Endocrine - Pancreas

Endocrine - PancreasA 23-year-old male is brought to the emergency room with weakness and confusion. He has experienced polyuria, polydipsia and increased appetite recently. His breath has a fruity odor. This patient is deficient in a substance that normally: Increases glucagon secretion Decreases glucagon secretion Facilitates the action of glucagon Increases renal glucose production Increases the renal threshold for glucose reabsorption

A 23-year-old male is brought to the emergency room with weakness and confusion. He has experienced polyuria, polydipsia and increased appetite recently. His breath has a fruity odor. This patient is deficient in a substance that normally: Increases glucagon secretion Decreases glucagon secretion Facilitates the action of glucagon Increases renal glucose production Increases the renal threshold for glucose reabsorption

This patient is exhibiting classic signs and symptoms of diabetic ketoacidosis (DRA). The three cardinal signs of diabetes mellitus (DM) are polyuria, polydipsia and polyphagia. Undiagnosed DM can progress to DKA. DKA can be the initial presentation of DM, especially in patients lacking regular health follow-up. DKA results from a deficiency of insulin and an excess of glucagon coupled with adrenergic activation and increased levels of cortisol and growth hormone. Insulin and glucagon normally act in opposition to one another, with insulin inhibiting glucagon release. Patients with DM (especially type I DM) however, are unable to synthesize sufficient insulin to prevent hyperglycemia and to inhibit glucagons effects. Because glucose is inadequately transported into cells in patients with DM and DKA, the body perceives hypoglycemia and a starved state despite high serum glucose levels. Adrenergic nervous system activation and increased glucagon production result. Glucagon stimulates ketoacid synthesis in adipose tissue because during starvation ketoacids can be used by cells for energy in place of glucose. Glucagon also increases glycogenolysis, gluconeogenesis, lipolysis, and urea production. Patients with DKA clinically exhibit nausea and vomiting, severe abdominal pain, tachycardia, tachypnea, dry mucous membranes and lethargy. There is classically a fruity odor on their breath due to the presence of ketone bodies. (Choice A) Factors that increase glucagon secretion are hypoglycemia, increased serum amino acid concentration, adrenergic stimulation cholecystokinin and acetylcholine. (Choice D) Insulin promotes glucose storage in the form of glycogen. Glucagon, not insulin, stimulates glucose production (gluconeogenesis). (Choice E) Normally all glucose filtered from the blood in the glomerular capillaries into Bowmans capsule is reabsorbed in the proximal convoluted tubule. Insulin does not affect this process.

A 45-year-old male is diagnosed with diabetes mellitus during a routine check-up. His urine is negative for glucose and ketones, however. Treatment with which of the following agents would increase the C-peptide level in this patients blood? Acarbose Glyburide Metformin Rosiglitazone Enalapril Low-calorie diet

A 45-year-old male is diagnosed with diabetes mellitus during a routine check-up. His urine is negative for glucose and ketones, however. Treatment with which of the following agents would increase the C-peptide level in this patients blood? Acarbose Glyburide Metformin Rosiglitazone Enalapril Low-calorie diet

This patient likely has type 2 diabetes with some residual pancreatic [3-cell function. He does not have glycosuria or ketosis because his islet cells are secreting some insulin. Insulin is derived from single-chain proinsulin in pancreatic 13-cells. Within the endoplasmic reticulum of these cells endopeptidases cleave proinsulin to form insulin and C peptide. C peptide and mature insulin are subsequently packaged into secretory granules in the Golgi apparatus. C peptide and insulin are secreted in equimolar concentrations, but unlike insulin, C peptide is not significantly extracted on first pass through the liver. Thus, its circulating levels in plasma can be used as a marker of the total rate of 13-cell endogenous insulin secretion under steady-state conditions. Essentially this question asks us which of the agents listed increases the rate of insulin secretion by residual pancreatic islet j3-cells in patients with type 2 diabetes. Glyburide is an oral hypoglycemic agent (a sulfonylurea) that stimulates insulin release in type 2 diabetics.

(Choice A) Acarbose inhibits a-glucosidase in the intestinal brush border, which impairs the hydrolysis of sugars and postprandial absorption of ingested polymeric glucose. By reducing postprandial hyperglycemia, acarbose decreases endogenous insulin secretion and C peptide levels in type 2 diabetics with residual pancreatic [3cell function. (Choices C and D) Metformin (a biguanide) and rosiglitazone (a thiazolidinedione) increase the sensitivity of target tissues to insulin. They have little effect on insulin secretion. (Choice E)The ACE-inhibitor enalapril is a reno protective agent that decreases diabetic proteinuria. It does not have significant effects on blood glucose levels or endogenous insulin secretion. (Choice F) Fasting and decreased caloric intake would decrease the rate of endogenous insulin secretion and corresponding C peptide levels.

It has been shown that in the presence of insulin D-glucose transport across the plasma membrane of adipose cells is much faster than L-glucose transport. Which of the following best explains the observed effect? Simple diffusion Receptor-mediated endocytosis Carrier-mediated transport Primary active transport Exchange transport

It has been shown that in the presence of insulin D-glucose transport across the plasma membrane of adipose cells is much faster than L-glucose transport. Which of the following best explains the observed effect? Simple diffusion Receptor-mediated endocytosis Carrier-mediated transport Primary active transport Exchange transport

Glucose is the major source of energy for all cells of the body. In the majority of tissues glucose transport occurs along its concentration gradient, from higher concentrations outside the cell towards lower concentrations inside the cell. Glucose transport into cells that occurs by means of transport proteins without the expenditure of energy is called facilitated diffusion.

Glucose transporters are transmembrane proteins that belong to the GLUT family. They are stereo selective and preferentially catalyze the entrance of D-glucose rather than L-glucose into cells. GLUT4 is the insulin-sensitive transporter found in skeletal and cardiac muscle cells as well as adipocytes. In these cells, the GLUT4 protein is stored in cytoplasmic vesicles. Under the influence of insulin the transporter protein is incorporated into the cell membrane. An increased number of transporters in the membrane lead to an increase in the rate of glucose uptake by the cells. Another important glucose transporter is GLUT2. It is located in the liver, small intestine and kidneys and facilitates export of glucose from cells. In contrast to facilitated diffusion transport of glucose against its concentration gradient requires the expenditure of energy. This process is executed by the Na/glucose cotransporter and is an example of secondary active transport. This form of transport classically occurs in the intestinal epithelium and renal tubular epithelium.

(Choice A) Simple diffusion refers to the movement of particles along their concentration gradient through the permeable membrane. Carrier proteins do not participate in simple diffusion. (Choice B) Endocytosis is the process of uptake of substances into the cell by the formation of membrane-bound, typically clathrin-coated, vesicles. Uptake of cholesterol by cells occurs by means of receptor-mediated endocytosis (mediated by the LDL receptor). (Choices D and E) Primary active transport refers to the movement of a substance against its concentration gradient. This type of transport requires energy as well as transport proteins. The key difference between primary and secondary active transport is that in primary active transport the energy required for the reaction is released during transport by the hydrolysis of ATP. In secondary active transport (exchange transport) the energy required for the reaction is generated by coupling with transport of sodium along its gradient.

A group of investigators studies glucose transporters that facilitate glucose diffusion in various tissues. The following graph plots the number of glucose transporters found on the cell surface of two types of cells (circles versus squares) against insulin concentration. Respectively, which cell types do the circles and square most likely represent? Adipocytes and skeletal muscle cells Hepatocytes and cortical pyramidal cells Hepatocytes and renal tubular cells Skeletal muscle cells and renal tubular cells Pancreatic beta cells and intestinal epithelial cells

A group of investigators studies glucose transporters that facilitate glucose diffusion in various tissues. The following graph plots the number of glucose transporters found on the cell surface of two types of cells (circles versus squares) against insulin concentration. Respectively, which cell types do the circles and square most likely represent? Adipocytes and skeletal muscle cells Hepatocytes and cortical pyramidal cells Hepatocytes and renal tubular cells Skeletal muscle cells and renal tubular cells Pancreatic beta cells and intestinal epithelial cells

The figure shows that for the cell type represented by circles, an increasing insulin concentration corresponds with a progressively increasing expression of glucose transporters. On the other hand, there is no change in the expression of glucose transporter in the cell type depicted by squares. Of 5 major facilitative glucose transporters, only glucose transporter4 (GLUT-4) is responsive to insulin. GLUT-4 is predominantly expressed in muscle cells and adipocytes. This receptor is normally sequestered in the cytoplasm, but with insulin action, it moves to the plasma membrane, which allows glucose transport down the concentration gradient to within the cell. In the absence of insulin, muscle cells and adipocytes are impermeable to glucose. In contrast to GLUT-4 the other glucose transporters are always present on the plasma membrane to constitutively transport glucose. Choice D is the only response that clearly shows one cell type with an insulin-responsive glucose transporter (skeletal muscle) and one cell type with an insulin-unresponsive glucose transporter (renal tubular cells).(Choice A) Both muscle cells and adipocytes have insulin-responsive GLUT4. (Choices B, C and E) All of the cells in rest of the choices have insulin-independent glucose transporters. The following table summarizes the five major types of glucose transporters, their distribution and distinctive characteristics.

A 27-year-old Caucasian male experiences disorientation, palpitations, tremulousness and excessive sweating, all of which quickly ameliorate after drinking some honey dissolved in water. He has had type 1 diabetes mellitus for 4 years and his insulin regimen has been stable for the last six months. Which of the following most likely precipitated this patients symptoms? Respiratory infection Moderate to severe pain Exercise Weight gain Sleep deprivation

A 27-year-old Caucasian male experiences disorientation, palpitations, tremulousness and excessive sweating, all of which quickly ameliorate after drinking some honey dissolved in water. He has had type 1 diabetes mellitus for 4 years and his insulin regimen has been stable for the last six months. Which of the following most likely precipitated this patients symptoms? Respiratory infection Moderate to severe pain Exercise Weight gain Sleep deprivation

The patient has typical symptoms of hypoglycemia: confusion, sweating, tremors, and heart palpitations. Honey-water, or any intake of carbohydrate, will ameliorate symptoms. Exercise is an important cause of hypoglycemia in diabetics. Exercise is generally associated with lowering of blood sugar both in diabetic and non-diabetic individuals. Exercise increases glucose uptake by muscle cells through two main mechanisms: (1) Sensitization of muscle cells to the action of insulin, and (2) increased insulin-independent glucose uptake into the exercising muscles. In normal individuals, a drop in blood glucose will stop insulin release from beta cells, which prevents a further drop in blood glucose. However, diabetics do not have this feedback mechanism because they are treated with exogenous insulin or sulfonylurea agents (insulin secretogogue) which causes circulating insulin levels to remain elevated despite low blood glucose levels. Moreover, circulating insulin levels can jump even higher secondary to the rapid absorption of insulin injected into an exercising limb. In general, the following rules are extremely helpful in reducing the occurrence of hypoglycemia in insulin-treated diabetic: Eat about 15-40gm of immediately-available carbohydrate before performing exercise. Check blood sugars before, during and after exercise (useful in prolonged exercise). Time dosage so that insulins peak effect will not occur during exercise. Do not inject insulin in limbs that will be exercised.

(Choices A, B and E) Blood glucose tends to increase during infection, pain, and sleep deprivation. Stressful situations increase catecholamine release, which causes hyperglycemia. Catecholamines increase blood sugars by decreasing the release of insulin, by increasing glycogenolysis, and by increasing gluconeogenesis. (Choice D) One side effect of insulin therapy is weight gain. Lowering of blood sugar reduces glucosuria so that sugar-calories are no longer lost in urine. Furthermore, insulin has a lipogenic effect on adipocytes.

A 24-year-old male who was diagnosed with diabetes two years ago temporarily loses consciousness after he skipped a meal that was to follow his insulin injection. His girlfriend administered glucagon immediately, as instructed by the physician and the patient recovered consciousness in ten minutes. Metabolic changes in which of the following organs are mostly responsible for this patients recovery? Small intestine Liver Pancreas Skeletal muscles Adrenals Adipose tissue Kidney

A 24-year-old male who was diagnosed with diabetes two years ago temporarily loses consciousness after he skipped a meal that was to follow his insulin injection. His girlfriend administered glucagon immediately, as instructed by the physician and the patient recovered consciousness in ten minutes. Metabolic changes in which of the following organs are mostly responsible for this patients recovery? Small intestine Liver Pancreas Skeletal muscles Adrenals Adipose tissue Kidney

Glucagon increases serum glucose by increased production of glucose from the liver. This is achieved by increasing glycogenolysis (breakdown of glycogen) and increase in gluconeogenesis (production of glucose from non- carbohydrate sources). (Choice C) Glucagon stimulates insulin secretion from the pancreas. However, patients with type 1 diabetes typically do not have residual beta cells. Therefore, glucagon will not have a significant effect on the pancreas of type 1 diabetics. (Choices D, E and F) Epinephrine increases glucose by multiple mechanisms, including increased glycogenolysis and gluconeogenesis in the liver. In skeletal muscle, epinephrine decreases glucose uptake. Epinephrine also causes increased alanine release from skeletal muscle, which serves as a source of gluconeogenesis in the liver. In adipose tissue, epinephrine increases the breakdown of triglycerides thereby increasing free fatty acids and glycerol in the circulation: these can be utilized as gluconeogenetic substrates as well. Glucagon has insignificant effect on skeletal muscle cells and adipocytes. (Choice G) During first 24-hours of fasting the liver is the main organ responsible for providing glucose. When hypoglycemia is sustained gluconeogenesis in the kidneys becomes an important source. Glucagon does not have any substantial effect on gluconeogenesis in the kidneys.

A 20-year-old female presents to the ER with extreme weakness, abdominal pain, and nausea. For the past few weeks, she has had polyuria and excessive thirst. She unintentionally lost 10 lbs in last month. Physical examination shows tachycardia and dry mucus membranes. Laboratory studies show: Chemistry panel Serum sodium 130 mEq/L Chloride 93 mEq/L Bicarbonate 12 mEq/L Blood urea nitrogen (BUN) 30 mg/dL Serum creatinine 1.2 mg/dL Calcium 10.0 mg/dL Blood glucose 698 mg/dL Which of the following potassium values would be most likely in this patient?Intracellular potassium Extracellular potassium Decreased increased Increased decreased Increased increased Decreased decreased No Change No change

A 20-year-old female presents to the ER with extreme weakness, abdominal pain, and nausea. For the past few weeks, she has had polyuria and excessive thirst. She unintentionally lost 10 lbs in last month. Physical examination shows tachycardia and dry mucus membranes. Laboratory studies show: Chemistry panel Serum sodium 130 mEq/L Chloride 93 mEq/L Bicarbonate 12 mEq/L Blood urea nitrogen (BUN) 30 mg/dL Serum creatinine 1.2 mg/dL Calcium 10.0 mg/dL Blood glucose 698 mg/dL Which of the following potassium values would be most likely in this patient?Intracellular potassium Extracellular potassium Decreased increased Increased decreased Increased increased Decreased decreased No Change No change

This young patient has both clinical and biochemical features of diabetic ketoacidosis (DKA); she has high blood glucose, low bicarbonate, a high anion gap, and decreased sodium. Most patients in DKA have decreased levels of intracellular potassium with normal to increased extracellular potassium levels. Potassium loss occurs via osmotic diuresis induced by glycosuria. Acidosis also pulls potassium from the intracellular compartment leading to normal to elevated serum potassium levels. Lack of insulin is also responsible for movement of potassium outside the cells because insulin normally promotes the intracellular movement of potassium. The net result of all these events is low total body potassium and low intracellular potassiumwith normal to increased extracellular potassium. Then when insulin and intravenous fluids are given to resuscitate the dehydrated and hyperglycemia patient, they push the potassium back into the cells, which cause a precipitous drop in serum potassium because there is still an overall potassium deficiency. When a patient comes to the hospital in DKAI that patient will have low total potassium, even though labs will return with a normal or even elevated serum potassium level.

(Choice B) Increase in intracellular potassium with decreased extracellular potassium is seen with glucose and insulin administration. Stimulation of beta-adrenergic receptors also causes an increased transfer of potassium to the intracellular compartment. (Choice C) The renal excretion of potassium is impaired in most patients with chronic renal failure, resulting in high intra- as well as extracellular potassium. (Choice D) A decrease in both intra- and extravascular potassium is seen with mineralocorticoids excess, diuretic use, and gastrointestinal losses.

A 60-year-old Caucasian male presents to your office for a routine checkup. He has no complaints. His blood pressure is 165/110 mmHg, and heart rate is 75/mm. Physical examination reveals a moderately overweight man (BMI = 28.3 kg/m2) with predominantly central fat distribution. Lab work demonstrates a blood glucose level of 150 mg/dL. If present, which of the following is most likely responsible for the resistance of peripheral tissues to the action of insulin in this patient? High low density lipoprotein (LDL) Low high density lipoprotein (HDL) High free fatty acids (FFA) High serum C-peptide level High serum beta-hydroxybutyrate High homocysteine

A 60-year-old Caucasian male presents to your office for a routine checkup. He has no complaints. His blood pressure is 165/110 mmHg, and heart rate is 75/mm. Physical examination reveals a moderately overweight man (BMI = 28.3 kg/m2) with predominantly central fat distribution. Lab work demonstrates a blood glucose level of 150 mg/dL. If present, which of the following is most likely responsible for the resistance of peripheral tissues to the action of insulin in this patient? High low density lipoprotein (LDL) Low high density lipoprotein (HDL) High free fatty acids (FFA) High serum C-peptide level High serum beta-hydroxybutyrate High homocysteine

One of the important actions of insulin is the facilitation of glucose uptake by adipocytes and muscle cells. Several genetic and environmental factors can cause insulin resistance. High free fatty acid levels are one environmental factor that results in insulin resistance. The mechanism by which free fatty acid induces insulin resistance is unclear. Serine phosphorylation of the insulin receptors beta subunit could be involved. This phosphorylation of serine interferes with down-stream signaling because serine kinase, instead of tyrosine kinase, becomes activated. Serine phosphorylation is a known mechanism of insulin resistance induced by TNF-alpha, glucagon, and glucocorticoids. Free fatty acids also act to decrease insulin secretion, which prevents the compensatory rise of insulin that is required to overcome insulin resistance. The induction of insulin resistance and beta cell dysfunction along with high free fatty acids is termed lipo toxicity. Lowering free fatty acids improves beta cell function and insulin resistance. The other choices listed do not interfere with insulin secretion or insulin action. (Choices A and B) LDL is metabolized by receptor-mediated endocytosis, mainly in the liver. LDL levels are governed by diet, liver production, and receptor-mediated LDL uptake. Insulin is not directly involved in LDL metabolism. High serum triglycerides and free fatty acids are commonly seen in insulin resistance and uncontrolled diabetes mellitus. The surface phospholipids in LDL particles are replaced by triglycerides in diabetics. The subsequent removal of surface triglyceride in the liver by hepatic lipase results in highly atherogenic small dense LDL particles. Serum HDL is generally low in diabetics because the altered cell surface composition accelerates the clearance of HDL. In contrast to free fatty acids, LDL and HDL do not alter insulin signaling. (Choice D) C-peptide is secreted in equimolar amount with insulin from pancreatic beta cells. It is true that increased C-peptide levels are present in insulin resistance, but C-peptide does not have any biological effect. (Choice E) Beta hydroxybutyrate is a marker of insulin deficiency and would be present only in type 1 diabetes mellitus. Patients with type 2 diabetes mellitus do not have high beta hydroxybutyrate because they do not have absolute deficiency of circulating insulin. Beta hydroxybutyrates do not interfere with the actions of insulin. (Choice F) Homocystinemia has been linked to atherosclerosis. Lowering of homocysteine levels by folic acid treatment has been shown to decrease the progression of atherosclerosis in some studies. However, high homocysteine levels do not interfere with insulin action.

A 58-year-old Caucasian male is hospitalized by the sudden onset of chest pain. His blood pressure is 160/110 mmHg, and his heart rate is 90/mm. His BMI is 30.5 kg/rn2. A baseline ECG reveals non-specific ST segment and T wave changes, and serial troponin measurements are normal. His fasting plasma glucose level is found to be 160 mg/dL, although he has never been diagnosed with diabetes mellitus. Which of the following would correlate most with the resistance of tissues to the action of insulin in this patient? Arm circumference Triceps area skin thickness Waist-to-hip ratio Increase in liver glycogen Urinary ketone excretion

A 58-year-old Caucasian male is hospitalized by the sudden onset of chest pain. His blood pressure is 160/110 mmHg, and his heart rate is 90/mm. His BMI is 30.5 kg/rn2. A baseline ECG reveals non-specific ST segment and T wave changes, and serial troponin measurements are normal. His fasting plasma glucose level is found to be 160 mg/dL, although he has never been diagnosed with diabetes mellitus. Which of the following would correlate most with the resistance of tissues to the action of insulin in this patient? Arm circumference Triceps area skin thickness Waist-to-hip ratio Increase in liver glycogen F. Urinary ketone excretion

The patient described in this vignette has hypertension obesity and possible type 2 diabetes mellitus. The pathophysiology of type 2 diabetes mellitus involves insulin resistance along with defective insulin secretion from pancreatic beta cells. Although still controversial, many researchers believe that insulin resistance is the main defect in type 2 diabetes mellitus. Insulin resistance is a heterogenous disorder caused by number of genetic and environmental factors. Genetic defects include receptor and post-receptor mutations that result in faulty insulin signaling. Environmental factors that increase insulin resistance include lack of physical activity and obesity. Increased BMI is very commonly associated with insulin resistance and type 2 diabetes mellitus. A high BMI typically connotes a higher body fat content, although a very muscular person (like a bodybuilder) might have a high BMI, also. There are two different types of fat in the body: visceral fat and subcutaneous fat. In general, the visceral deposition of fat (fat surrounding internal organs) has a much stronger correlation with insulin resistance than does subcutaneous fat. Measuring of the waist-to-hip ratio (VVHR) indirectly measures the visceral fat to subcutaneous fat as the abdomen contains mainly viscera and hips have only subcutaneous fat. A high waist hip ratio is associated with insulin resistance, metabolic syndrome and type 2 diabetes mellitus. The metabolic syndrome is a group of risk factors that include hypertension, abdominal obesity, atherogenic dyslipidemia, insulin resistance and other factors. (Choices A and B) Measuring the whole arm circumference or triceps skin fold thickness correlates poorly with insulin resistance and type 2 diabetes mellitus. These parameters indirectly measure muscle mass and/or subcutaneous fat deposition. (Choice D) An increase in liver fat suggests insulin resistance; whereas, an increase in glycogen deposition suggests enhanced insulin action (after glycogen storage diseases have been excluded). Insulin increases glycogen synthesis in the liver and in skeletal muscles. (Choice E) Increase in urine ketone production usually occurs with absolute insulin deficiency as seen in type 1 diabetes mellitus. Although type 2 diabetics are relatively deficient in insulin the absence is not complete. In fact patients with type 2 diabetes mellitus generally have high circulating insulin which suppresses ketogenesis.