Sodium-glucose transport protein 2 inhibitors (SGLT2i) are becoming commonplace in many chronic diseases: type 2 diabetes mellitus, heart failure, and chronic kidney disease. We present the case of a 65-year-old male with a history of type 2 diabetes who had been on an SGLT2i for over 12 months and was found to have euglycemic diabetic ketoacidosis (eDKA) occurring concurrently with a thyroid storm. This case report illustrates a unique scenario of two endocrine emergencies occurring simultaneously.

BACKGROUND Cytosolic phosphoenolpyruvate carboxykinase (PEPCK-C) deficiency is an extremely rare autosomal recessive inherited error of metabolism in which gluconeogenesis is impaired, resulting in life-threatening episodes of hypoglycemia and metabolic acidosis. The diagnosis of gluconeogenesis disorders is challenging. In the diagnostic pathway, the molecular test plays a paramount role. CASE REPORT The aim of the paper is to present the case report of a girl with recurrent episodes of severe hypoglycemia, in whom molecular diagnosis enabled the confirmation of PEPCK - C deficiency. The patient experienced 4 episodes of severe hypoglycemia. Most of them were accompanied by hyperlacticaemia, metabolic acidosis, and elevated liver enzymes. All of the metabolic decompensations were triggered by infectious agents. The episodes resolved after continuous infusion of high-dose glucose. Due to the recurrent character of the disease, a genetic condition was suspected. The differential diagnosis included metabolic and endocrinological causes of hypoglycemia. Two variants in the PCK1 gene were detected: c.265G>A p.(Glu89Lys) in exon 3 and c.925G>A p.(Gly309Arg) in exon 6. As c.925G>A p.(Gly309Arg) is a known pathogenic variant, the second variant was first described in June 2023 in the ClinVar database and described as \"with unknown clinical significance\". CONCLUSIONS According to the clinical symptoms observed in the presented case, the variant c.265G>A p.(Glu89Lys) in PCK1 gene should be considered likely pathogenic. We suggest considering molecular diagnostics in every patient presented with recurrent, severe hypoglycemia with accompanying liver damage as most accurate, feasible, and reliable method.

BACKGROUND: Fructose-1,6-bisphosphatase deficiency is a rare autosomal recessive disorder characterized by impaired gluconeogenesis. Fructose-1,6-bisphosphatase 1 (FBP1) mutations demonstrate ethnic patterns. For instance, Turkish populations commonly harbor exon 2 deletions. We present a case report of whole exon 2 deletion in a Syrian Arabian child as the first recording of this mutation among Arabian ethnicity and the first report of FBP1 gene mutation in Syria.
METHODS: We present the case of a 2.5-year-old Syrian Arab child with recurrent hypoglycemic episodes, accompanied by nausea and lethargy. The patient\'s history, physical examination, and laboratory findings raised suspicion of fructose-1,6-bisphosphatase deficiency. Whole exome sequencing was performed, revealing a homozygous deletion of exon 2 in the FBP1 gene, confirming the diagnosis.
CONCLUSIONS: This case highlights a potential novel mutation in the Arab population; this mutation is well described in the Turkish population, which suggests potential shared mutations due to ancestral relationships between the two ethnicities. Further studies are needed to confirm this finding.

Hypoglycemia is an uncommon clinical problem among non-diabetic patients. It requires systematic evaluation to determine the etiology. It may be related to critical illness, hepatic insufficiency, renal insufficiency, cardiac insufficiency, drugs, alcohol, cortisol insufficiency, growth hormone insufficiency, insulinoma, gastric bypass surgery, and paraneoplastic (insulin-like growth factor-2-related) immune-mediated or inherited metabolic disorders. We aimed to summarize the literature and present a case who suffered from hypoglycemia throughout his life and was diagnosed with fructose-1, 6 bisphosphatase deficiency in adulthood to attract attention to the rare causes of hypoglycemia in adulthood.

Data on protein post-translational modifications (PTMs) increased exponentially in the last years due to the refinement of mass spectrometry techniques and the development of databases to store and share datasets. Nevertheless, these data per se do not create comprehensive biochemical knowledge. Complementary studies on protein biochemistry are necessary to fully understand the function of these PTMs at the molecular level and beyond, for example, designing rational metabolic engineering strategies to improve crops. Phosphoenolpyruvate carboxykinases (PEPCKs) are critical enzymes for plant metabolism with diverse roles in plant development and growth. Multiple lines of evidence showed the complex regulation of PEPCKs, including PTMs. Herein, we present PEPCKs as an example of the integration of combined mechanisms modulating enzyme activity and metabolic pathways. PEPCK studies strongly advanced after the production of the recombinant enzyme and the establishment of standardized biochemical assays. Finally, we discuss emerging open questions for future research and the challenges in integrating all available data into functional biochemical models.

BACKGROUND: Defining the metabolic syndrome (MetS) in children remains challenging. Furthermore, a dichotomous MetS diagnosis can limit the power to study associations. We sought to characterize the serum metabolite signature of the MetS in early childhood using high-throughput metabolomic technologies that allow comprehensive profiling of metabolic status from a biospecimen.
METHODS: In the Family Atherosclerosis Monitoring In earLY life (FAMILY) prospective birth cohort study, we selected 228 cases of MetS and 228 matched controls among children age 5 years. In addition, a continuous MetS risk score was calculated for all 456 participants. Comprehensive metabolite profiling was performed on fasting serum samples using multisegment injection-capillary electrophoresis-mass spectrometry. Multivariable regression models were applied to test metabolite associations with MetS adjusting for covariates of screen time, diet quality, physical activity, night sleep, socioeconomic status, age, and sex.
RESULTS: Compared to controls, thirteen serum metabolites were identified in MetS cases when using multivariable regression models, and using the quantitative MetS score, an additional eight metabolites were identified. These included metabolites associated with gluconeogenesis (glucose (odds ratio (OR) 1.55 [95% CI 1.25-1.93]) and glutamine/glutamate ratio (OR 0.82 [95% CI 0.67-1.00])) and the alanine-glucose cycle (alanine (OR 1.41 [95% CI 1.16-1.73])), amino acids metabolism (tyrosine (OR 1.33 [95% CI 1.10-1.63]), threonine (OR 1.24 [95% CI 1.02-1.51]), monomethylarginine (OR 1.33 [95% CI 1.09-1.64]) and lysine (OR 1.23 [95% CI 1.01-1.50])), tryptophan metabolism (tryptophan (OR 0.78 [95% CI 0.64-0.95])), and fatty acids metabolism (carnitine (OR 1.24 [95% CI 1.02-1.51])). The quantitative MetS risk score was more powerful than the dichotomous outcome in consistently detecting this metabolite signature.
CONCLUSIONS: A distinct metabolite signature of pediatric MetS is detectable in children as young as 5 years old and may improve risk assessment at early stages of development.

Pyruvate dehydrogenase (PDH) deficiency is an inherited metabolic disorder caused by a defect in any subunit of the pyruvate dehydrogenase complex (PDHC), which has an essential role in glucose metabolism. The causes of disease progression in PDH deficiency are not fully understood yet. Based on repeated observations of a patient with PDH deficiency at our center, we hypothesized that stress-induced gluconeogenesis contributes to rapid exacerbation of the disease. This link has not been established previously.

In this issue of Cell Host & Microbe, De Filippis et al. (2019) report that Prevotella copri strain-level diversity in the gut microbiome can be shaped by host diet. Individual signatures were analyzed by marker gene profiling in assembled pangenomes, providing a strong rationale for the functional adaptation of individual microbial ecosystems in response to diet.

BACKGROUND: Lactic acidosis (LA) is the most common form of metabolic acidosis, defined by lactate values greater than 5 mmol/L and pH<7.34. The pathogenesis of LA involves hypoxic causes (type A) and non-hypoxic (type B), often coexisting. Identification and removal of the trigger are mandatory in the therapeutic management of LA. The case: A 38 years-old male patient entered the Emergency Ward for dyspnea, fever, vomiting and hyporexia. An important respiratory distress with hyperventilation due to severe LA was found, together with severe hypoglicemia, without renal impairment. Past medical history unremarkable, except for reported episodic hypoglicemia in the childhood, with fructose \"intolerance\", without any other data. No evidence of intoxications, septic shock or significant cytolysis. No drugs causing LA. The patient underwent orotracheal intubation, glucose infusion, and continuous haemodiafiltration for 36-hrs. A rapid general improvement was obtained with stabilization of acid-base balance. A diagnosis of fructose-1,6-diphosphatase deficiency was made. It is an autosomical recessive gluconeogenesis abnormality, with recurrent episodes of hypoglicemia and lactic acidosis after fasting, potentially lethal. The therapy is based on avoiding prolonged fasts, glucose infusion, and a specific diet, rich in glucose without fructose intake.
CONCLUSIONS: The presence of not-otherwise-explained lactic acidosis in young patients has to place the suspect of an underlying and unknown metabolic derangement; in these cases, the involvement of the nephrologist appears to be pivotal for the differential diagnosis of the abnormalities of the acid-base balance, and for setting the best treatment.

Bacillus subtilis possesses two glyceraldehyde-3-phosphate dehydrogenases with opposite roles, the glycolytic NAD-dependent GapA and the NADP-dependent GapB enzyme, which is exclusively required during gluconeogenesis but not active under conditions promoting glycolysis. We propose that proteins that are no longer needed will be recognized and proteolyzed by Clp proteases and thereby recycled. To test this postulation, we analyzed the stability of the glycolytic enzyme GapA and the gluconeogenetic enzyme GapB in the presence and absence of glucose. It turned out that GapA remained rather stable under both glycolytic and gluconeogenetic conditions. In contrast, the gluconeogenetic enzyme GapB was degraded after a shift from malate to glucose (i.e., from gluconeogenesis to glycolysis), displaying an estimated half-life of approximately 3 h. Comparative in vivo pulse-chase labeling and immunoprecipitation experiments of the wild-type strain and isogenic mutants identified the ATP-dependent ClpCP protease as the enzyme responsible for the degradation of GapB. However, arginine protein phosphorylation, which was recently described as a general tagging mechanism for protein degradation, did not seem to play a role in GapB proteolysis, because GapB was also degraded in a mcsB mutant, lacking arginine kinase, in the same manner as in the wild type.IMPORTANCE GapB, the NADP-dependent glyceraldehyde-3-phosphosphate dehydrogenase, is essential for B. subtilis under gluconeogenetic conditions. However, after a shift to glycolytic conditions, GapB loses its physiological function within the cell and becomes susceptible to degradation, in contrast to GapA, the glycolytic NAD-dependent glyceraldehyde-3-phosphate dehydrogenase, which remains stable under glycolytic and gluconeogenetic conditions. Subsequently, GapB is proteolyzed in a ClpCP-dependent manner. According to our data, the arginine kinase McsB is not involved as adaptor protein in this process. ClpCP appears to be in charge in the removal of inoperable enzymes in B. subtilis, which is a strictly regulated process in which the precise recognition mechanism(s) remains to be identified.