Relationship between serum concentrations of saturated fatty acids and unsaturated fatty acids and the homeostasis model insulin resistance index in Japanese patients with type 2 diabetes mellitus

Kusunoki, Masataka; Tsutsumi, Kazuhiko; Nakayama, Meiho; Kurokawa, Tsuyoshi; Nakamura, Toshio; Ogawa, Hitoshi; Fukuzawa, Yoshitaka; Morishita, Munehiko; Koide, Tatsurou; Miyata, Tetsuro

doi:10.2152/jmi.54.243

Cited by 63 publications

(42 citation statements)

References 15 publications

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“…Presently, 20:2n-6 and 20:3n-3 are widely considered dead-end products, in part because their conversion to LCPUFA has not been unequivocally established (43). However, recent studies have associated 20:2n-2 with FADS2 polymorphisms and/or fatty acid compositions in humans (32,44), including patients with cardiovascular disease (31) and type 2 diabetes mellitus (45). In addition, apolipoprotein D knockout mice, a model for psychiatric disorders, show increased CNS 20:2n-6 and 18:2n-6 compared with wild-type mice (46).…”

Section: Discussionmentioning

confidence: 99%

An alternate pathway to long-chain polyunsaturates: the FADS2 gene product Δ8-desaturates 20:2n-6 and 20:3n-3

Park

Kothapalli

Lawrence

et al. 2009

Journal of Lipid Research

188

151

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The mammalian #6-desaturase coded by fatty acid desaturase 2 (FADS2; HSA11q12-q13.1) catalyzes the first and rate-limiting step for the biosynthesis of long-chain polyunsaturated fatty acids. FADS2 is known to act on at least five substrates, and we hypothesized that the FADS2 gene product would have #8-desaturase activity. Saccharomyces cerevisiae transformed with a FADS2 construct from baboon neonate liver cDNA gained the function to desaturate 11,14-eicosadienoic acid (20:2n-6) and 11,14,17-eicosatrienoic acid (20:3n-3) to yield 20:3n-6 and 20:4n-3, respectively. Competition experiments indicate that #8-desaturation favors activity toward 20:3n-3 over 20:2n-6 by 3-fold. Similar experiments show that #6-desaturase activity is favored over #8-desaturase activity by 7-fold and 23-fold for n-6 (18:2n-6 vs 20:2n-6) and n-3 (18:3n-3 vs 20:3n-3), respectively. In mammals, 20:3n-6 is the immediate precursor of prostaglandin E1 and thromboxane B1. 20:3n-6 and 20:4n-3 are also immediate precursors of long-chain polyunsaturated fatty acids arachidonic acid and eicosapentaenoic acid, respectively. These findings provide unequivocal molecular evidence for a novel alternative biosynthetic route to long-chain polyunsaturated fatty acids in mammals from substrates previously considered to be dead-end products.-Park, W. J., K. S. D. Kothapalli, P. Lawrence, C. Tyburczy, and J. T.Brenna. An alternate pathway to long-chain polyunsaturates: the FADS2 gene product #8-desaturates 20:2n-6 and 20:3n-3. J. Lipid Res. 2009Res. . 50: 1195Res. -1202 Supplementary key words polyunsaturated fatty acid biosynthesis • dihomo-g-linolenic acid • eicosanoid precursor biosynthesis Long-chain polyunsaturated fatty acids (LCPUFAs) are ubiquitous in mammalian tissue, achieving highest concentrations in the membranes of neural and other excitable tissue (1). LCPUFA of the n-3 and n-6 families, especially eicosapentaenoic acid (EPA; 20:5n-3), docosahexaenoic acid (22:6n-3), and arachidonic acid (20:4n-6), are bioactive components of membrane phospholipids and serve as substrates for signaling molecules (2). The degree of unsaturation of the membranes is determined by the action of enzymes involved in fatty acid biosynthesis and metabolism (3). Most organisms synthesize unsaturated fatty acids, but the pathways are specific to cell types and species.Fatty acid desaturases are enzymes that catalyze the introduction of cis double bonds at specific positions in a fatty acid chain (4). Desaturases in plants and lower animal species can introduce double bonds near the methyl end. Eukaryotic cells of higher animals, fungi, and dinoflagellates express membrane-bound acyl-CoA front-end desaturases (5, 6) catalyzing double bond introduction into the D6, D5, D8, and D4 positions. Mammalian front-end desaturases operate on diet-derived PUFA to synthesize LCPUFA, which can also be derived from the diet but possibly not in sufficient quantities to optimize health (7).The front-end desaturases are remarkable for their structural similarity and functiona...

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Section: Discussionmentioning

confidence: 99%

An alternate pathway to long-chain polyunsaturates: the FADS2 gene product Δ8-desaturates 20:2n-6 and 20:3n-3

Park

Kothapalli

Lawrence

et al. 2009

Journal of Lipid Research

188

151

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“…14). Similarly, multiple studies have also linked the SFA myristate (C14:0), which is a major constituent of milk fat, to insulin resistance and the metabolic syndrome in humans (14)(15)(16)(17). Strikingly, in wild-type C57BL/6J mice, this milk fat-based diet (MFBD) promoted profound insulin resistance and hyperglycemia by 8 weeks.…”

Section: Introductionmentioning

confidence: 99%

Ceramide synthase 5 mediates lipid-induced autophagy and hypertrophy in cardiomyocytes

Russo

Baicu²,

Laer³

et al. 2012

J. Clin. Invest.

186

182

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Diabetic cardiomyopathy (DbCM), which consists of cardiac hypertrophy and failure in the absence of traditional risk factors, is a major contributor to increased heart failure risk in type 2 diabetes patients. In rodent models of DbCM, cardiac hypertrophy and dysfunction have been shown to depend upon saturated fatty acid (SFA) oversupply and de novo sphingolipid synthesis. However, it is not known whether these effects are mediated by bulk SFAs and sphingolipids or by individual lipid species. In this report, we demonstrate that a diet high in SFA induced cardiac hypertrophy, left ventricular systolic and diastolic dysfunction, and autophagy in mice. Furthermore, treatment with the SFA myristate, but not palmitate, induced hypertrophy and autophagy in adult primary cardiomyocytes. De novo sphingolipid synthesis was required for induction of all pathological features observed both in vitro and in vivo, and autophagy was required for induction of hypertrophy in vitro. Finally, we implicated a specific ceramide N-acyl chain length in this process and demonstrated a requirement for (dihydro)ceramide synthase 5 in cardiomyocyte autophagy and myristate-mediated hypertrophy. Thus, this report reveals a requirement for a specific sphingolipid metabolic route and dietary SFAs in the molecular pathogenesis of lipotoxic cardiomyopathy and hypertrophy. IntroductionObesity and diabetes present two of the most important health challenges facing the Western world at this time. Patients suffering from type 2 diabetes (T2D) are subject to a number of major health risks, including a greatly increased risk of heart failure (1). This is due in part to the development of diabetic cardiomyopathy (DbCM), which occurs independently of other traditional risk factors (2). DbCM promotes cardiac remodeling and impairs cardiac function (1). Importantly, individuals with T2D and the metabolic syndrome present with dyslipidemia, and recent studies have suggested that DbCM may occur as a result of lipid overload and subsequent lipotoxic events (ref. 2, reviewed in ref. 3). In particular, oversupply of saturated fatty acids (SFAs) has been implicated in this process.Previous studies of lipotoxic DbCM in rodents have relied on several important transgenic models. The B6.Cg-Lep ob /J (ob/ob) and B6.BKS(D)-Lepr db /J (db/db) mouse models, which lack the genes encoding leptin and the leptin receptor, respectively, are both very popular models that develop obesity and a DbCM-like cardiac phenotype (reviewed in ref. 4). Other less common models, including the Atgl-knockout mouse and the LpL GPI transgenic mouse, also induce lipotoxic cardiomyopathy by perturbing cardiac lipid uptake, handling, or metabolism (reviewed in ref. 4). While these transgenic models robustly induce lipid overload in cardiomyocytes, the very disruptions that produce lipotoxic DbCM also drastically alter patterns of lipid uptake and handling in a nonphysiologic way. In contrast, wild-type mice fed standard lard-based high-fat diets (LBD) failed to develop a DbCM-like phenotyp...

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“…The importance of circulating palmitoleic acid in regulating insulin sensitivity in humans is unclear because of confl icting data from different studies, which have found that the percentage of palmitoleate in plasma FFA or lipids correlated directly with insulin sensitivity ( 3 ) or was greater in insulinresistant (IR) than insulin-sensitive (IS) subjects (4)(5)(6)(7)(8). Moreover, these studies did not measure absolute palmitoleate concentration, which provides a better assessment of palmitoleate availability to peripheral tissues, or palmitoleate within very low-density lipoprotein (VLDL), which may be an important contributor to tissue fatty acid delivery.…”

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confidence: 99%

Insulin sensitivity is not associated with palmitoleate availability in obese humans

Fabbrini

Magkos

et al. 2011

Journal of Lipid Research

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This article is available online at http://www.jlr.org However, data from studies conducted in rodents have shown that infusing palmitoleic acid (16:1n-7), which is normally produced in adipose tissue and the liver through lipogenesis, followed by desaturation of palmitic acid (16:0) by the stearoyl-CoA desaturase (SCD1) gene, augments skeletal muscle insulin signaling and increases insulin-mediated muscle glucose uptake ( 2 ). The importance of circulating palmitoleic acid in regulating insulin sensitivity in humans is unclear because of confl icting data from different studies, which have found that the percentage of palmitoleate in plasma FFA or lipids correlated directly with insulin sensitivity ( 3 ) or was greater in insulinresistant (IR) than insulin-sensitive (IS) subjects ( 4-8 ). Moreover, these studies did not measure absolute palmitoleate concentration, which provides a better assessment of palmitoleate availability to peripheral tissues, or palmitoleate within very low-density lipoprotein (VLDL), which may be an important contributor to tissue fatty acid delivery.The purpose of the present study was to determine whether impaired insulin-mediated skeletal muscle glucose uptake was associated with a decrease in plasma palmitoleic acid availability in obese people. Accordingly, we determined plasma free palmitoleic acid concentration, which is derived primarily from palmitoleate synthesized in adipose tissue, and palmitoleic acid content in VLDL, which is derived primarily from palmitoleate synthesized in the liver. Study subjects were specifi cally selected to be either IS or IR based on the increase in glucose uptake during a hyperinsulinemic-euglycemic clamp procedure. An increase in circulating free fatty acids (FFA) impairs insulin action in skeletal muscle and liver and likely contributes to the insulin resistance associated with obesity ( 1 ). DK-37948, UL1 RR-024992 (Clinical and Translational Science Award), DK 56341 (Nutrition and Obesity Research Center), and RR-00954 (Biomedical Mass Spectrometry Resource) Abbreviations: BMI, body mass index; BSA, body surface area; C t , threshold crossing; HISI, hepatic insulin sensitivity index; IR, insulin resistant; IS, insulin sensitive; Ra, rate of appearance; Rd, rate of disappearance; TG, triglyceride. This study was supported by National Institutes of Health Grants

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Relationship between serum concentrations of saturated fatty acids and unsaturated fatty acids and the homeostasis model insulin resistance index in Japanese patients with type 2 diabetes mellitus

Abstract: Some PUFA as well as SFA were positively correlated with HOMA-R. These results indicate that the intake of diet fatty acid must be well balanced in diabetic patients and it is not always true to refrain from taking SFA and increase the unsaturated fatty acids in their diets.

Cited by 63 publications

References 15 publications

An alternate pathway to long-chain polyunsaturates: the FADS2 gene product Δ8-desaturates 20:2n-6 and 20:3n-3

An alternate pathway to long-chain polyunsaturates: the FADS2 gene product Δ8-desaturates 20:2n-6 and 20:3n-3

Ceramide synthase 5 mediates lipid-induced autophagy and hypertrophy in cardiomyocytes

Insulin sensitivity is not associated with palmitoleate availability in obese humans

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