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Query: UMLS:C0020473 (hyperlipidemia)
 15,891 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Pancreatic beta cells are specialised endocrine cells that continuously sense the levels of blood sugar and other fuels and, in response, secrete insulin to maintain normal fuel homeostasis. During postprandial periods an elevated level of plasma glucose rapidly stimulates insulin secretion to decrease hepatic glucose output and promote glucose uptake into other tissues, principally muscle and adipose tissues. Beta cell mitochondria play a key role in this process, not only by providing energy in the form of ATP to support insulin secretion, but also by synthesising metabolites (anaplerosis) that can act, both intra- and extramitochondrially, as factors that couple glucose sensing to insulin granule exocytosis. ATP on its own, and possibly modulated by these coupling factors, triggers closure of the ATP-sensitive potassium channel, resulting in membrane depolarisation that increases intracellular calcium to cause insulin secretion. The metabolic imbalance caused by chronic hyperglycaemia and hyperlipidaemia severely affects mitochondrial metabolism, leading to the development of impaired glucose-induced insulin secretion in type 2 diabetes. It appears that the anaplerotic enzyme pyruvate carboxylase participates directly or indirectly in several metabolic pathways which are important for glucose-induced insulin secretion, including: the pyruvate/malate cycle, the pyruvate/citrate cycle, the pyruvate/isocitrate cycle and glutamate-dehydrogenase-catalysed alpha-ketoglutarate production. These four pathways enable 'shuttling' or 'recycling' of these intermediate(s) into and out of mitochondrion, allowing continuous production of intracellular messenger(s). The purpose of this review is to present an account of recent progress in this area of central importance in the realm of diabetes and obesity research.
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PMID:Regulation of insulin secretion: role of mitochondrial signalling. 2022 32

Insulin resistance arises when the nutrient storage pathways evolved to maximize efficient energy utilization are exposed to chronic energy surplus. Ectopic lipid accumulation in liver and skeletal muscle triggers pathways that impair insulin signaling, leading to reduced muscle glucose uptake and decreased hepatic glycogen synthesis. Muscle insulin resistance, due to ectopic lipid, precedes liver insulin resistance and diverts ingested glucose to the liver, resulting in increased hepatic de novo lipogenesis and hyperlipidemia. Subsequent macrophage infiltration into white adipose tissue (WAT) leads to increased lipolysis, which further increases hepatic triglyceride synthesis and hyperlipidemia due to increased fatty acid esterification. Macrophage-induced WAT lipolysis also stimulates hepatic gluconeogenesis, promoting fasting and postprandial hyperglycemia through increased fatty acid delivery to the liver, which results in increased hepatic acetyl-CoA content, a potent activator of pyruvate carboxylase, and increased glycerol conversion to glucose. These substrate-regulated processes are mostly independent of insulin signaling in the liver but are dependent on insulin signaling in WAT, which becomes defective with inflammation. Therapies that decrease ectopic lipid storage and diminish macrophage-induced WAT lipolysis will reverse the root causes of type 2 diabetes.
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PMID:The pathogenesis of insulin resistance: integrating signaling pathways and substrate flux. 2672 29