Acromegaly, a State of Growth Hormone Excess, Is Associated with Hyperglycemia and Insulin Resistance The major players in the growth hormone (GH) system are GH and IGF-1 (insulin-like growth factor-1). GH and IGF-1 affect glucose and fat metabolism, as well as growth. They have opposing effects on carbohydrate metabolism (Fig. 16.1). A family of IGF-binding proteins (IGF-BPs) affects tissue delivery, availability of IGF-1, and gene transcription, thereby altering the balance between growth hormone and IGF-1. In some tissues, the IGF effects cooperate with the GH effects (for example, growth of long bones) and in other tissues, they are antagonistic (the metabolic effects).
Fig. 16.1 Growth hormone (GH) and IGF-1 have opposite effects on glucose metabolism. Hepatic IGF-1 appears to be an insulin sensitizer and can lower blood glucose levels, while elevated GH raises blood glucose and is associated with insulin resistance
Growth, mediated by IGF-1, is an anabolic process that requires cellular uptake of building components, such as amino acids and glucose. Administered separately from growth hormone, IGF-1 lowers elevated blood glucose levels and can cause hypoglycemia. In fact, IGF-1 has been used to treat diabetic ketoacidosis in insulin-resistant individuals. Growth hormone can be regarded as the metabolic partner of IGF-1 because growth hormone provides substrate for the effects of IGF-1. GH-stimulated fat mobilization and new glucose formation (gluconeogenesis)
Cushing’s Syndrome, Glucocorticoids, and 11-β-Hydroxysteroid Dehydrogenase
Glucocorticoids were named for their ability to raise blood glucose. Excess glucocorticoid secretion or administration can lead to diabetes mellitus. Cushing’s syndrome results from excess endogenous glucocorticoid (cortisol) secretion from adrenal gland tumors; from pituitary or other tumors secreting excessive amounts of ACTH, which stimulates adrenal cortisol production; or from exogenously administered glucocorticoids used in the treatment of asthma or autoimmune disorders. Glucose intolerance and diabetes mellitus are common in Cushing’s syndrome, with frank diabetes or impaired glucose tolerance occurring in 50–90% of affected individuals. Cortisol is one of the counter-regulatory hormones and acts at many steps. One action is to increase the appetite, thereby increasing energy intake with an initial rise in blood glucose level. The lipogenic action of cortisol, to store nutrients in visceral fat tissue, contributes to insulin resistance. T
he major actions of cortisol, like those of growth hormone, lead to extrahepatic substrate mobilization. The lipolytic action of cortisol mobilizes energy from adipose tissue, providing precursors for increased hepatic glucose production. Cortisol antagonizes the effects of insulin in muscle, preventing protein synthesis and inhibiting glucose utilization; further, its catabolic actions include muscle breakdown,96 with the effect of delivering gluconeogenic precursors to the liver. In the liver, cortisol stimulates both gluconeogenesis and glycogen breakdown. The pivotal role that cortisol may play in insulin resistance and type 2 diabetes mellitus is highlighted by observations that increased cortisol production in visceral fat can be shown in a transgenic mouse model to recreate the metabolic syndrome of insulin resistance, diabetes, and hypertension (Fig. 16.2).
Pheochromocytomas, a general term applied to tumors of the adrenal medulla and the extra-adrenal chromaffin tissue, secrete catecholamines, especially norepinephrine. Headache related to extreme elevations of blood pressure (α1-adrenergic stimulation), palpitations (β1-adrenergic stimulation), anxiety, and diaphoresis dominates the clinical presentation. Diabetes occurs in up to 65% of pheochromocytomas, may mirror the paroxysmal rises in blood pressure, and has been demonstrated to resolve following tumor resection. Pheochromocytomas whose major secretory product is epinephrine are much more likely than norepinephrine-secreting tumors to present with arrhythmias, non-cardiac pulmonary edema, hypotension, and hyperglycemia. This distinct presentation reflects the combined α- and β-adrenergic stimulation of epinephrine (Fig. 16.3). The more common norepinephrine-secreting tumors may also cause hyperglycemia since norepinephrine is also a mixed agonist, although with less β activity than does epinephrine.
Fig. 16.2 Increased activity of 11-β-hydroxysteroid dehydrogenase type 1 in transgenic mice increases cortisol production in visceral fat and causes abdominal obesity and the metabolic syndrome resembling that seen in “apple-shaped” people
Fig. 16.3 The coordinated actions of elevated epinephrine in pheochromocytoma raise blood glucose
Thyroid hormone increases glucose transporters 4 (GLUT-4) in fat tissue and muscle, thereby enhancing the stimulatory effect of insulin. Given the increase in metabolic rate caused by thyroid hormones, it is logical that increased fuel would be made available to tissues. It is paradoxical then that hyperthyroidism is sometimes associated with deterioration of glucose control or with onset of frank diabetes mellitus. Partial explanations implicate increased growth hormone secretion; a hepatic gene expression profile that promotes gluconeogenesis and glycogenolysis, and decreases insulin action; and increased hepatic GLUT-2 transporters, through
which glucose effluxes out of the liver.
Primary hyperaldosteronism, the elevated secretion of the mineralocorticoid aldosterone resulting from adrenal cortical tumors, genetic mutations, or idiopathic hyperaldosteronism, is classified with the endocrinopathies that cause “other specific types” of diabetes mellitus. Yet, little is known about the occurrence, the mechanism, or the resolution of the glucose intolerance seen with hypersecretion of aldosterone. One retrospective study found a prevalence of diabetes of 5–24% in hyperaldosteronism. Physiologic potassium levels play a fundamental role in insulin secretion. Potassium stimulates glucose-induced insulin secretion, and insulin lowers serum potassium by driving the cation intracellularly. The hypokalemia that occurs with renal potassium wasting in primary
aldosteronism presumably has a restraining or inhibiting effect on insulin secretion and leads to glucose intolerance and diabetes in susceptible individuals. In addition, insulin resistance may occur. The diabetes that occurs with hyperaldosteronism may (personal observation) or may not resolve with cure of hyperaldosteronism.
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