Endocrine pancreas

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The Endocrine Pancreas

Overview

The endocrine pancreas is a diffuse organ scattered within the exocrine gland whose primary function is regulating blood glucose, fatty acid, and amino acid metabolism. It secretes four major hormones: insulin, glucagon, somatostatin, and pancreatic polypeptide (PP).

1. Islets of Langerhans - Structure & Histology

The endocrine cells are organized into clusters called the islets of Langerhans, which make up only 1-2% of total pancreatic mass. There are approximately 1 million islets, each containing about 2,500 cells, most numerous in the tail of the pancreas.

H&E section of pancreas showing islets of Langerhans (arrows) as pale-staining clusters among darker exocrine acini. x25.

H&E-stained pancreas: islets appear as round, pale-staining profiles (arrows) scattered among more intensely staining exocrine acini. - Histology: A Text and Atlas

Each islet consists of polygonal cells arranged in short, irregular cords, profusely invested with fenestrated capillaries. The cells develop between weeks 9-12 of gestation.

Cell Types

Cell Type	% of Islet	Hormone	Mallory-Azan Stain	TEM Granules
B (β)	60-70%	Insulin	Brownish orange	~300 nm; dense, crystalline angular core
A (α)	15-20%	Glucagon	Red	~250 nm; dense eccentric core, light halo
D (δ)	5-10%	Somatostatin	Blue	~325 nm; homogeneous matrix
PP	~5%	Pancreatic polypeptide	-	Small, irregular granules

Spatial arrangement: β cells occupy the central core; α cells line the outer rim; δ cells are interposed between α and β cells, allowing paracrine communication.

Schematic diagram of an islet of Langerhans showing β (core), α (rim), and δ (interposed) cells with their respective hormone outputs.

Immunofluorescence image of a human islet: insulin-secreting B cells (red, dominant), glucagon-secreting A cells (green, peripherally distributed), DAPI-stained nuclei (blue). x280.

Intra-islet Communication (Paracrine Mechanisms)

There are three communication pathways between islet cells:

Gap junctions - connect α-to-α, β-to-β, and α-to-β cells for rapid ionic and molecular transfer
Blood supply - arteries enter the islet core and flow outward; venous blood from β cells (carrying insulin) bathes α and δ cells before leaving the islet
Innervation - adrenergic, cholinergic, and peptidergic neurons; δ cells have neuron-like processes extending onto β cells

2. Insulin

Synthesis

Insulin is encoded on chromosome 11. The biosynthetic sequence is:

Preproinsulin → (signal peptide cleaved) → Proinsulin → (C-peptide cleaved) → Insulin + C-peptide

Insulin = two chains: A chain (21 amino acids) + B chain (30 amino acids), linked by disulfide bridges
Proinsulin folds in the ER; packaged in Golgi secretory granules; proteases cleave C-peptide during packaging
Insulin and C-peptide are co-secreted in equimolar amounts - C-peptide measurement reflects endogenous β-cell function (useful in insulin-treated patients)
Metabolized in liver and kidney by disulfide-cleaving enzymes

Regulation of Insulin Secretion

Mechanism (glucose-stimulated):

Glucose enters β cell via GLUT2 transporter
Phosphorylated to glucose-6-phosphate by glucokinase (rate-limiting step)
Oxidative metabolism generates ATP
↑ ATP/ADP ratio closes ATP-sensitive K⁺ channels (K_ATP)
Membrane depolarization opens voltage-gated Ca²⁺ channels
↑ Intracellular Ca²⁺ triggers exocytosis of insulin granules

Stimulatory Factors	Inhibitory Factors
↑ Blood glucose	↓ Blood glucose / fasting
↑ Amino acids	Somatostatin
↑ Fatty acids & ketoacids	α-Adrenergic agonists
Glucagon	Diazoxide
Cortisol	Exercise
GIP (incretin)	-
Vagal stimulation / acetylcholine	-
Sulfonylurea drugs (close K_ATP)	-
Obesity	-

Actions of Insulin ("Hormone of the Fed State")

Insulin acts on liver, muscle, and adipose tissue via its tyrosine kinase receptor:

Carbohydrate metabolism:

↑ GLUT4 insertion in muscle and adipose → ↑ glucose uptake → ↓ blood glucose
↑ Glycogen synthesis (liver and muscle)
↓ Glycogenolysis
↓ Gluconeogenesis (via ↑ fructose-2,6-bisphosphate → ↑ phosphofructokinase)

Fat metabolism:

↑ Fat deposition; ↓ lipolysis in adipose
↓ Ketoacid (β-hydroxybutyrate, acetoacetate) formation in liver

Protein metabolism (anabolic):

↑ Amino acid uptake into cells; ↑ protein synthesis; ↓ protein degradation

Other:

↑ Na⁺-K⁺ ATPase activity → ↑ K⁺ uptake into cells → ↓ serum K⁺
Growth-promoting effects

3. Glucagon

Synthesis & Secretion

Glucagon is a 29-amino acid peptide secreted by α cells. It is the hormone of starvation/fasting, counter-regulatory to insulin.

Stimulatory	Inhibitory
Fasting / ↓ blood glucose	Insulin
↑ Amino acids (arginine, alanine)	Somatostatin
CCK (fat/protein ingestion)	↑ Fatty acids & ketoacids
β-Adrenergic agonists	-
Acetylcholine	-

Key point: Insulin modulates glucagon release - in type 1 DM (no insulin), the glucagon response to hypoglycemia is exaggerated. Amino acids stimulate glucagon (but this effect is blunted by simultaneous glucose - opposite to insulin, which is stimulated by both).

Mechanism of Action

Glucagon binds its receptor → Gs protein → adenylyl cyclase → ↑ cAMP → PKA → phosphorylation of enzymes

Actions of Glucagon (primarily on liver)

Glucagon effects on nutrient flow: stimulates glycogenolysis, gluconeogenesis, and fatty acid mobilization from adipose, raising blood glucose, fatty acids, and ketoacids.

Action	Effect on Blood Level
↑ Glycogenolysis (liver)	↑ Glucose
↑ Gluconeogenesis	↑ Glucose
↑ Lipolysis (adipose)	↑ Fatty acids
↑ Ketoacid formation	↑ Ketoacids

4. Somatostatin (δ cells)

Suppresses both insulin and glucagon release (paracrine inhibition)
Has "neuronal" cytology - δ cells send dendrite-like processes onto β cells
Inhibited by: low blood glucose, certain nutrients
Also inhibits GI motility and other GI secretions

5. Pancreatic Polypeptide (PP cells, ~5%)

Stimulates gastric and intestinal enzyme secretion
Inhibits intestinal motility
Released after protein meals and fasting

6. Clinical Relevance

Diabetes Mellitus (most important endocrine pancreas disease)

A group of metabolic disorders characterized by hyperglycemia due to defects in insulin secretion, insulin action, or both.

ADA/WHO Diagnostic Criteria (any one, confirmed on separate day):

Fasting plasma glucose ≥ 126 mg/dL
Random plasma glucose ≥ 200 mg/dL (with symptoms)
2-hour glucose ≥ 200 mg/dL on 75 g OGTT
HbA1c ≥ 6.5%

Prediabetes: FPG 100-125 mg/dL or HbA1c 5.7-6.4%

	Type 1 DM	Type 2 DM
Mechanism	Autoimmune β-cell destruction	Insulin resistance + relative β-cell failure
Insulin	Absent	Relative deficiency
Prevalence	Minority	Vast majority (>90%)
Key feature	Prone to DKA	Prone to hyperosmolar state

Chronic hyperglycemia causes damage to kidneys (leading cause of ESRD), eyes (leading cause of adult-onset blindness), nerves, and blood vessels. In the US, diabetes affects >37 million people (~11% of population).

Sources:

Costanzo Physiology, 7th Edition, pp. 444-452
Histology: A Text and Atlas with Correlated Cell and Molecular Biology, pp. 1718-1722
Robbins & Kumar Basic Pathology (Robbins Pathology), pp. 742-743

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