Palpitation case 3

Palpitation case 3

A 23-year-old college senior with type 1 diabetes was preparing for an 11 a.m. examination. He had taken insulin that morning, but was very nervous about the test and forgot if he had eaten anything for breakfast. With time, he felt his heart pounding, his palms were sweaty, his hands were shaking, and he felt dizzy. He wanted to take a sugar tablet, but at that moment, his friend arrived and they rushed to school. In the car, he developed a headache and difficulties concentrating on the conversation, but he thought all of these symptoms were the result of the nervousness caused by the approaching exam. He was confused, the speech became slurred, and finally he lost consciousness. His friend brought him to the emergency department. On site, his blood glucose level was 40 mg/dL. After medical intervention, he successfully recovered without sequelae.

Q1

Administration of which of the following pancreatic hormones would be expected to help this patient?
/ A. Amylin
/ B. GIucagon
/ C. Insulin
/ D. Pancreatic polypeptide
/ E. Somatostatin

Q2

Beta-receptor antagonists prevent many of the premonitory signs of this condition, which are caused by an epinephrine response. Which of the following signs will still be present despite beta blockade?
/ A. BIurred vision
/ B. Palpitations
/ C. Sweating
/ D. Tachycardia
/ E. Trembling

Q3

Which additional action occurs as a result of this epinephrine response?
/ A. Inhibition of glucose uptake
/ B. Stimulation of gluconeogenesis
/ C. Stimulation of glucose uptake
/ D. Stimulation of glycogenolysis
/ E. Stimulation of glycogen synthesis

Q4

After he is successfully treated and released from the hospitaI, which of the following compounds will be the major substrate for his brain metabolism?
/ A. Fatty acids
/ B. GIucose
/ C. Ketone bodies
/ D. Mannose
/ E. Triacylglycerols

A5

If this patient's symptoms were due to ingestion of a drug, which of the following agents would he have most likely ingested?
/ A. CIozapine
/ B. Diazoxide
/ C. GIucocorticoids
/ D. Pentamidine
/ E. Thiazide diuretic

_____________________________________________________________________

Palpitation case 3 answers

A1
The correct answer is B. Glucagon is a single-chain peptide of 29 amino acids, produced by alpha cells of the endocrine pancreas, and is structurally related to the secretin family of peptide hormones. Glucagon is synthesized as proglucagon and processed to give glucagon within the pancreatic islets. Within the intestinal tract, proglucagon is processed to a family of glucagon-like peptides. The major effect of glucagon is to stimulate an increase in glucose concentrations. The mechanism involves stimulation of hepatic glycogenolysis and hepatic gluconeogenesis, and inhibition of glycogen synthesis. In the liver, glucagon also activates the transport of long-chain free fatty acids into mitochondria for oxidation and ketogenesis. It appears to have a minor effect of stimulating lipolysis in adipose tissue, thereby providing fatty acid fuels to most cells and conserving blood glucose. The molecular mechanism of glucagon action involves activation of adenylate cyclase via Gs and an increase in cAMP, which induces gene expression of PEPCK (phosphoenolpyruvate carboxykinase), a key gluconeogenic enzyme. On the other hand, cAMP-activated PKA (protein kinase A) activates phosphorylase and inactivates glycogen synthase in the liver. Glucagon is used to treat severe hypoglycemic episodes when oral glucose is inadequate, and IV glucose is not available (emergencies away from medical settings). The usual dose of glucagon in adults is 0.5 to 1.0 U given SC, IM. or IV.
Amylin (choice A) is a beta cell hormone that is colocalized and cosecreted with insulin. It appears to work in concert with insulin to regulate glycemia, suppressing the postprandial secretion of glucagon and slowing the rate of gastric emptying.
Insulin (choice C) is the only hormone that causes hypoglycemia.
F or D1 cells produce pancreatic polypeptide (choice D). The function of this hormone is still uncertain, but it is suggested that it may influence gastrointestinal function and promote intraislet homeostasis.
D cells produce somatostatin (choice E), which inhibits insulin and glucagon secretion locally (paracrine effect) within the pancreatic islets.


A2
The correct answer is C. Beta receptor blockade prevents the warning signs of hypoglycemia caused by epinephrine release. However, sweating will still occur despite the beta blockade. Human skin contains two types of sweat glands: eccrine (merocrine) and apocrine sweat glands. Eccrine sweat glands are the predominant type. They are found all over the body, particularly on the palms of the hands, soles of the feet and forehead. Apocrine glands are located in the perigenital area, and in the axilla. They produce a viscous, more protein-rich secretion than eccrine glands, and are innervated by the sympathetic adrenergic nerves via alpha1 receptors. Eccrine sweat glands are activated by sympathetic cholinergic nerves (muscarinic M3 receptors). Therefore, hypoglycemic sweating will still be evident in the presence of beta-adrenergic blockade.
Beta2-mediated epinephrine responses an cause relaxation of the ciliary muscle and consequent blurred vision (choice A).
Palpitations (choice B) are unpleasant sensations of irregular/and or forceful beating of the heart. They are elicited through activation of beta1 and beta2 receptors that result in increased automaticity (phase 4 depolarization) and conduction velocity, and via a separate set of beta2 adrenergic receptors, an increase in contractility.
Tachycardia (choice D) is a result of epinephrine-induced activation of beta1 and beta2 receptors located at the cells of the SA (sinoatrial) node.
Trembling (choice E) is mediated through beta-adrenergic receptors.


A3
The correct answer is D. Under normal conditions, increased glycogen release is the major counterregulatory response to hypoglycemia. However, in patients with diabetes mellitus, glucagon secretion in response to hypoglycemia is defective, and under these circumstances, epinephrine secretion becomes the critical counterregulatory factor. The absent glucagon response results from the loss of the intraislet insulin-inhibition of glucagon release. Stimulation of glycogenolysis in liver provides the major source for circulating glucose, because liver cells contain glucose-6-phosphatase. Epinephrine stimulates hepatic glycogenolysis via adrenergic beta2 receptors, thereby increasing the delivery of glucose to the circulation. It activates adenylate cyclase, and the increased cAMP activates protein kinase A (PKA). PKA catalyzes the phosphorylation of phosphorylase kinase to convert it from the inactive form b to the active form a. Subsequently, activated phosphorylase kinase a then catalyzes the phosphorylation of glycogen phosphorylase-b to produce an active form of the enzyme. At the same time, PKA converts glycogen synthase to the inactive form, which prevents resynthesis of glycogen. The hormone also stimulates glycogenolysis in muscle through the activation of beta2-adrenergic receptors. Because muscle lacks the enzyme glucose-6-phosphatase, the glucose-6-phosphate enters the glycolytic sequence to give pyruvate. Pyruvate is converted to lactate, and lactate produced in muscle is released to the blood stream and transported to the liver, where it is converted to glucose in the process of gluconeogenesis. The glucose is then returned to the blood and can be used as an energy source by the brain and by muscle. This cycle is termed the Cori cycle. Epinephrine also stimulates lipolysis in adipocytes through activation of alpha-adrenergic receptors, and glycerol, the product of fat tissue lipolysis, serves as an additional gluconeogenic substrate.
Cortisol inhibits glucose uptake (choice A), stimulates hepatic gluconeogenesis, stimulates protein breakdown in muscle, and stimulates lipolysis, all of which help restore the glucose level in hypoglycemia. However, the cortisol response is delayed, and less critical than the epinephrine response.
Growth hormone stimulate lipolysis in adipocytes, and gluconeogenesis (choice B) in liver, thereby acting as a second-line counterregulatory hormone.
Insulin stimulates glucose uptake into cells (choice C), which leads to hypoglycemia.
Insulin increases glucose storage as glycogen in liver. In skeletal muscle, insulin promotes glycogen synthesis (choice E) by increasing glucose transport, inducing glycogen synthase and inhibiting phosphorylase.


A4

The correct answer is B. The brain represents 2% of body weight, but receives 15% of the cardiac output, consumes 20% of the total O2, and utilizes 25% of the total glucose. Glucose is the major, and nearly the sole source of energy for the brain. Therefore, plasma glucose is normally very carefully regulated to maintain the level that ensures glucose transport into the brain at adequate rates. Insulin is not required for brain cells to utilize glucose. The carbohydrate reserves in brain tissues are extremely limited, and normal function depends upon continuous glucose supply. Under normal conditions, the brain takes three times more glucose than it needs from the circulation. At some critical glucose concentration (approx. 70 mg/dL), centers in the hypothalamus sense a fall in the blood glucose level, and the release of glucagon and epinephrine is triggered. If the blood glucose level is below 30 mg/dL, coma develops, and below 15 mg/dL, permanent brain damage and/or death ensue.
Astrocytes, a major class of glial cells in mammalian brain, play a pivotal role in the regulation of brain metabolism by providing neurons with anaplerotic metabolites and substrates for energy generation. Glucose enters the brain via an insulin-independent GLUT 1 transporter in cerebral capillaries. The entrance of glucose into the CNS from the capillaries occurs primarily into astrocytes, which metabolize glucose through the glycolytic pathway. This mechanism seems to be coupled with the transport of glutamate into astrocytes by a Na+-cotransporter, and this secondary active transport produces ADP, which serves as a major allosteric effector for glycolysis. Glycolysis produces lactate, which is taken up and metabolized by neurons, and through oxidative phosphorylation, ATP is produced. Amino acids, lipids, and proteins derived from glucose can be metabolized for energy only during certain conditions.
The blood brain barrier excludes free fatty acids (FFA) (choice A), preventing them from entering into brain metabolism.
Acetoacetate, beta-hydroxybutyrate, and acetone are known as ketone bodies (choice C). The rate of ketone transport into the brain is too slow to meet its energy requirements unless fasting ketone body plasma levels are markedly increased. But, under particular conditions, such as starvation, diabetes, or in breast-fed neonates, plasma levels of ketone bodies increase markedly, and the brain cells can switch to ketone bodies as substrates for their metabolism. Without ketone bodies, most of us would be unconscious after 48 hours of fasting.
Mannose (choice D) theoretically can substitute for glucose as an alternative substrate for brain metabolism. It crosses the blood-brain barrier and it is converted to fructose-6-phosphate, a physiological intermediate of the glycolytic pathway. However, mannose is not normally present in the blood, and cannot be considered a physiologic metabolic substrate.
Brain cells can sometimes use triacylglycerols (choice E) for energy metabolism, but the quantitative importance of this pathway is negligible.


Q5
The correct answer is D. Pentamidine is used to treat the Pneumocystis carinii pneumonia that occurs commonly in immunocompromised patients, such as cancer patients, AIDS patients, and transplant patients. Pentamidine side effects include metallic taste, coughing, bronchospasm in heavy smokers and asthmatics, decrease in urination, unusual bleeding or bruising, and hypoglycemia. Some patients may develop sudden, severe low blood pressure after receiving pentamidine. Therefore, it is recommended that the patient lie down during the administration of the medicine. This agent is also used in patients with cutaneous and visceral leishmaniasis (kala-azar) caused by Leishmania donovani, and trypanosomiasis (Trypanosoma brucei, gambiense, and rhodesiense). The drug's hypoglycemic effect is due to lytic destruction of pancreatic beta cells, causing acute hyperinsulinemia and hypoglycemia. Later on, insulinopenia and hyperglycemia may develop. IV glucose should be administered during pentamidine administration, and during the period immediately after that.
Clozapine (choice A) is a dibenzodiazepine derivative and an atypical antipsychotic. Besides well known-side effects, such as agranulocytosis, seizures, weight gain, constipation, and hypersalivation, recent studies show an association of clozapine with hyperglycemia and diabetes.
Diazoxide (choice B) opens potassium channels in vascular muscle cells, stabilizing the membrane potential and preventing smooth muscle contraction. This leads to arteriolar dilatation and reduction of mean arterial blood pressure. The use of this agent has been associated with hyperglycemia and hyperosmolar nonketotic coma. Diazoxide inhibits insulin secretion, and is used to treat hypoglycemia secondary to insulinoma.
Glucocorticoids (choice C) stimulate gluconeogenesis and decrease insulin sensitivity, which both lead to hyperglycemia.
Hyperglycemia secondary to thiazide diuretics (choice E) is thought to be related to the depletion of potassium. Thiazides may decrease insulin secretion and contribute to the development of insulin resistance. Other drugs, such as furosemide, nicotinic acid, and oral contraceptives also can induce a hyperglycemic state.