Mechanisms of Fasting-Induced Insulin Resistance
Insulin Resistance · Fasting-Induced Insulin Resistance
What this study involves
The registry does not currently label this study as recruiting. Ask about its status before planning a screening visit.
- Study type
- Interventional
- Phase
- Not applicable
- Age range
- 18 years - 40 years
- Sex eligible
- All sexes
- Healthy volunteers
- Accepted
- Participants
- 18 Estimated
These are starting points, not an eligibility decision. The research team must review the full requirements.
About the research
During prolonged fasting, the body shifts from using glucose toward using fat as its main energy source. At the same time, skeletal muscle becomes less sensitive to insulin, a hormone that helps regulate blood glucose levels. Although this response is a normal adaptation to fasting, the mechanisms responsible for it are not fully understood.
The DELIVER study aims to investigate how changes in fat metabolism, communication between tissues, and liver energy metabolism contribute to reduced insulin sensitivity during prolonged fasting.
In this randomized crossover study, 18 healthy adults will complete two conditions in random order: a 60-hour fasting period and a control condition involving a standard overnight fast. The conditions will be separated by at least four weeks.
During both conditions, researchers will assess insulin sensitivity, energy metabolism, and fat metabolism using blood and urine samples, magnetic resonance spectroscopy (MRS), measurements of energy expenditure, and small samples of skeletal muscle and abdominal fat tissue (biopsies). Insulin sensitivity will be measured using a hyperinsulinemic-euglycemic clamp, a procedure in which insulin and glucose are administered intravenously while blood glucose levels are closely monitored.
By comparing the two conditions, the study aims to improve understanding of how the body adapts to fasting and whether some of the mechanisms involved resemble those observed in insulin resistance associated with obesity and type 2 diabetes.
Read the full description
DELIVER is a single-center, randomized crossover study investigating the molecular and physiological mechanisms of insulin resistance induced by prolonged fasting. The study will enroll 18 healthy, sedentary men and women aged 18-40 years with a body mass index of 20-25 kg/m².
Each participant will undergo two experimental conditions in randomized order, separated by a washout period of at least four weeks: a 60-hour fasting condition and a control condition following a standard 12-hour overnight fast.
The primary objective is to determine whether fasting-induced skeletal muscle insulin resistance is associated with the accumulation of specific diacylglycerol (DAG) stereoisomers in distinct intracellular compartments, activation of protein kinase C (PKC) isoforms, and alterations in insulin signalling. Alternative mechanisms involving ceramides and PKCζ will also be investigated.
Secondary objectives include evaluating changes in adipose tissue metabolism and extracellular vesicle lipid cargo, assessing the effects of adipose tissue-derived extracellular vesicles on insulin sensitivity in cultured human skeletal muscle cells, and characterizing hepatic energy metabolism and insulin sensitivity during fasting. Potential sex differences will be examined as an exploratory objective.
Insulin sensitivity will be assessed using a two-step hyperinsulinemic-euglycemic clamp with stable glucose isotope tracers, allowing assessment of hepatic, adipose tissue, and peripheral insulin sensitivity. Skeletal muscle and subcutaneous abdominal adipose tissue biopsies will be obtained for lipidomic, molecular, mitochondrial, and extracellular vesicle analyses. Magnetic resonance spectroscopy will be used to assess skeletal muscle and liver lipid content and energy metabolism. Indirect calorimetry, blood sampling, 24-hour urine collection, continuous glucose monitoring, and physical activity monitoring will provide additional information on metabolic adaptations.
The crossover design allows each participant to serve as their own control. By integrating tissue-specific molecular analyses with measurements of whole-body metabolism, DELIVER aims to determine whether fasting-induced insulin resistance involves mechanisms similar to those implicated in obesity-associated insulin resistance or represents a distinct physiological adaptation.
Who may be able to participate?
The list below is the sponsor’s full registry wording. It can include conditions, prior treatment, test results and other requirements. A match in search does not mean you qualify.
Inclusion Criteria:
1. Healthy men and women, age 18-40 years
2. BMI 20-25 kg/m²
3. Sedentary lifestyle (\<3h structured exercise/week)
4. Able to provide signed and dated written informed consent prior to any study-specific procedures
For women specifically:
5. Regular menstrual cycle
6. Negative urine pregnancy test at screening and before each clamp visit
Exclusion Criteria:
1. Known diabetes mellitus (any type)
2. Untreated or inadequately controlled thyroid dysfunction.
3. Clinically significant hepatic or renal disease.
4. Uncontrolled hypertension, clinically significant cardiac arrhythmia, or cardiovascular disease that may increase the risk associated with study procedures.
5. Anaemia (haemoglobin below the laboratory reference range).
6. Known coagulation disorder.
7. Current use of anticoagulant or antiplatelet medication.
8. Known allergy to the local anaesthetic used for biopsy.
9. Current eating disorder or history of an eating disorder with a clinically relevant risk of recurrence during prolonged fasting.
10. Unstable psychiatric illness that may be exacerbated by prolonged fasting or interfere with informed consent or adherence to study procedures.
11. Current alcohol or substance use disorder.
12. Clinically significant sleep disorder that may interfere with metabolic assessments or participant safety.
13. Shift work disrupting normal sleep-wake patterns.
14. MRI-incompatible implants or devices, or other contraindications to MRI/MRS according to the applicable scanner safety requirements.
15. Claustrophobia precluding completion of MRI/MRS.
16. Pregnancy or breastfeeding.
17. Current use of hormonal contraception.
18. Unstable body weight in the preceding 3 months (greater than 5% change)
19. Previous bariatric surgery.
20. Current smoking or smoking cessation within the preceding 3 months.
Treatment, groups and participation
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- Assignment
- Random assignment
- Masking
- No masking
60-hour Fasting
Participants undergo 60 hours of complete fasting under medical supervision. At the end of the fasting period, insulin sensitivity and metabolic responses are assessed using a two-step hyperinsulinemic-euglycemic clamp, stable isotope tracers, magnetic resonance spectroscopy, indirect calorimetry, blood and urine sampling, and skeletal muscle and subcutaneous adipose tissue biopsies.
Other: 60-hour Fasting
Control (12-hour Overnight Fasting)
Participants undergo a standard 12-hour overnight fast before metabolic assessments, without prolonged fasting. The same principal metabolic and tissue assessments are performed as in the prolonged fasting condition, allowing within-participant comparison of insulin sensitivity, tissue lipid metabolism, and molecular responses.
Other: 12-hour Overnight Fasting (control)
60-hour Fasting OTHER
Participants undergo a 60-hour fasting period under medical supervision, during which water and broth are permitted according to the study protocol. The fasting period is followed by standardized metabolic assessments, including a two-step hyperinsulinemic-euglycemic clamp.
12-hour Overnight Fasting (control) OTHER
Standard overnight fasting for approximately 12 hours before metabolic assessments, serving as the control condition for comparison with prolonged fasting.
What researchers are measuring
Outcome measures describe what is being studied. They are not proof that a treatment works.
Primary measures
Skeletal muscle plasma membrane sn-1,2-diacylglycerol content
Time frame: At the end of each study condition in both crossover periods (washout of at least 4 weeks): Day 2 of the control condition, after a 12-hour overnight fast, and Day 4 of the fasting condition, after 60 hours of fasting.
Difference in plasma membrane-associated sn-1,2-diacylglycerol (DAG) stereoisomer content in skeletal muscle between the 60-hour fasting condition and the control condition, assessed in basal vastus lateralis muscle biopsies.
Secondary measures
Skeletal muscle DAG content in mitochondrial/endoplasmic reticulum and cytosolic fractions
Time frame: At the end of each study condition in both crossover periods (washout of at least 4 weeks): Day 2 of the control condition, after a 12-hour overnight fast, and Day 4 of the fasting condition, after 60 hours of fasting.
Difference in sn-1,2-diacylglycerol content in mitochondrial/endoplasmic reticulum and cytosolic fractions of basal skeletal muscle biopsies between fasting and control conditions
Skeletal muscle PKC translocation
Time frame: At the end of each study condition in both crossover periods (washout of at least 4 weeks): Day 2 of the control condition, after a 12-hour overnight fast, and Day 4 of the fasting condition, after 60 hours of fasting.
Difference in PKCθ, PKCε and PKCζ translocation, assessed as membrane-to-cytosol ratios in basal skeletal muscle biopsies between conditions
Skeletal muscle insulin signalling phosphorylation
Time frame: At the end of each study condition in both crossover periods (washout of at least 4 weeks): Day 2 of the control condition, after a 12-hour overnight fast, and Day 4 of the fasting condition, after 60 hours of fasting.
Difference in basal and insulin-stimulated phosphorylation of insulin receptor (Tyr1162/1163), IRS-1 (Tyr612, Ser307, Ser1101), Akt (Ser473, Thr308), TBC1D4 (Thr642), GSK3β (Ser9) and S6K1 (Thr389) between conditions
Skeletal muscle ceramide content and ratio
Time frame: At the end of each study condition in both crossover periods (washout of at least 4 weeks): Day 2 of the control condition, after a 12-hour overnight fast, and Day 4 of the fasting condition, after 60 hours of fasting.
Difference in skeletal muscle ceramide content and ceramide ratios between fasting and control conditions
Whole-body insulin sensitivity
Time frame: At the end of each study condition in both crossover periods (washout of at least 4 weeks): Day 2 of the control condition, after a 12-hour overnight fast, and Day 4 of the fasting condition, after 60 hours of fasting.
Difference in whole-body insulin sensitivity, expressed as M/I (glucose infusion rate corrected for changes in the glucose pool, divided by steady-state plasma insulin), during the last 30 minutes of the high-dose insulin step of the two-step hyperinsulinemic-euglycemic clamp, between fasting and control conditions.
Insulin-induced suppression of endogenous glucose production
Time frame: At the end of each study condition in both crossover periods (washout of at least 4 weeks): Day 2 of the control condition, after a 12-hour overnight fast, and Day 4 of the fasting condition, after 60 hours of fasting.
Difference in percentage suppression of EGP during the low-dose insulin step of the clamp, relative to basal EGP, between fasting and control conditions.
Insulin-induced suppression of plasma NEFA
Time frame: At the end of each study condition in both crossover periods (washout of at least 4 weeks): Day 2 of the control condition, after a 12-hour overnight fast, and Day 4 of the fasting condition, after 60 hours of fasting.
Difference in percentage suppression of plasma non-esterified fatty acids (NEFA) during the low-dose insulin step of the clamp, relative to basal NEFA, between fasting and control conditions.
Insulin clearance
Time frame: At the end of each study condition in both crossover periods (washout of at least 4 weeks): Day 2 of the control condition, after a 12-hour overnight fast, and Day 4 of the fasting condition, after 60 hours of fasting.
Difference in insulin clearance, calculated as insulin infusion rate divided by the steady-state increment in plasma insulin above baseline during the clamp, between fasting and control conditions.
Skeletal muscle intramyocellular lipid content
Time frame: On the day before the clamp in each study condition, in both crossover periods: Day 1 of the control condition, and Day 3 of the fasting condition, after approximately 42 hours of fasting.
Difference in intramyocellular lipid (IMCL) content in the tibialis anterior muscle, assessed by ¹H-magnetic resonance spectroscopy, between fasting and control conditions.
Hepatic ATP concentration
Time frame: On the clamp day of each study condition, before the start of insulin infusion, in both crossover periods: Day 2 of the control condition, after a 12-hour overnight fast, and Day 4 of the fasting condition, after 60 hours of fasting.
Difference in absolute hepatic γ-ATP concentration, assessed by ³¹P-magnetic resonance spectroscopy, between fasting and control conditions.
Adipose tissue transcriptomics
Time frame: At the end of each study condition in both crossover periods (washout of at least 4 weeks): Day 2 of the control condition, after a 12-hour overnight fast, and Day 4 of the fasting condition, after 60 hours of fasting.
Differences in adipose tissue gene expression profiles, assessed by transcriptomic analysis of subcutaneous abdominal adipose tissue biopsies, between fasting and control conditions.
Adipose tissue-derived extracellular vesicle lipid content
Time frame: At the end of each study condition in both crossover periods (washout of at least 4 weeks): Day 2 of the control condition, after a 12-hour overnight fast, and Day 4 of the fasting condition, after 60 hours of fasting.
Difference in diacylglycerol and ceramide content of extracellular vesicles isolated from subcutaneous abdominal adipose tissue biopsies, assessed by lipidomic profiling, between fasting and control conditions.
Other measures
Sex-by-condition interaction for skeletal muscle plasma membrane DAG content
Time frame: At the end of each study condition in both crossover periods (washout of at least 4 weeks): Day 2 of the control condition, after a 12-hour overnight fast, and Day 4 of the fasting condition, after 60 hours of fasting.
Exploratory comparison of the fasting-induced change in plasma membrane sn-1,2-DAG content between men and women (sex-by-condition interaction), reported with effect sizes and confidence intervals.
Sex-by-condition interaction for whole-body insulin sensitivity
Time frame: At the end of each study condition in both crossover periods (washout of at least 4 weeks): Day 2 of the control condition, after a 12-hour overnight fast, and Day 4 of the fasting condition, after 60 hours of fasting.
Exploratory comparison of the fasting-induced change in M/I between men and women (sex-by-condition interaction), reported with effect sizes and confidence intervals.
Sex-by-condition interaction for suppression of endogenous glucose production
Time frame: At the end of each study condition in both crossover periods (washout of at least 4 weeks): Day 2 of the control condition, after a 12-hour overnight fast, and Day 4 of the fasting condition, after 60 hours of fasting.
Exploratory comparison of the fasting-induced change in percentage EGP suppression during the low-dose insulin step between men and women (sex-by-condition interaction), reported with effect sizes and confidence intervals.
Review the complete result tables and limitations in the official record.
Open official results ↗Research locations (0)
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No locations are listed. Use the official study contact.
Study team and timeline
- Lead sponsor
- German Diabetes Center
- Study start
- 2027-01 Estimated
- Primary completion
- 2028-01 Estimated
- Study completion
- 2028-07 Estimated
- First posted
- Nov 10, 2026 Actual
- Last updated
- Nov 10, 2026 Actual
Official study contacts
Official study title
Diacylglycerol, Extracellular Vesicles, and Liver Energy Metabolism in Fasting-Induced Insulin Resistance
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Source: ClinicalTrials.gov API v2. Information is submitted by sponsors and investigators. NLM does not approve the safety or science of all listed studies. Registry disclaimer.
Retrieved: Nov 12, 2026 · Last registry update: Nov 10, 2026