Lipoproteins in plasma transport lipids between tissues, however, only high density lipoproteins (HDL) appear to traverse the blood brain barrier; thus, lipoproteins found in the brain must be produced within the central nervous system. Apolipoproteins E (ApoE) and ApoJ are the most abundant apolipoproteins in the brain, are mostly synthesized by astrocytes and are found on HDL. In the hippocampus and other brain regions lipoproteins help regulate neurobehavioral functions by processes that are lipoprotein receptor-mediated. Moreover, lipoproteins and their receptors also have roles in the regulation of body weight and energy balance, i.e. through lipoprotein lipase (LPL) and the LDL receptor-related protein (LRP). Thus, understanding lipoproteins and their metabolism in the brain provides a new opportunity with potential therapeutic relevance.
lipoprotein; metabolism; brain; lipoprotein receptor; neuron; astrocyte
The intent of this review is to update the science of emerging cardiometabolic risk factors that were listed in the National Cholesterol Education Program (NCEP) Adult Treatment Panel-III (ATP-III) report of 2001 (updated in 2004). At the time these guidelines were published, the evidence was felt to be insufficient to recommend these risk factors for routine screening of cardiovascular disease risk. However, the panel felt that prudent use of these biomarkers for patients at intermediate risk of a major cardiovascular event over the subsequent 10 years might help identify patients who needed more aggressive low density lipoprotein (LDL) or non-high density lipoprotein (HDL) cholesterol lowering therapy. While a number of other emerging risk factors have been identified, this review will be limited to assessing the data and recommendations for the use of apolipoprotein B, lipoprotein (a), homocysteine, pro-thrombotic factors, inflammatory factors, impaired glucose metabolism, and measures of subclinical atherosclerotic cardiovascular disease for further cardiovascular disease risk stratification.
Apolipoprotein B; Lipoprotein (a); C-reactive protein; Homocysteine
CCAAT/enhancer-binding protein β (C/EBPβ) plays a key role in initiation of adipogenesis in adipose tissue and gluconeogenesis in liver; however, the role of C/EBPβ in hepatic lipogenesis remains undefined. Here we show that C/EBPβ inactivation in Leprdb/db mice attenuates obesity, fatty liver, and diabetes. In addition to impaired adipogenesis, livers from C/EBPβ−/− x Leprdb/db mice had dramatically decreased triglyceride content and reduced lipogenic enzyme activity. C/EBPβ deletion in Leprdb/db mice down-regulated peroxisome proliferator-activated receptor γ2 (PPARγ2) and stearoyl-CoA desaturase-1 and up-regulated PPARα independent of SREBP1c. Conversely, C/EBPβ overexpression in wild-type mice increased PPARγ2 and stearoyl-CoA desaturase-1 mRNA and hepatic triglyceride content. In FAO cells, overexpression of the liver inhibiting form of C/EBPβ or C/EBPβ RNA interference attenuated palmitate-induced triglyceride accumulation and reduced PPARγ2 and triglyceride levels in the liver in vivo. Leptin and the anti-diabetic drug metformin acutely down-regulated C/EBPβ expression in hepatocytes, whereas fatty acids up-regulate C/EBPβ expression. These data provide novel evidence linking C/EBPβ expression to lipogenesis and energy balance with important implications for the treatment of obesity and fatty liver disease.
Lipoprotein lipase (LPL) is rate limiting in the provision of triglyceride-rich lipoprotein-derived lipids into tissues. LPL is also present in the brain, where its function has remained elusive. Recent evidence implicates a role of LPL in the brain in two processes: (a) the regulation of energy balance and body weight and (b) cognition. Mice with neuron-specific deletion of LPL have increases in food intake that lead to obesity, and then reductions in energy expenditure that further contribute to and sustain the phenotype. In other mice with LPL deficiency rescued from neonatal lethality by somatic gene transfer wherein LPL in the brain remains absent, altered cognition ensues. Taking into consideration data that associate LPL mutations with Alzheimer’s disease, a role for LPL in learning and memory seems likely. Overall, the time is ripe for new insights into how LPL-mediated lipoprotein metabolism in the brain impacts CNS processes and systems biology.
triglycerides; fatty acids; metabolism; energy balance; cognition
Adipose tissue located in the viscera is considered to be functionally and metabolically different from that found in the subcutaneous depot. However, subcutaneous adipose tissue in generalized regions is considered to be homogeneous in nature. Affymetrix GeneChip Human Exon 1.0 ST Arrays were used to determine differential gene expression in four subcutaneous adipose depots (upper abdomen, lower abdomen, flank and hip) in normal weight women. A total of 2890/24,409 transcripts were differentially expressed between all sites. When comparing the hip and flank to the lower abdomen, 248 and 83 genes were differentially expressed, respectively. When comparing the hip and flank to the upper abdomen, 2480 and 79 genes were differentially expressed, respectively. No genes were significantly different when the lower abdomen was compared to the upper abdomen and the hip to the flank. Genes involved in the complement and coagulation cascades and immune responses showed increased expression in the lower abdomen compared to the flank. In addition, two genes involved in the complement and coagulation cascade, CR1 and C7, were expressed more highly in the lower abdomen compared to the hip. Genes involved in basic biochemical metabolism including insulin signaling, the urea cycle, glutamate metabolism, arginine and proline metabolism and aminosugar metabolism had higher expression in the lower abdomen compared to the hip. These results in normal weight healthy women provide a new perspective on regional differences in subcutaneous adipose tissue biology that may have pathophysiologic implications when adiposity increases.
Vascular endothelial dysfunction develops with aging, as indicated by impaired endothelium-dependent dilation(EDD), and is related to increased cardiovascular disease risk. We hypothesized that short-term treatment with fenofibrate, a lipid-lowering agent with potential pleiotropic effects, would improve EDD in middle-aged and older normolipidemic adults by reducing oxidative stress. Brachial artery flow-mediated dilation (FMD), a measure of EDD, was assessed in 22healthy adults aged 50-77 years before and after 7days of fenofibrate (145 mg/d; n=12/7M) or placebo (n=10/5M). Brachial FMD was unchanged with placebo, but improved after 2 and 7 days of fenofibrate (5.1±0.7 vs. 2d: 6.0±0.7 and 7d: 6.4±0.6 %Δ; both P<0.005). The improvements in FMD after 7 days remained significant (P<0.05) after accounting for modest changes in plasma total and LDL-cholesterol. Endothelium-independent dilation was not affected by fenofibrate or placebo (P>0.05). Infusion (i.v.) of the antioxidant vitamin C improved brachial FMD at baseline in both groups and during placebo treatment (P<0.05), but not after 2 and 7 days of fenofibrate (P>0.05). Fenofibrate treatment also reduced plasma oxidized LDL, a systemic marker of oxidative stress, compared with placebo (P<0.05). In vascular endothelial cells sampled from peripheral veins of the subjects, endothelial nitric oxide synthase (eNOS) protein expression was unchanged with placebo and after 2 days of fenofibrate, but was increased after 7 days of fenofibrate (0.54±0.03 vs. 2d: 0.52±0.04 and 7d: 0.76±0.11 intensity/HUVEC control; P<0.05 7d). Short-term treatment with fenofibrate improves vascular endothelial function in healthy normolipidemic middle-aged/older adults by reducing oxidative stress and induces increases in eNOS.
aging; endothelial-dependent dilation; flow-mediated dilation
Smoking is the most common cause of preventable morbidity and mortality in the United States, in part because it is an independent risk factor for the development of insulin resistance and type 2 diabetes. However, mechanisms responsible for smoking-induced insulin resistance are unclear. In this study, we found smokers were less insulin sensitive compared with controls, which increased after either 1 or 2 weeks of smoking cessation. Improvements in insulin sensitivity after smoking cessation occurred with normalization of IRS-1ser636 phosphorylation. In muscle cell culture, nicotine exposure significantly increased IRS-1ser636 phosphorylation and decreased insulin sensitivity, recapitulating the phenotype of smoking-induced insulin resistance in humans. The two pathways known to stimulate IRS-1ser636 phosphorylation (p44/42 mitogen-activated protein kinase [MAPK] and mammalian target of rapamycin [mTOR]) were both stimulated by nicotine in culture. Inhibition of mTOR, but not p44/42 MAPK, during nicotine exposure prevented IRS-1ser636 phosphorylation and normalized insulin sensitivity. These data indicate nicotine induces insulin resistance in skeletal muscle by activating mTOR. Therapeutic agents designed to oppose skeletal muscle mTOR activation may prevent insulin resistance in humans who are unable to stop smoking or are chronically exposed to secondhand smoke.
This report examines what is known about the relationship between obesity and type 2 diabetes and how future research in these areas might be directed to benefit prevention, interventions, and overall patient care.
RESEARCH DESIGN AND METHODS
An international working group of 32 experts in the pathophysiology, genetics, clinical trials, and clinical care of obesity and/or type 2 diabetes participated in a conference held on 6–7 January 2011 and cosponsored by The Endocrine Society, the American Diabetes Association, and the European Association for the Study of Diabetes. A writing group comprising eight participants subsequently prepared this summary and recommendations. Participants reviewed and discussed published literature and their own unpublished data.
The writing group unanimously supported the summary and recommendations as representing the working group's majority or unanimous opinions.
The major questions linking obesity to type 2 diabetes that need to be addressed by combined basic, clinical, and population-based scientific approaches include the following: 1) Why do not all patients with obesity develop type 2 diabetes? 2) Through what mechanisms do obesity and insulin resistance contribute to β-cell decompensation, and if/when obesity prevention ensues, how much reduction in type 2 diabetes incidence will follow? 3) How does the duration of type 2 diabetes relate to the benefits of weight reduction by lifestyle, weight-loss drugs, and/or bariatric surgery on β-cell function and glycemia? 4) What is necessary for regulatory approval of medications and possibly surgical approaches for preventing type 2 diabetes in patients with obesity? Improved understanding of how obesity relates to type 2 diabetes may help advance effective and cost-effective interventions for both conditions, including more tailored therapy. To expedite this process, we recommend further investigation into the pathogenesis of these coexistent conditions and innovative approaches to their pharmacological and surgical management.
The bHLH-PAS transcription factor, CLOCK, is a key component of the molecular circadian clock within pacemaker neurons of the hypothalamic suprachiasmatic nucleus. Here we report that homozygous Clock mutant mice have a greatly attenuated diurnal feeding rhythm, are hyperphagic and obese, and develop a metabolic syndrome of hyperleptinemia, hyperlipidemia, hepatic steatosis and hyperglycemia, with insufficient compensatory insulin production, a hallmark of type 2 diabetes mellitus. In addition, the levels of expression of hypothalamic peptides associated with energy balance were greatly attenuated in the Clock mutant animals. Taken together, these results indicate that the circadian clock gene network plays an important role in mammalian energy balance that involves a number of central and peripheral tissues, and disruption of this network can lead to obesity and the metabolic syndrome in mice.
We present a consolidated view of the complexity and challenges of designing studies for measurement of energy metabolism in mouse models, including a practical guide to the assessment of energy expenditure, energy intake and body composition and statistical analysis thereof. We hope this guide will facilitate comparisons across studies and minimize spurious interpretations of data. We recommend that division of energy expenditure data by either body weight or lean body weight and that presentation of group effects as histograms should be replaced by plotting individual data and analyzing both group and body-composition effects using analysis of covariance (ANCOVA).
Recent studies reveal a strong relationship between reduced mitochondrial content and insulin resistance in human skeletal muscle, although the underlying factors responsible for this association remain unknown. To address this question, we analyzed muscle biopsy samples from young, lean, insulin resistant (IR) offspring of parents with type 2 diabetes and control subjects by microarray analyses and found significant differences in expression of ∼512 probe pairs. We then screened these genes for their potential involvement in the regulation of mitochondrial biogenesis using RNA interference and found that mRNA and protein expression of lipoprotein lipase (LPL) in skeletal muscle was significantly decreased in the IR offspring and was associated with decreased mitochondrial density. Furthermore, we show that LPL knockdown in muscle cells decreased mitochondrial content by effectively decreasing fatty acid delivery and subsequent activation of peroxisome proliferator–activated receptor (PPAR)-δ. Taken together, these data suggest that decreased mitochondrial content in muscle of IR offspring may be due in part to reductions in LPL expression in skeletal muscle resulting in decreased PPAR-δ activation.
OBJECTIVE—Skeletal muscle–specific LPL knockout mouse (SMLPL−/−) were created to study the systemic impact of reduced lipoprotein lipid delivery in skeletal muscle on insulin sensitivity, body weight, and composition.
RESEARCH DESIGN AND METHODS—Tissue-specific insulin sensitivity was assessed using a hyperinsulinemic-euglycemic clamp and 2-deoxyglucose uptake. Gene expression and insulin-signaling molecules were compared in skeletal muscle and liver of SMLPL−/− and control mice.
RESULTS—Nine-week-old SMLPL−/− mice showed no differences in body weight, fat mass, or whole-body insulin sensitivity, but older SMLPL−/− mice had greater weight gain and whole-body insulin resistance. High-fat diet feeding accelerated the development of obesity. In young SMLPL−/− mice, insulin-stimulated glucose uptake was increased 58% in the skeletal muscle, but was reduced in white adipose tissue (WAT) and heart. Insulin action was also diminished in liver: 40% suppression of hepatic glucose production in SMLPL−/− vs. 90% in control mice. Skeletal muscle triglyceride was 38% lower, and insulin-stimulated phosphorylated Akt (Ser473) was twofold greater in SMLPL−/− mice without changes in IRS-1 tyrosine phosphorylation and phosphatidylinositol 3-kinase activity. Hepatic triglyceride and liver X receptor, carbohydrate response element–binding protein, and PEPCK mRNAs were unaffected in SMLPL−/− mice, but peroxisome proliferator–activated receptor (PPAR)-γ coactivator-1α and interleukin-1β mRNAs were higher, and stearoyl–coenzyme A desaturase-1 and PPARγ mRNAs were reduced.
CONCLUSIONS—LPL deletion in skeletal muscle reduces lipid storage and increases insulin signaling in skeletal muscle without changes in body composition. Moreover, lack of LPL in skeletal muscle results in insulin resistance in other key metabolic tissues and ultimately leads to obesity and systemic insulin resistance.
Peroxisome proliferator-activated receptor (PPAR) delta is an important regulator of fatty acid (FA) metabolism. Angiopoietin-like 4 (Angptl4), a multifunctional protein, is one of the major targets of PPAR delta in skeletal muscle cells. Here we investigated the regulation of Angptl4 and its role in mediating PPAR delta functions using human, rat and mouse myotubes. Expression of Angptl4 was upregulated during myotubes differentiation and by oleic acid, insulin and PPAR delta agonist GW501516. Treatment with GW501516 or Angptl4 overexpression inhibited both lipoprotein lipase (LPL) activity and LPL-dependent uptake of FAs whereas uptake of BSA-bound FAs was not affected by either treatment. Activation of retinoic X receptor (RXR), PPAR delta functional partner, using bexarotene upregulated Angptl4 expression and inhibited LPL activity in a PPAR delta dependent fashion. Silencing of Angptl4 blocked the effect of GW501516 and bexarotene on LPL activity. Treatment with GW501516 but not Angptl4 overexpression significantly increased palmitate oxidation. Furthermore, Angptl4 overexpression did not affect the capacity of GW501516 to increase palmitate oxidation. Basal and insulin stimulated glucose uptake, glycogen synthesis and glucose oxidation were not significantly modulated by Angptl4 overexpression. Our findings suggest that FAs-PPARdelta/RXR-Angptl4 axis controls the LPL-dependent uptake of FAs in myotubes, whereas the effect of PPAR delta activation on beta-oxidation is independent of Angptl4.
Animal data suggest that males, in particular, rely on PPAR-α activity to maintain normal muscle triglyceride metabolism. We sought to examine whether this was also true in men vs. women and its relationship to insulin sensitivity.
Normolipidemic obese men (n=9) and women (n=9) underwent an assessment of insulin sensitivity (IVGTT) and intramuscular triglyceride metabolism (GC/MS and GC/C/IRMS from plasma and muscle biopsies taken after infusion of [U-13C]palmitate) before and after 12 weeks of fenofibrate treatment.
Women were more insulin sensitive (Si; 5.2(0.7 vs. 2.4(0.4 ×10−4/uU/ml, W vs. M, p<0.01) at baseline despite similar intramuscular triglyceride (IMTG) concentration (41.9(15.5 vs. 30.8(5.1 ug/mg dry weight, W vs. M, p=0.43), and IMTG fractional synthesis rate (FSR; 0.27(0.07 vs. 0.35(0.06/hr, W vs. M, p=0.41) as men. Fenofibrate enhanced FSR in men (0.35(0.06 to 0.54(0.06, p=0.05), with no such change seen in women (0.27(0.07 to 0.32(0.13, p=0.73), and no change in IMTG concentration in either group (23.0(3.9 in M, p=0.26 vs. baseline; 36.3(12.0 in W, p=0.79 vs. baseline). Insulin sensitivity was unaffected by fenofibrate (p>0.68). Lower percent saturation of IMTG in women vs. men before (29.1(2.3 vs. 35.2(1.7%, p=0.06) and after (27.3(2.8 vs. 35.1(1.9%, p=0.04) fenofibrate most closely related to their greater insulin sensitivity (R2=0.34, p=0.10), and was largely unchanged by the drug.
PPAR-α agonist therapy had little effect on IMTG metabolism in men or women. IMTG saturation, rather than IMTG concentration or FSR, most closely (but not significantly) related to insulin sensitivity and was unchanged by fenofibrate administration.
Insulin resistance; isotopes; IMCL; muscle; sex
The goals of the study were to determine if moderate weight loss in severely obese adults resulted in 1) reduction in apnea/hypopnea index (AHI), 2) improved pharyngeal patency, 3) reduced total body oxygen consumption (VO2) and carbon dioxide production (VCO2) during sleep, and 4) improved sleep quality. The main outcome was the change in AHI from before to after weight loss. Fourteen severely obese (BMI>40 kg/m2) patients (3 males, 11 females) completed a highly controlled weight reduction program which included 3 months of weight loss and 3 months of weight maintenance. At baseline and post-weight loss, patients underwent pulmonary function testing, polysomnography, and MRI to assess neck morphology. Weight decreased from 134±6.6 kg to 118±6.1 kg (mean ± SEM; F=113.763, p<0.0001). There was a significant reduction in the AHI between baseline and post-weight loss (SUBJECT, F=11.11, p=0.007). Moreover, patients with worse sleep disordered breathing (SDB) at baseline had the greatest improvements in AHI (GROUP, F=9.00, p=0.005). Reductions in VO2 (285±12 to 234±16 ml/min; F=24.85, p<0.0001) and VCO2 (231±9 to 186±12 ml/min; F=27.74, p<0.0001) were also observed, and pulmonary function testing showed improvements in spirometry parameters. Sleep studies revealed improved minimum SaO2 (83.4±61.9% to 89.1±1.2%; F=7.59, p=0.016), and mean SaO2 (90.4±1.1% to 93.8±1.0%; F=6.89, p=0.022), and a significant increase in the number of arousals (8.1±1.4 at baseline, to 17.1±3.0 after weight loss; F=18.13, p=0.001). In severely obese patients, even moderate weight loss (~10%) boasts substantial benefit in terms of the severity of SDB and sleep dynamics.
Obesity; pharynx; diet; oxygen consumption; carbon dioxide production; AHI
Lipoprotein-associated phospholipase A2 (Lp-PLA2) is a lipoprotein-associated enzyme that cleaves oxidized phosphatidylcholines, generating pro-atherosclerotic lysophosphatidylcholine and oxidized free fatty acids. Lp-PLA2 is independently associated with cardiovascular disease (CVD) in a variety of populations. Coronary calcium is a measure of subclinical CVD, and progression of coronary calcification predicts future CVD events. In type 1 diabetes there is an increase in coronary calcium and CVD despite a favorable lipid profile. Levels of Lp-PLA2 in type 1 diabetes are not known, nor is the relationship between Lp-PLA2 and progression of coronary calcification.
The Coronary Artery Calcification in Type 1 Diabetes study measured coronary calcium by electron-beam computed tomography twice over a 2.6 ± 0.3-year interval. Lp-PLA2 mass and activity were measured at baseline (n = 1,097 subjects, 506 with and 591 without type 1 diabetes).
In type 1 diabetes Lp-PLA2 mass was marginally higher (285 ± 79 vs. 278 ± 78 ng/mL, P = 0.1), and Lp-PLA2 activity was significantly lower (137 ± 30 vs. 146 ± 36 nmol/min/mL, P < 0.0001) than in those without diabetes. There was a greater proportion of those with progression of coronary calcification in type 1 diabetes compared with those without diabetes (24% vs. 10%, P < 0.0001). Lp-PLA2 activity was independently associated with progression of coronary calcification in multivariate analysis (4th quartile verses bottom three quartiles, odds ratio = 1.77 [1.08–2.91], P = 0.02). LpPLA2 mass was not significantly associated with progression of coronary calcification in this cohort (P = 0.09).
Lp-PLA2 activity predicts progression of subclinical atherosclerosis in individuals with and without type 1 diabetes.
To assess insulin action on peripheral glucose utilization and nonesterified fatty acid (NEFA) suppression as a predictor of coronary artery calcification (CAC) in patients with type 1 diabetes and nondiabetic controls.
RESEARCH DESIGN AND METHODS
Insulin action was measured by a three-stage hyperinsulinemic-euglycemic clamp (4, 8, and 40 mU/m2/min) in 87 subjects from the Coronary Artery Calcification in Type 1 Diabetes cohort (40 diabetic, 47 nondiabetic; mean age 45 ± 8 years; 55% female).
Peripheral glucose utilization was lower in subjects with type 1 diabetes compared with nondiabetic controls: glucose infusion rate (mg/kg FFM/min) = 6.19 ± 0.72 vs. 12.71 ± 0.66, mean ± SE, P < 0.0001, after adjustment for age, sex, BMI, fasting glucose, and final clamp glucose and insulin. Insulin-induced NEFA suppression was also lower in type 1 diabetic compared with nondiabetic subjects: NEFA levels (μM) during 8 mU/m2/min insulin infusion = 370 ± 27 vs. 185 ± 25, P < 0.0001, after adjustment for age, sex, BMI, fasting glucose, and time point insulin. Lower glucose utilization and higher NEFA levels, correlated with CAC volume (r = −0.42, P < 0.0001 and r = 0.41, P < 0.0001, respectively) and predicted the presence of CAC (odds ratio [OR] = 0.45, 95% CI = 0.22–0.93, P = 0.03; OR = 2.4, 95% CI = 1.08–5.32, P = 0.032, respectively). Insulin resistance did not correlate with GHb or continuous glucose monitoring parameters.
Type 1 diabetic patients are insulin resistant compared with nondiabetic subjects, and the degree of resistance is not related to current glycemic control. Insulin resistance predicts the extent of coronary artery calcification and may contribute to the increased risk of cardiovascular disease in patients with type 1 diabetes as well as subjects without diabetes.
Sleep has been proposed to be a physiological adaptation to conserve energy, but little research has examined this proposed function of sleep in humans. We quantified effects of sleep, sleep deprivation and recovery sleep on whole-body total daily energy expenditure (EE) and on EE during the habitual day and nighttime. We also determined effects of sleep stage during baseline and recovery sleep on EE. Seven healthy participants aged 22 ± 5 years (mean ± s.d.) maintained ∼8 h per night sleep schedules for 1 week before the study and consumed a weight-maintenance diet for 3 days prior to and during the laboratory protocol. Following a habituation night, subjects lived in a whole-room indirect calorimeter for 3 days. The first 24 h served as baseline – 16 h wakefulness, 8 h scheduled sleep – and this was followed by 40 h sleep deprivation and 8 h scheduled recovery sleep. Findings show that, compared to baseline, 24 h EE was significantly increased by ∼7% during the first 24 h of sleep deprivation and was significantly decreased by ∼5% during recovery, which included hours awake 25–40 and 8 h recovery sleep. During the night time, EE was significantly increased by ∼32% on the sleep deprivation night and significantly decreased by ∼4% during recovery sleep compared to baseline. Small differences in EE were observed among sleep stages, but wakefulness during the sleep episode was associated with increased energy expenditure. These findings provide support for the hypothesis that sleep conserves energy and that sleep deprivation increases total daily EE in humans.
Whether intramuscular triglyceride (IMTG) concentration or flux is more important in the progression to type 2 diabetes is controversial. Therefore, this study examined IMTG concentration, as well as its fractional synthesis rate (FSR), in obese people with normal glucose tolerance (NGT; n = 20) vs. obese people with prediabetes (PD; n = 19), at rest and during exercise. Insulin action and secretion were assessed using an intravenous glucose tolerance test. [U-13C] palmitate was infused for 4 h before and throughout 1.5 h of treadmill walking at 50% VO2max. IMTG concentration was measured by gas chromatograph/mass spectrometer, and FSR by gas chromatography–combustion isotope ratio mass spectrometer, from muscle biopsies taken immediately before and after exercise. Basal IMTG concentration was higher (43 ± 5.7 vs. 27 ± 3.9 mg/mg dry weight, P = 0.03) and FSR trended lower (0.23 ± 0.04 vs. 0.32 ± 0.05/h, P = 0.075), as did insulin action (Si; 2.9 ± 0.43 vs. 3.3 ± 0.35 × 10−4/mU/ml, P = 0.07), in PD vs. NGT. IMTG concentration did not change significantly during exercise, but was no longer different in PD vs. NGT (45 ± 7.7 vs. 37 ± 5.8 mg/mg dry weight, P = 0.41). IMTG FSR suppressed during exercise in NGT (−81% to 0.06 ± 0.13/h, P = 0.02), but not PD (+4% to 0.24 ± 0.13%/h, P = 0.95). Palmitate oxidation was similar during rest (P = 0.92) and exercise (P = 0.94) between groups, but its source appeared different with more coming from muscle at rest and plasma during exercise in NGT, whereas the converse was true in PD. Altogether, higher basal IMTG concentration that is metabolically inflexible distinguishes obese people with PD from those with NGT.
Whether sex differences in intramuscular triglyceride (IMTG) metabolism underlie sex differences in the progression to diabetes are unknown. Therefore, the current study examined IMTG concentration and fractional synthesis rate (FSR) in obese men and women with normal glucose tolerance (NGT) vs. those with prediabetes (PD). PD (n = 13 men and 7 women) and NGT (n = 7 men and 12 women) groups were matched for age and anthropometry. Insulin action was quantified using a hyperinsulinemic–euglycemic clamp with infusion of [6,6-2H2]-glucose. IMTG concentration was measured by gas chromatography/mass spectrometry (GC/MS) and FSR by GC/combustion isotope ratio MS (C-IRMS), from muscle biopsies taken after infusion of [U-13C]palmitate during 4 h of rest. In PD men, the metabolic clearance rate (MCR) of glucose was lower during the clamp (4.71 ± 0.77 vs. 8.62 ± 1.26 ml/kg fat-free mass (FFM)/min, P = 0.04; with a trend for lower glucose rate of disappearance (Rd), P = 0.07), in addition to higher IMTG concentration (41.2 ± 5.0 vs. 21.2 ± 3.4 μg/mg dry weight, P ≤ 0.01), lower FSR (0.21 ± 0.03 vs. 0.42 ± 0.06 %/h, P ≤ 0.01), and lower oxidative capacity (P = 0.03) compared to NGT men. In contrast, no difference in Rd, IMTG concentration, or FSR was seen in PD vs. NGT women. Surprisingly, glucose Rd during the clamp was not different between NGT men and women (P = 0.25) despite IMTG concentration being higher (42.6 ± 6.1 vs. 21.2 ± 3.4 μg/mg dry weight, P = 0.03) and FSR being lower (0.23 ± 0.04 vs. 0.42 ± 0.06 %/h, P = 0.02) in women. Alterations in IMTG metabolism relate to diminished insulin action in men, but not women, in the progression toward diabetes.
The purpose of this article is to review the basic and clinical science relating plasma triglycerides and cardiovascular disease. Although many aspects of the basic physiology of triglyceride production, its plasma transport and tissue uptake have been known for several decades, the relationship of plasma triglyceride levels to vascular disease is uncertain. Are triglyceride rich lipoproteins, their influence on HDL and LDL, or the underlying diseases leading to defects in triglyceride metabolism the culprit? Animal models have failed to confirm that anything other than early fatty lesions can be produced by triglyceride-rich lipoproteins. Metabolic products of triglyceride metabolism can be toxic to arterial cells; however, these studies are primarily in vitro. Correlative studies of fasting and postprandial triglycerides and genetic diseases implicate VLDL and their remnants, and chylomicron remnants in atherosclerosis development; but the concomitant alterations in other lipoproteins and other risk factors obscure any conclusions about direct relationships between disease and triglycerides. Genes that regulate triglyceride levels also correlate with vascular disease. Human intervention trials, however, have lacked an appropriately defined population, and have produced outcomes without definitive conclusions. The time is more than ripe for new and creative approaches to understanding the relationship of triglycerides and heart disease.
lipoproteins; lipase; atherosclerosis; hyperlipidemia; vascular disease
Individuals with type 1 diabetes have a less atherogenic fasting lipid profile than those without diabetes but paradoxically have increased rates of cardiovascular disease (CVD). We investigated differences in lipoprotein subfraction cholesterol distribution and insulin resistance between subjects with and without type 1 diabetes to better understand the etiology of increased CVD risk.
RESEARCH DESIGN AND METHODS
Fast protein liquid chromatography was used to fractionate lipoprotein cholesterol distribution in a substudy of the Coronary Artery Calcification in Type 1 Diabetes (CACTI) study (n = 82, age 46 ± 8 years, 52% female, 49% with type 1 diabetes for 23 ± 8 years). Insulin resistance was assessed by a hyperinsulinemic-euglycemic clamp.
Among men, those with type 1 diabetes had less VLDL and more HDL cholesterol than control subjects (P < 0.05), but among women, those with diabetes had a shift in cholesterol to denser LDL, despite more statin use. Among control subjects, men had more cholesterol distributed as VLDL and LDL but less as HDL than women; however, among those with type 1 diabetes, there was no sex difference. Within sex and diabetes strata, a more atherogenic cholesterol distribution by insulin resistance was seen in men with and without diabetes, but only in women with type 1 diabetes.
The expected sex-based less atherogenic lipoprotein cholesterol distribution was not seen in women with type 1 diabetes. Moreover, insulin resistance was associated with a more atherogenic lipoprotein cholesterol distribution in all men and in women with type 1 diabetes. This lipoprotein cholesterol distribution may contribute to sex-based differences in CVD in type 1 diabetes.