Investigating the Link Between Advanced Glycation End Products (AGEs) and Muscle Wasting in Sarcobesity

Obesity Clinical Trial

— Westernage  

Official title:

Fighting Western-diet Derived AGEs to Mitigate Muscle Wasting in Sarcobesity:Observational Study on the Relationship Between AGE Levels and Sarcobesity in an Adult Population Affected by Obesity and Type 2 Diabetes Mellitus

Clinical Trial Details — Status: Not yet recruiting

Administrative data

• NCT number: NCT06438900
• Other study ID #: CE049/2024
• Status: Not yet recruiting
• Start date: June 15, 2024
• Est. completion date: May 15, 2026

Study information

• Verified date: May 2024
• Source: Azienda Ospedaliero Universitaria Maggiore della Carita
• Contact: Flavia Prodam, MD PhD
• Phone: +39-0321-660693
• Email: flavia.prodam[@]med.uniupo.it
• Is FDA regulated: No
• Study type: Observational

Clinical Trial Summary

The study aims to explore whether a high level of AGEs (Advanced Glycation end products) derived from the diet may mediate diet-related muscle loss in Western-type diet, influencing the onset and progression of sarcopenia, predisposing to earlier and more severe metabolic consequences, including type 2 diabetes (T2D).

The primary objective of the study is to investigate how the accumulation of AGEs is correlated with muscle loss in adult patients with obesity and type 2 diabetes or lipodystrophy in order to identify possible targets to mitigate the metabolic alterations caused by the Western diet (WD). Specifically, circulating AGEs levels on the skin will be evaluated and correlated with the stage of sarcopenia in a group of patients with obesity and a T2D diagnosis. Furthermore, the relationship between disease duration and AGE levels will be assessed.

A secondary objective will be to analyze the clinical data obtained to identify metabolites and metabolic pathways responsible for the phenotype induced by the WD.

The ultimate aim of the study is therefore to verify whether high levels of AGEs are correlated with an early and/or more pronounced onset of sarcopenia, concurrently with an increase in inflammation and oxidative stress.

Description:

The study in question is of a cross-sectional observational type. The reference population is defined by patients with obesity and a diagnosis of T2D within 15 years of entry into the study or patients with concomitant type 2 diabetes and lipodystrophy syndrome. This population was chosen because they are at high risk of sarcopenia.

Lipodystrophy includes a heterogeneous spectrum of genetic and acquired diseases characterized by loss of subcutaneous adipose tissue, ectopic fat accumulation, insulin resistance, metabolic and cardiovascular diseases, premature aging, sarcopenia, muscle pain, high-grade inflammation, epigenetic dysregulation, and mitochondrial dysfunction. Therefore, patients with T2D and lipodystrophy are highly inflamed as they generally present with a more severe T2D phenotype, presumed sarcopenic, and with a high rate of endogenous AGE production. Patients with concurrent lipodystrophy and T2D will be recruited as sarcopenic and obese subjects, representing an excellent strategy for comparison with diabetic individuals without lipodystrophy.

SUBJECTS AND METHODS A total of 195 consecutive subjects will be enrolled in the study from the Endocrinology Unit of the University of Eastern Piedmont between April 2024 and April 2026, who meet the inclusion criteria.

Study duration:

The study will last for two years corresponding to the enrollment period given the cross-sectional nature of the study.

Statistical Analysis

Descriptive statistics will be used to summarize sociodemographic, anthropometric, clinical, and lifestyle-related information collected. Categorical variables will be summarized using absolute frequencies and percentages, while numerical variables will be summarized using mean and standard deviation or median and interquartile range if not normally distributed according to the Shapiro-Wilk test and after observation of Q-Q plots (quantile-quantile plot).

The Pearson correlation coefficient or the corresponding non-parametric Spearman rank correlation coefficient and confidence intervals will be initially calculated to assess the correlation between the levels of individual AGEs and skeletal muscle mass (SMM), handgrip strength (HGS), parameters of body composition, and functional parameters of skeletal muscle. Subsequently, linear regression models will be used to evaluate the relationship between AGEs and sarcopenia-defining indices adjusted for age, sex, duration of diabetes, and other potential confounding factors such as inflammation, adherence to the Western diet, and levels of physical activity. The LASSO method will be used for variable selection in multivariable regression models.

Univariable and multivariable Poisson regression models with robust variance will be used to estimate relative prevalence risks for the association between AGEs and patient characteristics with sarcopenia presence and the corresponding confidence intervals.

An integration of clinical data, biochemical data, AGE levels, and patient omic signatures will be performed to develop a multifactorial diagnostic model using multivariate statistical analysis (e.g., factor analysis, principal component analysis, cluster analysis, discriminant analysis, partial least squares analysis, logistic regression) and data-driven approaches. Machine learning algorithms will be applied to prioritize and weigh risk factors. These analyses will be conducted with internal statistical consultation already utilized by the group.

Expected Results

With this study, the investigators expect to obtain further information and correlations between nutritional assessment and its impact on inflammation, sarcopenia definition, and progression, obesity, and T2D, based on body measurements and clinical parameters. Through biochemical, hormonal, and metabolomic analyses conducted on biological samples, te investigators expect to identify possible markers related to the presence of AGEs. In conclusion, the primary expected outcome would be to identify a positive correlation between AGE accumulation in at least one compartment (skin, plasma, urine) and the severity of sarcopenia, thus obtaining a rapid and non-invasive method to identify individuals at high risk of developing muscle wasting (MW) and identify correlations between AGE levels and other metabolic characteristics, even in lipodystrophic pathology.

Recruitment information / eligibility

• Status: Not yet recruiting
• Enrollment: 195
• Est. completion date: May 15, 2026
• Est. primary completion date: May 15, 2026
• Accepts healthy volunteers: Accepts Healthy Volunteers
• Gender: All
• Age group: 18 Years and older

Eligibility

Inclusion Criteria:

• Patients of both sexes.

• Adults.

• BMI compatible with obesity and a diagnosis of type 2 diabetes under good metabolic control (HbA1c < 7.5%) within 15 years of entry into the study or diagnosis of lipodystrophy (included in the European Consortium of Lipodystrophies (ECLip) Registry (eclip-web.org))

Exclusion Criteria:

• Age under 18 years.

• Secondary obesity or genetic diseases (Prader-Willi Syndrome, Down Syndrome); metabolic and endocrine disorders (Cushing's syndrome, hypothyroidism).

• Subjects with: Inflammatory Bowel Disease (IBD), cancer.

• Confirmed or planned pregnancy during the study participation months.

Related Conditions & MeSH terms

• Muscular Atrophy
• Obesity
• Sarcopenia

Locations

Country	Name	City	State
Italy	SCDU Endocrinology, AOU Ospedale Maggiore della Carità	Novara

Sponsors (1)

Lead Sponsor	Collaborator
Azienda Ospedaliero Universitaria Maggiore della Carita

Country where clinical trial is conducted

Italy, 

References & Publications (23)

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* Note: There are 23 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Skeletal mass functionality for sarcopenia definition	Functional parameters of skeletal muscle defined by muscle strength measured through hand grip strength (HGS) The test requires the patient to tighten the handle the dynamometer with the maximum possible force, then maintaining the contraction for at least 5 seconds; you should repeat the test on the other hand (it is normal that the dominant expresses a higher force) and possibly repeat the test 2-3 times, with a break between different attempts, then going to calculate the average oh the kg moved with the dynamometer	evaluation of sarcopenia state through study completion, an average of 1 year
Primary	Skeletall mass fuctionality for sarcopenia definition	Functional parameters of skeletal muscle defined by the chair test: five-times sit-to-stand test; time duration 30-second chair stand test. You measure by considering the ability in seconds to get up and sit down from the chair properly	evaluation of sarcopenia state through study completion, an average of 1 year
Primary	Skeletall mass calculation for sarcopenia definition	The percentage of skeletal muscle mass relative to body mass will be considered.; Skeletal mass will be calculated as follows: SM(Kg)=[(h^2/(BIA resistance)0.401)+(gender3.825)+(age*0.071)]+5.102 Where h indicates height measured in cm, gender is a dichotomous variable taking a value of 1 for males and 0 for females, and age is measured in years.; From this measurement, the percentage of skeletal muscle mass (%SMM) will be calculated: %SMM=(SM (Kg))/(Body mass (Kg))*100	evaluation of sarcopenia state through study completion, an average of 1 year
Primary	Number of participants with sarcopenia	According to consensus statement of European Society for Clinical Nutrition and Metabolism (ESPEN) and dell' European Association for the Study of Obesity (EASO) guidelines, individuals with altered skeletal muscle functionality parameters (HGS < 16 kg for females and < 27 kg for males or chair test >15 seconds for both males and females [27]), altered %BF(body fat) (= 25% for males and =35% for females [28]), and altered %SMM (<35.6% (=28.7% severe sarcopenia) for males, <28.4% (=23% severe sarcopenia) for females) will be defined as sarcopenic.	evaluation of sarcopenia state through study completion, an average of 1 year
Primary	Advanced glycation end products quantification	AGE levels will be measured using skin fluorescence, using the "AGE reader mu" device (range from 1.3 to 5 level of AGEs respect to the patient's age).	evaluation of AGEs through study completion, an average of 1 year
Primary	Endogenous and exogenous AGEs plasma quantification	AGEs will also be assessed at the plasma level in free form (ELISA, fluorescence assay) or bound to hemoglobin (HbA1c clinical practice test), both measured in pg/mL	evaluation of AGEs through study completion, an average of 1 year
Secondary	With questionnaires assessment of socio-demographic characteristics	Gender, date of birth, date of diabetes diagnosis (for diabetic subjects) are assessed through questionnaires and medical record	evaluation of socio-demographic characteristics through study completion, an average of 1 year
Secondary	Anthropometric measurements	weight is assessed in Kg with the use of the bioimpedance balance	evaluation of weight and body composition through study completion, an average of 1 year
Secondary	Anthropometric measurements	the height is measured in cm through a wall altimeter	evaluation of height through study completion, an average of 1 year
Secondary	Anthropometric measurements	the BMI (body mass index) is calculated by making the ratio of the weight to the square of the height	evaluation of BMI (body mass index) through study completion, an average of 1 year
Secondary	Anthropometric measurements	waist, hip, arm, and calf circumference are measured using an anelastic meter	evaluation of circumferences through study completion, an average of 1 year
Secondary	Dietary Inflammatory Index (DII)	Calculated using Alternative Healthy Eating Index-2010 (AHEI-2010) derived from basal metabolism assessment through fasting morning indirect calorimetry.	evaluation of DII through study completion, an average of 1 year
Secondary	Adherence level to the Western diet with European Prospective Investigation into Cancer and Nutrition (EPIC) questionnaires	Assessed with the use of questionnaire. EPIC is used for the bromatology evaluation of the diet, so there aren't scales but only indication about the macro and micronutrient composition. This is a qualitative questionnaires and not quantitative.	evaluation of DII through study completion, an average of 1 year
Secondary	Adherence level to the Western diet with 24h recall questionnaires	Assessed with the use of questionnaires. 24h recall questionnaire is used for the bromatology evaluation of the diet, so there aren't scales but only indication about the macro and micronutrient composition. This is a qualitative questionnaires and not quantitative.	evaluation of DII through study completion, an average of 1 year
Secondary	Level of physical activity, related to sarcopenia,using a questionnaire	Physical activity is assessed using the International Physical Activity Questionnaire (IPAQ), which provides results in Metabolic Equivalent of Tasks (METs). The questions refer to activities over the past 7 days, including work, transportation, and leisure time.; Moderate physical activity: Requires moderate effort and a slightly higher breathing rate than normal. One can speak but not sing during this activity.; Intense physical activity: Requires significant effort and a much higher breathing rate, causing sweating and making it difficult to talk.; The METs scale is as follows: Less than 700 METs: Inactive 700 to 2519 METs: Sufficiently active More than 2520 METs: Active	evaluation of METs through study completion, an average of 1 year