DODDRELL. Effect of rosiglitazone on insulin sensitivity and body composition in type 2 diabetic patients. Obes Res. 2002;10:1008 -1015. Objective: To investigate the effects of rosiglitazone (RSG) on insulin sensitivity and regional adiposity (including intrahepatic fat) in patients with type 2 diabetes. Research Methods and Procedures:We examined the effect of RSG (8 mg/day, 2 divided doses) compared with placebo on insulin sensitivity and body composition in 33 type 2 diabetic patients. Measurements of insulin sensitivity (euglycemic hyperinsulinemic clamp), body fat (abdominal magnetic resonance imaging and DXA), and liver fat (magnetic resonance spectroscopy) were taken at baseline and repeated after 16 weeks of treatment. Results: There was a significant improvement in glycemic control (glycosylated hemoglobin Ϫ0.7 Ϯ 0.7%, p Յ 0.05) and an 86% increase in insulin sensitivity in the RSG group (glucose-disposal rate change from baseline: 17.5 Ϯ 14.5 mol glucose/min/kg free fat mass, p Ͻ 0.05), but no significant change in the placebo group compared with baseline. Total body weight and fat mass increased (p Յ 0.05) with RSG (2.1 Ϯ 2.0 kg and 1.4 Ϯ 1.6 kg, respectively) with 95% of the increase in adiposity occurring in nonabdominal regions. In the abdominal region, RSG increased subcutaneous fat area by 8% (25.0 Ϯ 28.7 cm 2 , p ϭ 0.02), did not alter intra-abdominal fat area, and reduced intrahepatic fat levels by 45% (Ϫ6.7 Ϯ 9.7%, concentration relative to water). Discussion: Our data indicate that RSG greatly improves insulin sensitivity in patients with type 2 diabetes and is associated with an increase in adiposity in subcutaneous but not visceral body regions.

Phosphorus 31 magnetic resonance (MR) spectroscopy was used for the study of liver metabolism in vivo in seven healthy subjects. Subjects were examined in a 1.6 T whole-body magnet using surface coils for data acquisition. The region of the liver from which MR signals were collected was selected by magnetic-field profiling. The concentration ratios of adenosine triphosphate (ATP), inorganic phosphate (Pi) and sugar phosphates contained in liver cells could be reproducibly assessed. Cytosolic pH and the free magnesium concentration were determined to be 7.18 and 300 microM, respectively. During intravenous fructose tolerance tests the hepatic concentrations of sugar phosphates, ATP and Pi altered markedly. During the first 5 min following bolus injection of 250 mg fructose/kg body weight the concentration of sugar phosphates increased sevenfold whereas Pi and ATP decreased by three- to fourfold. Metabolism of sugar phosphates was complete within 20 min and could be followed by 31P MR with a time resolution of 5 min. Thus, 31P MR spectroscopy yields insight into liver metabolism which has not been accessible so far using conventional non-invasive methods. In conjunction with intravenous fructose loading, 31P MR spectroscopy may provide a means for the functional assessment of the liver.

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The potential clinical use of topical magnetic resonance spectroscopy (volume selection by static magnetic field gradients) was tested in 50 studies in volunteers. Topical magnetic resonance spectroscopy (MRS) was shown to be a straightforward method for localising 31P spectra of brain and liver. However, the spherical shape and fixed position of the selected volume posed serious limitations to the study of heart and transplanted kidney by topical MRS. Phosphorus-31 spectra of approximately 30 cm-3 of brain or liver could be obtained in 8 min. Ratios of metabolite concentrations could be determined with a coefficient of variation ranging from 10% to 30%. The ratios of phosphocreatine/ATP and inorganic phosphate/ATP in brain were 1.8 and 0.3, respectively. The ratio of inorganic phosphate/ATP in liver was 0.9. Intracellular pH was 7.03 in brain and 7.24 in liver. The T1 relaxation times of phosphocreatine, inorganic phosphate and gamma-ATP in brain were 4.8 s, 2.5 s and 1.0 s, respectively.

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Background The relationship of tissue chemistry to breast density and cancer risk has not been documented despite breast density being a known risk factor. Purpose To investigate whether distinct chemical profiles associated with breast density and cancer risk are identified in healthy breast tissue using in vivo two‐dimensional correlated spectroscopy (2D COSY). Study Type Prospective. Population One‐hundred‐seven participants including 55 at low risk and 52 at high risk of developing breast cancer. Field Strength/Sequence 3 T/ axial/ T1, T2, 2D COSY. Assessment Two radiologists defined breast density on T2. Interobserver variability assessed. Peak volumes normalized to methylene at (1.30, 1.30) ppm as internal shift reference. Statistical Tests Chi‐squared/Mann–Whitney/Kappa statistics/Kruskal Wallis/pairwise analyses. Significance level 0.05. Results Ten percentage were fatty breasts, 39% scattered fibroglandular, 35% heterogeneously dense, and 16% extremely dense. Interobserver variability was excellent (kappa = 0.817). Sixty percentage (64/107) were premenopausal. Four distinct tissue chemistry categories were identified: low‐density (LD)/premenopausal, high‐density (HD)/premenopausal, LD/postmenopausal, and HD/postmenopausal. Compared to LD, HD breast chemistry showed significant increases of cholesterol (235%) and lipid unsaturation (33%). In the low‐risk category, postmenopausal women with dense breasts recorded the largest significant changes including cholesterol methyl 540%, lipid unsaturation 207%, glutamine/glutamate 900%, and choline/phosphocholine 800%. In the high‐risk cohort, premenopausal women with HD recorded a more active chemical profile with significant increases in choline/phosphocholine 1100%, taurine/glucose 550% and cholesterol sterol 250%. Data Conclusion Four distinct chemical profiles were identified in healthy breast tissue based on breast density and menopausal status in participants at low and high risk. Gradual increase in neutral lipid content and metabolites was noted in both risk groups across categories in different order. In low risk, the HD postmenopausal category exhibited the highest metabolic activity, while women at high risk exhibited the highest lipid content and metabolic activity in the HD premenopausal category. Level of Evidence 2 Technical Efficacy Stage 3

Background An imbalance between inhibitory and excitatory neurometabolites has been implicated in chronic pain. Prior work identified elevated levels of Gamma-aminobutyric acid + macromolecules (“GABA+”) using magnetic resonance spectroscopy (MRS) in people with migraine. What is not understood is whether this increase in GABA+ is a cause, or consequence of living with, chronic migraine. Therefore, to further elucidate the nature of the elevated GABA+ levels reported in migraine, this study aimed to observe how GABA+ levels change in response to changes in the clinical characteristics of migraine over time. Methods We observed people with chronic migraine (ICHD-3) over 3-months as their treatment was escalated in line with the Australian Pharmaceutical Benefits Scheme (PBS). Participants underwent an MRS scan and completed questionnaires regarding migraine frequency, intensity (HIT-6) and disability (WHODAS) at baseline and following the routine 3 months treatment escalation to provide the potential for some participants to recover. We were therefore able to monitor changes in brain neurochemistry as clinical characteristics potentially changed over time. Results The results, from 18 participants who completed both baseline and follow-up measures, demonstrated that improvements in migraine frequency, intensity and disability were associated with an increase in GABA+ levels in the anterior cingulate cortex (ACC); migraine frequency (r = − 0.51, p = 0.03), intensity (r = − 0.51, p = 0.03) and disability (r = − 0.53, p = 0.02). However, this was not seen in the posterior cingulate gyrus (PCG). An incidental observation found those who happened to have their treatment escalated with CGRP-monoclonal antibodies (CGRP-mAbs) (n = 10) had a greater increase in ACC GABA+ levels (mean difference 0.54 IU IQR [0.02 to 1.05], p = 0.05) and reduction in migraine frequency (mean difference 10.3 IQR [2.52 to 18.07], p = 0.01) compared to those who did not (n = 8). Conclusion The correlation between an increase in ACC GABA+ levels with improvement in clinical characteristics of migraine, suggest previously reported elevated GABA+ levels may not be a cause of migraine, but a protective mechanism attempting to suppress further migraine attacks.