Lipid-associated metabolic signalling networks in pancreatic beta cell function

Abstract

Significant advances have been made in deciphering the mechanisms underlying fuel-stimulated insulin secretion by pancreatic beta cells. The contribution of the triggering/ATP-sensitive potassium (K ATP)-dependent Ca 2+ signalling and K ATP-independent amplification pathways, that include anaplerosis and lipid signalling of glucose-stimulated insulin secretion (GSIS), are well established. A proposed model included a key role for a metabolic partitioning 'switch', the acetyl-CoA carboxylase (ACC)/malonyl-CoA/carnitine palmitoyltransferase-1 (CPT-1) axis, in beta cell glucose and fatty acid signalling for insulin secretion. This model has gained overwhelming support from a number of studies in recent years and is now refined through its link to the glycerolipid/NEFA cycle that provides lipid signals through its lipolysis arm. Furthermore, acetyl-CoA carboxylase may also control beta cell growth. Here we review the evidence supporting a role for the ACC/malonyl-CoA/CPT-1 axis in the control of GSIS and its particular importance under conditions of elevated fatty acids (e.g. fasting, excess nutrients, hyperlipidaemia and diabetes). We also document how it is linked to a more global lipid signalling system that includes the glycerolipid/NEFA cycle.

New insights into carnitine‐acylcarnitine translocase deficiency from 23 cases: Management challenges and potential therapeutic approaches

“…25 This leads to hepatic steatosis that is further exacerbated if chronically excessive carbohydrate or medium chain triglyceride is given. 26,27 10/14 severe patients surviving infancy had evidence of steatohepatitis, 2/14 with gallstones and 1/14 developed liver fibrosis by 10 years of age. The hyperammonaemia in this patient (case 8) appeared less responsive to acute carbohydrate administration, possibly related to the reduction in GS expression in patients with liver cirrhosis.…”

β-cell SENP1 facilitates responsiveness to incretins and limits oral glucose intolerance in high fat fed mice

“…In these mice we see impaired in vivo insulin responses to glucose, but this may be compensated for in part by an increased fasting insulin (Suppl Fig 1) thus limiting glucose intolerance in the absence of metabolic stress. We should also recognize that other pathways facilitating insulin secretion could compensate for the loss of SENP1 in vivo, for example lipid-mediated signaling 32,33 , which may be minimized in in vitro experiments performed in minimal buffers without fatty acid. Nonetheless, high fat feeding revealed the importance SENP1-dependent insulin secretion in the maintenance of glucose homeostasis.…”

Neonatal Hypoglycemia Related to Glycine Levels in Uncontrolled Gestational Diabetes Mellitus during Mid-Late Pregnancy: Multicenter, Prospective Case-Cohort Observational Study

“…GDM is strongly correlated with fetal growth [37], but neonatal hypoglycemia was negative with different fetal carnitine levels in our study. Most studies reported that carnitine was associated with the development and progress of diabetes mellitus for multiperspectives such as microbiota [38] and lipid [39].…”