Insulin plays a central role in metabolic regulation, but its actions are modified or balanced by those of many other hormones, including glucagon, growth hormone, corticosteroids, thyroxine and adrenaline (epinephrine). Overproduction of these counterregulatory hormones may induce hyperglycaemia and other metabolic disturbances, particularly where insulin secretion is already deficient; conversely, failure of secretion can predispose to hypoglycaemia, especially in those treated with insulin. Endocrine dysfunction, although uncommon, should be considered in all those with newly-diagnosed diabetes, and in those on treatment for diabetes whose control becomes unstable for unknown reasons. Since endogenous insulin is still produced, the metabolic disturbance is typically mild, and can often be reversed by treating the endocrine disorder.
Although insulin can be considered the key modulator of intermediary metabolism, its actions are balanced (rather than "opposed") by a number of other hormones, including glucagon, corticosteroids, growth hormone, adrenaline and thyroxine. Overproduction of any of these can predispose to the development of diabetes, and analysis of this phenomenon provided early insight into the metabolic actions of the hormones involved.
Overproduction of a hormone implies loss of feedback regulation, often due to development of an endocrine tumour. The resultant hyperglycaemia is typically mild and develops only in a minority of those affected, presumable those with an existing predisposition to diabetes. Diabetes is often reversible by treatment of the endocrine disorder, but permanent diabetes may result following prolonged exposure.
Glucocorticoids may be produced in excess because of an ACTH-producing pituitary adenoma (pituitary Cushing's, or Cushing's disease), or from an adrenal tumour or hyperplasia (adrenal Cushing's), or from an ACTH-secreting tumour, typically a small cell tumour of the lung; this is paraneoplastic or ectopic Cushing's. The syndrome is however most commonly produced by administration of steroids, which may be a factor in up to 3% of all cases of diabetes.
Key features are central fat deposition resulting in a moon face, fat deposition over the clavicles and upper spine ("buffalo hump") and around the abdomen with production of stretch marks. Muscle wasting leads to thinning of the arms and legs, and increased hepatic glucose production due to accelerated gluconeogenesis is another consequence of increased catabolism. Other changes include thinning of the skin with easy bruising, delayed healing, and osteoporosis. Hypertension due to mineralocorticoid effects is another consequence.
Oversecretion of growth hormone (GH) from the anterior pituitary, most commonly caused by a benign pituitary adenoma, causes gigantism in childhood or adolescence or acromegaly in adults following fusion of the epiphyseal plates. In acromegaly growth continues in the bones of the face, hands and feet to produce the characteristic appearance associated with this condition. Overproduction of GH may rarely be due to excessive secretion of growth hormone releasing hormone (GHRH) produced by tumours elsewhere in the body. Growth hormone may be administered to children with small stature, and has been used in the attempt to improve sporting performance.
Clinical features include local effects due to expansion of the tumour. Pressure upon the optic nerves causes loss of peripheral vision, loss of secretion of other hormones produced by the pituitary, and headache. Systemic effects include enlargement of the heart and heart failure, arthritis, and the carpal tunnel syndrome. Palmar sweating and greasy skin due to increased sebum secretion by the face are also characteristic. GH opposes several of the actions of insulin to produce insulin resistance. Overt diabetes develops in about 20% and glucose intolerance in about 80% of cases.
Excessive secretion of thyroid hormone is commonly due to autoimmune Graves' disease in younger people, with a marked female excess, or to multinodular goitre or toxic adenoma in older people.
The classic symptoms of hyperthyroidism are weight loss, heat intolerance and sweating, palpitation, anxiety and tremor. Other classical symptoms are fatigue and weakness, insomnia, irritability, impaired concentration and diarrhoea. Exophthalmos is seen in Graves' disease.
The metabolic consequences of excess thyroid hormone are due to accelerated catabolism with increased breakdown of protein and fat, and increased hepatic glucose production due to accelerated gluconeogenesis. Secondary effects are due to increased sympathetic activity.
Graves' disease is associated with type 1 diabetes and hyperthyroidism should be considered in anyone with diabetes who develops unexplained weight loss in association with worsening metabolic control.
Phaeochromocytoma, a tumour of the chromaffin tissue of the adrenal medulla or sympathetic paraganglia, is characterized by the overproduction of catecholamines, usually adrenaline and noradrenaline.
Phaeochromocytoma may occur as a sporadic tumour or as an element in the syndrome of multiple endocrine neoplasia (MEN). In MEN IIa, it occurs in association with medullary thyroid or parathyroid neoplasia, and MEN IIb it is associated with a Marfanoid appearance, multiple benign tumours of the oral cavity, and an aggressive form of medullary cancer of the thyroid.
The glucagonoma syndrome is a rare paraneoplastic phenomenon identified as a slow-growing alpha cell tumour of the pancreatic islets of Langerhans. It was first described in 1942, and there are only around 250 cases in the world literature; glucagonoma is thought to cause 1% of all pancreatic neuroendocrine tumours with an incidence of around one in 20 million. Two thirds of cases present with necrolytic migratory erythema, which is characterised by erythema and blistering over pressure points; the condition is related to zinc and amino acid deficiencies. Glucagon levels may be elevated 1000-fold. Weight loss is characteristic and diabetes develops in 70-90% of cases.