DKA vs HHS pathophysiology: why only one makes acid
Both crises are hyperglycaemic and dehydrated, yet only diabetic ketoacidosis produces acid. The difference is how much insulin is left.
Explain why absolute insulin deficiency causes ketoacidosis in DKA, while residual insulin in HHS prevents ketosis but allows extreme hyperglycaemia and hyperosmolality.
The short version
- DKA is absolute or severe relative insulin deficiency with a surge of counter-regulatory hormones, so lipolysis, ketone bodies and a high anion gap metabolic acidosis follow.
- HHS has residual insulin: enough to restrain lipolysis and ketogenesis, not enough to control glucose, so glucose and osmolality climb without much acid.
- Anion gap = Na⁺ − (Cl⁻ + HCO₃⁻); above 12 is high.
- Effective osmolality = 2 × Na⁺ + glucose / 18; the classic HHS thresholds are glucose above 600 mg/dL and effective osmolality above 320 mOsm/kg.
- Both crises cause an osmotic diuresis and deep volume loss.
DKA vs HHS pathophysiology: two dehydrated patients, one acidosis
A 19-year-old with type 1 diabetes has run out of insulin. She breathes deep and fast, her breath smells fruity, and her glucose is 480 mg/dL. A 78-year-old with type 2 diabetes is drowsy and very dry, with a glucose of 910 mg/dL and almost no acidosis.
Both are dehydrated and both are hyperglycaemic, so why does only one of them make acid? The answer sits in the pathophysiology of DKA vs HHS: how much insulin remains decides whether fat is broken down into ketone bodies.[1][2]
Insulin's two jobs and the hormones that oppose it
Insulin has two jobs. It drives glucose into cells and shuts down glucose output from the liver, and it restrains fat breakdown in adipose tissue.[2]
Opposing it are the counter-regulatory hormones: glucagon, cortisol, catecholamines and growth hormone.[1][2]
In diabetic ketoacidosis (DKA), insulin is absent or severely deficient, and those opposing hormones surge.[1][2]
DKA: glucose rises, fat breaks down, ketones form
The insulin to glucagon ratio collapses. The liver makes glucose by gluconeogenesis and glycogenolysis, while muscle and fat cannot take glucose up. That is the hyperglycaemia.[1][2]
Now the fat. With no insulin brake, adipose tissue breaks triglyceride down into free fatty acids. The liver oxidises them to acetyl coenzyme A, and because the citric acid cycle cannot keep up, it turns that into ketone bodies.[1][2]
The ketone bodies are acetoacetate and beta-hydroxybutyrate, and both are strong acids.[2]
- Insulin falls, counter-regulatory hormones surgeThe insulin to glucagon ratio collapses.
- Glucose risesGluconeogenesis and glycogenolysis in the liver, poor uptake in muscle and fat.
- LipolysisAdipose triglyceride is broken down into free fatty acids.
- KetogenesisThe liver makes acetyl coenzyme A, then acetoacetate and beta-hydroxybutyrate.
Bicarbonate falls: the anion gap and Kussmaul breathing
Each ketoacid gives up a hydrogen ion, bicarbonate buffers it, and bicarbonate falls while the ketoanions pile up. That is a high anion gap metabolic acidosis.[1][2]
above 12 is high
- Na⁺ 138, Cl⁻ 98, HCO₃⁻ 6
- Cl⁻ + HCO₃⁻ = 98 + 6 = 104
- 138 − 104 = 34, a high anion gap
The lungs compensate with deep, fast Kussmaul breathing, and exhaled acetone gives the fruity smell.[1]
Glucose spills: osmotic diuresis and volume loss
Once glucose passes the renal threshold, about 180 to 200 mg/dL, it spills into the urine. That is an osmotic diuresis: water and electrolytes pour out, and volume falls.[1][2][4]
HHS: residual insulin holds back ketosis
In the hyperosmolar hyperglycaemic state (HHS) there is residual insulin. It cannot control glucose, but it is enough to hold back lipolysis and ketogenesis.[1][4]
So glucose keeps climbing, from liver output and poor uptake, but there are few ketones and little acid.[1][3]
| Feature | DKA | HHS |
|---|---|---|
| Insulin | Absent or nearly absent | Residual, enough to restrain lipolysis |
| Lipolysis and ketones | Unrestrained, ketone bodies form | Held back, few ketones |
| Acid-base | High anion gap metabolic acidosis | Little acid |
| Time course | Hours to a few days | Days to weeks |
| Both | Osmotic diuresis and deep volume loss | Osmotic diuresis and deep volume loss |
DKA can develop in hours to a few days, while HHS builds over days to weeks.[1]
Put simply, in HHS the liver still overproduces glucose and tissues still take it up poorly, so glucose keeps climbing. What residual insulin does is restrain adipose tissue from releasing free fatty acids and restrain ketogenesis in the liver, so few ketone bodies are made.[1][4]
Thresholds and effective osmolality
The classic HHS thresholds, still the usual exam numbers, are glucose above 600 mg/dL and effective osmolality above 320 mOsm/kg.[3][4]
Na⁺ in mEq/L, glucose in mg/dL, result in mOsm/kg
- Na⁺ 148, glucose 810
- 2 × 148 = 296
- 810 / 18 = 45
- 296 + 45 = 341, about 341 mOsm/kg
That hyperosmolality clouds cognition, and HHS mortality runs five to tenfold higher than in treated DKA.[1]
Practice question
Original · USMLE styleA 74-year-old man with type 2 diabetes mellitus is brought to the emergency department by his daughter after 10 days of worsening thirst, polyuria and drowsiness. His blood pressure is 92/58 mmHg, pulse is 112/min and respirations are 16/min and unlabored. Mucous membranes are dry. Laboratory studies show:
| Glucose | 1,120 mg/dL |
|---|---|
| Sodium | 141 mEq/L |
| Chloride | 106 mEq/L |
| Bicarbonate | 24 mEq/L |
| Arterial pH | 7.36 |
| Serum beta-hydroxybutyrate | 0.4 mmol/L (reference below 0.6) |
| Calculated effective serum osmolality | 344 mOsm/kg |
Common questions
What is the difference between DKA and HHS?
DKA is absolute or severe relative insulin deficiency with surging counter-regulatory hormones, so lipolysis, ketones and a high anion gap acidosis follow. HHS has residual insulin that restrains lipolysis and ketogenesis, so there is extreme glucose and osmolality with few ketones.
Why does DKA cause a high anion gap metabolic acidosis?
Ketone bodies (acetoacetate and beta-hydroxybutyrate) are strong acids. Bicarbonate buffers their hydrogen ions and falls, while the ketoanions accumulate.
How is effective osmolality calculated?
Effective osmolality = 2 × Na⁺ + glucose / 18. With sodium 148 and glucose 810, it is 296 + 45, about 341 mOsm/kg.
Why is there no ketoacidosis in HHS?
Residual insulin is enough to restrain adipose lipolysis and so hepatic ketogenesis, but not enough to control glucose.
Which crisis develops faster?
DKA can develop in hours to a few days. HHS builds over days to weeks.
Transcript
Read the full narration, by chapter685 words
0:00The case: two dehydrated patients, only one makes acid
A 19-year-old with type one diabetes has run out of insulin. She breathes deep and fast, her breath smells fruity, and her glucose is 480. A 78-year-old with type two diabetes is drowsy and bone dry, with a glucose of 910 and almost no acidosis. Both are dehydrated, both are hyperglycaemic. So why does only one of them make acid? Today: why absolute insulin lack causes ketoacidosis, and why a little insulin prevents it. Insulin has two jobs.
0:33Insulin's two jobs and the counter-regulatory hormones
It drives glucose into cells and shuts down glucose output from the liver, and it restrains fat breakdown in adipose tissue. Opposing it are the counter-regulatory hormones: glucagon, cortisol, catecholamines and growth hormone.
0:51DKA: glucose rises, fat breaks down, ketones form
In diabetic ketoacidosis, or DKA, insulin is absent or nearly absent, and those opposing hormones surge. The insulin to glucagon ratio collapses, so the liver makes glucose by gluconeogenesis and glycogenolysis, while muscle and fat cannot take glucose up. That is the hyperglycaemia. Now the fat. With no insulin brake, adipose tissue breaks triglyceride down into free fatty acids. The liver oxidises them to acetyl coenzyme A, and because the citric acid cycle cannot keep up, it turns that into ketone bodies. The ketone bodies are acetoacetate and beta-hydroxybutyrate, and both are strong acids. Each acid gives up a hydrogen ion,
1:39Bicarbonate falls: the anion gap and Kussmaul breathing
bicarbonate buffers it, and bicarbonate falls while the ketoanions pile up. That is a high anion gap metabolic acidosis. The anion gap is sodium minus both chloride and bicarbonate, and above 12 is high. Take sodium 138, chloride 98, bicarbonate six. The gap is 34. The lungs compensate with deep, fast Kussmaul breathing, and exhaled acetone gives the fruity smell. Meanwhile, once glucose passes the renal threshold,
2:13Glucose spills: osmotic diuresis and volume loss
about 180 to 200 milligrams per decilitre, it spills into the urine. That is an osmotic diuresis: water and electrolytes pour out, and volume falls. In the hyperosmolar hyperglycaemic
2:28HHS: residual insulin holds back ketosis
state, or HHS, there is residual insulin. It cannot control glucose, but it is enough to hold back lipolysis and ketogenesis. So glucose keeps climbing, from liver output and poor uptake, but there are few ketones and little acid. HHS builds over days to weeks,
2:49Time course, thresholds and effective osmolality
while DKA can develop in hours to a few days. The classic thresholds are glucose above 600 milligrams per decilitre, and effective osmolality above 320. Effective osmolality is two times sodium, plus glucose over 18. Sodium 148 and glucose 810: 296 plus 45, about 341.
3:15Why HHS is the more dangerous crisis
That hyperosmolality clouds cognition, and HHS mortality runs five to tenfold higher than in treated DKA. Same diabetes, same dehydration. The difference is how much insulin is left.
3:32Your turn: a practice question
Your turn. A 74-year-old man with type two diabetes is brought in after 10 days of thirst, polyuria and drowsiness. His blood pressure is 92 over 58, his pulse is 112, and he is breathing quietly. Glucose is 1120 milligrams per decilitre. Sodium 141, chloride one oh six, bicarbonate 24. Arterial pH 7.36, and beta-hydroxybutyrate 0.4 mmol/L. Which of the following best explains the absence of ketoacidosis in this patient? A, absent release of counter-regulatory hormones. B, impaired hepatic gluconeogenesis. C, increased renal excretion of ketoacids. D, residual insulin sufficient to restrain lipolysis. E, increased peripheral glucose uptake from hyperosmolality. Pause here and decide.
4:35The answer, one option at a time
A is out: even with those hormones present, ketogenesis is held back while some insulin remains. B is out: the liver is overproducing glucose in HHS, which is part of why glucose is so high. C is out: osmotic diuresis removes glucose and water, but it does not stop ketoacid production, and no ketoacids are being made here. E is out: hyperosmolality does not drive glucose into cells; peripheral uptake is reduced in HHS. So the answer is D. Enough insulin remains to restrain lipolysis and ketogenesis, but not enough to control the glucose.
5:22Recap pocket card and what comes next
Three things to keep. One: DKA is absolute insulin lack with surging counter-regulatory hormones, so lipolysis, ketones and a high anion gap acidosis. Two: HHS has residual insulin, so no ketosis but extreme glucose and osmolality. Three: both cause an osmotic diuresis and deep volume loss. Next, the acid-base side of DKA: the anion gap, and the hyperchloraemic phase during treatment.
Sources
Numbers in the text, e.g. [1], point here- Hyperglycaemic crises in adults with diabetes: a consensus report, Diabetologia 2024. pmc.ncbi.nlm.nih.gov/articles/PMC11343900/
- Diabetic ketoacidosis review, 2026. pmc.ncbi.nlm.nih.gov/articles/PMC13284666/
- Hyperosmolar hyperglycemic state, PMC. pmc.ncbi.nlm.nih.gov/articles/PMC12639725/
- Hyperglycemic crises review, PMC. pmc.ncbi.nlm.nih.gov/articles/PMC12547648/
The practice question is original and its patient is synthetic. Every fact is checked against the sources above in independent accuracy reviews. Always follow your local guidelines and your own laboratory’s ranges.
Image credits. Illustrations: Servier Medical Art (smart.servier.com), CC BY 4.0 (https://creativecommons.org/licenses/by/4.0/), adapted (cropped, recoloured, outlined): glucometer, young woman, elderly person, lungs, syringe, islet, adipocyte, liver, mitochondria, nephron, urine jar, brain. The diagrams, slips, cards and all handwriting are drawn in code (original). No AI-generated teaching images.
Corrections. None so far. Spotted an error? Email info@medservatory.com with the lesson code MS-S1-ENDO-002.
For exam study only, not medical advice. Read the medical disclaimer.
In this series
Playlist on YouTube- EP 01Hypothalamic-pituitary axes and feedback: primary, secondary, tertiary5:05
- EP 02Primary vs secondary endocrine disorders: paired hormone levels5:13
- EP 03Insulin secretion in the beta cell: from glucose to granule5:06
- EP 04Insulin vs glucagon signalling: receptors and effects5:19
- EP 05DKA vs HHS pathophysiology: why only one makes acid5:58
- EP 06Diabetes drugs by mechanism: where each class acts5:58
- EP 07Thyroid hormone synthesis, step by step5:14
- EP 08Calcium homeostasis: PTH, vitamin D and calcitonin5:28
- EP 09Adrenal steroidogenesis: zones, enzymes and the 17α-hydroxylase fork5:29
- EP 10Congenital adrenal hyperplasia: three enzymes, three patterns5:44
- EP 11Cushing syndrome: the dexamethasone suppression test and ACTH5:29
- EP 12Primary hyperaldosteronism: high aldosterone, low renin5:27
- EP 13SIADH vs diabetes insipidus: central vs nephrogenic DI5:44
- EP 14MEN1, MEN2A and MEN2B: match the gene to its tumours5:13