Glucose homeostasis requires that blood glucose be constrained within a narrow concentration. Homeostasis is accomplished through diverse physiologic mechanisms that work together to precisely regulate glycemia. Abnormalities in blood glucose (ie, hyperglycemia, hypoglycemia) occur when physiologic regulation is disrupted (eg, during disease states or metabolic disturbances). In some circumstances, medications and toxins may also affect blood glucose regulation; for example, many drugs produce glucose disturbances in humans and may cause similar disturbances in dogs and cats (see Drugs that Can Alter Blood Glucose in Humans).
Following are the author’s top 5 substances that exert significant effects on blood glucose regulation in dogs and cats and the clinical situations in which they may be encountered.
Insulin, secreted from β cells in the pancreatic islets of Langerhans, produces a potent hypoglycemic effect through its physiologic role as a hormone or when used as a replacement hormone to manage diabetes.1 Insulin-induced hypoglycemia caused by naturally occurring disease is rare, but clinical disorders (eg, canine insulinoma) can occur.2 In contrast, pharmacologic insulin preparations are the most potent hypoglycemic agents in routine clinical use.1 Various modifications have been made to alter the pharmacologic properties of endogenously produced insulin, the mainstay for diabetes treatment in dogs and cats. These modifications, which have expanded the clinical efficacy of insulin preparations, may also produce severe hypoglycemia when administered inappropriately or after overdose. The endogenous hormone and all insulin preparations produce hypoglycemia via identical mechanisms, but pharmacologic modifications may cause the magnitude and duration of the hypoglycemic effect to be more pronounced.3
In most tissues, especially muscle and adipose tissue, insulin binds to specific insulin receptors on the surface of most cells.4 After binding, receptor activation initiates a cascade of intracellular steps that culminates with the insertion of glucose transporters into the cell membrane and activation of cellular glucose uptake. In the liver, insulin serves as a regulator of glucose storage and production. Insulin activates glycogenesis and inhibits gluconeogenesis, both of which reduce blood glucose.5 The hypoglycemic effects wane when blood insulin is low or absent.
DRUGS THAT CAN ALTER BLOOD GLUCOSE IN HUMANS*
Drugs that Induce Hypoglycemia
Glucagon-like peptide-1 (GLP-1) analogs
Drugs that Induce Hyperglycemia
Calcineurin inhibitors (eg, cyclosporine)
*Hypo- or hyperglycemia has been reported as an adverse effect of many drugs used in human medicine. Some drug classes (eg, β blockers, quinolone antibiotics) appear on both lists because separate drugs within the class can cause hyper- and hypoglycemia. It is possible that these drugs exert similar actions on blood glucose in dogs and cats, although hypo- or hyperglycemic effects of many infrequently prescribed drugs are not well documented in these species.
Glucocorticoids are a chemical class of hormones and synthetic drugs that includes cortisol, hydrocortisone, prednisone, dexamethasone, and less familiar hormones and drugs. They exert a wide range of effects on carbohydrate, protein, and lipid metabolism and are involved in regulation of inflammatory processes and the immune system.6 The principal glucocorticoid effect on glucose homeostasis is promotion of hyperglycemia, which can be marked in the presence of supraphysiologic or pharmacologic glucocorticoid concentrations.7
Hyperglycemia caused by glucocorticoid excess can arise as a consequence of naturally occurring endocrine disorders or exposure to exogenous glucocorticoid substances.8,9 Any condition that increases adrenal production of glucocorticoids can produce hyperglycemia, including physiologic responses. In dogs, hyperadrenocorticism (ie, Cushing’s disease) is the most common endocrinopathy associated with glucocorticoid overproduction and hyperglycemia.10 In affected dogs, hyperglycemia occurs in the presence of excess plasma cortisol and other glucocorticoids, caused by adrenal hyperplasia or functional adrenocortical neoplasia.11 Physiologic distress (eg, due to illness or fear) can result in hyperglycemia caused by activation of an adrenal hormone response (ie, stress hyperglycemia), which includes hypercortisolemia and elevations in catecholamines.12 Stress hyperglycemia can occur during illness and is a common finding in otherwise healthy dogs and cats.
Exogenous glucocorticoids may also cause hyperglycemia.13 Glucocorticoid preparations are among the most frequently prescribed drugs in small animal medicine. The potency of synthetic glucocorticoids, including prednisone and dexamethasone, is much greater than hydrocortisone. Thus, these preparations may produce substantial side effects, even when used at appropriate pharmacologic doses.14 Hyperglycemia can develop as a side effect of oral, injectable, or topical glucocorticoid administration.15
Endogenous and exogenous glucocorticoids induce hyperglycemia by the same mechanism, referred to as insulin resistance.16 Glucocorticoids reduce tissue sensitivity to insulin, which antagonizes the hypoglycemic actions of insulin. The insulin-resistant state is characterized by a subnormal biologic response to normal concentrations of insulin.16
Xylitol is a 5-carbon sugar alcohol used as an artificial sweetener in many commercial products (eg, chewing gum, drugs, candies).17 Although safe for humans and most other mammals, xylitol induces severe hypoglycemia after ingestion in dogs.17 Along with hypoglycemia, xylitol toxicity may cause hepatic necrosis that may progress to liver failure in some dogs, which may contribute to hypoglycemia via a separate mechanism.18
Xylitol appears to be a potent stimulator of insulin secretion in dogs; this effect has not been observed in other mammals.19 The increase in plasma insulin induced by xylitol stimulates tissue uptake of glucose, leading to severe hypoglycemia. The mechanism that leads to hepatic necrosis, characterized by severely increased serum alanine transaminase (ALT) activity, is not completely known but may involve adenosine triphosphate (ATP) depletion.20
4. Growth Hormone
Growth hormone (GH; ie, somatotropin) is produced and secreted by the anterior pituitary.21 In adulthood, GH is a component of the counter-regulatory response to hypoglycemia and stress.22
GH secretion disorders are uncommon causes of blood glucose disturbances in dogs and cats. The most frequently encountered clinical disorder of GH secretion is feline acromegaly.23 Acromegaly in cats is caused by excessive GH secretion from a pituitary adenoma that causes hyperglycemia through induction of insulin resistance in muscle and adipose tissue.23,24 Hyperglycemia can be severe, and affected cats often have diabetes mellitus on presentation for hyperglycemia treatment.25
Progestins are a class of natural and synthetic compounds with actions that mimic those of progesterone.26 Exposure to progesterone or progestins may produce alterations in blood glucose homeostasis in dogs and cats, although the circumstance under which the aberration occurs differs between the species. In dogs, progesterone and synthetic progestins stimulate GH secretion from mammary tissue, which contributes to insulin resistance in body tissues.27 Progesterone-induced insulin resistance can be severe enough to induce diabetes mellitus in some pregnant dogs, which may resolve following pregnancy termination.28,29 In countries where long-acting progestins are used to impede estrus cycling, treated dogs may develop hyperprogestinemia and, eventually, acromegaly as a result of persistent stimulation of GH release.29
In cats treated with megestrol acetate, a synthetic progestin, hyperglycemia or even overt diabetes mellitus may develop.30 Progestin-induced hyperglycemia in cats does not have a clear link to elevated GH concentration, and the exact mechanism by which progestins induce carbohydrate intolerance in cats is unknown.31
GH = growth hormone