Cellular mechanisms of insulin resistance
Open accessAbstract
It is estimated that by the year 2020 there will be approximately 250 million people affected by type 2 diabetes mellitus worldwide (1). Although the primary factors causing this disease are unknown, it is clear that insulin resistance plays a major role in its development. Evidence for this comes from (a) the presence of insulin resistance 10–20 years before the onset of the disease (2, 3); (b) cross-sectional studies demonstrating that insulin resistance is a consistent finding in patients with type 2 diabetes (3–6); and (c) prospective studies demonstrating that insulin resistance is the best predictor of whether or not an individual will later become diabetic (2, 3). Here, I focus on some recent advances in our understanding of human insulin resistance that have been made using nuclear magnetic resonance spectroscopy (NMR). This technique takes advantage of the spin properties of the nuclei of certain isotopes, such as 1H, 13C, and 31P, which endow the isotopes with a magnetic component that can be used to measure the concentration of intracellular metabolites noninvasively and to assess biochemical differences between normal and diabetic subjects. Drawing on NMR studies from my laboratory and others, I first consider the control of glucose phosphorylation and transport in regulating muscle responses to insulin. I then turn to the effects of fatty acids on insulin responses, showing that commonly accepted models that attempt to explain the association of insulin resistance and obesity are incompatible with recent findings. Finally, I propose an alternative model that appears to fit these and other available data.
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In type 2 diabetes, hyperinsulinemia is frequently featured because insulin target tissues are unable to perform glucose-lowering responses at normal plasma insulin levels, resulting in increased insulin secretion to compensate.
“In T2D, hyperinsulinemia is frequently featured because insulin target tissues are unable to perform glucose-lowering responses at normal plasma insulin levels, resulting in increased insulin secretion to compensate [8,9].”
From Recent Experimental Studies of Maternal Obesity, Diabetes during Pregnancy and the Developmental Origins of Cardiovascular Disease (2022) · cites this paper as [9]
In “Contributions of muscle glycogen synthesis to whole-body insulin-stimulated glucose metabolism” (page not provided), the paper reports impaired insulin-stimulated glucose metabolism in people with type 2 diabetes. It does not establish that hyperinsulinemia is frequent in type 2 diabetes or that increased insulin secretion compensates for the impairment; its experiments used infused insulin. (LLM, conf=0.86)
Experimental — accuracy not yet measuredIt is likely that a fatty acid-derived intermediate, rather than intramyocellular triglyceride, is responsible for mediating the insulin resistance.
“it is likely that a fatty acid-derived intermediate, rather than intramyocellular triglyceride, is responsible for mediating the insulin resistance (23).”
From Leptin reverses insulin resistance and hepatic steatosis in patients with severe lipodystrophy (2002) · cites this paper as [23]
These data support the hypothesis that a similar mechanism for insulin resistance might occur in patients with severe lipodystrophy and more common forms of insulin resistance associated with obesity and type 2 diabetes.
“These data support the hypothesis that a similar mechanism for insulin resistance might occur in patients with severe lipodystrophy and more common forms of insulin resistance associated with obesity and type 2 diabetes (23).”
From Leptin reverses insulin resistance and hepatic steatosis in patients with severe lipodystrophy (2002) · cites this paper as [23]
In type 2 diabetic subjects, glucose uptake rather than glucose phosphorylation is the rate-limiting barrier for muscle glucose disposal.
“Using stable isotopes and NMR methodology these studies pointed to glucose uptake rather than glucose phosphorylation as the rate-limiting barrier for muscle glucose disposal in type 2 diabetic subjects (Shulman, 2000).”
From Lipid-Induced Mitochondrial Stress and Insulin Action in Muscle (2012) · cites this paper as Shulman, 2000
These lipids activate PKC and phosphorylate the serine of insulin receptor substrate-1 (IRS-1), interfering with PI3K activation and blocking GLUT4 translocation.
“These lipids activate PKC and phosphorylate the serine of insulin receptor substrate-1 (IRS-1), interfering with PI3K activation and blocking GLUT4 translocation [28].”
From Sarcopenic obesity, insulin resistance, and their implications in cardiovascular and metabolic consequences (2020) · cites this paper as [28]
In sarcopenic obesity, the increased lipid metabolites, such as including DAG and ceramides, activate serine/threonine kinases such as PKC, C-Jun NH2-terminal kinase (JNK), and IKK, resulting in the phosphorylation of serine/threonine in the insulin receptor protein and its substrates, resulting in impaired insulin signaling.
“In sarcopenic obesity, the increased lipid metabolites, such as including DAG and ceramides, activate serine/threonine kinases such as PKC, C-Jun NH2-terminal kinase (JNK), and IKK, resulting in the phosphorylation of serine/threonine in the insulin receptor protein and its substrates, resulting in impaired insulin signaling [28,56].”
From Sarcopenic obesity, insulin resistance, and their implications in cardiovascular and metabolic consequences (2020) · cites this paper as [28]
Fatty acid oxidation increases in mitochondria, causing increase in ATP/ADP ratio and decrease in electron transport chain that impairs oxidative phosphorylation, promoting ROS production, inflammation, and ultimately sarcopenia.
“As a consequence, fatty acid oxidation increases in the mitochondria, causing a concomitant increase in the ATP/ADP ratio and decrease in electron transport chain that impairs oxidative phosphorylation, thus promoting ROS production, inflammation, and ultimately sarcopenia (22).”
From Sarcopenic obesity: epidemiology, pathophysiology, cardiovascular disease, mortality, and management (2023) · cites this paper as [22]
Lipids accumulated in muscle can induce reduction of GLUT4 translocation via impairment of insulin signaling, leading to reduction of glucose uptake by skeletal muscle.
“These lipids can induce a reduction of GLUT4 translocation via impairment of insulin signaling, thereby leading to a reduction of glucose uptake by skeletal muscle.”
From Sarcopenic obesity: epidemiology, pathophysiology, cardiovascular disease, mortality, and management (2023) · cites this paper as [22]
Insulin resistance develops with the accumulation of fatty-acid metabolites (namely diacylglycerols) within insulin-responsive tissues.
“Insulin resistance develops with the accumulation of fatty-acid metabolites (namely diacylglycerols) within insulin-responsive tissues.46”
From Lipid-induced insulin resistance: unravelling the mechanism (2010) · cites this paper as [46]
Insulin resistance plays a major role in the pathogenesis of type 2 diabetes mellitus.
“Although it is clear that insulin resistance plays a major role in the pathogenesis of T2DM”
From Increased prevalence of insulin resistance and nonalcoholic fatty liver disease in Asian-Indian men (2006) · cites this paper as [13]
Insulin resistance is strongly associated with increases in hepatic and/or intramyocellular lipid content.
“and that insulin resistance is strongly associated with increases in hepatic (HTG) and ∕ or intramyocellular lipid content”
From Increased prevalence of insulin resistance and nonalcoholic fatty liver disease in Asian-Indian men (2006) · cites this paper as [13]
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Self-citation
- Authors
- Shulman, G. I.
- Affiliations
- Howard Hughes Medical Institute (US)
- Corresponding author
- Shulman, Gerald I.
- ORCID
- Shulman, Gerald I.
- Venue
- Journal of Clinical Investigation
- Published
- 2000-07-15
- Volume
- 106
- Issue
- 2
- Pages
- 171-176
- ISSN
- 0021-9738 (ISSN-L)
- PMC
- PMC314317
- OpenAlex
- W2126317966
- Cited by
- 2,714
- References
- 47
- Citations by year
- 2026: 46 · 2025: 34 · 2024: 54 · 2023: 47 · 2022: 58 · 2021: 56 · 2020: 88 · 2019: 76 · 2018: 95 · 2017: 97 · 2016: 102 · 2015: 110 · 2014: 114 · 2013: 146 · 2012: 164
- FWCI
- 6.04
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Journal of Clinical Investigation (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Howard Hughes Medical Institute
- National Institutes of Health (P30 DK, DK-45735)
- National Institute of Diabetes and Digestive and Kidney Diseases (R01DK049230, R01DK040936, P30DK045735)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Metabolism, Diabetes, and Cancer
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Diabetes, Cardiovascular Risks, and Lipoproteins
- Health Sciences › Medicine › Epidemiology › Adipokines, Inflammation, and Metabolic Diseases
- Keywords
- insulin resistance, type 2 diabetes, glucose phosphorylation, glucose transport, fatty acids, obesity, intracellular metabolites, NMR spectroscopy, insulin signaling
- MeSH terms
- Diabetes Mellitus, Fatty Acids, Glucose, Glycogen, Humans, Insulin, Insulin Resistance, Models, Biological, Muscles
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