ENDOCRINE DISORDERS AND DIABETES MELLITUS Prof Dr Jan

ENDOCRINE DISORDERS AND DIABETES MELLITUS Prof. Dr. Jan Škrha 3 rd Department of Internal Medicine, First Faculty of Medicine, Charles University, Prague 47. Jahrestagung DDG, Stuttgart

Hormone influence on glucose metabolism Hormone overproduction autonomous (tumors) insufficiency lacking h. activity (inflammation) changes in insulin secretion/action

Hypopituitary gland - adrenal axis related to diabetes • Acromegaly • GH deficiency • Hypercortisolism (Cushing´s sy) • Cortisol deficiency • Primary hyperaldosteronism • Feochromocytoma

GH & Insulin resistance GH IR in the liver and muscle - increased gluconeogenesis and glycogenolysis in the liver - decreased glucose uptake and utilisation in the muscles - lipolysis stimulation – FFA elevation - aggravated insulin resistance in the liver and muscle by Randle cycle - GH effect at postreceptor level

Acromegaly and diabetes mellitus GH causes insulin resistance (related to IGF-I) IGT – in 15 – 36 % acromegalic patients DM (usually NIDDM) – in 15 – 30 % (56%) pts with acromegaly When DM diagnosed - acromegaly lasts 5 -10 yrs GH suppression – decreasing IR, IRI, improved glucose tolerance

GH defficiency and glucose regulation Especially children with GHD are prone to severe hypoglycemia In insulin treated diabetic patients : newly developed GHD is associated with hypoglycemic episodes GH treatment in GHD adults – causes limited changes in plasma glucose and insulin levels

Hypercortisolism A. Endogenous 1. ACTH dependent - central - ectopic 2. ACTH independent - adenoma, carcinoma, bilateral hyperplasia B. Iatrogenous (the most frequent) daily and cummulative dose of corticoids

GC effects on glucose metabolism GS: insulin resistance in the liver and peripheral tissues at postreceptor level 1. decreased glucose transportation into cells, decreased glucose utilisation 2. increased gluconeogenesis in the liver - induction of key gluconeogenic enzymes increased protein catabolism in muscles increased lipolysis in adipose tissue - increase of gluconeogenic substrates 3. increased glycogen synthesis and decreased glycogenolysis

Hypocorticalism and diabetes mellitus Ethiology: - peripheral – Addison´s disease (in 80 % autoimmune, TBC, tumors, adrenex) - central (in hypopituitarism) Autoimmune Addison´s disease (AAD): - 2. 5 x more frequent in women, between 20. - 50. yrs - in 40 – 50 % APS II - Schmidt syndrome (+Hashimoto tyreoiditis, gonadal failure, - IDDM in 10 %, vitiligo, perniciose anemia, coeliac sprue) In 50 % AAD pts – in families tyreoiditis or IDDM

Hypocorticalism developed in IDDM patient - increased insulin sensitivity, decreased insulin needs decreased blood glucose levels (decreased gluconeogenesis) Hypoglycemia ! Corticoid substitution: - increased insulin needs - decreased hypoglycemia episodes

Primary hyperaldosteronism and glucose metabolism • In about 50 %: mild impaired glucose tolerance, DM is rare • Insulin secretion in OGTT is delayed and subnormal – caused by low serum potassium level • K+ improvement – improved insulin secretion

Pheochromocytoma Hyperglycemia: IGT in 30 up to 75 % Catecholamines: • Inhibit insulin secretion by stimulated α 2 - adrenergic receptors on B cells • Insulin resistance in peripheral tissue – impaired glucose utilisation (β-adrenergic receptors, at postreceptor level) increased FFA

Pheochromocytoma and glucose metabolism Catecholamines: • Glycogenolysis stimulation in the liver and muscles Gluconeogenesis stimulation - adrenalin • Lipolysis stimulation in adipose tissue - substrate for gluconeogenesis in the liver • Stimulation of glucagon secretion

Pheochromocytoma treatment • Surgical removal – improved IGT to normal • Blockade of α – adrenergic receptors – improved glucose tolerance and insulin secretion

Thyreotoxicosis Thyroxin: increases glucose production and release by the liver (glycogenolysis, gluconeogenesis, lipolysis, ketogenesis, proteolysis) increased insulin secretion peripheral insulin action: x x 0 IGT: 30 -50 % DM: worsening of glucose control, increased lability and prone to ketoacidosis

Hyperandrogenism (PCOS) plasma testosterone plasma SHBG PCOS: insulin insensitivity dependent on weight a) normal weight - normal insulin sensitivity b) overweight and obese increased insulin secretion IGT or DM dependent on PCOS duration and individual genetic disposition

Insulinoma and diabetes Extremely rare - association with T 2 DM - newly occuring severe hypoglycemia especially in the fasting state (morning!) - exclusion of the influence of diabetes treatment (oral agents)

HYPOGLYCEMIC SYMPTOMS 1) neurogenic: (adrenergic) sweating, palpitations, tachycardia, anxiety 2) neuroglycopenic: a) neurologic: headache, impaired or double vision, decreased abbility to concentrate, impaired speech and consciousness, cramps, epilepsy b) psychiatric: unusual hesitation, temper changes (depression, euphory) impaired thinking

Algorithm of diagnosis in endocrine tumors Clinical suspition Biochemical examination Diagnosis confirmed Diagnosis unconfirmed Topographic localisation CT Angiography Endosonography Localisation confirmed Localisation unconfirmed Surgery Tumor removed Tumor unremoved Conservative treatment

Clinical background • < 1 % patients with DM or IGT have primarily other endocrinopathy • DM may help to disclose other endocrinopathy Treatment of endocrinopathy may improve diabetes control

Clinical remarks - endocrinopathies are associated with changes in insulin action - IGT developes earlier than DM - screening of glucose changes has to be done in patients with endocrinopathies - improvement of insulin action is the main task for treatment - normalization of hormonal activity has to be associated with appropriate treatment of glucose metabolism

INSULIN RESISTANCE DETERMINATION

Insulin action measurement (IR) A) „Gold standard“ Isoglycemic and euglycemic hyperinsulinemic clamps (M, M/I, MCRG) B) Index HOMA = IRIB x Glucose. B 22. 5

HOMA

MCRG/I (ml/kg/min/m. U/lx 100, HOMA INSULIN ACTION IN INSULINOMA AND PRIMARY HYPERALDOSTERONISM * *

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