Plasma Ceramides Are Elevated in Obese Subjects With Type 2 Diabetes and Correlate With the Severity of Insulin Resistance
Jacob M. Haus 1 2 ,
Sangeeta R. Kashyap 3 ,
Takhar Kasumov 4 ,
Renliang ...Zhang 5 ,
Karen R. Kelly 1 6 ,
Ralph A. DeFronzo 7 and
John P. Kirwan 1 2 4 6
1 Department of Pathobiology, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio
2 Department of Physiology, Case Western Reserve University School of Medicine, Cleveland, Ohio
3 Department of Endocrinology, Diabetes, and Metabolism, Cleveland Clinic, Cleveland, Ohio
4 Department of Gastroenterology/Hepatology, Cleveland Clinic, Cleveland, Ohio
5 Department of Cardiovascular Medicine and Center for Cardiovascular Diagnostics and Prevention, Cleveland Clinic, Cleveland,
Ohio
6 Department of Nutrition, Case Western Reserve University School of Medicine, Cleveland, Ohio
7 Division of Diabetes, University of Texas Health Science Center, San Antonio, Texas
Corresponding author: John P. Kirwan, kirwanj{at}ccf.org
Abstract
OBJECTIVE— To quantitate plasma ceramide subspecies concentrations in obese subjects with type 2 diabetes and relate these plasma levels
to the severity of insulin resistance. Ceramides are a putative mediator of insulin resistance and lipotoxicity, and accumulation
of ceramides within tissues in obese and diabetic subjects has been well described.
RESEARCH DESIGN AND METHODS— We analyzed fasting plasma ceramide subspecies by quantitative tandem mass spectrometry in 13 obese type 2 diabetic patients
and 14 lean healthy control subjects. Results were related to insulin sensitivity measured with the hyperinsulinemic-euglycemic
clamp technique and with plasma tumor necrosis factor-α (TNF-α) levels, a marker of inflammation. Ceramide species (C18:1,
18:0, 20:0, 24:1, and 24:0) were quantified using electrospray ionization tandem mass spectrometry after separation with high-performance
liquid chromatography.
RESULTS— Insulin sensitivity (mg · kg −1 · min −1 ) was lower in type 2 diabetic patients (4.90 ± 0.3) versus control subjects (9.6 ± 0.4) ( P < 0.0001). Type 2 diabetic subjects had higher ( P < 0.05) concentrations of C18:0, C20:0, C24:1, and total ceramide. Insulin sensitivity was inversely correlated with C18:0,
C20:0, C24:1, C24:0, and total ceramide (all P < 0.01). Plasma TNF-α concentration was increased ( P < 0.05) in type 2 diabetic subjects and correlated with increased C18:1 and C18:0 ceramide subspecies.
CONCLUSIONS— Plasma ceramide levels are elevated in type 2 diabetic subjects and may contribute to insulin resistance through activation
of inflammatory mediators, such as TNF-α.
Footnotes
Published ahead of print at http://diabetes.diabetesjournals.org on 13 November 2008.
J.M.H., and S.R.K. contributed equally to this work.
Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work
is not altered. See http://creativecommons.org/licenses/by-nc-nd/3.0/ for details.
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore
be hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
Accepted November 5, 2008.
Received September 4, 2008.
DIABETES
BACKGROUND: Alternate day fasting (ADF; ad libitum “feed day”, alternated with 25% energy intake “fast day”), is effective for weight loss and cardio-protection in obese individuals. Whether these ...effects occur in normal weight and overweight individuals remains unknown. This study examined the effect of ADF on body weight and coronary heart disease risk in non-obese subjects. METHODS: Thirty-two subjects (BMI 20–29.9 kg/m²) were randomized to either an ADF group or a control group for 12 weeks. RESULTS: Body weight decreased (P < 0.001) by 5.2 ± 0.9 kg (6.5 ± 1.0%) in the ADF group, relative to the control group, by week 12. Fat mass was reduced (P < 0.001) by 3.6 ± 0.7 kg, and fat free mass did not change, versus controls. Triacylglycerol concentrations decreased (20 ± 8%, P < 0.05) and LDL particle size increased (4 ± 1 , P < 0.01) in the ADF group relative to controls. CRP decreased (13 ± 17%, P < 0.05) in the ADF group relative to controls at week 12. Plasma adiponectin increased (6 ± 10%, P < 0.01) while leptin decreased (40 ± 7%, P < 0.05) in the ADF group versus controls by the end of the study. LDL cholesterol, HDL cholesterol, homocysteine and resistin concentrations remained unchanged after 12 weeks of treatment. CONCLUSION: These findings suggest that ADF is effective for weight loss and cardio-protection in normal weight and overweight adults, though further research implementing larger sample sizes is required before solid conclusion can be reached.
Innovative non-pharmacological lifestyle strategies to treat non-alcoholic fatty liver disease (NAFLD) are critically needed. This study compared the effects of alternate day fasting (ADF) combined ...with exercise to fasting alone, or exercise alone, on intrahepatic triglyceride (IHTG) content. Adults with obesity and NAFLD (n = 80, 81% female, age: 23–65 years) were randomized to 1 of 4 groups for 3 months: combination of ADF (600 kcal/2,500 kJ “fast day” alternated with an ad libitum intake “feast day”) and moderate-intensity aerobic exercise (5 session per week, 60 min/session); ADF alone; exercise alone; or a no-intervention control group. By month 3, IHTG content was significantly reduced in the combination group (−5.48%; 95% CI, −7.77% to −3.18%), compared with the exercise group (−1.30%; 95% CI, −3.80% to 1.20%; p = 0.02) and the control group (−0.17%; 95% CI, −2.17% to 1.83%; p < 0.01) but was not significantly different versus the ADF group (−2.25%; 95% CI, −4.46% to −0.04%; p = 0.05). Body weight, fat mass, waist circumference, and alanine transaminase (ALT) levels significantly decreased, while insulin sensitivity significantly increased in the combination group compared with the control group. Lean mass, aspartate transaminase (AST), HbA1c, blood pressure, plasma lipids, liver fibrosis score, and hepatokines (fetuin-A, FGF-21, and selenoprotein P) did not differ between groups. Combining intermittent fasting with exercise is effective for reducing hepatic steatosis in patients with NAFLD but may offer no additional benefit versus fasting alone.
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•Adults with NAFLD followed an intermittent fasting plus exercise protocol for 3 months•Hepatic steatosis was significantly reduced by 5.5% versus controls•Body weight, fat mass, and waist circumference also decreased versus controls•By month 3, ALT was reduced, while insulin sensitivity increased, versus controls
Ezpeleta et al. examined the effect of alternate day fasting combined with aerobic exercise on hepatic steatosis in adults with non-alcoholic fatty liver disease (NAFLD). After 3 months, the combination therapy produced significant decreases in hepatic steatosis, body weight, fat mass, waist circumference, and ALT levels and increases in insulin sensitivity.
Exerkines in health, resilience and disease Chow, Lisa S; Gerszten, Robert E; Taylor, Joan M ...
Nature reviews. Endocrinology,
05/2022, Letnik:
18, Številka:
5
Journal Article
Recenzirano
Odprti dostop
The health benefits of exercise are well-recognized and are observed across multiple organ systems. These beneficial effects enhance overall resilience, healthspan and longevity. The molecular ...mechanisms that underlie the beneficial effects of exercise, however, remain poorly understood. Since the discovery in 2000 that muscle contraction releases IL-6, the number of exercise-associated signalling molecules that have been identified has multiplied. Exerkines are defined as signalling moieties released in response to acute and/or chronic exercise, which exert their effects through endocrine, paracrine and/or autocrine pathways. A multitude of organs, cells and tissues release these factors, including skeletal muscle (myokines), the heart (cardiokines), liver (hepatokines), white adipose tissue (adipokines), brown adipose tissue (baptokines) and neurons (neurokines). Exerkines have potential roles in improving cardiovascular, metabolic, immune and neurological health. As such, exerkines have potential for the treatment of cardiovascular disease, type 2 diabetes mellitus and obesity, and possibly in the facilitation of healthy ageing. This Review summarizes the importance and current state of exerkine research, prevailing challenges and future directions.
Obesity prevalence in the US has nearly tripled since 1975 and a parallel increase in prevalence of type 2 diabetes (T2D). Obesity promotes a myriad of metabolic derangements with insulin resistance ...(IR) being perhaps the most responsible for the development of T2D and other related diseases such as cardiovascular disease. The precarious nature of IR development is such that it provides a valuable target for the prevention of further disease development. However, the mechanisms driving IR are numerous and complex making the development of viable interventions difficult. The development of metabolic derangement in the context of obesity promotes accumulation of reactive metabolites such as the reactive alpha-dicarbonyl methylglyoxal (MG). MG accumulation has long been appreciated as a marker of disease progression in patients with T2D as well as the development of diabetic complications. However, recent evidence suggests that the accumulation of MG occurs with obesity prior to T2D onset and may be a primary driving factor for the development of IR and T2D. Further, emerging evidence also suggests that this accumulation of MG with obesity may be a result in a loss of MG detoxifying capacity of glyoxalase I. In this review, we will discuss the evidence that posits MG accumulation because of GLO1 attenuation is a novel target mechanism of the development of metabolic derangement. In addition, we will also explore the regulation of GLO1 and the strategies that have been investigated so far to target GLO1 regulation for the prevention and treatment of metabolic derangement.
We examined intramuscular endomysial collagen, cross-linking, and advanced glycation end products, as well as the general and contractile protein concentration of 20 young (25 +/- 3 yr) and 22 old ...(78 +/- 6 yr, range: 70-93 yr) sedentary men and women to better understand the underlying basis of changes in skeletal muscle mass and function that occur with aging. The old individuals had an impaired ability (increased time) (P < 0.05) to climb stairs (80%), rise from a chair (56%), and walk (44%), as well as lower (P < 0.05) quadriceps muscle volume (-29%), muscle strength (-35%), muscle power (-48%), and strength (-17%) and power (-33%) normalized to muscle size. Vastus lateralis muscle biopsies revealed that intramuscular endomysial collagen (young: 9.6 +/- 1.1, old: 10.2 +/- 1.2 microg/mg muscle wet wt) and collagen cross-linking (hydroxylysylpyridinoline) (young: 395 +/- 65, old: 351 +/- 45 mmol hydroxylysylpyridinoline/mol collagen) were unchanged (P > 0.05) with aging. The advanced glycation end product, pentosidine, was increased (P < 0.05) by approximately 200% (young: 5.2 +/- 1.3, old: 15.9 +/- 4.5 mmol pentosidine/mol collagen) with aging. While myofibrillar protein concentration was lower (-5%, P < 0.05), the concentration of the main contractile proteins myosin and actin were unchanged (P > 0.05) with aging. These data suggest that the synthesis and degradation of proteins responsible for the generation (myosin and actin) and transfer (collagen and pyridinoline cross-links) of muscle force are tightly regulated in aging muscle. Glycation-related cross-linking of intramuscular connective tissue may contribute to altered muscle force transmission and muscle function with healthy aging.
Increased dietary whole-grain intake may protect against cardiovascular disease (CVD).
The objective was to evaluate the efficacy of whole grains compared with refined grains on body composition, ...hypertension, and related mediators of CVD in overweight and obese adults.
We conducted a double-blind, randomized, controlled crossover trial in 40 overweight or obese men and women aged <50 y with no known history of CVD. Complete whole-grain and refined-grain diets were provided for two 8-wk periods, with a 10-wk washout between diets. Macronutrient composition was matched, except for the inclusion of either whole grains or refined grains (50 g/1000 kcal in each diet). Measurements included blood pressure, body composition, blood lipids and adiponectin, and markers of inflammation and glycemia.
Thirty-three participants (6 men and 27 women) completed the trial mean ± SD age: 39 ± 7 y; mean ± SD body mass index (in kg/m
): 33.1 ± 4.3. Decreases in diastolic blood pressure were -5.8 mm Hg (95% CI: -7.7, -4.0 mm Hg) after the whole-grain diet and -1.6 mm Hg (95% CI: -4.4, 1.3 mm Hg) after the control diet (between effect, P = 0.01). Decreases in plasma adiponectin were -0.1 (95% CI: -0.9, 0.7) after the whole-grain diet and -1.4 (95% CI: -2.6, -0.3) after the control diet (between effect, P = 0.05). Decreases in diastolic blood pressure correlated with the circulating adiponectin concentration (r = 0.35, P = 0.04). Substantial reductions in body weight, fat loss, systolic blood pressure, total cholesterol, and LDL cholesterol were observed during both diet periods, with no relevant difference between them.
The improvement in diastolic blood pressure was >3-fold greater in overweight and obese adults when they consumed a whole-grain compared with a refined-grain diet. Because diastolic blood pressure predicts mortality in adults aged <50 y, increased whole-grain intake may provide a functional approach to control hypertension. This may benefit patients at risk of vascular-related morbidity and mortality. This trial was registered at clinicaltrials.gov as NCT01411540.
Diagnostic computed tomography (CT) scans provide numerous opportunities for body composition analysis, including quantification of abdominal circumference, abdominal adipose tissues (subcutaneous, ...visceral, and intermuscular), and skeletal muscle (SM). CT scans are commonly performed for diagnostic purposes in clinical settings, and methods for estimating abdominal circumference and whole-body SM mass from them have been reported. A supine abdominal circumference is a valid measure of waist circumference (WC). The valid correlation between a single cross-sectional CT image (slice) at third lumbar (L3) for abdominal SM and whole-body SM is also well established. Sarcopenia refers to the age-associated decreased in muscle mass and function. A single dimensional definition of sarcopenia using CT images that includes only assessment of low whole-body SM has been validated in clinical populations and significantly associated with negative outcomes. However, despite the availability and precision of SM data from CT scans and the relationship between these measurements and clinical outcomes, they have not become a routine component of clinical nutrition assessment. Lack of time, training, and expense are potential barriers that prevent clinicians from fully embracing this technique. This tutorial presents a systematic, step-by-step guide to quickly quantify abdominal circumference as a proxy for WC and SM using a cross-sectional CT image from a regional diagnostic CT scan for clinical identification of sarcopenia. Multiple software options are available, but this tutorial uses ImageJ, a free public-domain software developed by the National Institutes of Health.
Skeletal muscle insulin resistance is a hallmark of Type 2 diabetes (T2DM) and may be exacerbated by protein modifications by methylglyoxal (MG), known as dicarbonyl stress. The glyoxalase enzyme ...system composed of glyoxalase 1/2 (GLO1/GLO2) is the natural defense against dicarbonyl stress, yet its protein expression, activity, and regulation remain largely unexplored in skeletal muscle. Therefore, this study investigated dicarbonyl stress and the glyoxalase enzyme system in the skeletal muscle of subjects with T2DM (age: 56 ± 5 yr.; BMI: 32 ± 2 kg/m
) compared with lean healthy control subjects (LHC; age: 27 ± 1 yr.; BMI: 22 ± 1 kg/m
). Skeletal muscle biopsies obtained from the vastus lateralis at basal and insulin-stimulated states of the hyperinsulinemic (40 mU·m
·min
)-euglycemic (5 mM) clamp were analyzed for proteins related to dicarbonyl stress and glyoxalase biology. At baseline, T2DM had increased carbonyl stress and lower GLO1 protein expression (-78.8%), which inversely correlated with BMI, percent body fat, and HOMA-IR, while positively correlating with clamp-derived glucose disposal rates. T2DM also had lower NRF2 protein expression (-31.6%), which is a positive regulator of GLO1, while Keap1 protein expression, a negative regulator of GLO1, was elevated (207%). Additionally, insulin stimulation during the clamp had a differential effect on NRF2, Keap1, and MG-modified protein expression. These data suggest that dicarbonyl stress and the glyoxalase enzyme system are dysregulated in T2DM skeletal muscle and may underlie skeletal muscle insulin resistance. Whether these phenotypic differences contribute to the development of T2DM warrants further investigation.
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