies for filling a half-full glass. Diabetes 2010;59:1285-1291.  
19. Printz RL, Magnuson MA, Granner DK. Mammalian glucokinase. Annu Rev Nutr 1993;13:463-496. 
20. Otaegui PJ, Ferre T, Pujol A, et al. Expression of glucokinase in skeletal muscle: a new approach to counteract diabetic hyperglycemia. Hum Gene Ther 2000;11:1543-1552. 

Managing Dogs with Insulin-Sensitive, Brittle Diabetes

My problem patient is a 13-year-old, female-spayed Yorkie with brittle diabetes mellitus. In contrast to many diabetic dogs that I see, this dog is very insulin sensitive, with frequent bouts of hypoglycemia. Fortunately, these hypoglycemic episodes do not appear to be causing clinical problems (i.e., no weakness or seizures have been observed), and she seems to be doing great at home. We have the owner feeding her several times a day to prevent hypoglycemia.

To complicate diabetic control in this dog, the owner's elderly father cares for the dog during the day. On the weekends, the owner works quite late so she "pre-fills" the insulin syringe in the morning so her father can give the insulin shot later that day. I've told the owner that the NPH insulin particles will likely be out of suspension by the evening (unless her father remembers to roll the syringe to remix the insulin suspension), but the owner says she doesn't have much choice.  I'm not sure how this is affecting the diabetic control, but it cannot be helping. We try to do her glucose curves toward the end of the week after the owner (rather than the father) has been injecting the insulin herself.

Below are two recent blood glucose curves, the first done about a month ago and the second one just done this week:

Glucose Curve 1

• 0800 hr—372 mg/dl (Fed; Gave 1 unit of NPH, SC)
• 1000 hr—109 mg/dl
• 1130 hr—Fed small meal
• 1200 hr—98 mg/dl
• 1400 hr—75 mg/dl
• 1530 hr—Fed small meal
• 1600 hr—67 mg/dl
• 1800 hr—214 mg/dl

I thought this curve indicated pretty good glycemic control. However, I found her latest glucose curve to be especially concerning.

Glucose Curve 2

• 0800 hr—310 mg/dl (Fed; Gave 1 unit of NPH, SC)
• 1000 hr—65 mg/dl
• 1015 hr—Fed small meal
• 1100 hr—101 mg/dl
• 1300 hr—24 mg/dl (Sample sent to lab confirmed hypoglycemia: 45 mg/dl)
• 1310 hr—Fed small meal (ate well)
• 1400 hr—98 mg/dl
• 1600 hr—240 mg/dl
• 1800 hr—270 mg/dl

Even with the very low blood glucose value at 1300 hr, this dog was acting fine and was not exhibiting any signs of hypoglycemia.

So I'm at a loss. I told the owner to decrease to 0.5 unit of the NPH twice daily and to feed more at each meal. However, I'm worried that it's going to be very difficult to give such a tiny dose of insulin. Can the NPH be diluted?

I'm also wondering if part of the problem here is a too short of a duration for NPH or a Somogyi effect (hypoglycemia-induced hyperglycemia). Should we try a different insulin?

My Response:

Obviously, this dog has a higher insulin sensitivity than is the typical dog with diabetes mellitus. Such an insulin-sensitive diabetic will require smaller amounts of insulin to lower blood glucose levels than the average canine diabetic with "normal" sensitivity or insulin resistance.

The glucose-lowering effect of insulin varies from diabetic dog to dog, depending on a number of factors including age, degree of insulin deficiency, and concurrent disease (1).  Generally speaking, having a higher sensitivity to insulin makes it easier to regulate the diabetic patient.  However, there are times when this increased sensitivity can be problematic. As in this dog, having high insulin sensitivity will increase the risk of hypoglycemia and can even make it difficult to accurately draw up a small enough dose.

Minimizing hypoglycemia in dogs with increased insulin sensitivity
So what can we do to minimize iatrogenic hypoglycemia in the insulin-sensitive diabetic?  Factors to consider include the following (1-4):

• Insulin dose
• Type of insulin (short, intermediate, or long-acting)
• Timing of food ingestion to insulin injection
• Exercise
• Decreased clearance of insulin

Lowering the insulin dose— You certainly could dilute the NPH insulin and lower the insulin dose to 0.5 U twice a day. Both Eli Lilly and Novo Nordisk make diluents for their brand of NPH insulin, but these diluents can be difficult to obtain (5).  Insulin can also be diluted with sterile water or saline solution, but these insulin solutions are not as stable.

A better option is to use a U-100 insulin syringe with 0.5 unit markings. Again, these syringes may be difficult to find, but are generally available at WalMart  (ask for ReliOn U-100 3/10 cc insulin syringes marked in 1/2 unit dosing).

Using a less potent type of insulin — In general, short-acting insulins (e.g., regular insulin, NPH, lente) have a more potent hypoglycemic effect than do the long-acting insulin preparations (protamine zinc insulin, glargine).  The reason for this is mainly because short-acting insulins are absorbed faster and result in higher levels of circulating insulin concentrations (1,6-8). Long-acting preparations, such as glargine (Lantus) or protamine zinc insulin (PZI, ProZinc) are absorbed much slower and result in much lower peak circulating insulin concentrations (1,6-10). The big exception to this rule is the long-acting insulin preparation detemir (Levemir), which turns out to be a very potent insulin in dogs (11).

Adjusting the timing of food ingestion and insulin injection—In general, I like to have owners inject insulin about 30 minutes before the dog eats in order to prevent severe post-prandial hyperglycemia and help regulate the dog's diabetic state (12).  In most dogs, I strongly discourage the feeding of extra meals or snack throughout the day, since it commonly leads to poor glycemic control when using twice daily insulin injections.

In dogs with severe insulin sensitivity, however, I would try the opposite approach. In these dogs, I feed the dog about 30 to 60 minutes before injecting the insulin to encourage a rise in blood sugar to help prevent the hypoglycemia that commonly occurs in these dogs shortly after the insulin injection.

Accounting for the effect of exercise—Although it does not appear to be a contributory factor in this dog, physical activity is well known to have insulin sensitizing effects, and this can also present a higher risk of hypoglycemia for patients on insulin (13). The insulin sensitizing effects of exercise can sometimes last for hours so it is important to be aware of the increased risk of hypoglycemia in these dogs.

Exclude disorders that result in a decreased clearance of insulin—The liver is responsible for about half of the total insulin degradation with the kidney responsible for the rest (14,15). Therefore, the development of severe liver disease or chronic kidney disease can contribute to the increased insulin sensitivity seen in a dog with diabetes. Again, this does not appear to be a contributory factor in your dog.

My Bottom Line

You certainly could lower the NPH insulin dose, but I don't think that's the best solution for this dog.  I would recommend switching to a longer-acting insulin preparation, such as ProZinc or Lantus.  Although not generally considered as first-choice insulin preparations, both of these long-acting insulin preparations have been reported to be effective in dogs (9,10). Because they are slowly absorbed, both of these insulins have a less potent hypoglycemic effect as compared with NPH insulin.

However, we can't forget about the "premixing" of the insulin dose that the owner does on the weekends, can we! When we throw that into the equation, my choice becomes more obvious. Let's change to Lantus, which is a solution so the insulin won't precipitate out of suspension like the premixed NPH insulin would likely do.

References:

1. Nelson RW. Canine diabetes mellitus. In: Ettinger SJ, Feldman EC (eds). Textbook of Veterinary Internal Medicine: Diseases of the Dog and Cat. Seventh Edition. Saunders Elsevier, St Louis. 2010;1782-1796.
2. Cryer PE, Davis SN, Shamoon H. Hypoglycemia in diabetes. Diabetes Care 2003;26:1902-1912. 
3. Cryer PE. Hypoglycemia risk reduction in type 1 diabetes. Exp Clin Endocrinol Diabetes 2001;109 Suppl 2:S412-423. 
4. Boyle PJ, Zrebiec J. Management of diabetes-related hypoglycemia. South Med J 2007;100:183-194. 
5. Insulin administration. Diabetes Care 2001;24:1984-1987. 
6. Goeders LA, Esposito LA, Peterson ME. Absorption kinetics of regular and isophane (NPH) insulin in the normal dog. Domest Anim Endocrinol 1987;4:43-50. 
7. Wallace MS, Peterson ME, Nichols CE. Absorption kinetics of regular, isophane, and protamine zinc insulin in normal cats. Domest Anim Endocrinol 1990;7:509-515. 
8. Clark M, Thomaseth K, Heit M, et al. Pharmacokinetics and pharmacodynamics of protamine zinc recombinant human insulin in healthy dogs. J Vet Pharmacol Ther 2012;35:342-350. 
9. Maggiore AD, Nelson RW, Dennis J, et al. Efficacy of protamine zinc recombinant human insulin for controlling hyperglycemia in dogs with diabetes mellitus. J Vet Intern Med 2012;26:109-115. 
10. Fracassi F, Boretti FS, Sieber-Ruckstuhl NS, et al. Use of insulin glargine in dogs with diabetes mellitus. Vet Rec 2012;170:52. 
11. Sako T, Mori A, Lee P, et al. Time-action profiles of insulin detemir in normal and diabetic dogs. Res Vet Sci 2011;90:396-403.
12. Cobry E, McFann K, Messer L, et al. Timing of meal insulin boluses to achieve optimal postprandial glycemic control in patients with type 1 diabetes. Diabetes Technol Ther 2010;12:173-177. 
13. Zisser H, Gong P, Kelley CM, et al. Exercise and diabetes. Int J Clin Pract Suppl 2011:71-75. 
14. Duckworth WC, Hamel FG, Peavy DE. Hepatic metabolism of insulin. Am J Med 1988;85:71-76. 
15. Rabkin R, Ryan MP, Duckworth WC. The renal metabolism of insulin. Diabetologia 1984;27:351-357. 
16. Gilor C, Graves TK. Synthetic insulin analogs and their use in dogs and cats. Vet Clin North America Small Anim Prac 2010;40:297-307. 

Obesity Epidemic Expanding in Dogs and Cats

The rates of overweight and obesity in dogs and cats in the U.S. continued to increase in 2012, with the number of overweight cats reaching an all-time high.

Results of the sixth annual National Pet Obesity Awareness Day Survey, conducted by the Association for Pet Obesity Prevention (APOP), revealed that 52.5% of dogs and 58.3% of cats were overweight or obese (Figure 1). That equals approximately 80 million U.S. dogs and cats at increased risk for weight-related disorders such as diabetes, osteoarthritis, hypertension, and many cancers.

Figure 1. Incidence of overweight and obesity in cats and dogs (from APOP website).

As Dr. Ernie Ward, APOP’s founder and lead veterinarian for the survey states. “Pet obesity remains the leading health threat to our nation’s pets. We continue to see an escalation in the number of overweight cats and an explosion in the number of type 2 diabetes cases.”

And veterinary endocrinologist and APOP board member Dr. Mark Peterson agrees: “The soaring rate of feline and canine obesity is taking a terrible toll on our animals’ health. There is a vast population of overweight cats and dogs facing an epidemic of diabetes. The best preventive measure a pet owner can make is to keep their dog or cat at a healthy weight. Diabetes is far easier to prevent than treat, especially when twice daily insulin injections are needed.”

For more information about the 2012 National Pet Obesity survey results or the Association for Pet Obesity Prevention in general, please visit their website at www.petobesityprevention.com.

Using a Glucagon Emergency Kit for Insulin-Induced Hypoglycemia

Metabolic and Hormonal Responses to Subcutaneous Glucagon in Healthy Beagles

Florian K. Zeugswetter, Elisa Schornsteiner, Georg Haimel, and Ilse Schwendenwein

Journal of Veterinary Emergency and Critical Care 2012;22:558-563. 

Hypoglycemia is a serious and frequent complication of insulin treatment, with over a third of human diabetic patients experiencing hypoglycemia-induced coma sometime during their diabetic lifetime (1).

In veterinary practice,  hypoglycemia is a well recognized complication of insulin treatment, but the true incidence of hypoglycemic events in diabetic dogs or cats is not known (2). One reason for this is related to the fact that, at least until recently, home blood glucose monitoring has played only a small role (if any) in the management of most diabetic animals (3). Therefore, as long as the diabetic dog or cat was not displaying clear overt signs of weakness or seizures, hypoglycemia would not be detected.

However, it is likely that hypoglycemia is a very frequent complication associated with insulin treatment in both dogs and cats. Recent studies revealed that 35% of cat owners and 40% of dog owners report at least occasional hypoglycemic episodes (4,5), a rate that is quite frightening when we consider the potential consequences. Even when frequent home blood glucose monitoring is being used to help improve diabetic regulation, use of continuous interstitial glucose monitoring have revealed a high incidence of asymptomatic hypoglycemia in these patients (6,7).

Glucagon is secreted from the alpha cells of the islets of Langerhans. It acts to raise circulating glucose concentrations by increasing the rates of both glycogenolysis and gluconeogenesis in the liver (8,9). Due to its rapid hyperglycemic effects, parenteral glucagon has successfully been used to treat impending or current hypoglycemia in human diabetics (10,11). It is effective and practical in home treatment, especially when vomiting or nausea prevents the patient from eating. Emergency glucagon kits for intramuscular or subcutaneous use are commercially available (12,13).

In veterinary medicine, glucagon is not routinely provided to owners of insulin-treated pets, despite the serious concerns surrounding hypoglycemia in both dogs and cats. Traditionally, treatment of insulin-induced hypoglycemia has been limited to providing a source of carbohydrates in the form of food, or applying a dextrose solution to the buccal mucosal (2).

The aim of this study by Zeugswetter et al (14) was to investigate the effects of a subcutaneous glucagon bolus injection on glucose, insulin, ACTH and cortisol secretion in healthy dogs. The main aims of this study was to determine if subcutaneous glucagon administration would reliably increase blood glucose concentrations, which is of practical importance since diabetic pet owners are used to giving subcutaneous injections.

Objective of Study – To compare the effects of subcutaneous (SC) and intravenous (IV) glucagon on glucose concentrations, and insulin and cortisol secretion.

Design – Prospective randomized 3-way crossover study.


Animals – Five healthy beagles.


Interventions – Diabetes mellitus and adrenal insufficiency were excluded by repeated glucose and fructosamine measurements, urinalysis, abdominal ultrasonography, and ACTH stimulation tests. Blood samples were collected before and after the SC and IV injection of 1 mg commercially available synthetic glucagon and analyzed for insulin-like immunoreactivity, glucose, ACTH and cortisol concentrations. The results were compared with those obtained after the SC injection of 1 mL saline (placebo). Measurements were performed over a period of up to 3 hours.

Measurements and Results – SC glucagon significantly increased glucose and insulin (P < 0.001 and 0.043, respectively). Peak glucose concentrations were observed after 20 minutes and were lower than after IV injection (mean ± SD: 6117.1 ± 19.8 mg/dL versus 167.6 ± 14.4 mg/dL; P = 0.001). The route of application had no significant effect on insulin (peak concentration: median: 12 μU/mL versus 28 μU/mL; P = 0.151). SC glucagon did not increase cortisol or ACTH concentrations at any time point of observation (P > 0.05). Aside from somnolence, no adverse events were recorded.

Conclusions – SC glucagon has the potential to be used as a simple and safe test in diabetic animals, but is of little use in animals with suspected corticotrophic insufficiency. The hyperglycemic effects are significant, implying that the commercially available human emergency kit could be useful in the home treatment of canine hypoglycemic emergencies.

My Bottom Line:

In this study (14), the investigators were able to document a significant and rapid rise in blood glucose concentrations following a single subcutaneous bolus of glucagon, with peak glucose concentrations occurring after only 20 minutes of injection. These findings are comparable to reports in human patients, which show rapid absorption of glucagon following subcutaneous administration ().

Based on this report, it appears that the commercially available human emergency kit could be useful in the home treatment of canine or feline hypoglycemic emergencies. However, it would still be useful to evaluate the use of glucagon in dogs and cats suffering from diabetes mellitus, especially in those experiencing frequently bouts of hypoglycemia.

Overall, as discussed very nicely in the accompanying editorial by Dr. Stijn Niessen (15), this study demonstrates that glucagon may be the “life saving trick” that we have been missing when dealing with a hypoglycemic dog (or cat). Providing these glucagon emergency kits to owners of our diabetic patients would likely help treat serious bouts of hypoglycemia. In addition, having such an "antidote" available to the diabetic pet owner may lessen the anxiety and worry about the risk of hypoglycemia in these animals on insulin treatment.

References:

1. Pramming S, Thorsteinsson B, Bendtson I, et al. Symptomatic hypoglycaemia in 411 type 1 diabetic patients. Diabet Med 1991;8:217-222. 
2. O'Brien MA. Diabetic emergencies in small animals. Vet Clin North Am Small Anim Pract 2010;40:317-333. 
3. Cook AK. Monitoring methods for dogs and cats with diabetes mellitus. J Diabetes Sci Technol 2012;6:491-495.
4. Niessen SJ, Powney S, Guitian J, et al. Evaluation of a quality-of-life tool for cats with diabetes mellitus. J Vet Intern Med 2010;24:1098-1105. 
5. Niessen SJ, Powney S, Guitian J, et al. Evaluation of a quality-of-life tool for dogs with diabetes mellitus. J Vet Intern Med 2012;26:953-961. 
6. Davison LJ, Slater LA, Herrtage ME, et al. Evaluation of a continuous glucose monitoring system in diabetic dogs. J Small Anim Pract 2003;44:435-442. 
7. Affenzeller N, Thalhammer JG, Willmann M. Home-based subcutaneous continuous glucose monitoring in 10 diabetic dogs. Vet Rec 2011;169:206. 
8. Connolly CC, Ivy RE, Adkins-Marshall BA, et al. Counterregulation by epinephrine and glucagon during insulin-induced hypoglycemia in the conscious dog. Diabetes Res Clin Pract 1996;31:45-56. 
9. Dobbins RL, Connolly CC, Neal DW, et al. Role of glucagon in countering hypoglycemia induced by insulin infusion in dogs. Am J Physiol 1991;261:E773-781. 
10. Hartley M, Thomsett MJ, Cotterill AM. Mini-dose glucagon rescue for mild hypoglycaemia in children with type 1 diabetes: the Brisbane experience. J Paediatr Child Health 2006;42:108-111. 
11. Haymond MW, Schreiner B. Mini-dose glucagon rescue for hypoglycemia in children with type 1 diabetes. Diabetes Care 2001;24:643-645. 
12. Glucagon for Injection (rDNA origin). Product information. Eli Lilly and Company. 
13. Treating severe lows with glucagon. www.myhumalogchild.com. Eli Lilly and Company. 
14. Zeugswetter FK, Schornsteiner E, Haimel G, et al. Metabolic and hormonal responses to subcutaneous glucagon in healthy beagles. J Vet Emerg Crit Care (San Antonio) 2012;22:558-563. 
15. Niessen SJ. Glucagon: are we missing a (life-saving) trick? J Vet Emerg Crit Care (San Antonio) 2012;22:523-525. 

Top Endocrine Publications of 2012: Canine Diabetes Mellitus

In my second compilation of the canine and feline endocrine publications of 2012, I’m moving on to the theme of canine diabetes mellitus.

Listed below are 31 research papers written in 2012 that deal with a variety of topics and issues related to the diagnosis, monitoring, and treatment of diabetes mellitus in dogs. I've already reviewed a few of these papers and, if so, I've included a link to that paper's review.

These range from the studies of the alternative sampling sites for home glucose testing (1) to a review of monitoring methods for dogs with diabetes (5); from studies of the use of long-acting insulin preparations (i.e., PZI, glargine, or detemir) in dogs (4,8,15,17) to evaluation of a quality-of-life tool for diabetic dogs (21); and from the investigation of insulin resistance in dogs associated with estrus, glucocorticoid excess, or  infection (6,9,10,11,14,16,22,23) to evaluation of "low" carbohydrate diets in the management of dogs with diabetes (7).

Other studies include an evaluation of the sodium-retaining effect of insulin in diabetic dogs (2) to the use of glucagon for management of insulin-induced hypoglycemia (19,31); and finally, from studies of a short-acting insulin analogue for treatment of ketoacidosis in dogs (24) to the investigations on the use of gene therapy as a potential cure for canine diabetes (20).

2012 Papers on Diabetes Mellitus in the Dog:

1. Borin-Crivellenti S, Crivellenti LZ, Tinucci-Costa M. The carpal pad as an alternative sampling site for blood glucose testing in dogs. J Small Anim Pract 2012;53:684-686. 
2. Brands MW, Manhiani MM. Sodium-retaining effect of insulin in diabetes. Am J Physiol Regul, Integr Comp Physiol 2012;303:R1101-1109. 
3. Clark L, Leece EA, Brearley JC. Diabetes mellitus affects the duration of action of vecuronium in dogs. Vet Anaesth Analg 2012;39:472-479.
4. Clark M, Thomaseth K, Heit M, et al. Pharmacokinetics and pharmacodynamics of protamine zinc recombinant human insulin in healthy dogs. J Vet Pharmacol Ther 2012;35:342-350. 
5. Cook AK. Monitoring methods for dogs and cats with diabetes mellitus. J Diabetes Sci Technol 2012;6:491-495. 
6. Declue AE, Nickell J, Chang CH, et al. Upregulation of proinflammatory cytokine production in response to bacterial pathogen-associated molecular patterns in dogs with diabetes mellitus undergoing insulin therapy. J Diabetes Sci Technol 2012;6:496-502. 
7. Elliott KF, Rand JS, Fleeman LM, et al. A diet lower in digestible carbohydrate results in lower postprandial glucose concentrations compared with a traditional canine diabetes diet and an adult maintenance diet in healthy dogs. Res Vet Sci 2012;93:288-295. 
8. Fracassi F, Boretti FS, Sieber-Ruckstuhl NS, et al. Use of insulin glargine in dogs with diabetes mellitus. Vet Rec 2012;170:52. Click here to see my review of this paper. 
9. Fukuta H, Mori A, Urumuhan N, et al. Characterization and comparison of insulin resistance induced by Cushing Syndrome or diestrus against healthy control dogs as determined by euglycemic- hyperinsulinemic glucose clamp profile glucose infusion rate using an artificial pancreas apparatus. J Vet Med Sci 2012;74:1527-1530. 
10. Gomes Poppl A, Costa Valle S, Hilario Diaz Gonzalez F, et al. Estrus cycle effect on muscle tyrosine kinase activity in bitches. Vet Res Commun 2012;36:81-84. 
11. Hofer-Inteeworn N, Panciera DL, Monroe WE, et al. Effect of hypothyroidism on insulin sensitivity and glucose tolerance in dogs. Am J Vet Res 2012;73:529-538.  Click here to see my review of this paper.
12. Hugler S. Diabetic alert dogs: A good nose for hypoglycemia. Dtsch Med Wochenschr 2012;137:p25. 
13. Jeong YW, Lee GS, Kim JJ, et al. Establishment of a canine model of human type 2 diabetes mellitus by overexpressing phosphoenolypyruvate carboxykinase. Int J Mol Med 2012;30:321-329. 
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15. Maggiore AD, Nelson RW, Dennis J, et al. Efficacy of protamine zinc recombinant human insulin for controlling hyperglycemia in dogs with diabetes mellitus. J Vet Intern Med 2012;26:109-115. Click here to see my review of this paper.  
16. Mared M, Catchpole B, Kampe O, et al. Evaluation of circulating concentrations of glucose homeostasis biomarkers, progesterone, and growth hormone in healthy Elkhounds during anestrus and diestrus. Am J Vet Res 2012;73:242-247. 
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20. Niessen SJ, Fernandez-Fuente M, Mahmoud A, et al. Novel diabetes mellitus treatment: mature canine insulin production by canine striated muscle through gene therapy. Domest Anim Endocrinol 2012;43:16-25. 
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24. Sears KW, Drobatz KJ, Hess RS. Use of lispro insulin for treatment of diabetic ketoacidosis in dogs. J Vet Emerg Crit Care (San Antonio) 2012;22:211-218. Click here to see my review of this paper. 
25. Tvarijonaviciute A, Ceron JJ, Caldin M. Serum butyrylcholinesterase activity in dogs with diabetes mellitus. Vet J 2012;192:494-497.
26. Tvarijonaviciute A, Ceron JJ, Holden SL, et al. Obesity-related metabolic dysfunction in dogs: a comparison with human metabolic syndrome. BMC Vet Res 2012;8:147. 
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