Week 9 Lecture 14 2023 PDF

Week 9 Lecture 14 Oral Glucose Tolerance Test  Diabetes Criteria Current criteria for the diagnosis of diabetes, based on the American Diabetes Association (ADA) Standards for Medical Care 2017 Guidelines, do not differentiate between type 1 and type 2 diabetes, and i...

Week 9 Lecture 14 Oral Glucose Tolerance Test  Diabetes Criteria Current criteria for the diagnosis of diabetes, based on the American Diabetes Association (ADA) Standards for Medical Care 2017 Guidelines, do not differentiate between type 1 and type 2 diabetes, and include1: Hemoglobin A1c greater than 6.5% Fasting glucose greater than 126 mg/dL Two-hour postprandial glucose ≥200 mg/dL during the oral glucose tolerance test Random plasma glucose ≥200 mg/dL in a patient with classic symptoms of hyperglycemia or hyperglycemic crisis Hemoglobin A1c Hemoglobin A carries oxygen in your blood. When glucose levels are high, hemoglobin becomes coated with glucose (glycated) molecules. Glycated hemoglobin is a diagnostic used to detect diabetes in people. Once the glucose sticks to the hemoglobin, it remains for the lifespan of the red blood cells, which is typically 3 months. HbA1c measures how much glucose is stuck to hemoglobin. Gives you a long term assessment of glucose control. A hemoglobin of 6.5% or more indicates type 2 diabetes.  Over 90% of people with newly diagnosed type 1 diabetes have measurable antibodies against specific β-cell proteins, 3 including insulin, glutamate decarboxylase, islet antigen 2, 2 zinc transporter 8, and tetraspanin-7. Most people with a single auto-antibody don’t show symptoms of diabetes. 1 2 or more autoantibodies increases the risk for type 1 diabetes. Most patients with 2 autoantibodies will develop type 1 diabetes before turning 18. DiMeglio LA, Evans-Molina C, Oram RA. Type 1 diabetes. Lancet. 2018 Jun 16;391(10138):2449-2462. doi: 10.1016/S0140-6736(18)31320-5. PMID: 29916386; PMCID: PMC6661119. The development of type 1 diabetes is thought to be initiated by the presentation of β-cell peptides by antigen-presenting cell (APCs). APCs bearing these autoantigens migrate to the pancreatic lymph nodes where they interact with autoreactive CD4+ T lymphocytes, which in turn mediate the activation of autoreactive CD8+T cells (A). These activated CD8+ T cells return to the islet and lyse β cells expressing immunogenic self-antigens on major histocompatibility complex class I surface molecules (B). β-cell destruction is further exacerbated by the release of proinflammatory cytokines and reactive oxygen species from innate immune cells (macrophages, natural killer cells, and neutrophils; C). This entire process is amplified by defects in regulatory T lymphocytes, which do not effectively suppress autoimmunity (D). Activated T cells within the pancreatic lymph node also stimulate B lymphocytes to produce autoantibodies against β-cell proteins. These autoantibodies can be measured in circulation and are considered a defining biomarker of type 1 diabetes (E).  Diabetic Ketoacidosis (DKA) Overproduction of ketone bodies Results from the lack of insulin or severe insulin resistance Lack of insulin leads to enhanced glucose production by the liver Due to acidic nature of b-hydroxybutyrate and acetoacetate, ketones lower pH in the blood Patients are typically dehydrated Along with being dehydrated, patients typically present with confusion, nausea, vomiting, and abdominal pain Because of the acidosis, patients often breathe very deeply and rapidly to eliminate carbon dioxide and cause respiratory alkalosis. insulin helps to resolve ketoacidosis. Insulin used for treating type 1 diabetes Glucose infusion rate: the amount of glucose that is pumped into the blood to maintain a set glucose level. Rapid acting insulin- onset of action of 5 to 15 minutes, peak effect in 1 to 2 hours and duration of action that lasts 4-6 hours. Regular acting insulin-onset of action of 1/2 hour to 1 hour, peak effect in 2 to 4 hours, and duration of action of 6 to 8 hours. Long acting insulin- onset of insulin effect in 1 1/2-2 hours. The insulin effect plateaus over the next few hours and is followed by a relatively flat duration of action that lasts 12-24 hours for insulin detemir and 24 hours for insulin glargine. Insulin used for treating type 1 diabetes Type 1 diabetics can receive insulin shots 3-4 times per day or have an insulin pump that controls insulin release directly into circulation. Insulin pumps require the use of continuous glucose monitoring devices that give live glucose levels. Basal insulin dose that helps maintain insulin in the system. Typically use of long acting insulin once per day. Three insulin doses with meals to prevent a sharp rise in glucose that occurs with meals. This will cover the carbohydrates that are consumed with food. This is typically fast acting insulin.  Type 2 diabetes drugs Metformin: Medication that reduces sugar production from the liver and improves insulin sensitivity Insulin releasing pills (secretagogues): Medication that increase insulin release from the pancreas. These include a large class of drugs called sulfonylureas SGLT2 Inhibitors: Medication that slows sugar absorption from the proximal convoluted tubule in kidneys Incretin based therapies: Medication that reduces sugar production in the liver and slow the absorption of food Amylin analogs: Injections that reduce sugar production in the liver and slow the absorption of food  Insulin Secretagogues Medication used to treat type 2 diabetes that stimulates insulin release. These drugs are useful when beta cells are no longer able to adapt to hyperglycemia. Gives beta cells a stimulus to promote insulin secretion. Sulfonylureas are the most commonly used insulin secretagogues. However, they risk leading to hyperinsulinemia, increasing the risk of hypoglycemia.  SGLT2 Inhibitors Medication that promotes glucose excretion in the urine by blocking the Sodium Glucose Linked Transporter 2 (SGLT2). SGLT2 inhibitors block the reabsorption of glucose in the proximal convoluted tubule. Leading to a drop in blood glucose levels. SGLT2 inhibitors are called Glifozins. Glifozins are often used in combination with Metformin. Typically Metformin is the first line of therapy. Side affects associated with SGLT2 inhibitors is genital infections and DKA. SGLT2 Inhibitors Promote Urinary Glucose Excretion  Incretins (GLP1) are Released by the Gut Incretins are a class of hormones released by the gut that stimulate insulin secretion. Glucagon-like peptide 1 (GLP1) is a 30 amino acid peptide that is produced by L-cells in the Ilium and colon in response to ingestion of nutrients. Half-life of GLP1 is less than 2 minutes. Therefore, drugs that inhibit the degradation of GLP1, and increase its half-life promote insulin secretion. DPP4 inhibitors increase the half-life of GLP1, leading to sustained activation of insulin secretion. DPP4 is an enzyme that degrades GLP-1.  Time-dependent Changes in Weight Loss After Semaglutide Administration Weekly treatment with semaglutide 2.4 mg as an adjunct to behavioral intervention in adults with overweight (with at least one weight-related comorbidity) or obesity. Found reduction in weight, waist circumference, blood pressure and HbA1c appeared to plateau around week 60 with semaglutide and sustained through 104 weeks’ treatment. STEP5 Trial: 2 year duration Garvey, W.T., Batterham, R.L., Bhatta, M. et al. Two-year effects of semaglutide in adults with overweight or obesity: the STEP 5 trial. Nat Med 28, 2083–2091 (2022). STEP1 Trial Highlights Weight Rebound After Completion of randomized trial STEP 1 Trial randomized 1961 adults with a body mass index ≥ 30 kg/m2 (or ≥ 27 kg/m2 with ≥ 1 weight-related co-morbidity) without diabetes to 68 weeks of once-weekly subcutaneous semaglutide 2.4 mg (including 16 weeks of dose escalation) or placebo, as an adjunct to lifestyle intervention. Wilding JPH, et al. STEP 1 Study Group. Once-Weekly Semaglutide in Adults with Overweight or Obesity. N Engl J Med. 2021 Mar 18;384(11):989-1002..  Weight Regain: Most Challenging Problem in Current Weight Loss Interventions Weight loss can be achieved through a variety of modalities, but long-term maintenance of lost weight is much more challenging. Obesity interventions typically result in early rapid weight loss followed by a weight plateau and progressive regain. In a meta-analysis of 29 long-term weight loss studies, more than half of the lost weight was regained within two years, and by five years more than 80% of lost weight was regained. Dieting leads to significant adaptations in the homeostatic system that controls body weight, which promotes overeating and the relapse to obesity. Can be explained by a reduction in resting energy expenditure and increased appetite. Incretins (GLP1) are Released by the Gut GLP1 activates the GLP1-Receptor and stimulates insulin secretion in beta cells, lowers glucagon secretion in alpha cells, and increases the number of beta cells. GLP1 lowers hepatic glucose production. GLP1 reduces gastric emptying, slowing digestion process. GLP1 lowers appetite and can impact long-term energy balance.  Amylin Analogs Block Glucagon Production Amylin is a 37 amino acid peptide that is co-secreted with insulin from the pancreatic beta cells. Amylin slows gastric emptying. This will delay the appearance of glucose- derived from meals into the blood stream. This delay prevents a large spike in glucose from meals. Amylin suppresses glucagon secretion in the postprandial state. Amylin promotes satiety and helps to lower blood glucose levels.