Photo: Colorized transmission electron micrograph of an endocrine cell from the anterior pituitary gland. The secretory vesicles (brown) contain hormones. From: Seeley’s Anatomy & Physiology 10th ed New York, NY: McGraw-Hill 2010.
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Learning Objectives cont. 5. Drugs to Treat Diabetes 1. The fundamental differences between type 1 and type 2 diabetes 2. Recognition of diagnostic criteria and therapeutic goals for treatment of diabetes. 3. The pharmacological differences between the various insulin formulations used in the treatment of diabetes especially their duration of action. Specifically, which insulin types are used for the control of post-prandial glucose levels versus those used for the control of fasting glucose levels. 4. The use and clinical benefits of an intensive insulin therapy regimen in the treatment of type 1 diabetes 5. The important role of diet and exercise in the treatment of type-2 diabetes
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Learning Objectives cont.
Drugs to Treat Diabetes cont. 6. The indications, mechanism of action, clinical effects, adverse effects and contraindications of drugs commonly used in the treatment of type 2 diabetes including: a) metformin b) sulfonylureas c) meglitinides d) thiazolidinediones, e) alpha-glucosidase inhibitors f) modulators of incretin pathway g) insulin and h) pramlintide 7. An understanding of which of the drugs used for the treatment of type-2 diabetes primarily affects either post-prandial or fasting glucose levels. 3
Learning Objectives cont. Drugs to Treat Diabetes cont. 8.The concept that effective treatment of type-2 diabetes will likely require combination therapy with one or more oral anti-diabetic agents, as well as potentially the use of insulin therapy. 9. An understanding of the current treatment algorithm approved by the American Diabetes Association for the treatment of type-2 diabetes. 10. The effectiveness of tight glycemic control in the prevention of the macroand microvascular complications of diabetes
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Drugs Used in Treatment of Diabetes Mellitus Insulins Rapid-acting Insulin aspart Insulin glulisine Insulin inhalation (limited availability) Insulin lispro Short-acting Regular insulin Intermediate-acting Neutral protamine Hagedorn (NPH) insulin Combination insulin Insulin aspart protamine and insulin aspart Insulin lispro protamine and insulin lispro Insulin NPH and insulin regular Long-acting Insulin glargine Insulin detemir Marc Imhotep Cray, MD
Oral Hypoglycemics
Oral Agents cont.
Sulfonylureas First generation Chlorpropamide Tolazamide Tolbutamide Second generation Gliclazide Glimepiride Glipizide Glyburide Meglitinides Nateglinide Repaglinide Biguanide Metformin
Îą-Glucosidase inhibitors Acarbose Miglitol Thiazolidinediones Pioglitazone Rosiglitazone Amylinomimetic Pramlintide Incretin-based Exenatide Sitagliptin
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Diabetes Mellitus (DM)
Marc Imhotep Cray, MD
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Drugs Used in the Treatment of DM Insulins Rapid-acting Insulin aspart Insulin glulisine Insulin inhalation (limited availability) Insulin lispro Short-acting Regular insulin Intermediate-acting Neutral protamine Hagedorn (NPH) insulin Combination insulin Insulin aspart protamine and insulin aspart Insulin lispro protamine and insulin lispro Insulin NPH and insulin regular Long-acting Insulin glargine Insulin detemir Marc Imhotep Cray, MD
Oral Hypoglycemics
Oral Agents cont.
Sulfonylureas First generation Chlorpropamide Tolazamide Tolbutamide Second generation Gliclazide Glimepiride Glipizide Glyburide Meglitinides Nateglinide Repaglinide Biguanide Metformin
Îą-Glucosidase inhibitors Acarbose Miglitol Thiazolidinediones Pioglitazone Rosiglitazone Amylinomimetic Pramlintide Incretin-based Exenatide Sitagliptin
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Case 43 Pancreas and Glucose Homeostasis A 12-year-old boy is brought to the office by his parents because of abdominal pain for the past day. Prior to this, the parents noted that he was drinking a lot of water and going to the bathroom frequently. He said that his mouth was very dry and he was very thirsty. Until the past day or two he was eating more than usual but was losing weight. He has no significant medical history, and the family history is unremarkable. On examination, he appears moderately ill, and his blood pressure is normal, but he is tachycardic. His mucous membranes are dry. His abdomen is diffusely tender but without rebound or guarding. A urine dipstick test in the office reveals the presence of large ketones and glucose. A glucose measurement from a drop of blood obtained by finger stick is markedly elevated at 550 mg/dL. You immediately admit the patient to the hospital for newly diagnosed type I diabetes mellitus in ketoacidosis and start an infusion of IV fluids and regular insulin. _ What is the structure of natural human insulin? _ What effect does insulin have on potassium? _ What is the effect of ι-adrenergic stimulation on insulin secretion? _ What is the effect of β-adrenergic stimulation on insulin secretion? Marc Imhotep Cray, MD
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Diabetes Mellitus Diabetes mellitus is inability to properly manage glucose metabolism (glucose intolerance) because of either inability to produce and secrete insulin as a result of autoimmune destruction of pancreatic b-cells (type 1) or inability of peripheral tissues to respond to circulating insulin as a result of diminished or impaired insulin receptor signaling (type 2) Drugs Used to Treat DM Insulin Sulfonylureas and Meglitinides Biguanides Thiazolidinediones (Glitazones) α-Glucosidase Inhibitors Marc Imhotep Cray, MD
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Pancreas and Insulin Production Pancreas is principal organ involved in production and secretion of hormones that maintain normal blood glucose levels (or euglycemia) Pancreatic β cells of islets of Langerhans produce, store, and secrete insulin Pancreas first produces a parent protein called preproinsulin which is then cleaved to form the smaller compound proinsulin Proinsulin is then cleaved to form insulin and peptide C Marc Imhotep Cray, MD
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Pancreas and Insulin Production cont. Pancreas also produces Glucagon (α), a hormone that increases blood glucose levels, and somatostatin (δ cells), a hormone that inhibits both insulin and glucagon secretion
Ingestion of carbohydrates prompts an increase in release of insulin and concomitant decrease in plasma glucagon levels Glucagon is released in response to low blood glucose levels and protein ingestion
It stimulates insulin secretion which in turn inhibits glucagon release in a negative feedback loop
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Insulin Secretion Insulin secretion is a highly regulated process that varies throughout day In a postprandial setting (after a meal), a burst of insulin secretion normally occurs in response to a transient increase in plasma glucose level In a post-absorptive period, pancreas reduces insulin secretion, which maintains low basal levels of circulating insulin Insulin is key to body’s use of glucose it promotes uptake of glucose, fatty acids, and amino acids, and it facilitates their conversion to forms used for storage in most tissues
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Insulin Secretion cont. Important metabolic sites that are sensitive to insulin include liver, where glycogen (main carbohydrate reserve, which is easily converted to glucose) is synthesized, stored, and broken down skeletal muscle, where glucose oxidation produces energy adipose tissue, where glucose is converted to fatty acids, glycerol phosphate, and triglycerides
Marc Imhotep Cray, MD
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Lack of lnsulin Without insulin, glucose is not transported across cell membranes leads to a cascade of metabolic events
Body reacts by inducing gluconeogenesis (liver converts glycogen to glucose) To produce energy skeletal muscle converts its structural proteins to amino acids which are carried to liver where they are converted to glucose Resultant excess glucose, still not being used by cells, leads to hyperglycemia Insulin deficiency increases fat catabolism: free fatty acids are broken down into keto acids to increase energy sources Marc Imhotep Cray, MD
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Lack of lnsulin cont. Kidneys eliminate keto acids produces ketonuria and ketonemia Keto acids also reduce blood Ph can result in ketoacidoses, coma, and death Diabetes is caused by a relative or absolute lack of insulin with hyperglycemia being hallmark medical finding Once thought of as 1 disease, diabetes is now believed to be a chronic heterogeneous group of disorders that result from pathologic processes that depend on diabetes type Marc Imhotep Cray, MD
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Type 1 Diabetes Mellitus In type 1 DM, insulin-producing β cells of pancreas are destroyed by either intrinsic genetic factors or extrinsic factors such as viruses or chemical toxins In one theory that involves an autoimmune-mediated mechanism, predisposed patients react abnormally to environmental triggers by producing antibodies that are directed against β cells Insulin secretion is impaired early in disease and eventually stops Type 1 DM usually develops abruptly during childhood or adolescence and usually presents with polydipsia, polyuria, and polyphagia Ketoacidosis is more likely to occur in type 1 DM than in type 2 DM Marc Imhotep Cray, MD
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Type 1 Diabetes Mellitus cont. Patients require lifelong treatment with exogenous insulin to control bld glucose levels and prevent short-term and longterm macrovascular and microvascular complications, such as nephropathy neuropathy retinopathy, and cardiovascular disease
Oral hypoglycemic agents are ineffective in patients with type 1 DM because functioning β cells are required Marc Imhotep Cray, MD
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Commonly Used Insulin Preparations Insulin Preparation
Onset of Activity
Time of Peak Activity
Duration of Action
Insulin lispro
5–15 min
1–2 h
3–4 h
Insulin aspart
5–15 min
1–2 h
3–4 h
Insulin glulisine
5–15 min
1–2 h
3–4 h
Regular insulin
30 min
2–4 h
6–8 h
NPH (neutral protamine Hagedorn) insulin
1–2 h
4–12 h
18–24 h
Insulin detemir
3–4 h
3–9 h
6–24 h
Insulin glargine
3–4 h
No peak
24 h or longer
Marc Imhotep Cray, MD
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Type 2 Diabetes Mellitus Central defects in type 2 DM are decreased insulin secretion and insulin resistance Before diabetes is diagnosed, patients, often obese, have hyperinsulinemia caused by excess dietary carbohydrates Pancreas malfunctions and fails to supply high insulin demands also, impaired secretion is complicated by insulin resistance: insulin resistance means insulin cannot decrease plasma glucose levels through suppression of hepatic glucose production and stimulation of glucose use in skeletal muscle and adipose tissue Resistance develops in several possible ways, eg, o chronic hyperinsulinemia causes insulin receptor downregulation leads to defects in insulin binding and post-receptor Marc Imhotep Cray, MD insulin signaling pathways
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Type 2 Diabetes Mellitus cont. Unlike type 1 DM, type 2 DM has a more gradual onset may not present with symptoms, and usually occurs in overweight patients older than 35 years Oral hypoglycemic agents decrease plasma glucose levels improve insulin resistance, and reduce long-term complications Many patients need insulin therapy as well Marc Imhotep Cray, MD
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Oral Agents for Type 2 Diabetes Patients with type 2 diabetes are managed pharmacologically by the following actions: Increasing pancreatic insulin secretion with sulfonylureas or meglitinides (known as insulin secretogogues) Decreasing hepatic gluconeogenesis with biguanides
Improving insulin sensitivity in peripheral tissues with thiazolidinediones Preventing breakdown of complex carbohydrates into simple sugars with α-glucosidase inhibitors Marc Imhotep Cray, MD
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DM Acute Manifestations and Diagnosis Acute Manifestations Polydipsia, polyuria, polyphagia, weight loss, DKA (type 1), hyperosmolar coma (type 2) Rarely, can be caused by unopposed secretion of GH and epinephrine Also seen in pts on glucocorticoid therapy (steroid diabetes) Diagnosis TEST HbA1c
DIAGNOSTIC CUTOFF ≥ 6.5%
FPG
≥ 126 mg/dL
2-hour OGTT
≥ 200 mg/dL
Marc Imhotep Cray, MD
NOTES Reflects average blood glucose over prior 3 months Fasting for > 8 hours 2 hours after consumption of 75 g of glucose in water 22
DM Chronic Complications Nonenzymatic glycation: Small vessel disease (diffuse thickening of basement membrane) retinopathy (hemorrhage, exudates, microaneurysms, vessel proliferation), glaucoma, neuropathy, nephropathy (nodular glomerulosclerosis, aka Kimmelstiel-Wilson nodules progressive proteinuria [initially microalbuminuria; ACE inhibitors are renoprotective] and arteriolosclerosis hypertension; both lead to chronic renal failure). Large vessel atherosclerosis, CAD, peripheral vascular occlusive disease, gangrene limb loss, cerebrovascular disease. MI most common cause of death Osmotic damage (sorbitol accumulation in organs with aldose reductase and decrease or absent sorbitol dehydrogenase): Neuropathy (motor, sensory [glove and stocking distribution], and autonomic degeneration) Marc Imhotep Cray, MD Cataracts
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Insulin Therapy Insulin is sole therapy for type 1 DM Also used (combination therapy or monotherapy) in type 2 DM poorly controlled with diet and oral agents
Exogenous insulin stimulates carbohydrate metabolism and helps with transfer of glucose into cardiac and skeletal muscle and adipose tissue Insulin also:
aids in conversion of glucose to glycogen stimulates lipogenesis and protein synthesis, and reduces serum potassium and magnesium levels
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Insulin Therapy cont. Insulin, a protein, is degraded in GI system if used orally so it is given subcutaneously, or, in emergencies, intravenously Absorption of an insulin product may vary in a patient from one injection to next, absorption being affected by site of injection, temperature, physical activity, and dose Insulin preparations differ in dose, onset, duration, and sources of origin, including biosynthetic and semisynthetic human (therapeutically equal) human insulin (least antigenic and most soluble), and beef and pork (replaced by human due to not infrequent antigenic rxns) Marc Imhotep Cray, MD
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Reactions to Insulin: Hypoglycemia and Adipose Tissue Changes Major predisposing factors to hypoglycemia, most common and serious adverse reaction to insulin, include inadequate food intake poor timing of injections exercise, and use of hypoglycemic drugs
Symptoms are autonomic (eg, sweating, trembling, feeling of warmth) or neuroglycopenic (eg, confusion, weakness, drowsiness) Hunger, tachycardia, blurred vision, and loss of consciousness also occur Elderly patients with neuropathy, patients with long standing diabetes (>10 years), and patients taking β blockers can have blunted symptoms Marc Imhotep Cray, MD
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Reactions to Insulin: Hypoglycemia and Adipose Tissue Changes cont. Use of sugar packets, candy, or pure glucose products can help with hypoglycemia Unconscious patients must be injected with glucagon or IV glucose or dextrose Insulin injection may also cause lipohypertrophy, which occurs in patients who use only 1 site rather than rotating sites Rotating sites solves problem Lipoatrophy, an immunologic reaction to insulin, is treated by changing to human insulin and injecting it into affected area
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Sulfonylureas Sulfonylureas, historical mainstay of therapy in type 2 DM, used as monotherapy or with insulin or other oral agents MOA act mainly by stimulating insulin secretion from pancreatic β cells, enhancing β-cell sensitivity to glucose, and reducing glucagon release They work only if β cells are functioning Older drugs (eg, chlorpropamide, tolbutamide) have been replaced by new agents (eg, glimepiride, glipizide, glyburide), with greater potency fewer drug interactions, and better pharmacokinetic profiles Marc Imhotep Cray, MD
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Sulfonylureas cont. If glucose control fails with long-term sulfonylurea use, other agents may be added instead of increasing sulfonylurea doses Sulfonylureas are best for patients diagnosed after age of 40 years or when disease duration is less than 5 years body weight is nearly ideal, and fasting glucose levels are less than 180 mg/dL Main adverse effects are hypoglycemia and weight gain others are GI-related effects allergic reactions hepatotoxicity hypothyroidism, and disulfiram reaction (chlorpropamide) Marc Imhotep Cray, MD
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Biguanides ď ą Metformin, only biguanide available in United States, is used as initial monotherapy or with insulin or other oral drugs in patients with type 2 DM who have secondary failure to sulfonylurea monotherapy (initial response but then failed glucose control with long-term use) ď ą MOA Metformin decreases blood glucose levels by reducing hepatic glucose production and glycogen metabolism and improving insulin resistance via enhancing insulin-mediated glucose uptake
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Biguanides cont. Metformin decreases triglyceride and total cholesterol levels, increases HDL levels, and causes weight loss and is ideal for overweight hyperlipidemic patients Hypoglycemia occurs only when metformin is used with insulin or hypoglycemic drugs Adverse effects are GI related and, of greatest concern, rare lactic acidosis, caused by inhibited conversion of lactate to glucose and greater lactate production o mostly affects patients with renal, hepatic, or cardiovascular disorders Marc Imhotep Cray, MD
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Meglitinides Meglitinides (repaglinide and nateglinide) are approved as monotherapy or in combination with metformin or TZDs in patients with type 2 DM MOA Similar to sulfonylureas, meglitinides cause an increase in insulin secretion from pancreatic β cells Unlike sulfonylureas, meglitinides have a rapid onset and a shorter duration necessitates dosing within 30 minutes of each meal especially useful for patients who have difficulty controlling postprandial hyperglycemia ideal for pts with postprandial hyperglycemia taken just before meals to reduce postprandial hyperglycemia o if a meal is skipped, the drugs should be skipped as well Marc Imhotep Cray, MD
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Meglitinides cont. Efficacy of meglitinides in producing reductions in glycosylated hemoglobin concentration (HbA1c) and fasting plasma glucose (FPG) level is comparable to that of sulfonylureas and metformin (reduces HbA1c by 1.5-2% and FPG level by 50-70 mg/dL) Adverse effects include mild hypoglycemia (particularly if administration is not followed with food) and weight gain TEST HbA1c
DIAGNOSTIC CUTOFF ≼ 6.5%
Marc Imhotep Cray, MD
NOTES Reflects average blood glucose over prior 3 months
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α-Glucosidase Inhibitors α-Glucosidase inhibitors (acarbose, miglitol) can be used singly or with insulin or other oral drugs for type 2 DM MOA inhibit glucosidases in small intestine brush border that break down (hydrolyze) complex polysaccharides and sucrose into absorbable monosaccharides Rate of carbohydrate digestion and glucose absorption is thus delayed leads to lower postprandial glucose spikes (by 25-50 mg/dL) These drugs work best in patients with postprandial hyperglycemia and when taken with a meal containing complex carbohydrates
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α-Glucosidase Inhibitors cont. α-Glucosidase Inhibitors decrease FPG slightly (20-30 mg/dL) and HbA1c levels by 0.5% to 1.0% Adverse effects are GI related (flatulence, diarrhea, abdominal pain), which result from fermentation of unabsorbed carbohydrates in the small intestine and are lessened by slow dose titration Used with insulin or other oral drugs, they can cause hypoglycemia Hepatic transaminase levels can increase (acarbose), so LFT results must be watched
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Thiazolidinediones (TZDs) or Glitazones Thiazolidinediones (rosiglitazone and pioglitazone) are a relatively new class of antihyperglycemic agents that can be used as monotherapy or in combination with insulin or other oral agents in patients with type 2 DM MOA TZDs reduce hyperglycemia and hyperinsulinemia by decreasing insulin resistance (via enhancement of insulin-mediated glucose uptake) at peripheral sites and in liver results in increased insulin-dependent glucose disposal and decreased hepatic glucose output These effects are accomplished by selective binding at peroxisome PPAR-γ, which is found in adipose tissue, skeletal muscle, and liver Receptor activation modulates transcription of several insulin responsive genes that control glucose and lipid metabolism Marc Imhotep Cray, MD
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TZD: Clinical Rationale and Adverse Effects Thiazolidinedione pharmacology is based on suggestions that patients with type 2 DM already have too much insulin Liver, however, is resistant to that insulin and therefore continues to produce large amounts of glucose Instead of stimulating pancreas to produce more insulin, sensitivity to existing insulin should be increased to slow hepatic glucose production
TZD effects on HbA1c and FPG fall between those of acarbose and sulfonylureas and metformin TZDs plus insulin enhance glycemic control and decrease insulin needs Marc Imhotep Cray, MD
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Glitazones: Clinical Rationale and Adverse Effects cont. TZDs also reduce triglyceride levels and increase HDL, but they also increase LDL levels First TZD (troglitazone) was withdrawn after causing hepatotoxicity The 2 drugs now used (rosiglitazone and pioglitazone) have not had hepatotoxic effects but LFTs should be checked before and during TZD therapy Adverse Effects TZDs cause hematologic effects (reduced hemoglobin, hematocrit, neutrophils), hypoglycemia (when used with other drugs), and edema (thus should be used with care in congestive heart failure) Marc Imhotep Cray, MD
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Question A 43-year-old woman with Type-2 diabetes has been taking insulin with meals as well as metformin. Her blood glucose remains poorly controlled. Her doctor prescribes an additional drug, which is an analog of an endogenous peptide that inhibits glucagon secretion. What is the most likely medication this patient is taking? (A) Exenatide (B) Glipizide (C) Miglitol (D) Pramlintide (E) Rosiglitazone
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The answer is D: Pramlintide. Glucagon is inhibited by two endogenous peptides: insulin and amylin. Pramlintide is an analog of amylin. Pramlintide also diminishes the postprandial blood glucose spike by slowing gastric emptying and suppressing the appetite. Currently, pramlintide is indicated only in patients with diabetes taking insulin with meals. (A) Exenatide mimics incretin secretion, which increases glucose-dependent insulin secretion. It does not inhibit secretion. (B) Glipizide is a second-generation sulfonylurea. These drugs enhance insulin secretion but do not block glucagon secretion. (C) Miglitol inhibits intestinal brush border Îą-glucosidase. This enzyme is needed for the final steps in carbohydrate breakdown before absorption, so miglitol decreases the amount of dietary carbohydrate absorbed. (E) Rosiglitazone lowers blood glucose by increasing insulin sensitivity in peripheral tissues. It does not inhibit glucagon secretion. Marc Imhotep Cray, MD
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Case 43 Answers Pancreas and Glucose Homeostasis Summary: A 12-year-old with newly diagnosed type I diabetes mellitus has ketoacidosis. • Structure of human insulin: A 51-amino acid polypeptide that consists of two chains linked by two disulfide bridges. • Effect of insulin on potassium: Promotes cellular K + uptake. • Effect of α-adrenergic stimulation: Inhibition of insulin secretion. • Effect of β-adrenergic stimulation: Increased insulin secretion. CLINICAL CORRELATION Insulin is a 51-amino acid polypeptide that is produced in pancreatic β cells and stored as a complex with Zn 2+ . The primary stimulus for insulin release is glucose, but amino acids, fatty acids, and ketone bodies may stimulate its release. Glucagon and somatostatin also modulate its secretion. α-Adrenergic stimulation is a predominant inhibitory mechanism, whereas β-adrenergic Marc Imhotep Cray, MD stimulation increases its release.
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Case 43 Answers Pancreas and Glucose Homeostasis cont. Insulin acts by binding to specific membrane receptors that have tyrosine kinase activity. Tyrosine in the receptor becomes phosphorylated and the phosphoreceptor in turn phosphorylates a number of intracellular substrates that lead to increased glucose uptake. In muscle and adipose tissue, glucose transport is mediated by the recruitment of hexose transport molecules (GLUT-4) into the plasma membrane. Among its many actions, insulin increases glucose transport, glycogen synthesis and deposition, lipogenesis, and protein synthesis. It decreases intracellular lipolysis and hepatic gluconeogenesis. Insulin also stimulates cellular potassium accumulation. Type I diabetes mellitus is a disease in which pancreatic β cells fail to produce adequate amounts of insulin.
Marc Imhotep Cray, MD
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Case 43 Answers Pancreas and Glucose Homeostasis cont. Insulin must then be supplemented. Currently used insulin preparations are all human insulin produced by recombinant deoxyribonucleic acid (DNA) techniques. There are short-, intermediate-, and long-acting insulin preparations available. The most widely used insulin products must be given by injection, usually requiring 1–4 subcutaneous injections a day or continuous subcutaneous infusion with an insulin pump. Regular insulin can also be given intravenously in the setting of diabetic ketoacidosis. An insulin product was available for inhalation use but it was removed from the market due to lack of demand, need for high doses, and need for recurrent lung function monitoring. Another inhaled insulin is going to be introduced shortly. Insulin injections are also used in type II diabetics, who cannot achieve adequate control with oral agents. The most significant risk of insulin therapy is the induction of hypoglycemia. Hypoglycemia may produce tachycardia, sweating, and confusion. In severe cases, hypoglycemia Marc Imhotep Cray, MD may progress to coma, seizures, or even death.
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THE END
See next slide for further study. Marc Imhotep Cray, MD
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Sources and further study: eLearning Endocrine cloud folder tools and resources MedPharm Guidebook: Unit 5 Drugs Used In Disorders of Endocrine System Endocrine and Reproductive System Pharmacology eNotes Clinical Pharmacology Cases 39 to 44 (Learning Triggers) Textbooks Brunton LL, Chabner BA , Knollmann BC (Eds.). Goodman and Gilman’s The Pharmacological Basis of Therapeutics. 12th ed. New York: McGraw-Hill, 2011 Katzung, Masters, Trevor. Basic and Clinical Pharmacology, 12th ed. New York: McGraw-Hill, 2012 Mulroney SE. and Myers AK. Netter's Essential Physiology. Philadelphia: Saunders, 2009 Raff RB, Rawls SM, Beyzarov EP. Netter's Illustrated Pharmacology, Updated Edition. Philadelphia: Sanders, 2014 Toy E C. et.al. Case Files-Pharmacology Lange 3rd ed. New York: McGraw-Hill 2014. Marc Imhotep Cray, MD
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