Cited by 225Pancreatic function and diabetesAdipokines, Inflammation, and Metabolic DiseasesDiabetes Treatment and Management

The DOI matches its Crossref record; 38 of the 39 references it cites were found in a registry or an index, and 1 are not checked yet; 2 of the 29 sources its claims cite were checked for support.

Treatment of Obesity and Diabetes Using Oxytocin or Analogs in Patients and Mouse Models

Open access

Abstract

Obesity is important for the development of type-2 diabetes as a result of obesity-induced insulin resistance accompanied by impaired compensation of insulin secretion from pancreatic beta cells. Here, based on a randomized pilot clinical trial, we report that intranasal oxytocin administration over an 8-week period led to effective reduction of obesity and reversal of related prediabetic changes in patients. Using mouse models, we further systematically evaluated whether oxytocin and its analogs yield therapeutic effects against prediabetic or diabetic disorders regardless of obesity. Our results showed that oxytocin and two analogs including [Ser4, Ile8]-oxytocin or [Asu1,6]-oxytocin worked in mice to reverse insulin resistance and glucose intolerance prior to reduction of obesity. In parallel, using streptozotocin-induced diabetic mouse model, we found that treatment with oxytocin or its analogs reduced the magnitude of glucose intolerance through improving insulin secretion. The anti-diabetic effects of oxytocin and its analogs in these animal models can be produced similarly whether central or peripheral administration was used. In conclusion, oxytocin and its analogs have multi-level effects in improving weight control, insulin sensitivity and insulin secretion, and bear potentials for being developed as therapeutic peptides for obesity and diabetes.

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Overview

AI snapshot

Written from the paper’s full text.

TL;DR

In an 8-week randomized pilot trial, intranasal oxytocin reduced body weight and BMI and improved lipid profiles in obese non-diabetic patients, with no reported adverse effects. In mouse models, oxytocin and two analogs improved insulin sensitivity and insulin secretion independently of body-weight reduction, including after streptozotocin-induced beta-cell damage.

Key findings

  • In the clinical trial, intranasal oxytocin (24 units 4 times/day) for 8 weeks reduced body weight by 8.9±5.4 kg and BMI by 3.2±1.9 kg/m² versus baseline (P<0.001); 4-week weight reduction was 4.6±3.2 kg. Placebo produced no therapeutic effect against obesity (n=9 oxytocin, n=11 placebo).
  • Oxytocin treatment significantly reduced serum LDL and cholesterol and tended to increase HDL; no adverse effects were reported, and no cardiovascular, liver, or kidney dysfunction was found.
  • In high-fat-diet-fed prediabetic mice, central oxytocin and analogs improved glucose intolerance and fasting insulin levels without body-weight change; [Ser4, Ile8]-oxytocin had more pronounced effects than native oxytocin, while [Asu1,6]-oxytocin was comparable to oxytocin but weaker than [Ser4, Ile8]-oxytocin.
  • In streptozotocin-induced diabetic mice, central oxytocin and analogs improved glucose tolerance and insulin secretion (first- and second-phase GSIS) without body-weight changes; peripheral i.p. [Ser4, Ile8]-oxytocin also improved glucose tolerance in both high-fat-diet and streptozotocin models.

Methods

  • Randomized placebo-controlled pilot clinical trial (ChiCTR-TRC-12002884) in patients with obesity (BMI ≥28 kg/m²), ages 20–60, excluding diabetes; oxytocin nasal spray 24 units 4 times/day before three meals and sleep for 8 weeks versus saline placebo; outcomes included body weight, BMI, waist/hip circumference, glucose, insulin, lipids, and safety labs.
  • Mouse studies used C57BL/6 mice: high-fat-diet-induced prediabetes (2 months) and streptozotocin-induced diabetes (40 mg/kg i.p. for 4 days); oxytocin or analogs [Ser4, Ile8]-oxytocin and [Asu1,6]-oxytocin were given centrally via third-ventricle cannula or peripherally i.p.; assessments included glucose tolerance tests, fasting insulin ELISA, and glucose-stimulated insulin secretion.
  • Statistics used repeated measures, ANOVA with post hoc tests, and two-tailed Student’s t tests; clinical data are mean±SD, animal data mean±SEM, with P<0.05 considered significant.

Limitations

  • The paper states that future studies with larger samples and longer duration are needed to fully evaluate efficacy and side-effect profiles of oxytocin nasal spray; the clinical trial excluded diabetic patients, so whether oxytocin treats diabetes in an obesity-independent manner in humans remains to be tested; and the mouse experiments did not address underlying signaling mechanisms.
  • Evident from the text: the clinical sample was small (n=20 total) with baseline imbalances (oxytocin group younger, heavier, and with higher BMI/waist circumference than placebo), and animal groups were small (n=4–8) with short acute treatment periods.

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Integrity signals

Registry

Crossref · 10.1371/journal.pone.0061477

Cites

38 of 39 references verified0 citation errors · 0 not checkable

Statistics

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Figures

Figure 1 Study design and flowchart for clinical trial of intranasal OXT treatment. Patients with obesity that fit with the designed inclusion and exclusion criteria were recruited and randomly assigned into OXT vs. placebo treatment groups, and followed for body weight and related metabolic parameters during 8-week treatment duration.
Figure 1 Study design and flowchart for clinical trial of intranasal OXT treatment. Patients with obesity that fit with the designed inclusion and exclusion criteria were recruited and randomly assigned into OXT vs. placebo treatment groups, and followed for body weight and related metabolic parameters during 8-week treatment duration.CC BY · PubMed Central
Figure 2 Effect of intranasal OXT treatment on obesity in humans. A–F: Patients with obesity received 8 weeks (W) of intranasal OXT vs. placebo treatment and were monitored for body weight (BW), BMI and waist and hip circumference (Cir) levels. Data show changes in BW (A and B), BMI (C and D), waist circumference (E), and hip circumference (F) between OXT and placebo treatment groups (A, C, E and F) or among individuals prior to (W0) and post 8-week (W8) OXT treatment (B and D). ***P<0.001; n = 9 for OXT treatment group, n = 11 for placebo treatment group. Error bars represent mean ± SD.
Figure 2 Effect of intranasal OXT treatment on obesity in humans. A–F: Patients with obesity received 8 weeks (W) of intranasal OXT vs. placebo treatment and were monitored for body weight (BW), BMI and waist and hip circumference (Cir) levels. Data show changes in BW (A and B), BMI (C and D), waist circumference (E), and hip circumference (F) between OXT and placebo treatment groups (A, C, E and F) or among individuals prior to (W0) and post 8-week (W8) OXT treatment (B and D). ***P<0.001; n = 9 for OXT treatment group, n = 11 for placebo treatment group. Error bars represent mean ± SD.CC BY · PubMed Central
Figure 3 Effects of OXT treatment on obesity-related metabolic changes in humans. A–F: Patients with obesity received 8 weeks (W) of intranasal OXT vs. placebo treatment as described in Figure 1, and monitored for blood glucose, insulin and lipid profiles. Data show 2-hr postprandial blood glucose (A) and insulin (B), and fasting serum levels of total cholesterol (C), low-density lipoprotein (LDL) (D), high-density lipoprotein (HDL) (E) and triglycerides (TG) (F) of the individuals prior to (W0) and post 8-week (W8) OXT treatment. Statistical values for the differences between prior and post OXT treatment are provided in individual figures.
Figure 3 Effects of OXT treatment on obesity-related metabolic changes in humans. A–F: Patients with obesity received 8 weeks (W) of intranasal OXT vs. placebo treatment as described in Figure 1, and monitored for blood glucose, insulin and lipid profiles. Data show 2-hr postprandial blood glucose (A) and insulin (B), and fasting serum levels of total cholesterol (C), low-density lipoprotein (LDL) (D), high-density lipoprotein (HDL) (E) and triglycerides (TG) (F) of the individuals prior to (W0) and post 8-week (W8) OXT treatment. Statistical values for the differences between prior and post OXT treatment are provided in individual figures.CC BY · PubMed Central
Figure 4 Acute central effects of OXT on obesity-related prediabetic changes in mice. A–C: C57BL/6 mice were kept on HFD feeding for 2 months to develop prediabetic disorders, and subsequently received third-ventricle injection of OXT or vehicle twice during an overnight fasting period. Data show the effects of drug treatment on glucose tolerance (A), fasting blood insulin levels (B) and body weight (C). *P<0.05; n = 5–8 (A and C) and n = 4–5 (B) mice per treatment group. Error bars represent mean ± SEM. GTT: glucose tolerance test, AUC: area under curve.
Figure 4 Acute central effects of OXT on obesity-related prediabetic changes in mice. A–C: C57BL/6 mice were kept on HFD feeding for 2 months to develop prediabetic disorders, and subsequently received third-ventricle injection of OXT or vehicle twice during an overnight fasting period. Data show the effects of drug treatment on glucose tolerance (A), fasting blood insulin levels (B) and body weight (C). *P<0.05; n = 5–8 (A and C) and n = 4–5 (B) mice per treatment group. Error bars represent mean ± SEM. GTT: glucose tolerance test, AUC: area under curve.CC BY · PubMed Central
Figure 5 Acute central effects of [Ser4, Ile8]-OXT on obesity-related prediabetic disorders. A–C: C57BL/6 mice were maintained on HFD feeding for 2 months to develop prediabetic metabolic changes. After that, these mice received third-ventricle injection of [Ser4, Ile8]-OXT vs. vehicle twice during an overnight fasting period. Data demonstrate the effects of drug treatment on glucose tolerance (A), fasting blood insulin levels (B) and body weight (C). *P<0.05, **P<0.01; n = 5–8 (A and C) and n = 4–5 (B) mice per treatment group. Error bars represent mean ± SEM. GTT: glucose tolerance test, AUC: area under curve.
Figure 5 Acute central effects of [Ser4, Ile8]-OXT on obesity-related prediabetic disorders. A–C: C57BL/6 mice were maintained on HFD feeding for 2 months to develop prediabetic metabolic changes. After that, these mice received third-ventricle injection of [Ser4, Ile8]-OXT vs. vehicle twice during an overnight fasting period. Data demonstrate the effects of drug treatment on glucose tolerance (A), fasting blood insulin levels (B) and body weight (C). *P<0.05, **P<0.01; n = 5–8 (A and C) and n = 4–5 (B) mice per treatment group. Error bars represent mean ± SEM. GTT: glucose tolerance test, AUC: area under curve.CC BY · PubMed Central
Figure 6 Acute central effects of [Asu1,6]-OXT on obesity-related prediabetic changes. A–C: C57BL/6 mice were fed on HFD feeding for 2 months to develop pre-diabetes, and then received third-ventricle injection of [Asu1,6]-OXT or vehicle twice during an overnight fasting period. Data show the effects of drug treatment on glucose tolerance (A), fasting blood insulin levels (B) and body weight (C). *P<0.05; n = 5–8 (A and C) and n = 4–5 (B) mice per therapy group. Error bars represent mean ± SEM. GTT: glucose tolerance test, AUC: area under curve.
Figure 6 Acute central effects of [Asu1,6]-OXT on obesity-related prediabetic changes. A–C: C57BL/6 mice were fed on HFD feeding for 2 months to develop pre-diabetes, and then received third-ventricle injection of [Asu1,6]-OXT or vehicle twice during an overnight fasting period. Data show the effects of drug treatment on glucose tolerance (A), fasting blood insulin levels (B) and body weight (C). *P<0.05; n = 5–8 (A and C) and n = 4–5 (B) mice per therapy group. Error bars represent mean ± SEM. GTT: glucose tolerance test, AUC: area under curve.CC BY · PubMed Central
Figure 7 Central effects of OXT on glucose and insulin in STZ-induced diabetic mice. A–D: C57BL/6 mice under normal chow feeding received 7-day third-ventricle delivery of OXT vs. vehicle, and were subjected to daily i.p. injections of STZ from Day 4 to 7 to impair insulin secretion. Sub-groups of OXT vs. vehicle-treated mice that did not receive STZ injections were included to provide baseline levels. Data show the effects of OXT treatment on glucose tolerance (A), fasting blood insulin levels (B), first-phase and second-phase glucose-stimulated insulin release (GSIS) (C) and body weight (D). *P<0.05, **P<0.01; n = 6 mice per group (Veh + STZ vs. OXT + STZ), and n = 4 mice per group (Veh vs. OXT). Error bars represent mean ± SEM. GTT: glucose tolerance test, AUC: area under curve.
Figure 7 Central effects of OXT on glucose and insulin in STZ-induced diabetic mice. A–D: C57BL/6 mice under normal chow feeding received 7-day third-ventricle delivery of OXT vs. vehicle, and were subjected to daily i.p. injections of STZ from Day 4 to 7 to impair insulin secretion. Sub-groups of OXT vs. vehicle-treated mice that did not receive STZ injections were included to provide baseline levels. Data show the effects of OXT treatment on glucose tolerance (A), fasting blood insulin levels (B), first-phase and second-phase glucose-stimulated insulin release (GSIS) (C) and body weight (D). *P<0.05, **P<0.01; n = 6 mice per group (Veh + STZ vs. OXT + STZ), and n = 4 mice per group (Veh vs. OXT). Error bars represent mean ± SEM. GTT: glucose tolerance test, AUC: area under curve.CC BY · PubMed Central
Figure 8 Effects of [Ser4, Ile8]-OXT on glucose and insulin in STZ-induced diabetes. A–D: Chow-fed C57BL/6 mice received 7-day third-ventricle administration of [Ser4, Ile8]-OXT vs. vehicle, and were subjected to daily i.p. injections of STZ from Day 4 to 7 to impair insulin secretion. Data show the effects of OXT treatment on glucose tolerance (A), fasting blood insulin levels (B), first-phase and second-phase glucose-stimulated insulin release (GSIS) (C) and body weight (D). *P<0.05, **P<0.01; n = 6 mice per group. Error bars represent mean ± SEM. GTT: glucose tolerance test, AUC: area under curve.
Figure 8 Effects of [Ser4, Ile8]-OXT on glucose and insulin in STZ-induced diabetes. A–D: Chow-fed C57BL/6 mice received 7-day third-ventricle administration of [Ser4, Ile8]-OXT vs. vehicle, and were subjected to daily i.p. injections of STZ from Day 4 to 7 to impair insulin secretion. Data show the effects of OXT treatment on glucose tolerance (A), fasting blood insulin levels (B), first-phase and second-phase glucose-stimulated insulin release (GSIS) (C) and body weight (D). *P<0.05, **P<0.01; n = 6 mice per group. Error bars represent mean ± SEM. GTT: glucose tolerance test, AUC: area under curve.CC BY · PubMed Central
Figure 9 Effects of [Asu1,6]-OXT on glucose and insulin in STZ-induced diabetes. A–D: C57BL/6 mice fed on a normal chow received 7-day third-ventricle injection of [Asu1,6]-OXT vs. vehicle, and were subjected to daily i.p. injections of STZ from Day 4 to 7 to impair insulin secretion. Data show the effects of OXT treatment on glucose tolerance (A), fasting blood insulin levels (B), first-phase and second-phase glucose-stimulated insulin release (GSIS) (C) and body weight (D). *P<0.05; n = 6 mice per treatment group. Error bars represent mean ± SEM. GTT: glucose tolerance test, AUC: area under curve.
Figure 9 Effects of [Asu1,6]-OXT on glucose and insulin in STZ-induced diabetes. A–D: C57BL/6 mice fed on a normal chow received 7-day third-ventricle injection of [Asu1,6]-OXT vs. vehicle, and were subjected to daily i.p. injections of STZ from Day 4 to 7 to impair insulin secretion. Data show the effects of OXT treatment on glucose tolerance (A), fasting blood insulin levels (B), first-phase and second-phase glucose-stimulated insulin release (GSIS) (C) and body weight (D). *P<0.05; n = 6 mice per treatment group. Error bars represent mean ± SEM. GTT: glucose tolerance test, AUC: area under curve.CC BY · PubMed Central
Figure 10 Effects of peripheral [Ser4, Ile8]-OXT delivery in treating diabetic changes. A: Adult C57BL/6 mice were maintained on HFD feeding for 2 months, and then received daily i.p. injections of [Ser4, Ile8]-OXT or vehicle. Data show the effects of drug treatment on glucose tolerance. B: C57BL/6 mice under normal chow feeding received daily i.p. injections of [Ser4, Ile8]-OXT vs. vehicle and injections of STZ as described in the method. Data show the effects of [Ser4, Ile8]-OXT treatment on glucose tolerance. *P<0.05; n = 6 mice per treatment group. Error bars represent mean ± SEM. GTT: glucose tolerance test, AUC: area under curve.
Figure 10 Effects of peripheral [Ser4, Ile8]-OXT delivery in treating diabetic changes. A: Adult C57BL/6 mice were maintained on HFD feeding for 2 months, and then received daily i.p. injections of [Ser4, Ile8]-OXT or vehicle. Data show the effects of drug treatment on glucose tolerance. B: C57BL/6 mice under normal chow feeding received daily i.p. injections of [Ser4, Ile8]-OXT vs. vehicle and injections of STZ as described in the method. Data show the effects of [Ser4, Ile8]-OXT treatment on glucose tolerance. *P<0.05; n = 6 mice per treatment group. Error bars represent mean ± SEM. GTT: glucose tolerance test, AUC: area under curve.CC BY · PubMed Central

Verification

Claims the paper makes

41 Own result · 21 Own interpretation · 20 Not checked yet · 9 Own method · 1 Supported · 1 Partly supported · 1 No basis given · accuracy not yet measured

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  • Probably not a substantial claim. 16
  • It may state two separate claims as one. 15
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28 of 28
  • The paper relies on this without support.

    Obesity in humans is associated with pre-type 2 diabetes changes such as glucose intolerance, insulin resistance and hyperlipidemia.

    “Clinical epidemiology has established that obesity in humans is associated with pre-type 2 diabetes (T2D) changes such as glucose intolerance, insulin resistance and hyperlipidemia.”
  • The paper relies on this without support.

    Drug delivery via brain injection is impractical in humans.

    “given that drug delivery via brain injection is impractical in humans”
  • The paper relies on this without support.

    Peripherally delivered peptides often cannot effectively reach the central sites due to the physical and biological blockade of the blood-brain barrier.

    “peripherally delivered peptides often cannot effectively reach the central sites due to the physical and biological blockade of the BBB.”
  • The paper relies on this without support.

    Type 2 diabetes develops when insulin secretion is impaired to a level that cannot compensate for systemic insulin resistance, and obesity can potentiate the progression of both insulin resistance and impaired insulin secretion.

    “T2D develops when insulin secretion is impaired to a level that cannot compensate for systemic insulin resistance, and the presence of obesity can potentiate the progression of both insulin resistance and impaired insulin secretion.”
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Metadata

Authors
Zhang, H., Wu, C., Chen, Q., Chen, X., Xu, Z., Wu, J., & Cai, D.
Affiliations
  • Jiangsu University (CN)
  • Albert Einstein College of Medicine (US)
Corresponding author
Cai, Dongsheng
Venue
PLoS ONE
Published
2013-05-20
Volume
8
Issue
5
Pages
e61477
ISSN
1932-6203 (ISSN-L)
OpenAlex
W2076652575
Cited by
224
References
39
Citations by year
2026: 7 · 2025: 7 · 2024: 9 · 2023: 14 · 2022: 14 · 2021: 24 · 2020: 17 · 2019: 23 · 2018: 30 · 2017: 27 · 2016: 23 · 2015: 13 · 2014: 14 · 2013: 2
FWCI
17.07
Type
journal article
Language
en
Open access
Locations
  • PLoS ONE (publishedVersion, cc-by)
  • Europe PMC (PubMed Central) (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
  • Figshare (submittedVersion, cc-by)
Funders
  • National Institutes of Health (DK078750)
  • National Institute on Aging (R01AG031774)
  • National Institute of Diabetes and Digestive and Kidney Diseases (R01DK078750)
Topics
  • Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Pancreatic function and diabetes
  • Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Adipokines, Inflammation, and Metabolic Diseases
  • Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Diabetes Treatment and Management
Keywords
oxytocin, oxytocin analogues, obesity, type 2 diabetes, prediabetes, insulin resistance, insulin secretion, impaired glucose tolerance, intranasal administration, streptozotocin-induced diabetes, weight management, peptide therapeutics
MeSH terms
Insulin Secretion, Administration, Intranasal, Adult, Animals, Blood Glucose, Diabetes Mellitus, Experimental, Diabetes Mellitus, Type 2, Female, Humans, Hypoglycemic Agents, Insulin, Insulin Resistance, Male, Mice, Inbred C57BL, Middle Aged, Obesity, Oxytocin, Pilot Projects, Prediabetic State, Glucose Intolerance, Lipid Metabolism, Mice, Young Adult

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