Pancrease

Describe the different types of hormones the cells of the islets of Langerhans secrete

Cells of the islets of Langerhans:

• Insulin: B(β) cells – 65 ‐ 70% of the cells

• Glucagon: A (α) cells ‐ ~20% of the cells

• Somatostatin: D(δ) cells – is an inhibitory peptide (inhibits islets’ cells secretion)

• Gastrin (G-cells) - stimulates gastric acid secretion

Describe what hormones are secreted after a meal and their functions

After a meal:

• Amylin: 

  • reduces food intake,

  • slows gastric emptying,

  • suppresses postprandial glucagon release.

• Insulin:

  • anabolic hormone

  • promotes nutrient storage

• Glucagon:

  • catabolic hormone

  • mobilizes glycogen, fat, and protein during fasting

• Somatostatin:

  • inhibits pancreatic hormone secretion

1. When insulin is released, what other hormone is being released in equimolar amounts?

2. What is the function of this hormone?

3. Clinical importance of C-peptide?

C-Peptide:

Active insulin and C peptide are secreted by exocytosis in equimolar amounts

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Function:

• Plasma levels provide information about β‐ cell function

• Improves renal and neuronal functions in patients with diabetes

• Repairs the muscular layer of arteries

• Protects functional β-cell mass from oxidative stress

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Clinical Importance:

• potential therapeutic agent for the treatment of diabetes-associated complication

1. Describe what stimulates insulin secretion

   • Plasma levels?

   • Hormones?

   • Nervous System Stimulation?

2. Describe what Inhibits insulin secretion

   • Plasma levels?

   • Hormones?

   • Nervous System Stimulation?

Stimulators of insulin secretion:

• Plasma levels: Increase in Glucose, AA, FA, Ketones

• Hormones:

  • Gastrointestinal hormones:

    • Glucagon-like peptide-1(GLP-1)

    • cholecystokinin (CCK)

  • Glucagon,

  • epinephrine (β2‐AR)

• Nervous System:

  • Sympathetic stimulation (β2‐AR)

  • Parasympathetic stimulation (Ach)

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Inhibitors of insulin secretion:

• Plasma levels: Decrease in Glucose, AA, FA

• Hormones:

  • Somatostatin

  • Epi/Norepi (α2-AR)

• Nervous System:

  • Sympathetic stimulation (α2-AR)

Describe the mechanism which leads to insulin secretion by the pancreatic B cells:

• Glucose (major), amino acids (leucine) pathway?

• Adenylyl cyclase/cAMP pathway:

• Phospholipase C, DAG/IP3 pathway:

Glucose (major), amino acids (leucine) (steps):

Glucose enters (via Glut-2) as well as Leucine → ↑ATP & ↑NADH/NAD+ ratio →inhibits K+ channels→ ↓K+ efflux → cell depolarization → Opens the voltage-gates Ca2+ channels → ↑ Ca2+ influx → ↑ Ca2+ release from ER → insulin exocytosis

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Adenylyl cyclase/cAMP pathway:

• Activation (Gs)

  • glucagon

  • β2-adrenergic receptors (epi,NE)

  • GLP-1

• Inhibition (Gi)

  • α2-adrenergic receptors (Epi, NE)

  • somatostatin

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Phospholipase C pathway:

• Gq signal cascade (DAG/IP3)

• Ach, CCK

What is the Incretin Effect and why does this occur

Incretin Effect:

• Oral glucose > Intravenous administered glucose in regards to insulin response

• This is because oral glucose secrete gastrointestinal hormones which stimulates Insulin. Intravenous does not activate these gastrointestinal hormones

1. Describe the structure of insulin receptors IR ?

2. Effects?

3. Compare and contrast IR vs IGF1R

• transmembrane receptor with an extracellular ligand-binding domain and an intracellular tyrosine kinase domain

• Effects:

  • Cellular metabolism

  • Membrane transport

  • Cellular growth, development, survival

• IR vs IGF1R:

  • strucually similar

  • IGF primarily supports growth and development

Describe the mechanism and function of Insulin’s PI3K–Akt pathway vs RAS–MAPK pathway

PI3K–Akt pathway (Anabolic effects):

• Initiated by PI3K-mediated phosphorylation

• Promotes metabolic and anabolic processes

• Essential for glucose uptake via GLUT4

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RAS–MAPK pathway (Growth-promoting Effects):

• Regulates transcription factors

• Controls cell growth, differentiation, and survival

• Supports anti-apoptotic signals and membrane transport of ions and amino acids

1. Describe how Insulin helps w/ Glucose Uptake?

2. Describe the relationship between Insulin and K+

3. What other substances does Insulin help cellular uptake of?

Glucose uptake:

Insulin induces vesicle translocation and fusion of GLUT-4 in insulin sensitive tissues (skeletal muscles/adipose tissues)

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K+ and other substance’ relationship to Insulin

• K+

  • Lowers plasma level by increasing Na⁺/K⁺‐ATPase pump

  • Aid in hyperkalemia management

• Insulin also enhances cellular uptake of:

  • AA, Mg²⁺, and PO₄³⁻

  • Via specific channels/transporters

Describe Insulin’s Effect in:

• Brain

• Kidney

• Cardiovascular

• Bone

Brain:

• CNS growth, development, and metabolism (neurotrophic)

• improve cognitive function and reduce depressive symptoms

  • (prefrontal cortex and hippocampus)

• suppress appetite and reduce body weight

  • (hypothalamic nuclei)

  • ***GLUCAGON ALSO DOES THIS***

• Does not directly regulate glucose uptake

  • Instead, affecting the expression and translocation of GLUT1 and GLUT3 transporters

• Supports reproductive competence via the hypothalamic pituitary‐gonadal axis

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Kidney (glomerular, mesangial cells, epithelial and endothelial cells):

• Regulates glomerular and tubular functions

  • Increase Na Reabsorption

  • Increases Plasma Volume

• GNG

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Cardiovascular System:

• Increases in

  • contractility

  • HR

  • Glucose Uptake

  • blood flow (via NO-dependent vasodilation)

  • ***Glucagon also Increases HR and CONTRACTILITY***

• Decrease Apoptosis

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Bone (osteoblasts):

• Controls osteoblasts’ development and metabolism

• Diabetes I is linked to osteoporosis and bone fragility

1. What G-proteins does Glucagon use?

2. Metabolic Effects of Glucagon?

3. Major Target Organs?

4. What Hormone does Glucagon Stimulate?

Glucagon Receptors (GCGRs):

• Gs: cAMP is the second messenger

• Gq: PLC/IP3/Ca+

Metabolic effects- Increases:

• glucose

• FA

• keto acids,

• AA

• urea production

Major Target Organ:

• liver and adipose tissue

Stimulation:

• also stimulates Insulin Production

1. Explain the potential Potential Therapeutic Effects of GLP-1 agonists

   1. Obesity?

   2. Diabetes?

   3. Cardiovascular health?

   4. Fatty Liver Disease?

   5. Neurodegenerative Disorders?

2. Potential Side Effects?

Potential therapeutic Effects and side effects of GLP-1 agonists :

• Obesity:

  • Appetite suppression,

  • weight loss

• Type 2 Diabetes:

  • Enhances insulin release,

  • lowers blood glucose

• Cardiovascular Health:

  • BP control,

  • risk reduction

• Fatty Liver Disease:

  • Improves liver metabolism

• Neurodegenerative Disorders:

  • May benefit Alzheimer’s and Parkinson’s

  • anti‐inflammatory and neuroprotective effects

• Neuropathic Pain

• Addiction & Psychiatric Disorders

Potential Side Effects:

• Common: Nausea, vomiting, diarrhea, constipation, headache, dizziness

• Rare but serious: Pancreatitis, worsening diabetic retinopathy

Describe what Stimulate/Inhibits glucagon Secretion

Stimulators:

• ↓Serum glucose

• ↑Serum amino acids* (arginine, alanine)

• Sympathetic stimulation (via β2‐AR)

• Glucocorticoids

• Prolonged fasting

• Exercise

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Inhibitors:

• ↑ Serum glucose

• Somatostatin

• Insulin

• GLP1

Describe what happens to Plasma glucose, glucagon and insulin level after a meal and after an overnight fast

1. How does Insulin and Glucagon interact w/ each other?

2. Describe I/G ratio of:

   • Large carb meal

   • Small meal

   • low-carb diet

   • Overnight fast

   • Starvation

Hormonal integration

• Insulin inhibits glucagon secretion

• Glucagon stimulates insulin secretion

I/G ratio:

• Large carb meal (10 or higher)

• Small meal (7) vs. low-carb diet (1.8)

• Overnight fast (2.3)

• Starvation (0.5 or less)

Differeneitate between mTORC1 vs AMPK pathways

mTORC1

• promoting anabolic processes & suppressing catabolism.

• Activation:

  • nutrients, insulin, and growth factors

AMPK:

• promotes catabolic pathways

• Activation:

  • energy stress (e.g., high AMP levels, low oxygen

  • Glucagon

1. What are the two types of Diabetes?

2. What are the mechanism of Hyperglycemia

Types of Diabetes:

• Type I: Insulin deficiency (low synthesis)

• Type II: Insulin resistance (defective insulin/receptor interaction or intracellular signaling pathway)

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Mechanism of hyperglycemia:

• Increased hepatic glucose output

• Decreased glucose uptake via insulin-dependent transport (GLUT4)

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Describe what happens to glucose levels Postprandial in a normal vs diabetic person

In a diabetic, higher peak in glucose levels and slower decline compared to a normal patient

1. What are the Metabolic results of DM?

2. Complications of constant hyperglycemia?

   • what are macrovascular complications?

   • Microvascular complications

Metabolic results of DM:

• Chronic hyperglycemia (most common)

• Dyslipidemia

• Skeletal muscle wasting

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Complications of constant Hyperglycemia:

• cellular damage → athophysiological mechanisms:

  • Mitochondrial dysfunction

  • Oxidative stress

  • Inflammation

  • Memorization Tip: “DSI” → Don’t Saturate It (glucose)

• plasma hyperosmolality and osmotic diuresis

  • May cause hyperosmolar coma (severe loss of intracellular fluid in the brain)

• Macrovascular Complications:

  • atherosclerosis

  • hypertension

• Microvascular (angiopathy):

  • neuropathy (nerve damage)

  • nephropathy (renal failure)

  • retinopathy (micro aneurysms, retinal hemorrhage)

Differentiate between the causes of Hypo/Hyper Glycemia

Causes of hypoglycemia:

• Overproduction of insulin in response to a meal

  • (may indicate high risk for diabetes or early stage of type II DM)

• Some medications (insulin and antidiabetic drugs)

• Alcohol intake

• Liver, kidney, or heart disorders

• Eating disorders

• Pregnancy

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Causes of hyperglycemia:

• Insulin deficiency or insulin resistance

• Medications (steroids)

• Illness or infection (stress-induced hyperglycemia)

• Being inactive

Differentiate the Early/Late (sever) clinical manifestations of hypo/hyper glycemia

Hypoglycemia:

Early Manifestations:

• Weakness

• Shakiness

• Palpitation, tachycardia

• Hunger

• Nausea

• Diaphoresis

• Anxiety, hyperventilation

Prolonged or severe

• Hallucinations

• Seizures

• Hypothermia

• Neurologic symptoms

• Coma

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Hyperglycemia

Early manifestations:

• Weakness

• Polyuria, polydipsia, dehydration

• Altered vision

• Weight loss

Prolonged or severe:

• Diabetic (keto)acidosis

• Kussmaul hyperventilation (deep and rapid breathing)

• Hypotension, arrhythmias

• Stupor

• Coma (hyperosmolar)

Describe how these hormones affect plasma glucose levels and how:

• Growth Hormone:

• Glucocorticoid

• Catecholamines

Growth Hormone:

• ↑ Plasma glucose via:

  • Stimulating insulin gene expression

  • Inducing insulin resistance (↓ glucose uptake)

  • ↑ Gluconeogenesis

  • ↑ Intestinal glucose absorption

  • May cause hyperinsulinemia

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Glucocorticoids:

• ↑ Plasma glucose via:

  • ↓ Insulin sensitivity (diabetogenic)

  • ↑ Gluconeogenesis

• Enhance glycogenolysis (permissive to glucagon, catecholamines, in response to acute stress)

• ↑ Calorigenic effect

• Promote glycogen synthesis (high insulin/glucagon ratio in chronic excess of glucocorticoids)

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Catecholamines:

• ↑ Plasma glucose via:

  • Stimulating glycogenolysis (liver & muscle)

  • ↑ Muscle glucose supply & glycolysis → lactate for gluconeogenesis

  • Direct gluconeogenesis via α₁ and β2 receptors

  • Inhibit insulin secretion via α₂ receptor;

  • Stimulate insulin secretion via β2 receptor

Describe the two strageties for Hyperglycemia prevention and management

1. Diet modifications

   • Limit carbohydrate intake

   • Focus on balanced nutrition to reduce postprandial glucose spikes
     

2. Exercise:

   • Promotes exercise-dependent glucose uptake

     • Muscle contraction → enhance GLUT4 transporter expression → increases glucose uptake

     • Insuline-independent effect.