Mednotes

L7 Metabolism Gluconeogenesis and response to trauma

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tagsmetabolism, lecture, biochemistry, endocrinology
aliasesGluconeogenesis and response to trauma

16 min read

Overview

This lecture covers gluconeogenesis (GNG) — the synthesis of glucose from non-carbohydrate precursors — and how it is regulated hormonally at the level of key enzymes, then extends to when GNG capacity is impaired (prematurity, alcoholism, rare enzyme deficiencies) and when it becomes pathologically overactive (insulin resistance, Type 2 diabetes, trauma). The second half covers the systemic metabolic response to trauma/injury/sepsis, its phases and endocrine drivers, the resulting insulin resistance, and a brief related note on the Warburg effect in cancer metabolism. The parts connect: the same enzymes and hormonal switches (insulin vs glucagon) that regulate everyday fasting GNG are the ones dysregulated in diabetes and hijacked during the catabolic response to injury.

Gluconeogenesis: overview and precursors

Gluconeogenesis (GNG) happens predominantly in the liver, and also occurs in the kidney. It is a highly regulated pathway that increases in importance during fasted and starved states. It is activated by glucagon and inhibited by insulin (with other regulators existing too). GNG is very important following trauma, and is very active and dysregulated in Type 2 Diabetes, where there are effectively unopposed glucagon effects due to insulin resistance.

Timeline of glucose utilisation after a single food intake: exogenous glucose is used first and drops steeply within hours; glycogen breakdown then supplies glucose, peaking around 8–12 hours before declining; gluconeogenesis rises steadily from near zero to become the dominant source of glucose, and after about 2 days all glucose production is from gluconeogenesis. The brain’s major fuel is glucose throughout the early phases, shifting to glucose and ketone bodies in the later (day-scale) phase.

Key precursors for gluconeogenesis:

  • Lactate — from muscle glycolysis, from anaerobic metabolism
  • Glycerol — from lipolysis of triacylglycerols (TAGs) in adipose tissue
  • Alanine — from proteins (muscle)

Pyruvate dehydrogenase (PDH) is unidirectional (pyruvate → acetyl-CoA only). Acetyl-CoA cannot be used to synthesise glucose, and fatty acids generally cannot be used to synthesise glucose.

The gluconeogenic pathway and the two bypasses

The core liver pathway: glucose ⇌ glucose-6-phosphate (G6P) ⇌ fructose-6-phosphate (F6P) ⇌ fructose-1,6-bisphosphate (F1,6bisP) ⇌ triose phosphate ⇌ phosphoenolpyruvate (PEP) ⇌ pyruvate. Glycogen also interconverts with G1P/G6P (glycogen breakdown = glycogen mobilisation; synthesis = glycogen synthesis, via UDPG). Triose phosphate also receives input from fructose (via F1P), glyceraldehyde, and glycerol (via glycerol-phosphate). Pyruvate connects to oxaloacetate (⇌ PEP), alanine, and lactate, and feeds forward (unidirectionally) into acetyl-CoA via PDH. Acetyl-CoA feeds ketogenesis (→ ketone bodies), is fed by β-oxidation of fatty acids, and feeds the citric acid cycle (→ CO2). Glucose exits the liver cell to the bloodstream. Glycerol, alanine and lactate are the three key gluconeogenic precursor entry points.

Going from pyruvate up to glucose requires bypassing two irreversible (glycolytic) steps:

  1. Pyruvate → PEP (bypassing pyruvate kinase)
  2. F1,6bisP → F6P (bypassing PFK-1)

Five key enzymes involved in gluconeogenesis regulation, important for bypassing these enzymic roadblocks:

  • Glucose-6-phosphatase
  • Fructose bisphosphatase
  • Pyruvate carboxylase (PC)
  • PEP carboxykinase (PEPCK)
  • Pyruvate dehydrogenase (PDH)

Bypass 1: pyruvate → PEP

Acetyl-CoA is produced by PDH and by fatty acid oxidation during fasting. Acetyl-CoA inhibits PDH and activates pyruvate carboxylase (PC); therefore fasting stimulates gluconeogenesis (fatty-acid-derived acetyl-CoA pushes pyruvate towards oxaloacetate/PEP rather than into the TCA cycle via PDH).

At this node: oxaloacetate ⇌ PEP via PEPCK; oxaloacetate ⇌ pyruvate via PC; pyruvate → PEP via pyruvate kinase (PK); pyruvate ⇌ alanine; pyruvate ⇌ lactate; pyruvate → acetyl-CoA via PDH.

Hormonal regulation of this node:

  • Glucagon promotes phosphorylation of pyruvate kinase, inhibiting it, and increases the expression of PEPCK.
  • Insulin promotes dephosphorylation of PK, activating it, and inhibits the expression of PEPCK.

Net effect: glucagon pushes flux towards gluconeogenesis (PK off, PEPCK up); insulin pushes flux towards glycolysis (PK on, PEPCK down).

PEPCK transcription is regulated by multiple factors acting on its gene promoter (a promoter region from about −1000 to 0 bp with four regions containing binding sites such as PPARRE/PPARγ2/RXR, AF1/AF2/GRE/RAR/HNF-3/GR, TRE/T3 receptor/Fos-Jun/C-EBP/HNF-1, and P1/CRE-1/TATA/NF-1/CREB-CREM/DBP-C-EBP/TBP/Pol II):

  • Inhibitors (red): insulin, metformin
  • Activators (green): cortisol, thyroid hormone, adrenaline, glucagon

Mechanistically, insulin blocks PEPCK and G6Pase transcription via the insulin/growth factor receptor → PI3K → PDK1 → Akt pathway, which inhibits the FOXO transcription factor. When insulin/growth factors are absent, FOXO remains in the nucleus and activates target genes for cell death, reactive oxygen species detoxification, DNA repair, cell cycle arrest, energy homeostasis, and glucose metabolism (G6Pase, PEPCK) — i.e. loss of insulin signalling (via FOXO derepression) drives gluconeogenic gene expression.

Bypass 2: F1,6bisP → F6P

This bypass is controlled at the level of the fructose-2,6-bisphosphate substrate cycle:

  • Insulin activates PFK2 via protein phosphatase 1 (PP1) (dephosphorylation), raising fructose-2,6-BP, which blocks gluconeogenesis.
  • Glucagon inhibits PFK2 via protein kinase A (PKA) (phosphorylation), lowering fructose-2,6-BP, which promotes gluconeogenesis.
  • Fructose-2,6-BP is an important allosteric effector: it stimulates PFK-1 (promoting glycolysis) and inhibits fructose-1,6-bisphosphatase (blocking gluconeogenesis).
  • Insulin also inhibits G6Pase transcription; glucagon activates G6Pase transcription.

Fructose-2,6-BP is the key allosteric switch between glycolysis and gluconeogenesis at this step: high fructose-2,6-BP (insulin-driven) favours glycolysis; low fructose-2,6-BP (glucagon-driven) favours gluconeogenesis.

Conditions of impaired or overactive gluconeogenesis

Impaired gluconeogenesis occurs in:

  • Premature babies, who have low glycogen stores and underdeveloped livers
  • High alcohol metabolism (increased NADH, low NAD)
  • Rare genetic diseases, e.g. fructose-1,6-bisphosphatase or glucose-6-phosphatase deficiency

Overactive gluconeogenesis occurs in:

  • Insulin resistance
  • Diabetes
  • Trauma

Insulin resistance

Many steps in gluconeogenesis are downregulated by insulin and upregulated by glucagon. In an insulin-resistant state, the insulin-dependent downregulation fails to occur properly, leaving the effects of glucagon unopposed. As a result, in Type 2 diabetes the liver makes too much glucose.

Alcoholism

Alcohol metabolism consumes significant amounts of NAD (ethanol → acetaldehyde via alcohol dehydrogenase (ADH), consuming NAD+ and producing NADH; acetaldehyde → acetate via aldehyde dehydrogenase (ALDH), again consuming NAD+ and producing NADH). NAD is needed to convert lactate into pyruvate, which is needed for gluconeogenesis — the pyruvate ⇌ lactate step competes for the same NAD+ pool that alcohol metabolism depletes. As a result, chronic alcoholics may have low pyruvate and can develop hypoglycaemia.

Metabolic response to trauma

Trauma has a surprisingly large effect on metabolism: elevated metabolic rate, increased energy needs, and increased gluconeogenesis. Many drivers contribute to this response, including adrenaline, glucagon, cortisol, and cytokines. This results in important insulin resistance.

Phases of the metabolic response to injury

The response unfolds over a timeline from injury (hour 0) through hours, weeks, and months, in four phases:

  1. “Anticipation” (fight, flight or fright) — roughly 0–12 hours
  2. Shock — roughly 12–24 hours
  3. Catabolic — weeks 1–3
  4. Anabolic — months (longer, less sharply defined duration)

Endocrine changes across these phases:

  • Sympathetic nervous activation (noradrenaline) and adrenal medullary secretion (adrenaline) — elevated from the anticipation phase through the catabolic phase
  • Pituitary secretion (ACTH, growth hormone, prolactin, arginine vasopressin) and cytokine secretion (IL-2, TNF-α) — elevated from the shock phase through the catabolic phase
  • Adrenal cortical secretion (cortisol) and pancreatic secretion (glucagon) — elevated during the catabolic phase

Effects of injury and sepsis on metabolism

Comparing normal subjects to those with injury or sepsis (all infused with glucose at a fixed energy rate):

  • Blood glucose rises: normal ~6 mM, injury ~10 mM, sepsis ~14.5 mM
  • Glucose oxidation + lipogenesis (as % of resting energy expenditure) falls: normal ~100%, injury ~65%, sepsis ~50%
  • Blood insulin rises in both injury and sepsis: normal ~450 pM, injury ~950 pM, sepsis ~920 pM
  • Fatty acid oxidation (% of resting energy expenditure) rises: normal ~−5%, injury ~22%, sepsis ~38%
  • Blood glucagon rises: normal ~45 pM, injury ~70 pM, sepsis ~55 pM
  • Protein oxidation (% of resting energy expenditure) rises: normal ~5%, injury ~12%, sepsis ~9%

Both insulin and glucagon are elevated together in injury/sepsis, and glucose oxidation as an energy source falls while fatty acid and protein oxidation rise despite elevated blood glucose — this pattern indicates insulin resistance.

Features of the catabolic phase

  • Increased metabolic rate
  • Weight loss
  • Evidence of muscle wasting (negative nitrogen balance)

Contributing factors:

  • Metabolic requirements of tissue repair and immune response
  • Insulin resistance
  • Cytokines and inflammatory mediators (TNFα, IL-2)
  • Lack of appetite

In burn patients, oral glucose tolerance testing across convalescence shows the glucose tolerance curve returning toward normal as recovery progresses: on the day of injury, peak blood glucose reached ~15 mM (highest, slowest to return to baseline); by the 4th day post-injury, the peak was only ~5.5 mM and returned close to baseline within 3–4 hours, most closely resembling a normal curve. This illustrates that insulin resistance is a major effect of trauma, which gradually resolves with convalescence.

A related case (Chen et al., Cell, 2012) showed blood glucose remaining stable (~95–100 mg/dL) until an RSV infection, after which it rose sharply and plateaued at ~140–150 mg/dL for several months (with glycated HbA1c rising to 6.4–6.7%, in the diabetic range), before gradually returning to baseline (~95–100 mg/dL, HbA1c 4.7–5.4%) following a lifestyle change. An earlier, different (rhinovirus) infection had not produced a glucose rise. This illustrates viral infection appearing to trigger transient Type 2 diabetes-like hyperglycaemia that resolved with lifestyle intervention.

Inter-organ coordination during stress and injury

During stress/injury, the liver, muscle, and adipose tissue coordinate via the bloodstream:

  • Adipose tissue: lipolysis of triacylglycerol is activated, releasing fatty acids (to liver and muscle) and glycerol (to liver, for gluconeogenesis). Glucose uptake/glycolysis and fatty acid synthesis in adipose tissue are inhibited.
  • Muscle: glucose uptake is reduced (dashed/inhibited arrow). Glycogen is broken down to pyruvate; pyruvate interconverts with lactate and alanine, both exported to blood (destined for the liver). Amino acids from protein breakdown feed alanine production. Triacylglycerol is broken down to fatty acids, which undergo fatty acid oxidation to acetyl-CoA and the TCA cycle; fatty acids are also exported to blood.
  • Liver: gluconeogenesis is activated, converting pyruvate to glucose, fed by glycerol, lactate and alanine arriving from the periphery. Glycogen breakdown feeds ketogenesis (activated). Glucose uptake by the liver is inhibited by ketone bodies (dashed inhibitory arrow).

Overall pattern: increased lipolysis and proteolysis supply gluconeogenic precursors (glycerol, lactate, alanine) to the liver; hepatic gluconeogenesis and ketogenesis increase; peripheral glucose uptake and glycolysis are reduced — this is the biochemical basis of the insulin resistance seen in trauma.

Tumour cells need large amounts of energy and have altered metabolism, especially involving glucose. Tumour cells primarily use glycolysis rather than oxidative metabolism, a pattern known as the Warburg effect. Features include:

  • Increased glucose import
  • Increased glycolysis
  • Increased lactate (production)
  • Negative nitrogen balance

These metabolic differences from non-cancer cells are being studied in anti-cancer therapy research [slide does not elaborate further on specific therapies].

Self-test

  1. Where does gluconeogenesis predominantly occur, and where else does it occur?
  2. What are the three key gluconeogenic precursors, and what tissue/process does each come from?
  3. Why can acetyl-CoA and fatty acids not be used to synthesise glucose?
  4. What are the two irreversible glycolytic steps that gluconeogenesis must bypass, and which enzymes bypass them?
  5. List the five key enzymes involved in regulating gluconeogenesis.
  6. How does acetyl-CoA regulate the pyruvate node, and why does this mean fasting stimulates gluconeogenesis?
  7. Describe how glucagon and insulin oppositely regulate pyruvate kinase and PEPCK.
  8. What are the red (inhibitor) and green (activator) regulators of PEPCK transcription listed on the promoter-region slide?
  9. Describe the FOXO/Akt mechanism by which insulin blocks PEPCK and G6Pase transcription.
  10. How do insulin and glucagon each regulate PFK2, and what is the downstream effect on fructose-2,6-bisphosphate?
  11. Explain how fructose-2,6-bisphosphate acts as an allosteric switch between glycolysis and gluconeogenesis.
  12. List three situations in which gluconeogenesis capacity is impaired, and three in which it is overactive.
  13. Explain why insulin resistance leads to excess hepatic glucose production in Type 2 diabetes.
  14. Explain the biochemical mechanism by which alcoholism impairs gluconeogenesis and can cause hypoglycaemia.
  15. Name and order the four phases of the metabolic response to injury, with their approximate timeframes.
  16. Which hormones/mediators are elevated in which phases of the metabolic response to injury?
  17. Describe how blood glucose, insulin, glucagon, and fuel oxidation (glucose, fatty acid, protein) each change from normal to injury to sepsis.
  18. List the features of the catabolic phase and its contributing factors.
  19. What did the burn-patient glucose tolerance data show across convalescence, and what does it indicate?
  20. A patient with a chronic illness caused by trauma shows both elevated insulin and elevated glucagon alongside high blood glucose and increased fatty acid/protein oxidation. What does this pattern indicate, and why?
  21. Describe the coordinated roles of liver, muscle, and adipose tissue in supplying and using fuels during the stress/injury response.
  22. What is the Warburg effect, and what metabolic features characterise it in tumour cells?
  23. A chronic alcoholic presents hypoglycaemic after a period of not eating. Using the biochemistry of gluconeogenesis, explain the likely mechanism.
  24. Integrative: Compare the roles of glucagon and cortisol in fasting-state gluconeogenesis versus the catabolic phase of the trauma response — what do they have in common?

Close the note. From memory, draw out the full gluconeogenesis pathway from pyruvate to glucose, marking both bypass steps, the three precursor entry points, and the enzymes/hormones that regulate each bypass, then check against The gluconeogenic pathway and the two bypasses.

Close the note. From memory, write out the inter-organ metabolic response to trauma (liver, muscle, adipose tissue) including which fuels/precursors move between them, then check against Inter-organ coordination during stress and injury.

Answers

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