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Table 10–3. Mediators Implicated in Regulation of Energy Balance Regulation and target effect Released in the duodenum during a meal. Stimulates the vagus nerve projecting to the NTS and signals within the hypothalamus to induce satiety. Produced primarily by the stomach. Levels increase before meals and decrease following a meal. Stimulates growth hormone release, increases food intake. Overall has anti-leptin action. Plasma levels are low in obese patients. Member of the NPY family, released in the distal small intestine and colon in response to food. Blood levels remain elevated between meals. Reduces food intake. Peptide produced in the intestinal cells in response to high intestinal luminal glucose concentrations. Amplifies glucose-induced insulin release from the -cell.

Mediator Cholecystokinin Ghrelin

Gastrointestinal tract

PYY3–36 GLP-1

Adipose tissue Adiponectin (AdipoQ) Acylationstimulating protein Leptin Resistin Hypothalamus NPY Produced by hypothalamic neurons that express AgRP. Release is under leptin, insulin, and cortisol regulation. Stimulates food intake via the NPY5 receptor. -MSH CART AgRP Orexins (A and B) Diabetes Diabetic ketoacidosis  Diabetic ketoacidosis arises from a number of metabolic derangements caused by insulin lack.  Treatment is by intravenous fluids, insulin and potassium.  Only in the most severe cases of DKA should sodium bicarbonate be used.  Close clinical and biochemical monitoring are required to tailor the management protocol to the individual patient.  Less common, severe metabolic disturbances of carb meta: hyperosmolar non-ketotic coma and lactic acidosis. Product of POMC in hypothalamic neuronal subset under leptin regulation. Decreases food intake through melanocortin-4 receptors in the hypothalamus. Peptide produced by hypothalamic POMC-expressing neurons stimulated by leptin and amphetamines. Reduces food intake. Released from hypothalamic NPY-expressing neurons. Inhibits neuronal melanocortin-4 receptors and increases food intake. Produced by neurons in the lateral hypothalamus perifornical area. Regulated by glucose, leptin, NPY, and POMC neurons. They stimulate food intake. Increases insulin sensitivity and tissue fat oxidation, resulting in reduced circulating fatty acid levels and reduced intramyocellular and liver triglyceride content. Levels decreased in obese patients; plasma levels correlate negatively with triglycerides. Stimulates triglyceride synthesis in adipocytes, resulting in more rapid postprandial lipid clearance. Stimulates translocation of glucose transporters to the cell surface. Secreted by fat cells in proportion to fat stores. Acts on hypothalamic neurons to decrease food intake. Leptin is necessary for maturation of the reproductive axis. Peptide hormone induced during adipogenesis. It antagonizes insulin action.

Hypoglycemia  Hypoglycemia is not diagnosis but is a biochemical sign associated w/ diverse group of diseases.  Management is by glucose therapy irrespective of the underlying cause.  Excess insulin, excess alcohol or low calorie intake in a diabetic patient are most common causes of hypoglycemia.  Insulinoma is characterized by hypoglycemia in the face of inappropriately high plasma insulin.  Hypoglycemia in the neonate may result in brain damage.  Fasting hypoglycemia: o Insulinoma. Insulin-producing β-cell tumors of pancreas may be isolated or part of wider multiple endocrine neoplasia (MEN) syndrome. Insulin-induced weight gain characteristic feature. Tumor localization difficult. o Malignancy. Hypoglycemia can be found w/ any advanced malignancy. Some tumors (retroperitoneal sarcomas) cause hypoglycemia by producing insulin-like growth factors. o Hepatic and renal disease. Both the liver and kidneys are capable of gluconeogenesis. Hypoglycemia is occasionally a feature of advanced hepatic or renal impairment, but this is not diagnostic dilemma. o Addison's disease. Glucocorticoids antagonize insulin actions, adrenal insufficiency  hypoglycemia Sepsis. Overwhelming sepsis may be associated with hypoglycemia; the mechanism is unclear.  Reactive o Insulin-induced. Inappropriate or excessive insulin predictably produces hypoglycemia. Occasionally it is important to distinguish between exogenous insulin (administered by the patient or someone else) and endogenous insulin. Standard assays for insulin cannot distinguish between the two kinds. However, insulin and its associated connecting peptide (or C-peptide) are secreted by the islet cells in equimolar amounts, and thus measurement of C-peptide along with insulin can differentiate between hypoglycemia due, for example, to an insulinoma (high C-peptide) and that due to exogenous insulin (low C-peptide) o Drug-induced. Oral hypoglycemic, (sulphonylureas)  hypoglycemia. Urinary screens for sulphonylureas exist. Other drugs include salicylate, paracetamol and β-blockers. B blockers may mask pt awareness of hypoglycemia, by blunting β-effect of adrenaline and reduce/eliminating warning symp (palpitation/tremor) o Alcohol. Hypoglycemia is not uncommon in alcoholic patients. Mechanisms include inhibition of gluconeogenesis, malnutrition and liver disease. o ‘Dumping syndrome’. Accelerated gastric emptying following gastric resection may result in the rapid absorption of large amounts of glucose with a resultant surge of insulin release. Smaller, more frequent meals may help to minimize this phenomenon.  Diabetic patients: insufficient carbohydrate intake, excess of insulin or sulphonylurea, strenuous exercise, excessive alcohol intake.  Neonatal: o Small-for-gestational-age infant. Dec glycogen stores/impaired gluconeogenesis contributes. o Babies of diabetic mothers. Fetus exposed to maternal hyperglycemia develops hyperplasia of islet cells and associated hyperinsulinemia. After delivery, neonate unable to suppress high insulin levels that are now inappropriate, and hypoglycemia results. o Nesidioblastosis. Hyperplasia of islet cells develop even if mom not diabetic; unk reason o Inborn errors of metabolism. Ex: FA oxidation defects, glycogen storage diseases and galactosaemia

Left: The differential diagnosis of hypoglycemia in presence high insulin levels. Right: The differential diagnosis of hypoglycemia in the absence of high insulin levels.