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Intracellular calcium leak lowers glucose storage in human muscle, promoting hyperglycemia and diabetes.

ABSTRACT: Most glucose is processed in muscle, for energy or glycogen stores. Malignant Hyperthermia Susceptibility (MHS) exemplifies muscle conditions that increase [Ca2+]cytosol. 42% of MHS patients have hyperglycemia. We show that phosphorylated glycogen phosphorylase (GPa), glycogen synthase (GSa) - respectively activated and inactivated by phosphorylation - and their Ca2+-dependent kinase (PhK), are elevated in microsomal extracts from MHS patients' muscle. Glycogen and glucose transporter GLUT4 are decreased. [Ca2+]cytosol, increased to MHS levels, promoted GP phosphorylation. Imaging at ~100 nm resolution located GPa at sarcoplasmic reticulum (SR) junctional cisternae, and apo-GP at Z disk. MHS muscle therefore has a wide-ranging alteration in glucose metabolism: high [Ca2+]cytosol activates PhK, which inhibits GS, activates GP and moves it toward the SR, favoring glycogenolysis. The alterations probably cause these patients' hyperglycemia. For basic studies, MHS emerges as a variable stressor, which forces glucose pathways from the normal to the diseased range, thereby exposing novel metabolic links.

SUBMITTER: Tammineni ER

PROVIDER: S-EPMC7282812 | biostudies-literature | 2020 May

REPOSITORIES: biostudies-literature

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Intracellular calcium leak lowers glucose storage in human muscle, promoting hyperglycemia and diabetes.

Tammineni Eshwar R ER Kraeva Natalia N Figueroa Lourdes L Manno Carlo C Ibarra Carlos A CA Klip Amira A Riazi Sheila S Rios Eduardo E

eLife 20200504

Most glucose is processed in muscle, for energy or glycogen stores. Malignant Hyperthermia Susceptibility (MHS) exemplifies muscle conditions that increase [Ca2+]cytosol. 42% of MHS patients have hyperglycemia. We show that phosphorylated glycogen phosphorylase (GPa), glycogen synthase (GSa) - respectively activated and inactivated by phosphorylation - and their Ca2+-dependent kinase (PhK), are elevated in microsomal extracts from MHS patients' musc ...[more]

PMID: 32364497

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Project description:ObjectiveCalcitonin Gene-Related Peptide α (CGRPα) is a multifunctional neuropeptide found in the central and peripheral nervous system with cardiovascular, nociceptive, and gastrointestinal activities. CGRPα has been linked to obesity and insulin secretion but the role of this circulating peptide in energy metabolism remains unclear. Here, we thought to utilize a monoclonal antibody against circulating CGRPα to assess its ability to improve glucose homeostasis in mouse models of hyperglycemia and diabetes.MethodsWe examined the outcome of anti-CGRPα treatment in mouse models of diabetes and diet-induced obesity, using db/db mice, Streptozotocin (STZ) treatment to eliminate pancreatic islets, and high fat diet-fed mice. We also correlated these data with application of recombinant CGRPα peptide on cultured mature adipocytes to measure its impact on mitochondrial bioenergetics and fatty acid oxidation. Furthermore, we applied recombinant CGRPα to primary islets to measure glucose-stimulated insulin secretion (GSIS) and gene expression.ResultsBL6-db diabetic mice receiving anti-CGRPα treatment manifested weight loss, reduced adiposity, improved glucose tolerance, insulin sensitivity, GSIS and reduced pathology in adipose tissue and liver. Anti-CGRPα failed to modulate weight or glucose homeostasis in STZ-treated animals. High fat diet-fed mice showed reduced adiposity but no benefit on glucose homeostasis. Considering these findings, we postulated that CGRPα may have dual effects on adipocytes to promote lipid utilization while acting on pancreatic β-cells to modulate insulin secretion. Analysis of CGRPα in the pancreas showed that the peptide localized to insulin-positive cells and perivascular nerves surrounding islets. Ex-vivo analysis of pancreatic islets determined that CGRPα blocked GSIS and reduced insulin-2 gene expression. Mechanistical analysis revealed that recombinant CGRPα was able to reduce glycolytic capacity as well as fatty acid oxidation in primary white adipocytes.ConclusionsThese results establish a multifaceted role in energy metabolism for circulating CGRPα, with the ability to modulate thermogenic pathways in adipose tissue, as well as pancreatic β-cell dependent insulin secretion. Reducing circulating CGRPα levels with monoclonal therapy presents therapeutic potential for type 2 diabetes as shown in BL6-db/db mice but has reduced potential for models of hyperglycemia resulting from loss of β-cells (STZ treatment).

Dataset Information

Intracellular calcium leak lowers glucose storage in human muscle, promoting hyperglycemia and diabetes.

Publications

Intracellular calcium leak lowers glucose storage in human muscle, promoting hyperglycemia and diabetes.

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