11 - Hormonal Regulation of Glycemia

TARGET DECK: MED::I::Signaling Pathways in Health and Disease::Metabolic Biochemistry::11 - Hormonal Regulation of Glycemia

Glycemia

The term glycemia refers to the concentration of glucose in the blood.

• Normal range: 70–90 mg/dL (90 mg/dL = 5 mM)
• $>110\text{ mg/dL}$ → Hyperglycemia
• $<70\text{ mg/dL}$ → Hypoglycemia

Glycemia is a good index of glucose metabolism.

Condition	Threshold	Symptoms
Hypoglycemia	$<70\text{ mg/dL}$	Trembling, sweating/chills, palpitations, hunger, altered mental status, confusion, headache
Hyperglycemia	$>110\text{ mg/dL}$	Extreme thirst, hunger, frequent urination, fatigue, confusion, vomiting/nausea, abdominal pain

https://www.ncbi.nlm.nih.gov/books/NBK581875/

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Normal blood glucose is {1:70–90 mg/dL}; values above {2:110 mg/dL} define hyperglycemia and below {3:70 mg/dL} define hypoglycemia.

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Factors Affecting Glycemia

• Dietary intake
• Liver metabolic pathways
  • Consuming glucose: Glycolysis, Glycogen synthesis, Pentose phosphate pathway, Biosynthesis of lipids (and amino acids)
  • Producing glucose: Glycogenolysis, Gluconeogenesis
• Metabolic pathways in extrahepatic tissues
  • Consuming glucose: Glycolysis, Glycogen synthesis
• Kidney filtration and reabsorption

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Digestion and Absorption of Carbohydrates

Major Dietary Carbohydrates

Type	Examples	Food Sources
Polysaccharides	Starch (amylose, amylopectin), glycogen	Potatoes, rice, bread, muscle, liver
Disaccharides	Sucrose, lactose, maltose	Desserts, sweets, milk
Monosaccharides	Glucose, fructose	Fruits, honey

https://doi.org/10.1016/j.mpaic.2023.07.006

Digestion of Polysaccharides

Hydrolysis of long-chain polysaccharides to short-chain glucose polymers is carried out by amylases (from salivary glands and pancreas), which act on α-1,4- and α-1,6-glucosidic bonds present in starch and glycogen.

Warning

Humans cannot digest β-glycosidic bonds (i.e., cellulose).

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Amylases act on {1:α-1,4- and α-1,6-glucosidic bonds} in starch and glycogen; humans cannot digest {2:β-glycosidic bonds} (cellulose).

Digestion of Disaccharides

Disaccharides are broken down into monosaccharides by enzymes in the brush border of the small intestinal wall:

$\text{Polysaccharides}\stackrel{\text{Amylase}}{\to }\text{Disaccharides}\stackrel{\text{Maltase / Sucrase / Lactase}}{\to }\text{Monosaccharides}$

https://opentextbc.ca/biology/chapter/15-3-digestive-system-processes/

Intestinal Absorption of Monosaccharides

Monosaccharides (end products of carbohydrate digestion) enter the capillaries of the intestinal villi.

Mechanism (apical → basal):

• Apical surface: Na⁺–glucose symporter (SGLT) — driven by high extracellular $[{\text{Na}}^{+}]$
• Basal surface: GLUT2 — facilitates downhill efflux into portal blood

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Glucose is absorbed across the apical membrane of enterocytes via the {1:Na⁺–glucose symporter (SGLT)}, driven by the sodium gradient, and exits at the basal surface via {2:GLUT2}.

Glycemic Peak After a Carbohydrate Meal

1. Monosaccharides enter capillaries of intestinal villi
2. Travel to the liver via the portal vein
3. In the liver, galactose and fructose are converted to glucose
4. Glucose enters general circulation → glycemic peak
5. Glycemic regulation by insulin and glucagon follows

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Glycemic Index (GI)

The glycemic index (GI) assigns a numeric score (0–100) to a food based on how drastically it raises blood sugar, with pure glucose = 100.

• The more processed a food, the higher its GI
• More fiber or fat → lower GI

GI Category	GI Range	Examples
Low GI	< 54	Broccoli, tomatoes, apple, chickpeas, all bran, lentils
Moderate GI	55–69	Banana (56), beetroot (64), cous cous (65), whole wheat bread (68)
High GI	> 70	Watermelon, soda drink, French fries, white bread, cornflakes, baked potato

https://doi.org/10.1016/j.mpaic.2023.07.006

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High-GI foods cause {1:rapid} rises in blood glucose; low-GI foods cause {2:slow, sustained} rises. More fiber or fat in a food {3:lowers} its GI.

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The Endocrine Pancreas

The endocrine portion of the pancreas consists of clusters of cells called islets of Langerhans (size: 50–300 µm). The human pancreas has up to two million islets, comprising 1–2% of the pancreatic mass.

Cell Type	Proportion	Hormone Secreted
α (alpha) cells	~20%	Glucagon
β (beta) cells	~65%	Insulin, Amylin (IAPP)
δ (delta) cells	~10%	Somatostatin
F cells	< 5%	Pancreatic polypeptide
ε (epsilon) cells	~1%	Ghrelin

https://doi.org/10.1016/j.mpaic.2023.07.006

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The β cells of the islets of Langerhans comprise approximately {1:65%} of islet cells and secrete {2:insulin and amylin}; α cells (~{3:20%}) secrete {4:glucagon}.

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Insulin

Factors Influencing Insulin Secretion

Stimulatory Factors	Inhibitory Factors
Raised serum glucose	Low serum glucose
Raised amino acids (arginine, leucine)	Somatostatin
Cortisol	Starvation
Potassium	Diazoxide
Vagal stimulation	α-adrenergic agonists
Glucose-dependent insulinotropic peptide (GIP)	—
Sulphonylurea drugs	—
β-adrenergic agonists	—

Mechanism of Insulin Secretion (Metabolism-Secretion Coupling)

The β-cell senses glucose through uptake and metabolism, not via a plasma membrane glucose receptor.

• Initial activation is rapid: glucose raises cytosolic ${\text{Ca}}^{2+}$ signals within < 2 minutes → triggers insulin granule exocytosis
• This link is termed metabolism-secretion coupling
• Mitochondria are essential: they generate metabolic signals including ATP that control β-cell electrical activity and associated ${\text{Ca}}^{2+}$ signals
• There is also an incretin effect acting as an amplifying pathway on ${\text{Ca}}^{2+}$

https://doi.org/10.1186/s12964-019-0326-6

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In β-cells, glucose stimulates insulin secretion by raising cytosolic {1:Ca²⁺} within less than {2:2 minutes}, triggering {3:exocytosis} of insulin granules — a process called {4:metabolism-secretion coupling}.

Insulin Synthesis

1. Synthesized in ribosomes of RER as preproinsulin
2. Cleavage → proinsulin → transported to Golgi
3. Further cleavage in Golgi → equimolar amounts of insulin + C-peptide packed in secretory granules
4. Structure: two polypeptide chains (A and B) linked by two disulfide bridges
5. Upon β-cell stimulation: granules undergo exocytosis → insulin, proinsulin, C-peptide released into portal circulation
6. Insulin half-life: 4 minutes (rapidly metabolized by liver and kidney)
7. C-peptide half-life: 30 minutes (not metabolized, excreted unchanged by kidneys)

Info

C-peptide is a useful biomarker for endogenous insulin production (e.g., in insulinoma — a tumor secreting endogenous insulin causing frequent hypoglycemic symptoms).

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Insulin is synthesized as {1:preproinsulin}, cleaved to {2:proinsulin}, then to insulin and {3:C-peptide} in equimolar amounts. Insulin half-life is {4:4 minutes}; C-peptide half-life is {5:30 minutes}.

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Effect of Insulin on Blood Glucose

Summary Table

Metabolic Effect	Target Enzyme
↑ Glucose uptake (liver)	↑ Glucokinase
↑ Glucose uptake (muscle)	↑ Glucose transporter (GLUT4)
↑ Glycolysis	↑ Phosphofructokinase-1 (PFK-1)
↑ Glycogen synthesis (liver, muscle)	↑ Glycogen synthase
↓ Glycogen breakdown (liver, muscle)	↓ Glycogen phosphorylase
↑ Acetyl-CoA production (liver, muscle)	↑ Pyruvate dehydrogenase complex
↑ Fatty acid synthesis (liver)	↑ Acetyl-CoA carboxylase
↑ Triacylglycerol synthesis (adipose tissue)	↑ Lipoprotein lipase

Important

In the liver, insulin activates several pathways consuming glucose: glycogen synthesis, glycolysis, lipid synthesis, and the pentose phosphate pathway.

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Insulin → ↑ Glucose Uptake (Liver): Glucokinase (GCK)

Glucokinase = Hexokinase IV

Step 1 of glycolysis (irreversible): Glucose → Glucose-6-phosphate

$\text{Glucose}+\text{ATP}\stackrel{\text{Glucokinase (GCK)}}{\to }\text{Glucose-6-phosphate}+\text{ADP}$

Properties of GCK (liver-specific):

• Acts only on glucose
• $K_m=20\text{ mmol/L}$ (low affinity for substrate)
• Acts only when blood glucose is $>100\text{ mg/dL}$
• Insulin increases GCK gene expression at the transcriptional level

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Glucokinase (GCK) has a $K_m$ of {1:20 mmol/L} (low affinity), acts only on {2:glucose}, is liver-specific, and is induced by {3:insulin} at the transcriptional level.

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Insulin → ↑ Glycolysis: Phosphofructokinase-1 (PFK-1)

Step 3 of glycolysis (irreversible): Fructose-6-phosphate → Fructose-1,6-bisphosphate

$\text{Fructose-6-P}+\text{ATP}\stackrel{\text{PFK-1}}{\to }\text{Fructose-1,6-bisphosphate}+\text{ADP}$

Properties of hepatic PFK-1:

• A specific liver isoform acts on fructose-6-phosphate
• Allosterically activated by: ADP, AMP, fructose-2,6-bisphosphate
• Allosterically inhibited by: ATP, citrate
• Insulin increases PFK-1 gene expression at the transcriptional level

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PFK-1 is allosterically activated by {1:ADP, AMP, and fructose-2,6-bisphosphate} and inhibited by {2:ATP and citrate}. Insulin upregulates PFK-1 at the {3:transcriptional} level.

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Insulin → ↑ Glycogen Synthesis: Glycogen Synthase (GS)

Glycogen synthase (GS) transfers glucose from UDP-glucose to the non-reducing end of a glycogen branch, forming a new α(1→4) linkage.

Mechanism of insulin-driven GS activation (signal cascade):

$\text{Insulin}\to \text{Tyrosine kinase (receptor)}\to \text{IRS-1}\to \text{PI-3K}\to {\text{PIP}}_2\to {\text{PIP}}_3\to \text{PDK-1}\to \text{PKB}\to \text{GSK3 (phosphorylated = inactivated)}$

$\text{GSK3 inactive}\to \text{PP1 dephosphorylates GS}\to \text{GS active}$

Tip

Dephosphorylation = activation of glycogen synthase. This follows inactivation of glycogen synthase kinase-3 (GSK3) via insulin-driven phosphorylation.

Additionally, insulin promotes glucose-6-phosphate (G-6-P) production, which allosterically activates GS.

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Insulin activates glycogen synthase by causing PKB to phosphorylate and {1:inactivate} GSK3, allowing {2:PP1} to {3:dephosphorylate} (activate) glycogen synthase.

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Insulin → ↓ Glycogen Breakdown: Glycogen Phosphorylase

Glycogen phosphorylase cleaves terminal glucose residues from the non-reducing end of glycogen using inorganic phosphate $P_i$:

$(\text{Glucose}{)}_n+P_i\stackrel{\text{Glycogen phosphorylase}}{\to }\text{Glucose-1-phosphate}+(\text{Glucose}{)}_{n-1}$

Insulin inhibits glycogen phosphorylase by:

When blood glucose is high → glucose binds to an allosteric site of phosphorylase a → conformational change exposes phosphorylated Ser residues → PP1 converts phosphorylase a (active) → phosphorylase b (less active) → slows glycogen breakdown.

Insulin stimulates PP1, thereby slowing glycogen breakdown.

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Glycogen phosphorylase a (active) is converted to phosphorylase b (less active) by {1:PP1 (phosphorylase a phosphatase)}, which is stimulated by {2:insulin and high blood glucose}.

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Insulin → ↑ Acetyl-CoA Production: Pyruvate Dehydrogenase Complex (PDH)

The pyruvate dehydrogenase (PDH) complex is located in the mitochondria of eukaryotic cells and oxidizes pyruvate to acetyl-CoA and ${\text{CO}}_2$:

$\text{Pyruvate}+{\text{NAD}}^{+}+\text{CoA}\stackrel{{\text{PDH complex (E}}_1+{\text{E}}_2+{\text{E}}_3\text{)}}{\to }\text{Acetyl-CoA}+{\text{CO}}_2+\text{NADH}$

Cofactors: TPP, lipoate, FAD, NAD⁺, CoA

Hormonal regulation:

• Regulation does not involve cAMP-dependent protein kinase
• Instead: changes in intracellular calcium levels activate a phosphatase
• Dephosphorylated form = active PDH
• Insulin activates PDH (via calcium-induced dephosphorylation)

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Insulin activates the pyruvate dehydrogenase complex by increasing intracellular {1:calcium}, which activates a {2:phosphatase} that {3:dephosphorylates} PDH (dephosphorylated = active form).

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Insulin → ↑ Fatty Acid Synthesis: Acetyl-CoA Carboxylase

Fatty acid biosynthesis requires malonyl-CoA (a 3-carbon intermediate).

Formation of malonyl-CoA from acetyl-CoA:

$\text{Acetyl-CoA}+{\text{HCO}}_3^{-}+\text{ATP}\stackrel{\text{Acetyl-CoA carboxylase}}{\to }\text{Malonyl-CoA}+\text{ADP}+P_i$

Acetyl-CoA carboxylase is an example of an enzyme whose phosphorylation is increased by insulin and whose activity is acutely modulated by insulin.

CC(=O)SCC(=O)O

(Malonyl-CoA simplified)

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The rate-limiting step of fatty acid synthesis is the formation of {1:malonyl-CoA} from acetyl-CoA, catalyzed by {2:acetyl-CoA carboxylase}, which is activated by {3:insulin}.

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Insulin → Pentose Phosphate Pathway

The pentose phosphate pathway runs parallel to glycolysis and generates:

• NADPH
• Ribose-5-phosphate (precursor for nucleotide synthesis)

Rate-limiting enzyme: Glucose-6-phosphate dehydrogenase (G6PD)

$\text{Glucose-6-phosphate}+{\text{NADP}}^{+}\stackrel{\text{G6PD}}{\to }\text{6-Phosphoglucono-δ-lactone}+\text{NADPH}+{\text{H}}^{+}$

Insulin induces an increase in G6PD activity, assumed to be via de novo enzyme biosynthesis involving new RNA production.

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The rate-limiting enzyme of the pentose phosphate pathway is {1:glucose-6-phosphate dehydrogenase (G6PD)}, which is upregulated by {2:insulin} through {3:de novo biosynthesis (new RNA production)}.

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Insulin Effects in Muscle and Adipose Tissue

The passive uptake of glucose by muscle and adipose tissue is catalyzed by the GLUT4 transporter.

• In the absence of insulin: most GLUT4 molecules are sequestered in membrane vesicles within the cell
• When blood glucose rises: insulin triggers GLUT4 translocation to the plasma membrane → increased glucose uptake

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In the absence of insulin, GLUT4 is {1:sequestered in intracellular membrane vesicles}. Insulin stimulates {2:translocation of GLUT4 to the plasma membrane} in muscle and adipose tissue.

Integrated Insulin Signaling in the Liver

$\text{High blood glucose}\to \uparrow \text{Insulin}\to \uparrow \text{Insulin-sensitive protein kinase}\to \uparrow \text{PKB}$

$\to \{\begin{array}{l}\uparrow \text{PP1}\to \downarrow \text{GSK-3}\to \downarrow \text{Phosphorylase kinase}\to \uparrow \text{Glycogen synthase}\\ \downarrow \text{Glycogen phosphorylase}\end{array}$

$\to \uparrow \text{Glycogen synthesis},\uparrow \text{Glycolysis}$

Additionally: synthesis of hexokinase II, PFK-1, pyruvate kinase.

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Glucagon

Role of Glucagon

During fasting, glucagon activates pathways producing glucose to be released into the blood:

• Glycogenolysis
• Gluconeogenesis

Effects of Glucagon on Blood Glucose (Liver)

Metabolic Effect	Effect on Glucose Metabolism	Target Enzyme
↓ Glycolysis (liver)	Less glucose used as fuel in liver	↓ Phosphofructokinase-1
↑ Glycogen breakdown (liver)	Glycogen → glucose	↑ Glycogen phosphorylase
↓ Glycogen synthesis (liver)	Less glucose stored as glycogen	↓ Glycogen synthase
↑ Gluconeogenesis (liver)	Amino acids, glycerol → glucose	↑ Fructose-1,6-bisphosphatase; ↓ Pyruvate kinase
↑ Fatty acid mobilization (adipose)	Less glucose used as fuel	↑ Triacylglycerol lipase

Important

Skeletal muscle lacks:

• Glucagon receptors
• Glucose-6-phosphatase
• Gluconeogenesis

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Skeletal muscle lacks {1:glucagon receptors}, {2:glucose-6-phosphatase}, and {3:gluconeogenesis}, so it cannot export glucose to the blood.

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Glucagon → Glycogenolysis: Glycogen Phosphorylase Activation

Glucagon acts via G-protein-associated receptors:

$\text{Glucagon}\to \uparrow \text{cAMP}\to \uparrow \text{PKA}\to \uparrow \text{Phosphorylase kinase}\to \text{Phosphorylase b}\to \text{Phosphorylase a (active)}$

Glycogen phosphorylase a (phosphorylated) = active
Glycogen phosphorylase b (dephosphorylated) = less active

Signal amplification cascade:
$1\text{ ATP}\to \sim 10\times \text{cAMP}\to \sim 20\times \text{phosphorylase b kinase (active)}\to \sim 100\times \text{phosphorylase b kinase}\to \sim 1000\times \text{glycogen phosphorylase a (active)}$

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Glucagon activates glycogen phosphorylase via the cascade: glucagon → {1:↑ cAMP} → {2:PKA} → {3:phosphorylase kinase} → phosphorylase b → phosphorylase {4:a} (active).

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Glucagon → Gluconeogenesis: Bypass of Irreversible Glycolytic Steps

Three irreversible steps in glycolysis are bypassed by gluconeogenic enzymes:

1. Pyruvate → PEP via oxaloacetate
   • Enzymes: Pyruvate carboxylase then PEP carboxykinase

$\text{Pyruvate}+{\text{CO}}_2+\text{ATP}\stackrel{\text{Pyruvate carboxylase}}{\to }\text{Oxaloacetate}\stackrel{\text{PEP carboxykinase}}{\to }\text{PEP}+{\text{CO}}_2$

2. Fructose-1,6-bisphosphate → Fructose-6-phosphate

   • Enzyme: FBPase-1 (Fructose-1,6-bisphosphatase)

3. Glucose-6-phosphate → Glucose

   • Enzyme: Glucose-6-phosphatase

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The three irreversible glycolytic steps bypassed in gluconeogenesis are: (1) {1:pyruvate → PEP} (via pyruvate carboxylase + PEP carboxykinase), (2) {2:fructose-1,6-bisphosphate → fructose-6-phosphate} (FBPase-1), and (3) {3:glucose-6-phosphate → glucose} (glucose-6-phosphatase).

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Fructose-2,6-Bisphosphate: Key Regulator of Glycolysis/Gluconeogenesis

Fructose-2,6-bisphosphate (F-2,6-BP) is a potent allosteric:

• Activator of PFK-1 (stimulates glycolysis)
• Inactivator of FBPase-1 (inhibits gluconeogenesis)

PFK-2/FBPase-2: The Bifunctional Tandem Enzyme

The same protein contains both Phosphofructokinase-2 (PFK-2) and Fructose-2,6-bisphosphatase (FBPase-2), regulated by cAMP-dependent phosphorylation (PKA):

Hormone	Effect on Tandem Enzyme	[F-2,6-BP]	Net Effect
Insulin	Dephosphorylation → PFK-2 active	↑ High	↑ Glycolysis
Glucagon	Phosphorylation → FBPase-2 active	↓ Low	↑ Gluconeogenesis

$\text{Insulin}\to \text{PP2A}\to \text{Tandem enzyme dephosphorylated}\to \text{PFK-2 active}\to \uparrow \text{F-2,6-BP}\to \text{PFK-1 activated}\to \uparrow \text{Glycolysis}$

$\text{Glucagon}\to \uparrow \text{cAMP}\to \text{PKA}\to \text{Tandem enzyme phosphorylated}\to \text{FBPase-2 active}\to \downarrow \text{F-2,6-BP}\to \text{FBPase-1 activated}\to \uparrow \text{Gluconeogenesis}$

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Glucagon causes phosphorylation of the bifunctional enzyme PFK-2/FBPase-2, activating {1:FBPase-2}, decreasing {2:fructose-2,6-bisphosphate}, thereby inhibiting {3:PFK-1} and activating {4:FBPase-1}, promoting {5:gluconeogenesis}.

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Insulin activates {1:PFK-2} (via dephosphorylation of the tandem enzyme), increasing {2:fructose-2,6-bisphosphate}, which stimulates {3:PFK-1} and inhibits {4:FBPase-1}, promoting {5:glycolysis}.

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Integrated Glucagon Signaling Summary

$\text{Low blood glucose}\to \uparrow \text{Glucagon}\to \uparrow \text{cAMP}\to$

$\{\begin{array}{l}\uparrow \text{Phosphorylase kinase}\to \uparrow \text{Glycogen phosphorylase}\to \uparrow \text{Glycogen breakdown}\\ \downarrow \text{PFK-2}\to \downarrow \text{F-2,6-BP}\to \uparrow \text{FBPase-1}\to \uparrow \text{Gluconeogenesis}\\ \downarrow \text{Glycogen synthase}\to \downarrow \text{Glycogen synthesis}\\ \downarrow \text{Pyruvate kinase}\to \downarrow \text{Glycolysis}\end{array}$

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Other Hormones Affecting Glycemia

Hormone	Source	Receptor Type	Effect on Glycemia
Insulin	Pancreatic β cells	Tyrosine kinase receptor	↓ Blood glucose
Glucagon	Pancreatic α cells	G-protein-associated receptor	↑ Blood glucose
Epinephrine (Adrenaline)	Adrenal medulla	G-protein-associated receptor	↑ Blood glucose
Cortisol	Zona fasciculata of adrenal cortex	Cytoplasmic (nuclear) receptor	↑ Blood glucose

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Epinephrine (Adrenaline)

• Acts via G-protein-associated receptors → ↑ cAMP → ↑ PKA → ↑ glycogen phosphorylase → ↑ glycogenolysis
• Signal amplification analogous to glucagon

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Cortisol

• Synthesized from cholesterol in the zona fasciculata of the adrenal cortex
• Steroid hormone → too hydrophobic to dissolve readily in blood → travels on specific carrier proteins
• Does not bind to plasma membrane receptors

Mechanism of Action (Nuclear Receptor):

1. Cortisol diffuses through plasma membrane (simple diffusion)
2. Binds to intracellular receptor protein in the nucleus
3. Hormone-receptor complex acts as a transcriptional transactivator
4. Binds to hormone response elements (HREs) in DNA adjacent to specific genes
5. Alters gene expression → changes mRNA levels → cellular response

Metabolic Effects of Cortisol:

• In liver: ↑ rate of gluconeogenesis
• In muscle: ↓ glucose uptake → hyperglycemia
• Suppresses immune response, inflammation, and allergic responses

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Cortisol, a steroid hormone, acts by binding to {1:intracellular (nuclear) receptors} which then bind {2:hormone response elements (HREs)} in DNA, altering {3:gene expression}. It promotes {4:gluconeogenesis} in the liver and decreases {5:glucose uptake} in muscle.

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Physiological Response to Hypoglycemia

Blood Glucose (mg/100 mL)	Physiological Effects
~100	Normal range
Subtle drop	Neurological signs; hunger
Further drop	Release of glucagon, epinephrine, cortisol
~60	Sweating, trembling
Lower	Lethargy
Very low	Convulsions, coma
Prolonged severe	Permanent brain damage
Extreme	Death

The minute-by-minute adjustments that keep blood glucose near 4.5 mM involve the combined actions of insulin, glucagon, epinephrine, and cortisol on liver, muscle, and adipose tissue.

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Renal Handling of Glucose

Normal Conditions

In physiological conditions, glucose is absent in urine (fully reabsorbed).

Mechanism of Renal Glucose Reabsorption

Two sodium-dependent glucose cotransporter (SGLT) proteins:

Transporter	Location	Affinity	Capacity	% Reabsorbed
SGLT2	S1 segment (proximal convoluted tubule)	Low affinity	High capacity	~90%
SGLT1	S3 segment	High affinity	Low capacity	~10%

doi:10.1038/ki.2010.509

Tubular Maximum ($T_m$) and Glucosuria

• Tubular reabsorption increases linearly with filtered load (glomerulotubular balance)
• When reabsorption reaches tubular capacity ($T_m$) → glucose appears in urine (glucosuria)

$\text{Renal threshold}\approx 180-200\text{ mg/dL plasma glucose}$

Glucosuria occurs in:

1. Defects of tubular reabsorption (with normal glycemia) — renal glucosuria
2. Diabetes mellitus — glycemia exceeds $T_m$

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Approximately {1:90%} of filtered glucose is reabsorbed by {2:SGLT2} in the S1 segment; the remaining {3:10%} by {4:SGLT1} in the S3 segment. Glucosuria occurs when plasma glucose exceeds the {5:tubular maximum ($T_m$)}.

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Diabetes Mellitus

Type I Diabetes

• Autoimmune destruction of pancreatic β cells → absent insulin production
• Absolute insulin deficiency
• Requires exogenous insulin

Type II Diabetes

• Usually develops after age 40
• Often in overweight or obese individuals
• Insulin resistance (desensitized insulin receptors)
• Early stages are reversible
• Often undiagnosed for a period

How Excess Fat Causes Insulin Resistance (Type II):

1. Large adipocytes → pro-inflammatory state → macrophages infiltrate adipose tissue
2. Macrophages produce TNFα → favors export of fatty acids from adipocytes
3. Fatty acids exported to muscle → ectopic lipid deposits form
4. Ectopic lipid activates PKC → interferes with GLUT4 movement to myocyte surface
5. Result: insulin resistance → reduced glucose uptake → hyperglycemia

$\text{High caloric intake}\to \text{Lipogenesis}\to \text{Obesity}\to \uparrow \text{FFA, DAG}\to \uparrow \text{Malonyl-CoA}$

$\to \downarrow \text{Fatty acid oxidation}+\text{Altered mitochondrial function}+\uparrow \text{ROS}\to \text{Insulin resistance}\to \text{Hyperglycemia}$

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In type II diabetes, macrophages in adipose tissue produce {1:TNFα}, promoting fatty acid export to muscle where {2:ectopic lipid} activates {3:PKC}, impairing {4:GLUT4 translocation} to the plasma membrane, causing insulin resistance.

Diabetes Complications

Warning

Chronic complications of diabetes mellitus:

• Peripheral neuropathy
• Retinopathy (blindness)
• Nephropathy
• Peripheral vasculopathy (diabetic foot, gangrene)
• Coronaropathy (myocardial infarction)
• Brain vasculopathy (stroke)
• Sexual disturbances (male impotence)

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Summary: Glucokinase, PFK-1, Glycogen Synthase, Glycogen Phosphorylase, FBPase

Enzyme	Activated by	Inhibited by	Role
Glucokinase (GCK)	Insulin (transcription), high glucose	—	Step 1 glycolysis (liver)
PFK-1	ADP, AMP, F-2,6-BP, insulin (transcription)	ATP, citrate	Step 3 glycolysis
Glycogen synthase	Insulin (via dephosphorylation/PP1), G-6-P	GSK3 (phosphorylation)	Glycogen synthesis
Glycogen phosphorylase a	Glucagon/epinephrine (via PKA)	Insulin (via PP1), glucose	Glycogenolysis
FBPase-1	Glucagon (↓ F-2,6-BP), ATP	F-2,6-BP, AMP	Gluconeogenesis

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TLDR

Tldr

Hormonal Regulation of Blood Glucose — Complete Summary

• Glycemia = blood glucose concentration; normal: 70–90 mg/dL. Hypoglycemia < 70, hyperglycemia > 110.
• Glucose digestion: polysaccharides → disaccharides (amylases) → monosaccharides (maltase, sucrase, lactase). Humans lack β-glycosidase, so cannot digest cellulose.
• Intestinal absorption: SGLT (apical, Na⁺-driven) → GLUT2 (basal efflux). Galactose and fructose converted to glucose in the liver.
• Glycemic index (GI): scores how rapidly a food raises blood glucose (0–100). More fiber/fat = lower GI. More processing = higher GI.
• Islets of Langerhans: α cells (~20%) → glucagon; β cells (~65%) → insulin + amylin; δ cells (~10%) → somatostatin.
• Insulin secretion: triggered by high glucose via metabolism-secretion coupling; β-cells use ATP generation to raise cytosolic Ca²⁺ → exocytosis of granules within < 2 min. Incretin effect amplifies this.
• Insulin synthesis: preproinsulin → proinsulin → insulin + C-peptide (equimolar). C-peptide: half-life 30 min, useful biomarker (e.g., insulinoma).
• Insulin actions (liver): ↑ glucokinase (transcription), ↑ PFK-1 (transcription), ↑ glycogen synthase (via GSK3 inactivation and PP1), ↓ glycogen phosphorylase (via PP1), ↑ PDH complex (via Ca²⁺-activated phosphatase), ↑ acetyl-CoA carboxylase, ↑ G6PD (pentose phosphate pathway).
• Insulin actions (muscle/adipose): GLUT4 translocation to plasma membrane → ↑ glucose uptake.
• Fructose-2,6-bisphosphate: key regulator controlled by bifunctional PFK-2/FBPase-2 tandem enzyme. Insulin → PFK-2 active → ↑ F-2,6-BP → ↑ glycolysis. Glucagon → FBPase-2 active → ↓ F-2,6-BP → ↑ gluconeogenesis.
• Glucagon actions (liver): ↑ cAMP → PKA → ↑ glycogen phosphorylase (glycogenolysis), ↓ glycogen synthase, ↓ PFK-1 (via ↓ F-2,6-BP), ↑ FBPase-1 (gluconeogenesis). Gluconeogenesis bypasses irreversible glycolytic steps via pyruvate carboxylase + PEP carboxykinase, FBPase-1, glucose-6-phosphatase.
• Epinephrine: adrenal medulla, G-protein receptor → ↑ cAMP → glycogenolysis (in liver and muscle).
• Cortisol: adrenal cortex (zona fasciculata), nuclear receptor → binds HREs → ↑ gluconeogenesis (liver), ↓ glucose uptake (muscle) → hyperglycemia.
• Skeletal muscle: lacks glucagon receptors, glucose-6-phosphatase, gluconeogenesis — cannot export free glucose.
• Renal glucose handling: SGLT2 (S1, ~90%) + SGLT1 (S3, ~10%) reabsorb all filtered glucose under normal conditions. Glucosuria occurs when plasma glucose exceeds $T_m$ (~180–200 mg/dL), as in diabetes mellitus.
• Type I diabetes: autoimmune β-cell destruction → no insulin → requires exogenous insulin.
• Type II diabetes: insulin resistance (post-40, obesity-linked). Mechanism: macrophage-derived TNFα → fatty acid export → ectopic muscle lipid → PKC activation → impaired GLUT4 translocation → hyperglycemia.
• Diabetic complications: neuropathy, retinopathy, nephropathy, vasculopathy, coronaropathy, stroke, impotence.