Historical profile. Give a person glucose by mouth and their pancreas generally releases more insulin than it does when glucose is delivered intravenously to reproduce the same blood-glucose profile.
That difference is called the incretin effect, and it is one of the foundational biological principles behind modern GLP-1 medicines, from Ozempic to Mounjaro.
It is also an idea that scientists nearly abandoned.
In the early twentieth century, researchers suspected that the intestine might release chemical signals capable of stimulating pancreatic insulin secretion. Experiments produced contradictory results. By 1940, negative findings had cast such serious doubt on the hypothesis that research largely stopped for more than two decades.
The concept returned in the 1960s, when new methods made it possible to measure insulin directly in blood.
One of the scientists who subsequently helped turn that revived idea into a rigorous experimental field was Werner Creutzfeldt, a German physician whose research at the University of Göttingen helped establish how gut hormones influence insulin secretion in people with type 2 diabetes.
His most important work did not consist of discovering a drug or inventing a new hormone.
It consisted of asking increasingly precise questions about a biological effect that had remained poorly understood for decades.
In 1979, he argued that the gut hormone GIP could not fully explain the incretin effect. In 1986, his Göttingen colleagues demonstrated that the effect was substantially reduced in people with type 2 diabetes. In 1993, the group helped show that GLP-1 retained much of its insulin-stimulating activity even when another incretin hormone did not.
That sequence of discoveries helped establish the therapeutic rationale for an entire class of diabetes medicines.
This historical profile draws on Creutzfeldt’s published research, his own review of incretin history, and contemporary biographical accounts. It does not attribute invented quotations or undocumented experiments to him.
A Physician-Scientist in Göttingen
Werner Otto Carl Creutzfeldt was born on May 11, 1924, in Kiel, Germany, according to the obituary published in Digestion by gastroenterologist Burkhard Göke.
The Royal College of Physicians also identifies Kiel as his birthplace and records that he grew up in Berlin.
His father was Hans Gerhard Creutzfeldt, the neurologist associated with the identification of Creutzfeldt-Jakob disease. His brother, Otto Detlev Creutzfeldt, became a distinguished neurophysiologist.
Werner studied at the universities of Freiburg, Kiel and Tübingen, completing his medical doctorate at the Institute of Anatomy in Kiel in 1950.
His first scientific publication appeared in 1953 and examined pancreatic findings associated with diabetes mellitus and insulinoma, a tumor that can cause excessive insulin secretion.
That early interest in pancreatic biology would remain central to his career.
After qualifying as a university lecturer in Freiburg in 1957, Creutzfeldt spent time as a research fellow in Boston and St. Louis in 1959.
He returned to Germany and, in 1964, became professor of internal medicine at the University of Göttingen.
He remained there until 1992, turning down opportunities elsewhere and helping develop a research environment that produced influential work in diabetes and gastrointestinal endocrinology.
Creutzfeldt also served as editor-in-chief of the journal Digestion from 1979 to 1992.
His publications addressed subjects ranging from pancreatic hormone secretion and neuroendocrine tumors to gastrointestinal physiology and liver metabolism.
What connected much of that work was a fascination with chemical communication between organs.
The pancreas was not operating in isolation. The gut, nervous system and endocrine organs formed a coordinated network, and understanding that network required much more than measuring blood sugar alone.
It required understanding what happened between a meal entering the intestine and insulin appearing in the bloodstream.
The Incretin Idea That Nearly Died
The idea of a gut-derived signal affecting pancreatic secretion began long before Creutzfeldt’s career.
In 1902, William Bayliss and Ernest Starling demonstrated that a substance released by the intestine could travel through the blood and stimulate pancreatic digestive secretions.
That substance was secretin, one of the discoveries that established the modern concept of hormones.
Researchers soon began asking whether a similar chemical signal might stimulate the pancreas’s internal secretion, including the release of insulin.
Between 1906 and 1935, numerous investigators tested extracts prepared from intestinal tissue, attempting to determine whether those substances altered blood-glucose concentrations in animals or humans.
The results were contradictory.
Some experiments suggested an effect, while others failed to reproduce it.
In a historical review published in Regulatory Peptides in 2005, Creutzfeldt described how a series of negative dog experiments in 1940 persuaded influential researchers that the proposed incretin mechanism was questionable.
According to his account, the field then experienced more than twenty years of greatly reduced research activity.
The problem was partly technological.
Before reliable insulin assays, investigators often measured the possible hormonal effect indirectly through changes in blood sugar. Those changes could be influenced by multiple physiological processes.
The development of radioimmunoassay transformed the field by allowing researchers to measure circulating insulin with far greater specificity.
In 1964, studies by other investigators provided convincing evidence that oral glucose produced a greater insulin response than intravenous glucose when blood-glucose concentrations were appropriately matched.
This finding helped revive the incretin hypothesis.
The excess insulin response could not be explained simply by the amount of glucose circulating in the blood.
Something associated with glucose passing through the gastrointestinal tract was contributing to insulin secretion.
The incretin effect was not a discovery made once. It was a hypothesis tested, questioned and revived when scientists finally acquired better tools to measure it.
One leading candidate was gastric inhibitory polypeptide, or GIP, subsequently also known as glucose-dependent insulinotropic polypeptide.
Research during the 1970s established GIP as an important contributor to the insulin response after eating.
But an important question remained unanswered.
Was GIP responsible for the entire incretin effect, or was another intestinal hormone involved?
GIP Is Not the Only Incretin
In February 1979, Creutzfeldt published a review in Diabetologia titled The Incretin Concept Today.
The paper described the state of a rapidly developing field and placed incretin hormones within a larger physiological network linking the gastrointestinal tract and the pancreas.
Creutzfeldt called this network the enteroinsular axis.
GIP was the strongest established candidate among the chemically identified gastrointestinal hormones.
Yet experimental evidence suggested that it could not account for everything.
Creutzfeldt noted that administering antibodies directed against GIP only partially abolished the incretin effect.
If blocking GIP left part of the response intact, then GIP alone was insufficient to explain the phenomenon.
His conclusion was concise: GIP was important, but it was not the only incretin.
That distinction became important as researchers investigated peptides produced from the proglucagon gene.
Among those peptides was glucagon-like peptide-1, or GLP-1.
Creutzfeldt did not personally discover GLP-1. Its identification and recognition as an insulin-stimulating hormone involved several research groups and contributions from scientists including Svetlana Mojsov, Joel Habener and Jens Juul Holst.
Pivotal experimental demonstrations of GLP-1’s glucose-dependent insulin-stimulating activity appeared in 1987.
What made Creutzfeldt’s work important was the connection between this emerging hormone biology and the impaired insulin response seen in people with type 2 diabetes.
It was one thing to identify a peptide capable of stimulating insulin in experimental systems.
It was another to determine whether it could remain effective in humans whose glucose regulation was already severely disturbed.
That question would become the defining contribution of the Göttingen research program.
Measuring the Incretin Effect in Type 2 Diabetes
In January 1986, a Göttingen research group led by Michael Nauck, together with F. Stöckmann, R. Ebert and Werner Creutzfeldt, published an important study in Diabetologia.
The researchers examined 14 patients with type 2 diabetes and eight age- and weight-matched healthy participants.
Each participant received a 50-gram oral glucose load.
On a separate occasion, glucose was administered intravenously using an isoglycemic infusion designed to reproduce the blood-glucose profile observed after oral administration.
This comparison allowed the researchers to estimate how much of the insulin response was attributable to factors associated with glucose entering through the gastrointestinal tract rather than to circulating glucose alone.
In the healthy participants, incretin factors accounted for an estimated 72.8% of the integrated insulin response to oral glucose.
In participants with type 2 diabetes, the corresponding estimate was only 36.0%.
The difference was statistically significant.
Measurements of C-peptide, another indicator of pancreatic insulin secretion, supported the finding that the incretin contribution was substantially impaired in the diabetes group.
The study was small, with only 22 participants in total.
But it provided controlled human evidence that the normal relationship between oral nutrient intake and pancreatic insulin secretion was disrupted in type 2 diabetes.
It also suggested that simply measuring the amount of GIP released after glucose intake would not necessarily explain the loss of incretin action.
The question now became more specific.
Was the reduced incretin effect caused by the failure to release a hormone, the failure of pancreatic cells to respond to it, or a combination of mechanisms?
In January 1993, Nauck and colleagues, including Creutzfeldt, published a study in the Journal of Clinical Investigation comparing the effects of administered GIP and GLP-1 in nine people with relatively mild type 2 diabetes and nine matched healthy controls.
The participants received GIP, GLP-1 or placebo during experiments in which blood-glucose concentrations were held at a controlled elevated level.
Both incretin hormones stimulated insulin secretion.
However, the maximum insulin-stimulating response to GIP was 54% lower in the diabetes group than in the healthy control group.
GLP-1 behaved differently.
Participants with type 2 diabetes retained much of their insulin-secretory response to GLP-1, reaching 71% of the C-peptide response increments observed in healthy participants, without a statistically significant between-group difference in that measure.
GLP-1 also lowered glucagon concentrations in both groups, whereas GIP did not show the same effect in those experiments.
This was a crucial physiological distinction.
The diminished incretin effect in type 2 diabetes did not mean that every gut-hormone pathway had stopped working.
One pathway, involving GLP-1, remained responsive enough to be considered a potential therapeutic target.
A separate study published in August 1993 tested that possibility more directly.
This time, the researchers administered GLP-1(7-36 amide) intravenously to ten people with poorly controlled type 2 diabetes.
The participants had an average HbA1c of 11.6%, indicating markedly elevated blood-glucose concentrations over the preceding months.
Their average fasting plasma glucose concentration was approximately 13.1 mmol/L before treatment.
Within four hours of GLP-1 infusion, fasting plasma glucose fell to approximately 4.9 mmol/L, within the normal fasting range.
That normalization did not occur with placebo.
As glucose concentrations approached normal levels, insulin secretion returned toward baseline even though the GLP-1 infusion continued.
That observation supported an important property of GLP-1 physiology: its stimulation of insulin secretion depends strongly on the prevailing glucose concentration.
The response suggested a potential way to lower elevated blood sugar without continuously stimulating pancreatic insulin secretion to the same extent at normal glucose levels.
It did not establish that GLP-1 treatment could never cause hypoglycemia, or demonstrate long-term treatment benefits.
But the experiment helped establish that GLP-1 could produce a clinically meaningful glucose-lowering response in people with type 2 diabetes.
The important discovery was not simply that GLP-1 could stimulate insulin. It was that much of its activity remained available in patients whose normal incretin effect was impaired.
From an Infusion Bag to a Weekly Injection Pen
The Göttingen studies helped establish GLP-1’s therapeutic potential, but they did not produce a practical medicine.
Native GLP-1 is rapidly broken down in the circulation, principally by the enzyme dipeptidyl peptidase-4, or DPP-4.
Its circulating half-life is only about one to two minutes.
That makes the native hormone poorly suited to ordinary outpatient treatment without some method of extending its activity.
The 1993 experiment depended on a continuous intravenous infusion. A therapy requiring that arrangement would be impractical for routine long-term diabetes care.
Drug developers needed molecules that could reproduce useful GLP-1 receptor activity while remaining active long enough for patients to take them conveniently.
That challenge helped drive the development of DPP-4-resistant GLP-1 receptor agonists, longer-acting peptide analogs and molecular designs that slow drug clearance.
In April 2005, the U.S. Food and Drug Administration approved exenatide, marketed as Byetta, as a treatment for adults with type 2 diabetes.
It was the first approved GLP-1 receptor agonist in the United States.
Exenatide required twice-daily administration. Later treatments achieved once-daily and eventually once-weekly schedules.
Semaglutide, the molecule used in Ozempic and Wegovy, incorporates structural modifications that help protect against rapid degradation and extend its activity through albumin binding.
Grey Pepper previously explained those modifications in our article on semaglutide’s half-life and peptide engineering.
The story also took an unexpected turn with GIP.
Creutzfeldt’s group had demonstrated that GIP’s insulin-stimulating action was substantially impaired in people with type 2 diabetes.
Yet decades later, tirzepatide, the active compound in Mounjaro and Zepbound, successfully combined GIP receptor agonism with GLP-1 receptor agonism.
That development does not invalidate the earlier physiological experiments. Acute responses to native GIP in established diabetes are not the same as the effects of sustained treatment with an engineered dual-receptor agonist.
It demonstrates how far therapeutic design has moved beyond the experimental conditions of the original incretin studies.
Newer compounds combine GLP-1 and GIP activity with additional pathways, including glucagon receptor agonism.
Grey Pepper explored that approach in our explanation of retatrutide’s triple-agonist science.
The modern incretin field therefore extends far beyond Creutzfeldt’s original research questions.
It also depends on contributions from many other scientists.
The 1964 experiments that revived the incretin concept were performed by other research groups. GLP-1’s discovery and physiological characterization involved multiple laboratories. Many of the central human studies from Göttingen were led by Michael Nauck and his collaborators.
Creutzfeldt should not be credited as the sole discoverer of incretin biology or as the inventor of GLP-1 medicines.
His contribution was more specific and more interesting.
He helped build a research program that repeatedly asked whether gut hormones could account for the difference between normal insulin regulation and what happens in type 2 diabetes.
The 1979 review identified a gap in the prevailing explanation. The 1986 study quantified a physiological defect. The 1993 studies demonstrated that one hormonal pathway retained enough activity to offer a potential treatment strategy.
Those experiments were small and short. They did not demonstrate the long-term cardiovascular, metabolic or weight-loss benefits later established in large clinical trials of incretin medicines.
They did something more fundamental: they showed researchers where to look.
Werner Creutzfeldt died on August 30, 2006, at the age of 82, roughly sixteen months after the first GLP-1-based drug received U.S. approval.
He had lived to see the incretin concept move from a once-questioned hypothesis to a clinically useful pharmacological strategy.
Today, millions of people use medicines built around GLP-1 receptor activation, and researchers continue investigating how gut-derived signaling pathways can be modified to treat diabetes, obesity and related metabolic diseases.
The modern medicines are the product of many discoveries. Creutzfeldt’s work helped establish one of the questions that made them possible.
The gut was never simply a tube for digesting food. It was sending chemical instructions to the pancreas. Werner Creutzfeldt and his colleagues helped demonstrate how important those instructions were when insulin regulation began to fail.
Sources and Further Reading
- Göke B. Obituary for Prof. Dr. med. Dr. h.c. Werner Creutzfeldt, FRCP: May 11, 1924 to August 30, 2006. Digestion, 2006;74:55–56.
- Royal College of Physicians. Werner Otto Carl Creutzfeldt (1924–2006). Biographical profile.
- Creutzfeldt W. The [Pre-] History of the Incretin Concept. Regulatory Peptides, June 15, 2005.
- Creutzfeldt W. The Incretin Concept Today. Diabetologia, February 1979;16:75–85.
- Nauck M, Stöckmann F, Ebert R, Creutzfeldt W. Reduced Incretin Effect in Type 2 (Non-Insulin-Dependent) Diabetes. Diabetologia, January 1986;29:46–52.
- Nauck MA, Heimesaat MM, Orskov C, Holst JJ, Ebert R, Creutzfeldt W. Preserved Incretin Activity of GLP-1 but Not GIP in Patients With Type 2 Diabetes. Journal of Clinical Investigation, January 1993.
- Nauck MA, Kleine N, Orskov C, Holst JJ, Willms B, Creutzfeldt W. Normalization of Fasting Hyperglycaemia by Exogenous GLP-1(7-36 Amide) in Type 2 Diabetic Patients. Diabetologia, August 1993.
- The Discovery and Development of GLP-1-Based Drugs That Have Revolutionized the Treatment of Obesity. Historical scientific review, 2024.
- Amylin Pharmaceuticals and Eli Lilly. FDA Approval of Byetta (Exenatide) Injection. April 29, 2005.
