GLP-1 and metabolic disease — NIH Funding Overview

Why this matters now

The clinical and commercial success of GLP-1 agonists has reshaped diabetes and obesity research priorities. NIH portfolios now emphasize understanding why some patients respond and others do not, neuropsychiatric effects, long-term safety, and applications beyond metabolism — including addiction, neurodegeneration, and inflammation.

How NIH funds this area

NIDDK is the dominant funder; NHLBI funds cardiovascular outcomes; NIA funds aging-related applications; NIDA funds substance-use applications. The data below covers all NIH awards mentioning GLP-1 in any field.

Yearly NIH Awards for GLP-1 and metabolic disease

Counts and total funding per fiscal year from NIH RePORTER. Recent fiscal years may understate final totals because of reporting lag.

Open the full interactive trends view for GLP-1 and metabolic disease →

Top NIH Institutes (last 90 days)

Which NIH institutes funded the most GLP-1 projects in the most recent 90-day window.

Common Activity Codes (last 90 days)

Which grant mechanisms (R01, R21, U01, P30, etc.) appeared most often for GLP-1 in the recent period.

Most Active Institutions (last 90 days)

Universities and research organizations with the most GLP-1 awards in the most recent 90-day window.

1. JOHNS HOPKINS UNIVERSITY — 5 awards
2. UNIVERSITY OF PITTSBURGH AT PITTSBURGH — 3 awards
3. BRIGHAM AND WOMEN'S HOSPITAL — 3 awards
4. UNIVERSITY OF CINCINNATI — 2 awards
5. UNIVERSITY OF MICHIGAN AT ANN ARBOR — 2 awards
6. UNIVERSITY OF SOUTHERN CALIFORNIA — 2 awards
7. UNIVERSITY OF TEXAS HLTH SCIENCE CENTER — 2 awards
8. VANDERBILT UNIVERSITY — 2 awards

Recently Awarded GLP-1 and metabolic disease Grants

Twelve most recent awards mentioning GLP-1, drawn from NIH RePORTER. Click through to Find PIs for the full investigator search.

• Remote Loading of Melanocortin and GLP-1 Peptides in Polymers for Treatment of Obesity

  1R56DK141545-01A1
  STEVEN SCHWENDEMAN · UNIVERSITY OF MICHIGAN AT ANN ARBOR, MI · $231,000 · awarded Apr 17, 2026 · R56

  ABSTRACT Rates of obesity have steadily increased in the US, with about 50% of Americans projected to be obese by 2030. Recent advances include GLP-1 peptides, such as semaglutide, approved in 2021 for adult obesity, and setmelanotide, approved in 2020 for early-onset syndromic obesity due to POMC and leptin receptor deficiency. However, setmelanotide is not sufficiently effective for MC4R haploinsufficiency or common dietary obesity, causes hyperpigmentation, and requires daily injections. GLP-1 therapies also show variable efficacy, with 23% of patients losing less than 5% of body weight after two years and up to 30% experiencing nausea. To improve the potency and specificity of MC4R peptide agonists like setmelanotide, we performed extensive structure-activity relationship work involving the synthesis and characterization of 426 new melanocortin peptides (MCs). This work led to discovery of MCs with 4X increased potency relative to setmelanotide, and with reduced hyperpigmentation. Also exciting, we recently discovered that MCs increase the dose-sensitivity to GLP-1s without increasing malaise or activity in the brain’s emesis center. This finding could help reduce well-known toxicity of GLP-1s, allowing more patients to benefit from GLP-1s. To realize cost-effective and facile PLGA microsphere encapsulation and delivery of the MCs and GLP-1s, we recently discovered an extremely simple, efficient, and generalizable water-based remote encapsulation method for peptides, involving short-term mixing of aqueous peptides and empty poly(lactic-co-glycolic acid) (PLGA) microspheres. In this R56 grant our team will further develop and optimize the remote-loading method for GLP-1s, while further advancing the mechanism of the rapid and spontaneous remote peptide loading based on peptide-polymer binding with or without additional excipients at physiological temperature. The new encapsulation method will allow for the combination of multiple formulations of sterile empty PLGA microspheres that encapsulate the peptide drugs to achieve constant drug release. We will determine the dosing of both single MC and MC/GLP-1 combinations in acute and chronic animal models of both genetic (MC4R+/-) and dietary obesity. For MCs we will use remote-loaded setmelanotide formulations already developed in the lab. We will evaluate pharmacokinetics of the remote-loaded GLP-1s to facilitate microsphere combination for constant peptide release and to test their release performance in vivo. Hence, this new drug delivery approach using MCs and their GLP-1 combinations could be useful for future treatments of a wide variety of forms of obesity.

• Metabolite Markers of Diabetic Kidney Disease

  1R01DK143234-01A1
  Kumar Sharma · UNIVERSITY OF TEXAS HLTH SCIENCE CENTER, TX · $825,255 · awarded Apr 17, 2026 · R01

  PROJECT SUMMARY / ABSTRACT: Diabetic kidney disease (DKD) threatens roughly 40 % of individuals living with type 1 diabetes (T1D), driving kidney failure and cardiovascular death even in the era of continuous glucose monitoring and automated insulin delivery. Hypoxia, obesity and insulin resistance, now common features of T1D, disrupt mitochondrial metabolism and initiate DKD long before albuminuria, yet people with T1D have been excluded from the renal outcome trials that transformed DKD management in type 2 diabetes. Our multi-omic work identifies endogenous adenine, generated by the enzyme methylthioadenosine phosphorylase (MTAP), as an early, reversible driver of DKD and spatial metabolomics localizes adenine to injured tubules and vessels in T1D kidney biopsies. Additionally, in our mouse models of DKD, dietary adenine accelerates fibrosis, and MTAP inhibition normalizes mTORC1 signaling, fibrosis and glomerular filtration rate (GFR). Molecular docking and preliminary data reveal that adenine binds the ATP pocket of the tubular insulin receptor, activating the PI3K/Akt/mTORC1 cascade, while SGLT2-inhibitor therapy lowers urine adenine in adults with T1D. Aim 1 will integrate single-cell RNA-seq, spatial transcriptomics and metabolomics from 44 T1D versus 12 healthy kidney biopsies to map cellular adenine sources and injury pathways, and will quantify urine and plasma adenine in four longitudinal T1D cohorts (N = 1,430) to test adenine as a predictor of rapid estimated GFR decline. Aim 2 will analyze paired biopsies from the placebo-controlled ATTEMPT trial to determine whether SGLT2 inhibition suppresses tubular MTAP expression, adenine abundance and downstream mTORC1 activity. Aim 3 will use 15N-adenine tracing in insulin receptor-deficient cells with reconstituted of full-length or mutant insulin receptors, proximal tubule-specific insulin receptor KO mice, tubule-specific inducible MTAP KO mice, and MTAP inhibition in multiple T1D models to prove that MTAP-derived adenine promotes DKD progression via insulin receptor-mTORC1 signaling and the therapeutic potential of MTAP inhibition. Successful completion will establish adenine as both a causal biomarker and therapeutic target, clarify how SGLT2 inhibition modulates this pathway, and provide pre-clinical proof that MTAP blockade or SGLT2 therapy can blunt adenine-mediated kidney injury, thereby enabling precision trials that enroll high-adenine T1D patients and test MTAP-targeted interventions.

• Neural Mechanisms of Nausea, Vomiting, and Energy Dysregulation

  5R01DK112812-09
  Bart DE JONGHE · UNIVERSITY OF PENNSYLVANIA, PA · $639,550 · awarded Apr 10, 2026 · R01

  Project Summary Nausea and vomiting promote mammalian survival. Paradoxically, emetic “side effects” are ubiquitously reported for FDA-approved pharmacotherapeutics for obesity, diabetes, and cancer pharmacotherapies and present alongside polymorbidities that contribute to detrimental life-threatening outcomes, such as poor nutrition, quality of life, and patient prognosis. Here, we address two broad unmet clinical needs: 1) All existing FDA-approved glucagon-like peptide-1 (GLP-1)-based therapeutics for the treatment of diabetes and obesity elicit nausea and vomiting in a significant percentage of patients. 2) Despite existing antiemetic treatments available, virtually all patients undergoing chemotherapy continue to exhibit profound debilitating symptoms, such as severe nausea, vomiting, and cachexia. We use modern behavioral and neurogenetic approaches, and appropriate, comparative, preclinical animal models that are critical to produce novel, effective, long-term controls of nausea and vomiting to advance modern metabolic health care. Intestinally derived GIP regulates postprandial glucose through direct action on GIP receptors (GIPR) expressed on pancreatic beta cells. GIP analog efficacy as a monotreatment of diabetes and obesity is at best limited and controversial, however, the expression of CNS GIPRs in regions implicated in nausea/emesis have spawned investigation of central actions of GIP ligands as potential adjunct therapeutics to reduce unwanted adverse events. Specifically, our data support that GIPR and GLP-1R dual agonism provide body weight loss, hypophagia, and glucoregulatory control without nausea and emesis, compared to GLP-1R agonism alone, through activation of the GIP system. The area postrema (AP) and nucleus tractus solitarius (NTS) of the dorsal vagal complex (DVC) play a critical role in ingestive behavior, emesis, and nausea. Widely used emetogenic chemotherapeutics (e.g., cisplatin) and all FDA- approved GLP-1-based ligands activate AP/NTS neurons. Our collective works suggest hindbrain GIPRs block nausea and vomiting induced by GLP-1R and cisplatin chemotherapy in several animal species, suggesting translational broad-spectrum antiemetic potential for GIPR agonists. We have identified cellular phenotypes of AP/NTS GIPR- and GLP-1R- expressing cells, as well as shown the attenuation in AP/NTS neuron activity, and preliminary data). Additionally, we have discovered a molecularly distinct GABA-ergic neuronal DVC population that is modulated by chemotherapy but rescued by GIPR agonism. We hypothesize that there exists an antiemetic system characterized by inhibitory (i.e., GABA-ergic) neurons expressing GIP receptors (GIPR). Here, we will: Aim I: Examine behavioral, anatomical, and transcriptomic mechanisms by which GIPR-GABA+ AP/NTS neurons exhibit antiemetic action. Aim II: Examine GIP antiemetic action in conjunction with established antiemetics using a multi-species approach. Our data in multiple species all indicate that GIP agonism has an antiemetic effect and here we use our unique multi-species approach to define the mechanisms of the GIP system in reducing and/or preventing therapeutic drug-induced nausea and emesis.

• Enhancing Host Defense Against Bacterial Pneumonia in Lipodystrophy: Evaluating the Therapeutic Potential of Leptin and Tirzepatide

  1R21AI196410-01
  PETER MANCUSO · UNIVERSITY OF MICHIGAN AT ANN ARBOR, MI · $429,000 · awarded Apr 7, 2026 · R21

  Abstract Respiratory tract infections are a leading cause of death for lipodystrophy patients. Lipodystrophy syndromes are rare disorders characterized by selective loss of adipose tissue, hyperphagia, severe insulin resistance, type 2 diabetes, hepatic steatosis, and leptin deficiency. The life spans of lipodystrophy patients are reduced by 30 years compared with the general population. While metabolic complications of lipodystrophy are well-documented, the impact on immune function and susceptibility to infections remains poorly understood. Metreleptin, an FDA approved treatment, significantly improves metabolic complications of lipodystrophy but its impact on respiratory tract infections has not been determined. We have shown that leptin deficient mice have impaired host defense against bacterial pneumonia and that exogenous leptin improves pulmonary bacterial clearance and survival. While metreleptin treatment is effective, many patients discontinue treatment due to the development of anti-leptin antibodies. As an alternative, treatment with tirzepatide, a dual acting glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic peptide (GIP) agonist, was shown to be effective in a clinical trial to control metabolic complications of lipodystrophy. However, little is known regarding the impact of tirzepatide on the risk of respiratory tract infections in lipodystrophy or diabetic patients. To address the lack of research on lipodystrophy and bacterial pneumonia, we infected adipocyte-specific lamin A/C knockout (Lmna ADKO) mice, a model of lipodystrophy, and wild type (WT) mice with an intrapulmonary dose of Klebsiella pneumoniae (K.pneumoniae) a common cause of pneumonia in diabetic patients. Lmna ADKO mice exhibited higher lung bacterial burdens as compared with their WT counterparts. In addition, alveolar macrophage phagocytosis of K. pneumoniae and reactive oxygen intermediate production were reduced in cells from Lmna ADKO mice. The long-term goal of this research is to understand how metabolic disease impairs host defense against respiratory tract infections. The overall objective of the proposed research is to determine if leptin, tirzepatide, or a combination of these drugs improve host defense in Lmna ADKO mice following infection with K. pneumoniae. The results of these studies will determine if correcting glucose homeostasis and leptin deficiency with leptin or correcting glucose homeostasis alone with tirzepatide improves host defense. Results from our studies will inform clinicians regarding the best course of treatment for lipodystrophy to normalize glucose homeostasis and mitigate the risk of respiratory tract infections. The central hypothesis is that lipodystrophy impairs host defense against Klebsiella pneumonia by impairing alveolar macrophage phagocytosis and bacterial killing due to metabolic disturbances and leptin deficiency. Correcting these defects by administering leptin will be more effective than tirzepatide and combining leptin and tirzepatide will result in the most effective improvements in host defense against Klebsiella pneumonia.

• Specificity, Phenotype and Function of Pancreatic CD8 T Cells in Human Type 1 Diabetes

  5R01AI092453-13
  Estefania Quesada Masachs · UNIVERSITY OF MIAMI SCHOOL OF MEDICINE, FL · $460,500 · awarded Apr 3, 2026 · R01

  Title: Specificity, Phenotype and Function of Pancreatic CD8 T Cells in Human Type 1 Diabetes Project Summary Human type 1 diabetes (T1D) is characterized by the immune-mediated destruction of insulin-producing pan- creatic beta cells. CD8 T cells are the most common cell found in insulitis lesions and are the principal T cell type implicated in beta cell destruction. Insulin and its precursors have been identified as key autoantigens in humans and mice due to their local abundance. The previous funding cycles for this grant have enabled us to lead the field of human islet cell investigation in T1D. Using samples from the national pancreatic organ donor consortium (nPOD) we have detected, precisely quantified, and identified the exact location of autoreactive pre-proinsulin (PPI) specific CD8 lymphocytes within the pancreata of human donors. Studies performed within this project have already revealed significant and novel findings. We first identified auto-reactive CD8 T cells in the islets of patients with T1D using a specially designed method of tetramer staining. We found that their frequency is high and likely the most predominant autoreactive cell type (1), a finding which has been inde- pendently confirmed with other methods by Nakayama et al. (2). More recently (3) we defined the precise location of these cells within a pseudo-timeline of disease development and concluded that PPI cytotoxic T lymphocytes (CTL) are already present in healthy pancreata and appear to become 'attracted' to islets during the development of T1D. This seminal observation indicates that the islets appear to expose themselves to immune recognition, and thus become a key culprit in driving T1D development. A new key development of this grant is the Orion (Rarecyte) technology that allows for highly multiplexed studies in whole tissue sec- tions, combined with state-of-the-art analysis software. The study of the whole section and multiple targets simultaneously allows to define the islet/immune interface and the communication between PPI CTL and other immune cells more precisely and with a much reduced number of samples. The present proposal will define the precise location and function of these interactions, and corroborate these findings in highly innova- tive human islet microtissues and living donor pancreatic tissue slices using dynamic in vitro models. Finally, this proposal will decipher mechanistically how some aspects of the islet immune interface can be reset/restored by the action of GLP1 agonists, building on our recent work which has shown that this drug class can maintain beta cell function (glucose-induced insulin secretion) in vitro and in vivo during the devel- opment of T1D (4). Overall, our findings should give us an unprecedented and unique understanding of how and why T1D develops, and provide mechanistic information using our novel in vitro systems, thus ultimately aiding the development of new therapeutic options.

• Attenuation of sepsis-induced microvascular permeability and inflammation with the GLP-1R agonist liraglutide.

  3F31HL178162-01S1
  David Aslaner · VANDERBILT UNIVERSITY, TN · $3,000 · awarded Apr 2, 2026 · F31

  Project Abstract Sepsis is a critical problem around the world causing 20% of all global deaths. The lack of effective therapeutics leaves critically ill patients with systemic organ dysfunction often caused by damage to the vascular endothelium. The damage induces micro-vessel dysfunction and increased permeability. Increased permeability can be attributed to tight junction and adherens junction disruption within endothelial cells. All blood vessels are lined with a single cell layer of endothelial cells that regulate exchanges between the bloodstream and the surrounding tissues and modulate inflammation. During sepsis, endothelial cells secrete circulating inflammatory mediators such as monocyte chemoattractant protein-1 (MCP-1) which cause upregulation of cell adhesion molecules that facilitate leukocyte trafficking and also MCP-1 also disrupts tight junctions in endothelial cells. Given the widespread vascular inflammation and breakdown of endothelial tight junctions in sepsis, therapeutic approaches to maintain and restore endothelial tight junctions is a compelling treatment strategy. GLP-1R agonists have unexpected anti-inflammatory and permeability attenuation effects. Preliminary in vitro studies suggest that the protective effects of the GLP-1R agonist, liraglutide, in sepsis are mediated through microvascular endothelium. Pre-treatment of primary human lung microvascular endothelial cells with liraglutide improved lipopolysaccharide-induced barrier dysfunction indicating important effects of liraglutide in protecting the endothelial barrier. In Aim 1, I will define the ability of liraglutide to attenuate microvascular permeability in vitro and in a clinically relevant murine model of polymicrobial abdominal sepsis. Additionally, in my preliminary studies, treatment of wild type mice with the GLP-1R agonist liraglutide significantly decreased plasma MCP-1, attenuated organ injury, and increased survival in a model of polymicrobial abdominal sepsis. MCP-1 secretion is regulated by p38 MAPK pathway activation. Interestingly, GLP-1R agonists regulate the activation of MAPK. Therefore, there is rationale that liraglutide inhibits MCP-1 secretion via MAPK regulation. MCP-1 attracts monocytes to the site of inflammation, but also promotes their adhesion by inducing them to upregulate ICAM-1 that is expressed in the activated endothelium. My preliminary data suggests that liraglutide decreases endothelial ICAM expression in vitro. These adhesion molecules allow the attachment of leukocytes to the endothelium and permit their transmigration into peripheral tissue. In Aim 2, I will define the mechanism by which Liraglutide restores the endothelial barrier through downregulation of MCP-1 and the subsequent leukocyte recruitment and tight junction and adherens junction stability. Completion of these aims will determine whether liraglutide attenuates sepsis-induced microvascular permeability and how liraglutide is vasculoprotective through an anti-inflammatory mechanism. This proposal will promote advancement of an endothelial targeted drug to treat sepsis and further my goal to become an independently funded principal investigator studying the mechanisms of endothelial injury in sepsis.

• Assessing Patient-Centric Factors and Enhancing Risk Communication to Improve Treatment Persistence in Kidney and Cardiovascular Care

  5K23DK144712-02
  Jesse Ikeme · UNIVERSITY OF CALIFORNIA, SAN FRANCISCO, CA · $190,836 · awarded Apr 1, 2026 · K23

  ABSTRACT Sodium glucose cotransporter 2 inhibitors (SGLT2i) and glucagon-like peptide 1 receptor agonists (GLP1RA) are two classes of medications poised to revolutionize chronic kidney disease (CKD) care after repeatedly demonstrating their ability to prevent cardiovascular disease (CVD) and CKD progression in clinical trials. With pleiotropic benefits across type 2 diabetes mellitus (T2DM), CKD, and CVD, these medications are the central therapeutic elements of an ongoing shift in CVD prevention from disjointed risk factor control toward comprehensive, multi-organ care for Cardio-Kidney-Metabolic (CKM) syndrome. This new CKM approach holds great promise for mitigating the CVD risk that threatens over 14 million adults with T2DM and CKD within the U.S.; however, prior work from our group and others indicates that the adoption of SGLT2i and GLP1RA in CKD care is being tragically limited by poor treatment persistence. Achieving the full benefit of these medications will require novel approaches to motivate and reinforce their persistence; however, such undertakings in individuals with T2DM and CKD can be challenging — many are unaware of their diagnosis, providers underestimate their CVD risk, and the unique benefit of these medications may not be fully appreciated among the myriad of other clinical problems that arise in this medically complex, high-risk population. To tackle this enormous challenge, the proposed project will rigorously develop an effective Risk Communication Aid to translate individualized CVD risk estimation and the benefits of SGLT2i and GLP1RA treatment into joint patient-provider efforts to prevent CVD through persistent treatment. We will accomplish these goals by first investigating how the complexity of care in persons with T2DM and CKD is associated with persistent SGLT2i and GLP1RA use across a national integrated health care system using detailed clinical data from the Veterans Health Administration (VHA) (Aim 1). Then, interviews of patients and providers across the landscape of CKM care will contextualize insights from Aim 1 by pinpointing key barriers to persistent treatment using an implementation science framework (Aim 2). Finally, the knowledge gained from Aim 2 and an iterative, stakeholder-driven development process will be used to create a novel CVD Risk Communication Aid to facilitate patient-provider discussions promoting persistent SGLT2i and GLP1RA use. This tool will be piloted in the primary care setting among persons with T2DM and CKD (Aim 3). This proposal will leverage the unique advantages of VHA to develop innovations in healthcare delivery that are minimally influenced by costs to patients. Dr. Ikeme has assembled an unparalleled team of mentors with expertise in CVD risk prediction, innovative kidney care delivery, implementation science, risk communication, and biostatistics. With their guidance, this work will place Dr. Ikeme at the forefront of effective CVD prevention in CKD and lay the foundation for an independent R01-level project evaluating a Risk Communication Aid to improve the persistence of CVD preventive treatment in CKD.

• Impact of Perinatal Western Diet on Offspring GLP1 Circuits

  1R01DK143059-01A1
  Linda Rinaman · FLORIDA STATE UNIVERSITY, FL · $592,841 · awarded Mar 31, 2026 · R01

  Project Summary/Abstract In humans, rodents, and other mammals, the perinatal period of offspring development (i.e., gestational and lactational) is marked by significant neurodevelopment and plasticity. During this period, maternal nutrition strongly shapes the developmental assembly and later function of offspring neural circuits. Compelling clinical and pre-clinical evidence indicates that maternal consumption of "Western Diets" (WD) high in fat and sugar content promote offspring susceptibility to obesity, at least in part by increasing offspring preference for WD-type foods. Based on a strong foundation of published literature and pilot data obtained in our novel Gcg- Cre::tdTom reporter rat model, we propose that the deleterious effects of perinatal WD exposure in offspring occur, at least in part, as a consequence of developmental plasticity and persistently altered function of central glucagon-like 1 (GLP1) signaling pathways. We specifically hypothesize that perinatal maternal WD alters the structure and function of GLP1 axonal projections in offspring, thereby reducing endogenous GLP1R signaling in reward- related brain regions that control palatable food intake. To test predictions arising from this overarching hypothesis, we will (1) document the nature and persistence of perinatal WD- induced plasticity in central GLP1 signaling pathways in male and female offspring, (2) examine how alterations in the structure and function of central GLP1 signaling pathways are associated with behavioral and physiological outcomes, and (3) investigate whether adolescent-onset treatment with the brain-penetrant GLP1R analogue semaglutide (SEMA) abrogates the effects of perinatal WD on offspring behavior, physiology, and endogenous GLP1R signaling. By elucidating for the first time how perinatal WD exposure impacts the structure and function of the central GLP1 system, results from this project will provide new insights regarding how the early nutritional environment modifies food reward-driven behaviors and lifespan metabolic health. If our data support this hypothesis, the results will have implications for developing strategies to combat long-term health adversities associated with early life exposure to WD.

• Identifying a novel player in skeletal muscle performance and metabolism

  5R01DK138635-03
  Vishwajeet Puri · OHIO UNIVERSITY ATHENS, OH · $589,326 · awarded Mar 31, 2026 · R01

  Project Abstract Skeletal muscle (SkM) function and strength, and intrinsic muscle quality are closely linked to the pathogenesis and pathophysiology of metabolic disease. However, the regulatory molecular mechanisms in SkM performance remain elusive. The current proposal will focus on identifying novel molecular pathways regulating muscle function and insulin signaling via the muscle-specific role of Fat Specific Protein 27 (FSP27). While the adipocyte actions of FSP27 have been well-recognized in the metabolic field, we unexpectedly discovered high FSP27 protein expression in SkM. Our preliminary data in humans identified a positive correlation of SkM FSP27 expression with indices of muscle performance such as aerobic capacity, muscle strength, and responsivity to exercise training. Also, our study in whole-body Fsp27-/- mice displayed severely impaired muscle endurance, muscle strength, and loss of fat in the SkM. Intramyocellular fat is a crucial source to meet the energy demand in the SkM for its function. Therefore, we hypothesized that FSP27 plays a major role in muscle performance and insulin sensitivity primarily via its role in regulating fat handling in the SkM. As a first step in understanding the clinical relevance of FSP27 in SkM insulin signaling and muscle function, we have generated an innovative gain-of-function transgenic mouse model expressing the human-FSP27 transgene, (M-FSP27tg), specifically in SkM without altering the expression of endogenous mouse Fsp27. Also, we have generated a loss-of-function muscle model through muscle-specific ablation of FSP27 (M-Fsp27-/-). Our preliminary studies in these mouse models are in-line with our hypothesis and suggest a critical role of SkM-specific FSP27 in muscle performance. We will utilize a three-pronged approach to identify the physiological and molecular mechanism of FSP27-mediated SkM function. In Aim 1, we will study the physiological action of FSP27 in SkM performance, and its role in protection against obesity-induced whole-body insulin resistance. In Aim 2, we will test our hypothesis that FSP27 handles intramyocellular fat fuel via its action on the motor activity of the cytoskeletal proteins along the FSP27-Rab18-p150-Dyenin axis in the SkM. In aim 3, we will test our hypothesis that in addition to its effect on cytoskeleton motor activity, FSP27 regulates exercise endurance and insulin sensitivity via the glucagon-like peptide 1 receptor (GLP1R)-AMPK pathway. A strength of this proposal is an interdisciplinary collaboration formed between Dr. Puri (expert in basic and translational research in lipid metabolism and signaling), Dr. Consitt (expert in SkM metabolism), Dr. Baumann (expert in SkM physiology), and Dr. Lee (expert in tissue insulin signaling), which will utilize their complementary expertise and build upon their collaborative work in this project. Successful completion of the proposed studies will identify a novel regulatory player in SkM performance and muscle biology.

• The role of G protein-dependent and -independent EP3 signaling in beta-cell compensation and diabetes

  5R01DK137505-03
  Michelle Kimple · UNIVERSITY OF WISCONSIN-MADISON, WI · $648,973 · awarded Mar 30, 2026 · R01

  SUMMARY/ABSTRACT: Diabetes is a costly and complex chronic illness and a serious public health problem. The number of individuals with diabetes, particularly obesity-linked type 2 diabetes (T2D), is certain to increase over the next decades. Shockingly, the children of today have an estimated overall lifetime risk of developing diabetes of nearly 50%. Therefore, developing new methods to prevent T2D and properly treat T2D patients is exceptionally timely and of great significance. The progression to T2D is increasingly being linked with changes in cellular and molecular signaling pathways in the insulin-secreting pancreatic β-cell, preventing adequate insulin secretion to stimulate the body’s cells to take up glucose from the blood. Yet, few T2D drugs specifically target the β-cell, and those that do are not effective in all individuals and are controversially linked with β-cell failure long-term. Two molecules that are cornerstones of our research program are prostaglandin EP3 receptor (EP3), a G protein-coupled receptor (GPCR) for the arachidonic acid metabolite, prostaglandin E2 (PGE2), and its associated G protein alpha subunit, Gαz. Work from our group and others has definitively shown EP3 expression and signaling is increased in β-cells of T2D mice and human organ donors and blocking EP3 signaling can stimulate β-cell insulin secretion and proliferation. These exciting results suggest targeting EP3 and/or Gαz might increase the number of functional β-cells in T2D; yet, much more work is necessary to achieve this. Our long-term goal is to fully characterize the EP3 and Gαz activation and signaling pathways during the progression to T2D at the whole body, tissue, cellular, and molecular levels, providing us key information on how to target this β-cell pathway in T2D. The overall objective of this work, which is the next logical step in pursuit of our goal, is to define the molecular signaling pathways responsible for the impact of EP3 signaling, both Gɑz-dependent and -independent, on mouse and human β-cell compensation and β-cell failure. Our central hypothesis is EP3 and Gαz, when active, modulate intracellular signaling pathways critical for β-cell compensation in obesity but, when chronically active, contribute to β-cell dysfunction and loss in T2D. We will test our central hypothesis with a combination of innovative cellular imaging, metabolomics, and proteomics assays, correlating changes in EP3 and Gɑz signaling pathways with measurements of β-cell function in response to glucose and glucagon-like peptide 1: a well-accepted class of T2D drugs. We will accomplish this goal by pursuing the following three Specific Aims: 1. Determine effects of EP3 on discrete cellular pools of β-cell Ca2+ and cAMP and downstream β-cell function and mass; 2. Quantify Gɑz-dependent Rap1GAP translocation, Rap1GAP phosphorylation, and their effects on β-cell function and mass; and 3. Quantify changes in the human islet arachidonic acid metabolome, and the functional consequence of these changes, during the progression to T2D. This work, when completed, will provide a much more complete understanding of the role of the β-cell and its signaling molecules in the progression to and pathophysiology of T2D.

• Discovery and design of novel insulin evologs from venomous marine cone snails

  5R01DK139317-03
  Helena Safavi-Hemami · UTAH STATE HIGHER EDUCATION SYSTEM--UNIVERSITY OF UTAH, UT · $318,584 · awarded Mar 30, 2026 · R01

  SUMMARY Insulin is a pancreatic peptide hormone that is of critical importance for glucose homeostasis. Disruption of insulin production or function can result in diabetes mellitus. Insulin therapy is the only effective treatment for type 1 diabetes (T1D) and is used by many people with type 2 diabetes (T2D) and some individuals with gestational diabetes (GDM). Despite major advances in insulin therapy, achieving efficient glycemic control to prevent short- and long-term complications remains a major challenge in diabetes management. This is in part due to the fact that insulin and its current therapeutic analogs self-associate into dimers and hexamers that form subcutaneous depots, which delays their onset of action and leads to prolonged duration of action. Our recent discovery of specialized monomeric insulins from the venom of fish-hunting cone snails that rapidly lower blood glucose in animal models of diabetes provides the unique opportunity to address these persistent limitations of current diabetes therapeutics. Furthermore, shaped by millions of years of predator-prey evolution, venom insulins have evolved unique ways of engaging with the vertebrate insulin receptor (hIR), thus providing a unique toolset to study diverse molecular modes of hIR activation. Proof of concept for the high translational impact of this proposal is provided by Con-Insulin G1, our first discovered venom insulins that revealed the existence of a minimized insulin binding motif at the hIR and has already led to the design of a new therapeutic prandial insulin candidate. Our recent preliminary data demonstrates that Con-Ins G1 is only one of > 20 diverse insulins evolved by fish-hunting cone snails. We hypothesize that each one of these insulins represents a novel scaffold for the rational design of improved insulin therapeutics. The aim of this proposal is to survey the entire chemical diversity of naturally evolved insulin analogs (so-called evologs) for the discovery and development of new insulin drug candidates with advantageous properties over existing analogs (i.e., improved stability profiles, faster onset of action, reduced rates of post-injection hypoglycemia, and potentially improved metabolic signaling). We anticipate that these candidates have the potential to significantly improve diabetes therapy and enhance the performance of closed-loop systems in the future.

• Sex chromosomes and beta-cell function

  5K99DK140067-02
  Mirza Muhammad Fahd Qadir · TULANE UNIVERSITY OF LOUISIANA, LA · $88,775 · awarded Mar 30, 2026 · K99

  Project Summary. Although Type 2 diabetes (T2D) has been established as a disease affecting insulin producing pancreatic β-cells, surprisingly little is known on the molecular differences across sex. Recent work demonstrates that sex affects T2D pathogenesis, and therapeutic response. Generally, sex differences across disease are due to 1) sex chromosome genes, and/or 2) sex hormones. Sex chromosome genes consist of unique epigenetic modifiers which alter the transcriptome owing to dichotomous gene regulation. Similarly, sex hormones target conserved sex hormone receptors which effect cellular function via 1) direct genomic interaction and 2) extra-genomic cytoplasmic effects. These differences confer dichotomous advantages to cells from each sex. However molecular studies describing transcriptional regulation of sex differences across pancreatic cells in humans are lacking, primarily owing to the lack of a human islet culture system enabling the study of sex differences. I developed a novel long term culture system using human pancreatic slices establishing this as a model to study islet biology. Furthermore, to decipher transcriptional sex differences across islets, I have performed an multiomic study utilizing scRNAseq, snATACseq and dynamic hormone secretion. Together this work has established the foundation for my ongoing work on identifying novel regulators of islet function across sex. I have successfully set up the pancreatic slice system and performed multi-pronged screening interrogating novel genes in the context of sex differences. These studies combined network analysis of differentially expressed genes across the transcriptome and gene accessibility across the genome in islet cells, to discover differences across sex. This data reveals two important aspects on sex differences in islets 1) in a hormone free environment sex differences are restricted to sex chromosome genes, 2) female islet cells suppress their mitochondrial electron transport chain genes in T2D preventing oxidative stress. In Aim 1.1, I hypothesize that sex differences in β-cell function and resilience during T2D result from a combination of sex hormone effects observed only within the in vivo environment, and cell autonomous sex chromosome effects, moreover sex hormone effects are driven by the action of sex steroid estrogen receptor (ER)α. I intend to answer this by answering two questions utilizing the four-core mouse model 1) does ERα agonist action rely on sex chromosome complement? and 2) how the molecular landscape of ERα signaling drive resilience to metabolic stress in islets. In Aim 1.2, I propose to study if androgen receptor (AR) signaling has a similar effect to that of ERα in promoting a resilient molecular landscape in female islet cells. Aim 2 will establish if genes observed in Aim 1.1 drive similar pathways supporting β-cell in human islets. I will perform this by 1) utilizing human pancreatic slices to establish differences in physiological function and 2) use scRNAseq and snATACseq to dissect the molecular architecture of sex differences. These data will open exciting avenues of research by understanding the impact of sex chromosomes and hormones of islet physiology.

Related topics

• Diabetes research
• Obesity research