Do any cells make both GIP and GLP-1?

Yes - the figure quoted is that more than 80% of labelled cells make only one, which leaves a minority making both. Those dual-positive cells are part of why the two populations look transcriptomically close.

Is GIP secreted more proximally than GLP-1?

The classical distribution places K cells more proximally and L cells more distally, and the density gradients are real. The point of this work is that the sensing machinery is largely shared regardless of where the cells sit.

Could a drug raise GLP-1 without raising GIP?

The receptors that differ between the cell types make it conceivable, and that is what the review suggests. Conceivable is not demonstrated, and no such agent is licensed.

Does this affect how tirzepatide should be understood?

Not directly - tirzepatide acts at the receptors, not on secretion. It is relevant context for the wider argument about whether GIP signalling should be increased or blocked, because it shows the secretion side is a separate and largely unexplored lever.

GLP-1 & Incretin Science

Two Nearly Identical Cells Releasing Opposite-Tempered Hormones

JMWritten & reviewed by Jack Muncaster · Founder, UK PeptidesLast reviewed 2026-08-242 cited sources

GIP is released by K cells and GLP-1 by L cells. More than 80% of labelled cells produce only one of the two, but the populations are transcriptomically close and share their principal glucose-sensing mechanism, differing mainly in other lipid sensors.

Key facts

K cell hormone: GIP
L cell hormone: GLP-1
Cells producing only one hormone: More than 80% in labelled models
Shared glucose sensor: SGLT1, in both
Shared fatty acid receptors: FFAR1 (GPR40) and FFAR4 (GPR120)
Documented for GLP-1 specifically: GPR119, FFAR2, FFAR3
Selectively inhibits GIP: Endocannabinoid receptor type 1 agonists
Implication drawn by the authors: The two secretions might be modulated differentially

Why the distinction is usually drawn too sharply

The standard account presents K cells and L cells as separate populations in separate parts of the gut releasing separate hormones - K cells proximally releasing GIP, L cells distally releasing GLP-1. The reality Reimann and Gribble describe is messier and more interesting. In human tissue and in murine models expressing fluorescent markers under the control of the two hormone promoters, the majority of labelled cells - more than 80% - do produce only one of the two hormones, so the distinction is real. But transcriptomic analysis shows a close relationship between small intestinal K and L cells, and the remainder produce both.

They sense glucose the same way

The glucose-sensing mechanism appears similar in both cell types, with a predominant role for electrogenic uptake through SGLT1 in each. That is a substantial shared component: the stimulus that most obviously accompanies a meal is read by the same machinery in both populations. It also means that anything acting on intestinal glucose handling engages both incretin-secreting populations rather than one, which is worth knowing when reasoning about interventions at that level.

And they share the main fat receptors

Both cell types produce FFAR1 (GPR40) and FFAR4 (GPR120), the long-chain fatty acid receptors. So the two principal macronutrient signals - glucose and long-chain fat - are detected by the same sensors in both populations. On the sensing side, K cells and L cells are more alike than the tidy proximal-versus-distal story suggests.

Where they differ, and why it is the interesting part

The differences sit in the other lipid-sensing receptors. GPR119 and FFAR2/3 have clearly documented roles in GLP-1 secretion, while agonists for the endocannabinoid receptor type 1 have been found to show largely selective inhibition of GIP secretion. So there are handles that move one hormone and not the other - in both directions. The authors' conclusion is exactly this: although the populations overlap and share key nutrient-sensing mechanisms, subtle differences might be exploited to differentially modulate GIP or GLP-1 secretion.

Why that matters given how this field has gone

The most unresolved question in incretin pharmacology is what to do about GIP. Tirzepatide agonises the GIP receptor alongside GLP-1 and works extremely well. Other programmes have pursued GIP receptor antagonism alongside GLP-1 agonism and also report substantial effects. The debate is conducted almost entirely at the level of receptors. This work points out that the same question exists one step earlier, at the level of secretion: it may be possible to change how much of each incretin is released, not only what happens when it binds. Nothing has been made of that observation commercially, and it remains a stated possibility rather than a demonstrated strategy.

What this does not change

The therapeutic agents in use are receptor agonists, not secretagogues, and everything about their exposure profile differs from endogenous secretion. Understanding that K and L cells are close relatives explains the physiology and does not alter how the drugs work. None of the compounds discussed here is supplied on this site, and licensed incretin medicines are prescription products that research material is not a version of.

Quick reference

	K cell	L cell
Hormone	GIP	GLP-1
Glucose sensing	SGLT1, electrogenic	SGLT1, electrogenic
FFAR1 / FFAR4	Present	Present
GPR119	Less documented	Documented role in secretion
FFAR2 / FFAR3	Less documented	Documented role in secretion
CB1 agonists	Selectively inhibit secretion	Not the main target

Extended research context

The GLP-1 & Incretin Science deep dive

Deep dive: the two routes to a bigger effect

Every compound trying to beat GLP-1 alone has taken one of two routes. The first adds more receptors from the same hormone family — GIP in tirzepatide, GIP and glucagon in retatrutide. The second adds a non-incretin satiety hormone, which in practice means amylin: CagriSema combines cagrilintide with semaglutide, and amycretin engages both receptors from one molecule. Both routes work, because they recruit signalling pathways that do not fully overlap. Neither has escaped the constraint that binds all of them, which is that gastrointestinal tolerability worsens as effect size grows.

Deep dive: why a percentage is not a result

The most-quoted numbers in this field are the least comparable. REDEFINE 1 reported 22.7% and 20.4% for the same compound in the same trial — the first among participants who adhered to treatment, the second across everyone randomised. TRIUMPH-1 reported 28.3% in an uncomplicated obesity population while TRIUMPH-3 reported up to 22.6% in adults with established cardiovascular disease, using the same compound. Before any two figures can be compared they have to match on estimand, population, duration, comparator and whether the number is placebo-adjusted. Most published comparisons match on none of them.

Deep dive: what happens after the trial stops

Every headline figure describes weight while treatment continues. The STEP-1 extension found that a year after semaglutide was stopped, participants had given back roughly two-thirds of what they lost, moving from 17.3% mean reduction to a net 5.6% — though average weight remained below baseline and nearly half stayed at least 5% down. Meta-analysis puts regain at around 0.8 kg per month. This is why maintenance studies such as TRIUMPH-6 matter more to the field's future than another two points of peak reduction.

Research applications

▸Comparing incretin and amylin compounds on a like-for-like basis
▸Interpreting estimands, thresholds and placebo-adjusted figures in trial reports
▸Tracking the obesity pipeline across sponsors and jurisdictions
▸Understanding receptor pharmacology behind GLP-1, GIP, glucagon and amylin
▸Distinguishing licensed medicines from investigational compounds

Handling checklist

✓Identify which estimand a quoted percentage comes from before citing it
✓Check the trial population and baseline BMI against the comparison you are making
✓Confirm the duration and whether the reduction curve had plateaued
✓Read discontinuation rates alongside efficacy figures
✓Verify every NCT identifier against ClinicalTrials.gov rather than secondary reporting

Common research-handling mistakes

Learnt from thousands of researcher orders across our UK labs.

✗ Comparing headline percentages across different trials

Fix: Population, duration, estimand and comparator all differ; the numbers are not interchangeable.

✗ Quoting the larger of two figures from the same trial

Fix: Name the estimand. Efficacy and treatment-policy answer different questions.

✗ Treating peak reduction as a durable outcome

Fix: Substantial regain follows cessation across the class; peak figures describe a maintained state.

✗ Assuming an oral route means a weaker mechanism

Fix: Route and receptor count are independent. Orforglipron is weaker because it hits one receptor, not because it is a tablet.

✗ Reading investigational compounds as available treatments

Fix: Most of this pipeline holds no authorisation anywhere; mazdutide is approved only in China.

Continue researching

Peer-reviewed guides, comparators and matched reference materials.

Frequently asked questions

Do any cells make both GIP and GLP-1?: Yes - the figure quoted is that more than 80% of labelled cells make only one, which leaves a minority making both. Those dual-positive cells are part of why the two populations look transcriptomically close.
Is GIP secreted more proximally than GLP-1?: The classical distribution places K cells more proximally and L cells more distally, and the density gradients are real. The point of this work is that the sensing machinery is largely shared regardless of where the cells sit.
Could a drug raise GLP-1 without raising GIP?: The receptors that differ between the cell types make it conceivable, and that is what the review suggests. Conceivable is not demonstrated, and no such agent is licensed.
Does this affect how tirzepatide should be understood?: Not directly - tirzepatide acts at the receptors, not on secretion. It is relevant context for the wider argument about whether GIP signalling should be increased or blocked, because it shows the secretion side is a separate and largely unexplored lever.

Primary sources & clinical trials

Peer-reviewed research and registered trials from PubMed, ClinicalTrials.gov, PubChem, FDA and NIH. All links open in a new tab and point to the primary source, so every claim can be verified at origin.

Written and reviewed by

Jack Muncaster · Founder, UK Peptides

Jack founded UK Peptides in Manchester after repeatedly receiving research compounds with missing or recycled paperwork. He is responsible for supplier selection, batch release decisions and the content published in this research library. Every article here is sourced to primary literature and every product page to a signed third-party certificate.

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