Diabetes Mellitus: Pancreatic Function

• Insulin is a peptide hormone produced in the pancreas.
• The main job of insulin is to allow glucose to enter tissues like muscle and fat, enabling cells to use glucose efficiently.
• Insulin helps to reduce blood glucose levels.
• Diabetes Mellitus is due to the body's inability to produce insulin (type 1) or a failure to respond properly to insulin (type 2), leading to high blood glucose levels.

Pancreas

• The pancreas has both exocrine and endocrine functions.
• Exocrine cells (acinar cells) secrete digestive juices into the duodenum.
• Endocrine cells, found in the Islets of Langerhans, secrete insulin, glucagon, somatostatin, and pancreatic polypeptide.
• Islet cells are well-supplied with blood (10-15% of pancreatic flow) and are controlled by the parasympathetic and sympathetic nervous systems.

Pancreas Tissues & Cells

• There are 5 types of endocrine cells in the Islets of Langerhans.
• Alpha cells secrete glucagon.
• Beta cells secrete insulin.
• Delta cells secrete somatostatin.
• PP cells (F cells) secrete pancreatic polypeptide.
• Epsilon cells secrete ghrelin.

Paracrine signals in the islet

• Alpha (α) cells produce glucagon, which stimulates beta cells to release insulin, but insulin inhibits glucagon release from alpha cells.
• Beta (β) cells produce insulin, which inhibits glucagon release from alpha cells and modulates somatostatin release from delta cells.
• Delta (δ) cells produce somatostatin, which inhibits both insulin and glucagon release, acting as a local regulatory feedback mechanism.

Synthesis of Insulin

• Insulin is a polypeptide hormone with two chains (A and B), consisting of 51 amino acids.
• Pre-proinsulin is synthesized in the rough ER ribosomes as a single polypeptide chain.
• Pre-proinsulin is cleaved in the ER to form proinsulin.
• Proinsulin is then transported to the Golgi apparatus.
• Disulfide bonds form between the A and B chains in the Golgi.
• Proinsulin is packaged into secretory granules.
• In secretory granules, proinsulin is cleaved into equimolar amounts of insulin and C-peptide.
• The final product is ready for exocytosis.

Synthesis of insulin: processing

• Proteases cleave C-peptide from proinsulin to produce mature insulin.
• Mature insulin then forms a zinc-containing crystalline granule inside vesicles.
• Vesicles fuse that contain the insulin and C-peptide fuse with the plasma membrane, releasing their contents via exocytosis.
• Insulin has a short half-life of 3-5 minutes due to removal by insulinases in the liver and kidney.
• C-peptide have a longer half-life and it is 35 minutes, not removed during portal first pass.
• Insulinases ensure glucose levels are regulated by degrading excess insulin.

C-Peptide (Clinical Relevance)

• Reflects insulin section because it is produced in a 1:1 ratio with insulin
• Has a longer half-life (35 minutes) than insulin (3-8 minutes)
• C-Peptide is retained during portal circulation and insulin is not.
• Can be used to assess endogenous insulin secretion in patients with diabetes.

Mechanism of Insulin Secretion

• High blood glucose leads to glucose uptake via GLUT2, increasing glycolysis & respiration, resulting in increased ATP.
• ATP-sensitive K+ channels close, reducing potassium efflux and causing membrane depolarization.
• Voltage-gated Ca++ channels open, resulting in an influx of Ca++.
• Vesicles fuse with the membrane, leading to exocytosis of insulin and C-Peptide.

Modulation of Insulin Secretion

• Glucose metabolism is the primary trigger for insulin secretion.
• Glucokinase acts as a glucose sensor and is stimulated by insulin.
• The breakdown of glucose, amino acids, and fats increases ATP.
• High ATP levels close K+ channels, leading to beta-cell depolarization and insulin release.
• Mutations in K+ channels cause neonatal hyperinsulinemia.
• Sulfonylurea drugs close K+ channels, enhancing insulin release by mimicking glucose action.
• Gut hormones (GIP, GLP-1) increase cAMP, enhancing calcium influx and insulin secretion.
• Adrenaline and somatostatin inhibit adenylate cyclase, reducing cAMP and calcium influx, suppressing insulin release.

Regulation of insulin secretion

• Meal constituents directly stimulate insulin secretion :Glucose, amino acids, and free fatty acids.
• Gastrointestinal hormones enhance the response and they include : GIP (Gastric Inhibitory Peptide), GLP-1 (Glucagon-like Peptide-1).
• Stimulators of insulin : increase in serum glucose, serum amino acids,serum free fatty acids, increase in serum ketone bodies.
• Inhibitors of insulin secretion: Decrease in glucose, Decrease in amino acids, Decrease in free fatty acids, hormones: somatostatin, epinephrine (α -receptor).

Phases of Insulin Release

• First phase is 3-5 minutes: Triggered by acute glucose rise (2-3x normal fasting levels), Plasma insulin spikes 10-fold, initial burst drops halfway shortly after.
• Second phase is over 1 hour: Gradual increase follows initial drop.
• It reflects the release of preformed insulin and ongoing new synthesis.
• Insulin granules near capillaries are rapidly exocytosed in phase 1 immediate.
• Granules are further from capillaries with newly synthesized insulin contribute to sustained release.

Insulin Receptor Activation and Effects

• Insulin binds to the receptor's alpha subunits, causing autophosphorylation of the beta subunits.
• This activates tyrosine kinase activity.
• Insulin Transduction is the Phosphorylation of insulin receptor substrate (IRS) proteins.
• This initiates downstream signaling cascades

Effect of Insulin

• Insulin binding to its receptor on liver cells triggers glucose uptake.
• Insulin promotes glycogen production and storage by upregulating enzymes involved in glycogenesis.
• Glycolysis: Insulin increases glycolysis, breaking down glucose for energy.
• Insulin stimulates the synthesis of fats (lipogenesis) for energy storage.
• Insulin also promotes protein synthesis.

Glucose Transport & Insulin Action

• Increases glucose uptake in muscles and adipose tissue.
• Brain neurons do not require insulin for glucose uptake.
• GLUT4 (Insulin-Dependent Glucose Transporter)Stored in vesicles within muscle and adipose cells.
• Insulin binding triggers vesicle fusion with the cell membrane.
• GLUT4 transporters are inserted into the membrane, this glucose uptake begins within seconds.
• GLUT4 vesicles return to intracellular storage: Insulin Is Removed.
• Glucose uptake decreases as transporters are recycled.
• Insulin-bound receptors are endocytosed into the cell.
• Insulin is degraded and the receptor is recycled back to the membrane for reuse.

Glucose Transporters

• GLUT1 is located in Ubiquitous, RBC, placenta, colon, kidney and it is used for facilitated diffusion
• GLUT2 is located in liver, small intestine, pancreas and it is used for facilitated diffusion bidirectional
• GLUT3 is located in Ubiquitous, brain, placenta, kidney and it is used for facilitated diffusion
• GLUT4 is located in skeletal muscle, heart muscle, adipose tissue and it is used for facilitated diffusion (insulin dependent)
• GLUT5 is located in jejunum, intestine, kidney tubules and it is used for secondary active transport using Na gradient.

Effects of Insulin on Metabolism

• This increases glucose uptake into muscle and adipose and it works through GLUT4
• This activates glycogen synthase which glycogen synthesis
• Inhibits Glycogen Breakdown by inhibiting glycogen phosphorylase.
• Promote glucose storage in liver
• Supports NADPH production for biosynthesis.
• Reduces hepatic glucose production.

Effects of Insulin on Fats (Metabolism)

• Activates capillary lipoprotein lipase, breaks down VLDL & chylomicrons FA uptake into adipocytes
• This will increase increase glucose transport into adipose, glycerol-3-phosphate production triglyceride synthesis
• Inhibits hormone-sensitive lipase in adipose tissue.
• Glucose directed to fatty acid synthesis: when glycogen stores are full VLDL formation.

Insulin deficiency & lipid metabolism

• Use of stored fat for energy is increased in the absence of insulin
• Lipolysis: FA release from adipose, plasma free fatty acid levels rise.
• There is a rise with plasma Cholesterol & Lipoproteins.
• There is a risk of Ketosis/Acidosis: Uncontrolled fat breakdown

Effects of Insulin on Metabolism (Proteins)

• Protein Synthesis is increased
• There will be an increase of transcription of genes
• Amino acid uptake by cells is stimulated
• Reduces the breakdown of proteins of protein Catabolism
• Amino Acid Release from muscle and other tissues occurs
• There is a decrease in Gluconeogenesis in the liver
• Insulin inhibits enzymes involved in gluconeogenesis, this helps preserve amino acids for protein synthesis.

Summary of Actions

• Carbohydrates Metabolism: increase in Glucose Uptake, Glycogen Synthesis, Liver Glucokinase Activity and Pentose Phosphate Pathway but a decrease in Gluconeogenesis.
• Lipid Metabolism: increase in Lipogenesis but a decrease of Lipolysis, Glucose directed to fatty acid synthesis which is only found with the liver: This will happen when glycogen stores are full VLDL formation.
• Protein Metabolism: increase in Protein Synthesis but a decrease in Protein Catabolism,Amino Acid Release from Muscle and Other Tissues, plus Gluconeogenesis.

Insulin Counterregulatory hormones

• It includes Catecholamines (Epinephrine & Norepinephrine), Glucocorticoids (Cortisol) and Growth Hormone (GH):
• Glycogenolysis happens when Catecholamines are a factor and breaks down glycogen in muscle and liver.
• Lipolysis: Mobilizes fatty acids from adipose tissue occurs in catecholamines
• Plasma Lactate from glycolysis in muscle happens in catecholamines
• There are Catabolic Effects with the hormone Glucocorticoids
• Protein Breakdown – In muscle and liver happens with Glucocorticoids.
• FA Mobilization Releases fatty acids from adipose tissue happens with Glucocorticoids.
• Gluconeogenesis Produces glucose from amino acids and glycerol happens with Glucocorticoids.
• There are 3 factors that happen from the hormone Growth Hormone and they are : Lipolysis, Gluconeogenesis with the last one being a decrease with glucose uptake Reduces glucose entry into muscle cells.

Glucose Homeostasis

• Normal range: Fasting blood glucose 3.9–5.6 mmol/L (70–100 mg/dL).
• Hypoglycemia is <3.9 mmol/L and causes neurological issues, coma, and death if severe in causes
• This is due to An acute Complication: Most common in glucose-lowering therapy, Hyperinsulinism (exogenous or endogenous)
• Can be treated with a secretion of counterregulatory hormones (catecholamines, cortisol, glucagon).
• Chronic Hyperglycemia increases intracellular glucose, which will damage tissue, Complications: Diabetes, nephropathy, neuropathy.

Hyperinsulinism and Hypoglycemia

• High levels of insulin and low levels of glucose:
• This happens from : Congenital Hyperinsulinism , Transient Neonatal Hyperinsulinism Glucokinase Mutations
• There are genetic disorders like KATP Channel Disorders is another reason this can happen
• Tumours like Insulinomas could be a reason this can happen
• Too much consumption of Drugs increase this, like Sulfonylureas.
• Excess insulin from medications or injections causes Exogenous insulin
• Treatment Options*
• Diazoxide
• Nifedipine
• Surgery

Diabetes Mellitus

• Type 1 Diabetes is 10% where there is where this is Autoimmune destruction of beta cells insulin deficiency
• Type 2 Diabetes is 90% where there is Insulin resistance + reduced insulin production occurs, Lifestyle Modification and Insulin injections are treatments for this
• Risk Factors of Diabetes: Obesity, middle-aged or older, rising in youth

Diabetes diagnostic criteria

• Fasting Plasma Glucose should be ≥7.0 mmol/L (126 mg/dL)
• HbA1c should be ≥6.5%.
• Two-hour plasma glucose after 75g oral glucose load ≥11.1 mmol/L or 200 mg/dL (oral glucose tolerance test (OGTT)) + symptoms of hyperglycemia

Oral Glucose tolerance test

• Give 75 g glucose orally (adult, WHO) to fasting individual
• Follow its rise blood glucose levels to determine wheather the patient rise is normal or higher then normal
• Diabetes has much higher than normal rise (≥200 mg/dL (11.1 mmol/L))
• Not used for patient suspected of having T1D.
• Not commonly used for screening other than during pregnancy because of inconvenience.

Diabetic Ketoacidosis (DKA)

• May result in ketoacidosis typically in T1D due to lack of insulin
• Without insulin, there is increased lipolysis and fatty acid production
• Fatty acids convert to ketones in liver
• It is life-threatening and needs immediate treatment, if Ketones build up in the blood which can lead to ketoacidosis (DKA)
• Patients with Shortness of breath, fruity smelling breath and abdominal pain most likely has DKA
• Typical in T1D however can be seen in other forms

Explore pancreatic function in diabetes mellitus, focusing on insulin secretion, cellular processes, and Islets of Langerhans. Scenarios cover blood glucose regulation, paracrine signaling, and effects of tumors or drug interventions on pancreatic cells.