Pancreas Anatomy and Function

Pancreas Anatomy

• A glandular organ in the abdominal cavity.
• Has two lobes, one behind the stomach, the other in apposition to the proximal duodenum

Pancreas Micro Anatomy

• Has Exocrine and Endocrine functions
• Exocrine Pancreas: Acinar and duct cells that produce and secrete digestive enzymes into the lumen of the duodenum
• Endocrine Pancreas: Has four types of cells organized in Islets, that produce and secrete hormones into the blood, and is involved in glucose metabolism; this section makes up 2-3% of the pancreas tissue

Endocrine Pancreas - Islets of Langerhans

• There are four cell types that produce four hormones (all polypeptides)
• Alpha α cells (20%) secrete glucagon
• Beta β cells (>70%) secrete insulin
• Delta δ cells (D cells) (5%) secrete somatostatin
• F cells (PP cells, γ cells) (< 5%) secrete pancreatic polypeptide
• The hormones above regulate glucose metabolism and blood glucose levels

Peptide Hormones

• All pancreatic hormones are polypeptides like insulin, glucagon, somatostatin, and pancreatic polypeptide.
• Circulate unbound in the blood because they are hydrophilic
• It has a short half-life of ≤ 30 minutes
• Bind to cell surface receptors

Insulin Structure and Synthesis

• A polypeptide hormone produced by pancreatic beta cells in response to hyperglycemia
• Active insulin has two peptide chains called alpha and beta chains, which are connected by disulfide bridges
• Synthesized as preproinsulin within the rER
• Signal sequence (pink) is removed in the ER to form proinsulin
• Proinsulin goes to the Golgi apparatus, gets packaged into vesicles and cleaves the C-peptide to make a mature vesicle

C-Peptide Test

• Measures the amount of C-peptide in the blood or urine.
• Helps differentiate Type 1 or Type 2 diabetes.
• Helps evaluate the efficacy of treatment.
• Determines if the pancreas is synthesizing insulin.

Insulin structure across species

• The differences in amino acid sequences between species are small:
• Cattle, sheep, horses, dogs, and whales differ only in positions 8, 9, and 10 of the alpha chain
• Porcine insulin differs from human insulin by 1 amino acid
• Bovine insulin differs from cat insulin by 1 amino acid
• Porcine insulin differs from cat insulin by 3 amino acids
• Human insulin differs from cat insulin by 4 amino acids
• Porcine and canine insulin are exactly the same

Therapeutic Insulin Synthesis

• The ability to extract active insulin from animal sources marked a turning point in the therapy of diabetes (mainly bovine and porcine insulin were utilized).
• Recombinant DNA technology allows for in vitro synthesis of human insulin in quantities sufficient to meet clinical demand
• Is less immunogenic and less likely to cause atrophy of subcutaneous fat (lipoatrophy) at the site of injection
• Can alter the rate of onset and offset of its action by through modifications to the native insulin sequence
• Animal diabetes therapy uses animal-derived insulin (i.e., Porcine Lente insulins, like Vetsulin®/Caninsulin®) and synthetic human insulin (i.e., Humulin N® or Novolin N®)

Stimuli for Insulin Synthesis and Secretion.

• Nutritional, paracrine, and neural endocrine variables all dictate insulin release.
• A Secretagogue is a substance that stimulates the secretion of another substance
• The importance of the secretagogues depends on the natural diet and nutritional status of the species:
• Glucose is important for omnivores
• Amino acids are important for carnivores
• Fatty acids also stimulate insulin release in humans

Pancreatic Beta Cell Insulin Secretion

• Beta cells have a glucose transporter (GLUT2 - insulin independent) in the membrane surface
• The transporters allow glucose to diffuse into the cell following the concentration gradient
• Extracellular fluid glucose concentration directly affects glucose concentration inside beta cells
• High levels of glucose lead to insulin secretion and production

How do Sulfonylureas Affect Insulin Release from B-Cells?

• Sulfonylureas are an oral treatment that stimulate insulin release in the pancreatic beta cells
• They stimulate the release of the insulin, and cause insulin to stimulate cells to use and store blood sugar (glycolysis, glycogenesis, lipogenesis)

Insulin Release Kinetics

• Insulin secretion follows biphasic kinetics:
• Acute phase: secretion of pre-synthesized insulin Chronic phase: synthesis and secretion of insulin

Insulin Receptor Interaction

• After secretion from beta cells, insulin binds to specific membrane receptors on target tissues (RTK Receptor Tyrosine Kinase)

How Does Insulin Facilitate Glucose Entry Into Cells?

• Insulin facilitates glucose entry into cells by increasing the number of specific GLUCOSE TRANSPORTERS (GLUT4) in the cell membrane
• GLUT4 is the only insulin-dependent transporter
• Muscle and adipose tissue depend on insulin for glucose uptake

GLUT 4 and Exercise

• Resistance exercise can stimulate translocation of GLUT 4 to muscle membrane, increasing glucose uptake by the cell

Insulin Net Effect

• To lower blood concentration of glucose, fatty acids, and amino acids
• Facilitates glucose entry into cells
• Promotes intracellular conversion of these compounds to their storage forms, causing an anabolic effect
• Glucose to Glycogen
• Fatty acids to Triglycerides
• Amino acids to Proteins

How Does Insulin Act on Muscles?

• It impacts smooth, striated, and cardiac muscle:
• Stimulate glycogen synthesis enzymes
• Promotes storage of glucose molecules in the form of glycogen
• Promotes muscle to use glucose as fuel source
• Reduces fatty acid beta oxidation
• When there is an absence of insulin the muscle relies more on fatty acids as a fuel source
• Enhances amino acid uptake and promotes muscle growth (protein synthesis)

How Does Insulin Act on Adipose Tissue?

• Increases glucose uptake by adipocytes
• Stimulates Dihydroxyacetone phosphate (DHAP) pathway, stimulating Glycerol synthesis
• Stimulates glycolysis to cause formation of pyruvate which forms Acetyl CoA leading to Fatty acid synthesis
• Causes Glycerol + Fatty acids to create Triacylglycerol (TAG), which is stored in adipocytes through Lipogenesis
• Inhibits Lipolysis, the process of breaking down of triglycerides into fatty acids and glycerol

How Does Insulin Act on the Liver?

• Promotes fatty acid synthesis in hepatocytes
• Stimulates incorporation of fatty acids and triglycerides into lipoprotein (VLDL) for transport to adipocytes and peripheral tissue
• Stimulates glycogen synthesis (glycogenesis) and glycolysis (ATP production)
• Decreases gluconeogenesis and glycogenolysis
• Gluconeogenesis - the process of producing glucose from non-carbohydrate substrates (amino acids, glycerol, lactate)
• Decreases synthesis of ketone bodies
• Glycogenolysis - the process of breaking down glycogen into glucose

Insulin Sensitive Tissues

• Most important insulin-sensitive tissues: Liver, Muscle and Adipose
• Carbohydrate metabolism: glycogen synthesis, glycogenolysis, gluconeogenesis
• Lipid metabolism: lipogenesis, lipolysis, ketone bodies synthesis
• Protein metabolism: gluconeogenesis
• Muscle uses: glucose transport through GLUT 4, enhanced glycogen synthesis, and reduced glycogenolysis, amino acid uptake, and protein synthesis and degradation
• Adipose uses: glucose transport through GLUT 4 leading to enhanced lipogenesis and reduced lipolysis

How is Insulin Metabolized?

• Insulin is metabolized mainly by the liver and kidneys
• 80-60% of secreted insulin is cleared during first passage through the liver
• Receptor-mediated insulin uptake followed by degradation in hepatocytes constitutes the basic mechanism of insulin clearance
• The remaining insulin is delivered to the systemic circulation to act on target tissues (muscle, adipose tissue, kidneys, brain...) and undergoes receptor-mediated uptake and degradation
• It has an Insulin Clearance Half-life of 10 min