Research

MOTS-c metabolic research: insulin, glucose and body weight

Mouse studies linked MOTS-c to insulin sensitivity and diet-induced weight gain; human data are associations. A guide to the metabolic evidence by model.

By the MOTS-C Peptide editorial teamLast reviewed November 11, 2026Sources: editorially approved

Short answer

Metabolism is the most-studied area of MOTS-c research, with 104 indexed records. The animal findings are consistent: administered MOTS-c was associated with better glucose tolerance and less diet-induced weight gain in mice [Lee et al. 2015]. The 28 human studies in this set measured natural MOTS-c levels in different groups rather than giving the peptide.

Human observational: 28
Animal study (in vivo): 32
Tissue / sample study (ex vivo): 1
Cell study (in vitro): 5
Analytical / methods: 1
Review: 37

104 indexed records. Open this set in the evidence explorer.

Where the hypothesis came from

The discovery paper framed MOTS-c as a regulator of metabolic homeostasis. In cells it inhibited the folate cycle and activated AMPK; in mice, treatment was associated with protection against age-dependent and high-fat-diet insulin resistance, and against diet-induced obesity, with skeletal muscle as the apparent primary target [Lee et al. 2015]. Later work has largely tested parts of that account in other models rather than replacing it.

What the human studies measured

Human metabolic research on MOTS-c is observational. Cohorts of people with normal glucose tolerance, prediabetes and type 2 diabetes have been compared on circulating MOTS-c, sometimes stratified by glycaemic control, hypertension or cardiovascular disease. The reported direction is not uniform across studies, and sample sizes vary widely.

The genotype work is a partial exception, because a variant is fixed at birth and cannot be a consequence of disease. Men carrying the allele that produces K14Q-MOTS-c had a higher prevalence of type 2 diabetes in a Japanese cohort, concentrated among the least physically active, and the variant peptide showed reduced activity in mice and cells [Zempo et al. 2021]. That design argues more strongly for relevance than a blood-level comparison does, though it remains population-specific and sex-specific.

Other metabolic findings in animals

Cold-exposure work in mice reported an association with brown-fat thermogenic gene expression and white-fat browning, with the effect disturbed by ERK inhibition [Lu et al. 2019]. Lipid-handling and liver endpoints appear across several animal studies. These are separate models asking separate questions, and they do not combine into a single metabolic effect.

The trial that will test this directly

A Phase 2a randomised, double-blind, placebo-controlled trial in adults with prediabetes and overweight or obesity lists change from baseline in an oral-glucose-tolerance-derived insulin sensitivity index as a primary outcome, alongside treatment-emergent adverse events, with estimated completion in 2028 [NCT07505745]. It is the first registered study designed to answer the metabolic question in people.

Until it reports, FDA’s assessment stands as the regulatory reading of this literature: the pharmacology is limited to cell and rodent models, dose-response assessments are missing, and the clinical relevance of the nonclinical findings is currently unknown [FDA 2026].

Strongest metabolic records

Indexed MOTS-c metabolic studies ranked by evidence tier
Study	Model	What was reported	Limitations	Tier
Sonay 2026 J Clin Med Endogenous MOTS-c measured	Human obs. Patients with Hashimoto's thyroiditis and age- and sex-matched healthy controls; circulating MOTS-c	Measured lower circulating MOTS-c in patients with Hashimoto's thyroiditis than in matched controls, with inverse correlations with body mass index, fasting glucose, HbA1c, HOMA-IR, thyroid-stimulating hormone, C-reactive protein and thyroid autoantibodies. Reported that Hashimoto's thyroiditis and HOMA-IR were independent determinants of lower MOTS-c in regression analysis.	Cross-sectional design cannot establish direction; single-centre sample measured by ELISA at one time point; medication and iodine status largely unaccounted for beyond levothyroxine use.	Evidence tier B
Sączek 2026 Kidney Blood Press Res Endogenous MOTS-c measured	Human obs. Kidney transplant recipients and age-matched controls; serum nardilysin and MOTS-c by ELISA	Measured higher serum nardilysin and MOTS-c in kidney transplant recipients than in age-matched controls over a median follow-up of about 29 months. Reported no significant associations between MOTS-c and cardiometabolic features, and a non-significant trend toward lower allograft loss risk with higher MOTS-c, while nardilysin was inversely associated with prevalent cardiovascular disease.	MOTS-c was a secondary marker alongside nardilysin; single-centre observational design with a small control group and few outcome events; residual confounding likely.	Evidence tier B
Filibeli 2026 Arch Endocrinol Metab Several	Human obs. Adolescents aged 12-18 with polycystic ovary syndrome and controls; serum ELISA and m.1382A>C sequencing	Measured serum MOTS-c in adolescents with and without polycystic ovary syndrome and found higher mean levels in the PCOS group that did not reach statistical significance. Reported no significant association between MOTS-c levels and anthropometric or metabolic parameters, and all participants carried the wild-type A/A genotype at m.1382A>C.	Cross-sectional case-control design; the genotype analysis was uninformative because no variant carriers were found; single-centre adolescent sample.	Evidence tier B
Kutuk 2026 Sci Rep Endogenous MOTS-c measured	Human obs. Women with polycystic ovary syndrome and age- and BMI-matched controls; serum ELISA and vastus lateralis biopsies	Measured lower circulating MOTS-c concentrations and lower skeletal muscle MOTS-c expression in women with polycystic ovary syndrome than in matched controls. Reported that serum MOTS-c was inversely associated with total testosterone and total cholesterol in this cohort.	Cross-sectional case-control design cannot establish direction; muscle expression was assessed only in a subgroup; single-centre sample of women with weak correlation coefficients.	Evidence tier B
Yoon 2026 J Clin Transl Endocrinol Endogenous MOTS-c measured	Human obs. Lean adult controls and adults with obesity scheduled for bariatric surgery; adipose tissue from lean kidney donors and participants with obesity	Found higher circulating MOTS-c in adults with obesity than in lean adults, with BMI and HOMA-IR each independently predicting higher levels and a nonlinear relationship with HOMA-IR. Reported that adipose tissue MOTS-c expression did not differ between groups and did not correlate with circulating MOTS-c. Measured no change in circulating MOTS-c 6 months after bariatric surgery despite lower BMI in the 10 participants followed.	Small exploratory sample with only 10 participants followed after surgery, cross-sectional group comparison, adipose tissue controls drawn from kidney donors rather than the lean comparison group, and no sex-stratified analysis reported.	Evidence tier B
Jelinek 2025 Sci Rep Endogenous MOTS-c measured	Human obs. Adults stratified by HbA1c into normoglycaemic, prediabetic and diabetic groups with clinical, oxidative, inflammatory and mitochondrial biomarkers	Applied random forest and hierarchical random forest models to predict the atherogenic index of plasma in adults stratified by HbA1c. Reported that mitochondrial redox markers including humanin ranked among the top predictors in the normoglycaemic group, that oxidative stress markers were more informative in prediabetes, and that MOTS-c and IL-1β were key features in the group with diabetes, with waist-to-height ratio the main contributing variable overall.	Cross-sectional design with no reported sample size or external validation cohort, so stage-specific feature rankings may not be stable; MOTS-c appears only as one feature in a machine-learning model rather than as a prespecified outcome.	Evidence tier B
Ozkaya 2025 Arch Endocrinol Metab Endogenous MOTS-c measured	Human obs. Adults with obesity and adults with normal body mass index, sampled after an overnight fast	Measured serum MOTS-c in adults with and without obesity and found no significant difference between the groups. Reported a positive correlation between serum MOTS-c and HOMA-IR but no correlation with high-sensitivity C-reactive protein or asymmetric dimethylarginine, and found in multiple regression that MOTS-c was lower with older age and higher with greater insulin resistance in these participants.	Small single-centre cross-sectional sample with unequal groups and no longitudinal data; broad exclusions limit generalisability, endothelial function was assessed only by a single circulating marker, and the null primary comparison may be underpowered.	Evidence tier B
Luo 2025 Sleep Biol Rhythms Endogenous MOTS-c measured	Human obs. Adults undergoing polysomnography for suspected obstructive sleep apnea, and control participants	Measured serum MOTS-c in adults assessed by polysomnography and reported lower levels with greater obstructive sleep apnea severity. Reported that serum MOTS-c correlated with body mass index, apnea-hypopnea index and oxygen desaturation index independent of age, and that in analysis of covariance with body mass index as a covariate, OSA severity was an independent factor associated with serum MOTS-c levels in these participants.	Single-centre cross-sectional design with a modest sample and unequal group sizes (only 8 participants with mild OSA); no longitudinal follow-up, so temporal direction cannot be established.	Evidence tier B
Ikonomidis 2025 J Am Heart Assoc Endogenous MOTS-c measured	Human obs. Adults with type 2 diabetes at high cardiovascular risk receiving glucose-lowering drug regimens	Reported that circulating MOTS-c improved only in the SGLT-2 inhibitor and combined GLP-1 receptor agonist plus SGLT-2 inhibitor groups in adults with type 2 diabetes over 12 months of follow-up. Found that the decrease in GDF-15 was associated with increases in antioxidant capacity and MOTS-c, and that an increase in MOTS-c was associated with improved global longitudinal strain and constructive myocardial work.	Non-randomised observational comparison relying on propensity matching; MOTS-c was one of several secondary biomarkers; single-centre cohort with modest group sizes and no placebo arm.	Evidence tier B
Girişgen 2025 J Clin Res Pediatr Endocrinol Endogenous MOTS-c measured	Human obs. Serum MOTS-c and renal markers in children with type 1 diabetes and healthy children	Measured lower serum MOTS-c in children with type 1 diabetes than in healthy children, with no differences between subgroups defined by diabetes duration, metabolic control or renal findings, and no predictive association with diabetic kidney disease in regression analysis.	Controls were significantly younger than patients, and the single-centre design used one measurement per child; subgroup analyses were small and the study is cross-sectional.	Evidence tier B

Frequently asked questions

Does MOTS-c affect insulin resistance?

In mice, administered MOTS-c was reported to reduce age-dependent and diet-induced insulin resistance. In people, studies have compared natural MOTS-c levels between groups with and without metabolic disease, which is an association rather than a test of the peptide.

Is MOTS-c lower in people with type 2 diabetes?

Several cohort studies have reported differences in circulating MOTS-c between people with and without diabetes or prediabetes. Direction and significance vary between studies, and none of them establishes cause.

Does MOTS-c affect glucose metabolism?

Cell work reported enhanced glycolytic responses to glucose, and mouse work reported better glucose tolerance. A Phase 2a trial is now measuring an insulin sensitivity index in adults with prediabetes.

Has MOTS-c been tested for obesity in humans?

No. Mouse studies reported less diet-induced weight gain. FDA noted that obesity is a serious condition with approved therapies available, and that it found no human data on MOTS-c.

References

Lee C, Zeng J, Drew BG et al. (2015). The mitochondrial-derived peptide MOTS-c promotes metabolic homeostasis and reduces obesity and insulin resistance. Cell Metab. PubMed 25738459 · doi:10.1016/j.cmet.2015.02.009 · Study record[Animal, tier C]
Zempo H, Kim SJ, Fuku N et al. (2021). A pro-diabetogenic mtDNA polymorphism in the mitochondrial-derived peptide, MOTS-c. Aging (Albany NY). PubMed 33468709 · doi:10.18632/aging.202529 · Study record[Human obs., tier B]
Lu H, Tang S, Xue C et al. (2019). Mitochondrial-Derived Peptide MOTS-c Increases Adipose Thermogenic Activation to Promote Cold Adaptation. Int J Mol Sci. PubMed 31109005 · doi:10.3390/ijms20102456 · Study record[Animal, tier C]
ClinicalTrials.gov (2026-04-01). MOTS-c for Improving Insulin Sensitivity in Adults With Prediabetes and Overweight/Obesity (NCT07505745). Source[retrieved 2026-11-11]
U.S. Food and Drug Administration (2026-05-11). FDA Briefing Document: MOTS-c-Related Bulk Drug Substances (MOTS-c (free base) and MOTS-c acetate). Source[retrieved 2026-11-11]