Cardiorespiratory fitness predicts changes in adiposity in overweight Hispanic boys

We have previously shown that cardiorespiratory fitness predicts increasing fat mass during growth in white and African-American youth, but limited data are available examining this issue in Hispanic youth. Study participants were 160 (53% boys) overweight (BMI>or=85th percentile for age and gender) Hispanic children (mean+/-s.d. age at baseline=11.2+/-1.7 years). Cardiorespiratory fitness, assessed by VO2max, was measured through a maximal effort treadmill test at baseline. Body composition through dual-energy X-ray absorptiometry and Tanner stage through clinical exam were measured at baseline and annually thereafter for up to 4 years. Linear mixed models were used to examine the gender-specific relationship between VO2max and increases in adiposity (change in fat mass independent of change in lean tissue mass) over 4 years. The analysis was adjusted for changes in Tanner stage, age, and lean tissue mass. In boys, higher VO2max at baseline was inversely associated with the rate of increase in adiposity (beta=-0.001, P=0.03); this effect translates to a 15% higher VO2max at baseline resulting in a 1.38 kg lower fat mass gain over 4 years. However, VO2max was not significantly associated with changes in fat mass in girls (beta=0.0002, P=0.31). In overweight Hispanic boys, greater cardiorespiratory fitness at baseline was protective against increasing adiposity. In girls however initial cardiorespiratory fitness was not significantly associated with longitudinal changes in adiposity. These results suggest that cardiorespiratory fitness may be an important determinant of changes in adiposity in overweight Hispanic boys but not in girls.     

Real-time assessment of postprandial fat storage in liver and skeletal muscle in health and type 2 diabetes

Liver and skeletal muscle triglyceride stores are elevated in type 2 diabetes and correlate with insulin resistance. As postprandial handling of dietary fat may be a critical determinant of tissue triglyceride levels, we quantified postprandial fat storage in normal and type 2 diabetes subjects. Healthy volunteers (n = 8) and diet-controlled type 2 diabetes subjects (n = 12) were studied using a novel 13C magnetic resonance spectroscopy protocol to measure the postprandial increment in liver and skeletal muscle triglyceride following ingestion of 13C-labeled fatty acids given with a standard mixed meal. The postprandial increment in hepatic triglyceride was rapid in both groups (peak increment controls: +7.3 +/- 1.5 mmol/l at 6 h, P = 0.002; peak increment diabetics: +10.8 +/- 3.4 mmol/l at 4 h, P = 0.009). The mean postprandial incremental AUC of hepatic 13C enrichment between the first and second meals (0 and 4 h) was significantly higher in the diabetes group (6.1 +/- 1.4 vs. 1.7 +/- 0.6 mmol x l(-1) x h(-1), P = 0.019). Postprandial increment in skeletal muscle triglyceride in the control group was small compared with the diabetic group, the mean 24-h postprandial incremental AUC being 0.2 +/- 0.3 vs. 1.7 +/- 0.4 mmol x l(-1) x h(-1) (P = 0.009). We conclude that the postprandial uptake of fatty acids by liver and skeletal muscle is increased in type 2 diabetes and may underlie the elevated tissue triglyceride stores and consequent insulin resistance.     

Cardiorespiratory Fitness and the Risk of Overweight in Youth: The Healthy Hearts Longitudinal Study of Cardiometabolic Health

The primary objective of this longitudinal study was to determine the association between cardiorespiratory fitness and the risk of overweight status in youth. To accomplish this aim we analyzed data from annual school‐based surveys of cardiorespiratory fitness and anthropometry conducted between 2004 and 2006. The first analysis was performed on a cohort of 902 youth aged 6–15 years followed for 12 months to assess the association between cardiorespiratory fitness levels determined from a graded maximal field test and the risk of becoming overweight. The second analysis was conducted on a cohort of 222 youth followed for 2 years to assess the continuous association between annual changes fitness and weight gain. Children with low cardiorespiratory fitness were characterized by higher waist circumference and disproportionate weight gain over the 12‐month follow‐up period (P < 0.05). Within the entire cohort, the 12‐month risk of overweight classification was 3.5‐fold (95% confidence = 2.0–6.0, P < 0.001) higher in youth with low cardiorespiratory fitness, relative to fit peers. A time series mixed effects regression model revealed that reductions in cardiorespiratory fitness were significantly and independently associated with increasing BMI (r = ?0.18, P < 0.05) in youth. Accordingly, low cardiorespiratory fitness and reductions in fitness over time are significantly associated with weight gain and the risk of overweight in children 6–15 years old. An assessment of cardiorespiratory fitness using a common field test may prove useful for the identification of youth at risk of overweight and serve as a potential target for obesity prevention.     

The lowering of hepatic fatty acid uptake improves liver function and insulin sensitivity without affecting hepatic fat content in humans

Lipolysis may regulate liver free fatty acid (FFA) uptake and triglyceride accumulation; both are potential causes of insulin resistance and liver damage. We evaluated whether 1) systemic FFA release is the major determinant of liver FFA uptake in fasting humans in vivo and 2) the beneficial metabolic effects of FFA lowering can be explained by a reduction in liver triglyceride content. Sixteen healthy subjects were subdivided in two groups of similar characteristics to undergo positron emission tomography with [(11)C]acetate and [(11)C]palmitate to quantify liver FFA metabolism (n = 8), or magnetic resonance spectroscopy (MRS) to measure hepatic fat content (n = 8), before and after the acute lowering of circulating FFAs by using the antilipolytic agent acipimox. MRS was again repeated after a 1-wk treatment period. Acipimox suppressed FFA levels while stimulating hepatic fractional extraction of FFAs (P < 0.05). As a result, fasting liver FFA uptake was decreased by 79% (P = 0.0002) in tight association with lipolysis (r = 0.996, P < 0.0001). The 1-wk treatment induced a significant improvement in systemic (+30%) and liver (+70%) insulin sensitivity (P < 0.05) and decreased circulating triglycerides (-20%, P = 0.06) and liver enzymes (ALT -20%, P = 0.03). No change in liver fat content was observed after either acute or sustained FFA suppression. We conclude that acute and sustained inhibitions of lipolysis and liver FFA uptake fail to deplete liver fat in healthy human subjects. Liver FFA uptake was decreased in proportion to FFA delivery. As a consequence, liver and systemic insulin sensitivity were improved, together with liver function, independently of changes in hepatic triglyceride accumulation.     

Differences in the Serum Nonesterified Fatty Acid Profile of Young Women Associated with a Recent History of Gestational Diabetes and Overweight/Obesity

BackgroundNonesterified fatty acids (NEFA) play pathophysiological roles in metabolic syndrome and type 2 diabetes (T2D). In this study, we analyzed the fasting NEFA profiles of normoglycemic individuals at risk for T2D (women with a recent history of gestational diabetes (GDM)) in comparison to controls (women after a normoglycemic pregnancy). We also examined the associations of NEFA species with overweight/obesity, body fat distribution and insulin sensitivity.ResultsWomen after GDM had a lower molar percentage of total saturated fatty acids (SFA; 38.55% vs. 40.32%, p = 0.0002) than controls. At an explorative level of significance several NEFA species were associated with post-GDM status (with and without adjustment for body mass index (BMI) and HbA1c): The molar percentages of 14:0, 16:0, 18:0 and 18:4 were reduced, whereas those of 18:1, 18:2, 20:2, 24:4, monounsaturated fatty acids (MUFA), polyunsaturated fatty acids (PUFA) and total n-6 NEFA were increased. BMI and the amount of body fat correlated inversely with several SFA and MUFA and positively with various PUFA species over the whole study cohort (abs(ρ)≥0.3 for all). 14:0 was inversely and BMI-independently associated with abdominal visceral adiposity. We saw no correlations of NEFA species with insulin sensitivity and the total NEFA concentration was similar in the post-GDM and the control group.ConclusionIn conclusion, we found alterations in the fasting NEFA profile associated with a recent history of gestational diabetes, a risk marker for T2D. NEFA composition also varied with overweight/obesity and with body fat distribution, but not with insulin sensitivity.     

Intracerebroventricular leptin infusion improves glucose homeostasis in lean type 2 diabetic MKR mice via hepatic vagal and non-vagal mechanisms

MKR mice, lacking insulin-like growth factor 1 receptor (IGF-1R) signaling in skeletal muscle, are lean yet hyperlipidemic, hyperinsulinemic, and hyperglycemic, with severe insulin resistance and elevated hepatic and skeletal muscle levels of triglycerides. We have previously shown that chronic peripheral administration of the adipokine leptin improves hepatic insulin sensitivity in these mice independently of its effects on food intake. As central leptin signaling has been implicated in the control of peripheral glucose homeostasis, here we examined the ability of central intracerebroventricular leptin administration to affect energy balance and peripheral glucose homeostasis in non-obese diabetic male MKR mice. Central leptin significantly reduced food intake, body weight gain and adiposity, as well as serum glucose, insulin, leptin, free fatty acid and triglyceride levels relative to ACSF treated controls. These reductions were accompanied by increased fat oxidation as measured by indirect calorimetry, as well as increased oxygen consumption. Central leptin also improved glucose tolerance and hepatic insulin sensitivity determined using the euglycemic-hyperinsulinemic clamps relative to pair fed vehicle treated controls, as well as increasing the rate of glucose disappearance. Hepatic vagotomy only partially reversed the ability of central leptin to improve glucose tolerance. These results demonstrate that central leptin dramatically improves insulin sensitivity independently of its effects on food intake, in a lean mouse model of type 2 diabetes. The findings also suggest that: 1) both hepatic vagal and non-vagal pathways contribute to this improvement, and 2) central leptin alters glucose disposal in skeletal muscle in this model.     

Association of Breakfast Skipping With Visceral Fat and Insulin Indices in Overweight Latino Youth

Few studies have investigated the relationship between breakfast consumption and specific adiposity or insulin dynamics measures in children. The goal of this study is to determine whether breakfast consumption is associated with adiposity, specifically intra‐abdominal adipose tissue (IAAT), and insulin dynamics in overweight Latino youth. Participants were a cross‐sectional sample of 93 overweight (≥85th percentile BMI) Latino youth (10–17 years) with a positive family history of type 2 diabetes. Dietary intake was assessed by two 24‐h recalls, IAAT, and subcutaneous abdominal adipose tissue (SAAT) by magnetic resonance imaging, body composition by dual energy X‐ray absorptiometry, and insulin dynamics by a frequently sampled intravenous glucose tolerance test and minimal modeling. Participants were divided into three breakfast consumption categories: those who reported not eating breakfast on either day (breakfast skippers; n = 20), those who reported eating breakfast on one of two days (occasional breakfast eaters; n = 39) and those who ate breakfast on both days (breakfast eaters; n = 34). Using analyses of covariance, breakfast omission was associated with increased IAAT (P = 0.003) independent of age, Tanner, sex, total body fat, total body lean tissue mass, and daily energy intake. There were no significant differences in any other adiposity measure or in insulin dynamics between breakfast categories. Eating breakfast is associated with lower visceral adiposity in overweight Latino youth. Interventions focused on increasing breakfast consumption are warranted.     

Cardiorespiratory fitness in youth: relationship to insulin sensitivity and beta-cell function

Objective: We examined whether the relationship between cardiorespiratory fitness (CRF) and insulin sensitivity (IS)/secretion is independent of adiposity in healthy African‐American (n = 65) and white (n = 57) youth. Research Methods and Procedures: IS and β‐cell function were evaluated by a 3‐hour hyperinsulinemic‐euglycemic and a 2‐hour hyperglycemic (12.5 mM) clamp, respectively. Total fat was measured by DXA and abdominal fat with computed tomography. CRF (peak volume of oxygen) was measured using a graded maximal treadmill test. Results: Independent of race, CRF was inversely (p < 0.05) related to total and abdominal fat, fasting insulin and first phase insulin secretion, and positively (p < 0.05) related to IS. When subjects were categorized into low (≤50th) and high (>50th) CRF groups, IS was significantly (p < 0.05) higher in the high compared with the low CRF group independently of race. Furthermore, first and second phase insulin secretion were lower (p < 0.05) in the high CRF group in comparison with the low CRF group in both races. However, in multiple regression analyses CRF was not (p > 0.05) an independent predictor of IS and acute insulin secretion after accounting for total adiposity. Discussion: Our findings demonstrate that low CRF is associated with decreased IS compensated by higher insulin secretion in both African‐American and white youth. However, this relationship disappears after adjusting for differences in adiposity, suggesting that the association between fitness and IS is mediated, at least in part, through fatness.     

Adiposity gain during childhood, ACE I/D polymorphisms and metabolic outcomes

We aimed to (i) determine the relative importance of childhood gain in upper body adiposity for insulin resistance (IR) and triglyceridemia (TG); (ii) examine whether the associations between adiposity and metabolic indices were more evident in those with the ACE DD genotype. We examined a birth cohort study of 292 children with measures in the neonatal period (day 4) including subscapular and triceps skinfolds; repeat skinfold measures at age 8, cardiorespiratory (CR) fitness, IR by the homeostasis model assessment (HOMA) equation (HOMA-IR) and serum triglyceride (TG) concentrations and measures of ACE I/D gene variants. A multiple linear regression analysis incorporating a life course approach was undertaken. Childhood gain in upper body adiposity was positively associated with HOMA-IR and TG independently of neonatal skinfolds (P < or = 0.02). The magnitude of these associations was higher among those of the ACE DD genotype. For example, subscapular skinfold gain was not strongly associated with HOMA-IR or TG among those with II or ID genotype (b = 0.03, P = 0.05; b = 0.02, P = 0.18 respectively) but was positively associated among those with the DD genotype (b = 0.11, P = 0.001; b = 0.08, P = 0.003); difference in effect P = 0.05; P = 0.01 respectively. Upper body fat accumulation during childhood was positively associated with HOMA-IR and TG independently of neonatal skinfolds. Further, the stronger associations for those with the ACE DD genotype is consistent with randomised controlled trial findings that ACE inhibition is associated with a reduced risk of developing type 2 diabetes. Further work is required to confirm and extend these findings.     

Visceral and not subcutaneous abdominal adiposity reduction drives the benefits of a 1-year lifestyle modification program

Excess visceral adipose tissue (VAT) is associated with an increased cardiometabolic risk. The study examined whether changes in cardiometabolic risk markers after a 1-year lifestyle intervention in viscerally obese men were associated with changes in VAT or with changes in subcutaneous abdominal adipose tissue (SAT). The relative contributions of changes in global adiposity vs. changes in cardiorespiratory fitness to changes in VAT were also quantified. One hundred and forty four men were selected on the basis of an increased waist circumference (≥ 90 cm) associated with dyslipidemia (triglycerides ≥ 1.69 and/or high-density lipoprotein (HDL)-cholesterol <1.03 mmol/l); 117 men completed the 1-year intervention which consisted in a healthy eating, physical activity/exercise program. Body weight, body composition, and fat distribution were assessed by anthropometry and dual-energy X-ray absorptiometry (DEXA)/computed tomography. Cardiorespiratory fitness, plasma adipokine/inflammatory markers, fasting lipoprotein-lipid profile, and oral glucose tolerance test (OGTT) were assessed. VAT volume decreased by 26%, cardiorespiratory fitness improved by 20% (P < 0.0001) after 1 year. Plasma adipokine/inflammatory markers, lipids/lipoproteins, and glucose homeostasis were improved. One-year changes in triglyceride (r = 0.29), apolipoprotein B (r = 0.21), 120-min OGTT-glucose (r = 0.27), and fasting insulin (r = 0.27) levels correlated with changes in VAT (all P < 0.05) after adjustment for changes in SAT. Using a multilinear regression model, VAT reduction was independently associated with SAT reduction and with improvement in cardiorespiratory fitness (R(2) = 0.58, P < 0.0001). Therefore, this healthy eating-physical activity/exercise program improved the cardiometabolic risk profile of viscerally obese men in relation to the reduction of VAT. Furthermore, the reduction in VAT was independently related to the reduction in global adiposity and to the improvement in cardiorespiratory fitness.     

Differential effects of pharmacological liver X receptor activation on hepatic and peripheral insulin sensitivity in lean and ob/ob mice

Liver X receptor (LXR) agonists have been proposed to act as anti-diabetic drugs. However, pharmacological LXR activation leads to severe hepatic steatosis, a condition usually associated with insulin resistance and type 2 diabetes mellitus. To address this apparent contradiction, lean and ob/ob mice were treated with the LXR agonist GW-3965 for 10 days. Insulin sensitivity was assessed by hyperinsulinemic-euglycemic clamp studies. Hepatic glucose production (HGP) and metabolic clearance rate (MCR) of glucose were determined with stable isotope techniques. Blood glucose and hepatic and whole body insulin sensitivity remained unaffected upon treatment in lean mice, despite increased hepatic triglyceride contents (61.7 +/- 7.2 vs. 12.1 +/- 2.0 nmol/mg liver, P < 0.05). In ob/ob mice, LXR activation resulted in lower blood glucose levels and significantly improved whole body insulin sensitivity. GW-3965 treatment did not affect HGP under normo- and hyperinsulinemic conditions, despite increased hepatic triglyceride contents (221 +/- 13 vs. 176 +/- 19 nmol/mg liver, P < 0.05). Clamped MCR increased upon GW-3965 treatment (18.2 +/- 1.0 vs. 14.3 +/- 1.4 ml x kg(-1) x min(-1), P = 0.05). LXR activation increased white adipose tissue mRNA levels of Glut4, Acc1 and Fasin ob/ob mice only. In conclusion, LXR-induced blood glucose lowering in ob/ob mice was attributable to increased peripheral glucose uptake and metabolism, physiologically reflected in a slightly improved insulin sensitivity. Remarkably, steatosis associated with LXR activation did not affect hepatic insulin sensitivity.     

Fatty liver in type 2 diabetes mellitus: relation to regional adiposity,fatty acids,and insulin resistance

The current study was undertaken to examine metabolic and body composition correlates of fatty liver in type 2 diabetes mellitus (DM). Eighty-three men and women with type 2 DM [mean body mass index (BMI): 34 +/- 0.5 kg/m2] and without clinical or laboratory evidence of liver dysfunction had body composition assessments of fat mass (FM), visceral adipose tissue (VAT), liver and spleen computed tomography (CT) attenuation (ratio of liver to spleen), muscle CT attenuation, and thigh adiposity; these assessments were also performed in 12 lean and 15 obese nondiabetic volunteers. Insulin sensitivity was measured with a euglycemic insulin infusion (40 mU. m-2. min-1) combined with systemic indirect calorimetry to assess glucose and lipid oxidation, and with infusions of [2H2]glucose for assessment of endogenous glucose production. A majority of those with type 2 DM (63%) met CT criteria for fatty liver, compared with 20% of obese and none of the lean nondiabetic volunteers. Fatty liver was most strongly correlated with VAT (r = -0.57, P < 0.0001) and less strongly but significantly associated with BMI (r = -0.42, P < 0.001) and FM (r = -0.37, P < 0.001), but only weakly associated with subcutaneous adiposity (r = -0.29; P < 0.01). Fatty liver was also correlated with subfascial adiposity of skeletal muscle (r = -0.44; P < 0.01). Volunteers with type 2 DM and fatty liver were substantially more insulin resistant those with type 2 DM but without fatty liver (P < 0.001) and had higher levels of plasma free fatty acids (P < 0.01) and more severe dyslipidemia (P < 0.01), a pattern observed in both genders. Plasma levels of cytokines were increased in relation to fatty liver (r = -0.34; P < 0.01). In summary, fatty liver is relatively common in overweight and obese volunteers with type 2 DM and is an aspect of body composition related to severity of insulin resistance, dyslipidemia, and inflammatory markers.     

Familiality of metabolic abnormalities is dependent on age at onset and phenotype of the type 2 diabetic proband

To determine the impact of a family history of the common form of type 2 diabetes and the phenotype of the proband on anthropometric and metabolic variables in normoglycemic first-degree relatives, we studied 2,100 first-degree relatives of patients with the common form of type 2 diabetes (FH+) and 388 subjects without a family history of diabetes (FH-). All subjects participated in an oral glucose tolerance test to allow measurement of insulin secretion [30-min incremental insulin/glucose (I/G 30)] and insulin sensitivity [homeostasis model assessment (HOMA) of insulin resistance (IR)]. A subset participated in a euglycemic clamp (n = 75) and an intravenous glucose tolerance test (n = 300). To study the effect of a particular phenotype of the proband, insulin secretion and sensitivity were also compared between first-degree relatives of diabetic probands with high and low waist-to-hip ratio (WHR) and probands with early and late onset of diabetes. FH+ subjects were more insulin resistant, as seen from a higher HOMA-IR index (P = 0.006) and a lower rate of insulin-stimulated glucose uptake (P = 0.001) and had more features of the metabolic syndrome (P = 0.02, P = 0.0002) compared with FH- subjects. Insulin secretion adjusted for insulin resistance (disposition index, DI) was also lower in the FH+ vs. FH- subjects (P = 0.04). Relatives of diabetic probands with a high WHR had reduced insulin-mediated glucose uptake compared with relatives of probands with a low WHR (P = 0.04). Relatives of diabetic patients with age at onset <44 yr had higher HOMA IR (P < 0.005) and lower DI (P < 0.005) than relatives of patients with age at onset >65 yr (highest quartile). We conclude that early age at onset of type 2 diabetes and abdominal obesity have a significant influence on the metabolic phenotype in the nondiabetic first-degree relative.     

Insulin Action,Regional Fat,and Myocyte Lipid: Altered Relationships with Increased Adiposity

Objective: Abdominal fat and myocyte triglyceride levels relate negatively to insulin sensitivity, but their interrelationships are inadequately characterized in the overweight. Using recent methods for measuring intramyocyte triglyceride, these relationships were studied in men with a broad range of adiposity. Research Methods and Procedures: Myocyte triglyceride content (¹H‐magnetic resonance spectroscopy of soleus and tibialis anterior muscles and biochemical assessment of vastus lateralis biopsies), regional fat distribution (DXA and abdominal magnetic resonance imaging), serum lipids, insulin action (euglycemic hyperinsulinemic clamp), and substrate oxidation rates (indirect calorimetry) were measured in 39 nondiabetic men (35.1 ± 7.8 years) with a broad range of adiposity (BMI 28.6 ± 4.1 kg/m², range 20.1 to 37.6 kg/m²). Results: Relationships between insulin‐stimulated glucose disposal and regional body fat depots appeared more appropriately described by nonlinear than linear models. When the group was subdivided using median total body fat as the cut‐point, insulin‐stimulated glucose disposal correlated negatively to all regional body fat measures (all p ≤ 0.004), serum triglycerides and free fatty acids (p < 0.02), and both soleus intramyocellular lipid (p = 0.003) and vastus lateralis triglyceride (p = 0.04) in the normal/less overweight group. In contrast, only visceral abdominal fat showed significant negative correlation with insulin‐stimulated glucose disposal in more overweight men (r = ?0.576, p = 0.01), some of whom surprisingly had lower than expected myocyte lipid levels. These findings persisted when the group was subdivided using different cut‐points or measures of adiposity. Discussion: Interrelationships among body fat depots, myocyte triglyceride, serum lipids, and insulin action are generally absent with increased adiposity. However, visceral abdominal fat, which corresponds less closely to total adiposity, remains an important predictor of insulin resistance in men with both normal and increased adiposity.     

Variants in the CD36 gene locus determine whole-body adiposity, but have no independent effect on insulin sensitivity

CD36 variants have been associated with type 2 diabetes, features of the metabolic syndrome, and alterations in lipid metabolism. In contrast, the effect of single-nucleotide polymorphisms (SNPs) in CD36 on insulin resistance is controversial in literature. Therefore, we investigated whether genetic variation within the CD36 gene locus affects insulin resistance in a well-phenotyped cohort of white European subjects at increased risk for type 2 diabetes. We genotyped 1,790 subjects (1,174 women, 616 men) for six SNPs tagging 100% of common variants (minor allele frequency ≥0.05) within the CD36 gene locus with an r2 ≥ 0.8. All subjects underwent an oral glucose tolerance test (OGTT) and a subset additionally a hyperinsulinemic-euglycemic clamp (n = 523). Ectopic hepatic lipids (n = 346) were assessed by magnetic resonance spectroscopy. After appropriate adjustment and Bonferroni correction for multiple comparisons, the four CD36 SNPs rs9784998, rs3211883, rs3211908, and rs3211956 significantly associated with BMI and rs3211883 and rs3211908 significantly associated with waist circumference (all P < 0.0042). In contrast, CD36 SNPs rs3211816 and rs3211960 were not associated with measures of adiposity (all P ≥ 0.11). No reliable association was detected between the six CD36 SNPs and insulin sensitivity or ectopic hepatic lipid accumulation after adjustment for age, gender, and BMI. In the long run, genetic variation within the CD36 locus may contribute to metabolic disease via its effect on body adiposity, but not via an independent effect on insulin sensitivity.     

Exercise-induced alterations in intramyocellular lipids and insulin resistance: the athlete's paradox revisited

We previously reported an "athlete's paradox" in which endurance-trained athletes, who possess a high oxidative capacity and enhanced insulin sensitivity, also have higher intramyocellular lipid (IMCL) content. The purpose of this study was to determine whether moderate exercise training would increase IMCL, oxidative capacity of muscle, and insulin sensitivity in previously sedentary overweight to obese, insulin-resistant, older subjects. Twenty-five older (66.4 +/- 0.8 yr) obese (BMI = 30.3 +/- 0.7 kg/m2) men (n = 9) and women (n = 16) completed a 16-wk moderate but progressive exercise training program. Body weight and fat mass modestly but significantly (P < 0.01) decreased. Insulin sensitivity, measured using the euglycemic hyperinsulinemic clamp, was increased (21%, P = 0.02), with modest improvements (7%, P = 0.04) in aerobic fitness (Vo2peak). Histochemical analyses of IMCL (Oil Red O staining), oxidative capacity [succinate dehydrogenase activity (SDH)], glycogen content, capillary density, and fiber type were performed on skeletal muscle biopsies. Exercise training increased IMCL by 21%. In contrast, diacylglycerol and ceramide, measured by mass spectroscopy, were decreased (n = 13; -29% and -24%, respectively, P < 0.05) with exercise training. SDH (19%), glycogen content (15%), capillary density (7%), and the percentage of type I slow oxidative fibers (from 50.8 to 55.7%), all P < or = 0.05, were increased after exercise. In summary, these results extend the athlete's paradox by demonstrating that chronic exercise in overweight to obese older adults improves insulin sensitivity in conjunction with favorable alterations in lipid partitioning and an enhanced oxidative capacity within muscle. Therefore, several key deleterious effects of aging and/or obesity on the metabolic profile of skeletal muscle can be reversed with only moderate increases in physical activity.     

PPARalpha /gamma ragaglitazar eliminates fatty liver and enhances insulin action in fat-fed rats in the absence of hepatomegaly

Peroxisome proliferator-activated receptor (PPAR)alpha and PPARgamma agonists lower lipid accumulation in muscle and liver by different mechanisms. We investigated whether benefits could be achieved on insulin sensitivity and lipid metabolism by the dual PPARalpha/gamma agonist ragaglitazar in high fat-fed rats. Ragaglitazar completely eliminated high-fat feeding-induced liver triglyceride accumulation and visceral adiposity, like the PPARalpha agonist Wy-14643 but without causing hepatomegaly. In contrast, the PPARgamma agonist rosiglitazone only slightly lessened liver triglyceride without affecting visceral adiposity. Compared with rosiglitazone or Wy-14643, ragaglitazar showed a much greater effect (79%, P < 0.05) to enhance insulin's suppression of hepatic glucose output. Whereas all three PPAR agonists lowered plasma triglyceride levels and lessened muscle long-chain acyl-CoAs, ragaglitazar and rosiglitazone had greater insulin-sensitizing action in muscle than Wy-14643, associated with a threefold increase in plasma adiponectin levels. There was a significant correlation of lipid content and insulin action in liver and particularly muscle with adiponectin levels (P < 0.01). We conclude that the PPARalpha/gamma agonist ragaglitazar has a therapeutic potential for insulin-resistant states as a PPARgamma ligand, with possible involvement of adiponectin. Additionally, it can counteract fatty liver, hepatic insulin resistance, and visceral adiposity generally associated with PPARalpha activation, but without hepatomegaly.     

Measuring aerobic cycling power as an assessment of childhood fitness

The emergence of obesity, insulin resistance, and type 2 diabetes in children requires a rational, effective public health response. Physical activity remains an important component of prevention and treatment for obesity, type 2 diabetes, and insulin resistance. Studies in adults show cardiovascular fitness to be more important than obesity in predicting insulin resistance. We recently demonstrated that a school-based fitness intervention in children who are overweight could improve cardiovascular fitness, body composition, and insulin sensitivity, but it remains unclear whether accurate assessment of fitness could be performed at the school or outside of an exercise laboratory. To determine whether new methodology using measurement of cycling power could estimate cardiovascular aerobic fitness (as defined by VO2max) in middle school children who were overweight. Thirty-five middle school children (mean age 12 +/- 0.4 years) who were overweight underwent testing on a power sensor-equipped Cycle Ops indoor cycle (Saris Cycling Group, Fitchburg, WI) as well as body composition by dual x-ray absorptiometry and VO2max by treadmill determination. Insulin sensitivity was also estimated by fasting glucose and insulin. Maximal heart rate (MHR) was determined during VO2max testing, and power produced at 80%MHR was recorded. Spearman's rank correlation was performed to evaluate associations. Mean power determined on the indoor cycle at 80% of MHR was 129 +/- 77 watts, and average power at 80% MHR divided by total body weight was 1.5 +/- 0.5. A significant correlation between watts and total body weight was seen for VO2max (P = 0.03), and significant negative correlation was seen between watts/total body weight and fasting insulin (P < 0.05). Among middle school children who were overweight, there was a significant relationship between the power component of fitness and cardiovascular aerobic fitness (measured by VO2max). This more accessible and less intimidating field-based measure of power may prove useful in predicting changes in cardiovascular fitness. Thus, accurate assessment of childhood aerobic fitness may be achievable by measurement of power, possibly within the school environment, at substantially less cost and effort than laboratory-based measurements.     

Liver steatosis coexists with myocardial insulin resistance and coronary dysfunction in patients with type 2 diabetes

Nonalcoholic fatty liver (NAFL) is a common comorbidity in patients with type 2 diabetes and links to the risk of coronary syndromes. The aim was to determine the manifestations of metabolic syndrome in different organs in patients with liver steatosis. We studied 55 type 2 diabetic patients with coronary artery disease using positron emission tomography. Myocardial perfusion was measured with [15O]H2O and myocardial and skeletal muscle glucose uptake with 2-deoxy-2-[18F]fluoro-D-glucose during hyperinsulinemic euglycemia. Liver fat content was determined by magnetic resonance proton spectroscopy. Patients were divided on the basis of their median (8%) into two groups with low (4.6 +/- 2.0%) and high (17.4 +/- 8.0%) liver fat content. The groups were well matched for age, BMI, and fasting plasma glucose. In addition to insulin resistance at the whole body level (P = 0.012) and muscle (P = 0.002), the high liver fat group had lower insulin-stimulated myocardial glucose uptake (P = 0.040) and glucose extraction rate (P = 0.0006) compared with the low liver fat group. In multiple regression analysis, liver fat content was the most significant explanatory variable for myocardial insulin resistance. In addition, the high liver fat group had increased concentrations of high sensitivity C-reactive protein, soluble forms of E-selectin, vascular adhesion protein-1, and intercellular adhesion molecule-1 (P < 0.05) and lower coronary flow reserve (P = 0.02) compared with the low liver fat group. In conclusion, in patients with type 2 diabetes and coronary artery disease, liver fat content is a novel independent indicator of myocardial insulin resistance and reduced coronary functional capacity. Further studies will reveal the effect of hepatic fat reduction on myocardial metabolism and coronary function.     

The ENPP1 K121Q polymorphism is not associated with type 2 diabetes and related metabolic traits in an Iranian population

The K121Q polymorphism of the ectoenzyme nucleotide pyrophosphate phosphodiesterase 1 (ENPP1) gene has been variably associated with insulin resistance and type 2 diabetes (T2D) in several populations. However, this association has not been studied in Iranian subjects and we hypothesized that the K121Q variant might be associated with T2D and related metabolic traits in this population. The K121Q genotypes were determined by PCR-restriction fragment length polymorphism in 377 normoglycemic controls and 155 T2D patients. T2D patients had significantly higher values for systolic and diastolic blood pressure, BMI, glucose, cholesterol, triglyceride, LDL, apoB, insulin, and HOMA-IR, and lower levels of HDL than the normoglycemic subjects. The frequency of the Q allele did not differ between T2D and normoglycemic subjects (OR 0.96, 95% CI 0.90-2.00, P?=?0.70). The Q allele frequency was 16.5% in T2D and 15.2% in normoglycemic subjects. The ENPP1 genotype (KQ?+?QQ) was not associated with the systolic and diastolic blood pressure, glucose, triglyceride, cholesterol, LDL-C and HDL-C, apo B, BMI, HOMA-IR, and insulin levels in both normoglycemic and T2D groups. Our results suggest that the ENPP1 121Q allele might not be associated with T2D and related metabolic traits among Iranian subjects.