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The aetiology and molecular landscape of insulin resistance

Abstract

Insulin resistance, defined as a defect in insulin-mediated control of glucose metabolism in tissues — prominently in muscle, fat and liver — is one of the earliest manifestations of a constellation of human diseases that includes type 2 diabetes and cardiovascular disease. These diseases are typically associated with intertwined metabolic abnormalities, including obesity, hyperinsulinaemia, hyperglycaemia and hyperlipidaemia. Insulin resistance is caused by a combination of genetic and environmental factors. Recent genetic and biochemical studies suggest a key role for adipose tissue in the development of insulin resistance, potentially by releasing lipids and other circulating factors that promote insulin resistance in other organs. These extracellular factors perturb the intracellular concentration of a range of intermediates, including ceramide and other lipids, leading to defects in responsiveness of cells to insulin. Such intermediates may cause insulin resistance by inhibiting one or more of the proximal components in the signalling cascade downstream of insulin (insulin receptor, insulin receptor substrate (IRS) proteins or AKT). However, there is now evidence to support the view that insulin resistance is a heterogeneous disorder that may variably arise in a range of metabolic tissues and that the mechanism for this effect likely involves a unified insulin resistance pathway that affects a distal step in the insulin action pathway that is more closely linked to the terminal biological response. Identifying these targets is of major importance, as it will reveal potential new targets for treatments of diseases associated with insulin resistance.

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Fig. 1: Tissue-specific regulation of metabolism during fasting, feeding and insulin resistance.
Fig. 2: Progression from insulin resistance to type 2 diabetes.
Fig. 3: Dose–response characteristics of insulin action.
Fig. 4: Putative factors that contribute to insulin resistance.
Fig. 5: Putative intracellular drivers of insulin resistance.

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Acknowledgements

D.E.J. is an Australian Research Council Laureate Fellow. The authors are extremely grateful to S. Klein for his thoughtful discussion of the manuscript and to P. Titchenell, G. Cooney, A. Diaz and M. Nelson for carefully reading and commenting on the manuscript.

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The authors contributed equally to all aspects of the article.

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Correspondence to David E. James or Morris J. Birnbaum.

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D.E.J. and J.S. declare no competing interests. M.J.B. is a full-time employee and stockholder of Pfizer Inc. and sits on the Board of Directors of Cerevel Therapeutics.

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Nature Reviews Molecular Cell Biology thanks M. Czech, B. Goodpaster, T. Kadowaki, D. Neufer and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.

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Supplementary information

Glossary

Hepatic glucose output

Refers to the release of glucose from the liver into the bloodstream that is upregulated during fasting and suppressed with insulin. It is mediated via the breakdown of liver glycogen (glycogenolysis) or recycling of breakdown products such as lactate from peripheral tissues (gluconeogenesis).

Impaired fasting glucose

According to the American Diabetes Association, this is defined as fasting plasma glucose levels between 100 and 125 mg dl−1 (between 5.6 and 6.9 mmol l−1).

Impaired glucose tolerance

According to the American Diabetes Association, this is defined as 2-h plasma glucose levels between 140 and 199 mg dl−1 (between 7.8 and 11.0 mmol l−1) measured during a 75-g oral glucose tolerance test.

Relative hyperinsulinaemia

The situation where individuals with type 2 diabetes despite having insufficient insulin secretion to normalize their hyperglycaemia still display significantly higher circulating insulin levels than those observed in healthy people.

Gluconeogenesis

A metabolic pathway that is particularly important in liver metabolism in which glucose is regenerated essentially via reverse glycolysis from a range of substrates, such as lactate, amino acids, glycerol or acetate.

Metabolic diseases

Diseases that exhibit dysregulated metabolism of carbohydrates and lipids. Metabolic diseases include type 2 diabetes, cardiovascular disease and liver disease.

14-3-3 proteins

A ubiquitously expressed family of proteins comprising seven members in mammals that bind to Ser/Thr phosphorylation motifs and are thought to be one of the major conduits by which kinases such as AKT regulate the function of substrates.

Retromer

A heteropentameric complex of proteins originally discovered in yeast to regulate protein trafficking between endosomes and the trans-Golgi network

Fat depots

Distinct fat depots are named after their location. Subcutaneous fat is the layer of fat found just beneath the skin, whereas visceral or abdominal fat is located in the peritoneal cavity. Subcutaneous fat serves as an energy store, a protective layer of tissue and a potential source of heat for thermoregulation. Visceral fat plays a more important role in releasing fat into the circulation for use by other tissues.

Lipodystrophy

A condition whereby individuals are unable to produce adipose tissue leading to excessive deposition of fat ectopically. The two common forms are congenital, caused by mutations in genes that regulate adipogenesis, or acquired. The most common form of acquired lipodystrophy is caused by older generations of antiretroviral drugs used to treat HIV. Both forms are associated with insulin resistance and other metabolic disorders.

Insulinomas

Small pancreatic tumours that produce and secrete excess insulin into the circulation. This is a rare endocrine disorder that is treated surgically.

Western diet

A diet that generally contains a high content (40–60%) of fat and is rich in simple sugars (sucrose).

C57BL/6J mice

Inbred mouse strain that is the preferred mouse model used in metabolic research to study the effects of a Western diet and for genetic manipulations.

Metabolic flux

The rate at which metabolites are metabolized by intracellular pathways. The metabolic flux is modulated by changing the levels or activity of metabolic enzymes, or by altering the supply or demand of the metabolite.

TBC1D4

A RAB GTPase-activating protein that regulates the GTPase RAB10 and several other RABs. It is phosphorylated by AKT and is integral to insulin regulation of glucose transport in muscle and fat.

Novel PKCs

A subclass of protein kinase C (PKC), a family of Ser/Thr kinases that are activated by diacylglycerols (DAGs) without the need for Ca2+.

JNK

JUN N-terminal kinase is a Ser/Thr kinase that belongs to the family of mitogen-activated protein kinases (MAPKs), which respond to stress stimuli, including cytokines.

mTOR

A Ser/Thr kinase that plays a major role in nutrient sensing in all eukaryotes.

S6 kinase

A Ser/Thr kinase named after its best-known substrate, the ribosomal protein S6. S6 kinase is activated by mTOR, and phosphorylation of its substrate S6 induces protein synthesis.

PDGF receptor

(PDGFR). A receptor that, like the insulin receptor, belongs to the receptor tyrosine kinase family of cell surface receptors. PDGF binding to PDGFR triggers a signal transduction pathway analogous to insulin, involving PI3K and AKT. Importantly, PDGF signalling bypasses IRS and thus provides a tool to test the role of IRS in insulin resistance.

Carbonylation

A protein oxidation reaction that is commonly found on the amino acids lysine and arginine, among other amino acids.

Lipid peroxidation

A process whereby oxidants attack (unsaturated) lipids and via multiple reactions this results in the formation of toxic and/or mutagenic lipid hydroperoxides. The lipid peroxidation process is a chain reaction that propagates until it is terminated by antioxidants.

Adipokine

A molecule, such as a protein, a lipid, a metabolite or a microRNA, that is secreted from adipose tissue to potentially regulate functions in other tissues. It is notable that most adipokines are not produced by adipocytes but derive from stromal cells in the adipose tissue.

Beige adipocytes

A subtype of thermogenic adipocytes that arises in white adipose tissue, most commonly in subcutaneous fat, in response to various stimuli, such as cold exposure, catecholamines, exercise, thiazolidinediones and injury. They are capable of uncoupled mitochondrial respiration via the activity of uncoupling proteins such as UCP1 to produce heat at the expense of ATP, and their emergence has been associated with improved metabolic health.

Leptin

The first adipokine to be discovered, by Friedman and colleagues in 1994. The obese (ob) gene long known to regulate appetite in rodents was found to encode leptin and was subsequently shown to play a key role in metabolic homeostasis and the starvation response in mammals.

Regulatory T cells

A subpopulation of T cells that are involved in immune function.

C-reactive protein

(CRP). A protein secreted primarily by the liver in response to inflammatory cytokines. In the clinic, circulating levels of CRP are a measure of inflammation or infection.

Genome-wide association studies

A statistical method that identifies genetic variants that are associated with a particular trait, disease or phenotype.

Prediabetes

The clinical term to describe individuals who exhibit ‘impaired glucose tolerance’ but do not fulfil the requirements for type 2 diabetes classification.

Ceramides

A class of lipids composed of sphingosine and a fatty acid. Distinct ceramide species contain different fatty acids with various carbon chain lengths, and the ceramides are distinguished and named after the carbon length of the fatty acid.

AMPK

Adenosine 5′-monophosphate (AMP)-activated kinase. AMPK is activated in most cells in response to cellular and/or metabolic stress to buffer cellular energy charge.

Diacylglycerols

(DAGs). Two fatty acid moieties linked to glycerol. DAGs were first identified through their role in binding and activating various members of the protein kinase C (PKC) family.

Oxidative phosphorylation

(OXPHOS). The most notorious function of mitochondria, which is to oxidize various nutrients such as fat and carbohydrate via a series of complex chemical reactions to create the basic energy unit ATP.

Mitophagy

The engulfment of mitochondria by an autophagosome, undergoing autophagy. Dysfunctional mitochondria are targeted for mitophagy for removal and degradation. Mitochondrial fission is necessary for mitophagy.

Mitochondrial fission

A process of mitochondrial fragmentation catalysed by regulated fission machinery. Mitochondrial fission plays an essential role in the removal of damaged mitochondria from cells but has also been associated with reduced bioenergetics.

Coenzyme Q

(CoQ). Also known as ubiquinone, this coenzyme plays an essential role in transporting electrons between various components of the electron transport chain and so is essential to mitochondrial energy production. CoQ also serves as an antioxidant.

Acylcarnitines

A form of fatty acid that are conjugated to carnitine to be transported into the mitochondria for oxidative metabolism.

Endoplasmic reticulum stress

Endoplasmic reticulum (ER) stress is a form of stress in which the ability of the ER to fold proteins is exceeded, leading to the initiation of the ER stress response, an ancient signal transduction pathway that initiates a series of events to help clear the ER of misfolded proteins.

Sodium–glucose co-transporter 2

Also known as SGLT2 or SLC5A2, a transmembrane glucose transporter protein that is predominantly responsible for glucose reabsorption in the kidney.

Glucagon-like peptide 1

(GLP1). A small peptide hormone derived from the proglucagon protein that is secreted from enteroendocrine L cells in the intestine. Among its functions is an incretin activity, which promotes insulin secretion from the pancreas.

Mitochondrial permeability transition pore

(mPTP). A multisubunit protein complex that forms a non-specific channel in the inner mitochondrial membrane. The mPTP opens in response to calcium and/or oxidative stress and allows transit of molecules of up to 1,500 Da from inside mitochondria to the cytosol.

Palmitate

The most prevalent saturated fatty acid found in animals. It is obtained either from dietary sources or by biosynthesis from de novo lipogenesis. It contains an aliphatic tail with a chain length of 16 carbons.

Insulin-like growth factor 1

A hormone that is very similar to insulin that plays a central role in early development in mammals and probably other animals. It is produced and secreted by the liver in response to growth hormone.

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James, D.E., Stöckli, J. & Birnbaum, M.J. The aetiology and molecular landscape of insulin resistance. Nat Rev Mol Cell Biol (2021). https://doi.org/10.1038/s41580-021-00390-6

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