1.
Lipids activate skeletal muscle mitochondrial fission and quality control networks to induce insulin resistance in humans.
Axelrod, CL, Fealy, CE, Erickson, ML, Davuluri, G, Fujioka, H, Dantas, WS, Huang, E, Pergola, K, Mey, JT, King, WT, et al
Metabolism: clinical and experimental. 2021;121:154803
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Insulin resistance is a key pathophysiological mechanism in the development and progression of type 2 diabetes. Abnormalities in lipid metabolism and ectopic lipid accumulation are known to directly contribute to the onset of insulin resistance. Authors hypothesised that lipid infusion would increase dynamin related protein 1 [a type of protein]-mediated mitochondrial fission in skeletal muscle independent of function and content, consequently reducing peripheral insulin sensitivity. The study included sedentary but otherwise healthy adults who were prospectively randomized to receive either lipid or saline infusion to isolate the direct contribution of fatty acids to skeletal muscle mitochondrial dynamics. Results show that mitochondrial fission and quality control networks are activated in response to lipid infusion which occurs independent of changes in mitochondrial content or capacity and contributes to the onset of insulin resistance in healthy humans. Authors conclude that treatments that limit lipid-induced activation of mitochondrial fission and/or quality control processes may have therapeutic value in the treatment of insulin resistance.
Abstract
BACKGROUND AND AIMS A diminution in skeletal muscle mitochondrial function due to ectopic lipid accumulation and excess nutrient intake is thought to contribute to insulin resistance and the development of type 2 diabetes. However, the functional integrity of mitochondria in insulin-resistant skeletal muscle remains highly controversial. METHODS 19 healthy adults (age:28.4 ± 1.7 years; BMI:22.7 ± 0.3 kg/m2) received an overnight intravenous infusion of lipid (20% Intralipid) or saline followed by a hyperinsulinemic-euglycemic clamp to assess insulin sensitivity using a randomized crossover design. Skeletal muscle biopsies were obtained after the overnight lipid infusion to evaluate activation of mitochondrial dynamics proteins, ex-vivo mitochondrial membrane potential, ex-vivo oxidative phosphorylation and electron transfer capacity, and mitochondrial ultrastructure. RESULTS Overnight lipid infusion increased dynamin related protein 1 (DRP1) phosphorylation at serine 616 and PTEN-induced kinase 1 (PINK1) expression (P = 0.003 and P = 0.008, respectively) in skeletal muscle while reducing mitochondrial membrane potential (P = 0.042). The lipid infusion also increased mitochondrial-associated lipid droplet formation (P = 0.011), the number of dilated cristae, and the presence of autophagic vesicles without altering mitochondrial number or respiratory capacity. Additionally, lipid infusion suppressed peripheral glucose disposal (P = 0.004) and hepatic insulin sensitivity (P = 0.014). CONCLUSIONS These findings indicate that activation of mitochondrial fission and quality control occur early in the onset of insulin resistance in human skeletal muscle. Targeting mitochondrial dynamics and quality control represents a promising new pharmacological approach for treating insulin resistance and type 2 diabetes. CLINICAL TRIAL REGISTRATION NCT02697201, ClinicalTrials.gov.
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The effect of different sources of fish and camelina sativa oil on immune cell and adipose tissue mRNA expression in subjects with abnormal fasting glucose metabolism: a randomized controlled trial.
de Mello, VD, Dahlman, I, Lankinen, M, Kurl, S, Pitkänen, L, Laaksonen, DE, Schwab, US, Erkkilä, AT
Nutrition & diabetes. 2019;9(1):1
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Dietary fish oils, particularly omega-3 fatty acids eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) found in oily fish, nuts and seeds have long been researched and purported to have both anti-inflammatory and glucose-stabilising effects when consumed orally and it is widely believed that in reducing low-grade inflammation and stabilising blood glucose levels, the risk of suffering from type 2 diabetes, heart disease or a stroke is reduced. Lean fish on the other hand has been far less researched with regards to its protective effects. This study was a randomised controlled study designed to assess and compare the protective effects of fish oils and Camelina Sativa oil (CSO - a seed oil containing alpha-linolenic acid) on inflammatory-related genes in subjects with suggestive pre-diabetes. Subjects were allocated to a randomised group and instructed to consume a given amount of either fatty fish, lean fish, camelina oil, or no fish/oil (control group). The study was carried out on 72 participants over a 12-week period. Although no significant change could be seen on inflammatory gene expression for the group consuming fatty fish, there was a modest decrease in inflammatory gene markers in the group consuming lean fish and a significant decrease in the group consuming CSO. Implications from this study suggest that CSO exerts its protective effect by reducing inflammation, therefore possibly decreasing the risk of strokes and cardiovascular episodes. The authors suggest that consuming a variety of fish, especially lean fish 4 times/ week could also play a protective role in cardiovascular health and type 2 diabetes.
Abstract
BACKGROUND/OBJECTIVES Molecular mechanisms linking fish and vegetable oil intakes to their healthy metabolic effects may involve attenuation of inflammation. Our primary aim was to examine in a randomized controlled setting whether diets enriched in fatty fish (FF), lean fish (LF) or ALA-rich camelina sativa oil (CSO) differ in their effects on the mRNA expression response of selected inflammation-related genes in peripheral blood mononuclear cells (PBMCs) and subcutaneous adipose tissue (SAT) in subjects with impaired fasting glucose. SUBJECTS/METHODS Samples from 72 participants randomized to one of the following 12-week intervention groups, FF (n = 19), LF (n = 19), CSO (n = 17) or a control group (n = 17), were available for the PBMC study. For SAT, 39 samples (n = 8, n = 10, n = 9, n = 12, respectively) were available. The mRNA expression was measured at baseline and 12 weeks by TaqMan® Low Density Array. RESULTS In PBMCs, LF decreased ICAM1 mRNA expression (P < 0.05), which was different (P = 0.06, Bonferroni correction) from the observed increase in the FF group (P < 0.05). Also, compared to the control group, LF decreased ICAM1 mRNA expression (P < 0.05). Moreover, the change in ICAM1 mRNA expression correlated positively with the intake of FF (P < 0.05) and negatively with the intake of LF (P < 0.05), independently of study group. A diet enriched in CSO, a rich source of alpha-linolenic acid (ALA), decreased PBMC IFNG mRNA expression (P < 0.01). The intake of CSO in the CSO group, but not the increase in plasma ALA proportions, correlated inversely with the IFNG mRNA expression in PBMCs (P = 0.08). In SAT, when compared with the control group, the effect of FF on decreasing IL1RN mRNA expression was significant (P < 0.03). CONCLUSION We propose that CSO intake may partly exert its benefits through immuno-inflammatory molecular regulation in PBMCs, while modulation of ICAM1 expression, an endothelial/vascular-related gene, may be more dependent on the type of fish consumed.