Type 2 Diabetes MellitusSmartAgeNCT04841668
Gut-Brain-axis: Targets for Improvement of Cognition in the Elderly
An observational study of Type 2 Diabetes Mellitus, run by Institut d'Investigació Biomèdica de Girona Dr. Josep Trueta at 1 site in Spain.
Trial summary
Cognitive disorders increase with age and in the presence of metabolic diseases such as Type 2 Diabetes Mellitus (T2DM). In addition, digestive disorders, changes in dietary pattern and decreased activity negatively influence the microbiome. Read more about this study
- Who is it for?
- Ages 65 to 80 years
- Conditions the study is for
- Type 2 Diabetes Mellitus
- What is being tested?
- Metformin
- Type of treatment
- Pill or oral medicine
- How many people
- 50 participants
- Where
- 1 siteSpain
- Study dates
- 10 Apr 2021to 3 Dec 2024
- Phase
- Observational
- Are there results?
- None posted in the registry
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 65 to 80 years
- All sexes
- No healthy volunteers
- Older adult
Study population: Group A Study population Adult patients (≥ 65 years of age) recently diagnosed with T2DM according to the WHO and who have not been treated with metformin. Group B Study population Adult patients (≥ 65 years of age) diagnosed with long-term T2DM according to the WHO classification, regardless of whether they take metformin or other treatment.
Who may be able to join
- Age between 55 and 80 years.
- Patients with recently diagnosed T2DM (last 6 months), according to the WHO classification.
- Patients in whom written informed consent has been obtained for participation in the study.
- Age between 65 and 80 years.
- Patients with long-term T2DM according to the WHO classification
- Patients in whom written informed consent has been obtained for participation in the study.
Who cannot join
- HbA1c ≥ 9%
- Metformin treatment in the past 6 months
- Creatinine greater than 1.2 and glomerular filtration rate less than 40
- Serious systemic disease not related to obesity, including any type of cancer, severe kidney disease or liver disease, and known type 1 diabetes.
- Systemic diseases with intrinsic inflammatory activity such as rheumatoid arthritis, Crohn's disease, asthma, or chronic infection (e.g., HIV, active tuberculosis) or any type of infectious disease.
- Current treatment for malignant neoplasia, other than basal cell or squamous cell skin cancer.
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- Class III or IV heart disease, known ischemic cardiovascular disease
- Kidney failure, history of kidney transplant, or current dialysis treatment
- Serum liver enzymes (GOT, GPT) above twice the upper limit of normal. Obvious signs or symptoms of liver disease, acute or chronic hepatitis.
- Chronic constipation (stool habit ≥ 7 days)
- Pregnancy or breastfeeding
- Treatments that affect glucose metabolism or the intestinal microbiota with biguanides, sulfonylurea secretagogues or non-sulfonylurea secretagogues, insulin sensitizers, insulin, thiazolidinediones, alpha glucosidase inhibitors, incretin mimetics, Dipeptidyl peptidase IV inhibitors, use of cathartics.
- Chronic anti-inflammatory treatment with steroidal drugs (during the previous 3 months).
- Symptoms and / or clinical signs of infection in the previous month.
- Antibiotic, antifungal or antiviral treatment active in the previous 3 months.
- Treatment with glucocorticoids chronic or during the 2 months prior to inclusion in the study.
- Treatment with a weight loss product during the previous two months
- Immunosuppressant treatment.
- Excessive alcohol consumption (alcohol intake greater than 40 g per day (women) or 80 g / day (men)) either acute or chronic, or drug use. History of drug or alcohol abuse.
- Patients with severe eating disorders
- History of alterations in iron balance (known chronic hemoglobinopathies or anemia, genetic hemochromatosis, hemosiderosis from any cause, atransferrinemia, paroxysmal nocturnal hemoglobinuria).
- Important psychiatric history.
- Participation in any other study.
- People whose freedom is under legal or administrative requirement.
- Group B
- HbA1c ≥ 9%
- Creatinine greater than 1.2 and glomerular filtration rate less than 40
- Serious systemic disease not related to obesity, including any type of cancer, severe kidney disease or liver disease, and known type 1 diabetes.
- Systemic diseases with intrinsic inflammatory activity such as rheumatoid arthritis, Crohn's disease, asthma, or chronic infection (e.g., HIV, active tuberculosis) or any type of infectious disease.
- Current treatment for malignant neoplasia, other than basal cell or squamous cell skin cancer.
- Class III or IV heart disease, known ischemic cardiovascular disease.
- Kidney failure, history of kidney transplant, or current dialysis treatment
- Serum liver enzymes (GOT, GPT) above twice the upper limit of normal. Obvious signs or symptoms of liver disease, acute or chronic hepatitis.
- Chronic constipation (stool habit ≥ 7 days)
- Pregnancy or breastfeeding
- Chronic anti-inflammatory treatment with steroidal drugs (during the previous 3 months).
- Symptoms and / or clinical signs of infection in the previous month.
- Antibiotic, antifungal or antiviral treatment active in the previous 3 months.
- Treatment with glucocorticoids chronic or during the 2 months prior to inclusion in the study.
- Treatment with a weight loss product during the previous two months.
- Immunosuppressant treatment.
- Excessive alcohol consumption (alcohol intake greater than 40 g per day (women) or 80 g / day (men)) either acute or chronic, or drug use. History of drug or alcohol abuse.
- Patients with severe eating disorders
- History of alterations in iron balance (known chronic hemoglobinopathies or anemia, genetic hemochromatosis, hemosiderosis from any cause, atransferrinemia, paroxysmal nocturnal hemoglobinuria).
- Important psychiatric history.
- Participation in any other study.
- People whose freedom is under legal or administrative requirement.
Trial locations and contacts
1 site in 1 country.
Spain1 site
Institut d'Investigació Biomèdica de Girona (IDIBGI)
Girona, Girona, 17007
About this study
Cognitive disorders increase with age and in the presence of metabolic diseases such as Type 2 Diabetes Mellitus (T2DM). In addition, digestive disorders, changes in dietary pattern and decreased activity negatively influence the microbiome.
The hypothesis is that pharmacological intervention with metformin will modify the composition of the gut microbiota and cognition.
Read more
The study has a pilot longitudinal design, where each patient with T2DM will be followed for one year. Two groups will be recruited:
- Group A: The aim will be to evaluate the associations between glucose (measured by continuous glucose monitoring (CGM)), cognitive function (by means of cognitive tests and magnetic resonance imaging (MRI)), physical activity (recorded by activity and sleep tracker devicer), metformin, diet (evaluated by nutritional survey) and composition of the microbiota (evaluated by metagenomics), during 12 months (6 months without metformin and 6 months with metformin treatment).
- Group B: The aim will be to evaluate the associations between glucose, diet (evaluated by nutritional survey), cognitive function (by means of cognitive tests), physical activity (measured by activity and sleep tracker device), the treatment and composition of the microbiota (evaluated by metagenomics), during 12 months.
Read the detailed description
Subjects and methods:
Longitudinal study:
Patients with T2DM previously scheduled at the Service of Endocrinology, Diabetes and Nutrition (UDEN) of the Hospital "Dr. Josep Trueta" of Girona (Spain) will be recruited and studied.
GROUP A
This study consists of an initial phase, where the patient will be submitted as the only treatment to a balanced diet with an energy intake, calculated individually according to whether he/she is normal weight (25 Kcal x Kg) or overweight (20 Kcal x Kg of weight).
After this initial phase, in addition to continuing with the balanced diet treatment, patients will start treatment with metformin administered orally at an initial dose of 425 mg/d every 12 hours during the first 15 days and then continue with doses of 850 mg/d until the end of the study.
A glycemia sensor will be inserted for ten days, as well as an activity and sleep tracker device (Fitbit) to record physical activity during this period of time. Interstitial subcutaneous glucose concentrations will be monitored on an outpatient basis for a period of time of 10 consecutive days using a glucose sensor validated by the FDA (Dexcom G6 ®). The sensor will be inserted on day 0 and it will retire on day 10 midmorning.
This process will be repeated 10 days prior to the start of the of treatment with Metformin and 10 days before the end of the 6 month study phase with metformin. During the study, 6 visits will be made and each patient will be inserted with a total of 3 glycemia sensors and 3 physical activity monitors. In summary, the glycemia sensor and physical activity monitoring will be started at visits 1, 3, 5 and will be removed at visits 2,4,6.
Visit 1(day 1): Physical examination, Nutritional survey, Bioimpedance, Densitometry, CGM and Activity and sleep tracker device. Consent form
Visit 2 (day 10): Sample: blood, urine and feces. Diet, Neuropsychological test, CGM withdrawal, Activity and sleep tracker device withdrawal, MRI.
Visit 3 (day 170): Physical examination, Nutritional survey, Bioimpedance, CGM and Activity and sleep tracker device
Visit 4 (day 180): Sample: blood, urine and feces. Dietary follow-up, Neuropsychological test, CGM withdrawal and Activity and sleep tracker device withdrawal. Start of metformin treatment.
Visit 5 (day 350): Physical examination, Nutritional survey, Bioimpedance, CGM and Activity and sleep tracker device.
Visit 6 (day 360): Sample: blood, urine and feces. Dietary follow-up, Neuropsychological test, CGM withdrawal and Activity and sleep tracker device withdrawal. Metformin withdrawal.
GROUP B:
During the study, 5 visits will be made for this group:
Visit 1(day 1): Physical examination, Nutritional survey, Bioimpedance, Densitometry and Activity and sleep tracker device. Consent form.
Visit 2 (day 10): Sample: blood, urine and feces. Diet, Neuropsychological test and Activity and sleep tracker device withdrawal.
Visit 3 (day 180): Diet follow-up.
Visit 4 (day 350): Physical examination, Nutritional survey, Bioimpedance and Activity and sleep tracker device.
Visit 5 (day 360): Sample: blood, urine and feces. Diet follow-up, Neuropsychological test and Activity and sleep tracker device withdrawal.
DATA COLLECTION OF SUBJECTS LONGITUDINAL STUDIES:
- Subsidiary data: Age, sex and birth date.
- Clinical variables:
- Weight
- height,
- body mass index
- waist and hip perimeters
- waist-to-hip ratio
- blood pressure (systolic and diastolic)
- fat mass and fat free-mass (bioelectric impedance and DEXA)
- smoking status
- alcohol intake
- registry of usual medicines
- personal history of blood transfusion and/or donation
- record of family history of obesity, cardiovascular events and diabetes
- psychiatric and eating disorder history.
- Laboratory variables: 15cc of blood will be extracted from fasted subjects to determine the following variables using the usual routine techniques of the clinical laboratory:
- hemogram
- glucose
- bilirubin
- aspartate aminotransferase (AST/GOT)
- alanine aminotransferase (ALT/GPT)
- gamma-glutamyl transpeptidase (GGT)
- urea
- creatinine
- uric acid
- total proteins,
- albumin
- total cholesterol | HDL cholesterol | LDL cholesterol
- triglycerides,
- glycated haemoglobin (HbA1c)
- ferritin | soluble transferrin receptor
- ultrasensitive C reactive protein
- erythrocyte sedimentation rate
- lipopolysaccharide binding protein
- free thyroxine (free T4) | thyroid stimulating hormone (TSH) | baseline cortisol -plasma insulin
- inflammation markers | interleukin 6 (IL-6). An additional 15cc of blood (plasma-EDTA) will be extracted for further analyses.
- Stool samples collection: A stool sample will be provided from each patient. The sample should be collected at home or in the hospital, sent to the laboratory within 4 hours from the collection, fragmented and stored at -80ºC. -Analysis of intestinal microbiota in stool:
- Determination of bacterial DNA and mRNA and study of the LBP binding protein in blood for the detection of bacterial translocation. LBP binding protein in blood for the detection of bacterial translocation. Hiseq and Nextseq technology (qPCR and protein analysis (WB, ELISA), OMICS (RNAseq, 16S, Metabolomics, Metagenomics).
- Inflammatory and immunological markers will be determined using ELISA (enzyme-linked immunosorbent assay) and immunohistochemistry (IHC) equipment and quantitative real-time PCR validation. For qPCR, total RNA will be isolated from different tissues and will transcribe into cDNA.
- Determination of metabolic profile and metabolite analysis.
- Intestinal barrier function:Exposure to a lactulose:mannitol test before/after surgery. Plasma samples will be used to measure intestinal permeability markers: bacterial endotoxin, sCD14, LBP, ZO-1, and I-FABP.
- Urine sample collection: Necessary to determine alterations in the metabolic pathways involved in tryptophan metabolism, and to determine the role of the intestinal microbiota in these metabolic changes.
- MRI: The necessary sequences will be acquired for the calculation of the BrainAGE biomarker and the characterization of the networks involved in cognitive functions. For the acquisition a 1.5 T scanner (Ingenia; Philips Medical Systems) will be used 1,5 T scanner (Ingenia; Philips Medical Systems) will be used for the acquisition. First, recovery-inversion sequence (T2-FLAIR) will be used to exclude subjects with pre-existing brain lesions. Subsequently, structural sequences will be acquired sequences will then be acquired to measure the integrity of cerebral gray matter (T1-weighted), tracts of weighted), of the white matter tracts (DTI), iron accumulation (R2*), and (R2*), and functional sequences in resting-state (T2*-weighted echo-planar imaging, EPI).
- Neuropsychological examination: Different domains of cognition will be explored: memory (Test aprendizaje verbal-TAVEC, Rey-Osterrieth Complex Figure) attention and executive function(WAIS-IV, Trail making test (Part A y B), Stroop test). In addition, cognitive impairment will be evaluated with Lobo's Mini-Cognitive Exam. These tests will be useful to define the changes in the cognitive profile associated with the pharmacological intervention with metformin.
The information will remain registered in a notebook and will be computerized in the database of the study.
STATICAL METHODS:
Sample size: Since this is intended as a pilot study, no formal sample size calculation is required. A general rule is to recruit 30 or more patients to estimate a parameter and 15-20 participants per group to obtain reasonable estimates for medium to large effect sizes.
Statistical analyses: It will be based on a descriptive analysis (mean, standard deviation, sample size, median, minimum and maximum) of the quantitative parameters and the indication of the frequency of the remaining categorical parameters. Comparisons between groups will be based on a paired samples t-test or a chi-square test. The results of these analyses may be useful to assess whether further analyses are needed to adjust for possible imbalance in the baseline characteristics of the patients.
The changes in the composition of the gut microbiota after the intervention with metformin will be analyzed using Heatmaps, Principal Component Analysis (PCA) and PLSDA. For the multivariate statistical analysis (PLSDA and hierarchical clustering). The variables that comprise the characteristics of the intestinal microbiota and cognitive tests will be logarithmically transformed, filtered with interquartile range estimation and staggered by autoscale calculation (mean and divided by the standard deviation of each variable) by using the Metaboanalyst platform.
The changes determined in the gut microbiota and cognition variables will be explored in relation to the changes in the secondary variables (metabolic, metabolome, inflammation parameters) by linear regression analysis in SPSS. Brain image variables will be analyzed with specialized programs (MATLAB, SPM12).
- Conditions
- Type 2 Diabetes Mellitus
- Being tested
- Metformin
- Keywords
- Type 2 Diabetes Mellitus, Continous Glucose Monitoring, Cognition, Metformin, Gut microbiome, Magnetic resonance imaging, Physical activity monitor
- Medical subject headings
- Diabetes Mellitus, Type 2
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
MetforminDrug
Patients will begin treatment with metformin administered orally at a starting dose of 425 mg / day every 12 hours for the first 15 days and then continue with a dose of 850 mg / day until the end of the study. The beginning of this treatment phase will be following the recommendations of the clinical guidelines (Comprehensive Approach to Type 2 Diabetes Mellitus, SEEN V2019.2)
| Study group | Role | What they receive |
|---|---|---|
| Patients with recently diagnosed T2DM | This group will consist of 36 recently diagnosed T2DM, according to the World Health Organization (WHO) patients (last 6 months), who have not received treatment with metformin. Receives: Drug: Metformin | |
| Patients with long-term T2DM | The group will consist of 100 patients with long-term T2DM, according to the WHO classification, regardless of whether they take metformin or another treatment. |
What is being measured
The primary outcome is the main question the study is designed to answer.
Gut microbiota composition.
It will be identified in the stool by cultures and DNA and mRNA expression after metformin treatment.
Measured: 12 months
Cognitive impairment
It will be measured by Mini-Examen Cognoscitivo (MEC).
Measured: 12 months
Audioverbal memory
It will be measured by Test aprendizaje verbal-TAVEC.
Measured: 12 months
Visual memory
It will be measured by Rey-Osterrieth Complex Figure.
Measured: 12 months
Depressive symptomatology
It will be measured by Patient Health Questionnaire-9 (PHQ-9).
Measured: 12 months
Impulsivity
It will be measured by UPPS Impulsive Behavior Scale.
Measured: 12 months
Food Addiction
It will be measured by Yale Food Addiction Scale.
Measured: 12 months
Behavioral inhibition
It will be measured by Sensitivity to Punishment and Sensitivity to Reward (SPSRQ).
Measured: 12 months
Behavioral activation
It will be measured by Sensitivity to Punishment and Sensitivity to Reward (SPSRQ).
Measured: 12 months
Visoconstructive function
It will be measured by Rey-Osterrieth Complex Figure.
Measured: 12 months
Visuospatial perception
It will be measured by Judgment Line Orientation.
Measured: 12 months
Naming
It will be measured by Boston Naming Test.
Measured: 12 months
Selective and alternating attention
It will be measured by Trail making test (Part A y B).
Measured: 12 months
Attention and working memory
It will be measured by the Wechsler Adult Intelligence Scales, Fourth Edition (WAIS-IV).
Measured: 12 months
Inhibition
It will be measured by Stroop Color-Word Test.
Measured: 12 months
Phonemic verbal fluency
It will be measured by PMR
Measured: 12 months
Semantic verbal fluency
It will be measured by Animals
Measured: 12 months
Secondary outcomes (6)
The percentage of time in glucose target range (glucose level 70mg/dl-180mg/dl)
Measured: 12 months
Effect on gut microbiota
Gut microbiota will be analysed by metagenomics and metabolomics.
Measured: 12 months
The percentage of time in glucose range (glucose level below 100 mg/dl)
Measured: 12 months
The percentage of time in glucose range (glucose level between 100-125 mg/dl)
Measured: 12 months
The percentage of time in glucose range (glucose level between 126-139 mg/dl)
Measured: 12 months
The percentage of time in glucose range (glucose level between 140-199 mg/dl)
Measured: 12 months
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted12 Apr 2021
- Study start10 Apr 2021
- Primary completion3 Dec 2024
- Study completion3 Dec 2024
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (53)Papers the sponsor has linked to this study.
- Other trials for Type 2 Diabetes MellitusStudies of the same condition, open and under way.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Observational
- Observational model
- Cohort
- Time perspective
- Prospective
- Enrolment
- 50 participants (actual)
Sponsor and investigators
- Lead sponsor
- Institut d'Investigació Biomèdica de Girona Dr. Josep Trueta
- Sponsor type
- University, hospital or other
- Responsible party
- Principal investigator, José Manuel Fernández-Real, Institut d'Investigació Biomèdica de Girona Dr. Josep Trueta
- Investigators
- José M Fernández-Real, Ph.D., Principal investigator, Institut d'Investigació Biomèdica de Girona (IDIBGI)
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT04841668
- Sponsor's protocol ID
- SMARTAGE-2020.133
- Acronym
- SmartAge
- Status last verified
- Mar 2026
- First submitted
- 6 Apr 2021
- Last updated
- 31 Mar 2026
- Results posted
- No
- FDA-regulated drug
- No
- FDA-regulated device
- No
Publications
Fama R, Sullivan EV. Thalamic structures and associated cognitive functions: Relations with age and aging. Neurosci Biobehav Rev. 2015 Jul;54:29-37. doi: 10.1016/j.neubiorev.2015.03.008. Epub 2015 Apr 9.
PubMed 25862940Williams KN, Kemper S. Interventions to reduce cognitive decline in aging. J Psychosoc Nurs Ment Health Serv. 2010 May;48(5):42-51. doi: 10.3928/02793695-20100331-03.
PubMed 20415290Aigbogun MS, Stellhorn R, Krasa H, Kostic D. Severity of memory impairment in the elderly: Association with health care resource use and functional limitations in the United States. Alzheimers Dement (Amst). 2017 Apr 20;8:51-59. doi: 10.1016/j.dadm.2017.04.001. eCollection 2017.
PubMed 28492059Plassman BL, Langa KM, Fisher GG, Heeringa SG, Weir DR, Ofstedal MB, Burke JR, Hurd MD, Potter GG, Rodgers WL, Steffens DC, McArdle JJ, Willis RJ, Wallace RB. Prevalence of cognitive impairment without dementia in the United States. Ann Intern Med. 2008 Mar 18;148(6):427-34. doi: 10.7326/0003-4819-148-6-200803180-00005.
PubMed 18347351Muriach M, Flores-Bellver M, Romero FJ, Barcia JM. Diabetes and the brain: oxidative stress, inflammation, and autophagy. Oxid Med Cell Longev. 2014;2014:102158. doi: 10.1155/2014/102158. Epub 2014 Aug 24.
PubMed 25215171Adelantado-Renau M, Esteban-Cornejo I, Rodriguez-Ayllon M, Cadenas-Sanchez C, Gil-Cosano JJ, Mora-Gonzalez J, Solis-Urra P, Verdejo-Roman J, Aguilera CM, Escolano-Margarit MV, Verdejo-Garcia A, Catena A, Moliner-Urdiales D, Ortega FB. Inflammatory biomarkers and brain health indicators in children with overweight and obesity: The ActiveBrains project. Brain Behav Immun. 2019 Oct;81:588-597. doi: 10.1016/j.bbi.2019.07.020. Epub 2019 Jul 19.
PubMed 31330300Tan BL, Norhaizan ME. Effect of High-Fat Diets on Oxidative Stress, Cellular Inflammatory Response and Cognitive Function. Nutrients. 2019 Oct 25;11(11):2579. doi: 10.3390/nu11112579.
PubMed 31731503Gareau MG. Cognitive Function and the Microbiome. Int Rev Neurobiol. 2016;131:227-246. doi: 10.1016/bs.irn.2016.08.001. Epub 2016 Sep 9.
PubMed 27793221Rea K, Dinan TG, Cryan JF. The microbiome: A key regulator of stress and neuroinflammation. Neurobiol Stress. 2016 Mar 4;4:23-33. doi: 10.1016/j.ynstr.2016.03.001. eCollection 2016 Oct.
PubMed 27981187Sherwin E, Dinan TG, Cryan JF. Recent developments in understanding the role of the gut microbiota in brain health and disease. Ann N Y Acad Sci. 2018 May;1420(1):5-25. doi: 10.1111/nyas.13416. Epub 2017 Aug 2.
PubMed 28768369Ou Z, Kong X, Sun X, He X, Zhang L, Gong Z, Huang J, Xu B, Long D, Li J, Li Q, Xu L, Xuan A. Metformin treatment prevents amyloid plaque deposition and memory impairment in APP/PS1 mice. Brain Behav Immun. 2018 Mar;69:351-363. doi: 10.1016/j.bbi.2017.12.009. Epub 2017 Dec 15.
PubMed 29253574Martin-Montalvo A, Mercken EM, Mitchell SJ, Palacios HH, Mote PL, Scheibye-Knudsen M, Gomes AP, Ward TM, Minor RK, Blouin MJ, Schwab M, Pollak M, Zhang Y, Yu Y, Becker KG, Bohr VA, Ingram DK, Sinclair DA, Wolf NS, Spindler SR, Bernier M, de Cabo R. Metformin improves healthspan and lifespan in mice. Nat Commun. 2013;4:2192. doi: 10.1038/ncomms3192.
PubMed 23900241Metformin in Longevity Study (MILES). - Full Text View - ClinicalTrials.gov [Internet]. [cited 2020 May 19]. Availablefrom: https://clinicaltrials.gov/ct2/show/NCT02432287
Sun L, Xie C, Wang G, Wu Y, Wu Q, Wang X, Liu J, Deng Y, Xia J, Chen B, Zhang S, Yun C, Lian G, Zhang X, Zhang H, Bisson WH, Shi J, Gao X, Ge P, Liu C, Krausz KW, Nichols RG, Cai J, Rimal B, Patterson AD, Wang X, Gonzalez FJ, Jiang C. Gut microbiota and intestinal FXR mediate the clinical benefits of metformin. Nat Med. 2018 Dec;24(12):1919-1929. doi: 10.1038/s41591-018-0222-4. Epub 2018 Nov 5.
PubMed 30397356Kattenstroth JC, Kalisch T, Holt S, Tegenthoff M, Dinse HR. Six months of dance intervention enhances postural, sensorimotor, and cognitive performance in elderly without affecting cardio-respiratory functions. Front Aging Neurosci. 2013 Feb 26;5:5. doi: 10.3389/fnagi.2013.00005. eCollection 2013.
PubMed 23447455
Study at a glance
From the registry record, last updated by the sponsor on 31 Mar 2026. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Gut-Brain-axis: Targets for Improvement of Cognition in the Elderly
- ClinicalTrials.gov ID
- NCT04841668
- Acronym / sponsor ID
- SmartAge / SMARTAGE-2020.133
- Conditions
- Type 2 Diabetes Mellitus
- Keywords
- Type 2 Diabetes Mellitus, Continous Glucose Monitoring, Cognition, Metformin, Gut microbiome, Magnetic resonance imaging, Physical activity monitor
- Study type
- Observational
- Recruitment status
- Completed
- Enrolment
- 50 participants (actual)
- Lead sponsor
- Institut d'Investigació Biomèdica de Girona Dr. Josep TruetaUniversity, hospital or other
- Study start
- 10 Apr 2021 (actual)
- Primary completion
- 3 Dec 2024 (actual)
- Study completion
- 3 Dec 2024 (actual)
- First posted
- 12 Apr 2021 (actual)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
Cognitive disorders increase with age and in the presence of metabolic diseases such as Type 2 Diabetes Mellitus (T2DM). In addition, digestive disorders, changes in dietary pattern and decreased activity negatively influence the microbiome.
The hypothesis is that pharmacological intervention with metformin will modify the composition of the gut microbiota and cognition.
The study has a pilot longitudinal design, where each patient with T2DM will be followed for one year. Two groups will be recruited:
- Group A: The aim will be to evaluate the associations between glucose (measured by continuous glucose monitoring (CGM)), cognitive function (by means of cognitive tests and magnetic resonance imaging (MRI)), physical activity (recorded by activity and sleep tracker devicer), metformin, diet (evaluated by nutritional survey) and composition of the microbiota (evaluated by metagenomics), during 12 months (6 months without metformin and 6 months with metformin treatment).
- Group B: The aim will be to evaluate the associations between glucose, diet (evaluated by nutritional survey), cognitive function (by means of cognitive tests), physical activity (measured by activity and sleep tracker device), the treatment and composition of the microbiota (evaluated by metagenomics), during 12 months.
Detailed description
Subjects and methods:
Longitudinal study:
Patients with T2DM previously scheduled at the Service of Endocrinology, Diabetes and Nutrition (UDEN) of the Hospital "Dr. Josep Trueta" of Girona (Spain) will be recruited and studied.
GROUP A
This study consists of an initial phase, where the patient will be submitted as the only treatment to a balanced diet with an energy intake, calculated individually according to whether he/she is normal weight (25 Kcal x Kg) or overweight (20 Kcal x Kg of weight).
After this initial phase, in addition to continuing with the balanced diet treatment, patients will start treatment with metformin administered orally at an initial dose of 425 mg/d every 12 hours during the first 15 days and then continue with doses of 850 mg/d until the end of the study.
A glycemia sensor will be inserted for ten days, as well as an activity and sleep tracker device (Fitbit) to record physical activity during this period of time. Interstitial subcutaneous glucose concentrations will be monitored on an outpatient basis for a period of time of 10 consecutive days using a glucose sensor validated by the FDA (Dexcom G6 ®). The sensor will be inserted on day 0 and it will retire on day 10 midmorning.
This process will be repeated 10 days prior to the start of the of treatment with Metformin and 10 days before the end of the 6 month study phase with metformin. During the study, 6 visits will be made and each patient will be inserted with a total of 3 glycemia sensors and 3 physical activity monitors. In summary, the glycemia sensor and physical activity monitoring will be started at visits 1, 3, 5 and will be removed at visits 2,4,6.
Visit 1(day 1): Physical examination, Nutritional survey, Bioimpedance, Densitometry, CGM and Activity and sleep tracker device. Consent form
Visit 2 (day 10): Sample: blood, urine and feces. Diet, Neuropsychological test, CGM withdrawal, Activity and sleep tracker device withdrawal, MRI.
Visit 3 (day 170): Physical examination, Nutritional survey, Bioimpedance, CGM and Activity and sleep tracker device
Visit 4 (day 180): Sample: blood, urine and feces. Dietary follow-up, Neuropsychological test, CGM withdrawal and Activity and sleep tracker device withdrawal. Start of metformin treatment.
Visit 5 (day 350): Physical examination, Nutritional survey, Bioimpedance, CGM and Activity and sleep tracker device.
Visit 6 (day 360): Sample: blood, urine and feces. Dietary follow-up, Neuropsychological test, CGM withdrawal and Activity and sleep tracker device withdrawal. Metformin withdrawal.
GROUP B:
During the study, 5 visits will be made for this group:
Visit 1(day 1): Physical examination, Nutritional survey, Bioimpedance, Densitometry and Activity and sleep tracker device. Consent form.
Visit 2 (day 10): Sample: blood, urine and feces. Diet, Neuropsychological test and Activity and sleep tracker device withdrawal.
Visit 3 (day 180): Diet follow-up.
Visit 4 (day 350): Physical examination, Nutritional survey, Bioimpedance and Activity and sleep tracker device.
Visit 5 (day 360): Sample: blood, urine and feces. Diet follow-up, Neuropsychological test and Activity and sleep tracker device withdrawal.
DATA COLLECTION OF SUBJECTS LONGITUDINAL STUDIES:
- Subsidiary data: Age, sex and birth date.
- Clinical variables:
- Weight
- height,
- body mass index
- waist and hip perimeters
- waist-to-hip ratio
- blood pressure (systolic and diastolic)
- fat mass and fat free-mass (bioelectric impedance and DEXA)
- smoking status
- alcohol intake
- registry of usual medicines
- personal history of blood transfusion and/or donation
- record of family history of obesity, cardiovascular events and diabetes
- psychiatric and eating disorder history.
- Laboratory variables: 15cc of blood will be extracted from fasted subjects to determine the following variables using the usual routine techniques of the clinical laboratory:
- hemogram
- glucose
- bilirubin
- aspartate aminotransferase (AST/GOT)
- alanine aminotransferase (ALT/GPT)
- gamma-glutamyl transpeptidase (GGT)
- urea
- creatinine
- uric acid
- total proteins,
- albumin
- total cholesterol | HDL cholesterol | LDL cholesterol
- triglycerides,
- glycated haemoglobin (HbA1c)
- ferritin | soluble transferrin receptor
- ultrasensitive C reactive protein
- erythrocyte sedimentation rate
- lipopolysaccharide binding protein
- free thyroxine (free T4) | thyroid stimulating hormone (TSH) | baseline cortisol -plasma insulin
- inflammation markers | interleukin 6 (IL-6). An additional 15cc of blood (plasma-EDTA) will be extracted for further analyses.
- Stool samples collection: A stool sample will be provided from each patient. The sample should be collected at home or in the hospital, sent to the laboratory within 4 hours from the collection, fragmented and stored at -80ºC. -Analysis of intestinal microbiota in stool:
- Determination of bacterial DNA and mRNA and study of the LBP binding protein in blood for the detection of bacterial translocation. LBP binding protein in blood for the detection of bacterial translocation. Hiseq and Nextseq technology (qPCR and protein analysis (WB, ELISA), OMICS (RNAseq, 16S, Metabolomics, Metagenomics).
- Inflammatory and immunological markers will be determined using ELISA (enzyme-linked immunosorbent assay) and immunohistochemistry (IHC) equipment and quantitative real-time PCR validation. For qPCR, total RNA will be isolated from different tissues and will transcribe into cDNA.
- Determination of metabolic profile and metabolite analysis.
- Intestinal barrier function:Exposure to a lactulose:mannitol test before/after surgery. Plasma samples will be used to measure intestinal permeability markers: bacterial endotoxin, sCD14, LBP, ZO-1, and I-FABP.
- Urine sample collection: Necessary to determine alterations in the metabolic pathways involved in tryptophan metabolism, and to determine the role of the intestinal microbiota in these metabolic changes.
- MRI: The necessary sequences will be acquired for the calculation of the BrainAGE biomarker and the characterization of the networks involved in cognitive functions. For the acquisition a 1.5 T scanner (Ingenia; Philips Medical Systems) will be used 1,5 T scanner (Ingenia; Philips Medical Systems) will be used for the acquisition. First, recovery-inversion sequence (T2-FLAIR) will be used to exclude subjects with pre-existing brain lesions. Subsequently, structural sequences will be acquired sequences will then be acquired to measure the integrity of cerebral gray matter (T1-weighted), tracts of weighted), of the white matter tracts (DTI), iron accumulation (R2*), and (R2*), and functional sequences in resting-state (T2*-weighted echo-planar imaging, EPI).
- Neuropsychological examination: Different domains of cognition will be explored: memory (Test aprendizaje verbal-TAVEC, Rey-Osterrieth Complex Figure) attention and executive function(WAIS-IV, Trail making test (Part A y B), Stroop test). In addition, cognitive impairment will be evaluated with Lobo's Mini-Cognitive Exam. These tests will be useful to define the changes in the cognitive profile associated with the pharmacological intervention with metformin.
The information will remain registered in a notebook and will be computerized in the database of the study.
STATICAL METHODS:
Sample size: Since this is intended as a pilot study, no formal sample size calculation is required. A general rule is to recruit 30 or more patients to estimate a parameter and 15-20 participants per group to obtain reasonable estimates for medium to large effect sizes.
Statistical analyses: It will be based on a descriptive analysis (mean, standard deviation, sample size, median, minimum and maximum) of the quantitative parameters and the indication of the frequency of the remaining categorical parameters. Comparisons between groups will be based on a paired samples t-test or a chi-square test. The results of these analyses may be useful to assess whether further analyses are needed to adjust for possible imbalance in the baseline characteristics of the patients.
The changes in the composition of the gut microbiota after the intervention with metformin will be analyzed using Heatmaps, Principal Component Analysis (PCA) and PLSDA. For the multivariate statistical analysis (PLSDA and hierarchical clustering). The variables that comprise the characteristics of the intestinal microbiota and cognitive tests will be logarithmically transformed, filtered with interquartile range estimation and staggered by autoscale calculation (mean and divided by the standard deviation of each variable) by using the Metaboanalyst platform.
The changes determined in the gut microbiota and cognition variables will be explored in relation to the changes in the secondary variables (metabolic, metabolome, inflammation parameters) by linear regression analysis in SPSS. Brain image variables will be analyzed with specialized programs (MATLAB, SPM12).
Study design
- Observational model
- Cohort
- Time perspective
- Prospective
- Number of arms
- 2
| Arm | Type | Receives |
|---|---|---|
| Patients with recently diagnosed T2DM | – | Drug: MetforminThis group will consist of 36 recently diagnosed T2DM, according to the World Health Organization (WHO) patients (last 6 months), who have not received treatment with metformin. |
| Patients with long-term T2DM | – | –The group will consist of 100 patients with long-term T2DM, according to the WHO classification, regardless of whether they take metformin or another treatment. |
Who may qualify
- Ages
- 65 to 80 years
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Older adult
- Study population
- Group A Study population Adult patients (≥ 65 years of age) recently diagnosed with T2DM according to the WHO and who have not been treated with metformin. Group B Study population Adult patients (≥ 65 years of age) diagnosed with long-term T2DM according to the WHO classification, regardless of whether they take metformin or other treatment.
Key inclusion criteria (6 listed)
- Age between 55 and 80 years.
- Patients with recently diagnosed T2DM (last 6 months), according to the WHO classification.
- Patients in whom written informed consent has been obtained for participation in the study.
- Age between 65 and 80 years.
- Patients with long-term T2DM according to the WHO classification
Key exclusion criteria (47 listed)
- HbA1c ≥ 9%
- Metformin treatment in the past 6 months
- Creatinine greater than 1.2 and glomerular filtration rate less than 40
- Serious systemic disease not related to obesity, including any type of cancer, severe kidney disease or liver disease, and known type 1 diabetes.
- Systemic diseases with intrinsic inflammatory activity such as rheumatoid arthritis, Crohn's disease, asthma, or chronic infection (e.g., HIV, active tuberculosis) or any type of infectious disease.
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| MetforminPatients will begin treatment with metformin administered orally at a starting dose of 425 mg / day every 12 hours for the first 15 days and then continue with a dose of 850 mg / day until the end of the study. The beginning of this treatment phase will be following the recommendations of the clinical guidelines (Comprehensive Approach to Type 2 Diabetes Mellitus, SEEN V2019.2) | Drug | Patients with recently diagnosed T2DM |
Primary outcome
Gut microbiota composition.
Time frame: 12 months
It will be identified in the stool by cultures and DNA and mRNA expression after metformin treatment.
Cognitive impairment
Time frame: 12 months
It will be measured by Mini-Examen Cognoscitivo (MEC).
Audioverbal memory
Time frame: 12 months
It will be measured by Test aprendizaje verbal-TAVEC.
Visual memory
Time frame: 12 months
It will be measured by Rey-Osterrieth Complex Figure.
Depressive symptomatology
Time frame: 12 months
It will be measured by Patient Health Questionnaire-9 (PHQ-9).
Impulsivity
Time frame: 12 months
It will be measured by UPPS Impulsive Behavior Scale.
Food Addiction
Time frame: 12 months
It will be measured by Yale Food Addiction Scale.
Behavioral inhibition
Time frame: 12 months
It will be measured by Sensitivity to Punishment and Sensitivity to Reward (SPSRQ).
Behavioral activation
Time frame: 12 months
It will be measured by Sensitivity to Punishment and Sensitivity to Reward (SPSRQ).
Visoconstructive function
Time frame: 12 months
It will be measured by Rey-Osterrieth Complex Figure.
Visuospatial perception
Time frame: 12 months
It will be measured by Judgment Line Orientation.
Naming
Time frame: 12 months
It will be measured by Boston Naming Test.
Selective and alternating attention
Time frame: 12 months
It will be measured by Trail making test (Part A y B).
Attention and working memory
Time frame: 12 months
It will be measured by the Wechsler Adult Intelligence Scales, Fourth Edition (WAIS-IV).
Inhibition
Time frame: 12 months
It will be measured by Stroop Color-Word Test.
Phonemic verbal fluency
Time frame: 12 months
It will be measured by PMR
Semantic verbal fluency
Time frame: 12 months
It will be measured by Animals
6 secondary outcomes
The percentage of time in glucose target range (glucose level 70mg/dl-180mg/dl)
Time frame: 12 months
Effect on gut microbiota
Time frame: 12 months
The percentage of time in glucose range (glucose level below 100 mg/dl)
Time frame: 12 months
The percentage of time in glucose range (glucose level between 100-125 mg/dl)
Time frame: 12 months
The percentage of time in glucose range (glucose level between 126-139 mg/dl)
Time frame: 12 months
The percentage of time in glucose range (glucose level between 140-199 mg/dl)
Time frame: 12 months
Results and safety
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 31 Mar 2026.
- Background: PubMed 25862940Fama R, Sullivan EV. Thalamic structures and associated cognitive functions: Relations with age and aging. Neurosci Biobehav Rev. 2015 Jul;54:29-37. doi: 10.1016/j.neubiorev.2015.03.008. Epub 2015 Apr 9.
- Background: PubMed 20415290Williams KN, Kemper S. Interventions to reduce cognitive decline in aging. J Psychosoc Nurs Ment Health Serv. 2010 May;48(5):42-51. doi: 10.3928/02793695-20100331-03.
- Background: PubMed 28492059Aigbogun MS, Stellhorn R, Krasa H, Kostic D. Severity of memory impairment in the elderly: Association with health care resource use and functional limitations in the United States. Alzheimers Dement (Amst). 2017 Apr 20;8:51-59. doi: 10.1016/j.dadm.2017.04.001. eCollection 2017.
- Background: PubMed 18347351Plassman BL, Langa KM, Fisher GG, Heeringa SG, Weir DR, Ofstedal MB, Burke JR, Hurd MD, Potter GG, Rodgers WL, Steffens DC, McArdle JJ, Willis RJ, Wallace RB. Prevalence of cognitive impairment without dementia in the United States. Ann Intern Med. 2008 Mar 18;148(6):427-34. doi: 10.7326/0003-4819-148-6-200803180-00005.
- Background: PubMed 25215171Muriach M, Flores-Bellver M, Romero FJ, Barcia JM. Diabetes and the brain: oxidative stress, inflammation, and autophagy. Oxid Med Cell Longev. 2014;2014:102158. doi: 10.1155/2014/102158. Epub 2014 Aug 24.
- Background: PubMed 31330300Adelantado-Renau M, Esteban-Cornejo I, Rodriguez-Ayllon M, Cadenas-Sanchez C, Gil-Cosano JJ, Mora-Gonzalez J, Solis-Urra P, Verdejo-Roman J, Aguilera CM, Escolano-Margarit MV, Verdejo-Garcia A, Catena A, Moliner-Urdiales D, Ortega FB. Inflammatory biomarkers and brain health indicators in children with overweight and obesity: The ActiveBrains project. Brain Behav Immun. 2019 Oct;81:588-597. doi: 10.1016/j.bbi.2019.07.020. Epub 2019 Jul 19.
- Background: PubMed 31731503Tan BL, Norhaizan ME. Effect of High-Fat Diets on Oxidative Stress, Cellular Inflammatory Response and Cognitive Function. Nutrients. 2019 Oct 25;11(11):2579. doi: 10.3390/nu11112579.
- Background: PubMed 27793221Gareau MG. Cognitive Function and the Microbiome. Int Rev Neurobiol. 2016;131:227-246. doi: 10.1016/bs.irn.2016.08.001. Epub 2016 Sep 9.
- Background: PubMed 27981187Rea K, Dinan TG, Cryan JF. The microbiome: A key regulator of stress and neuroinflammation. Neurobiol Stress. 2016 Mar 4;4:23-33. doi: 10.1016/j.ynstr.2016.03.001. eCollection 2016 Oct.
- Background: PubMed 28768369Sherwin E, Dinan TG, Cryan JF. Recent developments in understanding the role of the gut microbiota in brain health and disease. Ann N Y Acad Sci. 2018 May;1420(1):5-25. doi: 10.1111/nyas.13416. Epub 2017 Aug 2.
- Background: PubMed 29253574Ou Z, Kong X, Sun X, He X, Zhang L, Gong Z, Huang J, Xu B, Long D, Li J, Li Q, Xu L, Xuan A. Metformin treatment prevents amyloid plaque deposition and memory impairment in APP/PS1 mice. Brain Behav Immun. 2018 Mar;69:351-363. doi: 10.1016/j.bbi.2017.12.009. Epub 2017 Dec 15.
- Background: PubMed 23900241Martin-Montalvo A, Mercken EM, Mitchell SJ, Palacios HH, Mote PL, Scheibye-Knudsen M, Gomes AP, Ward TM, Minor RK, Blouin MJ, Schwab M, Pollak M, Zhang Y, Yu Y, Becker KG, Bohr VA, Ingram DK, Sinclair DA, Wolf NS, Spindler SR, Bernier M, de Cabo R. Metformin improves healthspan and lifespan in mice. Nat Commun. 2013;4:2192. doi: 10.1038/ncomms3192.
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
José M Fernández-Real, Ph.D. principal investigator
Institut d'Investigació Biomèdica de Girona (IDIBGI)
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
An observational study of Type 2 Diabetes Mellitus, run by Institut d'Investigació Biomèdica de Girona Dr. Josep Trueta at 1 site in Spain.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 6 inclusion and 47 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: finished, as of the sponsor's last update on 31 Mar 2026. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in Spain. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
Are results available for this study?
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Gut microbiota composition. (time frame: 12 months). The study lists 17 primary outcomes in all. It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT04841668, which also lists 53 linked publications.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 31 Mar 2026.