Lori, who is an insulin guru, has explained the hard science behind insulin's role in skeletal muscle below in the Serious Bioscience Bits.
I've summarized her science in a vastly simplified form in the green boxes throughout the text. The green boxes are for those who want it quick and easy.
Skeletal muscle are the muscles that connect to your bones. They make up 30-40% of your body mass and use 80% of the glucose you consume. Glucose is broken down through glycolysis to extract energy molecules which ultimately make ATP.
Muscles can store extra glucose as glycogen. Fun fact: the bigger the muscle, the more energy it can store. This gives people with large thighs an advantage in athletic sports.
Having thicc thighs is healthy too. In a large study (9,520 women and men aged over 40 years) a larger thigh circumference was associated with lower systolic blood pressure, diastolic blood pressure, fasting glucose, and total cholesterol (Shi et al. 2020).
Skeletal muscles have three types of fibers; type I, IIa, and IIx. Type I is slow twitch and used in endurance exercise. Both IIa and IIx are fast twitch used for explosive power. People who have metabolic syndrome, obesity and type 2 diabetes have lower type I fiber content and higher type II fibers. Lori has more about it below.
Insulin helps skeletal muscle take up glucose. It also keeps blood vessels healthy.
Simple Summary: Due to obesity, lipids and triglyceride-rich lipoproteins (TGRL) accumulate in muscle as saturated fatty acids. Fat in muscles promotes inflammation and insulin resistance (IR). Other lipid intermediates, diglycerides and ceramides, disrupt insulin signaling. All of this causes impaired skeletal muscle glucose uptake.
The accumulation of intramyocellular lipids stem from an increase in circulating triglyceride-rich lipoproteins (TGRL) which are derived from gut chylomicrons and liver-derived very low density lipoproteins. Normally the hydrolysis of TGRLs results in free fatty acids that the muscle uses as an energy source. In obesity, hydrolysis of VLDLs results in the production of increased amounts of saturated fatty acids which get deposited in, between and surrounding the muscle fibers (Wu & Ballantyne 2017, Wu & Ballantyne 2020).
Intermuscular/intermyocellular adipose tissue (IMAT) and perimuscular adipose tissue (PMAT) increase with obesity, are highly associated with insulin resistance, become inflamed and promote secretion of pro-inflammatory chemokines and cytokines (Goodpaster et al., 2000; Boettcher et al., 2009; Zoico et al., 2010; Sachs et al., 2019).
Other mechanisms that involve the impairment of the insulin signaling cascade are the effects of lipid intermediates, diglycerides (DAG) and ceramides. In studies of lipid infused humans, lipid intermediates, DAG and ceramides disrupted the insulin stimulated tyrosine phosphorylation of IRS1 and PI3K activation via activation of novel protein kinase C (nPKC) (Samuel & Shulman, 2016). Protein kinase C activates IKKβ and JNK, transcription factors that aid in the phosphorylation of serine residues in the IRS1, which disrupts its activity (Paz et al., 1997; Zhande et al., 2002; Hotamisligil et al., 1993; Hotamisligil 2008).
Furthermore, lipid infused humans provide evidence that saturated fatty acids inhibit the tyrosine phosphorylation of IRS1 and PI3K/Akt activity in skeletal muscle. Studies show that palmitate (a saturated fatty acid) activates IKKβ and JNK which in turn affect the insulin signaling (Radin et al., 2008; Yuan et al., 2001; Jove et al., 2006). SFAs can also activate TLR4 to promote activation of JNK and IKKβ to lead to competitive phosphorylation of serine residues. This series of events blocks the skeletal muscle glucose uptake. In addition, hyperinsulinemia promotes serine and threonine phosphorylation of IRS1 which inhibits the translocation of both IRS1 and GLUT4, a major problem in the skeletal muscle (Garvey, 1998).
Recently researchers discovered proteins that contribute to the impairment of glucose uptake in adipose tissue and skeletal muscle as well as clearance of triglyceride-rich lipoproteins in the liver. During periods of inactivity, phosphotyrosine interacting domain-containing protein (PID 1) resides in the endosomal storage vesicle and acts to retain signaling and endocytic receptors (Fischer et al., 2018). It inhibits insulin stimulated PI3K/AKT pathway in adipocytes and skeletal muscle cells (Wu et al., 2018). Specifically, PID1 regulates the activity of endocytic receptor LDL receptor-related protein (LRP 1) that mediates the clearance of triglyceride-rich lipoproteins and modulates the insulin -responsiveness of GLUT4 translocation to the plasma membrane for glucose disposal.
These actions contribute to the dyslipidemia and hyperglycemia seen in Metabolic Syndrome, insulin resistance and type 2 diabetes (T2D).
Researchers found that PID 1 was inversely associated with the glucose disposal in adipocytes and myotubes (Chen et al., 2018). Fischer and colleagues (2019) showed that deletion of PID 1 in diet-induced insulin resistant mice resulted in an increase in the abundance of LRP 1, an increase in GLUT4 glucose uptake and improved glucose tolerance. A previous study showed that PID 1 deletion resulted in an increase in LRP1 at the cell surface to increase LDLR-dependent endocytosis of postprandial lipoproteins and lower plasma triglycerides (Fischer et al., 2018).
Researchers suggest that PID 1 interacts with a non-phosphorylated domain of LRP 1 to retain it in the GLUT4 storage vesicles of the perinuclear compartment. Insulin-mediated phosphorylation of the LRP 1 domain causes the LRP1-PID1 complex to dissociate and allows for LRP1 and GLUT4 to translocate to the cell surface for glucose uptake in the postprandial state. Irrespective of insulin signaling, a lack of PID 1 or deficiency result improved glucose tolerance, increased glucose uptake while not increasing hypoglycemia in diet induced insulin resistance (Fischer et al., 2019).
Simple Summary: Muscle have three types of fibers; slow twitch (Type I) and fast twitch fibers (Type IIa and IIx). Type I slow twitch fibers are more efficient at handling glucose.
The skeletal muscle is an insulin sensitive tissue that takes up glucose as a fuel source and uses the majority (80%) of glucose in two ways through glycolysis and glycogen synthesis. Glycolysis is the process of hydrolysis to break down glucose into components to be used for ATP synthesis in the electron transport chain of the mitochondria. Any additional glucose beyond the muscle cell’s own usage is stored in the muscle as glycogen for future use. The insulin-stimulated processes of glycolysis and glycogen synthesis provide the muscle with fuel substrates.
The skeletal muscle is made up of three types of fibers. Type I fibers are slow twitch or slow oxidative fibers that contract slowly and are used in endurance events. They use aerobic respiration to produce ATP and have numerous capillaries and mitochondria. High myoglobin content of these fibers deliver oxygen to the tissue.
Type II fibers or fast twitch fibers use aerobic respiration but switch to anaerobic respiration (glycolysis). There are two subtypes of type II fibers, IIa (oxidative/glycolytic) and IIx (glycolytic). They make ATP quickly for muscle contractions but do not contain significant amounts of myoglobin.
Studies suggest that insulin-stimulated glucose metabolism varies according to different muscle fiber types. Albers and colleagues (2015) studied various muscle fibers in type 2 diabetics and controls of lean and obese, glucose tolerant subjects. Type I fibers had higher protein content of insulin receptor, GLUT4, hexokinase II, glycogen synthase and pyruvate dehydrogenase – E1α suggesting that type I fibers have enhanced glucose phosphorylation, oxidation and glycogen synthesis therefore greater glucose handling capability compared to type II fibers. It has been shown that insulin resistant subjects including those with metabolic syndrome, obesity and type 2 diabetes have lower type I fiber content and higher type II fibers which may lower their capacity for glucose disposal (Stuart et al., 2013; Oberbach et al., 2006; Gaster et al., 2001). The subject’s physical activity level was not measured in the Albers’ study.
Insulin has various functions in the skeletal muscle (SM) microvasculature that facilitates glucose uptake. The microvasculature system is made up of venules, arterioles, and capillaries which in part are regulated by insulin. The system regulates the vascular pressure, resistance and tone, and transfers blood solutes (e.g., nutrients and oxygen) across the epithelium to the myocyte. Healthy individuals respond to insulin by increasing blood flow which aids in glucose uptake.
Additionally, insulin maintains the balance of vasodilation and vasoconstriction via activation of signaling component PI3K, epithelial nitric oxide synthase (eNOS) and nitric oxide (NO) production. It also aids in the delivery of glucose and its uptake in the skeletal muscle by favoring the process of vasodilation, increasing blood flow to the capillary beds, and altering the arteriolar vasomotor respiration (Ugwoke et al., 2022).
Simple Summary: When muscle cells become insulin resistant they accumulate disruptive lipids which can affect mitochondria, blood vessels and glucose transport.
As the skeletal muscle cells become insulin resistant, there is an accumulation of myocellular and intermuscular lipids and the generation of lipid intermediates. These lipids cause disruption to the insulin signaling pathway and GLUT4 transport. Other effects include alterations to the SM vasculature resulting in reduced blood flow and vascular insulin resistance. Lipids also affect the mitochondria dynamics by altering gene expression of proteins that regulate fission and fusion, stimulate inflammation, and generate increased levels of reactive oxygen species.
Simple summary: Insulin helps maintain blood vessels. Obesity and metabolic disorders cause muscles to develop insulin resistance. This decreases blood flow. Eating too many calories or too much fat contributes to this process by increasing free fatty acids (FFAs) in the bloodstream. FFAs kick off insulin dysfunction.
Insulin’s role in maintaining vasodilation, regulating the vasculature and blood flow is impaired in obesity-related skeletal muscle insulin resistance. Evidence shows that overweight, obese individuals and type 2 diabetics have impaired insulin-mediated blood flow (Clerk et al., 2006; Reynolds et al., 2022). Evidence from animal studies fed high calorie or high fat diets show that increased FFAs and lipid deposits contribute to a decrease in microvascular blood flow (MBF) (Kubota et al., 2011). Healthy women and men (14 people) consuming a high fat high calorie diet for seven days had elevated insulin and reduced meal-induced muscle skeletal muscle microvascular blood flow after the meal (Brayner et al. 2024).
A human lipid infusion study (22 young, healthy women and men) demonstrated that after 3 hours of infusion plus a mixed meal challenge, FFA levels were raised by 18-fold, blocked microvascular blood flow, and increased plasma glucose levels (Liu et al., 2009).
Another study of lean young men (20 people, 18-30 years old) consuming a high calorie diet (60% increase in calories, 25% from fat) showed an impairment of SM MBF and an increase in AT MBF indicating that nutrients were being redirected towards storage while protecting SM from IR (Emanuel et al., 2020).
People who have relatives with type 2 diabetes (T2D) have impaired adipose tissue blood flow after a meal. Impaired adipose tissue blood flow is associated dysfunctional suppression of fat oxidation (Roberts-Thomson et al. 2022).
Fats may be responsible for the impairment of the Akt signaling pathway in endothelial cells that line the blood vessels. A study of healthy individuals given a high calorie diet for 7 days showed a decline in insulin induced eNOS phosphorylation in skeletal muscle arterioles and glucose uptake (Parry et al., 2020).
The researchers suggested that the reduction in eNOS may have reduced NO production and muscle microvascular blood flow thereby impairing glucose disposal. Capillary recruitment is critical for insulin-mediated glucose uptake which is dependent on activation of the endothelial PI3K pathway, phosphorylation of IR, IRS1/2, PDK1 and Akt.
In the initial stages of muscle microvasculature dysfunction, increases in FFAs downregulate the endothelial AMPK-PI3K/Akt-eNOS pathway affecting vasodilation of blood vessels (Mallick and Duttaroy 2022). These impairments contribute to vascular insulin resistance in skeletal muscle (Samuel & Shulman, 2016; Jiang et al., 1999).
Studies show that the accumulation of TGs in the muscle fibers are muscle and fiber specific, so some fibers accumulate fat more than others. Under obesogenic conditions, increases in circulating FFAs affect endothelial dysfunction in several ways via reduction of phosphorylation of the insulin receptor substrate 1/2 and eNOS, impaired ATP-induced mobilization and influx of Ca 2+ in endothelial cells, and increased reactive oxygen species (ROS) production by PKC activated NADPH oxidase (Dresner et al., 1999; Inoguchi et al., 2000; Romero-García et al., 2025). The decrease in the expression of IRS1/2, decreased phosphorylation of Akt and eNOS are the primary factors in vascular insulin resistance in skeletal muscle.
The adipocytokine, TNF-α induces vascular insulin resistance by reducing IRS-1 phosphorylation and decreasing NO release via effects on the Pi3K/AKT/eNOS pathway (Kanety et al., 1995). Previous studies in obese mice showed that blocking TNF-α lead to increased vascular insulin sensitivity (Liang et al., 2008).
Other researchers took a step further and looked at phosphatase and tensin homologue (PTEN), a regulator of insulin and AKT signaling that is closely associated with TNF-α. PTEN is a lipid phosphatase that converts the PIP3 (AKT substrate) to PIP2 (Umek et al., 2019). Studies show that inhibition of PTEN in mice myoblast cell line and skeletal muscle tissue protects against SM insulin resistance, but would PTEN inhibition protect against vascular insulin resistance (Lee et al., 2013; Wijesekara et la., 2005). Researchers assessed this hypothesis using mice fed a high fat diet and looked at the effects of TNF-α deletion and PTEN inhibition on mesenteric arteries. Obese mice with the TNF deletion were protected from high fat diet induced insulin resistance and glucose intolerance not seen in the control mice. When obese mice were treated with a PTEN inhibitor, the mice did not develop vascular IR in their mesenteric arteries. Further when vessels were treated with a combination of TNF-α and PTEN inhibitors, the effects of TNF-α on insulin vasodilation were reversed. This study showed that PTEN regulates the effects of TNF-α on nitric oxide bioavailability in mesenteric arteries (de Costa et al.,2016).
TNF-α is elevated in obese and insulin resistance subjects. In excess amounts TNF-α causes chronic inflammation, leads to development of certain autoimmune diseases, and alters lipid metabolism by inhibiting lipoprotein lipase resulting in decreases in lipogenesis and FFA uptake and increases lipolysis from the adipose tissue (Kim and Bajaj 2014; Jang et al. 2021).
Lastly, obesity alters the SM endothelium by decreasing endothelial NO production and insulin-stimulated vasomotion. In IR, reduced capillary density leads to impaired insulin mediated capillary recruitment, capillary blood flow and microvasculature dilatation (DeJongh et al., 2004). Increased white blood cell adhesion, oxidative stress and increased TNF-α levels characterized the early phase of this deterioration. Nitric oxide bioavailability is impaired in the late stage. In obesity the ultrastructural changes in the capillary epithelium result in impairment of trans-endothelial insulin transport (Williams et al., 2020).
Boettcher M, Machann J, Stefan N, Thamer C, Häring HU, Claussen CD, Fritsche A, Schick F. Intermuscular adipose tissue (IMAT): association with other adipose tissue compartments and insulin sensitivity. J Magn Reson Imaging. 2009 Jun;29(6):1340-5. doi: 10.1002/jmri.21754. Full paper.
Brayner B, Keske MA, Roberts-Thomson KM, Parker L, Betik AC, Thomas HJ, Mason S, Way KL, Livingstone KM, Hamilton DL, Kaur G. Short-term high-calorie high-fat feeding induces hyperinsulinemia and blunts skeletal muscle microvascular blood flow in healthy humans. Am J Physiol Endocrinol Metab. 2024 Jul 1;327(1):E42-E54. doi: 10.1152/ajpendo.00070.2024. Full paper.
Clerk LH, Vincent MA, Jahn LA, Liu Z, Lindner JR, Barrett EJ. Obesity blunts insulin-mediated microvascular recruitment in human forearm muscle. Diabetes. 2006 May;55(5):1436-42. doi: 10.2337/db05-1373. Abstract.
da Costa RM, Neves KB, Mestriner FL, Louzada-Junior P, Bruder-Nascimento T, Tostes RC. TNF-α induces vascular insulin resistance via positive modulation of PTEN and decreased Akt/eNOS/NO signaling in high fat diet-fed mice. Cardiovasc Diabetol. 2016 Aug 25;15(1):119. doi: 10.1186/s12933-016-0443-0. Full paper.
de Jongh RT, Serné EH, IJzerman RG, de Vries G, Stehouwer CD. Impaired microvascular function in obesity: implications for obesity-associated microangiopathy, hypertension, and insulin resistance. Circulation. 2004 Jun 1;109(21):2529-35. doi: 10.1161/01.CIR.0000129772.26647.6F. Full paper.
Dresner A, Laurent D, Marcucci M, Griffin ME, Dufour S, Cline GW, Slezak LA, Andersen DK, Hundal RS, Rothman DL, Petersen KF, Shulman GI. Effects of free fatty acids on glucose transport and IRS-1-associated phosphatidylinositol 3-kinase activity. J Clin Invest. 1999 Jan;103(2):253-9. doi: 10.1172/JCI5001. Full paper.
Emanuel AL, Meijer RI, Woerdeman J, van Raalte DH, Diamant M, Kramer MHH, Serlie MJ, Eringa EC, Serné EH. Effects of a Hypercaloric and Hypocaloric Diet on Insulin-Induced Microvascular Recruitment, Glucose Uptake, and Lipolysis in Healthy Lean Men. Arterioscler Thromb Vasc Biol. 2020 Jul;40(7):1695-1704. doi: 10.1161/ATVBAHA.120.314129. Full paper.
Gaster M, Staehr P, Beck-Nielsen H, Schrøder HD, Handberg A. GLUT4 is reduced in slow muscle fibers of type 2 diabetic patients: is insulin resistance in type 2 diabetes a slow, type 1 fiber disease? Diabetes. 2001 Jun;50(6):1324-9. doi: 10.2337/diabetes.50.6.1324. Full paper.
Garvey WT, Maianu L, Zhu JH, Brechtel-Hook G, Wallace P, Baron AD. Evidence for defects in the trafficking and translocation of GLUT4 glucose transporters in skeletal muscle as a cause of human insulin resistance. J Clin Invest. 1998 Jun 1;101(11):2377-86. doi: 10.1172/JCI1557. Full paper.
Goodpaster BH, Kelley DE, Thaete FL, He J, Ross R. Skeletal muscle attenuation determined by computed tomography is associated with skeletal muscle lipid content. J Appl Physiol (1985). 2000 Jul;89(1):104-10. doi: 10.1152/jappl.2000.89.1.104. Full paper.
Hotamisligil GS. Inflammation and endoplasmic reticulum stress in obesity and diabetes. Int J Obes (Lond). 2008 Dec;32 Suppl 7(Suppl 7):S52-4. doi: 10.1038/ijo.2008.238. Full paper.
Hotamisligil GS, Shargill NS, Spiegelman BM. Adipose expression of tumor necrosis factor-alpha: direct role in obesity-linked insulin resistance. Science. 1993 Jan 1;259(5091):87-91. doi: 10.1126/science.7678183. Abstract.
Inoguchi T, Li P, Umeda F, Yu HY, Kakimoto M, Imamura M, Aoki T, Etoh T, Hashimoto T, Naruse M, Sano H, Utsumi H, Nawata H. High glucose level and free fatty acid stimulate reactive oxygen species production through protein kinase C--dependent activation of NAD(P)H oxidase in cultured vascular cells. Diabetes. 2000 Nov;49(11):1939-45. doi: 10.2337/diabetes.49.11.1939. Full paper.
Jang DI, Lee AH, Shin HY, Song HR, Park JH, Kang TB, Lee SR, Yang SH. The Role of Tumor Necrosis Factor Alpha (TNF-α) in Autoimmune Disease and Current TNF-α Inhibitors in Therapeutics. Int J Mol Sci. 2021 Mar 8;22(5):2719. doi: 10.3390/ijms22052719. Full paper.
Jiang ZY, Lin YW, Clemont A, Feener EP, Hein KD, Igarashi M, Yamauchi T, White MF, King GL. Characterization of selective resistance to insulin signaling in the vasculature of obese Zucker (fa/fa) rats. J Clin Invest. 1999 Aug;104(4):447-57. doi: 10.1172/JCI5971. Full paper.
Kanety H, Feinstein R, Papa MZ, Hemi R, Karasik A. Tumor necrosis factor alpha-induced phosphorylation of insulin receptor substrate-1 (IRS-1). Possible mechanism for suppression of insulin-stimulated tyrosine phosphorylation of IRS-1. J Biol Chem. 1995 Oct 6;270(40):23780-4. doi: 10.1074/jbc.270.40.23780. Full paper.
Kim JK, Kim YJ, Fillmore JJ, Chen Y, Moore I, Lee J, Yuan M, Li ZW, Karin M, Perret P, Shoelson SE, Shulman GI. Prevention of fat-induced insulin resistance by salicylate. J Clin Invest. 2001 Aug;108(3):437-46. doi: 10.1172/JCI11559. Full paper.
Kim and Bajaj. Normal Adipose "Tissue Biology: Adipocytokines and Inflammation" in Pathobiology of Human Disease 2014 ed. McManus and Mitchell, Academic Press.
Kim JA, Montagnani M, Koh KK, Quon MJ. Reciprocal relationships between insulin resistance and endothelial dysfunction: molecular and pathophysiological mechanisms. Circulation. 2006 Apr 18;113(15):1888-904. doi: 10.1161/CIRCULATIONAHA.105.563213. Full paper.
Kubota T, Kubota N, Kumagai H, Yamaguchi S, Kozono H, Takahashi T, Inoue M, Itoh S, Takamoto I, Sasako T, Kumagai K, Kawai T, Hashimoto S, Kobayashi T, Sato M, Tokuyama K, Nishimura S, Tsunoda M, Ide T, Murakami K, Yamazaki T, Ezaki O, Kawamura K, Masuda H, Moroi M, Sugi K, Oike Y, Shimokawa H, Yanagihara N, Tsutsui M, Terauchi Y, Tobe K, Nagai R, Kamata K, Inoue K, Kodama T, Ueki K, Kadowaki T. Impaired insulin signaling in endothelial cells reduces insulin-induced glucose uptake by skeletal muscle. Cell Metab. 2011 Mar 2;13(3):294-307. doi: 10.1016/j.cmet.2011.01.018. Full paper.
Liang H, Yin B, Zhang H, Zhang S, Zeng Q, Wang J, Jiang X, Yuan L, Wang CY, Li Z. Blockade of tumor necrosis factor (TNF) receptor type 1-mediated TNF-alpha signaling protected Wistar rats from diet-induced obesity and insulin resistance. Endocrinology. 2008 Jun;149(6):2943-51. doi: 10.1210/en.2007-0978. Abstract.
Lee H, Jee Y, Hong K, Hwang GS, Chun KH. MicroRNA-494, upregulated by tumor necrosis factor-α, desensitizes insulin effect in C2C12 muscle cells. PLoS One. 2013 Dec 11;8(12):e83471. doi: 10.1371/journal.pone.0083471. Full paper.
Liu Z, Liu J, Jahn LA, Fowler DE, Barrett EJ. Infusing lipid raises plasma free fatty acids and induces insulin resistance in muscle microvasculature. J Clin Endocrinol Metab. 2009 Sep;94(9):3543-9. doi: 10.1210/jc.2009-0027. Full paper.
Oberbach A, Bossenz Y, Lehmann S, Niebauer J, Adams V, Paschke R, Schön MR, Blüher M, Punkt K. Altered fiber distribution and fiber-specific glycolytic and oxidative enzyme activity in skeletal muscle of patients with type 2 diabetes. Diabetes Care. 2006 Apr;29(4):895-900. doi: 10.2337/diacare.29.04.06.dc05-1854. Full paper.
Parry SA, Turner MC, Woods RM, James LJ, Ferguson RA, Cocks M, Whytock KL, Strauss JA, Shepherd SO, Wagenmakers AJM, van Hall G, Hulston CJ. High-Fat Overfeeding Impairs Peripheral Glucose Metabolism and Muscle Microvascular eNOS Ser1177 Phosphorylation. J Clin Endocrinol Metab. 2020 Jan 1;105(1):dgz018. doi: 10.1210/clinem/dgz018. Full paper.
Paz K, Hemi R, LeRoith D, Karasik A, Elhanany E, Kanety H, Zick Y. A molecular basis for insulin resistance. Elevated serine/threonine phosphorylation of IRS-1 and IRS-2 inhibits their binding to the juxtamembrane region of the insulin receptor and impairs their ability to undergo insulin-induced tyrosine phosphorylation. J Biol Chem. 1997 Nov 21;272(47):29911-8. doi: 10.1074/jbc.272.47.29911. Full paper.
Radin MS, Sinha S, Bhatt BA, Dedousis N, O'Doherty RM. Inhibition or deletion of the lipopolysaccharide receptor Toll-like receptor-4 confers partial protection against lipid-induced insulin resistance in rodent skeletal muscle. Diabetologia. 2008 Feb;51(2):336-46. doi: 10.1007/s00125-007-0861-3. Full paper.
Mallick R, Duttaroy AK. Modulation of endothelium function by fatty acids. Mol Cell Biochem. 2022 Jan;477(1):15-38. doi: 10.1007/s11010-021-04260-9. Full paper.
Reynolds LJ, Credeur DP, Manrique C, Padilla J, Fadel PJ, Thyfault JP. Obesity, type 2 diabetes, and impaired insulin-stimulated blood flow: role of skeletal muscle NO synthase and endothelin-1. J Appl Physiol (1985). 2017 Jan 1;122(1):38-47. doi: 10.1152/japplphysiol.00286.2016. Full paper.
Roberts-Thomson KM, Hu D, Russell RD, Greenaway T, Betik AC, Parker L, Kaur G, Richards SM, Premilovac D, Wadley GD, Keske MA. Impaired postprandial adipose tissue microvascular blood flow responses to a mixed-nutrient meal in first-degree relatives of adults with type 2 diabetes. Am J Physiol Endocrinol Metab. 2022 Nov 1;323(5):E418-E427. doi: 10.1152/ajpendo.00109.2022. Full paper.
Romero-García T, Vázquez-Jiménez JG, Sánchez-Hernández R, Olivares-Reyes JA, Rueda A. Insulin resistance, Ca2+ signaling alterations and vascular dysfunction in prediabetes and metabolic syndrome. Front Physiol. 2025 Jun 10;16:1535153. doi: 10.3389/fphys.2025.1535153. Full paper.
Sachs S, Zarini S, Kahn DE, Harrison KA, Perreault L, Phang T, Newsom SA, Strauss A, Kerege A, Schoen JA, Bessesen DH, Schwarzmayr T, Graf E, Lutter D, Krumsiek J, Hofmann SM, Bergman BC. Intermuscular adipose tissue directly modulates skeletal muscle insulin sensitivity in humans. Am J Physiol Endocrinol Metab. 2019 May 1;316(5):E866-E879. doi: 10.1152/ajpendo.00243.2018. Full paper.
Samuel VT, Shulman GI. Mechanisms for insulin resistance: common threads and missing links. Cell. 2012 Mar 2;148(5):852-71. doi: 10.1016/j.cell.2012.02.017. Full paper.
Samuel VT, Shulman GI. The pathogenesis of insulin resistance: integrating signaling pathways and substrate flux. J Clin Invest. 2016 Jan;126(1):12-22. doi: 10.1172/JCI77812. Full paper.
Shi J, Yang Z, Niu Y, Zhang W, Lin N, Li X, Zhang H, Gu H, Wen J, Ning G, Qin L, Su Q. Large thigh circumference is associated with lower blood pressure in overweight and obese individuals: a community-based study. Endocr Connect. 2020 Apr;9(4):271-278. doi: 10.1530/EC-19-0539. Full paper.
Stuart CA, McCurry MP, Marino A, South MA, Howell ME, Layne AS, Ramsey MW, Stone MH. Slow-twitch fiber proportion in skeletal muscle correlates with insulin responsiveness. J Clin Endocrinol Metab. 2013 May;98(5):2027-36. doi: 10.1210/jc.2012-3876. Full paper.
Wijesekara N, Konrad D, Eweida M, Jefferies C, Liadis N, Giacca A, Crackower M, Suzuki A, Mak TW, Kahn CR, Klip A, Woo M. Muscle-specific Pten deletion protects against insulin resistance and diabetes. Mol Cell Biol. 2005 Feb;25(3):1135-45. doi: 10.1128/MCB.25.3.1135-1145.2005. Full paper.
Williams IM, McClatchey PM, Bracy DP, Bonner JS, Valenzuela FA, Wasserman DH. Transendothelial Insulin Transport is Impaired in Skeletal Muscle Capillaries of Obese Male Mice. Obesity (Silver Spring). 2020 Feb;28(2):303-314. doi: 10.1002/oby.22683. Full paper.
Wu H, Ballantyne CM. Metabolic Inflammation and Insulin Resistance in Obesity. Circ Res. 2020 May 22;126(11):1549-1564. doi: 10.1161/CIRCRESAHA.119.315896. Full paper.
Wu H, Ballantyne CM. Skeletal muscle inflammation and insulin resistance in obesity. J Clin Invest. 2017 Jan 3;127(1):43-54. doi: 10.1172/JCI88880. Full paper.
Ugwoke CK, Cvetko E, Umek N. Skeletal Muscle Microvascular Dysfunction in Obesity-Related Insulin Resistance: Pathophysiological Mechanisms and Therapeutic Perspectives. Int J Mol Sci. 2022 Jan 13;23(2):847. doi: 10.3390/ijms23020847. Full paper.
Umek N, Horvat S, Cvetko E, Kreft M, Janáček J, Kubínová L, Stopar Pintarič T, Eržen I. 3D analysis of capillary network in skeletal muscle of obese insulin-resistant mice. Histochem Cell Biol. 2019 Nov;152(5):323-331. doi: 10.1007/s00418-019-01810-7. Abstract.
Zhande R, Mitchell JJ, Wu J, Sun XJ. Molecular mechanism of insulin-induced degradation of insulin receptor substrate 1. Mol Cell Biol. 2002 Feb;22(4):1016-26. doi: 10.1128/MCB.22.4.1016-1026.2002. Full paper.
Zoico E, Rossi A, Di Francesco V, Sepe A, Olioso D, Pizzini F, Fantin F, Bosello O, Cominacini L, Harris TB, Zamboni M. Adipose tissue infiltration in skeletal muscle of healthy elderly men: relationships with body composition, insulin resistance, and inflammation at the systemic and tissue level. J Gerontol A Biol Sci Med Sci. 2010 Mar;65(3):295-9. doi: 10.1093/gerona/glp155. Full paper.