Search

AIMS/HYPOTHESIS:In this prospective case-control study we tested the hypothesis that, while long-term improvements in insulin sensitivity (SI) accompanying weight loss after Roux-en-Y gastric bypass (RYGB) would be similar in obese individuals with and without type 2 diabetes mellitus, stimulated-islet-cell insulin responses would differ, increasing (recovering) in those with diabetes but decreasing in those without. We investigated whether these changes would occur in conjunction with favourable alterations in meal-related gut hormone secretion and insulin processing. METHODS:Forty participants with type 2 diabetes and 22 participants without diabetes from the Longitudinal Assessment of Bariatric Surgery (LABS-2) study were enrolled in a separate, longitudinal cohort (LABS-3 Diabetes) to examine the mechanisms of postsurgical diabetes improvement. Study procedures included measures of SI, islet secretory response and gastrointestinal hormone secretion after both intravenous glucose (frequently-sampled IVGTT [FSIVGTT]) and a mixed meal (MM) prior to and up to 24 months after RYGB. RESULTS:Postoperatively, weight loss and SI-FSIVGTT improvement was similar in both groups, whereas the acute insulin response to glucose (AIRglu) decreased in the non-diabetic participants and increased in the participants with type 2 diabetes. The resulting disposition indices (DIFSIVGTT) increased by three- to ninefold in both groups. In contrast, during the MM, total insulin responsiveness did not significantly change in either group despite durable increases of up to eightfold in postprandial glucagon-like peptide 1 levels, and SI-MM and DIMM increased only in the diabetes group. Peak postprandial glucagon levels increased in both groups. CONCLUSIONS/INTERPRETATION:For up to 2 years following RYGB, obese participants without diabetes showed improvements in DI that approach population norms. Those with type 2 diabetes recovered islet-cell insulin secretion response yet continued to manifest abnormal insulin processing, with DI values that remained well below population norms. These data suggest that, rather than waiting for lifestyle or medical failure, RYGB is ideally considered before, or as soon as possible after, onset of type 2 diabetes. TRIAL REGISTRATION:ClinicalTrials.gov NCT00433810.

Am J Physiol Endocrinol Metab 298: E49-E58, 2010. First published November 3, 2009; doi:10.1152/ajpendo.00317.2009.--Insulin resistance in skeletal muscle in obesity and T2DM is associated with reduced muscle oxidative capacity, reduced expression in nuclear genes responsible for oxidative metabolism, and reduced activity of mitochondrial electron transport chain. The presented study was undertaken to analyze mitochondrial content and mitochondrial enzyme profile in skeletal muscle of sedentary lean individuals and to compare that with our previous data on obese or obese T2DM group. Frozen skeletal muscle biopsies obtained from lean volunteers were used to estimate cardiolipin content, mtDNA (markers of mitochondrial mass), NADH oxidase activity of mitochondrial electron transport chain (ETC), and activity of citrate synthase and [beta]-hydroxyacyl-CoA dehydrogenase ([beta]-HAD), key enzymes of TCA cycle and [beta]-oxidation pathway, respectively. Frozen biopsies collected from obese or T2DM individuals in our previous studies were used to estimate activity of [beta]-HAD. The obtained data were complemented by data from our previous studies and statistically analyzed to compare mitochondrial content and mitochondrial enzyme profile in lean, obese, or T2DM cohort. The total activity of NADH oxidase was reduced significantly in obese or T2DM subjects. The cardiolipin content for lean or obese group was similar, and although for T2DM group cardiolipin showed a tendency to decline, it was statistically insignificant. The total activity of citrate synthase for lean and T2DM group was similar; however, it was increased significantly in the obese group. Activity of [beta]-HAD and mtDNA content was similar for all three groups. We conclude that the total activity of NADH oxidase in biopsy for lean group is significantly higher than corresponding activity for obese or T2DM cohort. The specific activity of NADH oxidase (per mg cardiolipin) and NADH oxidase/citrate synthase and NADH oxidase/ [beta]-HAD ratios are reduced two- to threefold in both T2DM and obesity. insulin resistance; [beta]-oxidation; cardiolipin; reduced nicotinamide adenine dinucleotide/nicotinamide adenine dinucleotide ratio; trichloroacetic acid cycle

Insulin resistance (IR) is typically more severe in obese individuals with type 2 diabetes (T2DM) than in similarly obese non-diabetics but whether there are group differences in body composition and whether such differences contribute to the more severe IR of T2DM is uncertain. DEXA and regional CT imaging were conducted to assess adipose tissue (AT) distribution and fat content in liver and muscle in 67 participants with T2DM (F39/M28, age 60 [+ or -] 7 yr, BMI 34 [+ or -] 3 kg/[m.sup.2]) and in 35 similarly obese, non-DM volunteers (F20/M15, age 55 [+ or -] 8 yr, BMI 33 [+ or -] 2 kg/[m.sup.2]). A biopsy of subcutaneous abdominal AT was done to measure adipocyte size. A glucose clamp was performed at an insulin infusion of 80 mU x [min.sup.-1] x [m.sup.-2]. There was more severe IR in T2DM (6.1 [+ or -] 2.3 vs. 9.9 [+ or -] 3.3 mg x [min.sup.1] x kg [FFM.sup.-1]; p < 0.01). Group comparisons of body composition parameters was performed after adjusting for the effect of age, gender, race, height and total fat mass (FM). T2DM was associated with less leg FM (-1.2 [+ or -] 0.4 kg, P < 0.01), more trunk FM (+1.1 [+ or -] 0.4 kg, P < 0.05), greater hepatic fat (P < 0.05), and more subfascial adipose tissue around skeletal muscle (P < 0.05). There was a significant group x sex interaction for VAT (P < 0.01), with greater VAT in women with T2DM (P < 0.01). Mean adipocyte size (AS) did not significantly differ across groups, and smaller AS was associated with increased leg FM, whereas larger AS was related to more trunk FM (both P < 0.05). Group differences in IR were less after adjusting for group differences in leg FM, trunk FM, and hepatic fat, but these adjustments only partially accounted for the greater severity of IR in T2DM. In summary, T2DM, compared with similarly obese nondiabetic men and women, is associated with less leg FM and greater trunk FM and hepatic fat. doi:10.1152/ajpendo.003934.2006 adipocytes; obesity; body composition; computed tomography

Skeletal muscle mitochondria are implicated with age-related loss of function and insulin resistance. We examined the effects of exercise on skeletal muscle mitochondria in older (age = 67.3 [+ or -] 0.6 years) men (n = 5) and women (n = 3). Similar increases in (p < .01) cardiolipin (88.2 [+ or -] 9.0 to 130.6 [+ or -] 7.5 [micro]g/mU creatine kinase activity [CK]) and the total mitochondrial DNA (1264 [+ or -] 170 to 1895 [+ or -] 273 copies per diploid of nuclear genome) reflected increased mitochondria content. Succinate oxidase activity, complexes 2-4 of the electron transport chain (ETC), increased from 0.13 [+ or -] 0.02 to 0.20 [+ or -] 0.02 U/mU CK (p < .01). This improvement was more pronounced (p < .05) in subsarcolemmal (127 [+ or -] 48%) compared to intermyofibrillar (56 [+ or -] 12%) mitochondria. NADH oxidase activity, representing total ETC activity, increased from 0.51 [+ or -] 0.09 to 1.00 [+ or -] 0.09 U/mU CK (p < .01) In conclusion, exercise enhances mitochondria ETC activity in older human skeletal muscle, particularly in subsarcolemmal mitochondria, which is likely related to the concomitant increases in mitochondrial biogenesis.

Glucose transport is regarded as the principal rate control step governing insulin-stimulated glucose utilization by skeletal muscle. To assess this step in human skeletal muscle, quantitative PET imaging of skeletal muscle was performed using 3-O-methyl-[[sup.11]C]glucose (3-[[sup.11]C]OMG) in healthy volunteers during a two-step insulin infusion [n = 8; 30 and 120 mU*[min.sup.-1*m.sup.-2], low (LO) and high (HI)] and during basal conditions (n = 8). Positron emission tomography images were coregistered with MRI to assess 3-[[sup.11]C]OMG activity in regions of interest placed on oxidative (soleus) compared with glycolytic (tibialis anterior) muscle. Insulin dose-responsive increases of 3-[[sup.11]C]OMG activity in muscle were observed (P < 0.01). Tissue activity was greater in soleus than in tibialis anterior (P < 0.05). Spectral analysis identified that two mathematical components interacted to shape tissue activity curves. These two components were interpreted physiologically as likely representing the kinetics of 3-[[sup.11]C]OMG delivery from plasma to tissue and the kinetics of bidirectional glucose transport. During low compared with basal, there was a sixfold increase in [k.sub.3], the rate constant attributed to inward glucose transport, and another threefold increase during HI (0.012 [+ or -] 0.003, 0.070 [+ or -] 0.014, 0.272 [+ or -] 0.059 [min.sup.-1], P < 0.001). Values for [k.sub.3] were similar in soleus and tibialis anterior, suggesting similar kinetics for transport, but compartmental modeling indicated a higher value in soleus for [k.sub.1], denoting higher rates of 3-[[sup.11]C]OMG delivery to soleus than to tibialis anterior. In summary, in healthy volunteers there is robust dose-responsive insulin stimulation of glucose transport in skeletal muscle. glucose transport; insulin sensitivity; skeletal muscle; positron emission tomography; 3-O-methylglucose

The mechanisms underlying leptin resistance are still being defined. We report here the presence in human blood of several serum leptin-interacting proteins (SLIPs), isolated by leptin-affinity chromatography and identified by mass spectrometry and immunochemical analysis. We confirmed that one of the major SLIPs is C-reactive protein (CRP). In vitro, human CRP directly inhibits the binding of leptin to its receptors and blocks its ability to signal in cultured cells. In vivo, infusion of human CRP into ob/ob mice blocked the effects of leptin upon satiety and weight reduction. In mice that express a transgene encoding human CRP, the actions of human leptin were completely blunted. We also found that physiological concentrations of leptin can stimulate expression of CRP in human primary hepatocytes. Recently, human CRP has been correlated with increased adiposity and plasma leptin. Thus, our results suggest a potential mechanism contributing to leptin resistance, by which circulating CRP binds to leptin and attenuates its physiological functions., Author(s): Ke Chen [1, 6]; Fanghong Li [1, 6]; Ji Li [1]; Hongbo Cai [2]; Steven Strom [2]; Alessandro Bisello [3]; David E Kelley [3]; Miriam Friedman-Einat [4]; Gregory A [...]

The current study was undertaken to address responsiveness of skeletal muscle mitochondrial electron transport chain (ETC) activity to weight loss (WL) and exercise in overweight or obese, sedentary volunteers. Fourteen middle-aged participants (7 male/7 female) had assessments of mitochondrial ETC activity and mitochondrial (mt)DNA in vastus lateralis muscle, obtained by percutaneous biopsy, before and after a 16-wk intervention. Mean WL was 9.7 (1.5%) and the mean increase in [VO.sub.2 max] was [means (SD)] 21.7 (3.7)%. Total ETC activity increased significantly, from 0.13 (0.02) to 0.19 (0.03) U/mU creatine kinase (CK; P < 0.001). ETC activity was also assessed in mitochondria isolated into subsarcolemmal (SSM) and intermyofibrillar (IMF-M) fractions. In response to intervention, there was a robust increase of ETC activity in SSM (0.028 (0.007) to 0.046 (0.011) U/mU CK, P < 0.001), and in IMF-M [0.101 (0.015) to 0.148 (0.018) U/mU CK, P < 0.005]. At baseline, the percentage of ETC activity contained in the SSM fraction was low and remained unchanged following intervention [19 (3) vs. 22 (2)%], despite the increase in ETC activity. Also, muscle mtDNA content did not change significantly [1665 (213) vs. 1874 (214) mtDNA/nuclear DNA], denoting functional improvement rather than proliferation of mitochondria as the principal mechanism of enhanced ETC activity. Increases in ETC activity were correlated with energy expenditure during exercise sessions, and ETC activity in SSM correlated with insulin sensitivity after adjustment for [VO.sub.2 max]. In summary, skeletal muscle ETC activity is increased by WL and exercise in previously sedentary obese men and women. We conclude that improved skeletal muscle ETC activity following moderate WL and improved aerobic capacity contributes to associated alleviation of insulin resistance. insulin resistance; exercise; mitochondria; mitochondrial DNA; succinate oxidase

Muscle glycogen content in type 2 diabetes mellitus. Am J Physiol Endocrinol Metab 287: E1002-E1007, 2004. First published July 13, 2004: doi:10.1152/ajpendo. 110015.2004.--Muscle contains the largest reservoir of glycogen (Glyc), a depot that is closely regulated and with influence on insulin sensitivity. The current study examines muscle Glyc in type 2 diabetes mellitus (T2DM) and obesity and with respect to muscle fiber type, intramyocellular lipid content (IMCL), and mitochondrial function (oxidative enzyme activity; OX-Enz). There is increasing interest in the relation of IMCL and mitochondrial dysfunction with insulin resistance (IR), yet the association with muscle Glyc has not been examined with regard to these parameters. Using a quantitative histological approach specific to muscle fiber types, we assessed muscle Glyc, IMCL, and OX-Enz in vastus lateralis obtained by percutaneous biopsy in lean nondiabetic (L; n = 16), obese nondiabetic (Ob; n = 15), and T2DM volunteers (n = 14). Insulin sensitivity was estimated using homeostasis model assessment (HOMA)-IR. Muscle Glyc was reduced in T2DM, a deficit evident for type IIa fibers, yet minor in types I and IIb fibers. Low Glyc in T2DM correlated with tasting hyperglycemia. Also, in T2DM and Ob, there was significantly higher IMCL and lower OX-Enz in all fiber types. The IMCL-to-OX-Enz ratio, especially for type I fibers, correlated strongly with IR. Similarly, a Glyc-to-OX-Enz ratio correlated with IR, particularly for type lib fibers. This ratio tended to be higher in Ob and T2DM. In summary, there is decreased muscle Glyc in T2DM yet a disproportional Glyc-to-OX-Enz relationship that is related to IR, although not as robustly as the IMCL-to-OX-Enz ratio. skeletal muscle; insulin resistance; intramyocellular lipid; mitochondria

Exercise training increases intramyocellular lipid and oxidative capacity in older adults. Am J Physiol Endocrinol Metab 287: E857-E862, 2004. First published June 29, 2004; doi:10.1152/ajpendo.00459.2003.--Intramyocellular lipid (IMCL) has been associated with insulin resistance. However, an association between IMCL and insulin resistance might be modulated by oxidative capacity in skeletal muscle. We examined the hypothesis that 12 wk of exercise training would increase both IMCL and the oxidative capacity of skeletal muscle in older (67.3 [+ or -] 0.7 yr), previously sedentary subjects (n = 13; 5 men and 8 women). Maximal aerobic capacity ([Vo.sub.2 max]) increased from 1.65 [+ or -] 0.20 to 1.85 [+ or -] 0.14 l/min (P < 0.05), and systemic fat oxidation induced by 1 h of cycle exercise at 45% of [Vo.sub.2 max] increased (P < 0.05) from 15.03 [+ or -] 40 to 19.29 [+ or -] 0.80 ([micro]mol*[min.sup.-1]*kg fat-free [mass.sup.-1]). IMCL, determined by quantitative histological staining in vastus lateralis biopsies, increased (P < 0.05) from 22.9 [+ or -] 1.9 to 25.9 [+ or -] 2.6 arbitrary units (AU). The oxidative capacity of muscle, determined by succinate dehydrogenase staining intensity, significantly increased (P < 0.05) from 75.2 [+ or -] 5.2 to 83.9 [+ or -] 3.6 AU. The percentage of type I fibers significantly increased (P < 0.05) from 35.4 [+ or -] 2.1 to 40.1 [+ or -] 2.3%. In conclusion, exercise training increases IMCL in older persons in parallel with an enhanced capacity for fat oxidation. skeletal muscle; physical activity; fiber type; triacylglycerol

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 [+ or -] 0.5 kg/[m.sup.2]] 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.sup.-2] * [min.sup.-1]) combined with systemic indirect calorimetry to assess glucose and lipid oxidation, and with infusions of [[sup.2][H.sub.2]]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. obesity; hepatic steatosis; visceral adiposity

In vivo insulin regulation of glucose transport and phosphorylation in skeletal muscle of healthy, lean volunteers was investigated. PET imaging and compartmental modeling of the time course of skeletal muscle uptake and utilization after a bolus injection of deoxy-D-glucose was conducted during metabolic steady-state conditions at four rates of euglycemic insulin infusion. Results showed an essential interaction between transport and phosphorylation in the control of insulin-stimulated glucose metabolism in skeletal muscle.