January 19, 2018

Hyperadrenocorticism and Diabetes in Dogs

What is at play—and what is the outcome—when dogs with Cushing disease develop concurrent diabetes mellitus?
By JoAnna Pendergrass, DVM
A team of Argentinian researchers studying concurrent canine hyperadrenocorticism (HAC; Cushing disease) and diabetes mellitus identified several risk factors pre-disposing dogs with HAC to diabetes. The researchers believe this is the first study to identify such risk factors, thus adding new insight into HAC’s well-known predisposition to diabetes.1

HAC and diabetes primarily affect middle-aged to senior dogs (Table). The diseases can appear independently or concurrently and share clinical signs (eg, polyuria/polydipsia) that can complicate diagnosis and treatment. Notably, HAC and diabetes concurrence has been studied extensively in human and veterinary medicine. In dogs, the percentage of HAC and diabetes concurrence ranges widely, likely due to diagnostic challenges.

RELATED:
Glucocorticoids, namely cortisol, antagonize insulin function. Such antagonism may cause pancreatic beta cells to secrete more insulin, eventually causing beta cell exhaustion and potential diabetes development. Interestingly, 1 previous study named glucocorticoids “diabetogenic.”2

Unlike in human medicine, there is no consensus on prediabetes parameters for dogs. A comparative analysis of obesity-related metabolic dysfunction in dogs and human metabolic syndrome determined a cut-off fasting blood glucose level of 5.6 mmol/L (100 mg/dL) for dogs.3



Diagnosis and Testing
From January 2011 to December 2015, researchers evaluated 235 dogs with HAC. Pituitary-dependent HAC (PDH) was diagnosed using clinical signs and elevated urine cortisol:creatinine ratio (UCCR) on a combined UCCR and low-dose dexamethasone sup-pression test.4 Adrenal-dependent HAC (ADH) was diagnosed using clinical signs, increased UCCR, and lack of suppression on a high-dose dexamethasone suppression test. If a dog had previously diagnosed diabetes, testing to confirm HAC was delayed until the diabetes was controlled adequately. Following diagnosis, HAC was treated with adrenalectomy (ADH) or medical therapy (PDH).

Diabetes was diagnosed using clinical signs and diagnostic test results (glucosuria, elevated fasting blood glucose levels). Treatment was twice-daily insulin and a commercial diabetic diet. Dogs with HAC were divided into 3 groups according to fasting blood glucose levels:
  • Group A (n=146): <100 mg/dL
  • Group B (n=70): 100–180 mg/dL
  • Group C (n=19): >180 mg/dL

The researchers assessed body condition score and measured blood levels of UCCR, glucose, tri-glycerides, and total cholesterol.

Results
Group Demographics
Groups were homogeneous in age, breed, and gender distribution. For example, each group had a median age of 9 to 10 years and was approximately two-thirds female. More dogs were overweight or obese in groups B and C (78%) than in group A (62%). However, excessive weight was not significantly associated with diabetes development.

Diabetes Findings
Thirty-two dogs with HAC—14% of the study population—also had diabetes, which was diagnosed before, after, or at the time of HAC diagnosis. The researchers noted that determining whether diabetes or HAC comes first can be challenging. For example, diabetes may be diagnosed first because it is easier to detect, but it may not have been the first condition present.

Nearly 95% of the dogs with diabetes had PDH, suggesting a greater predisposition to diabetes in dogs with PDH than ADH, potentially because PDH not treated with hypophysectomy prolongs hypercortisolism.

Measurements and Risk Factors
About 10% of dogs with HAC had fasting blood glucose levels greater than 120 mg/dL, the upper limit of normal, but did not have clinical diabetes. Total cholesterol and triglycerides were highest in group C, supporting previous findings that HAC disrupts lipid metabolism. Also, UCCR was higher in groups B and C than in group A.

Key risk factors for diabetes in dogs with HAC were as follows:
  • PDH
  • Intact female
  • UCCR >100 × 10-6
  • Triglycerides >45 mg/dL
  • Total cholesterol >164 mg/dL
  • Fasting blood glucose >100 mg/dL

The study’s intact females were in persistent anestrus due to chronic hypercortisolism, making it difficult to determine whether circulating sex hormones contributed to increased diabetes risk.

Compared with HAC, concurrent HAC and diabetes drastically reduced life expectancy (28 vs 14 months). In fact, 2 study dogs had diabetic ketoacidosis and died within days of hospitalization.

For the Future
Looking forward, the researchers proposed rapid detection and control of the risk factors identified in the study, allowing for “implementation of preventive therapy to reduce the incidence of diabetes in dogs with HAC.”

 
Dr. Pendergrass received her Doctor of Veterinary Medicine degree from the Virginia-Maryland College of Veterinary Medicine. Following veterinary school, she completed a postdoctoral fellowship at Emory University’s Yerkes National Primate Research Center. Dr. Pendergrass is the founder and owner of JPen Communications, a medical communications company.
References: 
  1. Miceli DD, Pignataro OP, Castillo VA. Concurrent hyperadrenocorticism and diabetes mellitus in dogs. Res Vet Sci. 2017;115:425-431. doi: 10.1016/j.rvsc.2017.07.026
  2. Van Raalte DH, Ouwens DM, Diamont M. Novel insights into glucocorticoid-mediated diabetogenic effects: towards expansion of therapeutic options? Eur J Clin Investig. 2009;39(2):81-93. Republished in Top Companion Anim Med. 2012 Feb;27(1):21-4.
  3. 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. doi: 10.1186/1746-6148-8-147.
  4. Kooistra HS, Galac S. Recent advances in the diagnosis of Cushing Syndrome in dogs. Vet Clin North Am Small Anim Pract. 2010;40(2):259-267. doi: 10.1016/j.cvsm.2009.10.002.
  5. Greco DS. Cushing disease (hyperadrenocorticism). Merck Veterinary Manual website. http://www.merckvetmanual.com/endocrine-system/the-pituitary-gland/cushing-disease-hyperadrenocorticism. Accessed January 6, 2018.
  6. Gallagher A. Hyperadrenocorticism in dogs. Clin Brief. 2014;59-63. http://www.cliniciansbrief.com/sites/default/files/attachments/COC_Hyperadrenocorticism%20in%20Dogs.pdf. Accessed January 7, 2018.
  7. Cohan M. Overview of hyperadrenocorticism. Vet Tech. 2007;28(6). http://www.vetfolio.com/internal-medicine/overview-of-hyperadrenocorticism. Accessed January 7, 2018.


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