The unfortunate thing about keto is that all the post-prandial chylomicron remnants are precisely the thing that causes muscular insulin resistance. It takes very little carbs (~10% E) before you start seeing keto & "ancestral" diet advocates fretting about their blood glucose.
Mei S et al. 2014. A Small Amount of Dietary Carbohydrate Can Promote the HFD-Induced Insulin Resistance to a Maximal Level.
It seems keto is only pragmatic in childhood epilepsy and metastatic cancer, where overriding health concerns favor an otherwise unpalatable diet, where numerous healthy foods are excluded.
Ideally, one could engineer a diet strictly around short chain fatty acids and resistant starch for these disorders, as its not fats in general that cause insulin resistance, but just the longer saturated fats (esp ceramide generating palmitate (16:0) and equally TLR4 activating stearate (18:0)).
For myself, 75% carbs (but no added sugars or fruit juice) seems to be working, with fasting glucose around 75 mg/dL and HbA1 below 5%. These were normal levels in parts of the world with starch based diets, before Western high-fat diets and Western diabetes risks arrived.
It seems paradoxical, but to reduce fasting glucose, one minimizes long-chain saturated fat intake.
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This isn't the ideal venue for it, but I feel like doing an info dump for ImmortalSpace's benefit, as I find the ignorance of some of the keto/low-carb gurus galling. The evidence that long-chain saturated fat intake is a primary cause of insulin resistance is overwhelming. Fructose has similar associations with other elements of metabolic syndrome, both saturated fats and excess fructose impair intestinal barrier function and bring endotoxemia, and there's much more detailing the connection between long-chain saturated fats, TLR4 activation, and inflammation in the etiology of insulin resistance, but I'll save those topics for another day.
Human studies
Roden M et al. 1996. Mechanism of free fatty acid-induced insulin resistance in humans. Journal of Clinical Investigation, 97(12), 2859.
Krssak M et al. 1999. Intramyocellular lipid concentrations are correlated with insulin sensitivity in humans: a 1H NMR spectroscopy study. Diabetologia, 42(1), 113-116.
Santomauro AT et al. 1999. Overnight lowering of free fatty acids with Acipimox improves insulin resistance and glucose tolerance in obese diabetic and nondiabetic subjects. Diabetes, 48(9), 1836-1841.
Maron DJ et al. 1991. Saturated fat intake and insulin resistance in men with coronary artery disease. Circulation, 84(5), 2020-2027.
Parker DR et al. 1993. Relationship of dietary saturated fatty acids and body habitus to serum insulin concentrations: the Normative Aging Study. The American journal of clinical nutrition, 58(2), 129-136.
Vessby B et al. 1994. Insulin sensitivity is related to the fatty acid composition of serum lipids and skeletal muscle phospholipids in 70-year-old men. Diabetologia, 37(10), 1044-1050.
Marshall JA et al. 1997. High saturated fat and low starch and fibre are associated with hyperinsulinaemia in a non-diabetic population: the San Luis Valley Diabetes Study. Diabetologia, 40(4), 430-438.
Jacob S et al. 1999. Association of increased intramyocellular lipid content with insulin resistance in lean nondiabetic offspring of type 2 diabetic subjects. Diabetes,48(5), 1113-1119.
Perseghin G et al. 1999. Intramyocellular triglyceride content is a determinant of in vivo insulin resistance in humans: a 1H-13C nuclear magnetic resonance spectroscopy assessment in offspring of type 2 diabetic parents. Diabetes,48(8), 1600-1606.
Roden M et al. 1999. Rapid impairment of skeletal muscle glucose transport/phosphorylation by free fatty acids in humans. Diabetes, 48(2), 358-364.
Manco M et al. 2000. Insulin resistance directly correlates with increased saturated fatty acids in skeletal muscle triglycerides.Metabolism, 49(2), 220-224.
Vessby B et al. 2001. Substituting dietary saturated for monounsaturated fat impairs insulin sensitivity in healthy men and women: The KANWU Study. Diabetologia, 44(3), 312-319.
Lovejoy JC. et al. 2002. Effects of diets enriched in saturated (palmitic), monounsaturated (oleic), or trans (elaidic) fatty acids on insulin sensitivity and substrate oxidation in healthy adults. Diabetes care, 25(8), 1283-1288.
Summers L et al. 2002. Substituting dietary saturated fat with polyunsaturated fat changes abdominal fat distribution and improves insulin sensitivity. Diabetologia, 45(3), 369-377.
Sparks LM et al. 2005. A high-fat diet coordinately downregulates genes required for mitochondrial oxidative phosphorylation in skeletal muscle. Diabetes, 54(7), 1926-1933.
Kusunoki M et al. 2007. 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. The Journal of Medical Investigation, 54(3, 4), 243-247.
Anderson EJ et al. 2009. Mitochondrial H2O2 emission and cellular redox state link excess fat intake to insulin resistance in both rodents and humans. The Journal of clinical investigation, 119(3), 573.
Das M et al. 2010. Association of metabolic syndrome with obesity measures, metabolic profiles, and intake of dietary fatty acids in people of Asian Indian origin. Journal of cardiovascular disease research, 1(3), 130-135.
Ebbesson SO et al. 2010. Individual saturated fatty acids are associated with different components of insulin resistance and glucose metabolism: the GOCADAN study. International journal of circumpolar health, 69(4), 344.
Corella D et al. 2011. A high intake of saturated fatty acids strengthens the association between the fat mass and obesity-associated gene and BMI. The Journal of nutrition, 141(12), 2219-2225.
Perez-Martinez P et al. 2011. Calpain-10 interacts with plasma saturated fatty acid concentrations to influence insulin resistance in individuals with the metabolic syndrome. The American journal of clinical nutrition, 93(5), 1136-1141.
González-Muniesa P. 2013. Differential proinflammatory and oxidative stress response and vulnerability to metabolic syndrome in habitual high-fat young male consumers putatively predisposed by their genetic background. International journal of molecular sciences, 14(9), 17238-17255.
Lee S et al. 2013. Effects of an overnight intravenous lipid infusion on intramyocellular lipid content and insulin sensitivity in African–American versus Caucasian adolescents. Metabolism, 62(3), 417-423.
Mayneris-Perxachs J et al. 2014. Plasma fatty acid composition, estimated desaturase activities, and their relation with the metabolic syndrome in a population at high risk of cardiovascular disease.Clinical nutrition, 33(1), 90-97.
Ceramides
Schmitz-Peiffer C et al. 1999. Ceramide generation is sufficient to account for the inhibition of the insulin-stimulated PKB pathway in C2C12 skeletal muscle cells pretreated with palmitate. Journal of Biological Chemistry, 274(34), 24202-24210.
Chavez JA et al. 2003. A role for ceramide, but not diacylglycerol, in the antagonism of insulin signal transduction by saturated fatty acids. Journal of Biological Chemistry, 278(12), 10297-10303.
Chavez JA. & Summers SA. 2003. Characterizing the effects of saturated fatty acids on insulin signaling and ceramide and diacylglycerol accumulation in 3T3-L1 adipocytes and C2C12 myotubes. Archives of biochemistry and biophysics, 419(2), 101-109.
Kelpe CL el al. 2003. Palmitate inhibition of insulin gene expression is mediated at the transcriptional level via ceramide synthesis. Journal of Biological Chemistry, 278(32), 30015-30021.
Powell D et al. 2004. Intracellular ceramide synthesis and protein kinase Czeta activation play an essential role in palmitate-induced insulin resistance in rat L6 skeletal muscle cells. Biochem. J, 382, 619-629.
Turpin SM et al. 2006. Apoptosis in skeletal muscle myotubes is induced by ceramides and is positively related to insulin resistance. American Journal of Physiology-Endocrinology and Metabolism, 291(6), E1341-E1350.
Holland WL et al. 2007. Inhibition of ceramide synthesis ameliorates glucocorticoid-, saturated-fat-, and obesity-induced insulin resistance. Cell metabolism, 5(3), 167-179.
Pickersgill L et al. 2007. Key role for ceramides in mediating insulin resistance in human muscle cells. Journal of Biological Chemistry, 282(17), 12583-12589.
Holland WL et al. 2011. Lipid-induced insulin resistance mediated by the proinflammatory receptor TLR4 requires saturated fatty acid–induced ceramide biosynthesis in mice. The Journal of clinical investigation,121(5), 1858.
Chavez JA et al. 2014. Ceramides and glucosylceramides are independent antagonists of insulin signaling. Journal of Biological Chemistry, 289(2), 723-734.
Other studies
Hunnicutt JW et al. 1994. Saturated fatty acid–induced insulin resistance in rat adipocytes. Diabetes,43(4), 540-545.
Lee JS et al. 2006. Saturated, but not n-6 polyunsaturated, fatty acids induce insulin resistance: role of intramuscular accumulation of lipid metabolites.Journal of applied physiology, 100(5), 1467-1474.http://dx.plos.org/1...al.pone.0100875
Matsuzaka T et al. 2007. Crucial role of a long-chain fatty acid elongase, Elovl6, in obesity-induced insulin resistance. Nature medicine, 13(10), 1193-1202.
Alkhateeb H et al. 2007. Two phases of palmitate-induced insulin resistance in skeletal muscle: impaired GLUT4 translocation is followed by a reduced GLUT4 intrinsic activity.American Journal of Physiology-Endocrinology and Metabolism, 293(3), E783-E793.
Matsuzawa-Nagata N et al. 2008. Increased oxidative stress precedes the onset of high-fat diet–induced insulin resistance and obesity. Metabolism,57(8), 1071-1077.
Hommelberg PP et al. 2009. Fatty acid-induced NF-κB activation and insulin resistance in skeletal muscle are chain length dependent. American Journal of Physiology-Endocrinology and Metabolism, 296(1), E114-E120.
Nolan CJ & Larter CZ. 2009. Lipotoxicity: why do saturated fatty acids cause and monounsaturates protect against it?. Journal of gastroenterology and hepatology, 24(5), 703-706.
Nakamura S et al. 2009. Palmitate induces insulin resistance in H4IIEC3 hepatocytes through reactive oxygen species produced by mitochondria. Journal of Biological Chemistry, 284(22), 14809-14818.
Jornayvaz FR et al 2010. A high-fat, ketogenic diet causes hepatic insulin resistance in mice, despite increasing energy expenditure and preventing weight gain. American Journal of Physiology-Endocrinology and Metabolism, 299(5), E808-E815.
Van den Berg SA et al. 2010. High levels of dietary stearate promote adiposity and deteriorate hepatic insulin sensitivity. Nutr Metab (Lond),7(24.2010).
Hirabara SM. et al. 2010. Saturated fatty acid‐induced insulin resistance is associated with mitochondrial dysfunction in skeletal muscle cells. Journal of cellular physiology, 222(1), 187-194.
Clegg DJ et al. 2011. Consumption of a high-fat diet induces central insulin resistance independent of adiposity. Physiology & behavior, 103(1), 10-16.
Hommelberg PP et al. 2011. Palmitate-induced skeletal muscle insulin resistance does not require NF-κB activation. Cellular and Molecular Life Sciences, 68(7), 1215-1225.
Sawada K et al. 2012. Ameliorative effects of polyunsaturated fatty acids against palmitic acid-induced insulin resistance in L6 skeletal muscle cells. Lipids Health Dis, 11(1), 36.
Talukdar S et al. 2012. Neutrophils mediate insulin resistance in mice fed a high-fat diet through secreted elastase. Nature medicine, 18(9), 1407-1412.
Eguchi K et al. 2012. Saturated fatty acid and TLR signaling link β cell dysfunction and islet inflammation
Junior SAO et al. 2013. Extensive impact of saturated fatty acids on metabolic and cardiovascular profile in rats with diet-induced obesity: a canonical analysis. Cardiovasc Diabetol, 12(1), 65.
Salvado L et al. 2013. Oleate prevents saturated-fatty-acid-induced ER stress, inflammation and insulin resistance in skeletal muscle cells through an AMPK-dependent mechanism. Diabetologia, 56(6), 1372-1382.
Galbo T et al. 2013. Saturated and unsaturated fat induce hepatic insulin resistance independently of TLR-4 signaling and ceramide synthesis in vivo. Proceedings of the National Academy of Sciences, 110(31), 12780-12785.
Mei S et al. 2014. A small amount of dietary carbohydrate can promote the HFD-induced insulin resistance to a maximal level. PLoS ONE, 9(7).
Reviews
Boden G. 1997. Role of fatty acids in the pathogenesis of insulin resistance and NIDDM. Diabetes, 46(1), 3-10.
McGarry JD & Dobbins RL. 1999. Fatty acids, lipotoxicity and insulin secretion. Diabetologia, 42(2), 128-138.
Riccardi G et al. 2005. Dietary fat, insulin sensitivity and the metabolic syndrome. Clinical nutrition, 23(4), 447-456.
Haag M & Dippenaar NG. 2005. Dietary fats, fatty acids and insulin resistance: short review of a multifaceted connection. Medical Science Monitor Basic Research, 11(12), RA359-RA367.
Schrauwen P. 2007. High-fat diet, muscular lipotoxicity and insulin resistance. In Proceedings - Nutrition Society of London. Vol. 66, No. 1, p. 33
Ye J. 2007. Role of insulin in the pathogenesis of free fatty acid-induced insulin resistance in skeletal muscle. Endocrine, Metabolic & Immune Disorders-Drug Targets, 7(1), 65-74.
Corcoran MP et al.2007. Skeletal muscle lipid deposition and insulin resistance: effect of dietary fatty acids and exercise. The American journal of clinical nutrition, 85(3), 662-677.
Galgani JE et al. 2008. Effect of the dietary fat quality on insulin sensitivity. British Journal of Nutrition, 100(03), 471-479.
Chavez JA & Summers SA. 2012. A ceramide-centric view of insulin resistance. Cell metabolism, 15(5), 585-594.
Martins AR et al. 2012. Mechanisms underlying skeletal muscle insulin resistance induced by fatty acids: importance of the mitochondrial function. Lipids Health Dis, 11(30), 1-11.
Estadella D et al. 2013. Lipotoxicity: effects of dietary saturated and transfatty acids. Mediators of inflammation, 2013.
Yang J et al. 2013. The mechanisms linking adiposopathy to type 2 diabetes. Frontiers of medicine, 7(4), 433-444.
Nourmohammdi M et al. 2014. Dietary fatty acid composition and metabolic syndrome: a review. Journal of Nutritional Sciences and Dietetics, 1(1), 28-36.
Note: the Talukdar et al 2012 study above exemplifies why one should avoid proinflammatory long-chain saturated fats in a skin preservation regimen. Elastase is enemy #1 in skin aging, and much of the harm of UV irradiation is due to elastase secretion.
Edited by Darryl, 24 July 2015 - 07:24 PM.