Biology subjects

Siebel, S.

Publications and source records attributed to Siebel, S..

3 recordsLinked to original sources

bioRxiv2025

Spatial Partitioning of Core Glycolysis Enables Tissue-Specific Metabolic Programs In Vivo

Tissues exhibit metabolic heterogeneity that tailors conserved pathways to distinct physiological demands, yet how this heterogeneity is achieved in vivo remains poorly understood. Here, we use Caenorhabditis elegans to investigate tissue-specific requirements for glucose-6-phosphate isomerase (GPI-1), a conserved reversible enzyme that links glycolysis and the pentose phosphate pathway (PPP). Tissue-specific metabolic-network modeling predicted differential glycolytic and PPP flux potential across adult tissues and identified tissue-specific biases in GPI-1 reaction directionality. Genetic disruption of gpi-1 produced germline defects consistent with impaired PPP-associated anabolic metabolism and somatic defects consistent with impaired glycolysis, indicating that GPI-1 supports distinct metabolic functions across tissues. We further discovered that two GPI-1 isoforms are differentially expressed and localized: GPI-1A is broadly expressed and cytosolic, whereas GPI-1B is enriched in the germline and localizes to endoplasmic reticulum-associated compartments. Isoform-specific perturbations revealed distinct requirements for GPI-1A and GPI-1B in somatic glycolysis and reproductive physiology. These findings implicate isoform-specific subcellular localization as a possible contributor to the partition of the functions of a conserved reversible enzyme, enabling tissue-specific anabolic and catabolic metabolism in vivo.

cell biology↗

bioRxiv2023

GDF15 is a Critical Renostat in the Defense Against Hypoglycemia

Episodic hypoglycemia is one of the best honed, evolutionary conserved phenomena in biology, because of the constant feast-fast cycles that have characterized most of history. The counterregulatory response to hypoglycemia, mobilizing substrate stores to produce glucose, is the primary adaptive mechanism to enable survival. Catecholamines and glucagon have long been considered the key hypoglycemia counterregulatory hormones, but here we identify a new hypoglycemia counterregulatory factor. We employed the insulin tolerance test (ITT) and hyperinsulinemic-hypoglycemic clamp to mimic the two common settings in which hypoglycemia can occur in patients: postprandial insulin overdose and elevated basal insulin administration, respectively. We found that Growth Differentiation Factor 15 (GDF15) production is induced in the S3 segment of the renal proximal tubules and its release increases hepatic gluconeogenesis by increasing intrahepatic lipolysis in a beta-adrenergic receptor-2 (Adrb2)-dependent manner. In addition, mice exposed to recurrent hypoglycemia and patients with T1D exhibit impaired GDF15 production in the setting of hypoglycemia. These data demonstrate that GDF15 acts acutely as a gluco-counterregulatory hormone and identify a critical role for kidney-derived GDF15 in glucose homeostasis under physiological and pathophysiological conditions.

physiology↗

bioRxiv2020

Pharmacologic activation of the mitochondrial phosphoenolpyruvate cycleenhances islet function in vivo

The mitochondrial GTP (mtGTP)-dependent phosphoenolpyruvate (PEP) cycle is an anaplerotic-cataplerotic mitochondrial shuttle utilizing mitochondrial PEPCK (PCK2) and pyruvate kinase (PK). PEP cycling stimulates insulin secretion via OxPhos-independent lowering of ADP by PK. We assess in vivo whether islet PCK2 is necessary for glucose sensing and if speeding the PEP cycle via pharmacological PK activators amplifies insulin secretion. Pck2-/- mice had severely impaired insulin secretion during islet perifusion, oral glucose tolerance tests and hyperglycemic clamps. Acute and chronic pharmacologic PK activator therapy improved islet insulin secretion from normal, high-fat diet (HFD) fed, or Zucker diabetic fatty (ZDF) rats, and glucolipotoxic or diabetic humans. A similar improvement in insulin secretion was observed in regular chow and HFD rats in vivo. Insulin secretion and cytosolic Ca2+ during PK activation were dependent on PCK2. These data provide a preclinical rationale for strategies, such as PK activation, that target the PEP cycle to improve glucose homeostasis. HighlightsO_LILoss of mitochondrial phosphoenolpyruvate (PEP) impairs insulin release in vivo. C_LIO_LIPyruvate kinase (PK) activators stimulate beta-cells in preclinical diabetes models. C_LIO_LIPEP cycling in vivo depends on PK and mitochondrial PEPCK (PCK2) for insulin release. C_LIO_LIAcute and 3-week oral PK activator amplifies insulin release during hyperglycemia. C_LI eTOC BlurbAbudukadier et al. show that small molecule pyruvate kinase activation in vivo and in vitro increases insulin secretion in rodent and human models of diabetes. The phosphoenolpyruvate (PEP) cycling mechanism and its amplification are dependent on mitochondrial PEPCK (PCK2).

physiology↗