Diabetes Management and Amylin

Pancreatic Glands

• Exocrine glands produce pancreatic digestive enzymes via pancreatic acini
• Endocrine glands form pancreatic islets (Islets of Langerhans) and secrete hormones

Cells of Pancreatic Islets

• Alpha cells secrete glucagon
• Beta cells secrete insulin
• Delta cells secrete somatostatin
• PP (F) cells secrete pancreatic polypeptide

Effects of Glucagon

• Stimulates glucose production in the liver (gluconeogenesis)
• Stimulates glycogen breakdown into glucose in skeletal muscles and liver cells (glycogenolysis)
• Stimulates triglyceride breakdown in adipose tissue and fatty acid release (lipolysis)

Effects of Insulin

• Accelerates glucose uptake and utilization by cells.
• Stimulates glycogen formation (glycogenesis)
• Stimulates triglyceride formation in adipose tissue (lipogenesis)
• Stimulates amino acid absorption and protein synthesis

Insulin vs. Glucagon Actions

• Insulin lowers blood glucose
• Glucagon raises blood glucose

Mechanism of Insulin Action

• Insulin binds specific insulin receptors on cell membranes
• This triggers signal transduction and gene expression/growth regulation
• Glucose utilization (glycogen, lipid, protein synthesis) increases

Main Target Organs of Insulin

• Liver
• Muscle
• Adipose tissue

Blood Glucose Levels

• Normal fasting blood glucose: 70-110 mg/dL
• Normal 2-hour postprandial blood glucose: <180 mg/dL
• Hypoglycemia: <70 mg/dL
• Hyperglycemia: >110 mg/dL (fasting)
• Impaired glucose tolerance: 110-180 mg/dL
• Diabetes mellitus: >180 mg/dL

Types of Diabetes Mellitus

• Primary DM:
  • Type 1 (Insulin-Dependent DM - IDDM): insulin deficiency
  • Type 2 (Non-Insulin Dependent DM - NIDDM): insulin resistance
• Secondary DM:
  • Pancreatic disease (e.g., pancreatitis, tumor)
  • Endocrine disease (e.g., Cushing's syndrome)
  • Drug induced (e.g., thiazide diuretics)
  • Infection (e.g., congenital rubella)
• Gestational DM: during pregnancy

Primary DM - Type 1 and Type 2

• Type 1:
  • Abnormality: β-cell destruction, insulin deficiency
  • Incidence: Less common
  • Age of onset: <30 years
  • Etiology: Autoimmune, often with precipitating factor
  • Autoantibodies: commonly present (60-85%)
• Type 2:
  • Abnormality: β-cell dysfunction, insulin resistance
  • Incidence: More common
  • Age of onset: >40 years
  • Etiology: Multifactorial (genetic and environmental)
  • Autoantibodies: rarely present (<10%)

Primary DM - Genetics, Body Weight, Diabetic Ketoacidosis, HHS

• Genetics: Lesser impact in type 1, greater impact in type 2
• Body weight: Low in type 1, overweight/obese in type 2
• Diabetic ketoacidosis: More common in type 1
• HHS: Less common in type 1, more common in type 2
• Treatment: Insulin for type 1, oral hypoglycemics + insulin for type 2

Obesity and Type 2 DM

• Obesity is linked to an increased risk of type 2 diabetes
• Increased body weight by 10kg increases risk of type 2 DM dramatically (3X)
• Obesity often leads to earlier onset of type 2 diabetes

Obesity, Inactivity, and Unhealthy Diet

• Obesity, inactivity, and unhealthy diet are risk factors for type 2 diabetes in both adults and children.

The Deadly Quartet

• Obesity, diabetes, hypertension, and dyslipidemia are linked and pose significant health risks.

Clinical Features of DM

• Polydipsia (excessive thirst)
• Polyuria (excessive urination)
• Nocturia (Frequent urination at night)
• Glycosuria (glucose in the urine)
• Complications (detailed in the further notes below)

Complications of DM

• Acute: DKA (Diabetic Ketoacidosis), HONK (Hyperosmolar Hyperglycemic Nonketotic Coma)
• Chronic:
  • Angiopathy
    • Microangiopathy (e.g., Retinopathy, Nephropathy)
    • Macroangiopathy (e.g., CAD, PAD, CVA)
• Other: Infection and skin issues

Treatment of DM

• Diet control
• Antidiabetic agents
• Management of complications

Diet Control

• Minimize sugar intake or adjust medication/insulin accordingly to control blood sugar
• Reduce body weight
• Increase physical activity

Antidiabetic Agents

• Insulin (more common with type 1)
• Oral Hypoglycemics (Type 2)

Insulin

• History: Frederick Banting first human trial in 1923
• Sources: Bovine, Porcine, Human Recombinant
• Administration: Injection (SC, IV, IM). Alternative methods: Pump
• Preparations: Fast-acting, short-acting, intermediate-acting, long-acting, ultra-long-acting, mixed types (combinations)
• Regimens: Conventional therapy (1-2 injections/day) Intensive therapy (multiple daily injections, glucose monitoring, and dose adjustment.)
• Daily Insulin Schedule (example)
• Absorption of SC Insulin (highly variable, affected by factors such as site of injection, blood flow, exercise, massage)
• Alternatives to Insulin Injection (insulin pumps, insulin pens, transdermal, inhaled, and oral formulations)
• Common Insulin Delivery Devices (insulin syringe, insulin pen, jet injector, insulin pump, inhaled insulin)
• Complications of Insulin Therapy (systemic and local)
  • Hypoglycemia, insulin allergy, insulin resistance, lipoatrophy, hypertrophy

Oral Hypoglycemics

• Sulfonylureas (first generation, second and third generation) ; Mechanism of Action; Pharmacokinetics; Drug interactions; Adverse Effects
• Biguanides (mechanism of action, indications, advantages, adverse effects [Metformin – commonly used]).
• Meglitinides (Mechanism of action, Indications, Adverse effects, [repaglinide & nateglinide])
• Thiazolidinediones (TZDs or glitazones) (Mechanism of action, indications, adverse effects, [Rosiglitazone & Pioglitazone])
• Alpha-glucosidase inhibitors (Mechanism of action, indications, side effects, [Example Acarbose])
• Recent Antidiabetic Agents (Glucagon-like peptide-1 (GLP-1), DPP-4, Amylin Analogues, Gliflozins).
  • GLP-1 agonists (Mechanism & Example Exenatide)
  • DPP-4 Inhibitors (Mechanism and examples [Sitagliptin and Saxagliptin])
  • Amylin analogues (Mechanism & Example Pramlintide)
  • Gliflozins (Mechanism, indications, adverse effects, example canagliflozin)