Type 2 diabetes is often associated with obesity and occurs as a consequence of a combined impairment in insulin secretion and insulin action. This results in loss of metabolic control, leading to increased concentrations of glucose and lipids in the circulation.
The decrease in insulin action — known as insulin resistance — is caused by several factors, including direct deleterious effects of excess lipids and other metabolic fuels on organs and tissues, enhanced inflammatory signalling, and activation of endoplasmic reticulum (ER) stress pathways.
Different tissues respond to excess metabolic fuels in different ways. Thus, excess glucose and lipid supplies in the liver favour the partitioning of lipids away from oxidative pathways in the mitochondria and into esterification pathways to produce lipids with signalling properties that can activate Ser kinases, which then phosphorylate and inactivate key insulin signalling molecules.
In muscle, excess lipids enhance fatty acid oxidation but do not coordinately induce the downstream tricarboxylic acid cycle. This leads to the accumulation of incompletely metabolized lipids in the mitochondria that can impair insulin signalling.
Glucose-stimulated insulin secretion from the β-cells of the pancreatic islets involves both triggering and amplifying signals. The triggering signal involves glucose-stimulated generation of ATP, inhibition of ATP-sensitive K+ channels and influx of Ca2+, whereas new evidence suggests that the amplifying signal is derived from anaplerotic pyruvate cycling pathways that include mitochondrial and cytosolic components.
β-cell failure of type 2 diabetes has a metabolic component, wherein exposure to excess lipids abrogates the normal glucose-induced increase in pyruvate cycling.
Overnutrition causes a demand for high rates of insulin secretion, ultimately leading to ER stress in β-cells that results in loss of β-cell mass. Amylin, another product of pancreatic islets, is hypersecreted under these conditions and accumulates as amyloid plaques, leading to β-cell damage and death. Metabolic stress, ER stress and amyloid-mediated cytotoxicity represent a 'perfect storm' that leads to β-cell failure, heralding the onset of full-blown type 2 diabetes.
Given the multiple organs that are affected by these diverse mechanisms, it is not surprising that there is currently no single drug that delivers fully efficacious and long-lasting therapy for type 2 diabetes. Future work must focus on battling the root causes of this disease, including excessive food intake, energy imbalance and inflammatory responses.
Nearly unlimited supplies of energy-dense foods and technologies that encourage sedentary behaviour have introduced a new threat to the survival of our species: obesity and its co-morbidities. Foremost among the co-morbidities is type 2 diabetes, which is projected to afflict 300 million people worldwide by 2020. Compliance with lifestyle modifications such as reduced caloric intake and increased physical activity has proved to be difficult for the general population, meaning that pharmacological intervention may be the only recourse for some. This epidemiological reality heightens the urgency for gaining a deeper understanding of the processes that cause metabolic failure of key tissues and organ systems in type 2 diabetes, as reviewed here.
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An abnormal elevation in blood glucose levels. The American Diabetes Association currently considers a fasting blood glucose of >126 mg ml−1 as the cut-off for diabetes.
A peptide hormone or cytokine that is produced and secreted by adipocytes, which regulate fuel use and storage in other peripheral tissues.
Abnormal or continuous food ingestion.
An abnormal elevation of circulating lipids, including triglycerides, free fatty acids and low-density lipoproteins, often accompanied by a decrease in high-density lipoprotein.
An abnormally low blood glucose level. Humans with blood glucose levels below 50 mg ml−1 are considered to be hypoglycaemic and manifest symptoms that are related to an inadequate delivery rate of glucose to the brain.
- Hepatic steatosis
The accumulation of stored lipids, most notably triglycerides, to abnormally high levels in the liver.
Division of fibres of the vagus nerve by surgery, a technique that is used to diminish acid secretion of the stomach.
One of a family of carnitine esters that are derived from acetyl CoA and acyl CoA intermediates of fatty acid and amino acid catabolism.
- Unfolded protein response
A transcriptional program that functions to slow protein synthesis and promote protein degradation in response to the accumulation of unfolded or misfolded proteins in the endoplasmic reticulum.
Repletion of the tricarboxylic acid cycle with intermediates that can condense with acetyl CoA to form citrate.
- Pyruvate cycling
The exchange of pyruvate with intermediates from the tricarboxylic acid cycle.
- Insulinoma cell line
A cell line that is derived from rodent pancreatic islet β-cells that are transformed by oncogene expression or another means of transformation.
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Muoio, D., Newgard, C. Molecular and metabolic mechanisms of insulin resistance and β-cell failure in type 2 diabetes. Nat Rev Mol Cell Biol 9, 193–205 (2008). https://doi.org/10.1038/nrm2327
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