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Metabolites May 2023The stimulus-secretion coupling of a glucose-induced release is generally attributed to the metabolism of the hexose in the β-cells in the glycolytic pathway and the... (Review)
Review
The stimulus-secretion coupling of a glucose-induced release is generally attributed to the metabolism of the hexose in the β-cells in the glycolytic pathway and the citric acid cycle. Glucose metabolism generates an increased cytosolic concentration of ATP and of the ATP/ADP ratio that closes the ATP-dependent K-channel at the plasma membrane. The resultant depolarization of the β-cells opens voltage-dependent Ca-channels at the plasma membrane that triggers the exocytosis of insulin secretory granules. The secretory response is biphasic with a first and transient peak followed by a sustained phase. The first phase is reproduced by a depolarization of the β-cells with high extracellular KCl maintaining the KATP-channels open with diazoxide (triggering phase); the sustained phase (amplifying phase) depends on the participation of metabolic signals that remain to be determined. Our group has been investigating for several years the participation of the β-cell GABA metabolism in the stimulation of insulin secretion by three different secretagogues (glucose, a mixture of L-leucine plus L-glutamine, and some branched chain alpha-ketoacids, BCKAs). They stimulate a biphasic secretion of insulin accompanied by a strong suppression of the intracellular islet content of gamma-aminobutyric acid (GABA). As the islet GABA release simultaneously decreased, it was concluded that this resulted from an increased GABA shunt metabolism. The entrance of GABA into the shunt is catalyzed by GABA transaminase (GABAT) that transfers an amino group between GABA and alpha-ketoglutarate, resulting in succinic acid semialdehyde (SSA) and L-glutamate. SSA is oxidized to succinic acid that is further oxidized in the citric acid cycle. Inhibitors of GABAT (gamma-vinyl GABA, gabaculine) or glutamic acid decarboxylating activity (GAD), allylglycine, partially suppress the secretory response as well as GABA metabolism and islet ATP content and the ATP/ADP ratio. It is concluded that the GABA shunt metabolism contributes together with the own metabolism of metabolic secretagogues to increase islet mitochondrial oxidative phosphorylation. These experimental findings emphasize that the GABA shunt metabolism is a previously unrecognized anaplerotic mitochondrial pathway feeding the citric acid cycle with a β-cell endogenous substrate. It is therefore a postulated alternative to the proposed mitochondrial cataplerotic pathway(s) responsible for the amplification phase of insulin secretion. It is concluded the new postulated alternative suggests a possible new mechanism of β-cell degradation in type 2 (perhaps also in type 1) diabetes.
PubMed: 37367856
DOI: 10.3390/metabo13060697 -
Diabetes Sep 2023Congenital hyperinsulinism (HI) is a genetic disorder in which pancreatic β-cell insulin secretion is excessive and results in hypoglycemia that, without treatment, can...
UNLABELLED
Congenital hyperinsulinism (HI) is a genetic disorder in which pancreatic β-cell insulin secretion is excessive and results in hypoglycemia that, without treatment, can cause brain damage or death. Most patients with loss-of-function mutations in ABCC8 and KCNJ11, the genes encoding the β-cell ATP-sensitive potassium channel (KATP), are unresponsive to diazoxide, the only U.S. Food and Drug Administration-approved medical therapy and require pancreatectomy. The glucagon-like peptide 1 receptor (GLP-1R) antagonist exendin-(9-39) is an effective therapeutic agent that inhibits insulin secretion in both HI and acquired hyperinsulinism. Previously, we identified a highly potent antagonist antibody, TB-001-003, which was derived from our synthetic antibody libraries that were designed to target G protein-coupled receptors. Here, we designed a combinatorial variant antibody library to optimize the activity of TB-001-003 against GLP-1R and performed phage display on cells overexpressing GLP-1R. One antagonist, TB-222-023, is more potent than exendin-(9-39), also known as avexitide. TB-222-023 effectively decreased insulin secretion in primary isolated pancreatic islets from a mouse model of hyperinsulinism, Sur1-/- mice, and in islets from an infant with HI, and increased plasma glucose levels and decreased the insulin to glucose ratio in Sur1-/- mice. These findings demonstrate that targeting GLP-1R with an antibody antagonist is an effective and innovative strategy for treatment of hyperinsulinism.
ARTICLE HIGHLIGHTS
Patients with the most common and severe form of diazoxide-unresponsive congenital hyperinsulinism (HI) require a pancreatectomy. Other second-line therapies are limited in their use because of severe side effects and short half-lives. Therefore, there is a critical need for better therapies. Studies with the glucagon-like peptide 1 receptor (GLP-1R) antagonist, avexitide (exendin-(9-39)), have demonstrated that GLP-1R antagonism is effective at lowering insulin secretion and increasing plasma glucose levels. We have optimized a GLP-1R antagonist antibody with more potent blocking of GLP-1R than avexitide. This antibody therapy is a potential novel and effective treatment for HI.
Topics: Animals; Mice; Antibodies; Blood Glucose; Congenital Hyperinsulinism; Diazoxide; Glucagon-Like Peptide 1; Glucagon-Like Peptide-1 Receptor; Hyperinsulinism; Mutation; Sulfonylurea Receptors
PubMed: 37358194
DOI: 10.2337/db22-1039 -
Frontiers in Molecular Biosciences 2023Diazoxide is a selective mitochondrial-sensitive potassium channel opening agent that has a definite effect on reducing myocardial ischemia/reperfusion injury (MIRI)....
Diazoxide is a selective mitochondrial-sensitive potassium channel opening agent that has a definite effect on reducing myocardial ischemia/reperfusion injury (MIRI). However, the exact effects of diazoxide postconditioning on the myocardial metabolome remain unclear, which might contribute to the cardioprotective effects of diazoxide postconditioning. Rat hearts subjected to Langendorff perfusion were randomly assigned to the normal (Nor) group, ischemia/reperfusion (I/R) group, diazoxide (DZ) group and 5-hydroxydecanoic acid + diazoxide (5-HD + DZ) group. The heart rate (HR), left ventricular developed pressure (LVDP), left ventricular end-diastolic pressure (LVEDP), and maximum left ventricular pressure (+dp/dtmax) were recorded. The mitochondrial Flameng scores were analysed according to the ultrastructure of the ventricular myocardial tissue in the electron microscopy images. Rat hearts of each group were used to investigate the possible metabolic changes relevant to MIRI and diazoxide postconditioning. The cardiac function indices in the Nor group were better than those in the other groups at the end point of reperfusion, and the HR, LVDP and +dp/dt of the Nor group at T2 were significantly higher than those of the other groups. Diazoxide postconditioning significantly improved cardiac function after ischaemic injury, and the HR, LVDP and +dp/dt of the DZ group at T2 were significantly higher than those of the I/R group, which could be abolished by 5-HD. The HR, LVDP and +dp/dt of the 5-HD + DZ group at T2 were significantly lower than those of the DZ group. The myocardial tissue in the Nor group was mostly intact, while it exhibited considerable damage in the I/R group. The ultrastructural integrity of the myocardium in the DZ group was higher than that in the I/R and 5-HD + DZ groups. The mitochondrial Flameng score in the Nor group was lower than that in the I/R, DZ and 5-HD + DZ groups. The mitochondrial Flameng score in the DZ group was lower than that in the I/R and 5-HD + DZ groups. Five metabolites, namely, L-glutamic acid, L-threonine, citric acid, succinate, and nicotinic acid, were suggested to be associated with the protective effects of diazoxide postconditioning on MIRI. Diazoxide postconditioning may improve MIRI via certain metabolic changes. This study provides resource data for future studies on metabolism relevant to diazoxide postconditioning and MIRI.
PubMed: 37304068
DOI: 10.3389/fmolb.2023.1196894 -
Molecules (Basel, Switzerland) May 2023Co-hydrothermal carbonization (co-HTC) of N-rich and lignocellulosic biomass is a potential way to produce hydrochar with high yield and quality, but the nitrogen will...
The Role of the Mannich Reaction in Nitrogen Migration during the Co-Hydrothermal Carbonization of Bovine Serum Albumin and Lignin with Various Forms of Acid-Alcohol Assistance.
Co-hydrothermal carbonization (co-HTC) of N-rich and lignocellulosic biomass is a potential way to produce hydrochar with high yield and quality, but the nitrogen will also enrich in a solid product. In this study, a novel co-HTC with acid-alcohol assistance is proposed, and the model compounds bovine serum albumin (BSA) and lignin were used to investigate the role of the acid-alcohol-enhanced Mannich reaction in nitrogen migration. The results showed that the acid-alcohol mixture could inhibit nitrogen enrichment in solids and the order of the denitrification rate was acetic acid > oxalic acid > citric acid. Acetic acid promoted solid-N hydrolysis to NH while oxalic acid preferred to convert it to oil-N. More tertiary amines and phenols were generated with oxalic acid-ethanol addition and then formed quaternary-N and N-containing aromatic compounds through the Mannich reaction. In the citric acid-ethanol-water solution, NH and amino acids were captured to form diazoxide derivatives in oil and pyrroles in solids through both nucleophilic substitution and the Mannich reaction. The results are able to guide biomass hydrochar production with the targeted regulation of nitrogen content and species.
Topics: Lignin; Carbon; Serum Albumin, Bovine; Nitrogen; Temperature; Ethanol; Biomass; Oxalates
PubMed: 37298884
DOI: 10.3390/molecules28114408 -
BioRxiv : the Preprint Server For... May 2023Chronic pain is a substantial health burden and options for treating chronic pain remain minimally effective. Ketogenic diets are emerging as well-tolerated, effective...
Chronic pain is a substantial health burden and options for treating chronic pain remain minimally effective. Ketogenic diets are emerging as well-tolerated, effective therapeutic strategies in preclinical models of chronic pain, especially diabetic neuropathy. We tested whether a ketogenic diet is antinociceptive through ketone oxidation and related activation of ATP-gated potassium (K) channels in mice. We demonstrate that consumption of a ketogenic diet for one week reduced evoked nocifensive behaviors (licking, biting, lifting) following intraplantar injection of different noxious stimuli (methylglyoxal, cinnamaldehyde, capsaicin, or Yoda1) in mice. A ketogenic diet also decreased the expression of p-ERK, an indicator of neuronal activation in the spinal cord, following peripheral administration of these stimuli. Using a genetic mouse model with deficient ketone oxidation in peripheral sensory neurons, we demonstrate that protection against methylglyoxal-induced nociception by a ketogenic diet partially depends on ketone oxidation by peripheral neurons. Injection of tolbutamide, a K channel antagonist, prevented ketogenic diet-mediated antinociception following intraplantar capsaicin injection. Tolbutamide also restored the expression of spinal activation markers in ketogenic diet-fed, capsaicin-injected mice. Moreover, activation of K channels with the K channel agonist diazoxide reduced pain-like behaviors in capsaicin-injected, chow-fed mice, similar to the effects observed with a ketogenic diet. Diazoxide also reduced the number of p-ERK cells in capsaicin-injected mice. These data support a mechanism that includes neuronal ketone oxidation and activation of K channels to provide ketogenic diet-related analgesia. This study also identifies K channels as a new target to mimic the antinociceptive effects of a ketogenic diet.
PubMed: 37292762
DOI: 10.1101/2023.05.22.541799 -
Clinical Case Reports Jun 2023Kabuki syndrome is a congenital condition characterized by a set of facial dysmorphic features that often help the clinician to suspect the diagnosis. However, more...
Kabuki syndrome is a congenital condition characterized by a set of facial dysmorphic features that often help the clinician to suspect the diagnosis. However, more insidious symptoms can rarely occur, such as manifestations of hypoglycemia in newborns with congenital hyperinsulinism hypoglycemia, especially when a variant of the gene is found. In those cases, a treatment with diazoxide can be started and can be replaced with lanreotide if a satisfying glycemic control is not achieved. We report the case of a female patient born at 37 weeks of gestational age, without any obvious facial dysmorphic features, after a non-complicated pregnancy, that presented with feeding difficulties, drowsiness, and irritability revealing a hyperinsulinemic hypoglycemia. Further testing at 6 months old found a mutation. The patient was initially treated by diazoxide alone, but its dosage had to be lowered because of the occurrence of treatment side effects, and lanreotide had been added to maintain acceptable blood sugar levels. A congenital hyperinsulinemia hypoglycemia revealed heterozygous truncating variant in the gene, also known as X-linked Kabuki syndrome in a newborn. In cases of neonatal hypoglycemia, the first-line therapy is diazoxide. Our report shows that analogues of somatostatin such as lanreotide should be considered if the diazoxide regimen is not tolerated.
PubMed: 37257167
DOI: 10.1002/ccr3.7336 -
Frontiers in Endocrinology 2023Insulinomas, with an incidence of 4 cases per million individuals per year, remain amongst the most frequent functional neuroendocrine tumors. The usual diameter of...
Insulinomas, with an incidence of 4 cases per million individuals per year, remain amongst the most frequent functional neuroendocrine tumors. The usual diameter of insulinomas usually remains under 3 cm of major axis. However, 44 exceptional cases of "giant insulinomas", have been reported worldwide, generally exceeding 9 cm in major axis. In this article, we report the case of a 38-year-old woman whom suffered from chronic hypoglycemia despite treatment with diazoxide. Abdominal CT-scan revealed a 88 x 73 mm mass located at the tail of the pancreas. Following surgical excision, histopathological analysis confirmed G1 neuroendocrine tumor, with focal cytoplasmic expression of insulin in tumor cells. After a 16-month follow-up period, the patient didn't address any specific complaint, and no disease recurrence and/or metastasis were observed. A Ga-DOTATATE-PET scan was performed 6 months after surgery, which came back normal. Genetic evaluation has not been performed in our patient. The physiopathology of giant insulinomas remain unexplained, however with possible relationship with type 1 multiple endocrine neoplasia, sporadic somatic mutations and possible transformation of bulky non-functional pancreatic neuroendocrine tumors to a functional phenotype, with slow insulin secretion. While giant insulinomas remain rare in the literature, multicentric genetic analysis of tumor samples might reveal unique features of this rare subtype of neuroendocrine pancreatic tumors. Insulinomas of large size tend to have greater malignancy and higher rates of invasiveness. Careful follow-up, especially for liver and lymph node metastases, must be performed using functional imaging techniques to avoid disease relapse.
Topics: Humans; Insulinoma; Neoplasm Recurrence, Local; Pancreatic Neoplasms; Hypoglycemia; Neuroendocrine Tumors
PubMed: 37234805
DOI: 10.3389/fendo.2023.1125772 -
Annals of Medicine and Surgery (2012) May 2023Nonislet cell tumor hypoglycemia (NICTH) is a rare cause of hypoglycemia. It results from the secretion of insulin-like growth factor 2 from various tumors, which acts...
UNLABELLED
Nonislet cell tumor hypoglycemia (NICTH) is a rare cause of hypoglycemia. It results from the secretion of insulin-like growth factor 2 from various tumors, which acts on insulin receptors, increasing glucose utilization by the tumor. Among the treatment options for patients with NICTH, steroids have the best palliative effects.
CASE PRESENTATION
The authors present the case of a man with metastatic lung cancer who had multiple hospitalizations for hypoglycemia and associated anorexia, weight loss, and depression. After receiving steroids, the patient's hospital admission rate due to hypoglycemia reduced, depression improved, and weight loss reversed.
CLINICAL DISCUSSION
Steroids, diazoxide, octreotide, glucagon infusion, and recombinant growth hormone have shown good results in treating NICTH. Steroids have many advantages: they are easy to administer and relatively inexpensive. In our patient, steroids had the added benefit of improving the appetite with subsequent weight gain and controlling depression. They also significantly reduced the readmission rate.
CONCLUSION
NICTH is a rare cause of hypoglycemia. Glucocorticoids show better palliative effects than other medical treatments. In our patient, steroids dramatically reduced the number of hospitalizations due to hypoglycemia while improving the appetite, weight, and depression.
PubMed: 37228993
DOI: 10.1097/MS9.0000000000000537 -
Pediatrics and Neonatology Sep 2023
Topics: Humans; Infant; Diazoxide; Trichlormethiazide; Trisomy 13 Syndrome; Body Water; Treatment Outcome
PubMed: 37225554
DOI: 10.1016/j.pedneo.2023.04.003 -
Journal of Neurophysiology Jun 2023Inhibition of glycolysis with 2-deoxyglucose (2-DG) produces antiseizure effects in brain slices and animal models, yet the mechanisms remain elusive. Here, we examined...
Inhibition of glycolysis with 2-deoxyglucose (2-DG) produces antiseizure effects in brain slices and animal models, yet the mechanisms remain elusive. Here, we examined two glycolysis-derived ATP-associated mechanisms: vacuole ATP pump (V-ATPase) and ATP-sensitive K channel (K). Epileptiform bursts were generated in the CA3 area of hippocampal slices by 0 Mg and 4-aminopyridine. 2-DG consistently abolished epileptiform bursts in the presence of pyruvate (to sustain tricarboxylic acid cycle for oxidative ATP production) at 30-33°C but not at room temperature (22°C). Under physiological conditions, 2-DG did not reduce the amplitude of evoked excitatory postsynaptic currents (EPSCs) or the paired-pulse ratio in CA3 neurons. During repetitive high-frequency (20 Hz, 20-50 pulses) stimulation, 2-DG did not accelerate the decline of EPSCs (i.e., depletion of transmitter release), even when preincubated with 8 mM K to enhance activity-dependent uptake of 2-DG. In addition, in 2-DG tetanic stimulation (200 Hz, 1 s) dramatically increased rather than diminished the occurrence of spontaneous EPSCs immediately after stimulation (i.e., no transmitter depletion). Moreover, a V-ATPase blocker (concanamycin) failed to block epileptiform bursts that were subsequently abolished by 2-DG. Furthermore, 2-DG did not induce detectable K current in hippocampal neurons. Finally, epileptiform bursts were not affected by either a K opener (diazoxide) or a K blocker (glibenclamide) but were blocked by 2-DG in the same slices. Altogether, these data suggest that 2-DG's antiseizure action is temperature dependent and achieved exclusively by inhibition of glycolysis and is not likely to be mediated by the two membrane-bound ATP-associated machinery mechanisms, V-ATPase and K Inhibition of glycolysis with 2-deoxyglucose (2-DG) represents a novel metabolic antiseizure approach, yet the mechanisms remain elusive. Here, we show that 2-DG's antiseizure action is both glycolysis and temperature dependent but not mediated by the vacuole ATP pump (V-ATPase) or ATP-sensitive K channel (K) Our data provide new insights to understand 2-DG's cellular mechanisms of action and, more broadly, neuronal metabolism and excitability.
Topics: Animals; Deoxyglucose; Vacuoles; Hippocampus; Adenosine Triphosphatases; Adenosine Triphosphate
PubMed: 37222440
DOI: 10.1152/jn.00124.2023