P3 DM 2025 Notes PDF

Diabetes Mellitus Part 1 RHCHP School of Pharmacy Integrated Pharmacotherapy 3 Spring 2025 Facilitators Reading and References LaToya Braun, PhD...

Diabetes Mellitus Part 1 RHCHP School of Pharmacy Integrated Pharmacotherapy 3 Spring 2025 Facilitators Reading and References LaToya Braun, PhD [email protected] Required 303-964-6698 Integrated Pharmacotherapy 3 Diabetes Mellitus Notes (this document) Chris Malarkey, PhD Insulins Handout & Type 1 DM Video [email protected] Optional 303-625-1244 2025 Diabetes Standards of Care, Section 9. Pharmacologic Approaches to Glycemic Treatment Leticia Shea, PharmD, BCACP Goodman and Gilman’s The Pharmacologic Basis of Therapeutics, Chapter 60 [email protected] Katzung’s Basic and Clinical Pharmacology, Chapter 41 303-847-9928 Diabetes Mellitus Part 1 RAT 1: Learning Objectives 1 – 43 (Pages 1 to 18) 1. Define diabetes mellitus (DM), type 1 DM, type 2 DM, and gestational DM. 2. List the macrovascular and microvascular complications associated with DM. 3. Describe the benefits of controlling blood glucose in patients with type 1 DM and type 2 DM with regards to macrovascular and microvascular complications. 4. Differentiate the prevalence of type 1 DM and type 2 DM. 5. Identify populations at highest risk for developing type 2 DM. 6. Describe the opposing regulatory effects of insulin and glucagon on glucose metabolism. 7. List the exocrine and endocrine functions of the pancreas. 8. Describe the functions of key anatomical structures of the pancreas (acini, islets of Langerhans, pancreatic duct). 9. Differentiate between α- and β-cells. 10. List and describe the processes that regulate the release of insulin. 11. Illustrate the cellular processes involved in insulin release. 12. Describe the structure and processing of insulin. 13. Define the effects of epinephrine signaling on glucose metabolism. 14. Describe the effects of insulin binding to insulin receptors. 15. List and describe the processes that regulate the release of glucagon. 16. Describe the structure and processing of glucagon. 17. Describe the effects of glucagon binding to glucagon receptors. 18. Explain the biological role of amylin. 19. Describe the role of renal sodium-glucose cotransporters in glucose homeostasis. 20. Explain the biological role of GLP-1 and GIP. 21. Describe the processes involved in the digestion, absorption, and transport of glucose. 22. Define the role of glucose metabolism in the context of cellular respiration. 23. Define cellular respiration and describe the balance between catabolic and anabolic pathways. 24. Outline the role of glucose, fats, and protein in the formation of energy. 25. List and describe the metabolic pathways involving glucose. 26. Describe the role of glucose phosphorylation. 27. Differentiate between hexokinase and glucokinase (enzyme activity, tissue distribution, regulation) and each enzyme’s role in glucose metabolism. 28. Describe glycolysis. 29. Describe the tricarboxylic acid cycle and oxidative phosphorylation and their role in cellular respiration. 30. Describe the function of glucose-6-phosphate, pyruvate, acetyl CoA, and NADH and FADH2. 31. Differentiate between glycogenesis and glycogenolysis. 32. Describe gluconeogenesis and its role in glucose metabolism. 33. Define the pentose phosphate pathway. 34. Discuss allosteric regulation of major glucose metabolic pathways. 35. Discuss hormonal regulation of major glucose metabolic pathways. 36. Identify energy using and energy producing steps of glucose metabolic pathways. 37. **Compare and contrast the metabolic changes in each tissue under the absorptive state and fasting state (liver, adipose, skeletal muscle). 38. **Compare and contrast the biological effects of insulin and glucagon on glucose uptake, glycogen synthesis, gluconeogenesis, gluconeolysis, and lipolysis. 39. Describe ketone body formation and define their biological role. 40. Compare and contrast pathophysiological elements of type 1 DM with type 2 DM. 41. Describe factors that contribute to insulin resistance. 42. Compare and contrast the acute and chronic complications of type 1 DM with acute and chronic type 2 DM (Glycation, DKA, HHS). 43. Understand the role of AGEs and RAGE in pro-inflammatory mechanisms. Diabetes Mellitus Part 1 RAT 2 & 3: Learning Objectives 44 – 89 (Page 19 to End) 44. Explain the classic symptoms presented in individuals with un-diagnosed diabetes. 45. Differentiate between the general characteristics of T1DM versus T2DM. 46. Determine if an individual is presenting with diabetes or are at risk for diabetes based on their A1c. 47. Define A1c or HbA1c so that a patient or caregiver understands what this lab value indicates. 48. Provide the A1c goal for the majority of individuals living with DM. 49. Explain factors that would establish a patient would be ideal for a more stringent A1c (i.e., 150 mg/dL) have been linked to insulin resistance and development of metabolic syndrome. Regulatory substances secreted by adipose tissue, including leptin, resistin, and adiponectin, may contribute to the development of insulin resistance. Adiponectin is a polypeptide hormone that regulates glucose and fatty acid metabolism through a common signaling pathway, adenosine monophosphate-activated kinase (AMPK). Adiponectin can improve insulin sensitivity, but secretion of this hormone is decreased in individuals with high body fat content. As a result, AMPK signaling via adiponectin is insufficient in obese individuals and insulin resistance can develop. Leptin is a polypeptide hormone that acts as a satiety factor and stimulates energy expenditure. Expression levels of leptin in adipocytes correlate with the proportion of body fat stores. As leptin levels increase in obese individuals, a loss of sensitivity to the hormone can develop, leading to a reduced ability of this hormone to restrict food intake. Leptin resistance will also lead to insulin resistance. Fibroblast growth factor 21 (FGF21) is a polypeptide hormone that regulates glucose homeostasis and lipid metabolism during both the fasting and fed states. Expression levels of FGF21 are induced in response to fasting and act on adipocytes promoting lipolysis. In the fed state, FGF21 also stimulates insulin-independent glucose uptake in adipocytes by inducing glucose transporter-1 (GLUT-1) expression, and has been postulated to act on glucagon metabolism by lowering glucagon secretion. FGF21 levels are generally increased in people with abdominal obesity, insulin resistance, and type 2 diabetes, indicative of the presence of FGF21 resistance or compensatory responses to metabolic stress. The metabolic abnormalities of T2D include hyperglycemia and dyslipidemia. Hyperglycemia can be exacerbated in patients with T2DM during situations of anxiety or high-stress. Recall that epinephrine, released by the adrenal gland during stressful episodes, can signal for decreased insulin release from pancreatic β-cells. The combination of insulin resistance and decreased insulin release can worsen the already poor glycemic control of these individuals. Acute Complications Associated with DM Diabetic Ketoacidosis (DKA) Under profound insulin deficiency or severe fasting, the liver utilizes acetyl-CoA from unregulated lipolysis to generate ketone bodies. See Figure 25 for an illustration of the pathogenesis of DKA. As you will recall, ketone bodies (primarily β-hydroxybutyrate and acetoacetate) are used by the brain as an energy source when glucose is not available. Because glucose is abundant in patients with DM, the ketones remain in the circulation and are not hydrolyzed by the brain. Elevated circulating ketones lower the blood pH beyond the buffering capacity of bicarbonate. The resulting acidosis can be partially compensated for by deep, rapid breathing called Kussmaul respirations, a form of hyperventilation. DKA is most commonly seen in patients with T1DM, but it can occur in some patients with T2DM. Causes of DKA include decreased or omitted insulin doses, emotional stress, starvation, excess alcohol and/or concomitant medications. DKA seldom occurs spontaneously in T2DM; when seen, it usually arises in individuals who are insulinopenic and already treated with insulin (missed or inadequate doses); in people with ketosis-prone type 2 diabetes; in association with the stress of another illness such as infection (COVID-19) or myocardial infarction; in association with illicit drug use (cocaine); in association with certain social determinants Integrated Pharmacotherapy 3 17 Diabetes Mellitus of health; or with the use of certain medications such as Figure 25. Pathogenesis of DKA and HHS (Taken from CMAJ 2003;168:859-866) glucocorticoids, second-generation antipsychotics, or SGLT2 inhibitors. Hyperosmotic Hyperglycemic State (HHS) Hyperglycemia can lead to the development of a hyperosmolar state that is caused by increased movement of water into the plasma as a result of the high glucose concentration. This leads to polyuria (frequent urination) that can deplete the blood volume and consequently raise the glucose concentration even higher. HHS is characterized by severe hyperglycemia, profound dehydration, and neurologic manifestations in the absence of significant ketosis. Ketosis does not occur in HHS because insulin deficiency is relative, not absolute. Therefore, this condition is more common in T2DM where insulin resistance, rather than deficiency, is the primary cause of disrupted glycemic control. Advanced Glycation End-Products Chronic complications of diabetes – premature atherosclerosis (including cardiovascular disease and stroke), retinopathy, nephropathy, and neuropathy – are caused by prolonged cellular toxicity due to the high levels of glucose in the circulation. Cellular toxicity is common in tissues that express GLUT-2 transporters (e.g., renal tubules, red blood cells, lens and cornea, and brain), rather than the insulin- dependent GLUT-4, because GLUT-2-expressing cells do not   require insulin to stimulate glucose transport across the plasma membrane. When an individual is hyperglycemic, GLUT-2-expressing cells will readily accumulate enough glucose to promote its condensation with cellular proteins, forming advanced glycation end-products (AGEs). AGEs bind to the receptor for advanced glycation end- products (RAGE), which then activates pro-inflammatory signalling cascades. Elevated AGEs and glucose metabolites (e.g., sorbitol) contribute to many forms of cellular damage, including swelling and rupture, due to water retention and the formation of reactive oxygen species. Furthermore, AGEs in the blood can that stimulate RAGE activate pro-inflammatory pathways, leading to vascular damage in many tissues including the kidney, peripheral nerves, and the retina of the eye. In red blood cells, glucose can condense with hemoglobin (Hgb or Hb), leading to accumulation of a glycated form of hemoglobin (referred to as HbA1c or A1c). The A1c will be discussed in further detail in the sections to follow. Integrated Pharmacotherapy 3 18 Diabetes Mellitus CLINICAL PRESENTATION Classic symptoms of hyperglycemia associated with DM include the 3 Ps – polyuria, polydipsia, and polyphagia. Additional symptoms of hyperglycemia include blurred vision, fatigue, poor wound healing or recurrent infections, dry mouth, and dry itchy skin. Table 3. Traditional characteristics of Type 1 DM and Type 2 DM Characteristics Type 1 DM Type 2 DM Age < 20 years (but can occur at any age) > 30 years (but can occur in overweight children) Onset Abrupt Gradual Body Lean overweight or obese Insulin resistance Absent Present Autoantibodies Often present Rarely present Weight loss at diagnosis Common Uncommon Ketones at diagnosis Present Usually absent Need for insulin therapy Immediate Variable Acute complications Diabetic ketoacidosis (DKA) Hyperosmolar hyperglycemic syndrome (HHS) Microvascular complications at diagnosis No Common Macrovascular complications at or before diagnosis Rare Common Polyuria, nocturia, polydipsia, polyphagia, and Symptoms at diagnosis Lethargy, polyuria, nocturia, and polydipsia weight loss T1DM vs T2DM Risk Factors for Type 2 Diabetes T1DM & T2DM are heterogeneous diseases in which clinical presentation Mellitus in Adult Populations and disease progression may vary considerably. Classification is important for BMI > 25 kg/m2 or BMI > 23 kg/m2 in Asian Americans determining personalized therapy, but some individuals cannot be clearly classified Physical inactivity as having T1DM or T2DM at the time of diagnosis. The traditional paradigms of Diet high in processed foods, saturated fats, and simple T2DM having onset only in adults and T1DM having onset only in children are carbohydrates not accurate, as both diseases occur in all age-groups. Children with T1DM often Certain genetic variants present with the hallmark symptoms of polyuria/polydipsia, and approximately First degree relative with DM half present with DKA. The onset of T1DM may be more variable in adults; they Members of high-risk populations (African American, Latino, may not present with the classic symptoms seen in children and may progress Native American, Asian American, Pacific Islander) to insulin replacement more slowly. The features most useful in determination Individuals who were diagnosed with gestational DM of T1DM include younger age at diagnosis ( 250 mg/dL presentation. Occasionally, people with T2DM may present with DKA, particularly Individuals with polycystic ovarian syndrome (PCOS) members of certain racial, ethnic, and ancestral groups (e.g., African American History of CVD and Hispanic/Latino adults). It is important for health care professionals to realize Patients with HIV that classification of diabetes type is not always straightforward at presentation and A1c > 5.7%, impaired glucose tolerance, or impaired fasting that misdiagnosis is common and can occur in ~ 40% of adults with new T1DM glucose on previous testing (adults with T1DM misdiagnosed as having T2DM). What determines DM diagnosis? 1. A1c ≥ 6.5% (point-of-care devices not recommended for diagnosis) Risk Factors for Type 2 Diabetes 2. Fasting (no caloric intake for at least 8 hours) blood glucose (BG) ≥ 126 mg/dL Mellitus in Pediatric Populations Family history of T2DM in first or second degree relative 3. 2-h PG ≥200 mg/dL (≥11.1 mmol/L) during oral glucose tolerance test (OGTT). The test should be performed as described by the WHO, using a glucose load containing the Members of high-risk populations (African American, Latino, equivalent of 75 g anhydrous glucose dissolved in water. Native American, Asian American, Pacific Islander) Signs of insulin resistance or conditions associated with 4. Random blood glucose test ≥ 200 mg/dL in the setting of hyperglycemia symptoms (i.e., 3 P’s and more...) insulin resistance (acanthosis nigricans, hypertension, dyslipidemia, polycystic ovarian syndrome (PCOS), or small *In the absence of unequivocal hyperglycemia, diagnosis requires two abnormal results from different for gestational age birth weight) tests which may be obtained at the same time (e.g., A1C and FPG), or the same test at two different time Maternal history of DM or gestational DM during the child’s points. gestation Integrated Pharmacotherapy 3 19 Diabetes Mellitus  HbA1c The HbA1c or simply A1c test is a common blood test used to diagnose DM, as well as to monitor DM once an individual is diagosed. The A1c test is also called the glycated hemoglobin, glycosylated hemoglobin, hemoglobin A1C or HbA1c test. As stated above, glucose can condense with hemoglobin (Hb) in red blood cells to form glycated hemoglobin. When red blood cells are exposed to high levels of BG, there is an accumulation of the glycated form of hemoglobin. Once a hemoglobin molecule is glycated, it remains that way. A buildup of glycated hemoglobin within the red blood cell therefore reflects the average level of glucose to which the cell has been exposed during its life cycle of 120 days or 4 months. The A1c is a measure of the glycated hemoglobin and reflects a weighted average of the blood glucose over the past 4 months. Specifically, 50% of the A1c is determined by the BG during the most recent month, 25% of the A1c is determined by the BG during the 1-month before that, and the remaining 25% of the A1c is determined by the BG level during the 2-month period before the first 2 months. Since the A1c is more heavily determined by the more recent months, it is often refered as a 3-month average of the patient’s BG (instead of a 4-month weighted average). Monitoring A1c helps healthcare providers and patients assess the overall effectiveness of therapy. The A1c should be measured at least annually in patients who are meeting treatment goals and have stable glycemic control and every 3 months when therapy has changed or A1c not at goal. For most patients, an A1c > 7% serves as a call to action to initiate or change therapy. (or evaluate adherence) It is important to note that a ‘normal’ A1c may be abnormal if the patient is experiencing episodes of hypoglycemia and hyperglycemia. The high and low blood sugars may average out to reflect a good A1c, but the reality is that there is a lack of glycemic control. Date of Download: 12/28/2024 Copyright © 2024 American Diabetes Association. All rights reserved. This is why both acute blood glucose Diabetes Care. 2024;48(Supplement_1):S128-S145. doi:10.2337/dc25-S006 measures (via continuous glucose Figure 26. Figure 26. A1c goal considerations monitors or glucometers) and the A1c are utilized to evaluate blood glucose control. The following equation is used to translate the A1c into an estimated average glucose (eAG): eAG = 28.7 x A1c – 46.7. Basal and postprandial hyperglycemia affect the A1c. The relative extent at which basal and postprandial affect the A1c depends on the A1c level. For example, when the A1c is near goal (e.g., 7% to 7.5%), postprandial hyperglycemia has a relatively greater impact on the A1c compared to basal hyperglycemia. However, at higher A1c levels (e.g., greater than 10%), basal hyperglycemia has a relatively greater impact on the A1c compared to postprandial hyperglycemia. In other words, when an individual has a really high A1c, they are exhibiting high blood sugar all the time (basal), rather than only elevated after they eat (post prandial). For most individuals, an A1c < 7% is the goal, but there are those in which different A1c goals are appropriate. The Figure 26 provides a depiction of when different A1c goals (< 6.5%,