Case 1: Stephen Golding

Pancreas Anatomy

Exocrine and endocrine organ

In lef upper quadrant

• Posterior to stomach

• Retroperitoneal except tail

Pancreas Sections

Head

Neck

Body Tail

Endocrine Pancreas: Histology

Islet of Langerhans organized around capillaries

Contains:

• Alpha cells

• Beta cells (middle of islet)

• Delta cells

• Pancreatic polypeptide (PP) cells

Endocrine Pancreas Physiology: Islet of Langerhans

Secrete insulin and glucagon directly into blood (capillaries)

Endocrine Pancreas Physiology: Alpha Cells

Secrete glucagon

Endocrine Pancreas Physiology: Beta Cells

Secrete insulin and amylin

• Amylin: Hormone inhibiting insulin secretion

Endocrine Pancreas Physiology: Delta Cells

Secrete somatostatin

Endocrine Pancreas Physiology: PP Cells

Secrete pancreatic polypeptide

Unknown function

Insulin: Structure

A and B chain

Linked by disulfide linkages + C chain peptide (C peptide)

Insulin: Production

In beta cells

1. Preproinsulin

• From insulin RNA in ER

2. Proinsulin

• Cleaved in ER

3. Insulin

• Cleaved Golgi apparatus

4. Secretion + Degradation

• Insulin and proinsulin in secretory granules

  • Increased from high blood glucose

• Cleared in 10-15 mins

  • Insulinase: In liver, kidneys, muscles

  • Degrade insulin

Insulin: Action

Bind insulin receptors (membrane receptor protein) → Penetrate into target cells

Inhibit glucagon secretion

Stimulate K+ uptake into cells

Insulin: Action on Carbs

Increase:

• Glucose uptake

• Glycogenesis (Glucose → Glycogen)

• Glycolysis (Glucose → ATP)

Decrease:

• Glycogenolysis (Glycogen → Glucose)

• Gluconeogenesis (Glucose synthesis)

Insulin: Action on Lipids

Increase:

• Lipid synthesis

• TGA storage

Decrease:

• Lipolysis (TGA → Glycerol + FFA)

• Ketogenesis

Insulin: Action on Proteins

Increase:

• Protein synthesis

• Amino acid uptake

Decrease:

• Proteolysis

Glucagon: Structure

Large polypeptide

Glucagon: Production

Increased from low blood glucose

Glucagon: Action

Increase blood glucose

Somatostatin: Production

Increased from…

• High blood glucose

• High amino acids

• High fatty acids

• High GI hormones from food intake

Somatostatin: Action

Inhibit insulin and glucagon secretion

Decrease stomach, duodenum, and gallbladder motility

Decrease secretion and absorption in GI

Insulin Effects: Carb Metabolism in Liver

Increase:

• Glucose storage → Glycogen

Decrease:

• Glycogenolysis

• Gluconeogenesis (Amino acids → Glucose)

Insulin Effects: Carb Metabolism in Skeletal Muscle

Increase:

• Glycogen synthesis

• Glucose uptake

Insulin Effects: Carb Metabolism in Adipose Tissue

Increase: Glucose uptake

Insulin Effects: Carb Metabolism in Brain

Increase: Glucose uptake

Counter-Regulatory Hormones to Insulin

Increase blood glucose during hypoglycemia

Earliest to latest secretion:

1. Glucagon: From alpha cells

2. Epinephrine/Norepinephrine: From adrenal medulla + sympathetic nerves

3. Cortisol: From adrenal cortex

4. Growth Hormone: From anterior pituitary

Ketone

Acidic compound

Synthesized by hepatocyte mitochondria from FFA

Energy source for peripheral tissues when no glucose

• Heart, brain, skeletal muscle

Produced during…

• Starvation

• Alcohol use

• Poor T1D management

Ketone Body Types

Acetoacetate

Beta-hydroxybutyrate

Acetone

• Acetoacetate and beta-hydroxybutyrate breakdown product

• Fruity smell

Ketogenesis

1. 2 acetyl-CoA → Acetoacetyl-CoA

2. Acetoacetyl-CoA + Acetyl-CoA → HMG-CoA

• HMG-CoA Synthase: Rate-limiting enzyme

3. HMG-CoA → Acetoacetate + Acteyl-CoA (ketone bodies)

4. Acetoacetate → Beta-hydroxybutyrate OR acetone

Ketogenesis Regulation

Fasting + DKA:

• Decreased oxaloacetate for gluconeogenesis = Increase acetyl-CoA = Increase ketogenesis

Alcohol Use:

• Excess NADH = Oxaloacetate → Malate

• Increased acetyl-CoA = Increase ketogenesis

Diabetes: Description

Metabolic disorders causing chronic hyperglycemia

T1D: Insulin-dependent

• 1A: Autoimmune

• 1B: Idiopathic

T2D: Non-insulin-dependent

Gestational: Glucose tolerance during pregnancy

Monogenic/Maturity-Onset Diabetes of the Young (MODY): Genetic defects → Beta-cell dysfunction

• Autosomal dominant inheritance

T1D: Epidemiology

Childhood onset

Risk factors:

• Family history (weak predisposition)

• HLA-DR3/4

• White populations

• Environmental factors (viral infection)

T1D: Etiology

Autoimmune beta-cell destruction

T1D: Pathophysiology

1. Genetic susceptibility + environmental changes = Immune dysregulation = Autoantibody production

2. Autoantibodies destroy beta-cells in islets of Langerhans = Absolute insulin deficiency

3. Decrease glucose uptake in tissues

T1D: Clinical Presentation

DKA (sudden onset)

Hyperglycemia symptoms

• Polyuria

• Polydipsia (thirst)

• Polyphagia (hunger)

Weight loss

Vision changes

Fatigue

Pruritis

Poor wound healing + increased infections

Calf cramps

T1D: Investigations

Hyperglycemia signs → Hyperglycemia tests

• Blood glucose

• HbA1c

• C-peptide

T1D: Blood Glucose

Random blood glucose

• ≥ 11 mmol/L

Fasting plasma glucose (FPG): After > 8 hours fasting

• ≥ 7.0 mmol/L

Oral glucose tolerance test (OGTT)

• 1-Step: Measure FPG + blood glucose 2 hours after consuming glucose

• 2-Step: For gestational diabetes

1. Give glucose + measure blood glucose after 1h

2. ≥ 7-8 mmol/L = Measure FPG + blood glucose 1-3 hours after consuming glucose

T1D: HbA1c

Glycated Hb

• Average blood glucose from past 2 months

≥ 6.5%

T1D: C-Peptide

Differentiate diabetes type

High: Insulin resistance + hyperinsulinemia = T2D

Low: Absolute insulin deficiency = T1D

T1D: Treatments

Lifestyle changes

Glucose monitoring

Pharmacologic: Insulin regimens

• Basal

• Prandial

• Mixed

• Automated insulin delivery systems (insulin pump)

T1D Treatment: Lifestyle Changes

Weight loss

Balanced diet (high-fibre)

Exercise

Smoking cessation

Vaccination

T1D Treatment: Glucose Monitoring

Self-Monitoring: At fixed times OR as needed

Continuous Monitoring: Subcutaneous device measures consistently

T1D Treatment: Pharmacologic

Basal: Intermediate/long-acting insulin once/twice daily

• Increase basal insulin levels

Prandial: Short-acting insulin bolus before meals

• + basal insulin

Mixed: Intermediate-acting + short-acting insulin

• Fewer injections

• Cannot miss meals → Hypoglycemia

Automated Insulin Delivery Systems (Insulin Pump): Continuous subcutaneous infusion

• Glucose levels/anticipated levels = Insulin calculator suggest bolus dose

T1D: Complications

Types:

• Metabolic

• Macrovascular

• Microvascular

Increase infections

Amyloidosis: Increased amylin (with insulin) = Deposit in pancreas

T1D: Metabolic Complications

From:

• Treatment non-compliance/insufficiency

• Undiagnosed

Hyperglycemic Crisis:

• DKA

• HHS

Hypoglycemia

T1D Metabolic Complications: DKA

More common in T1D

Pathophysiology: Insufficient insulin = Increase fat breakdown = Ketogenesis

Clinical Presentation:

• Polyuria

• Polydipsia

• Nausea/vomiting

• Hypovolemia

• Fruity breath (high acetone)

DKA: Treatment

Electrolyte + fluid replacement

• Until K+ > 3.5 mmol/L

IV insulin

COMPLICATIONS:

• Hypoglycemia (over-correction)

• Cerebral edema

T1D Metabolic Complication: Hyperglycemic Hyperosmolar State (HHS)

More common in T2D

No ketosis or acidosis

T1D Metabolic Complication: Hypoglycemia

Increased insulin

T1D Macrovascular Complication

Atherosclerosis

Pathophysiology: Metabolic dysfunction (dyslipidemia, hyperglycemia) = Increase vascular inflammation = Increase plaque formation

Clinical Presentation:

• CAD

• Stroke

• Peripheral arterial disease

T1D Microvascular Complication

Pathophysiology: Chronic hyperglycemia = Protein/lipid glycation = Thickened basal membrane = Tissue damage + organ dysfunction

Clinical Presentation:

• Retinopathy: Vision changes

  • Edema

  • Hemmorrhage

  • Retinal detachment

• Nephropathy: CKD

  • Nephrosclerosis

  • Glomerulosclerosis

• Neuropathy: Peripheral nerve damage

• Foot ulcers