C H A P T E R 79

Insulin, Glucagon, and Diabetes Mellitus

Pancreas & Hormonal Regulation

Dual Function of the Pancreas
• Exocrine function:
o Acinar cells → secrete digestive enzymes into the duodenum.
• Endocrine function:
o Islets of Langerhans → secrete insulin, glucagon, somatostatin, amylin, and
pancreatic polypeptide directly into the blood.

Islets of Langerhans
• Human pancreas contains 1–2 million islets.
• Each islet is arranged around dense capillary networks → rapid hormone release into
blood.

Major Cell Types in the Islets

1. Beta (β) cells — ~60%
• Located centrally.
• Secrete:
o Insulin (key hormone for glucose uptake & storage)
o Amylin (co-secreted with insulin; role not fully understood)
2. Alpha (α) cells — ~25%
• Secrete glucagon, a hormone that raises blood glucose.
3. Delta (δ) cells — ~10%
• Secrete somatostatin, which inhibits insulin and glucagon secretion.
4. PP cells (F cells)
• Secrete pancreatic polypeptide, function still unclear.

Cell-to-Cell Regulation Within Islets (Important Concept!)

• Insulin inhibits glucagon secretion
→ prevents excessive glucose release.
• Amylin inhibits insulin secretion
→ provides negative feedback.
• Somatostatin inhibits both insulin & glucagon
→ acts as a “local regulator” to dampen overall hormone output.

Insulin & Its Metabolic Effects

Insulin: Key Points
• First isolated in 1922 by Banting and Best → lifesaving therapy for diabetes.
• Secreted by β-cells of the pancreas.

Insulin Is the Hormone of “Energy Abundance”

• Insulin secretion increases after eating, especially after carbohydrate-rich meals.
• Purpose: Store excess energy for later use.
 Major Metabolic Roles of Insulin
1. Carbohydrate Metabolism
• Increases glucose uptake into most cells.
• Stimulates glycogen synthesis in liver & muscle.
• Converts excess glucose → fat when glycogen stores are full.
• Prevents hyperglycemia.

2. Fat Metabolism
• Converts excess carbohydrates → triglycerides for storage in adipose tissue.
• Reduces fat breakdown.
• Helps prevent ketoacidosis seen in insulin deficiency.

3. Protein Metabolism
• Increases amino acid uptake into cells.
• Stimulates protein synthesis.
• Inhibits protein breakdown → prevents muscle wasting.

Clinical Importance
• In untreated diabetes, insulin deficiency →
o Impaired carbohydrate use → hyperglycemia
o Excess fat breakdown → acidosis, atherosclerosis
o Protein catabolism → muscle wasting and organ dysfunction

Insulin Chemistry & Synthesis

Structure of Insulin
• Human insulin MW ≈ 5808 Da.
• Composed of two peptide chains (A & B).
• Chains are connected by disulfide bonds → essential for biologic activity.
• Separating A & B chains destroys insulin activity.

Synthesis Pathway (Inside β-cells)

• Preproinsulin (MW 11,500) synthesized on ribosomes in the ER.
• Cleaved → Proinsulin (MW 9000; chains A, B, and C).
• In the Golgi, proinsulin → Insulin (A+B) + C-peptide.
• Packaged into secretory granules and released in equimolar amounts.
• 5–10% of secreted product remains proinsulin.

C-Peptide
• Has very little insulin activity.
• May bind to a GPCR and influence:
o Na⁺/K⁺-ATPase
o Endothelial nitric oxide synthase (eNOS)
• Clinical use:
o C-peptide measurement reflects endogenous insulin production.
 o Type 1 diabetics → low or absent C-peptide.

Plasma Dynamics of Insulin

• Circulates unbound.
• Short half-life (~6 min) → rapid plasma clearance.
• Cleared mainly by insulinase in the liver, and also kidneys & muscles.
• Rapid removal allows tight/fast regulation of insulin action.

Insulin Receptor & Cellular Actions

Insulin Receptor Structure
• Large enzyme-linked receptor (~300 kDa).
• Made of 4 subunits linked by disulfide bonds:
o 2 α-subunits – extracellular; bind insulin.
o 2 β-subunits – transmembrane; cytoplasmic tails contain tyrosine kinase.

Binding → Activation
• Insulin binds α-subunits → autophosphorylation of β-subunits.
• Activates intracellular tyrosine kinase.
• Leads to phosphorylation of Insulin Receptor Substrates (IRS-1, IRS-2, IRS-3).
• IRS activation → multiple downstream metabolic pathways.

Major Cellular Effects of Insulin

Seconds — Rapid Transport Effects
• ↑ Glucose uptake in ~80% of body cells (especially skeletal muscle & adipose).
• Mechanism: GLUT4 translocation to membrane via insulin-triggered vesicles.
• Neurons do NOT require insulin for glucose uptake.
Seconds–Minutes — Increased Membrane Transport
• ↑ transport of:
o Amino acids
o K⁺
o Phosphate
• Supports anabolism, protein synthesis, and cell growth.
Minutes — Enzyme Activation/Inhibition
• Insulin changes phosphorylation states of key metabolic enzymes.
• Leads to:
o ↑ glycolysis
o ↓ gluconeogenesis
o ↑ glycogenesis
o ↑ fat synthesis
Hours–Days — Genomic Effects
• Insulin alters mRNA translation and gene transcription.
• Long-term changes include:
o ↑ synthesis of metabolic enzymes
o ↑ protein synthesis
o ↓ protein breakdown
Effects of Insulin on Carbohydrate Metabolism
After a High-Carbohydrate Meal
• ↑ Blood glucose → rapid insulin secretion.
• Insulin → promotes rapid uptake, storage, and use of glucose—especially by:
o Muscles
o Adipose tissue
o Liver

Insulin & Muscle Glucose Uptake

At Rest (Between Meals)
• Resting muscle membrane = low permeability to glucose.
• Low basal insulin → muscles rely mainly on fatty acids for energy.
Condition 1: Exercise
• Muscle contraction alone (independent of insulin) increases GLUT4 translocation.
• This greatly increases glucose uptake.
Condition 2: Post-Meal (High glucose + high insulin)
• Insulin stimulates massive glucose uptake into muscle cells.
• Muscles preferentially use glucose instead of fatty acids during this period.

Glycogen Storage in Muscle

• If glucose is abundant and the muscle is not exercising, insulin promotes:
o Glycogen synthesis and storage (up to 2–3% of muscle mass).
• Stored glycogen:
o Provides energy for future activity.
o Supports short bursts of anaerobic glycolysis → lactic acid formation.

Magnitude of Insulin’s Effect (Key Concept!)

• Insulin increases glucose transport into muscle by ≥15-fold.
o Without insulin: intracellular glucose remains near zero even at high blood glucose.
o With insulin: intracellular glucose rises dramatically.

Insulin & Liver Glucose Handling

Key Concept
The liver functions as a glucose buffer, storing glucose as glycogen after meals (under insulin
influence) and releasing glucose between meals (when insulin falls).

How Insulin Promotes Liver Glucose Uptake & Storage

1. Inhibits Glycogen Breakdown
• Insulin inactivates liver phosphorylase
→ prevents glycogen → glucose breakdown.
2. Increases Glucose Uptake Into Hepatocytes
• Insulin stimulates glucokinase, which:
o Phosphorylates glucose → glucose-6-phosphate
o “Traps” glucose inside the hepatocyte (cannot diffuse out)
3. Promotes Glycogen Synthesis
 • Insulin activates glycogen synthase, the key enzyme for glycogen polymer formation.
• Net effect: rapid glycogen storage
→ liver glycogen can reach 5–6% of liver mass (~100 g).

How the Liver Releases Glucose Between Meals

When blood glucose falls:
1. Insulin secretion decreases.
• Low insulin → stops glycogen synthesis.
• Low insulin → stops hepatic glucose uptake.
2. Activates glycogen breakdown
• Low insulin + ↑ glucagon → activates phosphorylase
→ glycogen → glucose-1-P → glucose-6-P.
3. Restores ability to release free glucose
• Low insulin activates glucose-6-phosphatase
→ removes the phosphate → produces free glucose.
• Free glucose diffuses into blood.

Overall Role
• After a meal: ~60% of ingested glucose is temporarily stored in the liver as glycogen.
• Between meals: Liver returns glucose to maintain stable blood glucose levels.

Insulin: Liver Fat Metabolism & Carbohydrate Effects

Insulin → Converts Excess Glucose to Fat
• When liver glycogen storage is maxed out, insulin diverts excess glucose to lipid
synthesis.
• Promotes fatty acid synthesis from excess glucose.
• Fatty acids → packaged as VLDL → transported to adipose tissue → stored as
triglycerides.
• Key concept: High carb intake → high insulin → increased lipogenesis.

Insulin → Inhibits Hepatic Gluconeogenesis

• Reduces enzymes needed for gluconeogenesis.
• Decreases amino acid availability by reducing proteolysis in muscle → fewer
gluconeogenic substrates reach the liver.
• Net effect: less new glucose production during fed state.

Insulin Has No Effect on Glucose Uptake in the Brain

• Brain cells are insulin-independent for glucose entry.
• Brain uses glucose exclusively under normal conditions.
• Critical concept: Hypoglycemia (<50 mg/dL) → neuroglycopenic symptoms
→ irritability, seizures, coma (“hypoglycemic shock”).

Insulin on Other Tissues (Non-Muscle, Non-Brain)

• Insulin increases glucose uptake in most peripheral tissues.
• In adipose tissue:
 o Glucose → provides glycerol backbone for triglyceride synthesis.
o Thus, insulin promotes fat storage indirectly.
Insulin & Fat Metabolism — High-Yield Summary
Insulin Promotes Fat Synthesis & Storage
• Insulin is a major “fat-storing / fat-sparing hormone.”
• Promotes glucose use → decreases fat oxidation (glucose preferred over fatty acids).
• Excess dietary glucose → converted into fatty acids in the liver, then packaged into
triglyceride-rich lipoproteins → stored in adipose tissue.

Mechanisms: How Insulin Increases Fat Synthesis

1. ↑ Glucose uptake by liver
→ After glycogen stores fill (5–6% liver mass), extra glucose → fatty acid synthesis.
2. ↑ Acetyl-CoA production from glycolysis
→ precursor for fatty acid synthesis.
3. ↑ Citrate & isocitrate (citric acid cycle overflow)
→ stimulate acetyl-CoA carboxylase, forming malonyl-CoA (first committed step in
lipogenesis).
4. Liver synthesizes triglycerides → secretes them as VLDL → stored in adipose tissue.

Insulin Enables Fat Storage in Adipose Tissue

1. Inhibits Hormone-Sensitive Lipase (HSL)
• HSL normally breaks down stored triglycerides into free fatty acids.
• Insulin inhibits HSL, preventing lipolysis → favors fat accumulation.
2. Promotes Glucose Entry Into Fat Cells
• Glucose → converted to α-glycerol phosphate
(glycerol backbone needed to form triglycerides).
• Without insulin → adipocytes cannot produce α-glycerol phosphate → fat storage is
impaired even if fatty acids are available.

Clinical Relevance
• Insulin deficiency → excess lipolysis → ↑ free fatty acids → atherosclerosis risk.
• Contributes to diabetes-related dyslipidemia and long-term cardiovascular complications.

Effects of Insulin Deficiency on Fat Metabolism — Condensed Summary

1. Insulin Deficiency → Massive Lipolysis
• Loss of insulin removes inhibition of hormone-sensitive lipase (HSL).
• HSL becomes highly active → breaks down stored triglycerides.
• Results in:
o ↑ Free fatty acids (FFA) in blood (rapid rise within minutes).
o ↑ Glycerol release for gluconeogenesis.
• FFAs become the primary energy source for most tissues (except brain).

2. ↑ Plasma Lipids → Atherosclerosis Risk

Insulin deficiency drives excess fatty acid flux to the liver, causing:
• ↑ Cholesterol synthesis
 • ↑ Phospholipid synthesis
• ↑ Triglyceride-rich lipoproteins
This leads to:
• 3× increase in plasma lipoproteins
• Accelerated atherosclerosis in severe diabetes

3. Ketosis & Ketoacidosis (DKA Development)

Excess FFAs → transported to liver → undergo β-oxidation → produce large amounts of acetyl-
CoA.
Because insulin is absent:
• Fatty acids enter mitochondria more easily (↑ carnitine shuttle activity).
• Liver converts excess acetyl-CoA into ketone bodies:
o Acetoacetic acid
o β-hydroxybutyric acid
o Acetone
Consequences:
• Peripheral tissues use ketones poorly → further accumulation
• Plasma ketone levels can reach >10 mEq/L
• Results in:
o Ketosis
o High anion gap metabolic acidosis
o Risk of diabetic ketoacidosis (DKA) → coma → death if untreated

Key Exam Points

• Lack of insulin = uncontrolled lipolysis, hyperlipidemia, and ketosis.
• HSL activation is the central mechanism.
• High FFAs → high cholesterol → long-term vascular damage.
• Excess ketones → acidosis (DKA hallmark).

Insulin and Protein Metabolism — High-Yield Summary

Insulin Promotes Protein Synthesis & Storage
Insulin is anabolic for proteins. Key mechanisms:
• ↑ Amino acid uptake into cells
o Especially valine, leucine, isoleucine, tyrosine, phenylalanine.
• ↑ Translation of mRNA → ↑ protein synthesis
o Insulin “turns on” ribosomes; without insulin, translation halts.
• ↑ Transcription (long-term effect)
o More mRNA → more proteins and metabolic enzymes.
• ↓ Protein breakdown (anti-catabolic)
o Reduced lysosomal protein degradation.
• ↓ Gluconeogenesis in liver
o Conserves amino acids that would otherwise be used to make glucose.
Net effect: insulin builds protein and prevents protein loss.

Insulin Deficiency → Protein Wasting

Without insulin:
• Protein synthesis stops
• Protein catabolism increases
• ↑ Plasma amino acids (due to release from tissues)
• ↑ Gluconeogenesis using amino acids → worsens protein loss
• ↑ Urea production from amino acid breakdown
• Severe muscle wasting & weakness
Protein depletion is a major cause of morbidity in uncontrolled diabetes mellitus.

Insulin + Growth Hormone = Synergistic Growth

• Insulin and GH are both essential for growth.
• Neither hormone alone can sustain normal growth.
• Together they:
o Promote amino acid uptake (different sets of amino acids)
o Stimulate protein synthesis
o Support cell growth and division
Classic physiology principle: GH needs insulin to exert full growth effects.

Mechanisms of Insulin Secretion — High-Yield Summary

Glucose is the Primary Stimulus
• Beta cells sense blood glucose via GLUT transporters.
• Glucose enters the cell → glucokinase converts it to glucose-6-phosphate (rate-limiting
step).
• This step acts as the main glucose sensor for insulin secretion.

ATP Production Triggers Insulin Release

• Glucose metabolism ↑ ATP levels.
• ↑ ATP closes ATP-sensitive K⁺ channels.
• Membrane depolarization occurs.
• Depolarization opens voltage-gated Ca²⁺ channels.
• Ca²⁺ influx triggers exocytosis of insulin-containing granules.

Other Nutrients Also Stimulate Secretion

• Certain amino acids (e.g., arginine, leucine) → ↑ ATP → ↑ insulin release.

Hormones/Signals that Enhance Insulin Secretion

Act mainly by increasing intracellular Ca²⁺ (but require glucose to be effective):
• Glucagon
• GLP-1 (glucagon-like peptide-1)
• GIP (glucose-dependent insulinotropic peptide)
• Acetylcholine (parasympathetic stimulation)

Hormones/Signals that Inhibit Insulin Secretion

• Somatostatin
• Norepinephrine (α-adrenergic receptors)
 Drug Mechanism: Sulfonylureas
• Bind to ATP-sensitive K⁺ channels.
• Close the channels → depolarization → Ca²⁺ influx → insulin secretion.
• Used in type 2 diabetes to boost endogenous insulin release.

Control of Insulin Secretion — High-Yield Summary

Glucose is the Primary Regulator
• Blood glucose ↑ → insulin secretion ↑
• Fasting glucose (80–90 mg/dL) → minimal insulin release.
• Glucose is the most powerful stimulus.

Biphasic Insulin Response to Glucose

When blood glucose rises rapidly (e.g., after a meal):
First Phase (Immediate — 3 to 5 minutes)
• Rapid 10-fold rise in plasma insulin.
• Due to exocytosis of preformed insulin.
• Falls halfway back within 5–10 minutes.
Second Phase (Delayed — begins ~15 minutes)
• Gradual sustained increase in insulin.
• Due to:
o Release of additional stored insulin.
o Synthesis of new insulin.

Feedback Control
• As blood glucose ↑ above ~100 mg/dL → insulin secretion increases steeply.
• Secretion may reach 10–25× the basal level at glucose 400–600 mg/dL.
• When glucose falls back to normal → insulin secretion turns off within minutes.
• This forms a tight negative feedback loop to maintain glucose homeostasis.

Other Important Regulators

(from Table 79-1 referenced in the text)
• Stimulators: Amino acids, GI hormones (GIP, GLP-1), parasympathetic activity.
• Inhibitors: Somatostatin, sympathetic α-adrenergic activity.

Other Factors That Stimulate Insulin Secretion — High-Yield Summary

Amino Acids
• Key stimulators: Arginine and lysine.
• Effect alone: only mild insulin increase.
• Effect with hyperglycemia: strong potentiation, doubling glucose-induced insulin secretion.
• Physiologic purpose: ensures protein synthesis by promoting:
o ↑ amino acid uptake into cells
o ↑ intracellular protein formation

Gastrointestinal (GI) Hormones — “Incretins”

 • Released after meals → anticipatory increase in insulin.
• Major incretins:
o GLP-1 (glucagon-like peptide-1)
o GIP (glucose-dependent insulinotropic peptide)
• Additional GI hormones that assist: gastrin, secretin, cholecystokinin.
• Actions:
o Potentiate glucose-stimulated insulin release
o Increase β-cell sensitivity to glucose
o Inhibit glucagon secretion
• Clinical relevance: basis for GLP-1 agonists used in diabetes treatment.

Other Hormones That Increase Insulin Secretion

• Glucagon
• Growth hormone
• Cortisol
• Progesterone and estrogen (lesser extent)
• Key concept: Chronic high levels → risk of β-cell exhaustion → can contribute to
secondary diabetes, e.g.:
o Acromegaly → excess GH
o Cushing’s → excess cortisol

Autonomic Nervous System Effects

Parasympathetic (vagal) stimulation
• Increases insulin secretion, especially during hyperglycemia.
Sympathetic stimulation
• ↑ Glucagon secretion
• ↓ Insulin secretion (via α-adrenergic receptors)
• Important during hypoglycemia → mobilizes glucose.
Glucose-sensing neurons
• Found in hypothalamus, brainstem, and peripheral tissues (e.g., liver).
• Help adjust autonomic and hormonal responses to blood glucose levels.

Switching Between Carbohydrate & Lipid Metabolism — High-Yield Summary

Insulin = Switch Toward Carbohydrate Use
• High blood glucose → ↑ insulin secretion.
• Insulin promotes carbohydrate use and suppresses fat use.
• Key actions:
o ↑ glucose uptake by tissues
o ↑ glycogen synthesis (liver + muscle)
o ↑ lipogenesis (liver → adipose storage)
o ↓ lipolysis and ↓ fatty acid oxidation
Bottom line: When insulin is high → the body uses glucose for fuel and stores excess carbs as
glycogen and fat.

Insulin Deficiency = Switch Toward Fat Use

 • Low blood glucose → ↓ insulin secretion.
• Tissues (except brain) shift to fatty acid oxidation as the primary energy source.
• Results in:
o ↑ lipolysis (via hormone-sensitive lipase)
o ↑ plasma FFAs
o ↑ ketone production (acetoacetate, β-hydroxybutyrate, acetone)
Bottom line: When insulin is low → the body uses fat for energy.

Blood Glucose = The Principal Signal for Switching

• Glucose level is the main regulator of the insulin “switch.”
• High glucose → insulin switches metabolism → carbohydrate use.
• Low glucose → insulin falls → fat becomes main fuel.

Other Hormones That Affect the Switch

These hormones oppose insulin and shift metabolism toward fat use, especially during fasting or
stress:
Growth Hormone (GH)
• Secreted during hypoglycemia.
• ↓ glucose uptake by cells.
• ↑ lipolysis and fat utilization.
• Slow onset (hours).
Cortisol
• Secreted in stress or hypoglycemia.
• ↓ glucose utilization; ↑ gluconeogenesis.
• ↑ lipolysis.
• Slow onset (hours).
Epinephrine
• Rapid “fight-or-flight” hormone.
• Dual metabolic effects:
o ↑ Glycogenolysis → ↑ blood glucose (liver).
o ↑ Lipolysis → large ↑ in plasma fatty acids.
• Strong, rapid shift to fat use, especially during:
o exercise
o circulatory shock
o acute stress/anxiety
Glucagon
• Secreted by α-cells when glucose is low.
• ↑ hepatic glucose output.
• Promotes fat use (via indirect actions).

Glucagon — High-Yield Summary for First-Year Physiology

What is Glucagon?
• Peptide hormone (29 amino acids; MW ≈ 3485).
• Secreted by α-cells of islets of Langerhans.
• Released when blood glucose falls.
 • Main function: raise blood glucose → opposite of insulin.
• Very potent: 1 µg/kg raises glucose by ~20 mg/dL in 20 minutes → “hyperglycemic
hormone.”

Major Metabolic Functions

Glycogenolysis (Primary & Rapid Effect)
Glucagon → liver glycogen breakdown → ↑ blood glucose within minutes.
Mechanism (classic cAMP cascade):
1. Glucagon binds hepatic receptor
2. → activates adenylyl cyclase
3. → ↑ cAMP
4. → activates protein kinase A (PKA)
5. → activates phosphorylase b kinase
6. → converts phosphorylase b → phosphorylase a
7. → glycogen → glucose-1-phosphate
8. → dephosphorylated → free glucose exits liver
Key concept:
This is a powerful amplification cascade (second messenger system), producing massive glucose
output from tiny amounts of glucagon.

Gluconeogenesis (Sustained Effect)

When liver glycogen is depleted, glucagon still raises glucose by:
• ↑ amino acid uptake into liver
• ↑ conversion of amino acids → glucose
• Activating key gluconeogenic enzymes
o Especially those converting pyruvate → phosphoenolpyruvate (PEP)
→ a rate-limiting step of gluconeogenesis
Outcome: Continued hyperglycemia even after glycogen stores are exhausted.

Key Physiologic Concepts

• Glucagon maintains blood glucose during fasting, exercise, and starvation.
• Acts mainly on liver, not on muscle (no glucagon receptors in muscle).
• Uses cAMP signaling — foundational example of second-messenger amplification.
• Balanced with insulin: insulin ↓ glucose; glucagon ↑ glucose.
Other Effects of Glucagon — High-Yield Summary
Lipid Metabolism
• Activates adipose tissue lipase (at high glucagon levels)
→ ↑ breakdown of triglycerides
→ ↑ plasma free fatty acids for energy.
• Inhibits hepatic triglyceride storage
→ liver removes fewer fatty acids from blood
→ more fatty acids available to peripheral tissues.

Cardiovascular Effects (High Glucagon Levels)

• ↑ Cardiac contractility (“positive inotropic effect”).
 • ↑ Renal blood flow.

Effects on Digestive Secretions

• ↑ Bile secretion.
• ↓ Gastric acid secretion.
Regulation of Glucagon Secretion — Condensed Summary
1. Blood Glucose (Most Important Regulator)
• ↓ Blood glucose → strong stimulation of glucagon.
Corrects hypoglycemia by increasing hepatic glucose output.
• ↑ Blood glucose → inhibition of glucagon.
Opposite of insulin response.

2. Amino Acids
• ↑ Amino acids (alanine, arginine) → ↑ glucagon.
• Prevents post-protein-meal hypoglycemia by promoting gluconeogenesis.
• Note: Amino acids stimulate both insulin and glucagon.

3. Exercise
• Intense exercise → 4–5× increase in glucagon
Mechanism unclear; may involve ↑ amino acids or β-adrenergic activation.
• Prevents exercise-induced hypoglycemia.

4. Somatostatin (from delta cells)

Stimulated by ↑ glucose, ↑ amino acids, ↑ fatty acids, and GI hormones.
Its actions:
1. Inhibits glucagon secretion
2. Inhibits insulin secretion
3. Slows GI motility and decreases GI secretion/absorption
Physiologic role:
Slows nutrient entry into bloodstream and prolongs nutrient availability.

5. Additional Note
Somatostatin is the same molecule as growth hormone inhibitory hormone (GHIH) from the
hypothalamus.

Summary of Blood Glucose Regulation — High-Yield

Normal Blood Glucose Levels
• Fasting: 80–90 mg/dL
• Post-meal (1 hr): 120–140 mg/dL
• Return to baseline: Within ~2 hours due to hormonal feedback
• Starvation: Liver uses gluconeogenesis to maintain glucose

1. Liver as a Glucose Buffer

• Stores ~2/3 of absorbed glucose as glycogen after meals (insulin-stimulated).
• Releases glucose between meals (when insulin ↓).
• Prevents large swings in blood glucose (reduces fluctuations by ~⅔).
 • Severe liver disease → poor glucose regulation.

2. Hormonal Feedback Systems

Insulin
• Secreted when glucose ↑
• Drives glucose uptake + storage → ↓ blood glucose
Glucagon
• Secreted when glucose ↓
• Stimulates glycogenolysis + gluconeogenesis → ↑ blood glucose
Relative importance
• Insulin = major regulator (fed state)
• Glucagon = essential during starvation, exercise, stress

3. Sympathetic Response to Hypoglycemia

• Severe hypoglycemia → hypothalamus activates sympathetic nervous system
• Epinephrine rapidly ↑ liver glucose output
• Critical defense against life-threatening hypoglycemia

4. Slow Hormonal Responses to Prolonged Hypoglycemia

• Growth hormone
• Cortisol
Both:
• ↓ glucose utilization in tissues
• ↑ shift to fat as energy
• Help restore glucose levels over hours to days

Why Tight Glucose Regulation is Essential

A. Brain & Other Glucose-Dependent Tissues
• Brain, retina, gonadal germ cells rely almost exclusively on glucose.
• These tissues cannot use fat adequately → hypoglycemia rapidly impairs CNS function.
B. Preventing Complications of Hyperglycemia
1. High osmotic pressure → cellular dehydration
2. Glucosuria when renal threshold exceeded
3. Osmotic diuresis → dehydration & electrolyte loss
4. Chronic hyperglycemia → vascular damage, leading to:
o Atherosclerosis
o MI, stroke
o Diabetic nephropathy
o Retinopathy

Key Concepts for Students

• Insulin & glucagon are the primary fast-acting regulators.
• Liver is the central organ for glucose buffering.
• The brain’s dependence on glucose is the fundamental reason for tight control.
• Epinephrine, GH, and cortisol serve as backup systems during stress or prolonged fasting.
 • Both hypoglycemia and hyperglycemia can be dangerous for different physiological
reasons.

Diabetes Mellitus — High-Yield Physiology Summary

Diabetes mellitus is a metabolic syndrome characterized by impaired carbohydrate, fat, and
protein metabolism due to:
• Insulin deficiency (absolute or relative)
• Insulin resistance

TYPES OF DIABETES
1. Type 1 Diabetes Mellitus (T1DM)
Primary problem:
Absolute lack of insulin due to destruction of pancreatic β-cells
Common causes:
• Autoimmune destruction
• Viral-triggered immune response
• Genetic susceptibility
• Rare idiopathic β-cell degeneration
Epidemiology:
• Typically begins in childhood/adolescence (peak ~14 years old)
• Can also appear in adults (LADA, late autoimmune diabetes of adulthood)
• Accounts for 5–10% of all diabetes cases
Pathophysiology:
• β-cell destruction → no insulin
• ↓ Glucose uptake by muscle & fat
• Hyperglycemia develops rapidly
• Body shifts to fat & protein catabolism
Key metabolic consequences:
1. Hyperglycemia (300–1200 mg/dL in severe cases)
2. ↑ Fat utilization → ↑ cholesterol & risk of ketoacidosis
3. Protein depletion → muscle wasting, weight loss

PATHOGENESIS OF HYPERGLYCEMIA
Why blood glucose rises in T1DM
• Peripheral tissues cannot take up glucose (no insulin)
• Liver continues gluconeogenesis and glycogenolysis
• Result: severe hyperglycemia

GLUCOSURIA AND RENAL THRESHOLD

• When blood glucose exceeds ~200 mg/dL, kidney transporters are saturated → glucose
appears in urine
• This is the renal threshold for glucose
Consequences:
At blood glucose 300–500 mg/dL, patients may lose ≥100 g of glucose/day in urine.
This leads to:
• Polyuria (osmotic diuresis): glucose drags water
 • Polydipsia (excess thirst)
• Dehydration + electrolyte loss

SUMMARY BOX (Perfect for Review)

Type 1 Diabetes
• Autoimmune destruction of β-cells
• Absolute insulin deficiency
• Rapid onset (days–weeks)
• Hyperglycemia + glucosuria
• Polyuria → dehydration
• ↑ Fat breakdown → ketoacidosis risk
• ↑ Protein breakdown → weight loss & weakness
Renal Glucose Threshold
• ~200 mg/dL
• Above this → glucosuria → osmotic diuresis

Diabetes Mellitus – Effects of Hyperglycemia (High-Yield Summary)

1. Hyperglycemia → Cellular Dehydration
• Glucose cannot freely diffuse into cells → stays in extracellular fluid (ECF).
• High ECF glucose = high osmotic pressure → water shifts out of cells.
• Result: intracellular dehydration (cells shrink).

2. Hyperglycemia → Osmotic Diuresis → Fluid Loss

• When blood glucose > renal threshold (~200 mg/dL) → glucose spills into urine.
• Glucose in renal tubules acts as an osmotic agent, preventing water reabsorption.
• Leads to:
o Polyuria (excess urine)
o Extracellular dehydration
o Secondary intracellular dehydration
o Polydipsia (excess thirst)
Classic early triad of diabetes:
Polyuria + Polydipsia + Cellular dehydration

3. Chronic High Glucose → Progressive Tissue Injury

Poor long-term control of blood glucose causes microvascular and macrovascular damage:
Vascular complications
• Heart attack (MI)
• Stroke
• Chronic kidney disease → ESRD
• Retinopathy → blindness
• Peripheral arterial disease → ischemia, gangrene
Nervous system complications
• Peripheral neuropathy → numbness, pain, loss of sensation
• Autonomic neuropathy →
o bladder dysfunction
 o abnormal heart reflexes
o GI dysmotility
o postural hypotension
Mechanisms:
Likely from chronic hyperglycemia causing chemical damage to endothelial proteins, smooth
muscle, and nerve cells. Hypertension and dyslipidemia accelerate injury.

4. Shift to Fat Metabolism → Ketoacidosis

In insulin deficiency (esp. Type 1 DM):
• Glucose cannot enter cells → body switches to fat breakdown.
• Liver produces excess ketoacids:
o Acetoacetic acid
o β-hydroxybutyric acid
• Production exceeds tissue utilization → ketoacidosis.
Consequences
• Metabolic acidosis
• Combined with dehydration → DKA (diabetic ketoacidosis)
• Can rapidly progress to:
o Kussmaul respirations (deep, rapid breathing)
o Bicarbonate depletion
o Coma
o Death (without urgent insulin treatment)
Physiologic compensations
• Lungs: deep/rapid breathing to remove CO₂ (respiratory compensation).
• Kidneys: retain and generate bicarbonate to buffer acids (if perfusion preserved).

ey Points: Severe Diabetes, Type 1 & Type 2 Diabetes (High-Yield Summary)

I. Consequences of Severe, Uncontrolled Diabetes

1. Severe Acidosis → Risk of Coma and Death
• In uncontrolled diabetes, ketone production rises → metabolic acidosis.
• If blood pH < 7.0 → acidotic coma and death within hours.
• Figure 79-11 (from text) shows falling pH, declining bicarbonate, and compensatory
changes.

2. Excess Fat Metabolism → Hyperlipidemia → Atherosclerosis

• Chronic fat use → ↑ cholesterol production in liver.
• Leads to:
o Accelerated arteriosclerosis
o Cardiovascular disease
o Increased risk of stroke and MI

3. Protein Depletion
• Without insulin, cells cannot use glucose → shift to fat AND protein catabolism.
• Results in:
o Muscle wasting
 o Weight loss
o Asthenia (fatigue)
o Polyphagia (eating more but still losing weight)
o Death may occur within weeks if untreated.

II. Treatment of Type 1 Diabetes

• Requires exogenous insulin to normalize carbohydrate, fat, and protein metabolism.
• Types:
o Regular insulin: 3–8 hrs duration
o Long-acting insulins (zinc or protein-modified forms): 10–48 hrs
• Standard regimen:
o Daily long-acting insulin
o Short-acting insulin at meals for post-prandial control
• Modern practice uses:
o Recombinant human insulin
o Prevents sensitization issues from animal insulin

III. Type 2 Diabetes Mellitus

(90–95% of diabetes cases)
1. Pathophysiology
• Primary defect: insulin resistance
• Pancreas compensates → hyperinsulinemia
• Gradual decline in β-cell function follows

2. Who gets Type 2 Diabetes?

• Traditionally in adults >30 years
• Now increasingly seen in adolescents due to rising obesity rates

3. Obesity → Insulin Resistance

• Excess visceral fat → decreased tissue response to insulin.
• Mechanisms:
o ↓ insulin receptors (possibly)
o Post-receptor signaling defects (primary mechanism)
o Lipid accumulation in liver and muscle is toxic and interferes with insulin signaling
• Leads to:
o Impaired glucose uptake
o Increased hepatic glucose production
o Hyperglycemia → further ↑ insulin

IV. Metabolic Syndrome (Insulin Resistance Syndrome)

Often precedes Type 2 diabetes.
Features:
1. Central obesity (abdominal fat)
2. Insulin resistance
3. Hyperglycemia
4. Dyslipidemia
 o ↑ triglycerides
o ↓ HDL
5. Hypertension
Why it matters:
• Greatly increases risk of:
o Cardiovascular disease
o Stroke
o Atherosclerosis
o Progression to Type 2 diabetes

V. Major Clinical Consequences

• Insulin resistance → hyperglycemia
• Hyperglycemia + dyslipidemia + hypertension → organ damage
• Type 2 diabetes → leading cause of:
o Heart disease
o Kidney failure
o Blindness
o Peripheral vascular disease → amputations

Insulin Resistance & Type 2 Diabetes — Key Physiology Summary

I. Other Causes of Insulin Resistance (Beyond Obesity)

1. Polycystic Ovary Syndrome (PCOS)
• Very common endocrine disorder in women (~6%).
• Characterized by:
o ↑ ovarian androgens
o Insulin resistance + hyperinsulinemia (80% of cases)
• Long-term risks:
o Type 2 diabetes, ↑ lipids, cardiovascular disease
2. Hormonal Excess States
• Cushing’s syndrome (↑ glucocorticoids)
• Acromegaly (↑ growth hormone)
• Both ↓ insulin sensitivity → may precipitate diabetes.
3. Genetic Causes
• Rare but severe defects in insulin signaling or obesity genes can lead to:
o Profound insulin resistance
o Metabolic syndrome
o Cardiovascular disease

II. Progression of Type 2 Diabetes

Early Stage
• Severe insulin resistance → pancreas compensates by ↑ insulin (hyperinsulinemia)
• Post-meal hyperglycemia begins
Late Stage
• β-cell exhaustion / dysfunction
o Pancreas can no longer sustain high insulin output
 o Fasting and post-meal hyperglycemia worsen
• Some obese individuals avoid diabetes due to strong β-cell reserve
• Genetics plays major role in β-cell resilience or burnout

III. Treatment of Type 2 Diabetes

1. Lifestyle Modifications (First-Line)
• Weight loss
• Caloric restriction
• Increased physical activity
• Can reverse early disease—often no insulin needed initially.

2. Drugs That Improve Insulin Sensitivity

• Thiazolidinediones (TZDs)
o Increase peripheral insulin sensitivity
• Metformin
o Decreases liver gluconeogenesis
o First-line therapy

3. Drugs That Increase Insulin Secretion

• Sulfonylureas
o Stimulate pancreatic insulin release (risk: hypoglycemia)

4. Incretin-Based Therapies
• GLP-1 analogues (e.g., exenatide)
o ↑ glucose-stimulated insulin secretion
o ↓ glucagon
o Slow gastric emptying
• DPP-4 inhibitors
o Prevent breakdown of GLP-1 and GIP
o Prolong incretin action → ↑ insulin, ↓ blood glucose

5. SGLT2 Inhibitors (Gliflozins)

• Block renal glucose reabsorption → glucose excreted in urine
• Benefits:
o ↓ blood glucose
o Cardio- and reno-protective effects
o Mild diuretic → ↓ blood pressure
• Risks:
o Dehydration
o Hypotension (especially with other diuretics)

6. Metabolic / Bariatric Surgery

• Indicated in severe obesity + type 2 diabetes not controlled by lifestyle/drugs
• Types:
o Gastric bypass
o Sleeve gastrectomy
 • Results:
o Rapid improvement in blood glucose—often before major weight loss
o Many patients enter diabetes remission
• Mechanisms → still being studied (likely hormonal, neural, and gut-pancreas axis
changes)

Physiology of Diagnosis of Diabetes Mellitus — High-Yield Summary

1. Urinary Glucose
• Normal: no detectable glucose in urine.
• Diabetes: glucosuria occurs when blood glucose exceeds renal threshold (~200 mg/dL).
• Reflects severity of hyperglycemia.

2. Fasting Blood Glucose (FBG) & Insulin Levels

• Normal FBG: 80–90 mg/dL
• Upper normal limit: ≤115 mg/dL
• Persistent FBG >115 mg/dL → diabetes or prediabetes.
In Type 1 DM:
• Insulin very low/undetectable, even post-meal.
In Type 2 DM:
• Insulin elevated (hyperinsulinemia) due to insulin resistance.

3. Glycated Hemoglobin (HbA1c)

• Formed when glucose binds to hemoglobin irreversibly.
• Reflects average blood glucose over 3 months (RBC lifespan ≈120 days).
• Higher HbA1c → prolonged hyperglycemia.
• Used for diagnosis and monitoring of diabetes.

4. Oral Glucose Tolerance Test (OGTT)

Normal Response:
• Glucose peaks at 120–140 mg/dL within 1 hr
• Returns to baseline in ~2 hrs (glucose tolerance curve).
Diabetic Response:
• Fasting glucose typically >115–140 mg/dL.
• After glucose load:
o Much higher peak
o Glucose returns to baseline only after 4–6 hrs
o Fails to drop below baseline
• Indicates either:
o ↓ Insulin secretion (Type 1), or
o ↓ Insulin sensitivity (Type 2).

5. Acetone Breath
• Severe insulin deficiency → ↑ ketone bodies (acetoacetate, β-hydroxybutyrate, acetone).
• Acetone breath: fruity odor → diagnostic clue for Type 1 DM or severe Type 2 with
ketoacidosis.
 • Ketones detectable in urine.

6. Long-term Effects of Chronic Hyperglycemia

• Causes vascular injury → major diabetic complications:
o Atherosclerosis
o Coronary artery disease
o Stroke
o Diabetic nephropathy
o Retinopathy & blindness
o Peripheral neuropathy
o Gangrene of limbs
• Mechanisms include:
o ↑ lipids, hypertension
o Endothelial and smooth muscle injury
o Persistently high glucose → glycation of proteins

7. Historical vs Modern Approach to Treatment

Old Approach:
• Severe carbohydrate restriction
• Result: ↓ glucosuria but no improvement in lipid abnormalities.
Modern Approach:
• Normal carbohydrate diet + adequate insulin therapy
• Improves:
o Glucose metabolism
o Lipid profile
o Reduces atherosclerosis progression
• Additional use of lipid-lowering drugs to prevent complications.

Insulinoma (β-cell tumor) & Hyperinsulinism — High-Yield Summary

What is an Insulinoma?
• A tumor of pancreatic β-cells that secretes excessive insulin.
• 10–15% malignant; metastases can continue producing insulin.
• May require extreme amounts of glucose (up to >1000 g/day) to prevent hypoglycemia.

Pathophysiology of Hyperinsulinism
• Excess insulin → excess glucose uptake into tissues → severe hypoglycemia.
• Brain is highly vulnerable because it depends on glucose (insulin-independent).

Insulin Shock (Hypoglycemic Shock)

A progression of CNS symptoms due to falling blood glucose:
Early symptoms (BG 50–70 mg/dL)
• CNS becomes hyperexcitable
• Nervousness, tremors
• Sweating
 • Possible hallucinations
Moderate hypoglycemia (BG 20–50 mg/dL)
• Clonic seizures
• Loss of consciousness
Severe hypoglycemia (<20 mg/dL)
• Seizures cease
• Coma due to neuronal energy failure
• Risk of permanent brain injury

Distinguishing from Diabetic Ketoacidotic Coma

Hypoglycemic (insulin shock) coma:
• No acetone breath
• No Kussmaul breathing
• Often pale, sweaty, tremulous
Diabetic ketoacidotic coma:
• Fruity (acetone) breath
• Deep, rapid breathing
• Dehydrated, flushed

Emergency Treatment
Immediate IV glucose is lifesaving
• Rapid awakening within 1 minute
• Prevents irreversible neuronal injury
Alternative treatments
• Glucagon injection
• Epinephrine (less effective)
→ Both stimulate glycogenolysis → raise blood glucose quickly.