Richard DiMarchi is a rare figure in metabolic medicine: a chemist whose scientific career connects a fast-acting insulin introduced in the 1990s with the multi-receptor peptide strategy now reshaping obesity treatment.
His contributions span two different ideas about pharmaceutical innovation. First, that a naturally occurring hormone could be chemically redesigned to work better as a medicine. Second, that one engineered peptide might activate several hormonal receptors at once, combining effects that traditionally required separate molecules.
In 2026, Karolinska Institutet and the Rolf Luft Foundation recognized that second line of research by awarding DiMarchi and his longtime collaborator, physician-scientist Matthias Tschöp, the Rolf Luft Award for their work on peptide chemistry and multi-receptor medicines for diabetes and obesity.
The award ceremony took place on September 10 at the Nobel Forum in Stockholm. DiMarchi’s prize lecture was titled “Learn, Unlearn, Relearn – Chemistry Enabling Biology,” a phrase that captures much of his career.
The story behind the recognition begins long before Ozempic, Mounjaro or the current obesity-drug market. It begins with a chemist learning that the sequence nature provides does not necessarily have to be the sequence used in a medicine.
A Brooklyn Chemist Who Returned to Indiana
Richard DiMarchi was born in Brooklyn, New York, in 1952. According to the National Inventors Hall of Fame, he developed an interest in chemistry while studying at Florida Atlantic University, where he earned his bachelor’s degree in 1974.
He continued his education at Indiana University, completing a PhD in chemistry in 1979. His subsequent postdoctoral research took him to Rockefeller University, where he worked with Bruce Merrifield, the scientist whose work on solid-phase peptide synthesis earned the 1984 Nobel Prize in Chemistry.
That training placed DiMarchi at the intersection of protein chemistry, biological research and a rapidly emerging pharmaceutical technology: the ability to manufacture proteins using genetically engineered microorganisms.
In 1981, he joined Eli Lilly Research Laboratories in Indianapolis. The following year, Humulin, recombinant human insulin developed through biotechnology, became the first recombinant DNA-derived medicine approved for human use.
Humulin was a landmark because it made it possible to manufacture insulin equivalent in amino acid sequence to the human hormone rather than relying on insulin extracted from animal pancreases.
But DiMarchi was interested in a question beyond reproducing the body’s natural proteins. If biotechnology could make a human hormone, could medicinal chemistry make that hormone more useful?
That question would become central to his work at Lilly, where he spent 22 years and eventually held senior research and development positions.
His industry contributions extended across several peptide and protein medicines, including Humalog, recombinant glucagon and the osteoporosis treatment Forteo. But it was the molecular design of Humalog that provided the clearest demonstration of his approach.
The Humalog Breakthrough: Two Amino Acids Changed Insulin
Human insulin is a protein made of two connected chains of amino acids. Its molecular structure allows insulin molecules to associate with one another, including forming six-molecule assemblies known as hexamers.
That self-association matters in pharmaceutical formulations. After subcutaneous injection, insulin must become available in forms that can move into the bloodstream. The time required for molecular assemblies to dissociate can influence how quickly a formulation begins working.
DiMarchi and colleagues investigated whether a small structural change could alter insulin’s association behavior without destroying its biological activity.
The solution involved reversing two adjacent amino acids near the end of insulin’s B-chain.
In natural human insulin, position B28 contains proline and position B29 contains lysine. In insulin lispro, their positions are exchanged: lysine occupies B28 and proline occupies B29.
The generic name lispro reflects the two residues involved, lysine and proline.
This modification reduces insulin’s tendency to remain associated after injection and allows more rapid absorption than conventional soluble human insulin. It does not mean that insulin lispro cannot form hexamers under formulation conditions.
Instead, the molecular redesign changes the behavior of the medicine after administration, making it better suited to controlling blood-glucose rises around meals.
DiMarchi and colleagues described the scientific rationale in a 1994 publication examining how structural similarities between insulin and insulin-like growth factor I could help guide the development of a faster-acting insulin analog.
The US Food and Drug Administration approved Humalog, marketed by Eli Lilly, on June 14, 1996.
The achievement was significant because insulin lispro was not simply another way of manufacturing the natural hormone. It was a deliberately modified insulin analog designed to improve its pharmacological properties.
DiMarchi’s contributions to insulin lispro led to his induction into the National Inventors Hall of Fame in 2014.
The chemistry was remarkably economical: the positions of two amino acids changed, while the larger insulin molecule retained the biological function necessary to regulate blood glucose.
The lesson would endure far beyond insulin.
Humalog demonstrated that a naturally occurring hormone could be a starting point for designing a medicine, rather than the final molecular blueprint.
From Eli Lilly to Indiana University and Biotechnology Startups
In 2003, after more than two decades at Lilly, DiMarchi moved to Indiana University Bloomington as the Linda and Jack Gill Chair in Biomolecular Science.
His transition from industry to academia allowed him to pursue longer-term research into peptide chemistry, metabolic hormones and unconventional approaches to treating obesity.
Indiana University’s faculty profile credits him with more than 100 US patents, over 275 peer-reviewed publications and the co-founding of eight biotechnology startups.
His academic research also became commercially important. In 2006, Marcadia Biotech was founded in Indiana, drawing on research associated with DiMarchi and his collaborators.
Roche acquired Marcadia in December 2010. Financial details disclosed the following year valued the transaction at $287 million upfront, with up to $250 million in additional milestone payments, for a potential total of $537 million.
That figure represented the possible transaction value, not a single guaranteed payment at the time of acquisition.
DiMarchi subsequently helped establish additional Indiana biotechnology ventures, including Calibrium and MB2. Novo Nordisk acquired both companies in 2015 for undisclosed amounts.
Fierce Biotech reported that the acquisitions gave Novo Nordisk access to peptide programs and intellectual property relevant to diabetes, obesity and other metabolic disorders.
The deals illustrated the commercial interest in research that was still largely emerging from academic laboratories.
For DiMarchi, they also demonstrated a recurring pattern: develop an unconventional molecular approach, establish evidence that it can change biological function, and connect that discovery with organizations capable of advancing it toward clinical development.
The approach was particularly well suited to the next scientific challenge he pursued with Matthias Tschöp.
One Peptide, Several Hormone Receptors
When DiMarchi returned to Indiana University, obesity medicine was far from the commercial field it has become.
Researchers knew that metabolic hormones influenced food intake, insulin secretion and energy regulation. But therapies aimed at a single pathway did not necessarily produce the full range of effects needed to address obesity and its complications.
DiMarchi began collaborating with Matthias Tschöp, then a researcher at the University of Cincinnati, on a different strategy: developing single peptide molecules capable of activating more than one metabolic hormone receptor.
Their research focused particularly on three related hormonal systems: glucagon-like peptide-1, or GLP-1; glucose-dependent insulinotropic polypeptide, or GIP; and glucagon.
GLP-1 receptor activation influences appetite, gastric emptying and glucose-dependent insulin secretion. GIP signaling also contributes to insulin regulation and metabolic responses. Glucagon, traditionally associated with increasing blood glucose, has additional effects on energy expenditure and nutrient metabolism.
The challenge was not simply to combine these three actions. It was to engineer molecules with useful balances of receptor activity while limiting undesirable physiological effects.
A drug that strongly activates glucagon receptors can potentially raise blood glucose. Excessive stimulation of other pathways may create tolerability or cardiovascular concerns. Multi-receptor drug design therefore requires careful control of molecular potency, exposure and biological response.
The resulting strategy became known as polyagonism, in which one engineered molecule activates several receptors to produce complementary therapeutic effects.
DiMarchi and Tschöp helped establish important scientific foundations for this approach. Their research influenced the direction of metabolic drug development, including the dual GLP-1/GIP receptor strategy represented commercially by tirzepatide.
Tirzepatide itself was developed by Eli Lilly, and its success reflects the work of many scientists, clinical researchers and pharmaceutical development teams. Foundational research on polyagonism should not be confused with sole invention of every commercial drug that subsequently used multiple hormone targets.
The same general scientific direction extends to triple-agonist medicines, including investigational molecules designed to activate GLP-1, GIP and glucagon receptors.
Grey Pepper has explained the pharmacology behind this approach in its analysis of retatrutide and the emerging triple-agonist strategy.
Not every multi-receptor compound succeeds, however. A 2025 publication in Molecular Metabolism, co-authored by DiMarchi and collaborators, examined NN1706, a once-daily GLP-1/GIP/glucagon receptor tri-agonist.
The molecule reduced body weight in preclinical models and produced dose-dependent weight loss in human studies. At the highest tested dose, participants with overweight or obesity experienced approximately 8.2% mean weight loss after ten weeks.
But increased heart rate was observed across treatment cohorts, creating concerns about further clinical development.
That result illustrates why combining more targets is not automatically better. A promising metabolic effect must be balanced against safety, tolerability, dosing and the overall benefit-risk profile.
The important scientific advance was not a simple formula that more receptors always produce a stronger medicine. It was the possibility of designing one molecule to coordinate several complementary metabolic signals.
Recognition, and the Question of Scientific Credit
DiMarchi’s career has now received recognition from several major scientific institutions.
He is a member of the National Academy of Medicine and was inducted into the National Inventors Hall of Fame in 2014 for his contribution to insulin lispro.
In 2024, the American Association for the Advancement of Science honored DiMarchi and Novo Nordisk scientist Lotte Bjerre Knudsen with the Mani L. Bhaumik Breakthrough of the Year Award.
The award recognized work associated with Science magazine’s 2023 Breakthrough of the Year, which highlighted the emergence of GLP-1 medicines as a major development in obesity treatment.
Knudsen’s research followed a different but complementary scientific route. Her work helped transform naturally short-lived GLP-1 biology into longer-acting therapeutic medicines, including liraglutide and semaglutide.
Grey Pepper has covered that contribution separately in its profile of Lotte Bjerre Knudsen and the development of long-acting GLP-1 medicines.
In September 2026, DiMarchi and Tschöp received the Rolf Luft Award at Karolinska Institutet for their foundational work on peptide chemistry and the development of dual and triple hormone receptor agonists.
The award ceremony was held on September 10 at the Nobel Forum. DiMarchi delivered his lecture on chemistry’s role in enabling biological discovery, while Tschöp discussed the development of polyagonism and the metabolic actions of glucagon and GIP.
Such recognition is significant, but scientific breakthroughs rarely belong to one person or one laboratory.
The history of GLP-1 research includes the discovery of the hormone, characterization of its physiological effects, chemical engineering of drug candidates and decades of clinical development. These achievements involved many researchers working in different institutions and disciplines.
The fairest account of DiMarchi’s influence is therefore not that he independently invented the modern obesity-drug market.
It is that his research helped establish two enduring ideas in medicinal peptide chemistry: natural hormonal sequences can be improved for drug use, and the effects of several hormones can be combined within a single engineered molecule.
Those contributions are specific, documented and substantial without requiring the erasure of other researchers’ work.
The Next Experiment: What If an Obesity Drug Doesn’t Need GLP-1?
DiMarchi’s most recent research presents a provocative new question for the obesity field: must an effective peptide-based weight-loss medicine activate the GLP-1 receptor at all?
In April 2026, researchers including DiMarchi, Tschöp and Diego Perez-Tilve published findings in Molecular Metabolism showing that combined activity at GIP and glucagon receptors could produce substantial weight reduction in experimental rodent models without requiring direct GLP-1 receptor activation.
The study investigated a compound called BWB3054, a fatty-acylated peptide designed to activate GIP and glucagon receptors while having very low activity at the GLP-1 receptor.
In laboratory receptor assays, BWB3054 displayed more than 100-fold lower activity at the mouse GLP-1 receptor than at the primary targets being investigated.
Researchers also used mice lacking functional GLP-1 receptors to investigate whether meaningful weight reduction could occur through the remaining hormone pathways.
The experiments supported the possibility that combined GIP and glucagon receptor activation can reduce excess body weight without relying on GLP-1 receptor activity.
That does not establish a treatment for human obesity. The principal published experiments involved rodents, and the results do not demonstrate that BWB3054 is clinically effective or better tolerated than existing medicines.
The hypothesis is commercially interesting because nausea, vomiting and other gastrointestinal adverse effects are among the common reasons patients struggle with GLP-1-based treatment.
If scientists could preserve substantial weight-loss efficacy while reducing those effects, a new class of medicines might become possible. But removing one receptor activity does not prove that gastrointestinal symptoms or other adverse effects will disappear.
The research was supported by BlueWater Biosciences, a biotechnology company associated with the investigators. The publication disclosed that DiMarchi and Tschöp were among the company’s cofounders and shareholders, along with additional research, licensing and intellectual-property relationships.
Those disclosures are relevant when assessing claims about the technology’s future commercial potential. They do not invalidate the animal experiments, but independent validation and carefully designed human studies will be necessary.
STAT reported on April 16 that the research could challenge a central assumption in modern obesity drug development: that GLP-1 receptor activation is indispensable to achieving strong weight loss.
The idea remains a preclinical hypothesis. Human efficacy, safety and tolerability have not been established for the experimental molecule.
There is a useful symmetry in the latest research. At Lilly, DiMarchi helped improve insulin by rearranging two amino acids. Decades later, he is investigating whether an entire hormonal component can be removed from a multi-receptor design without losing the desired biological effect.
Both approaches begin with the same principle: treat the natural hormone as a molecular framework that can be redesigned and tested.
The result is a career that traces a remarkable arc in pharmaceutical science, from recombinant insulin and rational protein modification to experimental medicines designed around the interaction of multiple metabolic pathways.
Whether the latest GLP-1-free candidate eventually succeeds in human trials remains unknown. Its success is not necessary to establish the scientific significance of the work that preceded it.
Richard DiMarchi’s lasting contribution is not a single drug or a single receptor combination. It is the demonstration that peptide medicines can be deliberately engineered beyond the functions of the natural hormones from which they began.
Sources and Further Reading
- National Inventors Hall of Fame: Richard DiMarchi’s Career, Humalog and Peptide Innovation, July 7, 2026.
- National Inventors Hall of Fame: Richard DiMarchi — Insulin Lispro, 2014 Inductee Profile.
- DiMarchi RD, et al. Preparation of an Insulin With Improved Pharmacokinetics Relative to Human Insulin Through Consideration of Structural Homology With Insulin-Like Growth Factor I. Hormone Research, 1994.
- DailyMed: Humalog (Insulin Lispro) Prescribing Information and Molecular Description.
- Indiana University Alumni: Behind the Ozempic Headlines — Richard DiMarchi and Peptide Research.
- Indiana University Gill Institute: Richard DiMarchi Faculty Profile and Research Contributions.
- Fierce Biotech: Marcadia Priced at up to $537 Million in Roche Buyout, February 2, 2011.
- Fierce Biotech: Novo Nordisk Acquires Calibrium and MB2, August 28, 2015.
- Indiana University: DiMarchi and Lotte Bjerre Knudsen Receive the 2024 Bhaumik Breakthrough of the Year Award.
- Karolinska Institutet: DiMarchi and Tschöp Receive the 2026 Rolf Luft Award, September 2026.
- Finan B, et al. A Once-Daily GLP-1/GIP/Glucagon Receptor Tri-Agonist (NN1706) Lowers Body Weight in Rodents, Monkeys and Humans. Molecular Metabolism, 2025.
- Perez-Tilve D, et al. GIPR:GCGR Co-Agonism Restores Normal Weight in Obese Rodents. Molecular Metabolism, 2026. DOI: 10.1016/j.molmet.2026.102365.
- STAT: Researchers Behind GLP-1 Obesity Drugs Advance a New Approach That Drops GLP-1 as a Target, April 16, 2026.
