Effect of tirzepatide on body fat distribution pattern in people with type 2 diabetes.

AIMS: To describe the overall fat distribution patterns independent of body mass index (BMI) in participants with type 2 diabetes (T2D) in the SURPASS-3 MRI substudy by comparison with sex- and BMI-matched virtual control groups (VCGs) derived from the UK Biobank imaging study at baseline and Week 52. METHODS: For each study participant at baseline and Week 52 (N = 296), a VCG of ≥150 participants with the same sex and similar BMI was identified from the UK Biobank imaging study (N = 40 172). Average visceral adipose tissue (VAT), abdominal subcutaneous adipose tissue (aSAT) and liver fat (LF) levels and the observed standard deviations (SDs; standardized normal z-scores: z-VAT, z-aSAT and z-LF) were calculated based on the matched VCGs. Differences in z-scores between baseline and Week 52 were calculated to describe potential shifts in fat distribution pattern independent of weight change. RESULTS: Baseline fat distribution patterns were similar across pooled tirzepatide (5, 10 and 15 mg) and insulin degludec (IDeg) arms. Compared with matched VCGs, SURPASS-3 participants had higher baseline VAT (mean [SD] z-VAT +0.42 [1.23]; p < 0.001) and LF (z-LF +1.24 [0.92]; p < 0.001) but similar aSAT (z-aSAT -0.13 [1.11]; p = 0.083). Tirzepatide-treated participants had significant decreases in z-VAT (-0.18 [0.58]; p < 0.001) and z-LF (-0.54 [0.84]; p < 0.001) but increased z-aSAT (+0.11 [0.50]; p = 0.012). Participants treated with IDeg had a significant change in z-LF only (-0.46 [0.90]; p = 0.001), while no significant changes were observed for z-VAT (+0.13 [0.52]; p = 0.096) and z-aSAT (+0.09 [0.61]; p = 0.303). CONCLUSION: In this exploratory analysis, treatment with tirzepatide in people with T2D resulted in a significant reduction of z-VAT and z-LF, while z-aSAT was increased from an initially negative value, suggesting a possible treatment-related shift towards a more balanced fat distribution pattern with prominent VAT and LF loss.

Risk stratification using magnetic resonance imaging-derived, personalized z-scores of visceral adipose tissue, subcutaneous adipose tissue, and liver fat in persons with obesity.

BACKGROUND: Individual patterns of fat accumulation (visceral, subcutaneous, and/or liver fat) can determine cardiometabolic risk profile. OBJECTIVE: To investigate risk stratification using personalized fat z-scores in persons with a body mass index (BMI) of 30-40 kg/m2 from the UK Biobank imaging study. SETTING: Population-based study. METHODS: Whole-body magnetic resonance (MR) images of 40,174 participants from the UK Biobank imaging study were analyzed for visceral adipose tissue (VAT), abdominal subcutaneous adipose tissue (aSAT), and liver fat (LF) and used to calculate sex- and body size-invariant fat z-scores (VATz, aSATz, LFz). Associations between z-scores and later incident cardiovascular disease (CVD) and type 2 diabetes (T2D) were investigated using Cox proportional hazards modeling and Kaplan-Meier curves in participants with BMI 30-40 kg/m2. RESULTS: A total of 6716 participants had BMI 30-40 kg/m2 and within this group, CVD was positively associated with VATz (crude hazard ratio (cHR) [95% CI]: 1.30 [1.20-1.40], P < .001) and negatively associated with aSATz and LFz (cHR: 0.91 [0.85-0.99], P = .028, and 0.88 [0.82-0.95], P = .002). All z-scores remained significant after adjustment for sex, BMI, and age, but only VATz was significant when previous CVD was added. T2D was positively associated with VATz and LFz (cHR: 1.53 [1.40-1.67], P < .001, and 1.35 [1.23-148], P < .001) and negatively associated with aSATz (cHR: 0.90 [0.81-0.99], P = .026). All z-scores remained significant after adjustment for sex, BMI, and age. CONCLUSIONS: Personalized MR-derived fat z-scores can identify phenotypes of obesity with specific cardiometabolic risk profiles regardless of BMI. Current guidelines for bariatric surgery based on BMI exclude some of these high-risk patients.

Pain and the biochemistry of fibromyalgia: patterns of peripheral cytokines and chemokines contribute to the differentiation between fibromyalgia and controls and are associated with pain, fat infiltration and content.

Objectives: This explorative study analyses interrelationships between peripheral compounds in saliva, plasma, and muscles together with body composition variables in healthy subjects and in fibromyalgia patients (FM). There is a need to better understand the extent cytokines and chemokines are associated with body composition and which cytokines and chemokines differentiate FM from healthy controls. Methods: Here, 32 female FM patients and 30 age-matched female healthy controls underwent a clinical examination that included blood sample, saliva samples, and pain threshold tests. In addition, the subjects completed a health questionnaire. From these blood and saliva samples, a panel of 68 mainly cytokines and chemokines were determined. Microdialysis of trapezius and erector spinae muscles, phosphorus-31 magnetic resonance spectroscopy of erector spinae muscle, and whole-body magnetic resonance imaging for determination of body composition (BC)-i.e., muscle volume, fat content and infiltration-were also performed. Results: After standardizing BC measurements to remove the confounding effect of Body Mass Index, fat infiltration and content are generally increased, and fat-free muscle volume is decreased in FM. Mainly saliva proteins differentiated FM from controls. When including all investigated compounds and BC variables, fat infiltration and content variables were most important, followed by muscle compounds and cytokines and chemokines from saliva and plasma. Various plasma proteins correlated positively with pain intensity in FM and negatively with pain thresholds in all subjects taken together. A mix of increased plasma cytokines and chemokines correlated with an index covering fat infiltration and content in different tissues. When muscle compounds were included in the analysis, several of these were identified as the most important regressors, although many plasma and saliva proteins remained significant. Discussion: Peripheral factors were important for group differentiation between FM and controls. In saliva (but not plasma), cytokines and chemokines were significantly associated with group membership as saliva compounds were increased in FM. The importance of peripheral factors for group differentiation increased when muscle compounds and body composition variables were also included. Plasma proteins were important for pain intensity and sensitivity. Cytokines and chemokines mainly from plasma were also significantly and positively associated with a fat infiltration and content index. Conclusion: Our findings of associations between cytokines and chemokines and fat infiltration and content in different tissues confirm that inflammation and immune factors are secreted from adipose tissue. FM is clearly characterized by complex interactions between peripheral tissues and the peripheral and central nervous systems, including nociceptive, immune, and neuroendocrine processes.