HbA1c and insulin: the pathway in the body · Biomarker & Laboratory Analysis

This page shows the biochemical pathway behind the laboratory value HbA1c: which stations follow one another, which enzymes carry out each step and which cofactors they use. Every statement has a source. The page describes general textbook knowledge and says nothing about any individual person.

In brief

HbA1c is haemoglobin to which glucose has become firmly attached without an enzyme. Because red blood cells circulate for several weeks, its share reflects the glucose level over that time; insulin controls how much glucose cells absorb. Insulin moves GLUT4 into the membrane.

The pathway step by step

Each station states what the compound does there. Three signs: ↑ supplies — builds up or makes available · ↓ depletes — inhibits, consumes or withholds · ↕ both, depending on amount. Behind it stands what the statement rests on: established physiology, observed in studies, or contested. The signs do not grade; they name the direction.

1. Carbohydrates → Glucose in blood Digestive enzymes From the gut, glucose travels in the blood to all tissues. The liver also releases or absorbs glucose, smoothing out the swings between meals. If a lot of it stays in the blood, it attaches to proteins more often. Source 7↑ supplies Glucose in the blood is the shared fuel of all tissues; the brain relies on it particularly. The liver keeps the amount close together between meals. established physiology Source 7
   ⚖ When the balance tips

   too much — If a lot of glucose stays in the blood for longer, it attaches more often to proteins without an enzyme, including haemoglobin; the share of HbA1c then grows with it.

   too little — If there is little glucose in the blood, the liver releases glucose from glycogen and new synthesis, and the beta cells release less insulin.

   established physiology · Source 2, 1, 7, 4

2. Glucose in blood → Insulin Glucokinase · ATP Beta cells of the pancreas absorb glucose. Glucokinase converts it; the more ATP this produces, the more insulin the cells release. Insulin lets muscle and fat cells absorb glucose. Source 4↑ supplies Insulin is the signal to store: it lets muscle and fat cells absorb glucose, has the liver build glycogen and slows the liver's release of glucose into the blood. established physiology Source 5, 4
   ⚖ When the balance tips

   too much — If a lot of insulin is released, the cells absorb glucose quickly and the amount in the blood falls; the liver then holds back its glucose.

   too little — If there is little insulin, little GLUT4 reaches the surface, the liver keeps releasing glucose, and glucose stays in the blood longer.

   established physiology · Source 5, 6

3. Insulin → Insulin receptor Insulin binds to its receptor from the outside. The receptor is itself an enzyme: it attaches phosphate groups to itself and to proteins inside the cell, passing the signal on. If it is passed on weakly, more insulin is needed. Source 5↑ supplies The receptor translates insulin into a signal inside the cell. Via IRS proteins and PI3K it sets glucose uptake and the build-up of glycogen, fat and protein in motion. established physiology Source 5
   ⚖ When the balance tips

   too much — If the signal stays on for a long time, the cell damps it itself: it attaches inhibitory phosphate groups to the IRS proteins and pulls receptors in from the surface.

   too little — If the signal is passed on weakly, more insulin is needed for the same glucose uptake.

   established physiology · Source 5

4. Insulin receptor → GLUT4 in the membrane PI3K, Akt · ATP Via the PI3K and Akt signalling chain, vesicles carrying the transporter GLUT4 move to the cell surface. Only then can glucose flow into muscle and fat cells. Muscle work also brings GLUT4 to the surface. Source 6, 5↑ supplies GLUT4 lets glucose flow down its gradient into muscle and fat cells. Muscle work also brings GLUT4 to the surface, by a separate route without insulin. established physiology Source 6
   ⚖ When the balance tips

   too much — If many GLUT4 sit in the membrane, glucose flows out of the blood quickly; the pace is then set by turnover inside the cell.

   too little — If few GLUT4 reach the surface, less glucose flows into muscle and fat, and it stays in the blood longer.

   established physiology · Source 6, 5

5. GLUT4 in the membrane → Glucose in the cell Hexokinase · ATP Inside the cell, hexokinase immediately attaches a phosphate group. The glucose is then either assembled into glycogen or broken down in glycolysis. The phosphate group holds it inside the cell. Source 7↑ supplies Inside the cell, glucose supplies ATP and building blocks via glycolysis. The attached phosphate group holds it in place so that it can no longer leave the cell. established physiology Source 7
   ⚖ When the balance tips

   too much — If more glucose arrives than the cell breaks down, it fills the glycogen stores; once these are full, the liver converts the rest into fat.

   too little — If little glucose arrives, muscle and liver draw on their glycogen, and the cells use more fatty acids as fuel.

   established physiology · Source 7

6. Glucose in red cells → Schiff base no enzyme Glucose attaches to an amino group of haemoglobin without any enzyme. This first bond, called an aldimine or Schiff base, is loose and easily comes apart again. With little glucose, it mostly comes apart again. Source 1↕ both, depending on amount The Schiff base forms and comes apart again: when there is a lot of glucose, more of it forms; when there is little, more of it dissolves. It therefore follows the glucose level quickly in both directions. established physiology Source 1
   ⚖ When the balance tips

   too much — If there is a lot of glucose, more Schiff bases form, and more of them can rearrange into the fixed form.

   too little — If there is little glucose, the loose bonds come apart again before they become fixed.

   established physiology · Source 1

7. Schiff base → HbA1c Amadori rearrangement Part of the loose compound slowly rearranges (Amadori rearrangement) and becomes fixed. This form is called HbA1c. It no longer comes apart but stays on the haemoglobin. In this way it records the glucose level of the past weeks. Source 1, 2↓ depletes The fixed attachment occupies an amino group of haemoglobin permanently and so records the glucose level over the lifetime of the blood cell. On other long-lived proteins, glycation can alter structure and function. established physiology Source 1, 2
   ⚖ When the balance tips

   too much — If a lot of glucose stays in the blood for a long time, more haemoglobin molecules become firmly glycated; over further steps, Amadori products can give rise to advanced glycation end products.

   too little — If there is little glucose over weeks, few fixed bonds form and the share of HbA1c stays small.

   established physiology · Source 2, 1, 3

8. HbA1c → Breakdown in the spleen Red blood cells are broken down after a number of weeks, and the bound HbA1c with them. Its share in the blood therefore reflects the period in which the cells were in circulation. If the cells live longer, the share turns out higher. Source 3↓ depletes Breakdown removes the oldest red blood cells and their HbA1c with them. The lifespan of the cells determines how long glucose can attach, and so helps set the share. established physiology Source 3
   ⚖ When the balance tips

   too much — If red blood cells are broken down earlier, the remaining ones are younger on average and carry less HbA1c at the same glucose level.

   too little — If red blood cells live longer, there is more time for attachment, and the share of HbA1c turns out higher at the same glucose level.

   established physiology · Source 3

Further stations

• Carbohydrates — from food Starch and sugar from food are broken down in the gut into simple sugars, mainly glucose. They supply the fuel glucose. Source 7↑ supplies Carbohydrates supply the glucose that goes into the cells as fuel. What is not needed straight away is stored by liver and muscle as glycogen. established physiology Source 7
  ⚖ When the balance tips

  too much — If more glucose arrives than the cells use and store as glycogen, the liver converts the excess into fatty acids.

  too little — If little carbohydrate arrives, the liver releases glucose from its glycogen and then makes new glucose from lactate, glycerol and amino acids.

  established physiology · Source 7

• Haemoglobin — protein in red blood cells Haemoglobin fills the red blood cell and carries oxygen. Its protein part offers free amino groups, among them the valine at the very start of the two β chains. Glucose attaches to these sites. Source 1, 2↑ supplies Haemoglobin binds oxygen in the lungs and releases it in the tissues. Its free amino groups are at the same time the sites to which glucose can attach. established physiology Source 1, 2
  ⚖ When the balance tips

  too much — More haemoglobin offers more binding sites; the share of HbA1c, however, depends on the amount of glucose and the lifespan of the cells, not on the amount of haemoglobin.

  too little — If there is little haemoglobin and red blood cells are replaced faster, they are younger on average and have had less time to bind glucose.

  established physiology · Source 3, 2

• Glucose in red cells — via GLUT1, without insulin Red blood cells absorb glucose through the transporter GLUT1. This route needs no insulin; inside, roughly the same level is reached as in the surrounding blood. So the level inside directly follows that in the blood. Source 2↑ supplies Without an insulin gate, glucose in the red blood cell directly follows the amount in the blood. It is the substance that attaches to haemoglobin inside. established physiology Source 2
  ⚖ When the balance tips

  too much — If there is a lot of glucose in the blood, it rises to the same degree in the red blood cell, and more of it meets haemoglobin.

  too little — If there is little glucose in the blood, there is little inside too, and bonds to haemoglobin form less often.

  established physiology · Source 2, 1

Cofactors in this pathway

• Zinc — Two zinc ions hold six insulin molecules together in the storage granules of the beta cell; this is how it is stored Source 8In the ORY catalogue as a laboratory value: Zink
• Magnesium — Accompanies ATP in kinases such as glucokinase and the insulin receptor; with little of it, they work more slowly Source 9In the ORY catalogue as a laboratory value: Magnesium
• Potassium — When the ATP-dependent potassium channels of the beta cell close, insulin release begins, via depolarisation Source 4In the ORY catalogue as a laboratory value: Kalium (intrazellulär)
• Calcium — Flows into the beta cell and triggers the release of insulin granules; without calcium influx there is no release Source 4In the ORY catalogue as a laboratory value: Calcium (intrazellulär)
• ATP — Formed as the beta cell breaks down glucose, and closes its potassium channels; the more ATP, the more insulin Source 4

Sources

1. Bunn HF, Higgins PJ. Reaction of monosaccharides with proteins: possible evolutionary significance. Science 1981 · PubMed 12192669
2. Shin A, Connolly S et al. Protein glycation in diabetes mellitus. Adv Clin Chem 2023 · PubMed 36858645
3. Xu Y, Bergenstal RM et al. Addressing shortfalls of laboratory HbA(1c) using a model that incorporates red cell lifespan. Elife 2021 · PubMed 34515636
4. Rorsman P, Ashcroft FM. Pancreatic β-Cell Electrical Activity and Insulin Secretion: Of Mice and Men. Physiol Rev 2018 · PubMed 29212789
5. Saltiel AR. Insulin signaling in health and disease. J Clin Invest 2021 · PubMed 33393497
6. Klip A, McGraw TE et al. Thirty sweet years of GLUT4. J Biol Chem 2019 · PubMed 31175156
7. Rui L. Energy metabolism in the liver. Compr Physiol 2014 · PubMed 24692138
8. Li YV. Zinc and insulin in pancreatic beta-cells. Endocrine 2014 · PubMed 23979673
9. de Sousa Melo SR, Dos Santos LR, da Cunha Soares T et al. Participation of Magnesium in the Secretion and Signaling Pathways of Insulin: an Updated Review. Biol Trace Elem Res 2022 · PubMed 35666386

Related pathways

• Iron and ferritin — haemoglobin
• Vitamin D — Zink, Magnesium
• Calprotectin — Zink, Calcium (intrazellulär)
• Estradiol — Zink, Magnesium
• GABA, glutamate and glutamine — Magnesium, Kalium (intrazellulär)

As of 2026-09-16. Draft written by Claude to schema v2; sources checked in PubMed; expert review pending
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