pancreas and DM.pptx

Insulin, glucagon and glucose homeostasis Normal Glucose Control (Glucose Homeostasis) 2 Pancreatic Islet Physiology • Pancreatic islets comprise 1-2% of the pancreatic volume • The pancreatic islet is highly vascularized and innervated • Pancreatic islets contain 5 cell types: - a-cells make u...

Insulin, glucagon and glucose homeostasis Normal Glucose Control (Glucose Homeostasis) 2 Pancreatic Islet Physiology • Pancreatic islets comprise 1-2% of the pancreatic volume • The pancreatic islet is highly vascularized and innervated • Pancreatic islets contain 5 cell types: - a-cells make up 15-20% of total islets cells and secrete glucagon - b-cells make up 60-85% of total islets cells and secrete insulin and amylin - d-cells make up 3-10% of total islets cells and secrete somatostatin - PP cells secrete pancreatic polypeptide - e-cells make up <1% of total islets cells and secrete ghrelin • Regulation of insulin secretion is achieved by a coordinate interplay between various nutrients, GI hormones, pancreatic hormones, and autonomic neurotransmitters 3 Discovery of Insulin Up until the 1920s a diagnosis of diabetes was a death sentence for patients. Most were type I diabetes. In 1889 Oscar Minkowski showed removal of the pancreas in dogs resulted in diabetes. Frederick Banting and Charles Best in 1921 reading the work of Minkowski ligated the pancreas to induce diabetes in dogs and then injected pancreatic extracts to “rescue” the dogs. Experiments lead to the preparation of insulin in 1922. Today recombinant human insulin is used to treat diabetes. Insulin • Insulin is a 51 amino acid protein= 5,800 Kd • Synthesized in the b-cells of the pancreatic islets of Langerhans from a single chain precursor called proinsulin • Insulin is formed by proteolysis yielding insulin, C-peptide and four basic amino acids • Insulin has two chains, A and B joined by two interchain disulfide bonds and one intrachain bond (A chain) 5 The Pancreatic b-Cell Sulfonylurea & meglitinide Diazoxide Distribution & Fate of Insulin • Insulin circulates unbound • Vd = extracellular fluid volume • Basal secretion 20  g/hour = 500 pg/ml; T½ = < 9 min • 50% “destroyed” by the liver in a single pass • Filtered by the glomerulus, reabsorbed by tubular epithelial cells which degrade it • Degradation of insulin primarily the result of receptor internalization 7 Insulin Receptor • The insulin receptor is a receptor tyrosine kinase composed of a/b subunit dimers • Erythrocytes have ~40 insulin receptors/cell while adipocytes and hepatocytes have ~300,000 insulin receptors/cell • The a-subunits inhibit the inherent tyrosine phosphorylation of the bsubunit. • Insulin binding to the a-subunit releases this inhibition allowing transphosphorylation of one b-receptor by the other and autophosphorylation of the intracellular tail of the receptor • Insulin receptor activation stimulates cell growth, protein synthesis, glycogen synthesis and translocation of GLUT4 enriched vesicles to the cell membrane 8 Insulin Action • The insulin receptor is expressed on almost all mammalian cells • Tissues critical for glucose regulation are liver, skeletal muscle, fat, specific regions of the brain and the pancreatic islet • The actions of insulin are anabolic and insulin signaling is critical for uptake, use and storage of glucose, lipids and amino acids • Insulin stimulates glycogenesis, lipogenesis and protein synthesis and inhibits catabolism of these compounds • Insulin stimulates the transport of substrates and ions into cells and promotes translocation of proteins between cellular compartments • Insulin regulates specific enzymes, and controls gene transcription and mRNA translation. 9 Glucagon • The pancreatic a-cell secretes glucagon in response to hypoglycemia • Glucagon synthesis begins with preproglucagon, which is processed in a cell-specific fashion into several biologically active peptides • • Under low glucose conditions, the SERCA pumps pancreatic a-cells are not as active, SOC are activated to increase intracellular Ca2+ that depolarizes the cell to release glucagon Under normal glucose conditions, the SERCA pumps are activated, SOC are closed and glucagon is not release. 10 Incretins • Glucagon like peptide-1 (GLP-1) and gastric inhibitory peptide (GIP) are GI hormones released after meals and stimulate insulin secretion • GLP-1 is derived from preproglucagon, a 180 amino acid precursor. • Pancreatic a-cells process proglucagon to glucagon and a large C-terminal peptide that contains GLP-1 and GLP-2 • • • • Intestinal L cells and specific regions of the hindbrain neurons process proglucagon into GLP-1 and GLP-2 and a larger N-terminal peptide that contains glucagon GLP-2 is a peptide hormone that affects proliferation of epithelial cells lining the GI tract The insulinotrophin effects of GLP-1 are glucose dependent GLP-1 is rapidly inactivated by DPP-4 and has a plasma t1/2 of 1-2 mins 11 Early understanding of diabetes 1500 BC Ancient Hindu writings showed early healers recognized that black ants were attracted to the urine of people with a mysterious and deadly disease. The writings described a disease that caused intense thirst, enormous urine output, and wasting away of the body. 250 BC Apollonius of Memphis probably was the first one to name “diabetes” with a literal translation “to go through” or “siphon” due to the polyuria Later the Latin word “mellitus” meaning sugar was added because of the link with sweet urine. 1000 AD a Greek physician prescribed a treatment “to employ moderate friction” to the body in the form of exercise to relive excess urination in diabetes. 1798 John Rollo documented excess sugar in the blood and urine Diabetes • Type 1 (IDDM): 0.5% prevalence –  -cell destruction leading to loss of insulin production – Increased HbA1C (glycated Hb), polyphagia, polydipsia, polyuria • Type 2 (NIDDM): 5% prevalence – Insulin may be present but it is not released properly or does not act appropriately (relative insulin resistance) – Type 2 is more prevalent and rates are increasing at an alarming rate in children due to obesity. • Carbohydrate intolerance associated with genetic syndromes e.g. MODY • Secondary diabetes (pancreatic disease, drug or chemical induced) • Gestational diabetes 13 Diabetes: Clinical Presentation • Hyperglycemia – glucose does not get into cells, less storage and increased gluconeogenesis • Hyperlipemia – unopposed action of hormone sensitive lipase in adipose tissue • Ketonemia – increased production of strong acids (acetoacetic acid and b-hydroxybutyrate) from amino acids by the liver • Ketoacidosis – from production of large amounts of strong acids • Azoturia – increased glucose production from protein leads to increased production of urea and ammonia 14 Diabetes Diagnostic Criteria (any of the following) • Symptoms of diabetes plus a casual plasma glucose concentration ≥ 200 mg/l (11.1 mM). • FPG ≥ 126 mg/dl (7.0 mM). Fasting is defined as no caloric intake for at least 8 h. • 2hPG ≥ 200 mg/dl during an OGTT. The test should be performed using a glucose load containing the equivalent of 75 - g anhydrous glucose dissolved in water. • HbA1c ≥ 6.5% 15 Type 1 Diabetes • Patients with type I diabetes have antibodies against pancreatic b-cells and to glutamic acid decarboxylase • The genetic contributions to type 1 DM involve multiple genes. • The concordance of type 1 in identical twins is 30 to 70%, indicating that additional modifying factors are involved in determining whether diabetes develops. • The major susceptibility gene for type 1 is located in the HLA complex on chromosome 6. Polymorphisms in the HLA complex account for 40 to 50% of the genetic risk of developing type 1. • This HLA region contains genes that encode the class II MHC molecules, which present antigen to helper T cells and thus are involved in initiating the immune response. 16 Type 1 Diabetes: Current insulin preparations and pharmacokinetics following subcutaneous injection 17 Insulin: Adverse Events • Hypoglycemia is the major risk • Modest weight gain using insulin for type 1 & 2 diabetes • Allergic reactions to aggregated or denatured recombinant human insulin or minor contaminants in formulations • Lipoatrophy at injection sites (older formulations) • Lipohypertrophy ascribed to the higher concentration of insulin (and insulins lipogenic action) near the injection site. Type 2 Diabetes • A heterogeneous syndrome characterized by dysregulated glucose homeostasis. • Type 2 diabetes has a strong genetic component with over 80 genetic loci identified. • Over 80% of patients with type 2 diabetes are obese or overweight • Type 2 diabetes develops gradually often over years • Type 2 diabetes is characterized by insulin resistance in which liver, skeletal muscle and adipose tissues are refractory to the action of insulin to maintain glucose levels within the normal range Oral Hypoglycemics for Type 2 diabetes Type Agent Mechanism of action HbA1c reduction Contraindications Biguanides Hepatic glucose production 1-2% CHF, Renal impairment Dipeptidyl peptidase 4 (DPP4) inhibitors Prolong GLP1 action 0.5-0.8% Renal impairment a-Glucosidase inhibitors Decrease glucose absorption 0.5-0.8% Renal/liver disease Sulfonylureas Increase insulin secretion 1-2% Renal/liver disease Megitinides Increase insulin secretion 1-2% Renal/liver disease Sodium-Glucose transporter 2 (SGLT2) inhibitors Increase renal excretion of Glucose 0.9-1.2% Renal disease Thiazolidinediones (the Glitazones) Decrease insulin resistance Increase glucose utilization 0.5-1.4% CHF/liver disease 20 Parenteral Hypoglycemics for Type 2 diabetes Type Agent Mechanism of action HbA1c reduction Contraindications Amylin agonists Slow gastric emptying Decrease glucagon 0.25-0.5% GI motility issues GLP-1R agonists Increase insulin, decrease glucagon, slow gastric emptying 0.5-1.5% Renal disease, pancreatitis, medullary carcinoma of the thyroid Insulin Increase glucose utilization, decrease hepatic glucose production, anabolic actions unlimited Hypoglycemia Other therapeutics for Type 2 diabetes Type Agent Mechanism of action HbA1c reduction Medical nutrition therapy and physical activity Decrease insulin resistance, increase insulin secretion 1-3% Inhaled Insulin Increase glucose utilization, decrease hepatic glucose production, anabolic actions 0.25-0.5% Contraindications Pulmonary disease, smoking 21 Treatment algorithm for the management of Type 2 diabetes Type 2 Diabetes Assess A1C Screen for Complications - Retinal exam - Microalbuminuria - Neuropathy exam - Vascular evaluation Diabetes Education Medical nutrition Therapy Physical Activity Metformin Reassess A1C Metformin + second agent Reassess A1C Metformin + 2 other agents Metformin + Insulin Reassess A1C Treat Comorbidities - Dyslipidemia - Hypertension - Obesity - CV disease Monogenic Diabetes and MODY • Mutations in key genes involved in glucose homeostasis cause monogenic diabetes. These fall into two broad categories: – Diabetes in the neonatal period (<6 months of age) – Diabetes in children or adults • Some forms of neonatal diabetes are caused by mutations in inward rectifying K+ channel on b-cells or mutations in the insulin gene • In other forms children, adolescences, young adults or adults present with monogenic forms of diabetes known as Maturity Onset Diabetes of the Young (MODY) • The most common causes are mutations in key b-cell transcription factors or GK. Most patients with MODY are treated with Sulfonylureas 23 Secondary Diabetes • • Chronic diseases of the pancreas (pancreatitis), cystic fibrosis, or endocrinopathies (acromegaly and Cushings disease) can cause diabetes A number of medications promote hyperglycemia or lead to diabetes by impairing insulin secretion or insulin action: Hyperglycemia Hypoglycemia Glucocorticoids, thyroid hormone b Adrenergic antagonists Atypical Antipsychotics Theophylline Protease inhibitors ACE inhibitors b Adrenergic agonists, epinephrine Salicylates, NSAIDs Thiazide diuretics LiCl Hydantoins (phenytoin) Ethanol Opioids (fentanyl, morphine) Pentamidine Diazoxide, nicotinic acid Bromocriptine Interferons, amphotericin B Acamprosate, basiliximab, aparaginase 24 Gestational Diabetes Mellitus • GDM affects between 2-10% of all pregnancies • Insufficient insulin is produced to overcome insulin resistance during pregnancy • The onset of diabetes and its duration during pregnancy affect the prognosis for good obstetric and perinatal outcomes • Potential risks of GDM include: - Larger baby increasing the risk of complications - Polyhydramnios (too much amniotic fluid) - Premature birth - Increase risk of pre-eclampsia - Increased risk for C-section - Higher risk of developing Type 2 Diabetes later in life • Treatment includes diet, exercise and medication (e.g. insulin) 25 Case Study 1 H.B. is a 45-year-old woman with central obesity (height is 5’ 4”; weight 165 lbs, BMI 27.5kg/m 2). Three months ago, she was referred to a diabetes clinic when her gynecologist, who had been treating her for recurrent vaginal monilial infections, noted glucosuria on a routine urinalysis. Subsequently, on two occasions, she was found to have a FBG of 150 and 167 mg/dL; an A1C was 8.2%. H.B. denies symptoms of polyphagia, polyuria, although lately she has been more thirsty than normal. She complains of recent lethargy and often takes afternoon naps. H.B.’s other medical problems include hypertension which is well controlled with Lisinopril 20mg/day, recurrent monilial infections, which are treated with fluconazole. She has given birth to four children (birth weights 7, 8, 10 and 11lbs), and was told during her last pregnancy that she has “borderline diabetes”. H.B. smokes one pack of cigarettes per day for the last 20 years, and occasionally drinks a glass of wine. She drinks two regular sodas every day and a “large” glass of orange juice in the morning. Physical activity involves routine walking to her car every day. Her family history includes a sister, aunt and grandmother all with Type 2 diabetes. She says that all had “weight problems”. H.B.’s mother is alive and well at age 77; her father died of a heart attack at age 47. On presentation at your clinic, fasting glucose is 147mg/dL, triglycerides 400 mg/dL, and A1C is 8.3%. All other lab tests (CBC, electrolytes, LFT, and renal function tests) are within normal ranges. 1. 2. 3. 4. 5. Based on her history, presentation and lab results, what is your diagnosis for H.B.? What is likely happening to insulin in this patient? What would you initially recommend for the management of H.B.’s condition? What pharmacologic therapy, if any, would you initially recommend? How should H.B.’s condition be monitored? 26 Case Study 2 A.H. is a 23-year-old male and a first-year medical student. A.H. was recently discharged from hospital for severe dehydration, mild ketoacidosis, and was referred to the diabetes clinic at the University Health Services Clinic. A fasting and random plasma glucose at the clinic were 190 and 250 mg/dL. Approximately 4 weeks before hospitalization, A.H. had moved across country to attend medical school. In retrospect, he remembers symptoms of polydipsia, nocturia (6 times per night), fatigue, and he lost 10lb in weight which he attributed to anxiety about attending medical school. His history is remarkable for a urinary tract infection, and recurrent respiratory infections over the past 6 months. There is no family history of diabetes and he takes no medications. Physical examination is within normal limits. A.H. weighs 70kg and is 5’ 9” tall. Lab tests show: FBG 280mg/dL; A1C 14%; trace urine ketones as measured by KetoDiastix. 1. 2. 3. 4. 5. On the basis of A.H.’s history and lab tests what is your presumptive diagnosis? What tests could be performed to confirm your diagnosis? What has occurred in A.H.’s pancreas to cause this condition? What medication is indicated for A.H.’s condition? While on this medication, what major life-threatening adverse action should be avoided? 27