Extramyocellular Lipid Content Research Articles

Quantitative magnetic resonance spectroscopy and imaging analysis of the lipid content in the psoas major and its association with intervertebral disc degeneration: a cross-sectional study

Aim: It is shown that the diminished function of the psoas major is mainly associated with increased lipid content; nonetheless, whether the fat content of the psoas major is associated with intervertebral disc degeneration (IVDD) is still under study. It is hypothesized that IVDD is correlated with the lipid content of the psoas major and that IVDD can be comprehensively investigated using quantitative magnetic resonance imaging (MRI). Consequently, this study aimed to analyse the association between the psoas major extramyocellular lipid (EMCL) and intramyocellular lipid (IMCL) content and disc degeneration quantified using MRI T2 mapping in patients with chronic low back pain (CLBP). Methods: In this study, 20 men and 23 women (mean age, 63.1 years ± 2.6 years) underwent magnetic resonance spectroscopy (MRS). The psoas major IMCL and EMCL content of patients was analysed. T2 values of the anterior annulus fibrosus (AF), nucleus pulposus (NP), and posterior AF were evaluated using MRI T2 mapping. Multiple linear regression analysis was used to determine the possible correlations of the psoas major EMCL and IMCL content with the T2 values of the anterior AF, NP, and posterior AF. Results: The EMCL content and T2 values of the anterior AF were significantly and negatively correlated [standardised partial regression coefficient (β) = −0.60, P < 0.01]. There were no significant correlations between the EMCL content and T2 values of the NP (β = −0.16, P = 0.30) or posterior AF (β = −0.14, P = 0.49) or between the IMCL content and T2 values of the anterior AF (β = −0.04, P = 0.82), NP (β = 0.05, P = 0.73), or posterior AF (β = −0.11, P = 0.58). Conclusions: The EMCL content and T2 values of the anterior AF were correlated. Conversely, the IMCL content and T2 values were not correlated.

Association Between Multifidus Intramyocellular Lipids and Pain-Related Disorders, Lumbar Spine Dysfunction, Gait Disturbance in Patients with Chronic Low Back Pain: A Cross-Sectional Study Using the Japanese Orthopaedic Association Back Pain Evaluation Questionnaire

Background and aims: Fat degeneration in the multifidus muscle (Mm) was more common than in other trunk muscles. We hypothesised that the lipid contents of the Mm and patient-reported quality of life (QOL) are related. However, there are no papers examining the association between fatty degeneration of the Mm and patient-reported QOL using magnetic resonance spectroscopy (MRS). This cross-sectional study aimed to investigate the association between patient-reported QOL, evaluated with the Japanese Orthopaedic Association Back Pain Evaluation Questionnaire (JOABPEQ), and the intramyocellular lipid (IMCL) and extramyocellular lipid (EMCL) contents of the Mm and psoas major (PM) by MRS in patients with chronic low back pain (CLBP). Materials and Methods: Forty-eight patients (mean age, 64.2 ± 13.2 years; age range, 41–79 years) with nonspecific CLBP underwent MRS for the quantification of IMCL and EMCL of the right Mm and PM in a volume of interest at L4/L5. All subjects underwent MRS and completed the JOABPEQ in the same day. We performed multiple linear regression analysis of the IMCL and EMCL contents of the Mm and PM with the five domains of the JOABPEQ adjusted for age, sex, and body mass index. Results: The IMCL content of the Mm was correlated with pain-related disorders (standardised partial regression coefficient (β)=−0.59, p<0.01), lumbar spine dysfunction (β=−0.64, p<0.01), and social life dysfunction (β=−0.31, p<0.01) which showed moderate negative correlation, but not with psychological disorders. The EMCL content of the Mm was not correlated with the five domains of the JOABPEQ. The IMCL and EMCL contents of the PM was not correlated with the five domains of the JOABPEQ. Conclusions: IMCL content of the Mm was significantly correlated with the pain-related disorders, lumbar spine dysfunction, gait disturbance, and social life dysfunction domain scores of the JOABPEQ. Future studies using magnetic resonance spectroscopy of the Mm in patients with CLBP may help optimize exercise strategies using IMCL as an index to enhance patient-reported quality of life.

ASSOCIATION BETWEEN CALF MUSCLE FATTY INFILTRATION AND PHYSICAL PERFORMANCE AMONG HEALTHY OLDER ADULTS

Abstract Muscle fatty infiltration is associated with impaired physical performance. However, the association between ectopic fat, such as lower extremity fat distribution, and sex-specific differences among older adults remains to be determined. This study aimed to examine sex-specific differences in calf muscle fat infiltration and their association with physical performance among healthy older adults aged 76 to 80 years. The pilot study comprised 40 subjects (20 men; 20 women) matched by age and body mass index. The participants underwent dual-energy X-ray absorptiometry, magnetic resonance imaging (MRI), and proton magnetic resonance spectroscopy (1H-MRS) to assess body composition and lower extremity fat distribution. The tibialis anterior intramyocellular lipid (IMCL) as assessed by 1H-MRS was negatively associated with the five-times sit-to-stand test scores (rs=0.518, p=0.023) in men, while the soleus IMCL content was negatively associated with the timed up-and-go test scores (rs=0.472, p=0.048) in women. However, the soleus extramyocellular lipid (EMCL) content was positively associated with the five-times sit-to-stand test scores (rs=−0.488, p=0.040) in women, but this association was not statistically significant in men. Regarding the calf cross-sectional area (CSA) parameters assessed by MRI, calf subcutaneous fat CSA was positively associated with the usual gait speed (rs=0.447, p=0.048) in women only. To conclude, this study showed an inverse correlation between IMCL content and physical performance in healthy older individuals and calf muscle-specific IMCL based on sex differences. Furthermore, our results suggest that greater EMCL content in the soleus and calf subcutaneous fat might affect physical performance positively in older women but not older men.

Sex-Specific Differences in Lower Body Fat Distribution and Association with Physical Performance among Healthy Community-Dwelling Older Adults: A Pilot Study.

This study aims to examine sex-specific differences in body composition and lower extremity fat distribution and their association with physical performance among healthy older adults. The pilot study comprises 40 subjects (20 men and 20 women) matched by age and body mass index. The participants undergo dual-energy X-ray absorptiometry, magnetic resonance imaging, and proton magnetic resonance spectroscopy (1H-MRS) to assess body composition and lower extremity fat distribution. 1H-MRS is used to measure the extramyocellular lipid (EMCL) and intramyocellular lipid (IMCL) contents of the lower leg muscles (soleus and tibialis anterior) at the maximum circumference of the calf after overnight fasting. The tibialis anterior IMCL, as assessed by 1H-MRS, is negatively associated with the five-times sit-to-stand test scores (rs = 0.518, p = 0.023) in men, while the soleus IMCL content is negatively associated with the timed up-and-go test scores (rs = 0.472, p = 0.048) in women. However, the soleus EMCL content is positively associated with the five-times sit-to-stand test scores (rs = −0.488, p = 0.040) in women, but this association is not statistically significant in men. This study shows an inverse correlation between IMCL content and physical performance in healthy older individuals and lower leg muscle-specific IMCL based on sex differences. Furthermore, our results suggest that greater EMCL content in the soleus and calf subcutaneous fat might affect physical performance positively in women but not men.

Is the Lipid Content of the Psoas Major Correlated with Chronic Low Back Pain and Spinopelvic Alignment? A Magnetic Resonance Spectroscopic Study

Study DesignCross-sectional observational study.PurposeThis study aimed to analyze any potential associations of extramyocellular lipid (EMCL) and intramyocellular lipid (IMCL) contents with (1) the intensity of low back pain (LBP); (2) age, cross-sectional area (CSA), and fatty infiltration (FI) of the psoas major; and (3) spinopelvic parameters.Overview of LiteratureThe psoas major has clinically relevant function; however, the association of this muscle with chronic LBP is controversial. Magnetic resonance spectroscopy enables a detailed analysis of the composition of muscular fat tissues such as its EMCL and IMCL contents.MethodsThe study population comprised 40 patients (19 males, 21 females; mean age, 61.7±2.4 years). Possible correlations of LBP Visual Analog Scale (VAS) scores, age, CSA, FI, and spinopelvic parameters with EMCL and IMCL contents of the psoas major were assessed.ResultsNo association was identified between the EMCL and IMCL contents and LBP VAS scores (r=0.05, p=0.79 and r=0.06, p=0.75, respectively). The EMCL content correlated with age (r=0.47, p<0.01), body mass index (BMI) (r=0.44, p<0.01), CSA (r=−0.59, p<0.01), and FI (r=0.49, p<0.01). EMCL content showed a significant negative correlation with sacral slope (SS) (r=−0.43, p<0.05) and positive correlation with pelvic tilt (PT) (r=0.56, p<0.01).ConclusionsEMCL content correlated with age, BMI, CSA, and FI of the psoas major, while IMCL content had no correlation. This study found correlations between SS and PT and EMCL content of the psoas major, but no correlations were found between spinopelvic parameters and IMCL content of the psoas major.

29-OR: Comparison of Empagliflozin and Sitagliptin on Ectopic Fat Accumulation and Tissue-Specific Insulin Sensitivity

Background: Ectopic fat accumulation is the major pathogenesis of insulin resistance, type 2 diabetes mellitus (T2DM), and cardiovascular diseases. To date, no prospective study compared the effects of sodium glucose cotransporter 2 inhibitors (SGLT2i) and dipeptidyl peptidase-4 inhibitors on ectopic fat accumulation and tissue-specific insulin sensitivity. Methods: This is the prospective, randomized, open-label, and blind-endpoint study in 44 Japanese patients with T2DM. Patients (HbA1c: 7.2±0.9%, known duration: 3.9±4.0 years, BMI: 29.1±4.8 kg/m2) were randomized to empagliflozin (Empa) add-on group or sitagliptin (Sita) add-on group, and treated for 12 weeks. The primary endpoint was the change of pericardial fat content estimated by magnetic resonance imaging. The secondary endpoints were the changes in the amount of intrahepatic, intra- and extra-myocellular lipid content estimated by proton magnetic resonance spectroscopy, and tissue-specific insulin sensitivity assessed by hyperinsulinemic-euglycemic clamp tests using stable isotope. Results: There was no difference in pericardial fat content between the groups. Interestingly, intrahepatic lipid content (IHL) was reduced significantly from baseline in Empa group compared to Sita (-23.0±26.3 vs. -3.9±19.8%, respectively, p&amp;lt;0.05). However, the change in clamped % suppression of endogenous glucose production was comparable between the groups. On the other hand, rate of glucose disappearance was significantly increased in Empa group compared to Sita (+18.5±55.2 vs. -8.6±20.2%, p&amp;lt;0.05), while the amount of intra- and extra-myocellular lipid content remained similar between the groups. Conclusion: This is the first study that compared Empa and Sita on ectopic fat content and tissue-specific insulin sensitivity. Empa significantly reduced IHL and increased insulin sensitivity in muscle compared to Sita. SGLT2i might be preferable in treatment of T2DM with hepatic steatosis. Disclosure S. Hiruma: None. F. Shigiyama: None. S. Hisatake: None. S. Mizumura: None. N. Shiraga: None. M. Hori: None. T. Ikeda: None. T. Hirose: Research Support; Self; Boehringer Ingelheim Pharmaceuticals, Inc., Daiichi Sankyo, Mitsubishi Tanabe Pharma Corporation, Ono Pharmaceutical Co., Ltd., Takeda Pharmaceutical Company Limited. Speaker’s Bureau; Self; AstraZeneca, Lilly Diabetes, Novo Nordisk Inc., Sanofi, Sumitomo Dainippon Pharma Co., Ltd. N. Kumashiro: Research Support; Self; Boehringer Ingelheim Pharmaceuticals, Inc. Speaker’s Bureau; Self; Novo Nordisk Inc., Ono Pharmaceutical Co., Ltd., Takeda Pharmaceutical Company Limited. Funding Nippon Boehringer Ingelheim Co., Ltd. (1245-0162)

Effects of aerobic exercise training on the arterial stiffness and intramyocellular or extramyocellular lipid in overweight and obese men

ABSTRACTIntramyocellular lipid (IMCL) and extramyocellular lipid (EMCL) of ectopic fat in muscles are associated with arterial stiffness in normal-weight individuals. Furthermore, aerobic exercise training-induced changes in IMCL or EMCL content are related to a decrease in arterial stiffness in elderly people. Though arterial stiffness is strongly related with obesity, but the effects of aerobic exercise training on IMCL or EMCL content, with a particular focus on arterial stiffness, in obese individuals remains unclear. Here, we investigated the effects of aerobic exercise training on IMCL or EMCL content and arterial stiffness in obese individuals. First, in a cross-sectional study, we examined the relationship between arterial stiffness and IMCL or EMCL content in 24 overweight and obese men. Secondly, we investigated the effects of aerobic exercise intervention on arterial stiffness and IMCL or EMCL content in 21 overweight and obese men. In the cross-sectional study, EMCL content was positively correlated with baPWV and β-stiffness index, whereas IMCL content was negatively correlated with baPWV. In the intervention study, there were no significant changes in baPWV, β-stiffness index, and IMCL and EMCL contents after aerobic exercise training. However, exercise-induced change in baPWV and β-stiffness index were positively correlated with changes in EMCL content. Moreover, the group of improvements in baPWV was only correlated significantly with reduced EMCL content. These results suggest that IMCL and EMCL contents may affect arterial stiffness in overweight and obese men.

Assessment of Lipid and Metabolite Changes in Obese Calf Muscle Using Multi-Echo Echo-planar Correlated Spectroscopic Imaging

Obesity-related conditions including heart disease, stroke, and type 2 diabetes are leading causes of preventable death. Recent evidence suggests that altered myocellular lipid metabolism in obesity may lead to increased insulin resistance (IR) that predisposes to these disorders. To test the hypothesis that muscles rich in type I vs. type II muscle fibers would exhibit similar changes in intramyocellular lipid (IMCL) and extramyocellular lipid (EMCL) content in obesity, we utilized a new four-dimensional multi echo echo-planar correlated spectroscopic imaging technique that allows separate determination of IMCL and EMCL content in individual calf muscles in obese vs. normal healthy human subjects. Calf muscles were scanned in 32 obese and 11 healthy subjects using a 3T MRI/MRS scanner, and IR in the obese subjects was documented by glucose tolerance testing. In obese subjects, elevation of both IMCL and EMCL content was observed in the gastrocnemius and tibialis anterior muscles (with mixed type I and II fiber content), while a significant increase in only IMCL content (+48%, p < 0.001) was observed in the soleus muscle (predominantly type I fibers). These observations indicate unexpected differences in changes in myolipid metabolism in type I vs. type II rich muscle regions in obesity, perhaps related to IR, and warrant further investigation.

Pioglitazone-induced improvements in insulin sensitivity occur without concomitant changes in muscle mitochondrial function

AimsPioglitazone (Pio) is known to improve insulin sensitivity in skeletal muscle. However, the role of Pio in skeletal muscle lipid metabolism and skeletal muscle oxidative capacity is not clear. The aim of this study was to determine the effects of chronic Pio treatment on skeletal muscle mitochondrial activity in individuals with type 2 diabetes (T2D). Materials and MethodsTwenty-four participants with T2D (13M/11F 53.38±2.1years; BMI 36.47±1.1kg/m2) were randomized to either a placebo (CON, n=8) or a pioglitazone (PIO, n=16) group. Following 12weeks of treatment, we measured insulin sensitivity by hyperinsulinemic–euglycemic clamp (clamp), metabolic flexibility by calculating the change in respiratory quotient (ΔRQ) during the steady state of the clamp, intra- and extra-myocellular lipid content (IMCL and EMCL, respectively) by 1H magnetic resonance spectroscopy (1H-MRS) and muscle maximal ATP synthetic capacity (ATPmax) by 31P-MRS. ResultsFollowing 12weeks of PIO treatment, insulin sensitivity (p<0.0005 vs. baseline) and metabolic flexibility (p<0.05 vs. CON) significantly increased. PIO treatment significantly decreased IMCL content and increased EMCL content in gastrocnemius, soleus and tibialis anterior muscles. ATPmax was unaffected by PIO treatment. ConclusionsThese results suggest that 12weeks of pioglitazone treatment improves insulin sensitivity, metabolic flexibility and myocellular lipid distribution without any effect on maximal ATP synthetic capacity in skeletal muscle. Consequently, pioglitazone-induced enhancements in insulin responsiveness and fuel utilization are independent of mitochondrial function.

Are hepatic and soleus lipid content, assessed by magnetic resonance spectroscopy, associated with low birth weight or insulin resistance in a rural Indian population of healthy young men?

To assess young healthy men from rural India, who had normal or low birth weights, using magnetic resonance spectroscopy to determine the potential differences in ectopic fat storage between birth weight groups, and to determine if ectopic fat storage was associated with insulin resistance in this population. A total of 54 lean men with normal birth weight and 49 lean men with low birth weight (age range 18-22 years) from rural India were recruited. All the men underwent anthropometry, magnetic resonance spectroscopy, a hyperinsulinaemic-euglycaemic clamp and a dual-energy X-ray absorptiometry. The median (interquartile range) values for hepatic cellular lipids, intramyocellular lipids and extramyocellular lipids, measured using magnetic resonance spectroscopy were 0.76 (0.1-1.8)%, 1.27 (1.0-2.3)% and 1.89 (1.3-3.2)%, respectively, for the normal birth weight group and 0.4 (0.1-1.3)%, 1.38 (0.9-2.2)% and 2.07 (1.2-2.8)%, respectively, for the low birth weight group (P > 0.05). No difference in ectopic fat storage was observed between the low and normal birth weight groups, with or without adjustment for age and total fat percentage. Homeostatic model assessment of insulin resistance values were not associated with hepatic cellular, intramyocellular or extramyocellular lipid content in any of the groups. Total fat percentage was the only independent predictor of intramyocellular and extramyocellular lipid content. Young and lean men from rural India with low birth weight were not observed to have ectopic fat storage in the liver or muscle, and the amount of liver and muscle fat was unrelated to insulin resistance. Older age and/or an urban affluent lifestyle may be required to show a potential role of ectopic fat storage on insulin resistance in Indian people with low or normal birth weight.

Intramyocellular and Extramyocellular Lipids Are Associated With Arterial Stiffness.

Obese and overweight patients are at increased risk of arterial stiffness, and visceral, epicardial and hepatic fat accumulation is associated with cardiovascular disease risk. In general, muscular lipids are stored either in interstitial adipose tissue (extramyocellular lipid (EMCL)) or in lipid droplets within muscle cells (intramyocellular lipid (IMCL)). However, the association between IMCL or EMCL content and arterial stiffness remains unclear. This cross-sectional study aimed to clarify this association. A total of 237 subjects (18-81 years) were enrolled in this study. The IMCL and EMCL contents of the right vastus lateralis muscle were evaluated by proton magnetic resonance spectroscopy. Arterial stiffness was estimated using brachial-ankle pulse wave velocity (baPWV). There were significant correlations between baPWV and the contents of both IMCL (R = -0.23, P < 0.001) and EMCL (R = 0.53, P < 0.001) in all subjects. The baPWV negatively correlated with IMCL content (R = -0.45, P < 0.001) in females only. In contrast, significant positive correlations were observed between baPWV and EMCL content in both males (R = 0.59, P < 0.001) and females (R = 0.55, P < 0.001). IMCL and EMCL contents contributed independently to baPWV variation after adjustment for age, sex, body mass index, visceral and subcutaneous abdominal fat, upper and lower limb fat, blood pressure, heart rate, and lipid profiles. These results suggest that IMCL and EMCL contents may be a risk factor for arterial stiffness, and this association differed with gender and age.

Muscle Fat Content and Abdominal Adipose Tissue Distribution Investigated by Magnetic Resonance Spectroscopy and Imaging in Obese Children and Youths

The degree of fat deposition in muscle and its implications for obesity-related complications in children and youths are not well understood. One hundred and fifty-nine patients (mean age: 13.3 years; range: 6–20) with a body mass index (BMI) >90th percentile for age and sex were included. Muscle fat content (MFC) was measured in the psoas muscle by proton magnetic resonance spectroscopy. The patients were assigned to two groups: MFC <5% or ≥5%. Visceral adipose tissue volume (VAT) and subcutaneous adipose tissue volume (SAT) were measured by magnetic resonance imaging. The data were analysed to detect associations between MFC and BMI standard deviation scores, VAT and SAT, blood values, pubertal stages, and physical activity scores. The mean BMI standard deviation score (SDS) was 3.04 (range 1.32–5.02). The mean MFC was 8.9% (range 0.8–46.7), and 118 (74.2%) of 159 patients had an MFC ≥5%. Children with an MFC ≥5%, compared with children with an MFC <5%, had a higher BMI SDS (P=0.03), a higher VAT (P=0.04), and elevated intramyocellular lipid (IMCL) and extramyocellular lipid (EMCL) contents (both P<0.0001). SAT, SAT/VAT ratio, blood values, pubertal stages and physical activity scores did not differ between the two groups. Severely obese children and youths tend to have a high MFC, which is associated with elevated VAT, IMCL, and EMCL contents. An increased MFC may be associated with impaired metabolic processes, which may predispose these young people to obesity-related complications.

Intramyocellular lipid content and insulin sensitivity are increased following a short-term low-glycemic index diet and exercise intervention.

The relationship between intramyocellular (IMCL) and extramyocellular lipid (EMCL) accumulation and skeletal muscle insulin resistance is complex and dynamic. We examined the effect of a short-term (7-day) low-glycemic index (LGI) diet and aerobic exercise training intervention (EX) on IMCL and insulin sensitivity in older, insulin-resistant humans. Participants (66 ± 1 yr, BMI 33 ± 1 kg/m(2)) were randomly assigned to a parallel, controlled feeding trial [either an LGI (LGI/EX, n = 7) or high GI (HGI/EX, n = 8) eucaloric diet] combined with supervised exercise (60 min/day, 85% HR(max)). Insulin sensitivity was determined via 40 mU·m(-2)·min(-1) hyperinsulinemic euglycemic clamp and soleus IMCL and EMCL content was assessed by (1)H-MR spectroscopy with correction for fiber orientation. BMI decreased (kg/m(2) -0.6 ± 0.2, LGI/EX; -0.7 ± 0.2, HGI/EX P < 0.0004) after both interventions with no interaction effect of diet composition. Clamp-derived insulin sensitivity increased by 0.91 ± 0.21 (LGI/EX) and 0.17 ± 0.55 mg·kg(-1)·min(-1) (HGI/EX), P = 0.04 (effect of time). HOMA-IR was reduced by -1.1 ± 0.4 (LGI/EX) and -0.1 ± 0.2 (HGI/EX), P = 0.007 (effect of time), P = 0.02 (time × trial). Although both interventions increased IMCL content, (Δ: 2.3 ± 1.3, LGI/EX; 1.4 ± 0.9, HGI/EX, P = 0.03), diet composition did not significantly effect the increase. However, the LGI/EX group showed a robust increase in the [IMCL]/[EMCL] ratio compared with the HGI/EX group (Δ: 0.5 ± 0.2 LGI/EX vs. 0.07 ± 0.1, P = 0.03). The LGI/EX group also demonstrated greater reductions in [EMCL] than the HGI/EX group (Δ: -5.8 ± 3.4, LGI/EX; 2.3 ± 1.1, HGI/EX, P = 0.03). Changes in muscle lipids and insulin sensitivity were not correlated; however, the change in [IMCL]/[EMCL] was negatively associated with the change in FPI (r = -0.78, P = 0.002) and HOMA-IR (r = -0.61, P = 0.03). These data suggest that increases in the IMCL pool following a low glycemic diet and exercise intervention may represent lipid repartitioning from EMCL. The lower systemic glucose levels that prevail while eating a low glycemic diet may promote redistribution of lipid stores in the muscle.

Hydrochlorothiazide, but not Candesartan, Aggravates Insulin Resistance and Causes Visceral and Hepatic Fat Accumulation

Treatment with angiotensin II receptor blockers is associated with lower risk for the development of type 2 diabetes mellitus compared with thiazide diuretics. The Mechanisms for the Diabetes Preventing Effect of Candesartan Study addressed insulin action and secretion and body fat distribution after treatment with candesartan, hydrochlorothiazide, and placebo. Twenty-six nondiabetic, abdominally obese, hypertensive patients were included in a multicenter 3-way crossover trial, and 22 completers (by predefined criteria; 10 men and 12 women) were included in the analyses. They underwent 12-week treatment periods with candesartan (C; 16 to 32 mg), hydrochlorothiazide (H; 25 to 50 mg), and placebo (P), respectively, and the treatment order was randomly assigned and double blinded. Intravenous glucose tolerance tests and euglycemic hyperinsulinemic (56 mU/m(2) per minute) clamps were performed. Intrahepatic and intramyocellular and extramyocellular lipid content and subcutaneous and visceral abdominal adipose tissue were measured using proton magnetic resonance spectroscopy and MRI. Insulin sensitivity (M-value) was reduced following H versus C and P (6.07+/-2.05, 6.63+/-2.04, and 6.90+/-2.10 mg/kg of body weight per minute, mean+/-SD; P<or=0.01). Liver fat content was higher (P<0.05) following H than both P and C. The subcutaneous to visceral abdominal adipose tissue ratio was reduced following H versus C and P (P<0.01). Glycosylated hemoglobin, alanine aminotransferase, aspartate aminotransferase, and high-sensitivity C-reactive protein levels were higher (P<0.05) after H, but not C, versus P. There were no changes in body fat, intramyocellular lipid, extramyocellular lipid, or first-phase insulin secretion. Blood pressure was reduced similarly by C and H versus P. In conclusion, visceral fat redistribution, liver fat accumulation, low-grade inflammation, and aggravated insulin resistance were demonstrated after hydrochlorothiazide but not candesartan treatment. These findings can partly explain the diabetogenic potential of thiazides.

The effects of rosiglitazone on insulin sensitivity, lipolysis, and hepatic and skeletal muscle triglyceride content in patients with type 2 diabetes.

We examined the effect of three months of rosiglitazone treatment (4 mg b.i.d.) on whole-body insulin sensitivity and in vivo peripheral adipocyte insulin sensitivity as assessed by glycerol release in microdialysis from subcutaneous fat during a two-step (20 and 120 mU.m(-2).min(-1)) hyperinsulinemic-euglycemic clamp in nine type 2 diabetic subjects. In addition, the effects of rosiglitazone on liver and muscle triglyceride content were assessed by (1)H-nuclear magnetic resonance spectroscopy. Rosiglitazone treatment resulted in a 68% (P < 0.002) and a 20% (P < 0.016) improvement in insulin-stimulated glucose metabolism during the low- and high- dosage-insulin clamps, respectively, which was associated with approximately 40% reductions in plasma fatty acid concentration (P < 0.05) and hepatic triglyceride content (P < 0.05). These changes were associated with a 39% increase in extramyocellular lipid content (P < 0.05) and a 52% increase in the sensitivity of peripheral adipocytes to the inhibitory effects of insulin on lipolysis (P = 0.04). In conclusion, these results support the hypothesis that thiazolidinediones enhance insulin sensitivity in patients with type 2 diabetes by promoting increased insulin sensitivity in peripheral adipocytes, which results in lower plasma fatty acid concentrations and a redistribution of intracellular lipid from insulin responsive organs into peripheral adipocytes.

Association of increased intramyocellular lipid content with insulin resistance in lean nondiabetic offspring of type 2 diabetic subjects.

Insulin resistance plays an important role in the pathogenesis of type 2 diabetes; however, the multiple mechanisms causing insulin resistance are not yet fully understood. The aim of this study was to explore the possible contribution of intramyocellular lipid content in the pathogenesis of skeletal muscle insulin resistance. We compared insulin-resistant and insulin-sensitive subjects. To meet stringent matching criteria for other known confounders of insulin resistance, these individuals were selected from an extensively metabolically characterized group of 280 first-degree relatives of type 2 diabetic subjects. Some 13 lean insulin-resistant and 13 lean insulin-sensitive subjects were matched for sex, age, BMI, percent body fat, physical fitness, and waist-to-hip ratio. Insulin sensitivity was determined by the hyperinsulinemic-euglycemic clamp method (for insulin-resistant subjects, glucose metabolic clearance rate [MCR] was 5.77+/-0.28 ml x kg(-1) x min(-1) [mean +/- SE]; for insulin-sensitive subjects, MCR was 10.15+/-0.7 ml x kg(-1) x min(-1); P<0.002). Proton magnetic resonance spectroscopy (MRS) was used to measure intramyocellular lipid content (IMCL) in both groups. MRS studies demonstrated that in soleus muscle, IMCL was increased by 84% (11.8+/-1.6 vs. 6.4+/-0.59 arbitrary units; P = 0.008 ), and in tibialis anterior muscle, IMCL was increased by 57% (3.26+/-0.36 vs. 2.08+/-0.3 arbitrary units; P = 0.017) in the insulin-resistant offspring, whereas the extramyocellular lipid content and total muscle lipid content were not statistically different between the two groups. These data demonstrate that in these well-matched groups of lean subjects, IMCL is increased in insulin-resistant offspring of type 2 diabetic subjects when compared with an insulin-sensitive group matched for age, BMI, body fat distribution, percent body fat, and degree of physical fitness. These results indicate that increased IMCL represents an early abnormality in the pathogenesis of insulin resistance and suggest that increased IMCL may contribute to the defective glucose uptake in skeletal muscle in insulin-resistant subjects.