Next Note MAIN : Feline Medicine : Feline Diabetes Mellitus II


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Feline Diabetes Mellitus II
Deborah S. Greco, DVM, PhD
Colorado State University
Fort Collins, CO, United States
Back to Feline Medicine  
18270169

Objectives

 Describe the rationale for the use of oral hypoglycemic agents in cats with presumed type 2 diabetes mellitus.

 Cover the pharmacology, dosage, and side effects of common oral hypoglycemic agents in cats.

 Describe the monitoring of cats treated with oral hypoglycemic agents.

Key Points

 Cats develop Type 2 diabetes mellitus characterized by amyloid deposition and insulin resistance; therefore, they are ideal candidates for oral hypoglycemic agents.

 Oral hypoglycemic agents work by decreasing hepatic glucose output (metformin), decreasing glucose absorption from the intestine (acarbose), increasing peripheral insulin sensitivity (transition metals, thiazolidinediones), and increasing insulin secretion from the pancreas (sulfonylureas).

 Feeding a low carbohydrate, high protein diet is complementary to oral hypoglycemic therapy and may allow management without insulin.

Overview

Treatment of NIDDM is aimed at attenuating the physiologic abnormalities of NIDDM by decreasing hepatic glucose output and glucose absorption from the intestine, increasing peripheral insulin sensitivity, and increasing insulin secretion from the pancreas. In cats, the differentiation of these catagories is almost impossible prior to treatment; therefore, the clinician must rely on the response to oral hypoglycemic agents as a guide to whether the cat has sufficient beta-cell function to be managed with oral hypoglycemic agents. Oral hypoglycemic agents include the sulfonylureas (glipizide, glyburide, glimiperide), biguanides (metformin), thiazolidinediones (troglitazone), alpha-glucosidase inhibitors (acarbose) and transition metals (chromium, vanadium). Indications for oral hypoglycemic therapy in cats include normal or increased body weight, lack of ketones, probable type II diabetics with no underlying disease (pancreatitis, pancreatic tumor), history of diabetogenic medications and owners willingness to administer oral medication rather than an injection. Reversal of glucose toxicity using a short course of insulin therapy prior to or in combination with oral hypoglycemic agents may improve the response to oral hypoglycemic agents. Diet should consist of low carbohydrate/high protein canned foods only.

Agents That Inhibit Intestinal Glucose Absorption

The alpha-glucosidase inhibitors impair glucose absorption from the intestine by decreasing fiber digestion and hence glucose production from food sources.(Goodman and Gilman, 1990) These drugs were initially developed as “starch blockers” to control obesity in humans and may have application to the treatment of obese diabetic cats. Acarbose is used as initial therapy in obese pre-diabetic patients suffering from insulin resistance or as adjunct therapy with sulfonylureas or biguanides to enhance the hypoglycemic effect in patients with diabetes mellitus. Side effects include flatulence, loose stool and diarrhea at high dosages. One advantage of these medications is that they are not absorbed systemically and may be used in conjunction with other oral hypoglycemics or insulin. They are not indicated in patients of low body weight because of their effects on nutrition. The author has had experience with acarbose at a dosage of 12.5 mg/cat BID with meals; side effects, although rare if diet is adjusted, include semi-formed stool or in some cases overt diarrhea. The glucose lowering effect of acarbose alone is mild with blood glucose concentrations decreasing only into the 250–300 mg/dl range. However, acarbose is an excellent agent when combined with insulin to improve glycemic control. Cats given acarbose will respond to a lower dosage of insulin and hypoglycemic episodes can be reduced.

Agents That Improve Peripheral Insulin Sensitivity

A new class of oral hypoglycemics that are receiving attention in human medicine are the thiazolidinedione compounds.(Saltiel and Olefsky, 1996) Thiazolidinediones facilitate insulin-dependent glucose disposal and inhibit hepatic glucose output by attenuation of gluconeogenesis and glycogenolysis; troglitazone (Rezulin®) increases transcription and translation of proteins necessary for glucose metabolism. Some authors have suggested that use of this drug early in the course of NIDDM may slow the progression of NIDDM.(Saltiel and Olefsky, 1996) Side effects of troglitazone were minimal and included transient mild decreases in WBC, platelets, and hemoglobin. (Berkowitz, 1996) No hypoglycemic reactions were described. The author has limited experience with these compounds in cats; however, in humans insulin therapy can be discontinued in 15% of patients using troglitazone. Improvement in fasting BG, glycosylated Hb, and diabetic complications were noted in all patients and were significant when compared with placebo.

Compounds containing the transition metals, vanadium and chromium, have been shown to have insulinomimetic properties when administered in the drinking water to mice and rats suffering from experimentally-induced DM (Type I and Type II). A recent USDA study of 180 patients with NIDDM found that administration of 1,000 µg of chromium picolinate once daily resulted in amelioration of the classic signs of diabetes and normalization of blood levels of hemoglobin A1c. In Type II diabetes, constant suppression of blood glucose is achieved with vanadium. (Brichard, 1989) Studies have documented restoration of secretion of insulin in Type II diabetics treated with vanadium suggesting reversal of "glucose toxicity.” Oral vanadate causes a marked and sustained improvement in glucose homeostasis in NIDDM by exerting an insulin-like effect on peripheral tissues; furthermore, vanadium prevents the exhaustion of insulin stores in the pancreas.

Current research indicates that transition metals bypass the insulin-receptor and activate glucose metabolism within the cell. (Schecter, 1990) By acting at a post-receptor site, vanadium/chromium compounds are an ideal treatment for Type II DM which results from a lack of insulin receptor responsiveness. Unlike insulin, vanadium and chromium do not lower blood glucose concentrations in normal animals. Studies in our laboratory indicate that low doses (0.2 mg/kg/day) of oral vanadium will decrease blood glucose and serum fructosamine concentrations and alleviate the signs of diabetes (polydypsia, polyuria) in cats with early type II diabetes mellitus. Side effects include anorexia and vomiting initially; however, most cats showed no ill effects when vanadium therapy was reinstituted. Humans ingest vanadium as a solution in juice and chromium as a tablet; however, cats will ingest vanadium more readily in food once daily.

Agents That Inhibit Hepatic Glucose Output

Metformin belongs to the biguanide group of oral hypoglycemic agents. The biguanides inhibit hepatic glucose release and improve peripheral insulin sensitivity. (Kahn, 1990) Biguanides may be used alone or in conjunction with other oral hypoglycemic agents to treat Type II diabetes mellitus in human beings. (DeFronzo, 1995) One advantage of the biguanides is that they do not promote insulin release; therefore, there is little potential for the development of hypoglycemia when metformin is used as a sole agent. Furthermore, metoformin does not cause progression of pancreatic amyloid deposition because it does not provoke insulin release. (DeFronzo, 1995) In a recent large randomized parallel group, double-blind control study, human patients with NIDDM underwent treatment with metformin alone or placebo. Compared with patients in the placebo group, the metformin group had lower mean fasting plasma glucose concentrations and glycosylated hemoglobin values. (DeFronzo, 1995) Side effects of the biguanides include lactic acidosis, nausea and diarrhea. Contraindications for metformin therapy in humans, and presumbly in cats, include concurrent renal disease, liver dysfunction, or cardiac disease. Experience with this drug as treatment for NIDDM in cats has been disappointing.

Agents That Promote Insulin Release From the Pancreas

The mechanism of action of the sulfonyureas is to increase insulin secretion and improve insulin resistance; however, some of these agents also cause an increase in hepatic glucose output. This leads to delayed hyperinsulinemia, weight gain, and athersclerosis in human beings undergoing sulfonylurea therapy. (Goodman and Gilman, 1985) Sulfonylureas, because of provocation of insulin release, may promote progression of pancreatic amyloidosis. In cats, glipizide has been used to successfully treat diabetes mellitus at a dosage of 2.5–5 mg BID when combined with dietary fiber therapy. The patient is evaluated weekly or every 2 weeks for a period of 2–3 months. If the fasting blood glucose decreases to less than 200 mg/dl, the glipizide should be continued a the same dosage and the cat reevaluated in 3–6 months. If the fasting blood glucose remains greater than 200 mg/dl after 2–3 months of therapy and the cat is still symptomatic (PU/PD, wt. loss), glipizide should be discontinued and insulin therapy or combination insulin/oral hypoglycemic therapy should be instituted. If the blood glucose remains greater than 200 mg/dl and the cat becomes asymptomatic, the glipizide should be continued indefinitely and the cats should be rechecked in 3–6 months. Initial experience with glipizide as an oral hypoglycemic agent in cats has been disappointing. However, this may be related to patient selection rather than to overt failure of the drug. Cats with early type II diabetes are most likely to respond to any oral hypoglycemic agent. Side effects of oral hypoglycemics include severe hypoglycemia (rare in cats), cholestatic hepatitis, and vomiting. Gastrointestinal side effects, which occur in about 15% of cats treated with glipizide, resolve when the drug is administered with food. (Ford 1995) A new sulfonylurea, glimepiride (Amaryl) has recently been introduced in the human market; this compound has fewer side effects than glipizide. Furthermore, glimepiride may be dosed once daily.

Combining Oral Hypoglycemics With Insulin: Changes to and from Insulin

Agents that impair glucose absorption from the intestine (acarbose) or increase insulin sensitivity (vanadium, metformin, troglitazone) may be combined with insulin to improve glucose control. Vanadium has been shown to be beneficial in conjunction with insulin in rat and mice models of IDDM. (Schecter, 1992) In the case of “brittle diabetics” where small incremental changes in insulin dose may precipitate hypoglycemia, addition of a drug that enhances the action of insulin may lead to a reduction in the insulin dosage required to attain euglycemia. In humans, acarbose and metformin are commonly used in conjunction with insulin and other oral hypoglycemics (sulfonylureas) that cause insulin release. (DeFronzo, 1995) Caution should be used in combining any oral hypoglycemic agent with insulin as hypoglycemic reactions may occur. Changes from insulin to oral hypoglycemic agents or vice versa may be necessary in some diabetic cats. If a cat is particularly sensitive to insulin or exhibits transient diabetes because of reversal of “glucose toxicity”, a change to an oral hypoglycemic should be considered. On the other hand, if a cat is being managed with oral hypoglycemic agents and ketosis develops, the oral hypoglycemic agents should be discontinues and the cat should be treated with insulin.

Additional Detail

Table 1: Oral hypoglycemic drugs used in the treatment of NIDDM in humans and cats.

Drug Trade name®

Dose

Frequency

Side Effect

Mech of Action

Chromium

1000 µg (H)

 200 µg (C)

q 24 hr

None at this dose

Increases insulin receptor sensitivity

Glipizide

2.5–5 mg (C)

BID

Vomiting, hepatotoxicity

Insulin release

Glimiperide Amaryl®

1–4 mg (H) unknown (C)

q 24 (H) unknown (C)

As above but lower incidence

as above

Metformin Glucophage®

500–750 mg (H) 5 mg/kg (C)

BID

Anorexia, vomiting

Inhibits hepatic glucose output

Precose Acarbose®

50 mg (H)

12.5 mg (C)

BID with meals

Flatulence, soft stool

alpha-1 glucosidase inhibitor

Troglitazone Rezulin®

200–400 mg (H) 200 mg (C)

q 24 hr

Mild decreases in WBC, platelet, and Hb counts

Increases insulin receptor sensitivity

Vanadium

0.2 mg/kg/day

q 24 hr in food or water

Anorexia, vomiting

Increases insulin sensitivity

Summary

Oral hypoglycemics are becoming increasingly popular for use in cats with Type 2 diabetes mellitus. Sulfonylureas are the most common class of drugs and glipizide has been used at a dosage of 5 mg BID PO to manage diabetes in cats for several years. Newer drugs, such as acarbose, may be used as adjunct therapy with other oral hypoglycemics and diet. Metformin and the thioazolodidiones have been recently studied in cats and may show promise particularly if combined with insulin or dietary therapy. Diet, utilizing the low carbohydrate, high protein formulations, may be key to successful management of diabetes in cats.

References

1.  Berkowitz K, Peters R, Kjos SL, et al: Effect of troglitazone on insulin sensitivity and pancreatic ß-cell function in women at high risk for NIDDM. Diabetes 45(11):1572, 1996.

2.  Brichard SM, Pottier AM, Henquin JC: Long term improvement of glucose homeostasis by vanadate in obese hyperinsulinemic fa/fa rats. Endocrinology 125:2510, 1989.

3.  Cam MC, Pederson RA, Brownsey RW, McNeill JH: Long-term effectiveness of oral vanadyl sulphate in streptozotocin-diabetic rats. Diabetologia 36:218, 1993.

4.  DeFronzo RA, Goodman AM. Efficacy of metformin in patients with non-insulin-dependent diabetes mellitus. N Engl J Med 333(9):541, 1995.

5.  Ford S. NIDDM in the cat: treatment with the oral hypglycemic medication, glipizide. Vet Clin N Amer Sm Anim Pract 25(3):599, 1995.

6.  Kahn CR, Shechter Y: Insulin, oral hypoglycemic agents and the pharmacology of the endocrine pancreas. In Goodman Gilman A, Rall TW, Nies AS, Taylor P (eds): The Pharmacological Basis of Therapeutics, 8th edPergamon Press, New York NY 1990, pp. 1463-1495.

7.  O'Brien TD, Butler PC, Westermark P, Johnson KH. Islet amyloid polypeptide: A review of its biology and potential roles in the pathogenesis of diabetes mellitus. Vet Pathol 1993;30:317-332.

8.  Saltiel AR, Olefsky JM, Thiazolidinediones in the treatment of insulin resistance and type II diabetes. Diabetes 45(12):1661, 1996.

9.  Shechter Y: Insulin-mimetic effects of vanadate: Possible implications for future treatment of diabetes. Diabetes 39:1, 1990.

10.   Unger RH, Foster DW: Diabetes Mellitus. In Wilson JD, Foster DW (eds): Textbook of Endocrinology, 7th ed. Philadelphia PA, WB Saunders, 1985, pp. 1062-1064.

Speaker Information
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Deborah S. Greco, DVM, PhD
Colorado State University
Fort Collins, CO, United States

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