The studies use different experimental systems and measure different endpoints. The sections below keep those findings separated by study and research model.
ARA-290 in Pancreatic Islet Research
The pancreatic study used Goto-Kakizaki rats to examine glucose regulation and pancreatic islet function. Researchers assessed glucose tolerance and HbA1c in the animals, then isolated pancreatic islets for experiments on glucose stimulated insulin secretion and related cellular responses.
Glucose-Stimulated Insulin Secretion
ARA-290-treated Goto-Kakizaki rats had lower plasma glucose concentrations after three and four weeks. HbA1c was approximately 20% lower after four weeks. Glucose tolerance testing also showed an improved glucose response. The study reported no change in whole-body or hepatic insulin sensitivity.
In isolated islets from treated Goto-Kakizaki rats, glucose-stimulated insulin secretion increased. Perifusion experiments showed a stronger first phase insulin response during high-glucose stimulation. The researchers described these findings as improved glucose stimulus-secretion coupling.
Islet Glucose Metabolism and Cellular Signaling
Under high-glucose conditions, ARA-290 increased glucose oxidation and ATP production. The investigators also recorded higher intracellular free Ca²⁺ concentrations and increased Ca²⁺ oscillation frequency in response to glucose, carbachol and KCl.
KATP-channel experiments used diazoxide to keep the channels open. Under those conditions, the ARA-290-associated increase in glucose-stimulated insulin secretion was reduced. When KCl was used to depolarize the cells, an additional ARA-290-associated secretion response remained. PKA inhibition with H89 abolished the ARA-290-associated increase in glucose-stimulated insulin secretion.
ARA-290 in Human Metabolic Research
A separate phase 2 placebo-controlled study examined ARA-290 in people with type 2 diabetes and painful neuropathy.
Glycemic and Lipid Measurements
The study reported an improvement in HbA1c during the 56-day observation period in the ARA-290 group. It also reported changes in lipid measurements, including the total-cholesterol-to-HDL ratio, HDL cholesterol, and triglycerides.
The article reported that the metabolic changes continued during the additional observation period after the initial 28-day experimental period. These findings represent measurements from the human study and are separate from the pancreatic-islet experiments.
Scope of the Human Evidence
The published human evidence comes from a phase 2 study. Participants had type 2 diabetes and painful neuropathy and the study included an ARA-290 group and a placebo group. The experimental period lasted 28 days, followed by an additional month of observation.
The study was relatively small and short. Its findings describe metabolic measurements from this particular trial and follow-up period. They do not establish how these findings would apply to other populations or longer treatment periods.
ARA-290 and Endothelial Colony-Forming Cells
A separate study examined ARA-290 effects on endothelial colony-forming cells (ECFCs) in vitro and after ECFC transplantation in mice with chronic hindlimb ischemia. The researchers assessed ECFC biological activity, transplanted-cell homing and vascular outcomes.
Endothelial Cell Proliferation, Migration, and Survival
ARA-290 increased ECFC proliferation and migration in cell-culture experiments. The researchers also exposed ECFCs to hydrogen peroxide to assess resistance to induced apoptosis. ARA-290 increased ECFC resistance to hydrogen peroxide-induced apoptosis.
Endothelial Cell Homing in Ischemic Tissue
The researchers transplanted radiolabeled ECFCs into mice with chronic hindlimb ischemia and used SPECT/CT to assess their distribution. Four hours after transplantation, ARA-290 increased the amount of transplanted ECFCs detected in the ischemic leg.
The researchers also neutralized CD31 on the transplanted ECFCs. This intervention inhibited the ARA-290-associated improvement in ECFC homing to the ischemic tissue.
Hindlimb Blood-Flow Recovery
After 28 days, ARA-290 increased the ischemic-to-non-ischemic hindlimb blood-flow ratio in mice that received ECFC transplantation. The study also found increased capillary density in the ischemic tissue.
ARA-290 in Experimental Vascular Repair
A different study examined ECFC-mediated vascular repair in the oxygen-induced retinopathy model. The researchers evaluated ECFC transplantation in ischemic retinal tissue with and without ARA-290.
Ischemic Retinal Vascular Repair
Following intravitreal transplantation, ECFCs incorporated into damaged retinal vasculature. The study measured the remaining avascular area and found a significant reduction following ECFC transplantation. The vasoreparative effect of ECFCs was enhanced in the presence of ARA-290.
The study also examined ECFC viability in cell culture under hydrogen peroxide-induced oxidative stress. ARA-290 enhanced cell viability under that experimental condition. The researchers therefore evaluated both ECFC cellular viability and retinal vascular repair within this study.
ARA-290 in Age-Associated Cardiovascular Research
A randomized controlled animal study examined ARA-290 during advanced aging in Fischer 344 × Brown Norway rats. The study used longitudinal and cross sectional assessments beginning with 18-month old rats and continuing to 33 months of age.
Researchers evaluated age related cardiovascular changes alongside late-life frailty and cellular measurements in isolated left ventricular cardiomyocytes.
Cardiac Function During Aging
Serial echocardiography showed age related changes in left ventricular function and structure. In saline-treated rats, left ventricular end-systolic volume increased by approximately twofold between 18 and 33 months, while left ventricular ejection fraction declined by about 14% after 22 months. The study also measured left ventricular wall thickness, wall thickening, and left ventricular mass. LV mass itself did not significantly change across the 18-to-33-month period.
ARA-290 significantly mitigated the age-associated increase in left ventricular end-systolic volume and blunted the decline in ejection fraction. The treatment did not significantly alter the measured age-associated structural changes in LV wall thickness or LV mass. Tail blood pressure increased with age, while ARA-290 significantly reduced this age-associated elevation.
Cardiomyocyte Autophagy and Mitochondrial Stress
The investigators isolated left ventricular cardiomyocytes from aged rats and measured autophagy flux, lipofuscin accumulation and the mitochondrial permeability-transition response to oxidant stress.
ARA-290-treated rats showed greater cardiomyocyte autophagy flux and lower lipofuscin accumulation. The mitochondrial permeability-transition pore also required a higher level of oxidant stress to trigger the measured response in cardiomyocytes from the ARA-290 group.
Frailty and Healthspan Measures
Body weight was measured repeatedly throughout the aging study. ARA-290 treatment blunted the decline in body weight observed during late life. At 33 months, the researchers also calculated a 31-parameter frailty index.
The ARA-290 group had a lower overall frailty index at the final assessment. The study therefore included body weight and multiple late-life functional measures as part of its assessment of organism-wide frailty.
Interpreting the Metabolic and Vascular Evidence
Experimental Models and Evidence Levels
The evidence spans cellular experiments, animal research, and human clinical research. These evidence levels address different research questions and provide different types of evidence. Findings from experimental models therefore provide a different level of evidence than findings from human clinical research.
Current Evidence Gaps
Researchers still lack evidence establishing the long term consistency of ARA-290 findings across metabolic, vascular and cardiovascular research. The available evidence also does not establish whether experimental findings translate into durable human outcomes.
Researchers need longer-term evidence to determine whether reported effects persist over time and whether different research settings produce consistent results.
Research Collection
Explore the peptide research collection from Direct SARMs for laboratory research information on available research compounds.
FAQs
References
- Muller C, Yassin K, Li LS, Palmblad M, Efendic S, Berggren PO, Cerami A, Brines M, Östenson CG. ARA290 Improves Insulin Release and Glucose Tolerance in Type 2 Diabetic Goto-Kakizaki Rats. Mol Med. 2016 May;21(1):969-978. PubMed ↗
- Brines M, Dunne AN, van Velzen M, Proto PL, Ostenson CG, Kirk RI, Petropoulos IN, Javed S, Malik RA, Cerami A, Dahan A. ARA 290, a nonerythropoietic peptide engineered from erythropoietin, improves metabolic control and neuropathic symptoms in patients with type 2 diabetes. Mol Med. 2015 Mar 13;20(1):658-66. PubMed ↗
- Hache G, Garrigue P, Bennis Y, Stalin J, Moyon A, Cerami A, Brines M, Blot-Chabaud M, Sabatier F, Dignat-George F, Guillet B. ARA290, a Specific Agonist of Erythropoietin/CD131 Heteroreceptor, Improves Circulating Endothelial Progenitors' Angiogenic Potential and Homing Ability. Shock. 2016 Oct;46(4):390-7. PubMed ↗
- O'Leary OE, Canning P, Reid E, Bertelli PM, McKeown S, Brines M, Cerami A, Du X, Xu H, Chen M, Dutton L, Brazil DP, Medina RJ, Stitt AW. The vasoreparative potential of endothelial colony-forming cells in the ischemic retina is enhanced by cibinetide, a non-hematopoietic erythropoietin mimetic. Exp Eye Res. 2019 May;182:144-155. PubMed ↗
- Winicki NM, Nanavati AP, Morrell CH, Moen JM, Axsom JE, Krawczyk M, Petrashevskaya NN, Beyman MG, Ramirez C, Alfaras I, Mitchell SJ, Juhaszova M, Riordon DR, Wang M, Zhang J, Cerami A, Brines M, Sollott SJ, de Cabo R, Lakatta EG. A small erythropoietin derived non-hematopoietic peptide reduces cardiac inflammation, attenuates age associated declines in heart function and prolongs healthspan. Front Cardiovasc Med. 2023 Jan 18;9:1096887. PubMed ↗
