Introducing My New Textbook: Feline Endocrinology - The First Book Fully Dedicated to Endocrine Disorders of the Cat

Over the last year, I have been hard at work editing and writing chapters for this book, the first one written exclusively about Feline Endocrinology.

Our primary goal for this book is to provide veterinarians, veterinary students, and others interested in cats with a concise and complete information resource on the pathophysiology, clinical signs, differential diagnosis, diagnosis, and treatment of endocrine disorders in cats.

If you are a veterinarian that sees cats with endocrine disorders, I highly recommend that you get this book. I have included everything I know about cats in this book!

Take a look at the video below, where we (the 3 editors) talk about the development of this valuable reference.

Click here to watch

The book is divided into 6 sections, including:

• Hypothalamus and pituitary
• Thyroid gland
• Calcium and parathyroid glands
• Adrenal glands
• Endocrine pancreas
• Blood pressure, body condition and nutrition

Moving forward, I will be blogging a series of posts about the 6 sections of this book, including the topics, authors, and even a few videos (included in the chapter) where applicable. 

Purchase the FELINE ENDOCRINOLOGY book here.

From the publisher:

Developed by 50 of the most renowned feline experts from 13 countries around the world, this unique and practical book of feline endocrinology is a most valuable tool for small animal veterinarians who want to deepen their understanding on the pathophysiology, clinical signs, diagnosis, treatment, and prognosis of every endocrine condition recognized in cats. Rather than have the authors treating cats as small dogs, a cat-only text will allow fully focused description of conditions in this one species. 

Allowing these experts in feline endocrinology space to fully teach us what they have learned about cats will result in a superior resource composed of text, figures, boxes, tables, algorithms, and videos (presented on an electronic version of the text).

Editors: Edward C. Feldman, Federico Fracassi, Mark E. Peterson

Hypothyroidism Associated with Acromegaly and Insulin-resistant Diabetes Mellitus in a Samoyed

PAPER REVIEW

Hypothyroidism Associated with Acromegaly and Insulin-resistant Diabetes Mellitus in a Samoyed

by T. Johnstone, E. Terzo, and C. Mooney

Australian Veterinary Journal 2014; 92:437-442.

Background

Although both hypothyroidism and diabetes mellitus are common disorders of dogs, it is relatively uncommon for a dog to develop both diseases concurrently. Insulin-resistant diabetes has been reported in a few dogs with underlying hypothyroidism (1-3), but the mechanisms underlying the insulin resistance is not clear. However, hypothyroidism may lead to alteration of other hormones that influence glucose metabolism, and previous studies of hypothyroid dogs have documented excessive production of growth hormone (GH), a known insulin antagonist (4,5). In one study, Beagles with radioiodine-induced hypothyroidism were reported to have a progressive elevation in serum GH concentrations (a known insulin antagonist), but none of those dogs developed overt diabetes (6).

The purpose of this case report by Johnstone et al. (7) is to describe a dog diagnosed with naturally occurring hypothyroidism that also had concurrent signs of acromegaly and diabetes. In this dog, the insulin resistance and associated diabetic state was reversed with appropriate L-thyroxine supplementation.

Case Report
A 4-year-old male entire Samoyed presented with an 8-month history of pedal hyperkeratosis and shifting lameness, which had been unresponsive to zinc supplementation, antibiotics, and glucocorticoid therapy. The dog also exhibited exercise intolerance of 12-months duration. Recently, polydipsia and polyuria were also noted.

Marked interdental spacing

On physical examination, obesity, poor coat condition, widened spaces between the teeth, and mild respiratory stridor were noted (see Figure).

Initial laboratory test results confirmed marked hyperglycemia, consistent with diabetes mellitus. Serum concentrations of total thyroxine (T4), free T4 by equilibrium dialysis, and free triiodothyronine (T3) were below the reference limits, and canine thyroid-stimulating hormone (cTSH) levels was above the reference limits, diagnostic for primary hypothyroidism.

Before treatment for diabetes and hypothyroidism was initiated, further tests were performed to investigate a potential link between these two conditions. An upper airway examination revealed mild soft tissue hypertrophy but normal laryngeal function. The pretreatment serum insulin concentration was above the reference limits, suggesting endogenous insulin resistance. A baseline serum IGF-1 concentration was within reference limits. However, basal serum GH concentrations were markedly elevated, and a further paradoxical increase in GH concentration was noted after administration of thyrotropin-releasing hormone (TRH). CT imaging of the pituitary suggested slight enlargement of the gland but no pituitary tumor was evident.

Overall, the high serum GH concentrations, together with the clinical features (e.g., widened interdental spaces, and mild respiratory stridor), was considered diagnostic for acromegaly.

Treatment was initiated using both insulin (Caninsulin, 20 IU every 12 h) and thyroid supplementation (levothyroxine, L-T4, 0.02 mg/kg every 24 h). Over the next few weeks, the exogenous insulin requirements started to decrease, and all exogenous insulin was discontinued 155 days later. The dog remained euglycemic 2 years after diagnosis, with continued daily supplementation of L-T4 alone.

My Bottom Line:

In this dog, diabetes mellitus was thought to be a secondary consequence of insulin resistance, as demonstrated by the high pretreatment serum insulin concentration. Insulin-resistant diabetes mellitus has been previously described in a few dogs with naturally occurring hypothyroidism (1-3), but the pathogenesis for the concurrent development of the two diseases is not totally understood.

It has been reported, however, that primary hypothyroidism can lead to with functional and morphological changes of the pituitary gland (4-6). Most notably, transdifferentiation of pituitary TSH-producing cells to cells producing both TSH and GH has been documented (6), which can result in increased GH production and secretion in these dogs. The high basal GH concentration and the paradoxical increase of GH after stimulation with TRH in this dog (7) confirmed that hypothyroidism-induced acromegaly and secondary diabetes was likely.

Although the true prevalence of hypothyroidism-induced acromegaly in dogs is not known, our clinical experience suggests that hypothyroidism is rarely associated with acromegaly. However, it is likely that acromegaly goes under-diagnosed in some hypothyroid dogs since many of the clinical signs of both disorders are similar. Furthermore, pituitary transdifferentiation of TSH to GH hypersecretion would be expected to take a long time to develop, and therefore, hypothyroidism-induced acromegaly may only become significant when hypothyroidism remains undiagnosed or untreated for several months to years (6).

In this dog, the fact that the diabetic state resolved during treatment with L-T4 suggests that the pituitary GH overproduction resolved as euthyroidism was achieved. Unfortunately, repeat TRH stimulation testing or serum GH measurements were not repeated after resolution of the diabetic state, so we can not say for certain that the acromegalic state truly resolved. Further studies certainly are needed to investigate hypothyroidism-induced GH production, but this interesting case certainly does add some insight to what may be going on in these dogs.

References:

1. Blois SL, Dickie E, Kruth SA, et al. Multiple endocrine diseases in dogs: 35 cases (1996-2009). J Am Vet Med Assoc 2011;238:1616-1621. 
2. Ford SL, Nelson RW, Feldman EC, et al. Insulin resistance in three dogs with hypothyroidism and diabetes mellitus. J Am Vet Med Assoc 1993;202:1478-1480. 
3. Hess RS, Saunders HM, Van Winkle TJ, et al. Concurrent disorders in dogs with diabetes mellitus: 221 cases (1993-1998). J Am Vet Med Assoc 2000;217:1166-1173. 
4. Lee WM, Diaz-Espineira M, Mol JA, et al. Primary hypothyroidism in dogs is associated with elevated GH release. J Endocrinol 2001;168:59-66. 
5. Diaz-Espineira MM, Galac S, Mol JA, et al. Thyrotropin-releasing hormone-induced growth hormone secretion in dogs with primary hypothyroidism. Domest Anim Endocrinol 2008;34:176-181. 
6. Diaz-Espineira MM, Mol JA, van den Ingh TS, et al. Functional and morphological changes in the adenohypophysis of dogs with induced primary hypothyroidism: loss of TSH hypersecretion, hypersomatotropism, hypoprolactinemia, and pituitary enlargement with transdifferentiation. Domest Anim Endocrinol 2008;35:98-111. 
7. Johnstone T, Terzo E, Mooney CT. Hypothyroidism associated with acromegaly and insulin-resistant diabetes mellitus in a Samoyed. Aust Vet J 2014;92:437-442. 

Blood Glucose Curves and the Fractious Diabetic Cat

My problem patient is a 12-year old, DSH, female spayed cat with a 2-year history of insulin-dependent diabetes mellitus. She has been treated with glargine insulin at a variable dose, but typically between 1-3 units, BID. This cat will not eat canned food so we are feeding higher protein, lower carb dry foods (Hill's MD and Purina DM).

Six months ago, the cat was diagnosed with immune-mediated hemolytic anemia (IMHA) and was treated successfully with prednisolone and cyclosporine (Atopica). This led to development of insulin resistance and loss of diabetic control, but the cat did relatively well after raising the insulin dose to 6 units while on prednisolone. After a long and slow taper, the cat is now off all glucocorticoids for the last month, and the insulin dose is back down to 2 U, twice daily. The cat remains on Atopica, probably for life.

We have periodically done in-house blood glucose curves to adjust her insulin dose, but she becomes extremely fractious when hospitalized, and we can't really handle her (she bites, scratches, cries, and screams louder than any other cat I've ever had!). The owner does not care to check blood glucose at home, and given the cat's nature, I doubt if they could even do it. Since weaning her off the prednisolone, we have seen a couple of hypoglycemic readings on spot blood glucose checks so we are now worried that the current insulin dose may be too high.

Therefore a week ago, we performed a serial glucose curve on 2 units glargine, BID. The results were as follows:

• 6 am = Insulin given
• 8 am = 317 mg/dl
• 10 am = 376 mg/dl
• 12 noon = 352 mg/dl
• 2 pm = 299 mg/dl
• 4 pm = 229 mg/dl

We were a bit surprised by the high glucose concentrations during the day on this curve, but we increased glargine from 2 to 3 units BID based on the severe and persistent hyperglycemia. However, when I checked a spot afternoon blood glucose value yesterday, it was low-normal at 69 mg/dl. I rechecked another blood glucose reading 30 minutes later, and it was even lower at 57 mg/dl. Right or wrong, I put her back down to 2 units glargine BID and pm spot check in 1 week.

My main question is this: could this cat's in-hospital curve be leading us astray because she is so fractious? I am aware that spot checks aren't ideal. However, this cat is relatively easy to handle during a quick exam and single spot check, but she become so angry when hospitalized throughout the day.

What would you do? How do I adjust the insulin dosage in this cat? We've been trying to get the cat into remission but it's not looking good!

My Response:

Well, first the bad news: I can almost guarantee that this cat's diabetes will not go into remission, given the fact that she has been diabetic for 2 years. A number of studies have reported that diabetic remission, when it does occur, will generally happen within the first 6 months of diagnosis (1,2). In addition, the fact that she has concurrent disease and has been treated with glucocorticoids certainly hasn't increased her chances for remission.

The good news is that once we decide that diabetic remission is no longer our goal, then we can be more lax with our glucose regulation. Our goal for diabetic cats should then be 3-fold:

1. Control clinical signs of diabetes (e.g., weight loss, polyuria, polydispsia)
2. Prevent diabetic ketoacidosis
3. Avoid hypoglycemia

To do this, it's not really necessary to do the tight glucose regulation and frequent blood glucose monitoring that we would ideally do if we are trying to increase the odds for diabetic remission (3-5).

In fractious diabetic cats, I would never recommend doing serial blood glucoses to determine the best insulin dose. The release of catecholamines during this excitable state can absolutely increase the glucose readings during the curve (commonly referred to as stress hyperglycemia) (6). Overall, this means that all of the serial blood glucose curves you have done in this cat are most likely next to meaningless and that such testing should be stopped.

Spot glucose checks can't hurt, but as you say, they can be hard to interpret and may be misleading. If the blood glucose reading is low, you might want to decrease the insulin dose, but if the blood glucose is in the ideal range or high, you could still be overdosing the insulin.

In cats like this, I'd recommend that you adjust the insulin dose based on the presence or absence of clinical signs, including body weight and water intake (7).  If the owners can measure water intake at home, that can be a very sensitive way to help determine if more insulin is needed. If there are no clinical signs of diabetes and the weight is stable, the cat is probably adequately controlled. Monitoring an occasional serum fructosamine level can also help (8,9), as well as home measurement of urine glucose, if the owner can do it (7,19,11). A weekly check for urinary ketones can also be used to monitor for pending ketoacidosis, and become extremely important if anorexia, vomiting, or any other signs of illness develop.

Bottom Line:
In fractious cats, I would not recommend in-hospital blood glucose curves for monitoring. Stress hyperglycemia will give you results that are meaningless, and one could easily be misled into giving higher doses of insulin than are actually needed. This is especially true in cats with long-term diabetes that are unlikely to ever develop remission.

In cats like this case, I use a combination of clinical signs and blood/urine values, looking at the overall trend in results rather than the specific or individual values. For example, I don't use serum fructosamine concentration as the sole means of judging control, but I still think it is helpful as one piece of the puzzle. If it is high, that suggests that the insulin dosage may have to be increased; if the fructosamine value is low to low-normal, this may indicate overdosage and hypoglycemia.

Believe me, both your hospital staff and the fractious diabetic cat will all be better off with this approach!

References:

1. Gottlieb S, Rand JS. Remission in cats: including predictors and risk factors. Vet Clinics North America 2013: 43: 245-249
2. Zini E, Hafner M, Osto M, et al. Predictors of clinical remission in cats with diabetes mellitus. J Vet Intern Med 2010;24:1314-1321.
3. Roomp K, Rand J. Intensive blood glucose control is safe and effective in diabetic cats using home monitoring and treatment with glargine. J Feline Med Surg 2009;11:668-682.
4. Roomp K, Rand J. Evaluation of detemir in diabetic cats managed with a protocol for intensive blood glucose control. J Feline Med Surg 2012;14:566-572.
5. Nack R, DeClue AE. In cats with newly diagnosed diabetes mellitus, use of a near-euglycemic management paradigm improves remission rate over a traditional paradigm. Vet Q 2014; 34:132-136.
6. Rand JS, Kinnaird E, Baglioni A, et al. Acute stress hyperglycemia in cats is associated with struggling and increased concentrations of lactate and norepinephrine. J Vet Intern Med 2002;16:123-132. 
7. Miller E. Long-term monitoring of the diabetic dog and cat. Clinical signs, serial blood glucose determinations, urine glucose, and glycated blood proteins. Vet Clin North Am Small Anim Pract 1995;25:571-584. 
8. Crenshaw KL, Peterson ME, Heeb LA, et al. Serum fructosamine concentration as an index of glycemia in cats with diabetes mellitus and stress hyperglycemia. J Vet Intern Med 1996;10:360-364. 
9. Thoresen SI, Bredal WP. Clinical usefulness of fructosamine measurements in diagnosing and monitoring feline diabetes mellitus. J Small Anim Pract 1996;37:64-68. 
10. Bennett N. Monitoring techniques for diabetes mellitus in the dog and the cat. Clin Tech Small Anim Pract 2002;17:65-69. 
11. Cook AK. Monitoring methods for dogs and cats with diabetes mellitus. J Diabetes Sci Technol 2012;6:491-495. 

Top Endocrine Publications of 2013: Feline Diabetes Mellitus

In my ninth compilation of the canine and feline endocrine publications of 2013, I’m moving on to disorders of the feline endocrine pancreas. I covered the canine diabetic publications in a blog post last spring. Click this link to review my list of 2013 research papers that pertain to diabetes in dogs.

Listed below are 29 papers published in 2013 that deal with a variety of diabetic topics of clinical importance for diabetic cats.

These topics range from a study of survival time and prognostic factors in cats with newly diagnosed diabetes (2) to studies involving pathogenesis or risk factors for development of diabetes (6,15,20,21,24); from the relationship between diabetes and kidney disease and pancreatits (1,3) to a review of what we know about diabetic remission (10); and, from reviews of insulin treatment of diabetic cats (4,16,26) to the use of oral hypoglycemia agent or incretin hormonal therapy in cats (22,25).

Other studies range from investigations of diet management of obese and diabetic cats (5,7,17,29) to studies of insulin antibodies in cats (28); from reviews of secondary diabetes, including acromegaly and hyperadrenocorticism (18,19) to ketoacidosis (16,23); and finally, from the use of routine home glucose monitoring (9) to continuous glucose monitoring in cats (11,27).

References:

1. Bloom CA, Rand JS. Diabetes and the kidney in human and veterinary medicine. Vet Clin North Am Small Anim Pract 2013;43:351-365. 
2. Callegari C, Mercuriali E, Hafner M, et al. Survival time and prognostic factors in cats with newly diagnosed diabetes mellitus: 114 cases (2000-2009). J Am Vet Med Assoc 2013;243:91-95. 
3. Caney SM. Pancreatitis and diabetes in cats. Vet Clin North Am Small Anim Pract 2013;43:303-317. 
4. Caney SM. Management of cats on Lente insulin: tips and traps. Vet Clin North Am Small Anim Pract 2013;43:267-282. 
5. Coradini M, Rand JS, Morton JM, et al. Fat mass, and not diet, has a large effect on postprandial leptin but not on adiponectin concentrations in cats. Domest Anim Endocrinol 2013;45:79-88. 
6. Dirtu AC, Niessen SJ, Jorens PG, et al. Organohalogenated contaminants in domestic cats' plasma in relation to spontaneous acromegaly and type 2 diabetes mellitus: A clue for endocrine disruption in humans? Environ Int 2013;57-58:60-67. 
7. Farrow HA, Rand JS, Morton JM, et al. Effect of dietary carbohydrate, fat, and protein on postprandial glycemia and energy intake in cats. J Vet Intern Med 2013;27:1121-1135. 
8. Fleischhacker SN, Bauersachs S, Wehner A, et al. Differential expression of circulating microRNAs in diabetic and healthy lean cats. Vet J 2013;197:688-693. 
9. Ford SL, Lynch H. Practical use of home blood glucose monitoring in feline diabetics. Vet Clin North Am Small Anim Pract 2013;43:283-301. 
10. Gottlieb S, Rand JS. Remission in cats: including predictors and risk factors. Vet Clin North Am Small Anim Pract 2013;43:245-249. 
11. Hafner M, Lutz TA, Reusch CE, et al. Evaluation of sensor sites for continuous glucose monitoring in cats with diabetes mellitus. J Feline Med Surg 2013;5:117-123. 
12. Hoenig M, Pach N, Thomaseth K, et al. Cats differ from other species in their cytokine and antioxidant enzyme response when developing obesity. Obesity (Silver Spring) 2013;21:E407-414. 
13. Hoenig M, Traas AM, Schaeffer DJ. Evaluation of routine hematology profile results and fructosamine, thyroxine, insulin, and proinsulin concentrations in lean, overweight, obese, and diabetic cats. J Am Vet Med Assoc 2013;243:1302-1309. 
14. Leal RO, Gil S, Brito MT, et al. The use of oral recombinant feline interferon omega in two cats with type II diabetes mellitus and concurrent feline chronic gingivostomatitis syndrome. Ir Vet J 2013;66:19. 
15. Link KR, Allio I, Rand JS, et al. The effect of experimentally induced chronic hyperglycaemia on serum and pancreatic insulin, pancreatic islet IGF-I and plasma and urinary ketones in the domestic cat (Felis felis). Gen Comp Endocrinol 2013;188:269-281. 
16. Marshall RD, Rand JS, Gunew MN, et al. Intramuscular glargine with or without concurrent subcutaneous administration for treatment of feline diabetic ketoacidosis. J Vet Emerg Crit Care (San Antonio) 2013;23:286-290.
17. Mimura K, Mori A, Lee P, et al. Impact of commercially available diabetic prescription diets on short-term postprandial serum glucose, insulin, triglyceride and free fatty acid concentrations of obese cats. J Vet Med Sci 2013;75:929-937. 
18. Niessen SJ. Update on feline acromegaly. In Practice 2013;35:2-6. 
19. Niessen SJ, Church DB, Forcada Y. Hypersomatotropism, acromegaly, and hyperadrenocorticism and feline diabetes mellitus. Vet Clin North Am Small Anim Pract 2013;43:319-350. 
20. O'Leary CA, Duffy DL, Gething MA, et al. Investigation of diabetes mellitus in Burmese cats as an inherited trait: a preliminary study. N Z Vet J 2013;61:354-358. 
21. Osto M, Zini E, Reusch CE, et al. Diabetes from humans to cats. Gen Comp Endocrinol 2013;182:48-53. 
22. Palm CA, Feldman EC. Oral hypoglycemics in cats with diabetes mellitus. Vet Clin North Am Small Anim Pract 2013;43:407-415. 
23. Rand JS. Diabetic ketoacidosis and hyperosmolar hyperglycemic state in cats. Vet Clin North Am Small Anim Pract 2013;43:367-379. 
24. Rand JS. Pathogenesis of feline diabetes. Vet Clin North Am Small Anim Pract 2013;43:221-231. 
25. Reusch CE, Padrutt I. New incretin hormonal therapies in humans relevant to diabetic cats. Vet Clin North Am Small Anim Pract 2013;43:417-433. 
26. Roomp K, Rand JS. Management of diabetic cats with long-acting insulin. Vet Clin North Am Small Anim Pract 2013;43:251-266. 
27. Surman S, Fleeman L. Continuous glucose monitoring in small animals. Vet Clin North Am Small Anim Pract 2013;43:381-406. 
28. Takashima S, Nishii N, Hachisu T, et al. Natural anti-insulin autoantibodies in cats: enzyme-linked immunosorbent assay for the determination of plasma anti-insulin IgG and its concentrations in domestic cats. Res Vet Sci 2013;95:886-890. 
29. Zoran DL, Rand JS. The role of diet in the prevention and management of feline diabetes. Vet Clin North Am Small Anim Pract 2013;43:233-243. 

Managing Diabetic Dogs with Exocrine Pancreatic Insufficiency

My problem patient is a 9-year old, female spayed Yorkie with concurrent exocrine pancreatic insufficiency (EPI) and diabetes mellitus. The stools, which had been very large and odoriferous, are smaller and not as smelly now that we have started the pancreatic enzyme replacement therapy.  However, the stools are still not completely normal. The dog remains very thin, but she has gained a pound over the past month.

The diabetic control has been more problematic. Six weeks ago, the dog was on 3 units of Novolin N every 12 hours and had serial blood glucose values running in the range of 400-600 mg/dl throughout the day.  After starting on the enzyme powder, the insulin dosage has fallen to only 0.5 unit twice daily. The current glucose curves start with a morning reading of 400 mg/dl, but the blood glucose then drops down during the day to values in the 100's or, at times, to as low as 45 mg/dl. The owner is trying to be as consistent as possible in feeding (the dog has a very good appetite) and giving the insulin. The dog has shown signs of clinical hypoglycemia, despite the low blood glucose values.  

What do you suggest? Is there a better insulin for this dog?  Would a special diet help?

My Response:

The vast majority of dogs with EPI have a concurrent B12 (cobalamin) deficiency; therefore, cobalamin should be part of this dog's treatment regimen (1). If this Yorkie weighs less than 7 kg, I would suggest administering 250 µg SC every 7 days for 8 weeks, then 250 µg every 14 days for 2 months, then 250 µg once monthly for a couple more months. The treatment may need to be repeated based on serum cobalamin levels.

In addition, some dogs with EPI have dysbiosis (the new term for bacterial overgrowth/gut microbial imbalance), so metronidazole or tylosin power given for a couple weeks plus a probiotic may be helpful. Lastly, if the stools don't get better with the above treatments then the dog may have inflammatory bowl disease (IBD) in addition to the EPI (2). This breed appears predisposed to developing IBD or lymphangietasia (2). As far as what to feed this dog, I'd recommend a diet low in fat because of the concurrent diabetes and GI issues (1).

As far as the insulin type, it looks like the duration of NPH activity is too short for this dog. Use of an insulin with a longer duration of action, such as Vetsulin or glargine, may be a better choice for this case. Based on the fact that the insulin dose is so small and the dog is so very sensitive to the insulin, I'd go with glargine, starting with 1 U,  twice daily. This insulin is much less potent than either NPH or Vetsulin in dogs, making hypoglycemia less unlikely (3).

References:

1. Wieberg, M. Exocrine pancreatic insufficiency in dogs. In: Bonagura JD, Twedt DC, eds. Kirk's Current Veterinary Therapy, Volume XV. Philadelphia: Saunders Elsevier, 2013;558-560.
2. Simmerson SM, Armstrong PJ, Wünschmann A, J., et al. Clinical features, intestinal histopathology, and outcome in protein-losing enteropathy in Yorkshire Terrier dogs. J Vet Intern Med. 2014;28:331-7. 
3. Fracassi F, Boretti FS, Sieber-Ruckstuhl NS, et al. Use of insulin glargine in dogs with diabetes mellitus. Vet Rec 2012;170:52. doi: 10.1136/vr.100070.

Top Clinical Endocrinology Research Abstracts, 2014 ACVIM Forum: Diabetes Part 3

Following last week’s post, this is the next installment of my review of the "top 12 list" of clinical endocrinology research abstracts presented at this year's American College of Veterinary Internal Medicine Forum.

As with last week's post, I've enlisted the help of Dr. Rhett Nichols, a well-known expert in endocrinology and internal medicine whose day-job is senior member of the veterinarian consulting service for Antech Diagnostics, the world's largest laboratory dedicated to animal health.  Rhett also serves as a consultant for the Animal Endocrine Clinic, so I talk to him almost every day about the more difficult cases I see in my practice.

In this post, we will review another of these "top 12" abstracts (finishing up with the diabetes abstracts). Next week, we will turn to the top clinical abstracts dealing with the adrenal gland, and then finish with disorders of the thyroid over the next 2 weeks. We hope you agree with our selections, but if you don't, remember that you can always post a comment and add your opinion.

Bertalan AV, Drobatz KJ. Hess RS. NPH and Lispro Insulin for Treatment of Dogs with Diabetes Mellitus. J Vet Intern Med 2014;28:1026.

Some dogs, treated with twice-daily NPH insulin and Hill's W/D diet, have postprandial hyperglycemia despite having clinically well-regulated diabetes mellitus (DM). The goal of this study was to determine whether postprandial hyperglycemia and fructosamine concentration can be decreased by adding lispro insulin to the treatment protocol.
      Six dogs were enrolled into this ongoing prospective study. Dogs were enrolled if they had clinically well-regulated DM while treated with NPH insulin and W/D q12 hours and if they had postprandial hyperglycemia defined as an increase in blood glucose concentration (BG) within two hours of NPH insulin administration and feeding. Fructosamine was quantified and BG was measured just before feeding and NPH insulin administration (T0), every 30 minutes for the first 2
hours (T30, T60, T90, T120), and every two hours thereafter for eight additional hours. Dogs were then treated at home with the same NPH insulin dose and W/D, but a separate lispro insulin injection of 0.1 Unit/kg SC was added to the NPH insulin and W/D protocol. Serial BG and fructosamine were measured two weeks later and compared to the original values using the Wilcoxon Signed Rank Test. Median [range] fructosamine (400 μmol/L [289–624 μmol/L]), and BG at T60 (313 mg/dl [187–376 mg/dl]) and T90 (239 mg/dl [166–332 mg/dl]) were significantly higher before lispro insulin was introduced compared to two weeks later (390 μmol/L [253–486 μmol/L]), p = 0.046, 117 mg/dl [42–307 mg/dl]), p = 0.028, and 94 mg/dl [48–197 mg/dl]), p = 0.028, respectively). 
      It is concluded that addition of lispro insulin to an NPH and W/D treatment protocol may significantly decrease fructosamine and postprandial hyperglycemia.

Comments— In this study, addition of a rapid-acting insulin analog (insulin lispro; Humalog, Lilly) to a standard twice-daily NPH insulin regimen appeared to improve glycemic control in dogs with clinically controlled diabetes. This finding is not unexpected, since it is well known that the administration of a short-acting insulin at time of meals will help lessen post-prandial hyperglycemia and lead to improved overall glycemic control in diabetic patients (1-4).

Rapid-acting insulin analogs— Although human recombinant regular insulin is still used as a short-acting insulin by most veterinarians, this insulin has been replaced for the most part with one of the more rapid-acting insulin analogs in human medicine (5-7). One of these newer rapid-acting insulin analogs is insulin lispro, which was the first commercially available insulin analog produced (6,7). Compared with regular human insulin, this insulin analog offers the advantages of faster subcutaneous absorption, an earlier and greater insulin peak, and a shorter duration of action. Although not used frequently in dogs, insulin lispro has been reported by this same group of investigators to be as effective as regular insulin in the treatment of ketoacidosis (8).

Long-acting insulin analogs and analog mixtures—Like human regular insulin, use of human NPH insulin is gradually being phased out and replaced with a mixture of rapid- and long-acting insulin analogs (5-7, 9-11). For example, newly diagnosed insulin-dependent human patients may be treated with a combination of once to twice daily injections of glargine (Lantus) or detemir (Levemir), together with a rapid-acting analog (e.g., insulin lispro or aspart) given at time of meals (11-14). Pre-mixed combinations of a short-acting synthetic insulin analog (i.e., lispro or aspart insulin) with a longer-acting insulin analog (i.e., lispro or aspart protamine insulin) are also commercially available as Humalog Mix 75/25 (Eli Lilly) or NovoLog Mix 70/30 (Novo Nordisk) (5,10). Both of these insulin analog mixtures are given twice daily with meals.

Time interval between insulin injection and meal intake— When a short-acting insulin (either human recombinant regular insulin or lispro) is added to the overall insulin regimen, it is standard protocol that the rapid-acting insulin be given shortly prior to ingestion of the meal (2-4,15,16). This allows enough time for the injected insulin to be absorbed into the circulation and blunt the post-prandial rise in blood glucose concentration. If the insulin injection is delayed until after the meal, severe post-prandial hyperglycemia may develop, which can lead to a clinical state resembling insulin resistance in some patients.

Most veterinarians fail to consider the importance of the time interval between insulin injection and meal intake when evaluating glycemic control in their diabetic dogs on standard insulin protocols. Whenever possible, I like to have my owners inject insulin (NPH, Vetsulin, or NPH/regular combinations) about 20-30 minutes before the dog eats, which allows enough time for insulin to to be partially absorbed and prevent severe post-prandial hyperglycemia (17).  With a more rapidly absorbed insulin, such as lispro, the timing between insulin injection and feeding can likely be shortened to less than 20 minutes. Of course, administering insulin injections prior to feeding is not always possible or even advisable, especially if the dog's appetite is poor or variable.

It is unclear what the time interval was between insulin injection and meal intake in this study by Bertalan et al., since it was not stated. If not given prior to feeding, however, the results might have been improved by using such a protocol.

The Bottom Line— In dogs with problem diabetes, addition of a short-acting insulin to the overall insulin regime may be helpful, especially in those dogs that experience severe post-prandial hyperglycemia.  The interval between insulin injection and meal intake must be taken into consideration when employing this protocol, and the addition of a short-acting insulin would likely be less effective when injected after eating. In any case, further research needs to be done on the effect on the timing of insulin injections and meals in dogs with diabetes mellitus.

Although insulin lispro works well in dogs, a major disadvantage of using any insulin analog, including lispro, is the high cost. All of the insulin analogs are approximately 3 to 5 times more costly than conventional human recombinant NPH, regular, or mixtures of NPH 70/30 insulins.

On a practical basis, there is little reason to use insulin lispro over human regular insulin in dogs, especially when you consider the great difference in cost. Premixed NPH/regular insulin is commercially available as Humulin 70/30 (Eli Lilly) or Novolin 70/30. Both of these commercial preparations contain a 100 U/ml pre-mixed combination of 30% short-acting (regular insulin) and 70% intermediate-acting insulin (NPH). In the USA, the cheapest place to purchase human regular, NPH, and 70/30 combinations is at Walmart, which sells these insulins as the ReliOn Novolin brand for around $25 per vial (19).

Another option, of course, is porcine lente insulin (Caninsulin or Vetsulin), which is actually a mixture of rapid-acting and long-acting insulins (Semi-lente and Ultralente, respectively) (20,21). Although more expensive than the ReliOn Novolin 70/30 insulin, Vetsulin is certainly much more cost effective than any of the insulin analogues. With either insulin preparation, I like to give the injection about 20-30 minutes prior to feeding to ensure that adequate insulin concentrations will be present in the circulation when the meal is absorbed to blunt the rise in blood glucose concentration and help better control the diabetic state (17).

References:

1. Brownlee M. Insulin treatment of diabetes. Hosp Pract 1979;14:85-94. 
2. Phillips M, Simpson RW, Holman RR, et al. A simple and rational twice daily insulin regime. Distinction between basal and meal insulin requirements. Q J Med 1979;48:493-506. 
3. Holman RR, Turner RC. A practical guide to basal and prandial insulin therapy. Diabet Med 1985;2:45-53. 
4. Zinman B. Insulin regimens and strategies for IDDM. Diabetes Care 1993;16 Suppl 3:24-28. 
5. Hirsch IB. Insulin analogues. N Engl J Med 2005;352:174-183. 
6. Campbell RK, Campbell LK, White JR. Insulin lispro: its role in the treatment of diabetes mellitus. Ann Pharmacother 1996;30:1263-1271. 
7. Noble SL, Johnston E, Walton B. Insulin lispro: a fast-acting insulin analog. Am Fam Physician 1998;57:279-286, 289-292. 
8. 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.
9. Kalra S. Newer basal insulin analogues: degludec, detemir, glargine. J Pak Med Assoc 2013;63:1442-1444. 
10. Garber AJ. Premixed insulin analogues for the treatment of diabetes mellitus. Drugs 2006;66:31-49. 
11. Hermansen K, Fontaine P, Kukolja KK, et al. Insulin analogues (insulin detemir and insulin aspart) versus traditional human insulins (NPH insulin and regular human insulin) in basal-bolus therapy for patients with type 1 diabetes. Diabetologia 2004;47:622-629. 
12. Ashwell SG, Gebbie J, Home PD. Optimal timing of injection of once-daily insulin glargine in people with Type 1 diabetes using insulin lispro at meal-times. Diabet Med 2006;23:46-52. 
13. Ashwell SG, Amiel SA, Bilous RW, et al. Improved glycaemic control with insulin glargine plus insulin lispro: a multicentre, randomized, cross-over trial in people with Type 1 diabetes. Diabet Med 2006;23:285-292. 
14. Lucchesi MB, Komatsu WR, Gabbay MA, et al. A 12-wk follow-up study to evaluate the effects of mixing insulin lispro and insulin glargine in young individuals with type 1 diabetes. Pediatr Diabetes 2012;13:519-524. 
15. MacGillivray MH, Mills BJ, Voorhess ML. Meal intolerance in type 1 diabetes mellitus: influence of time interval between insulin therapy and meal intake. J Med 1984;15:417-435. 
16. 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. 
17. Peterson ME. New development in the use of insulin mixtures and analogs for the problem diabetic. Proceedings of the 2013 American College of Veterinary Internal Medicine (ACVIM) Forum 2013;534-537.
18. Sawicki PT. Commentary: Does additional benefit justify additional costs of insulin analogues? BMJ 2011;343:d5858. 
19. ReliOn Insulins. http://relion.com/diabetes/insulin
20. Horn B, Mitten RW. Evaluation of an insulin zinc suspension for control of naturally occurring diabetes mellitus in dogs. Aust Vet J 2000;78:831-834. 
21. Monroe WE, Laxton D, Fallin EA, et al. Efficacy and safety of a purified porcine insulin zinc suspension for managing diabetes mellitus in dogs. J Vet Intern Med 2005;19:675-682.

Top Clinical Endocrinology Research Abstracts, 2014 ACVIM Forum: Diabetes Part 2

Following last week’s post, this is the next installment of my review of the "top 12 list" of clinical endocrinology research abstracts presented at this year's American College of Veterinary Internal Medicine Forum.

As with last week's post, I've enlisted the help of Dr. Rhett Nichols, a well-known expert in endocrinology and internal medicine whose day-job is senior member of the veterinarian consulting service for Antech Diagnostics, the world's largest laboratory dedicated to animal health.  Rhett also serves as a consultant for the Animal Endocrine Clinic, so I talk to him almost every day about the more difficult cases I see in my practice.

In this post, we will review 2 more of these "top 12" abstracts (both dealing with issues in diabetes), followed by the remaining 6 abstracts in the next 3 weeks' posts. We hope you agree with our selections, but if you don't, remember that you can always post a comment and add your opinion.

Claus P, Gimenes, AM, Castro, JR, Schwartz DS. Fructosamine Levels Do Not Agree with Clinical Classification Regarding Diabetic Compensation in Diabetic Dogs Under Treatment. J Vet Intern Med 2014;28:1034-1035.

Fructosamine levels are measured for diabetes management in veterinary medicine, but are rarely used in human clinical practice. A prospective, cross-sectional study was conducted between January 2010 and August 2012 to assess serum fructosamine levels of diabetic dogs under treatment in order to determine glycemic control compared to clinical classification of "compensated" versus "non-compensated," based on clinical signs and owner evaluation of the animal clinical status.
     The study population included 86 dogs: 25 were healthy, non-diabetic dogs (controls), 14 were diabetic dogs at diagnosis, 24 were diabetic under treatment (at least 30 days), and 23 had diabetic ketoacidosis (DKA).
     Compared to controls, serum fructosamine levels were significantly higher for all the diabetic groups, which were similar between each other. Considering all dogs, 8.3% were within the lower level (300–350 mg/dL), 11.9% had excellent glycemic control (350–400 mg/dL), 14.3% had good glycemic control (400–450 mg/dL), 14.3% had regular glycemic control (450–500 mg/dL) and 51.2% had poor control (> 500 mg/dL). Considering dogs under treatment, 95.8% were classified as having poor glycemic control and only 4.2% had a good control. Although 17/24 (70.8%) were clinically classified as "compensated," they all had fructosamine levels > 500 μmol/L; therefore, a poor glycemic control. Only one dog in this group had fructosamine levels indicating good glycemic control, but in this case, the owner had reported polyuria, polydipsia, polyphagia, and therefore, had been classified as non-compensated. Further studies must assess if insulin therapy adjustment based on fructosamine levels, and not only on clinical status, would lead to hypoglycemia episodes.

Study overview— Plasma fructosamine measurements are widely used as an indicator of glycemic control in diabetic dogs and cats (1-6). Because fructosamine is the product of an irreversible reaction between glucose and the amino groups of plasma proteins, it is assumed that its concentration reflects the mean blood glucose concentration of the preceding 1 to 2 weeks. Circulating fructosamine concentrations increase when glycemic control worsens and decrease when glycemic control improves.

In this abstract, the investigators determined that the vast majority (95.8%) of the 24 treated diabetic dogs would have been classified as having poor control, based on their high fructosamine levels (> 500 µmol/L). However, 17 of these 24 poorly-controlled dogs (based on the fructosamine level) were classified as well controlled or "compensated” diabetics based upon the history (i.e., no polyuria, polydipsia, or polyphagia). In contrast, 1 of the treated diabetic dogs was classified as having good control based on the fructosamine concentration, yet was classified clinically as an “uncompensated diabetic” because of owner complaints of continued polyuria, polydipsia and polyphagia. This discordancy between the clinical signs of diabetes and plasma fructosamine levels raised the question whether insulin dose adjustments could be based on fructosamine concentrations alone.

Comments—The discordancy between the clinical status of a treated diabetic patient (compensated versus uncompensated diabetes) and fructosamine levels that indicated poor control was somewhat surprising compared to the results of other published studies (1-4). However, there are several explanations that may account for these findings. These include the following:

1. The fructosamine reference interval “cut-off values” are too low.
2. Plasma Fructosamine is a “rear-view mirror” assessment of glycemic control.
3. Circulating fructosamine concentrations can be quite variable.

Reference interval cut-offs: Reference ranges for plasma fructosamine concentrations differ slightly between laboratories (5). This difference is often due to the commercially-available fructosamine test kit, and the reagents used by each laboratory. Claus et al. adopted a fructosamine reference range where the cut-off for poor regulation is > 500 µmol/L, while others have adopted a wider reference range where the cut-off for poor regulation is defined as a fructosamine > 600 µmol/L (5,6). If the reference range cut-off in this study was raised, many of the dogs categorized as having poor regulation would likely be reclassified as having moderate control.

Rear-view mirror assessment: Many dogs require at least 8 weeks or more to establish adequate glycemic control (6). Fructosamine determinations at 30-60 days may be too early to accurately assess the status of diabetic regulation. In other words, the finding of high plasma fructosamine concentrations, when sampled at 30-60 days after the start on insulin therapy, may be misleading, since fructosamine concentrations reflect the mean blood glucose levels over the preceding 1 to 2 weeks.

Variability: The range of plasma fructosamine concentrations associated with a given blood glucose concentration can be quite wide, even after the fructosamine concentration has plateaued (4). For example in one study, fructosamine concentrations ranged from 400 to 633 µmol/L, with a blood glucose concentration of 523 mg/d (4). Given the large range of plasma fructosamine concentrations for a given glucose concentration, the range of fructosamine concentrations from well controlled and poorly-controlled diabetics will likely overlap.

The Bottom Line—Fructosamine is far from a perfect test, but despite its shortcomings, it remains a valuable adjunct parameter to monitor glycemic control. However, it should always be interpreted in conjunction with the history, physical exam findings and body weight and never used alone to adjust an insulin dose (1,5-7).

References:

1. Reusch CE, Liehs MR, Hoyer M, et al. Fructosamine. A new parameter for diagnosis and metabolic control in diabetic dogs and cats. J Vet Intern Med 1993;7:177-182.
2. Thoresen SI, Bredal WP. Clinical usefulness of fructosamine measurements in diagnosing and monitoring feline diabetes mellitus. J Small Anim Pract 1996:37;64-68.
3. Crenshaw KL, Peterson ME, Heeb LA, et al. Serum fructosamine concentration as an index of glycemia in cats with diabetes mellitus and stress hyperglycemia. J Vet Intern Med1996:10:360-364.
4. Link KR, Rand JS. Changes in blood glucose concentration are associated with relatively rapid changes in circulating fructosamine concentrations in cats. J Fel Med Surg 2008;10;583-592
5. Reusch CE. Diabetic monitoring. In: Kirk’s Current Veterinary Therapy XV. Elsevier, St Louis, 2014; 193-199.
6. Feldman EC, Nelson RW. Canine diabetes mellitus. In: Canine and Feline Endocrinology and Reproduction. 3rd ed, Elsevier, St Louis, 2004; 510.
7. Briggs CE, Nelson RW, Feldman EC, et al. Reliability of history and physical examination findings for assessing control of glycemia in dogs with diabetes mellitus: 53 cases (1995-1998). J Am Vet Med Assoc 2000;217; 48-53.

Gostelow R, Scudder C, Keyte S, Forcada Y, Fowkes RC; Schmid HA, Church DB, Niessen SJM. Pasireotide (SOM230) Long-Acting Release Treatment for Feline Hypersomatotropism: A Proof of Concept Trial.  J Vet Intern Med 2014;28:1030.

Hypersomatotropism (HS) is a relatively common cause of feline diabetes mellitus. Attempts at its long-term medical management with somatostatin (sst) analogues have previously proven unrewarding. However, pasireotide (SOM230, Novartis, Basel, Switzerland), a novel sst analogue with binding affinity for sst receptor subtypes 1, 2, 3 and 5, was recently shown capable of decreasing serum insulin-like growth factor 1 (IGF-1) and improving insulin sensitivity in cats with HS when administered for 3 days as a short-acting, BID subcutaneous (SC) preparation. A long-acting release formulation (LAR) has been developed to allow convenient, once-monthly dosing and has led to successful biochemical control of human HS. The current study aimed to assess the potential of once-monthly pasireotide LAR as a treatment for feline HS.
      Feline HS was diagnosed in 12 diabetic cats based on increased serum IGF-1 (> 1000 ng/ml) and pituitary enlargement on computed tomography. Cats received 8 mg/kg SC pasireotide LAR once monthly for 6 months. Fructosamine concentration, IGF-1 concentration, and a 12-hour blood glucose curve (BGC) were performed at baseline and once monthly thereafter to monitor treatment response. A repeat CT-scan was performed at the end of the trial. A mixed-effects model was used to assess significance of changes in fructosamine, IGF-1 concentration, mean blood glucose (MBG) of BGCs, and insulin dose (U/kg).
       Seven of 12 cats completed the trial; 3 of 12 cats entered diabetic remission. Trial withdrawal occurred after a median of 2 months (range 1–4.5 months) due to persistence of uncontrolled diabetes mellitus (n = 1), diarrhoea (n = 2), a hypoglycemic event (n = 1), and an episode of diabetic ketoacidosis (n = 1). A significant decrease in IGF-1 (p < 0.001), insulin dose (p < 0.001), fructosamine (p = 0.04), though not MBG (p = 0.71) was documented. Adverse events included soft stools (9/12), worsening polyphagia (3/12), hypoglycaemia (4/12), and delayed hair regrowth (1/12). Maximum pituitary mass height had increased in 2/7, decreased in 4/7 and remained the same in 1/7 cats.
      In summary, pasireotide LAR is the first drug that shows potential to cause long-term biochemical and clinical improvement in cats with HS. In a proportion of cases, diabetic remission can even be achieved. Further work should focus on dose optimisation to enable higher success and lower withdrawal rates, specifically by trying to reduce adverse gastrointestinal events. The observed decrease in pituitary tumor size in some cats further establishes this as a useful primary, long-term treatment modality, although its preoperative use, enabling glycemic stabilization and tumor shrinkage before hypophysectomy, may also be of benefit.

Comments— Pasireotide (SOM230, trade name Signifor, Novartis) is an orphan drug approved for the treatment of Cushing’s disease in adult human patients when surgery has failed or is not an option (1). The drug is a somatostatin analog that targets multiple somatostatin receptors with high affinity. The result is apoptosis of those cells that produce ACTH, with significant lowering of plasma ACTH levels (2,3).

In addition, pasireotide has been shown to suppress GH and IGF -1 in rodents, as well as in human patients with acromegaly (4). Moreover, recent results of a phase III study of human patients treated with a long-acting release (LAR) form of pasireotide (Pasireotide LAR) showed that this novel form of therapy is significantly more effective than the current standard therapy with octreotide LAR or landreotide autogel (ATG) (5,6).

This study by Niessen's group showed that a once monthly injection of Pasireotide LAR to cats with acromegaly has the potential to cause a significant decrease in IGF-1 and GH levels, shrinkage of the GH-secreting pituitary tumor, and diabetic remission in cats with acromegaly.

The Bottom Line— To date, the only effectve treatment options for cats with acromegaly are transsphenoidal surgery or radiation therapy. Both of these treatments are quite costly and not widely available; in addition, they are associated with modest risk for patient morbidity and mortality and can have variable efficacy (7,8).

The idea that medical therapy for acromegaly is now a viable option is great news, but any new treatment that may change the therapeutic landscape for any disorder should be met with cautious optimism. In other words, it is important to remember that cats with acromegaly, just like in people with the same disorder, may have a variable response to medical therapy (9-12). For example, 5 of 12 cats in the current clinical trial had to be withdrawn from the study; 3 because of issues related to poor diabetes management and 2 because of diarrhea, which is a common adverse effect associated with somatostatin analogs. In addition, pituitary tumor shrinkage, which is a function of tumor size, tumor type (well differentiated versus poorly differentiated tumor cells), and the density and expression of specific somatostatin receptors, should not be expected to occur in all cases (9-12). Moreover, even if circulating GH values fall, diabetic remission or improved glycemic control may not occur for multiple reasons; for example, hyperglycemia is seen in a significant proportion of human patients treated with pasireotide, presumably because the drug inhibits insulin release (2-6).

And lastly, especially for cats, another drawback to use of pasireotide LAR is its high cost, which is estimated at $2000 per cat per year. However, it may be possible to use this agent at lower doses or at less frequent intervals, with obvious cost implications (13). Further research is obviously needed to determine these issues.

References:

1. Signifor Official Site - Signifor (Pasireotide) Injection. Signifor. US. 
2. Colao A, Petersenn S, Newell-Price J, et al. A 12-month phase 3 study of pasireotide in Cushing's disease. N Engl J Med 2012;366:914-924. 
3. McKeage K. Pasireotide: a review of its use in Cushing's disease. Drugs 2013;73:563-574. http://www.ncbi.nlm.nih.gov/pubmed/23605695
4. Petersenn S, Farrall AJ, Block C, et al. Long-term efficacy and safety of subcutaneous pasireotide in acromegaly: results from an open-ended, multicenter, Phase II extension study. 2014;17:132-140. 
5. Colao A, Bronstein MD, Freda P, et al. Pasireotide versus octreotide in acromegaly: a head-to-head superiority study. J Clin Endocrinol Metab 2014;99:791-799. 
6. Gadalha M, Bronstein M, Brue T, et al. Pasireotide LAR demonstrates superior efficacy versus Octreotide LAR and landreotide ATG in patients with inadequately controlled acromegaly: Results from a Phase III, multicenter, randomized study. 16th European Congress of Endocrinology. 2014; 35: P907. 
7. Melmed S, Colao A, Barkan A, et al. Guidelines for acromegaly management: an update. J Clin Endocrinol Metab 2009;94:1509-1517. 
8. Gittoes NJ, Sheppard MC, Johnson AP, et al. Outcome of surgery for acromegaly--the experience of a dedicated pituitary surgeon. QJM 1999;92:741-745. 
9. Casarini AP, Jallad RS, Pinto EM, et al. Acromegaly: correlation between expression of somatostatin receptor subtypes and response to octreotide-lar treatment. Pituitary 2009;12:297-303. 
10. Casarini AP, Pinto EM, Jallad RS, et al. Dissociation between tumor shrinkage and hormonal response during somatostatin analog treatment in an acromegalic patient: preferential expression of somatostatin receptor subtype 3. J Endocrinol Invest 2006;29:826-830. 
11. Ezzat S, Kontogeorgos G, Redelmeier DA, et al. In vivo responsiveness of morphological variants of growth hormone-producing pituitary adenomas to octreotide. Eur J Endocrinol 1995;133:686-690. 
12. Bhayana S, Booth GL, Asa SL, et al. The implication of somatotroph adenoma phenotype to somatostatin analog responsiveness in acromegaly. J Clin Endocrinol Metab 2005;90:6290-6295. 
13. Turner HE, Thornton-Jones VA, Wass JA. Systematic dose-extension of octreotide LAR: the importance of individual tailoring of treatment in patients with acromegaly. Clin Endocrinol (Oxf) 2004;61:224-231. 

Top Clinical Endocrinology Research Abstracts Presented at the 2014 ACVIM Meeting: Diabetes

Last week, I spent a week in Nashville, Tennessee attending the the 2014 American College of Veterinary Internal Medicine Forum. As part of that meeting, a number of research abstracts were presented (oral and poster presentations) that dealt with various aspects of canine and feline endocrinology. I plan to take the next four blog posts to discuss some of the newest and best research findings featured at the ACVIM meeting.

Of all of the excellent endocrine research abstracts presented, I've selected a "top 12 list" of the ones that have the most potential to change what I do in my clinical practice. To do this, I've enlisted the help of Dr. Rhett Nichols, a well-known expert in endocrinology and internal medicine whose day-job is senior member of the veterinarian consulting service for Antech Diagnostics, the world's largest laboratory dedicated to animal health. However, since Rhett also serves as a consultant for the Animal Endocrine Clinic (my practice), it was not that difficult to get him involved in this project!

In this post, we will review 3 of these top 12 abstracts, followed by the remaining 9 abtracts in the upcoming 3 posts. We hope you agree with our selections, but if you don't, remember that you can always post a comment and add your opinion.

Borin-Crivellenti S, Bonagura, JD, Gilor G. Comparison of Precision and Accuracy of U100 and U40 Insulin Syringes. J Vet Intern Med 2014;28:1029.

Day-to-day variability of insulin action is an important factor in attaining glycemic control in diabetics. In part, this variability is caused by imprecise dosing of insulin. 

We hypothesized that a U40 insulin syringe (U40) would be more precise than a U100 insulin syringe (U100). We dispensed 1, 2.5, and 4 international unit (IU) of insulin using 24 syringes for each dose from a BD Ultra-Fine 0.3-cc U100 (1⁄2 Unit Markings) and a VetOne 0.3-cc U40. Each dose was weighed on an analytical scale, and accuracy (mean [± SD] of actual dose–target dose*100/target dose) and precision (the coefficient of variation [SD/Mean] of the actual dose) were calculated. The proportions of CID (clinically important deviation: ≥ ± 20% off target) outcomes were compared between syringe types. 

U40 was more accurate for 1, 2.5 and 4IU (13.2 ± 8.7%; 6.0 ± 2.76%; 3.2 ± 1.6%, respectively) than U100 (28.2 ± 15.4%; 10.7 ± 8.0%; 4.6 ± 2.9%, respectively) (p < 0.05). Precision was lowest for 1IU but improved with increasing dose (U40: 1IU = 15.8%, 2.5IU = 6.4%, 4IU = 3.5%; U100: 1IU = 15.1%, 2.5IU = 8.1%, 4IU = 3.3%). U40 was more precise than U100 for dosing of 2.5IU (p < 0.05) despite the 1/2-unit markings on U100. CID outcomes were more frequent in U100 vs. U40 in 1IU (16/24 vs. 8/24 respectively, p = 0.02) and 2.5IU (3/24 vs. 0/24 respectively, p = 0.07) but did not occur in 4IU. 

For administration of small insulin doses, U40 are more accurate and precise than U100 and are less likely to result in clinically important over- or under-dosing. These results favor the use of U40 for administration of small doses of insulin.

Comments— Although the administration of low doses of U100 insulin (e.g., glargine, detemir, NPH) is common practice in veterinary medicine, this study reveals remarkably high dose error when doses of 4 units or less of U100 insulin are administered.  Since similar findings were reported in human pediatric patients given low doses of insulin (1-3) one to two decades ago, the results of this study should not be all that surprising. The use of U100 syringes can be dangerously inaccurate with administering very low insulin doses, and the use of syringes with 1/2 unit markings has not been shown to improve accuracy or precision (3).

Most human diabetologists recommend diluting the insulin when low doses of U100 insulin must be given (1-3). However, one must remember that there are many problems associated with dilution of these U100 insulins (4,5). First of all, glargine should never be diluted under any circumstances. Other U100 insulins, such as NPH or detemir, can be diluted, but this may alter the absorption kinetics of the insulin. For NPH (Humulin N), one can obtain the special diluent from the insulin manufacturer (Eli Lilly) or the pharmacy. For detemir (Levemir, Novo Nordisk), the insulin manufacturer has a special diluting medium, but the company generally will not provide the diluent to veterinarians. Detemir can be diluted with sterile water or saline, but this dilutes the insulin's antimicrobial additive and increases the risk of bacterial contamination. Therefore, because of the risk of bacterial contamination and changes with efficacy, diluting detemir is not generally recommended (5).

In both human patients and dogs, the use of insulin pen devices have consistently shown to be more accurate than dosing with insulin syringes (2,3,6). In one recent veterinary report (6), an insulin pen device was found to be more accurate than the insulin syringes when low doses (<8 units) of insulin were administered. In that study, insulin syringes tended to over-deliver by approximately 20-25% for very low doses (1 unit). However, for higher doses (16 units), the insulin pen and insulin syringe were comparable in accuracy.

The Bottom Line—Administration of low doses of insulin can be very inaccurate and imprecise, especially when using a U100 insulin and syringe. Use of U40 insulin improves accuracy but still is far from perfect. Either dilution of U-100 insulin (if possible) or use of an insulin pen device will help to improve accuracy when low-dose insulin administration is required.

References:

1. Casella SJ, Mongilio MK, Plotnick LP, et al. Accuracy and precision of low-dose insulin administration. Pediatrics 1993;91:1155-1157. 
2. Gnanalingham MG, Newland P, Smith CP. Accuracy and reproducibility of low dose insulin administration using pen-injectors and syringes. Arch Dis Child 1998;79:59-62. 
3. Keith K, Nicholson D, Rogers D. Accuracy and precision of low-dose insulin administration using syringes, pen injectors, and a pump. Clin Pediatr (Phila) 2004;43:69-74. 
4. Pet Diabetes: Diluting insulin. http://petdiabetes.wikia.com/wiki/Diluting_insulin
5. Roomp K, Rand JS. Management of diabetic cats with long-acting insulin. Vet Clin North Am Small Anim Pract 2013;43:251-266. 
6. Burgaud S, Riant S, Piau N. Comparative laboratory evaluation of dose delivery using a veterinary insulin pen (abstract 121). Proceedings of the WSAVA//FECAVA/BSAVA Congress; 12-15 April 2012;567.

Hall MJ, Adin CA, Borin-Crivellenti S, Rudinsky AJ, Gilor C. Pharmacology of the GLP-1 Analog Liraglutide in Healthy Cats. J Vet Intern Med 2014;28:1025-1026.

GLP-1 is an intestinal hormone that induces glucose-dependent stimulation of insulin secretion while suppressing glucagon secretion and increasing beta cell mass, satiety and gastric-emptying time. Liraglutide is a fatty-acid derivative of GLP-1 with a protracted pharmacokinetic profile that is used in people for treatment of type II diabetes mellitus and obesity. The aim of this study was to determine the pharmacodynamics of liraglutide in healthy cats.

A hyperglycemic clamp was performed on day-1 (Clamp-I) and 13 (Clamp-II) in seven healthy cats. Liraglutide was administered subcutaneously (0.6 mg/cat) once daily on days 7 through 13. During the clamp blood glucose concentrations were measured every 5 minutes and 20% dextrose infusion was adjusted to achieve hyperglycemia (225 mg/dl) at 30 min and to maintain that level of glycemia for 60 min. Plasma insulin and glucagon concentrations were measured at -15, 0, 30, 45, 60, 75, and 90 min.

Weight loss was recorded in all cats at day 13 (9%; P = 0.006). Appetite was subjectively decreased in all cats and one cat was withdrawn on day 10 because of 48 hrs of anorexia. Compared to Clamp-I, there was a trend during Clamp-II towards increased 60 min total glucose infused (median [range] 29% [1-178%], P = 0.087) and insulin concentrations (47% [-11-234%], P = 0.084). Glucagon concentrations (P = 0.67) and baseline glucose concentrations (P = 0.66) did not differ significantly between clamps.

Liraglutide may aid in weight loss in overweight cats but further evaluation is needed to determine its efficacy on improving glycemic control in diabetic cats.

Rudinsky AJ, Adin CA, Borin-Crivellenti S, Hall MJ, Gilor C. The Pharmacology of Exenatide Extended-Release in Healthy Cats. J Vet Intern Med 2014;28:1026.

GLP-1 is an intestinal hormone that induces glucose-dependent stimulation of insulin secretion while suppressing glucagon secretion and increasing beta cell mass, satiety and gastric- emptying time. Exenatide extended-release (ER) is a microencapsulated formulation of the GLP- 1-receptor agonist exenatide. It has a protracted pharmacokinetic profile that allows a once- weekly injection to replace insulin therapy safely and effectively in type-II diabetic people.

Here we studied the pharmacology of exenatide-ER in six healthy cats. A single, subcutaneous injection of exenatide-ER (0.13 mg/kg) was administered on day 0. A hyperglycemic clamp was performed on days -7 (Clamp-I) and 21 (Clamp-II). During the clamp, blood glucose concentrations (BG) were measured every 5 minutes and 20% dextrose infusion was adjusted to achieve hyperglycemia (225 mg/dl) at 30 min and to maintain that level of glycemia for the subsequent 60 min. Plasma insulin and glucagon concentrations were measured at -15, 0, 30, 45, 60, 75, and 90 min. Glucose tolerance was defined as the amount of glucose required to maintain hyperglycemia during the 60 minutes of the clamp.

Comparing Clamp-1 to Clamp-2 using paired t-tests, fasting BG decreased (mean [± SD] = -11 ± 8 mg/dl, p = 0.02), glucose tolerance improved (median [range] +33% [4–138%], p = 0.04) and median glucagon concentrations decreased (-4.7% [0–12.1%], p = 0.04). Insulin concentrations did not differ significantly. No side effects were observed throughout the study.

Exenatide-ER was safe and effective in improving glucose tolerance 3 weeks after a single injection. Further evaluation is needed to determine its efficacy and duration of action in diabetic cats.

Comments on the above 2 GLP-1 studies— Exenatide and liraglutide belong to a class of agents referred to as incretin mimetics. These agents are novel therapeutic options for type 2 diabetes in humans (1). Incretins are hormones released from the gastrointestinal tract during a meal, which potentiate insulin secretion from the beta cells of the pancreas (2). The major and most potent incretin is glucagon-like peptide 1 or GLP-1 (3). The biological actions of GLP-1 is highly glucose dependent, and therefore hypoglycemia does not occur. Additional benefits include stimulation of insulin biosynthesis, beta cell proliferation, resistance to apoptosis, enhanced beta cell survival, and inhibition of glucagon secretion (4,5,6). Extrapancreatic effects include delayed gastric emptying, decreased gastrointestinal motility, and central nervous system effects of satiety and weight loss (4,7).

Because native GLP-1 is rapidly degraded by a ubiquitous enzyme, GLP-1 agonists that are resistant to enzyme degradation were developed (8).  Two agonists are now available commercially:

1. Exenatide was the first GLP-1 agonist used for the treatment of type 2 diabetes in humans and was approved by the FDA in 2005. It is a synthetic peptide discovered in the saliva of the gila monster with a 53% homology with human GLP-1 (9). 
2. Liraglutide was the first genetically engineered GLP-1 agonist and has a 97% homology with native GLP-1 (1,10). It was approved by the FDA in 2010. Adverse effects of these GLP-1 agonists in people include vomiting, nausea, inappetence, and acute pancreatitis (1,9,10).

In these two studies by investigators from The Ohio State University, the pharmacokinetics of the extended-release formulation of exenatide (exenatide-ER) given once SC over a 3 week period and liraglutide given SC daily for 7 days was evaluated in healthy cats using a common research tool called a hyperglycemic clamp (11). With this procedure, glucose is infused into the patient and “clamped”, or held at a certain concentration (225 mg/dl) over time. How much glucose that needs to be infused to keep the blood sugar at that constant high level is a measure of how fast glucose is metabolized. In essence, the hyperglycemic clamp is a way to quantify the beta cell response to glucose. The results of the study showed that all liraglutide-treated cats lost weight and subjectively had a decreased appetite. In addition, there was a trend toward increased glucose utilization and insulin secretion. The exenatide-ER treated cats showed increased glucose tolerance, with no side effects being observed.

The Bottom Line— Preliminary results in normal cats would suggest that liraglutide may aid in weight loss in overweight cats and exenatide-ER may improve glucose tolerance in preclinical and overt diabetic cats without causing adverse side effects.

Clearly, further evaluation of both these agents is needed to determine their efficacy in diabetic cats. The hope is that these agents could one day be used as monotherapy to improve glucose tolerance without causing hypoglycemia and, in addition, increase beta-cell mass with minimal adverse effects such as nausea, vomiting, and inappetence. One potential drawback to their wide use in the treatment of preclinical and overt diabetic cats is their considerable cost.

References:

1. Gallwitz B. GLP-1 analogues for type 2 diabetes mellitus: current and emerging agents. Drugs 2011;72:1675-88
2. Moore B. Edie ES, Abram JH. On the treatment of diabetes mellitus by acid extract of duodenal mucous membrane. Biochem J 1906;1;28-38
3. Kim W, Egan JM. The role of incretins in glucose homeostasis and diabetes treatment. Pharmacol Rev 2008;60:470-512
4. Drucker DJ. The biology of incretin hormones. Cell Metab 2006;3:153-65
5. Li Y, Hansotia T, Yusta B, et al. Glucagon-like peptide-1 receptor signaling modulates beta cell apoptosis. J Biol Chem 2003;278:471-478. 
6. Farilla L, Bulotta A, Hirshberg B, et al. Glucagon-like peptide 1 inhibits cell apoptosis and improves glucose responsiveness of freshly isolated human islets. Endocrinology 2003;144:5149-5158. 
7. Drucker DJ, Nauck MA. The incretin system: glucagon-like peptide-1 receptor agonists and dipeptidyl peptidase-4 inhibitors in type 2 diabetes. Lancet 2006;368:1696-1705. 
8. Mudaliar S, Henry RR. The incretin hormones: from scientific discovery to practical therapeutics. Diabetologia 2012;55:1865-1868. 
9. Eng J, Kleinman WA, Singh L, et al. Isolation and characterization of exendin-4, an exendin-3 analogue, from Heloderma suspectum venom. Further evidence for an exendin receptor on dispersed acini from guinea pig pancreas. J Biol Chem 1992;267:7402-7405. 
10. Phillips LK, Prins JB. Update on incretin hormones. Ann N Y Acad Sci 2011;1243:E55-74. 
11. DeFronzo RA, Tobin JD, Andres R. Glucose clamp technique: a method for quantifying insulin secretion and resistance. Am J Physiol 1979;237:E214-223.