Diabetes Type 2 Quiz

Pharmacology of Diabetes Mellitus

• Learning Outcomes:
  • Describe the mechanism of action of insulin, recognize its therapeutic and adverse effects.
  • Compare and contrast different types of insulin preparations and regimens, identifying their advantages and disadvantages.
  • Discuss potential future directions for insulin therapy in diabetes mellitus, including new formulations, devices, and technologies.
  • Recognize the principles of pharmacotherapy for type 2 diabetes, including different drug classes, their mechanism of action, and adverse effects.
  • Evaluate the clinical efficacy of antidiabetic drugs, including effects on glycemic control, weight, blood pressure, lipid profiles, and other outcomes.

Diagnosis

• Fasting Plasma Glucose: ≥7.0 mmol/L (126 mg/dL)
• HbA1c: ≥48 mmol/mol (equivalent to 6.5%)
• Two-hour Plasma Glucose (OGTT): ≥11.1 mmol/L (200 mg/dL)
• Random Plasma Glucose (symptoms of hyperglycemia): ≥11.1 mmol/L (200 mg/dL)

Type 2 vs Type 1 Diabetes

• Type 2 Diabetes:
  • Insulin resistance with relative insulin deficiency
  • Gradual onset of hyperglycemia with progressive decline in beta-cell function (initially silent).
  • Treatable with oral medications.
  • Associated with increasing age and obesity.
• Type 1 Diabetes:
  • Absolute insulin deficiency
  • Abrupt onset of hyperglycemia and propensity for diabetic ketoacidosis (DKA).
  • Requires insulin.
  • Associated with autoimmune antibodies.
  • Predominant type of diabetes in individuals younger than 30.

Management of Diabetes Mellitus

• Type 2 Diabetes:
  • Multidisciplinary approach: patient education and support.
  • Lifestyle modifications (diet, physical activity, and weight loss).
  • Pharmacologic therapies (oral, GLP-1 agonists, and insulin).
  • Bariatric surgery may be considered.
• Type 1 Diabetes:
  • Multidisciplinary approach: patient education and support.
  • Dietary advice (carb counting, glycemic index diets, and dietary advice) and physical activity advice.
  • Insulin therapy (injections or insulin pump).
  • Potential for new treatments (e.g., islet cell or stem cell therapies) in the future.

Indications for Insulin

• Type 1 diabetes
• Inadequately controlled type 2 diabetes
• Temporary use during hospitalization/surgery
• Pregnancy
• Renal disease (when oral medications are limited)
• Severe new-onset type 2 diabetes requiring initial glycemic control.

A Century of Insulin Therapy

• Timeline of insulin therapy developments, including the first human treated, NPH insulin, pump therapy, human insulin, and insulin analogs.

Treatment of Type 1 Diabetes

• Insulin replacement therapy
• Dosing adjustments based on carbohydrate intake, exercise regimen, and blood glucose profile.
• Regular blood glucose monitoring and insulin dose adjustments.
• Monitoring for complications.

Bolus Insulin

• Rapid or short-acting insulin administered before meals to cover food intake or correct hyperglycemia.
• Includes: regular, aspart, lispro, and glulisine.

Basal Insulin

• Aims to mimic physiological insulin secretion, maintaining euglycemia in the fasting state.
• Intermediate-acting insulin (NPH) administrated once or twice daily.
• Long-acting insulin (e.g., glargine, Detemir, and Degludec) administered once or twice daily.

NPH Insulin

• Neutral protamine Hagedorn, first basal insulin (1936).
• A suspension of zinc insulin combined with protamine.
• Intermediate duration of action (10-20 hours).
• Advantage: Combination with other insulins.
• Disadvantage: Peak effect increases hypoglycemia risk.

Insulin Glargine

• Peakless 24-hour insulin.
• Insulin modifications: glycine substituted at A21, and two arginines added at B30.
• Unique release pattern at the injection site.

Pharmacodynamics of Insulin

• Table summarizing onset of action, peak, and duration of action for various insulin preparations.

Summary of Insulin Activity

• Graph depicting the activity profiles of different insulin preparations over time.

Insulin Administration Regimens

• Conventional: basal insulin only, twice-daily mixed (intermediate + short-acting).
• Basal-bolus: long-acting insulin + rapid-acting insulin with each meal, continuous subcutaneous insulin infusion (insulin pump).

Pitfalls of Conventional Twice-Daily Split-Mixed Regimen

• Chart illustrating potential challenges of twice-daily split-mixed insulin regimen, including potential dawn phenomenon and hyperglycemia.

Mimicking Nature: Basal-Bolus Insulin Concept

• Diagram illustrating how the basal-bolus insulin regimen mimics the natural release pattern of insulin throughout the day.

Insulin Pump Therapy

• Insulin pump delivers insulin through a catheter in the abdominal fat, controlling blood sugar levels.

Pharmacokinetic Advantages of the Insulin Pump (CSII)

• Uses rapid-acting insulin.
• Single injection site for basal insulin.
• Mini-boluses every 5 minutes (closed-loop technology).

Automated Insulin Delivery Systems (Hybrid Closed Loop Devices)

• Combining an insulin pump with a continuous glucose monitor for automated insulin adjustments.
• Algorithm adjusts basal rates based on glucose levels.
• Still typically requires pre-meal insulin boluses.
  • Increased time in target glucose range.
  • Reduced hypogylcemia.
  • Issues: higher cost.

Inhaled Insulin

• Rapid-acting insulin adsorbed to carrier particles delivered via inhalation.
  • Max effect: 53 minutes.
  • Duration of action: 160 minutes.
  • Approved for covering prandial requirements in non-smoking adults with no pulmonary disease.
  • Less effective than subcutaneous route.
  • Potential for pulmonary toxicity.

Advances in Insulin Delivery

• Overview of various insulin delivery devices, including inhalers, insulin pumps, and other advanced technologies

Insulin Side Effects

• Very safe when used appropriately.
• Hypoglycemia: most common complication.
• Insulin lipodystrophies (lipoatrophy and lipohypertrophy).
• Allergy (local and systemic).

Summary

• Insulin is used in treating type 1 and 2 diabetes.
• Multiple daily injections (basal-bolus) are commonly used.
• Hypoglycemia is a common side effect.
• Patient education is crucial.
• Basal-bolus regimen is the most physiological approach.

Principles of Glucose Lowering Agents in Type 2 Diabetes

• Multiple drugs with tissue-specific action available.
• Most are contraindicated in pregnancy, except some sulfonylureas (glyburide) and metformin.
• Can be used in various combinations, with some exceptions.
• Metformin is generally a first choice.
• Patients can start with multiple classes of medications.

Insulin Resistance and Associated Clinical Conditions

• Chart illustrating interconnectedness of conditions often associated with insulin resistance (e.g. hypertension, type 2 diabetes, impaired glucose tolerance, etc.).

Pathogenesis of Hyperglycemia in Type 2 Diabetes

• Diagram illustrating underlying hyperglycemia mechanisms in T2D, including insulin resistance, increased liver glucose production, and insufficient peripheral glucose uptake.

Organs Regulating Plasma Glucose

• Diagram illustrating complex organ interactions in regulating plasma glucose levels (including effects of diabetes medications).

Metformin (Glucophage)

• Action:
  • Acts on liver (activates AMPK).
  • Reduces hepatic glucose output (reduces gluconeogenesis).
  • Decreases glucose absorption in large intestine.
  • Increases insulin-mediated glucose uptake in peripheral tissues.
• Associated with mild weight loss
• Does not cause hypoglycemia.
• Efficacy: can lower HbA1c as much as 2%.
• Most frequently prescribed drug for T2D.

Side Effects and Contraindications of Metformin

• Side effects:
  • GI upset (e.g., anorexia, nausea, diarrhea) – most typical
  • Lactic acidosis: rare but severe threat.
  • Vitamin B12 deficiency (reduced absorption).
• Contraindications:
  • Patients prone to metabolic acidosis
  • Type 1 diabetes
  • Renal failure (eGFR < 30 mL/min, or 30-45 mL/min requiring dose reductions.)

Insulin Secretagogues: 1. Sulfonylureas

• Name: Glipizide, glimepiride, glyburide
• Action: Stimulates pancreatic insulin release for 12-24 hours.
• Mechanism: Binds to potassium channels (K+) in beta cells, initiating insulin release.

Insulin Secretagogues: 1. Sulfonylureas (continued)

• Immediate Effect: primarily on pre-meal glucose.
• Metabolism: Hepatic, primarily excreted via kidneys. Care needed with kidney impairment.
• Contraindications: Type 1 diabetes, diabetic ketoacidosis (DKA), sulfa allergy.
• Adverse Effects: hypoglycemia, weight gain, hunger.
• Efficacy: Lowers A1c up to 1.5-2 %.

2. Meglitinides/Glinides

• Name: Repaglinide
• Action: Stimulates insulin secretion for 3-4 hours, primarily after meals. Faster onset of action compared to sulfonylureas.
• Mechanism: Similar to sulfonylureas in mechanism.
• Fast onset: lower blood glucose more rapidly, shortly after eating
• Side effects: low blood sugar (hypoglycemia) , weight gain.
• Disadvantage: patient compliance is a concern.
• Contraindications: Type 1 diabetes, liver failure, DKA, sulfa allergies.
• Metabolism: Hepatic, with most (96%) excreted via the gastrointestinal (GI) tract.
• Efficacy: Lowers A1c approximately 1.4%.

Alpha-Glucosidase Inhibitors

• Name: Acarbose
• Mechanism: Delays carbohydrate absorption from the intestine, reducing post-prandial blood glucose spikes
• Action: affects digestive system, delaying carbohydrate digestion
• Effects: post-prandial glucose only.
• Administration: taken with meals.
• Side effects: flatulence, abdominal bloating
• Contraindications: Gastrointestinal (GI) disorders, especially inflammatory bowel disease (IBD).
• Metabolism: primarily excreted unchanged in the urine.
• Does not induce hypoglycemia.
• Efficacy: Lowers A1c by about 0.4-0.8%.

Incretin Hormones

• Released from the gut after eating.
• Enhance insulin secretion.
• GLP-1 and GIP are the primary incretin hormones.
• Impaired incretin effect is common in type 2 diabetes (T2DM).
• This contributes to poor glucose regulation and reduced insulin secretion from the pancreas in T2DM.

The Incretin System

• Diagram illustrating the roles of GLP-1 and GIP in the incretin system

GLP-1 Receptor Agonists (GLP-1 RA)

• Names: Semaglutide, liraglutide, dulaglutide,.
• Mechanism: Enhances glucose-dependent insulin secretion, slows gastric emptying, and reduces post-prandial glucagon and food intake.
• Action: potent glucose-dependent insulin secretion, inhibits glucagon secretion, and indirectly slows gastric emptying, stimulates satiety.
• Administration: subcutaneous injection (daily or weekly), some are orally available (e.g. Semaglutide).

GLP-1 Receptor Agonists (GLP-1 RA) (Continued)

• Side effects: GI issues (nausea, vomiting, diarrhea), pancreatitis (<1% risk).
• Contraindications: pancreatitis.
• Does not induce hypoglycemia.
• Efficacy: Lowers A1c by 0.5-2.0 %, weight loss.
• Benefits in patients with T2DM and CVD: reductions in cardiovascular outcomes and CV mortality.

GIP/GLP-1 Receptor Agonist

• Name: Tirzepatide
• Mechanism: synthetic dual-acting agonist targeting GIP and GLP-1 receptors.
• Action: potent glucose-dependent insulin secretion, inhibits glucagon secretion, and indirectly slows gastric emptying, stimulating satiety.
• Administration: subcutaneous injection weekly.

GIP/GLP-1 Receptor Agonist (Continued)

• Side effects: GI issues (nausea, vomiting, diarrhea), pancreatitis (<1% risk).
• Contraindications: pancreatitis.
• Does not induce hypoglycemia.
• Efficacy: Lowers A1c by approximately 2%, significant weight loss.

DPP IV Inhibitors

• Names: Sitagliptin, linagliptin, vildagliptin, saxagliptin.
• Action: Increases the duration of action of GLP-1 and GIP by inhibiting DPP-4.
• Mechanism: Inhibit the enzyme dipeptidyl peptidase-4 (DPP-4), extending the effects of GLP-1/GIP.
• Metabolism: Sitagliptin/saxagliptin are not metabolized; excreted by kidneys; adjust dose with kidney problems. Linagliptin metabolized by liver.
• Administration: Taken orally, once a day. Most are taken orally once a day
• Contraindications: pancreatitis.
• Adverse Effects: gastrointestinal issues.
• Does not induce hypoglycemia.
• Efficacy: lowers A1c by approximately 0.7-1.2%.

Normal Renal Glucose Handling

• Summary graph on renal glucose handling
• Majority of glucose is reabsorbed by SGLT2 (90%) in the kidneys.
• Remaining absorbed by SGLT1 (10%).
• SGLTs are responsible for reabsorption.

SGLT2 Inhibitors

• Mechanism: block SGLT2 in the kidney, increasing urinary glucose excretion. Reduced glucose reabsorption leads to glucose elimination in the urine.

SGLT2 Inhibitors (continued)

• Name: Empagliflozin, canagliflozin, dapagliflozin.
• Mechanism: Excretion of 50-100 grams glucose/day primarily.
• Metabolism: Primarily hepatic with some metabolites excreted by the kidneys.
• Contraindications: Severe renal impairment, ESRD, or on dialysis.
• Side effects: Vulvovaginal candidiasis, vulvovaginal mycotic infection, urinary tract infections, and polyuria, mild risk of euglycemic DKA.
• Efficacy: Lower A1c by 0.7-1.0%.
• Weight Loss: 2.2% or more.
• Cardiovascular benefit: also approved for heart failure and CKD.

Summary (Diabetes Medications)

• Table summarizing adverse effects, effect on weight, and cautions for various diabetes medication classes. Includes relevant information that was previously not detailed.

Test your knowledge about type 2 diabetes, including its characteristics, treatment options, and future directions in medicine. This quiz will help you understand the differences between type 1 and type 2 diabetes and the pharmacotherapy involved in managing type 2 diabetes.