RPEP-00075 · 1988Six opioid-related substances were tested on isolated rat adipocytes (fat cells):
- Beta-endorphin, dynorphin, met-enkephalin, leu-enkephalin, and morphine (agonists)
- Naloxone (antagonist)
None altered insulin binding to fat cells. None changed 2-deoxy-glucose uptake (a measure of sugar absorption). None affected glucose incorporation into lipids (fat production). None showed lipolytic (fat-breaking) activity.
The conclusion: endogenous opioids do not directly affect fat cell metabolism. The glucose problems seen with opioid drugs must happen through other mechanisms, likely in the brain, liver, or pancreas.
Hauner, H; Glatting, G; Ditschuneit, H H; Pfeiffer, E F · In Vitro
RPEP-00102 · 1989Beta-endorphin had a dose-dependent biphasic effect on insulin secretion. Low doses inhibited and high doses stimulated insulin release. Met-enkephalin only inhibited. Dynorphin A had no effect.
Ahrén, B · Animal Study
RPEP-00119 · 1989Lidocaine increased plasma beta-endorphin equally in patients and controls, but pain relief in diabetic neuropathy was not correlated with beta-endorphin changes.
Kastrup, J; Bach, F W; Petersen, P; Dejgård, A; Ekman, R; Jensen, S; Angelo, H · Cross Sectional
RPEP-00149 · 1990All three opioid peptide families are present in the guinea pig endocrine pancreas but in different cell types, with processing pathways distinct from other organs.
Cetin, Y · Animal Study
RPEP-00162 · 1990Pancreas and liver contain substantial opioid peptide levels exceeding brain content, with functional delta and kappa receptors on pancreatic islets. These peripheral opioids could regulate blood glucose.
Khawaja, X Z; Green, I C; Thorpe, J R; Titheradge, M A · Animal Study
RPEP-00313 · 1994Specific beta-endorphin binding sites were localized to pancreatic islet cells, blocked by mu and delta receptor ligands, confirming opioid receptors on insulin-producing cells.
Zhang, M; Zheng, M; Schleicher, R L · In Vitro
RPEP-00467 · 1998Glucose stimulation induced prodynorphin gene expression in pancreatic beta-cell lines, with dynorphin peptides being processed and secreted, suggesting a novel opioid-mediated feedback mechanism in glucose regulation.
Josefsen, K; Buschard, K; Sørensen, L R; Wøllike, M; Ekman, R; Birkenbach, M · In Vitro
RPEP-00531 · 1999STZ-induced diabetes decreased POMC mRNA by significant amounts in the hypothalamic arcuate nucleus and anterior pituitary by 2-4 weeks, with insulin treatment (3 weeks) normalizing expression levels.
Kim, E M; Grace, M K; Welch, C C; Billington, C J; Levine, A S · Animal Study
RPEP-00551 · 1999BPC-157 significantly attenuated alloxan-induced gastric lesions in rats (200 mg/kg SC) and mice (400 mg/kg IP), reducing lesion severity and accelerating healing over the observation period.
Petek, M; Sikiric, P; Anic, T; Buljat, G; Separovic, J; Stancic-Rokotov, D; Seiwerth, S; Grabarevic, Z; Rucman, R; Mikus, D; Zoricic, I; Prkacin, I; Sebecic, B; Ziger, T; Coric, V; Turkovic, B; Aralica, G; Rotkvic, I; Mise, S; Hahn, V · Animal Study
RPEP-01116 · 2006Exubera was approved in 2006 as the first inhaled insulin and the first peptide hormone successfully delivered via the pulmonary route for clinical use. Clinical trials demonstrated that it was effective at controlling blood glucose, apparently safe, and preferred by patients compared to subcutaneous mealtime insulin injections.
The review highlights that the lungs' rich vascularity, large surface area, and immunotolerant characteristics make them an ideal target for peptide delivery, overcoming the traditional barrier of poor bioavailability that had limited inhaled peptide drugs. The authors noted that Exubera could reduce injection burden for both type 1 and type 2 diabetes patients and encourage earlier insulin initiation.
Bellary, Srikanth; Barnett, Anthony H · Review
RPEP-01146 · 2006Ghrelin reduced hepatic insulin sensitivity (increased gluconeogenesis) while showing different effects on peripheral insulin sensitivity in mice, demonstrating tissue-specific ghrelin-insulin interactions with implications for diabetes pathophysiology.
Heijboer, A C; van den Hoek, A M; Parlevliet, E T; Havekes, L M; Romijn, J A; Pijl, H; Corssmit, E P M · Animal Study
RPEP-01147 · 2006The gut-brain glucose regulatory axis operates through incretin peptides (GLP-1, GIP), neural signals, and other gut hormones to control glucose metabolism — pharmacological exploitation has produced GLP-1 agonists and DPP-4 inhibitors as major diabetes drug classes.
Heijboer, A C; Pijl, H; Van den Hoek, A M; Havekes, L M; Romijn, J A; Corssmit, E P M · Review
RPEP-01161 · 2006Bariatric surgery produced comprehensive gut hormone profile transformation: elevated GLP-1, PYY3-36, and oxyntomodulin with suppressed ghrelin, creating an anorectic hormonal milieu that facilitates weight loss and improves glucose metabolism beyond mechanical restriction.
le Roux, Carel W; Aylwin, Simon J B; Batterham, Rachel L; Borg, Cynthia M; Coyle, Frances; Prasad, Vyas; Shurey, Sandra; Ghatei, Mohammad A; Patel, Ameet G; Bloom, Stephen R · Clinical Trial
RPEP-01234 · 2007GLP-1 receptor agonists and DPP-4 inhibitors exploit the incretin system for diabetes treatment, providing glucose-dependent insulin stimulation, weight loss (GLP-1 agonists), and low hypoglycemia risk — the most significant new diabetes drug class.
Green, Dina E · Review
RPEP-01285 · 2007Quinazolinone ghrelin receptor antagonists showed oral bioavailability, reduced food intake, and improved glucose tolerance in animal models — positioning orally active ghrelin blockade as a dual-mechanism drug approach for treating both diabetes and obesity simultaneously.
Rudolph, Joachim; Esler, William P; O'connor, Stephen; Coish, Philip D G; Wickens, Philip L; Brands, Michael; Bierer, Donald E; Bloomquist, Brian T; Bondar, Georgiy; Chen, Libing; Chuang, Chih-Yuan; Claus, Thomas H; Fathi, Zahra; Fu, Wenlang; Khire, Uday R; Kristie, James A; Liu, Xiao-Gao; Lowe, Derek B; McClure, Andrea C; Michels, Martin; Ortiz, Astrid A; Ramsden, Philip D; Schoenleber, Robert W; Shelekhin, Tatiana E; Vakalopoulos, Alexandros; Tang, Weifeng; Wang, Lei; Yi, Lin; Gardell, Stephen J; Livingston, James N; Sweet, Laurel J; Bullock, William H · Animal Study
RPEP-01295 · 2007SS-31 (mitochondria-targeted peptide) prevented mitochondrial depolarization and apoptosis in pancreatic islet cells, preserved glucose-stimulated insulin secretion, and improved glycemic control in diabetic animals — protecting the beta-cells that diabetes progressively destroys.
Thomas, Dolca A; Stauffer, Craig; Zhao, Kesheng; Yang, Hua; Sharma, Vijay K; Szeto, Hazel H; Suthanthiran, Manikkam · Animal Study
RPEP-01364 · 2008Hormone-based fuel metabolism drugs span GLP-1 agonists (semaglutide class), amylin analogs (pramlintide), PYY analogs, and ghrelin modulators for integrated obesity/diabetes treatment — exploiting endogenous regulatory peptide systems for superior metabolic control.
Kesty, Nicole C; Roth, Jonathan D; Maggs, David · Review
RPEP-01370 · 2008New diabetes drugs include GLP-1 agonists (exenatide, liraglutide: injectable, weight loss, low hypo risk), DPP-4 inhibitors (sitagliptin, vildagliptin: oral, weight neutral), and amylin analog (pramlintide) — peptide-based drugs transforming type 2 diabetes treatment.
Krentz, Andrew J; Patel, Mayank B; Bailey, Clifford J · Review
RPEP-01395 · 2008GLP-1 agonists and DPP-4 inhibitors combine synergistically with metformin (first-line), sulfonylureas, thiazolidinediones, and insulin for T2DM, with combination selection guided by patient weight, hypo risk, and HbA1c target — practical combination pharmacotherapy guidance.
Over, Rebecca K; Ratner, Robert E · Review
RPEP-01404 · 2008Ghrelin and GHRP-6 restored gastric contractile activity and emptying in diabetic gastroparesis mice, with effects mediated through smooth muscle and neural pathways — confirming GH secretagogues as gastroprokinetic agents for diabetic GI dysfunction.
Qiu, Wen-Cai; Wang, Zhi-Gang; Wang, Wei-Gang; Yan, Jun; Zheng, Qi · Animal Study
RPEP-01405 · 2008Ghrelin and GHRP-6 restored gastric emptying in streptozotocin-diabetic rats with gastroparesis, improving gastric motility through GHS-R activation — validating GH secretagogues as therapeutic agents for diabetic gastroparesis, a common and debilitating complication.
Qiu, Wen-cai; Wang, Zhi-gang; Wang, Wei-gang; Yan, Jun; Zheng, Qi · Animal Study
RPEP-01430 · 2008Managed care analysis of exenatide (GLP-1 agonist: weight loss, injectable), sitagliptin (DPP-4 inhibitor: oral, weight neutral), and pramlintide (amylin analog: injectable, weight loss) for T2DM positioning — incretin drugs transforming diabetes pharmacotherapy economics.
VanDeKoppel, Shawna; Choe, Hae Mi; Sweet, Burgunda V · Review
RPEP-01992 · 2012Co-administration of [D-Leu-4]-OB3, a synthetic leptin-like peptide, with exenatide resulted in mice that were 4.2% lighter than their starting weight after 14 days — a stark contrast to the 19.7% weight gain in control mice and the 13.9% gain with exenatide alone.
For blood glucose, co-delivery of [D-Leu-4]-OB3 with exenatide reduced levels by 38.3% (vs. 20.4% for exenatide alone), and co-delivery with pramlintide acetate reduced glucose by 50.5% (vs. 30.2% for pramlintide alone). Notably, the leptin-like peptide also moderated insulin levels, suggesting it may improve insulin sensitivity rather than simply driving more insulin secretion.
Leinung, Matthew C; Grasso, Patricia · Animal Study
RPEP-03044 · 2016Adding liraglutide to insulin therapy in type 1 diabetes modestly improved blood sugar control (HbA1c reduced 0.20% more than placebo at the 1.8 mg dose), reduced total insulin requirements by 8%, and produced significant weight loss (up to 4.9 kg at 1.8 mg vs placebo). However, these benefits came with increased rates of symptomatic hypoglycemia across all doses and a significantly higher rate of hyperglycemia with ketosis at the 1.8 mg dose (2.22× higher than placebo).
The safety trade-offs — more low blood sugar episodes and more ketosis events — were judged to limit the clinical usefulness of liraglutide in type 1 diabetes.
Mathieu, Chantal; Zinman, Bernard; Hemmingsson, Joanna Uddén; Woo, Vincent; Colman, Peter; Christiansen, Erik; Linder, Martin; Bode, Bruce · Rct
RPEP-03331 · 2017The review evaluated multiple strategies for oral delivery of antidiabetic peptides (insulin, GLP-1, and GLP-1 analogs), identifying two main barriers that must be overcome: degradation by proteolytic enzymes in the gastrointestinal tract and poor absorption through the intestinal wall.
Among all approaches reviewed — including absorption enhancers, enzyme inhibitors, chemical modifications, and various carrier systems — nanocarrier systems emerged as the most promising platform. These include polymeric nanoparticles, solid lipid nanoparticles, liposomes, and micelles, each with distinct advantages for protecting peptides from degradation and enhancing their absorption. However, the authors noted that no FDA-approved oral antidiabetic peptide delivery system existed at the time of publication, and further development was needed.
Ismail, Ruba; Csóka, Ildikó · Review
RPEP-03747 · 2018Gastrin family peptides — specifically a modified CCK fragment called (pGlu-Gln)-CCK-8 and gastrin-17 — directly stimulate insulin secretion from pancreatic beta cells and promote beta-cell growth and survival. In cell studies, both peptides increased insulin release and boosted beta-cell proliferation while protecting against toxic damage. In live mice, (pGlu-Gln)-CCK-8 improved glucose disposal, enhanced insulin release, and reduced appetite.
The study also revealed that diabetes changes how CCK and gastrin are expressed in pancreatic islets: in diabetic mice, CCK shifted toward glucagon-producing alpha cells while gastrin shifted toward insulin-producing beta cells, suggesting these peptide systems actively adapt during disease.
Khan, Dawood; Vasu, Srividya; Moffett, R Charlotte; Irwin, Nigel; Flatt, Peter R · Preclinical Study (Cell + Animal)
RPEP-04833 · 2020In mice lacking the adiponectin gene (Adipoq-/- knockouts), MOTS-c levels in blood and muscle were significantly lower than normal. This directly links adiponectin to MOTS-c production.
In muscle cells (C2C12 myotubes), adiponectin treatment increased MOTS-c gene expression. The researchers traced the signaling chain: adiponectin activates APPL1, which activates SIRT1, which activates PGC-1alpha, which drives MOTS-c production. Blocking any step in this chain (with inhibitors or siRNA) stopped the MOTS-c increase.
In mice on a high-fat diet, both exercise and injected adiponectin or MOTS-c raised MOTS-c levels in blood and muscle. This was accompanied by improved insulin sensitivity, suggesting MOTS-c is a key mediator of adiponectin's metabolic benefits.
Overexpressing SIRT1 amplified the adiponectin effect on MOTS-c, while blocking PGC-1alpha eliminated it. This establishes the APPL1-SIRT1-PGC-1alpha pathway as the mechanism.
Guo, Qi; Chang, Bo; Yu, Qiong-Li; Xu, Si-Tong; Yi, Xue-Jie; Cao, Shi-Cheng · Animal Study (Mice) + In Vitro
RPEP-04840 · 2020The cost-of-control analysis compared oral semaglutide 14 mg against six injectable GLP-1 receptor agonists for type 2 diabetes. The calculation divides annual drug cost by the proportion of patients reaching HbA1c targets.
For the HbA1c ≤6.5% target, costs per patient achieving control: injectable semaglutide 1 mg was cheapest at $15,430, followed by oral semaglutide 14 mg at $17,383. All others (dulaglutide, exenatide once-weekly and twice-daily, liraglutide, lixisenatide) cost more per controlled patient.
For HbA1c <7.0%: injectable semaglutide 1 mg led at $12,627, followed by oral semaglutide at $13,493. The pattern was consistent.
Oral semaglutide was likely cost-effective versus all comparators except injectable semaglutide. This matters because some patients strongly prefer pills over injections.
Hansen, B B; Nuhoho, S; Ali, S N; Dang-Tan, T; Valentine, W J; Malkin, S J P; Hunt, B · Cost Effectiveness Analysis
RPEP-04854 · 2020The review synthesizes preclinical and clinical evidence for cardiovascular effects of GLP-1 receptor agonists (GLP-1RAs):
GLP-1 receptors are abundantly present in heart tissue, providing a direct mechanism for cardiac effects. Stimulating these receptors affects multiple cardiovascular parameters.
Heart rate increases slightly with GLP-1RAs, typically 2-4 beats per minute. Blood pressure decreases modestly. Both effects are consistent across drugs in the class.
Lipid profiles improve: reductions in postprandial triglycerides and total cholesterol. Inflammatory markers decrease, which may contribute to reduced atherosclerosis progression.
Microvascular function improves in human mechanistic studies, potentially protecting small blood vessels in the heart, kidneys, and other organs.
These individual effects, taken together, likely explain the reduced rates of heart attacks, strokes, and cardiovascular death seen in landmark trials like LEADER (liraglutide), SUSTAIN-6 (semaglutide), and REWIND (dulaglutide).
Heuvelman, Valerie D; Van Raalte, Daniël H; Smits, Mark M · Review
RPEP-04868 · 2020Prior cardiovascular outcome trials showed semaglutide reduced MACE (major adverse cardiovascular events: CV death, non-fatal stroke, non-fatal MI) in high-risk patients. This post hoc analysis asked: does the benefit extend to lower-risk patients?
A cardiovascular risk prediction model was developed from LEADER trial data and validated on the semaglutide dataset (area under the curve: 0.77, indicating good predictive performance).
Key finding: semaglutide reduced both relative and absolute risk of MACE versus comparators across the entire continuum of cardiovascular risk. The relative risk reduction tended to be largest in patients with low CV risk scores. The absolute risk reduction was largest for intermediate to high risk scores (because these patients had more events to prevent).
Previous data: SUSTAIN-6 showed HR 0.74 [0.58-0.95] for injectable semaglutide vs placebo. PIONEER 6 showed HR 0.79 [0.57-1.11] for oral semaglutide vs placebo. This analysis extends those findings across the risk spectrum.
Similar patterns were seen for individual MACE components and when only placebo comparator data were included.
Husain, Mansoor; Bain, Stephen C; Holst, Anders Gaarsdal; Mark, Thomas; Rasmussen, Søren; Lingvay, Ildiko · Post Hoc Analysis Of Phase 3 Clinical Trials
RPEP-04869 · 2020Combining individual patient-level data from SUSTAIN 6 (injectable semaglutide) and PIONEER 6 (oral semaglutide) versus placebo:
Overall MACE: HR 0.76 (95% CI 0.62-0.92), a 24% reduction. This was statistically significant.
Individual components: non-fatal stroke showed the strongest effect at HR 0.65 (95% CI 0.43-0.97), a 35% reduction. CV death and non-fatal MI showed numerical reductions but individual confidence intervals were wider.
Heart failure hospitalization: HR 1.03 (95% CI 0.75-1.40), no benefit. Notably, patients with prior heart failure also showed no MACE benefit (interaction P = 0.046).
Subgroup analyses: consistent MACE reduction in patients with and without established CV disease or chronic kidney disease, and in patients with and without prior MI or stroke (all interaction P > 0.05 except HF).
In the combined glycemic efficacy trials (where comparators included active drugs, not just placebo), MACE HR was 0.85 (95% CI 0.55-1.33).
Husain, Mansoor; Bain, Stephen C; Jeppesen, Ole K; Lingvay, Ildiko; Sørrig, Rasmus; Treppendahl, Marianne B; Vilsbøll, Tina · Pooled Post Hoc Analysis Of Cardiovascular Outcome Trials
RPEP-04874 · 2020The review covers multiple GLP-1 receptor agonists and their non-glycemic benefits:
Cardiovascular events: semaglutide and liraglutide demonstrated significant reduction in MACE with similar cardiovascular mortality rates. GLP-1RA use was associated with reduced cardiovascular and all-cause mortality versus placebo.
Safety: no increased risk of pancreatitis or thyroid cancer compared to placebo, addressing two common safety concerns.
Blood pressure and weight: exenatide and liraglutide decreased blood pressure values and body weight, and improved dyslipidemia.
Vascular biology: liraglutide specifically improved blood circulation by increasing nitric oxide levels and inhibiting adhesion molecules and procoagulant factors, both in lab experiments and clinical settings.
Cardiac remodeling: liraglutide showed beneficial effects on cardiac remodeling after heart attack in animal models, though more large trials were needed.
Guideline impact: international guidelines now recommend GLP-1RAs as first-line therapy in type 2 diabetes patients with high cardiovascular risk or as first-line in metformin-intolerant patients.
Iorga, Roua Anamaria; Bacalbasa, Nicolae; Carsote, Mara; Bratu, Ovidiu Gabriel; Stanescu, Ana Maria Alexandra; Bungau, Simona; Pantis, Carmen; Diaconu, Camelia Cristina · Review
RPEP-04882 · 2020This massive real-world study compared outcomes across multiple diabetes drug combinations:
Worst performer: metformin plus sulfonylurea (SU) had the highest risk of cardiovascular events and death. Metformin plus basal insulin had the highest severe hypoglycemia risk.
Best cardiovascular protection: regimens including a GLP-1 receptor agonist had the lowest MACE risk.
Best overall: metformin + SGLT2 inhibitor + GLP-1 had the lowest risk for all three endpoints (cardiovascular events, severe hypoglycemia, and all-cause mortality).
Key clinical insight: adding GLP-1 to metformin + basal insulin reduced all three endpoints compared to metformin + insulin alone, especially severe hypoglycemia. This suggests GLP-1 agonists should be considered before or alongside insulin.
The results do not support sulfonylurea as the second-line treatment choice, a finding that aligns with evolving guidelines moving away from SU.
Jensen, Morten Hasselstrøm; Kjolby, Mads; Hejlesen, Ole; Jakobsen, Poul Erik; Vestergaard, Peter · Population Based Cohort Study
RPEP-04887 · 2020Salmon skin collagen was broken down by four different enzymes. The trypsin-digested version showed the strongest DPP-IV inhibition at 66% at 10 mg/mL.
After separating the fragments by size, the smallest fraction (under a certain molecular weight) had an IC50 of 0.79 mg/mL. Further purification identified a novel peptide, LDKVFR, with an IC50 of 0.1 mg/mL (128.71 micromolar).
Molecular docking showed LDKVFR binds to DPP-IV through six hydrogen bonds and eight hydrophobic interactions, explaining its inhibitory activity.
Jin, Ritian; Teng, Xiangyu; Shang, Jiaqi; Wang, Dangfeng; Liu, Ning · In Vitro
RPEP-04890 · 2020Annual per-patient costs were similar across all four GLP-1 receptor agonists in the UK market. However, once-weekly semaglutide consistently outperformed the others in getting patients to treatment goals.
For the composite endpoint of HbA1c below 7.0% without weight gain or low blood sugar episodes, the competing drugs fell short: exenatide ER was 50.0% less effective, liraglutide was 51.3% less effective, and dulaglutide was 21.6% less effective than semaglutide.
Semaglutide also led in single endpoints including HbA1c targets (below 7.0% and below 7.5%) and meaningful weight loss (5% or more body weight reduction).
Johansen, Pierre; Sandberg, Anna; Capehorn, Matthew · Cost Effectiveness Analysis
RPEP-04896 · 2020Mice were fed a high-fat, high-fructose, high-cholesterol diet for 36 weeks to develop NASH with fibrosis, then treated for 8 weeks. Low-dose glucagon or GIP alone did not affect body weight, liver fat, or liver damage scores. But when combined with GLP-1 receptor activation, both glucagon and GIP provided additional benefits.
The triple combination (GLP-1 + glucagon + GIP) and a dual GLP-1/glucagon peptide both significantly reduced the NAFLD activity score more than high-dose liraglutide. This happened at comparable levels of weight loss, meaning the extra liver improvement came from the hormones themselves, not just from losing weight.
This supports the idea that multi-receptor agonists targeting two or three gut hormone receptors could be more effective for NASH than GLP-1 drugs alone.
Kannt, Aimo; Madsen, Andreas Nygaard; Kammermeier, Claire; Elvert, Ralf; Klöckener, Tim; Bossart, Martin; Haack, Torsten; Evers, Andreas; Lorenz, Katrin; Hennerici, Wolfgang; Rocher, Corinne; Böcskei, Zsolt; Guillemot, Jean-Claude; Mikol, Vincent; Pattou, Francois; Staels, Bart; Wagner, Michael · Animal Study
RPEP-04940 · 2020No statistical heterogeneity in cardiovascular (MACE) or nephropathy outcomes across blood pressure categories for either liraglutide or semaglutide vs placebo.
Leiter, Lawrence A; Bain, Stephen C; Bhatt, Deepak L; Buse, John B; Mazer, C David; Pratley, Richard E; Rasmussen, Søren; Ripa, Maria Sejersten; Vrazic, Hrvoje; Verma, Subodh · Post Hoc Analysis Of RCTs
RPEP-04944 · 2020Dulaglutide protected chondrocytes from AGE-induced cartilage matrix degradation by reducing MMP-3/13, ADAMTS-4/5, inflammatory cytokines, and ROS via NF-κB pathway inhibition.
Li, Hai; Chen, Jianhai; Li, Biao; Fang, Xiaoyan · In Vitro
RPEP-04964 · 2020Single 100 mg/kg dose of analytical-grade STZ induced complete diabetes in cynomolgus monkeys with destroyed beta cells and <0.5 ng/mL stimulated C-peptide, without organ toxicity.
Liu, Zhengzhao; Lu, Ying; Hu, Wenbao; Hara, Hidetaka; Dai, Yifan; Cai, Zhiming; Mou, Lisha · Animal
RPEP-04976 · 2020Insulin receptors are expressed on a specific subset of sensory neurons in both the central and peripheral nervous system. Quantitative studies revealed that visceral (organ-supplying) sensory neurons express more insulin receptors than somatic (skin/muscle) sensory neurons.
InsR co-localizes with TRPV1 (a pain channel), CGRP, and substance P in these neurons. This co-expression means insulin signaling can directly modulate pain transmission and neurogenic inflammation.
The functional significance includes modulation of ion channels involved in pain, regulation of neuropeptide release (CGRP and substance P), and neurotrophic effects on nerve growth, development, and regeneration. Recent studies reveal important roles for insulin in axonal growth and repair.
Lázár, Bence András; Jancsó, Gábor; Sántha, Péter · Review
RPEP-04984 · 2020GLP-1 receptor agonists reduced 3-point MACE by 12% (HR 0.88), stroke by 16%, CV death by 12%, all-cause mortality by 11%, and HF hospitalization by 8% across 56,004 patients — with no significant difference between those with or without established CVD.
Marsico, Fabio; Paolillo, Stefania; Gargiulo, Paola; Bruzzese, Dario; Dell'Aversana, Simona; Esposito, Immacolata; Renga, Francesco; Esposito, Luca; Marciano, Caterina; Dellegrottaglie, Santo; Iesu, Ivana; Perrone Filardi, Pasquale · Meta Analysis
RPEP-04997 · 2020Mitochondrial-derived peptides serve as retrograde metabolic signals — declining in metabolic disease but rising during adaptive stress responses like exercise — and can improve insulin sensitivity when administered therapeutically.
Merry, Troy L; Chan, Alex; Woodhead, Jonathan S T; Reynolds, Joseph C; Kumagai, Hiroshi; Kim, Su-Jeong; Lee, Changhan · Review
RPEP-05011 · 2020Dulaglutide reduced HbA1c 0.24% more than liraglutide in real-world clinical practice (p=0.003), confirmed by meta-analysis of observational studies.
Morieri, Mario Luca; Rigato, Mauro; Frison, Vera; Simioni, Natalino; D'Ambrosio, Michele; Tadiotto, Federica; Paccagnella, Agostino; Lapolla, Annunziata; Avogaro, Angelo; Fadini, Gian Paolo · Observational
RPEP-05012 · 2020GLP-1 receptor agonists reduce macro-albuminuria in cardiovascular safety trials, with multiple proposed kidney-protective mechanisms including anti-inflammatory, hemodynamic, and metabolic effects.
Mosterd, Charlotte M; Bjornstad, Petter; van Raalte, Daniël H · Review
RPEP-05013 · 2020Amylin and pramlintide increased amyloid-beta production by modulating APP and γ-secretase in lipid rafts, leading to increased Aβ burden, synaptic loss, and neuroinflammation in TgSwDI Alzheimer's mice.
Mousa, Youssef M; Abdallah, Ihab M; Hwang, Misako; Martin, Douglas R; Kaddoumi, Amal · Animal
RPEP-05038 · 2020GLP-1 RAs significantly reduced MACE (OR 0.87), all-cause mortality (OR 0.89), and showed a trend toward heart failure reduction (OR 0.93) without increasing atrial fibrillation risk across 43 trials.
Nreu, Besmir; Dicembrini, Ilaria; Tinti, Federico; Sesti, Giorgio; Mannucci, Edoardo; Monami, Matteo · Meta Analysis
RPEP-05043 · 2020Active NBD peptide reduced albuminuria by >40%, decreased podocyte loss and basement membrane thickness, and modulated inflammatory markers in a type 2 diabetic nephropathy mouse model.
Opazo-Ríos, Lucas; Plaza, Anita; Sánchez Matus, Yenniffer; Bernal, Susana; Lopez-Sanz, Laura; Jimenez-Castilla, Luna; Carpio, Daniel; Droguett, Alejandra; Mezzano, Sergio; Egido, Jesús; Gomez-Guerrero, Carmen · Animal Study
RPEP-05055 · 2020Semaglutide subcutaneous was superior to dulaglutide and exenatide ER for HbA1c and weight reduction in head-to-head trials, with both semaglutide and dulaglutide showing cardiovascular and renal benefits.
Patel, Dhiren · Review
RPEP-05065 · 2020Semaglutide demonstrated cardiovascular superiority in SUSTAIN 6, with a safety profile typical of GLP-1RAs. The only concerning signal was increased diabetic retinopathy events, likely related to rapid glucose lowering rather than direct drug toxicity.
Peter, Rajesh; Bain, Steve C · Review
RPEP-05071 · 2020Tβ4 at 10 ng/mL improved diabetic EPC migration, tubule formation, and angiogenic factor secretion in vitro, and increased capillary density in vivo, but only non-Tβ4-treated EPCs significantly improved left ventricular ejection fraction.
Poh, Kian Keong; Lee, Poay Sian Sabrina; Djohan, Andie Hartanto; Galupo, Mary Joyce; Songco, Geronica Gorospe; Yeo, Tiong Cheng; Tan, Huay Cheem; Richards, Arthur Mark; Ye, Lei · Animal Study