Defects In Glucose Metabolism Research Articles

Non-insulin Medications for the Management of Type 2 Diabetes.

Type 2 diabetes (T2D) is predicted to affect 366 million people over the age of 65 years by the year 2030. As the understanding of the core defects associated with T2D advanced, researchers recognized management should target multiple defects in glucose metabolism. As a result, efforts to manage T2D focus on developing new drug therapies aimed at addressing each of the identified metabolic defects. Optimal treatment of T2D is necessary to decrease the risk for coronary heart disease, stroke, and vascular diseases. This article discusses non-insulin pharmacologic treatments for T2D that are guided by glycemic efficacy, safety profiles, effects on weight and hypoglycemia risk, tolerability, patient comorbidities, route of administration, patient preference, and cost.

GRIM19 deficiency aggravates metabolic disorder and ovarian dysfunction in PCOS

ContextPolycystic ovary syndrome (PCOS) is one of the most common endocrine disorders in women. Retinoid-interferon-induced mortality 19 (GRIM19) is a functional component of mitochondrial complex I that plays a role in cellular energy metabolism. However, the role of GRIM19 in the pathogenesis of PCOS is still unclear. ObjectiveTo investigate the role of GRIM19 in the pathogenesis of PCOS. DesignWe first measured the expression of GRIM19 in human granulosa cells (hGCs) from patients with and without PCOS (n = 16 per group), and then established a PCOS mouse model with WT and Grim19+/− mice for in vivo experiments. Glucose uptake-related genes RAC1 and GLUT4 and energy metabolism levels in KGN cells were examined in vitro by knocking down GRIM19 in the cell lines. Additionally, ovulation-related genes such as p-ERK1/2, HAS2, and PTX3 were also studied to determine their expression levels. ResultsGRIM19 expression was reduced in hGCs of PCOS patients, which was negatively correlated with BMI and serum testosterone level. Grim19+/− mice with PCOS exhibited a markedly anovulatory phenotype and disturbed glycolipid metabolism. In vitro experiments, GRIM19 deficiency inhibited the RAC1/GLUT4 pathway, reducing insulin-stimulated glucose uptake in KGN cells. Moreover, GRIM19 deficiency induced mitochondrial dysfunction, defective glucose metabolism, and apoptosis. In addition, GRIM19 deficiency suppressed the expression of ovulation-related genes in KGN cells, which was regulated by dihydrotestosterone mediated androgen receptor. ConclusionsGRIM19 deficiency may mediate ovulation and glucose metabolism disorders in PCOS patients. Our results suggest that GRIM19 may be a new target for diagnosis and treatment.

TRNA m1G9 modification depends on substrate-specific RNA conformational changes induced by the methyltransferase Trm10

The methyltransferase Trm10 modifies a subset of tRNAs on the base N1 position of the ninth nucleotide in the tRNA core. Trm10 is conserved throughout Eukarya and Archaea, and mutations in the human gene (TRMT10A) have been linked to neurological disorders such as microcephaly and intellectual disability, as well as defects in glucose metabolism. Of the 26 tRNAs in yeast with guanosine at position 9, only 13 are substrates for Trm10. However, no common sequence or other posttranscriptional modifications have been identified among these substrates, suggesting the presence of some other tRNA feature(s) that allow Trm10 to distinguish substrate from nonsubstrate tRNAs. Here, we show that substrate recognition by Saccharomyces cerevisiae Trm10 is dependent on both intrinsic tRNA flexibility and the ability of the enzyme to induce specific tRNA conformational changes upon binding. Using the sensitive RNA structure-probing method SHAPE, conformational changes upon binding to Trm10 in tRNA substrates, but not nonsubstrates, were identified and mapped onto a model of Trm10-bound tRNA. These changes may play an important role in substrate recognition by allowing Trm10 to gain access to the target nucleotide. Our results highlight a novel mechanism of substrate recognition by a conserved tRNA modifying enzyme. Further, these studies reveal a strategy for substrate recognition that may be broadly employed by tRNA-modifying enzymes which must distinguish between structurally similar tRNA species.

OR34-04 Defective FGFR1 Signaling Disrupts Glucose Regulation In Humans: Evidence From Patients With Isolated Hypogonadotropic Hypogonadism Harboring FGFR1 Mutations

Abstract Disclosure: M. Stamou: None. C.J. Chiu: None. S. Jadhav: None. K. Salnikov: None. L. Plummer: None. S.B. Seminara: None. R. Balasubramanian: None. Introduction: Recent studies have shown that antibody-mediated activation of FGFR1 receptor improves metabolic health in rodents, nonhuman primates, and humans. Hence, disruption of the FGFR1 receptor may lead to glucose dysregulation. FGFR1 mutations contribute to 12% of the genetic background of subjects with isolated hypogonadotropic hypogonadism (IHH), a rare Mendelian disease caused by GnRH deficiency. In this study, we examined glucose effectiveness and insulin sensitivity in IHH subjects with rare FGFR1 variants and hypothesized that these subjects will display defective glucose metabolism compared healthy non-carrier controls. Methods: Nine subjects with IHH (7 males and 2 females) with heterozygous rare FGFR1 variants were enrolled [7 subjects with protein truncating variants: p.Q680*, p.R622*, p.Q52*, p.I347Nfs*61, p.R576Pfs*77, p.Q309*, c.1553-2A>G and 2 subjects with deleterious missense variants: p.G97S & p.Y701C. Thirty healthy controls (17 males and 13 females) with no FGFR1 variants were enrolled from the Mass General Brigham Biobank. Medical history, physical exam, laboratory evaluation, a bone density scan, and an intravenous glucose tolerance test (IVGTT) were performed. The area under the curve (AUC) for glucose, insulin, and C-peptide response to 50% dextrose (0.3g/kg, t=0min) and an insulin bolus (0.03u/kg, t=20 min) were estimated for each subject. The glucose effectiveness (Sg), insulin sensitivity (SI), acute insulin response to glucose (AIR), and the disposition index (DI= AIRG*SI) were calculated using the Minimal Model Analysis. Statistical comparisons were performed with t-test and non-parametric Wilcoxon rank sum test. A linear regression model was used to adjust the t-test outcomes for potential confounders. Results: Despite similar BMIs (28 vs. 26.5, p=0.29), IHH FGFR1 positive subjects demonstrated higher % fat mass compared to controls (38 vs. 31, p=0.02). IHH patients were supplemented with sex-steroids at the time of the study. Male patients demonstrated similar testosterone levels compared to controls (385 vs. 451 ng/dL, p=0.52). IHH FGFR1 positive subjects demonstrated a higher AUC for C-peptide compared to controls (167 vs. 92, p=0.001), that remained significant after adjusting for age, gender, BMI, and % fat mass. Non-parametric test showed higher AUC for glucose, insulin, and C-peptide (p 0.01, 0.01 & 0.005 respectively) as well as lower SI (p=0.01) and higher AIRg (p=0.037) in the IHH FGFR1 positive group compared to non-carrier controls. Discussion: This is the first study to evaluate glucose metabolism in humans with naturally occurring FGFR1 variants. IHH FGFR1 positive subjects showed higher insulin response to glucose and lower insulin sensitivity during an IVGTT test compared to the healthy non-carrier controls. These findings confirm that FGFR1 signaling is a key regulator of insulin secretion and action in humans. Presentation: Sunday, June 18, 2023

Genetic activation of glycolysis in osteoblasts preserves bone mass in type I diabetes

Type I diabetes (T1D) impairs bone accrual in patients, but the mechanism is unclear. Here in a murine monogenic model for T1D, we demonstrate that diabetes suppresses bone formation resulting in a rapid loss of both cortical and trabecular bone. Single-cell RNA sequencing uncovers metabolic dysregulation in bone marrow osteogenic cells of diabetic mice. Invivo stable isotope tracing reveals impaired glycolysis in diabetic bone that is highly responsive to insulin stimulation. Remarkably, deletion of the insulin receptor reduces cortical but not trabecular bone. Increasing glucose uptake by overexpressing Glut1 in osteoblasts exacerbates bone defects in T1D mice. Conversely, activation of glycolysis by Pfkfb3 overexpression preserves both trabecular and cortical bone mass in the face of diabetes. The study identifies defective glucose metabolism in osteoblasts as a pathogenic mechanism for osteopenia in T1D, and furthermore implicates boosting osteoblast glycolysis as a potential bone anabolic therapy.

Analytical Method Development by HPLC to Evaluate the Stress Degradation Stability Profile of Ertugliflozin

Diabetes is a chronic disease in which the body does not make or properly utilize the insulin, a hormone that is required to convert blood sugar, starches, and other food into energy by circulate the glucose from blood into the body cells”. People are going on making new drugs and new formulations of the existing drugs within very short period of time. To get the regulatory permission for marketing, company has to submit required data including the analysis reports as to prove that their drug product is of required quality for its intended use. T2DM, the predominant type of diabetes accounting for >90% of all diabetes cases, is a progressive disease involving parallel defects of glucose metabolism in multiple tissues. Common risk factors for T2DM include increasing age, smoking, being overweight or obese, physical inactivity and poor nutrition. Ertugliflozin is an oral, selective inhibitor of sodium glucose co-transporter-2 (SGLT2) which inhibits renal glucose reabsorption and results in urinary glucose excretion (UGE) and reductions in plasma glucose and haemoglobin A1c (A1C) in patients with type 2 diabetes mellitus (T2DM).The present developed analytical method was developed using 0.1% Formic acid in water: 0.1% Formic acid in ACN as the mobile phase. The developed method was found to be sensitive and time and cost effective with the reduced the use of organic chemicals in the mobile phase. Improved stability-indicating RP-HPLC method was developed for the estimation of ertugliflozin. Retention times compared to the best method reported. The developed method could be suitable for routine analysis of the drugs in bulk and tablet formulation after complete validation as per ICH guideline.

Osteoblast-intrinsic defect in glucose metabolism impairs bone formation in type II diabetic male mice.

Skeletal fragility is associated with type 2 diabetes mellitus (T2D), but the underlying mechanism is not well understood. Here, in a mouse model for youth-onset T2D, we show that both trabecular and cortical bone mass is reduced due to diminished osteoblast activity. Stable isotope tracing in vivo with 13C-glucose demonstrates that both glycolysis and glucose fueling of the TCA cycle are impaired in diabetic bones. Similarly, Seahorse assays show suppression of both glycolysis and oxidative phosphorylation by diabetes in bone marrow mesenchymal cells as a whole, whereas single-cell RNA sequencing reveals distinct modes of metabolic dysregulation among the subpopulations. Metformin not only promotes glycolysis and osteoblast differentiation in vitro, but also improves bone mass in diabetic mice. Finally, osteoblast-specific overexpression of either Hif1a, a general inducer of glycolysis, or Pfkfb3 which stimulates a specific step in glycolysis, averts bone loss in T2D mice. The study identifies osteoblast-intrinsic defects in glucose metabolism as an underlying cause of diabetic osteopenia, which may be targeted therapeutically.

Abstract #1408177: Spinal Muscle Atrophy Presenting with Non-Diabetic Ketoacidosis

Spinal muscle atrophy (SMA) is an untreatable neurodegenerative disease related to loss of survival motor neuron (SMN) 1 gene resulting in muscle atrophy leading to significant morbidity and mortality. Patients with SMA may present with metabolic disturbances including impaired glucose tolerance, fatty acid metabolism and hyperlipidemia. We present a case of SMA presenting with recurrent metabolic acidosis. 51-year-old female with hypertension, osteoporosis, and SMA (homozygous deletion of exon 7 in the SMN1 gene) with quadriplegia and chronic ventilator dependent respiratory failure was admitted with diarrhea, poor oral intake, nausea, and abdominal pain. She did not report sick contacts or fever and had no history of diabetes. She had similar past episodes of metabolic acidosis with acute illness. Vital signs were BP 135/74mmHg, HR 110/min, RR 20/min, afebrile, and SpO2 96% on room air. On exam she appeared ill and debilitated with dry oral mucosa, + abdominal distension and tenderness with no rebound. Labs showed anion gap metabolic acidosis, Na 136mEq/L, K 3.9mEq/L, Cl 102 mEq/L, CO2 12 mEq/L, Anion gap 22, pH 7.13, Creatinine <0.01mg/dl, glucose 110 mg/dl, 2+ urine ketones, beta hydroxybutyrate 7.39 mmol/L, WBC 23.97 K/ul and HbA1c 5.2%. She was treated for non-diabetic ketoacidosis with IV fluids and fixed dose IV insulin infusion with dextrose infusion in tandem. She had hypernatremia, hypocalcemia, hypophosphatemia and hypokalemia likely due to poor nutrition and dehydration, and with aggressive electrolyte replacement, she showed significant clinical improvement during hospitalisation. Patients with SMA are prone to metabolic derangements e.g. ketoacidosis. Several factors may contribute to ketoacidosis such as decreased muscle mass, defects in endocrine pancreatic function and abnormal fatty acid metabolism regardless of triggering factors. One study investigated glucose metabolism and pancreas development in the Smn (2B/-) intermediate SMA mouse model and type I SMA patients. In mice it demonstrated a dramatic cell fate imbalance within pancreatic islets, with a predominance of glucagon-producing α cells at the expense of insulin-producing β cells and mice displayed fasting hyperglycemia, hyperglucagonemia, and glucose resistance. Similar abnormalities in pancreatic islet cells were seen in deceased children with the severe infantile form of SMA indicating that defects in glucose metabolism may play an important contributory role in SMA pathogenesis. There are no present guidelines to manage this entity, but case reports indicated a role of volume resuscitation and electrolyte replacement for improvement and future prevention by avoiding fasting.

Altered glucose metabolism in Alzheimer's disease: Role of mitochondrial dysfunction and oxidative stress.

Increasing evidence suggests that abnormal cerebral glucose metabolism is largely present in Alzheimer's disease (AD). The brain utilizes glucose as its main energy source and a decline in its metabolism directly reflects on brain function. Weighing on recent evidence, here we systematically assessed the aberrant glucose metabolism associated with amyloid beta and phosphorylated tau accumulation in AD brain. Interlink between insulin signaling and AD highlighted the involvement of the IRS/PI3K/Akt/AMPK signaling, and GLUTs in the disease progression. While shedding light on the mitochondrial dysfunction in the defective glucose metabolism, we further assessed functional consequences of AGEs (advanced glycation end products) accumulation, polyol activation, and other contributing factors including terminal respiration, ROS (reactive oxygen species), mitochondrial permeability, PINK1/parkin defects, lysosome-mitochondrial crosstalk, and autophagy/mitophagy. Combined with the classic plaque and tangle pathologies, glucose hypometabolism with acquired insulin resistance and mitochondrial dysfunction potentiate these factors to exacerbate AD pathology. To this end, we further reviewed AD and DM (diabetes mellitus) crosstalk in disease progression. Taken together, the present work discusses the emerging role of altered glucose metabolism, contributing impact of insulin signaling, and mitochondrial dysfunction in the defective cerebral glucose utilization in AD.

Dysfunctional Glucose Metabolism in Alzheimer's Disease Onset and Potential Pharmacological Interventions.

Alzheimer’s disease (AD) is the most common age-related dementia. The alteration in metabolic characteristics determines the prognosis. Patients at risk show reduced glucose uptake in the brain. Additionally, type 2 diabetes mellitus increases the risk of AD with increasing age. Therefore, changes in glucose uptake in the cerebral cortex may predict the histopathological diagnosis of AD. The shifts in glucose uptake and metabolism, insulin resistance, oxidative stress, and abnormal autophagy advance the pathogenesis of AD syndrome. Here, we summarize the role of altered glucose metabolism in type 2 diabetes for AD prognosis. Additionally, we discuss diagnosis and potential pharmacological interventions for glucose metabolism defects in AD to encourage the development of novel therapeutic methods.

Immunometabolic rewiring of tubular epithelial cells in kidney disease.

Kidney tubular epithelial cells (TECs) have a crucial role in the damage and repair response to acute and chronic injury. To adequately respond to constant changes in the environment, TECs have considerable bioenergetic needs, which are supported by metabolic pathways. Although little is known about TEC metabolism, a number of ground-breaking studies have shown that defective glucose metabolism or fatty acid oxidation in the kidney has a key role in the response to kidney injury. Imbalanced use of these metabolic pathways can predispose TECs to apoptosis and dedifferentiation, and contribute to lipotoxicity and kidney injury. The accumulation of lipids and aberrant metabolic adaptations of TECs during kidney disease can also be driven by receptors of the innate immune system. Similar to their actions in innate immune cells, pattern recognition receptors regulate the metabolic rewiring of TECs, causing cellular dysfunction and lipid accumulation. TECs should therefore be considered a specialized cell type - like cells of the innate immune system - that is subject to regulation by immunometabolism. Targeting energy metabolism in TECs could represent a strategy for metabolically reprogramming the kidney and promoting kidney repair.

A multi-omics analysis reveals that the lysine deacetylase ABHD14B influences glucose metabolism in mammals

The sirtuins and histone deacetylases are the best characterized members of the lysine deacetylase (KDAC) enzyme family. Recently, we annotated the “orphan” enzyme ABHD14B (α/β-hydrolase domain containing protein # 14B) as a novel KDAC and showed this enzyme’s ability to transfer an acetyl-group from protein lysine residue(s) to coenzyme-A to yield acetyl-coenzyme-A, thereby, expanding the repertoire of this enzyme family. However, the role of ABHD14B in metabolic processes is not fully elucidated. Here, we investigated the role of this enzyme using mammalian cell knockdowns in a combined transcriptomics and metabolomics analysis. We found from these complementary experiments in vivo that the loss of ABHD14B results in significantly altered glucose metabolism, specifically the decreased flux of glucose through glycolysis and the citric acid cycle. Further, we show that depleting hepatic ABHD14B in mice also results in defective systemic glucose metabolism, particularly during fasting. Taken together, our findings illuminate the important metabolic functions that the KDAC ABHD14B plays in mammalian physiology and poses new questions regarding the role of this hitherto cryptic metabolism-regulating enzyme.

Elevated prohibitin 1 expression mitigates glucose metabolism defects in granulosa cells of infertile patients with endometriosis.

Endometriosis is a common disease in women of childbearing age and is closely associated with female infertility. However, the pathogenesis of endometriosis-related infertility is still not fully understood. Prohibitin 1 (PHB1), a highly conserved protein related to mitochondrial function, is differentially expressed in the endometrium of patients with endometriosis. However, the role of PHB1 in glucose metabolism in granulosa cells remains unclear. In this study, we investigated whether PHB1 expression and glucose metabolism patterns differ in the granulosa cells of patients with endometriosis and those of patients serving as controls. We then evaluated these changes after PHB1 was upregulated or downregulated in the human granulosa cell line (KGN) using a lentivirus construct. In the granulosa cells of patients with endometriosis, significantly elevated PHB1 expression, increased glucose consumption and lactic acid production, as well as aberrant expression of glycolysis-related enzymes were found compared to those without endometriosis (P < 0.05). After PHB1 expression was upregulated in KGN cells, and the expression of enzymes related to glucose metabolism, glucose consumption and lactic acid production was strikingly increased compared to controls (P < 0.05). The opposite results were found when PHB1 expression was downregulated in KGN cells. Additionally, the cell proliferation and apoptosis rates, ATP synthesis, reactive oxygen species (ROS) levels and mitochondrial membrane potential (MMP) were significantly altered after down-regulation of PHB1 expression in KGN cells (P < 0.05). This study suggested that PHB1 plays a pivotal role in mitigating the loss of energy caused by impaired mitochondrial function in granulosa cells of patients with endometriosis, which may explain, at least in part, why the quality of oocytes in these patients is compromised.

Mitochondrial and glucose metabolic dysfunctions in granulosa cells induce impaired oocytes of polycystic ovary syndrome through Sirtuin 3

Mitochondrial function and glucose metabolism play important roles in bidirectional signaling between granulosa cells (GCs) and oocytes. However, the factors associated with mitochondrial function and glucose metabolism of GCs in polycystic ovary syndrome (PCOS) are poorly understood, and their potential downstream effects on oocyte quality are still unknown. The aim of this study was to investigate whether there are alterations in mitochondrial-related functions and glucose metabolism in ovarian GCs of women with PCOS and the role of Sirtuin 3 (SIRT3) in this process. Here, we demonstrated that women with PCOS undergoing in vitro fertilization and embryo transfer had significantly lower rates of metaphase II oocytes, two-pronuclear fertilization, cleavage, and day 3 good-quality embryos. Germinal vesicle- and metaphase I-stage oocytes from women with PCOS exhibited increased mitochondrial reactive oxygen species (ROS), decreased mitochondrial membrane potential, and downregulation of glucose-6-phosphate dehydrogenase. GCs from women with PCOS presented significant alterations in mitochondrial morphology, amount, and localization, decreased membrane potential, reduced adenosine triphosphate (ATP) synthesis, increased mitochondrial ROS and oxidative stress, and insufficient oxidative phosphorylation (OXPHOS) together with decreased glycolysis. SIRT3 expression was significantly decreased in GCs of PCOS patients, and knockdown of SIRT3 in KGN cells could mimic the alterations in mitochondrial functions and glucose metabolism in PCOS GCs. SIRT3 knockdown changed the acetylation status of NDUFS1, which might induce altered mitochondrial OXPHOS, the generation of mitochondrial ROS, and eventually defects in the cellular insulin signaling pathway. These findings suggest that SIRT3 deficiency in GCs of PCOS patients may contribute to mitochondrial dysfunction, elevated oxidative stress, and defects in glucose metabolism, which potentially induce impaired oocytes in PCOS.

MO1037: Insulin Sensitivity in Children with Autosomal Dominant Polycystic Kidney Disease

Abstract BACKGROUND AND AIMS Autosomal Dominant Polycystic Kidney Disease (ADPKD) is the most common inherited kidney disorder. Defective glucose metabolism was identified as a key feature in ADPKD, and several ‘metabolic’ approaches are currently under evaluation in adults with ADPKD. Whether this defective glucose metabolism could be an early primary event and a potential therapeutic option in the early disease stages is still unknown. In this study, we evaluated the insulin sensitivity profile in genotyped children with ADPKD. METHOD We performed a cross-sectional study to evaluate the insulin sensitivity profile in a genotyped cohort of ADPKD children (&amp;lt;19 years) with preserved renal function [estimated glomerular filtration rate (eGFR) ≥60 mL/min/1.73 m2]. Overweight/obese children were respectively defined as body mass index (BMI) 25–30 and &amp;gt; 30 kg/m2. The Homeostasis Model Assessment Index (HOMA-IR) was calculated: fasting insulin (μIU mL− 1) x fasting glucose (mmol L − 1)/22.5. The Quantitative Insulin Sensitivity Check Index (QUICKI) was calculated: 1/[log (fasting insulin μU/mL) + log (fasting glucose mg/dL)]. RESULTS A total of 37 ADPKD patients (22 boys) were included with a mean ($ \pm $ SD) age at diagnosis was 10.3 $ \pm $ 4.2 years. A total of 36 patients had PKD1 mutation (one GANAB mutation). Median BMI was 16.8 ± 4.3 kg/m2. Median serum fasting glucose: 86.0 ± 9.3 mg/dL, median fasting insulin: 6.1 ± 7.2 μU/mL and median serum C-peptide: 0.4 ± 0.3 nmol/L. Median HOMA-IR was 1.4 ± 1.7 and median QUICKI was 0.4 ± 0.1. A total of 16 patients presented a HOMA-IR &amp;gt; 1.6 and 6 normal-weight children had a HOMA-IR &amp;gt; 2.3. No patient displayed glucosuria. An oral glucose tolerance test was performed on five overweight patients, four of them showed insulin resistance and were treated with metformin. CONCLUSION Even with normal BMI, ADPKD children displayed a high index of insulin resistance. Further clinical studies are needed to determine whether ADPKD could be an additional risk factor for insulin resistance.

MO016: Feasibility and Effectiveness of Short-Term Ketogenic Interventions in Autosomal Dominant Polycystic Kidney Disease (ADPKD): Results from the Reset-Pkd Study

Abstract BACKGROUND AND AIMS Over the last years, there has been increasing evidence that defects in the energy metabolism of polycystic kidney disease (PKD) cyst lining cells, especially increased glucose dependency and defects in fatty acid oxidation, may underlie the pathogenesis of ADPKD, Rowe et al. (Defective glucose metabolism in polycystic kidney disease identifies a new therapeutic strategy. Nat Med 2013; 19(4): 488–493). Based on these data, ketogenic dietary interventions have effectively been used in PKD animal models, Kipp et al. (A mild reduction of food intake slows disease progression in an orthologous mouse model of polycystic kidney disease. Am J Physiol Renal Physiol 2016;310(8):F726-F31), Torres et al. (Ketosis ameliorates renal cyst growth in polycystic kidney disease. Cell Metab 2019;30(6):1007–23 e5) and Warner et al. (Food restriction ameliorates the development of polycystic kidney disease. J Am Soc Nephrol 2016;27(5):1437–1447). As a first-in-human pilot study, the RESET-PKD study now strives to translate these promising results in the clinical setting. METHOD The present study enrolled 10 ADPKD patients with rapid disease progression. After a screening visit (V1), patients followed their usual carbohydrate-rich diet for up to 4 weeks. In a second visit (V2), patients chose to either perform a 3-day water fast (WF) or a 14-day ketogenic diet (KD) until a third study visit (V3), after which they returned to their normal high-carbohydrate diet for 3–6 weeks until a final visit (V4). At all visits, total kidney volume (TKV) and total liver volume (TLV) were monitored using MRI; anthropometric parameters, body composition and biochemical parameters (i.e. serum creatinine, complete blood cell count, glucose, β-hydroxybutyrate in fingerstick blood and acetone in breath) were measured. Ketone bodies were evaluated at all visits and in between. Feasibility was examined using respective questionnaires. Undesirable effects such as feelings of hunger and discomfort were documented in a study diary. RESULTS All participants (KD: n = 5, WF: n = 5; age: 39.8 ± 11.6 years; eGFR: 82 ± 23.5 mL/min; TKV: 2224 ± 1156 mL) were classified as Mayo Class 1C to 1E. Serum creatinine values were not altered by the ketogenic dietary interventions (V2: 1.17 ± 0.33 mg/dL versus V3: 1.20 ± 0.35 mg/dL, P = 0.826), but serum glucose levels decreased significantly (V2: 84 ± 3 mg/dL, V3: 70 ± 13 mg/dL, P = 0.004). BHB blood levels as well as acetone levels in breath increased in both study arms (V1 to V2 average acetone: 2.6 ± 1.18 ppm, V2 to V3: 22.8 ± 11.9 ppm, P &amp;lt; 0.0001; V1 to V2 average BHB: 0.22 ± 0.08 mmol/L, V2 to V3: 1.89 ± 0.92 mmol/L, P &amp;lt; 0.0001). Nine out of 10 patients reached a ketogenic state during the intervention and 90% evaluated ketogenic interventions as being feasible while 80% of patients both reached the metabolic endpoint and rated ketogenic dietary interventions as feasible. TKV changes during KD and WF did not show any significant differences compared to the period on carbohydrate-rich diet (ΔTKV V1 to V2: 0.75 ± 0.54%, ΔTKV V2 to V3: −1.06 ± 1.16%). CONCLUSION The RESET-PKD study demonstrates feasibility of short-term ketogenic interventions both regarding reliable attainment of ketosis and patient-reported feasibility of this intervention in everyday life. In this proof of principle study, short-term ketogenic interventions could not show a significant reduction in TKV. However, this endpoint is likely to require long-term exposure to ketogenesis. Future large-scale clinical trials examining such long-term dietary interventions—e.g. the KETO-ADPKD study—will be of great importance to further evaluate long-term feasibility and the therapeutic potential of ketogenic diets in ADPKD.

Glycolytic metabolism supports microglia training during age-related neurodegeneration.

Glucose is a major energy source for the brain, necessary to preserve proper neurophysiological functions; aberrant glucose metabolism in the brain has been documented in chronic neurodegenerative pathologies. In addition, glucose-dependent metabolic pathways, including substrates of the Krebs cycle, are involved in peripheral and central innate immune activation through a molecular program known as trained immunity. Notably, it seems that defective glucose metabolism favors trained immunity in the brain, leading to neuronal damage and neurodegeneration. In addition, defective glucose metabolism in the brain correlates with a positive proinflammatory profile and microglia activation, as was found in postmortem samples of neurodegenerative pathologies. We hypothesized that fluctuations in glucose supply or metabolism in the brain during aging may alter microglial training, turning these cells to unresponsive or overresponsive to a challenge during age-related neurodegeneration. This review will cover the most significant advances in glucose-dependent metabolic pathways that favor innate trained immunity of microglia and their contribution to neurodegeneration.

Autosomal Dominant Polycystic Kidney Disease: From Pathophysiology of Cystogenesis to Advances in the Treatment

Autosomal dominant polycystic kidney disease (ADPKD) is the most common genetic renal disease, with an estimated prevalence between 1:1000 and 1:2500. It is mostly caused by mutations of the PKD1 and PKD2 genes encoding polycystin 1 (PC1) and polycystin 2 (PC2) that regulate cellular processes such as fluid transport, differentiation, proliferation, apoptosis and cell adhesion. Reduction of calcium ions and induction of cyclic adenosine monophosphate (sAMP) promote cyst enlargement by transepithelial fluid secretion and cell proliferation. Abnormal activation of MAPK/ERK pathway, dysregulated signaling of heterotrimeric G proteins, mTOR, phosphoinositide 3-kinase, AMPK, JAK/STAT activator of transcription and nuclear factor kB (NF-kB) are involved in cystogenesis. Another feature of cystic tissue is increased extracellular production and recruitment of inflammatory cells and abnormal connections among cells. Moreover, metabolic alterations in cystic cells including defective glucose metabolism, impaired beta-oxidation and abnormal mitochondrial activity were shown to be associated with cyst expansion. Although tolvaptan has been recently approved as a drug that slows ADPKD progression, some patients do not tolerate tolvaptan because of frequent aquaretic. The advances in the knowledge of multiple molecular pathways involved in cystogenesis led to the development of animal and cellular studies, followed by the development of several ongoing randomized controlled trials with promising drugs. Our review is aimed at pathophysiological mechanisms in cystogenesis in connection with the most promising drugs in animal and clinical studies.

Is autosomal dominant polycystic kidney disease an early sweet disease?

The clinical course of autosomal dominant polycystic kidney disease (ADPKD) starts in childhood. Evidence of the beneficial impact of early nephron-protective strategies and lifestyle modifications on ADPKD prognosis is accumulating. Recent studies have described the association of overweight and obesity with rapid disease progression in adults with ADPKD. Moreover, defective glucose metabolism and metabolic reprogramming have been reported in distinct ADPKD models highlighting these pathways as potential therapeutic targets in ADPKD. Several "metabolic" approaches are currently under evaluation in adults, including ketogenic diet, food restriction, and metformin therapy. No data are available on the impact of these approaches in childhood thus far. Yet, according to World Health Organization (WHO), we are currently facing a childhood obesity crisis with an increased prevalence of overweight/obesity in the pediatric population associated with a cardio-metabolic risk profile. The present review summarizes the knowledge about the role of glucose metabolism in the pathophysiology of ADPKD and underscores the possible harm of overweight and obesity in ADPKD especially in terms of long-term cardiovascular outcomes and renal prognosis.

Exploring the antihyperglycemic potential of tetrapeptides devised from AdMc1 via different receptor proteins inhibition using in silico approaches.

Introduction:Diabetes mellitus is a heterogenous group of chronic metabolic disorders that results due to deficiency in insulin secretion and signalling. Multiple factors held responsible for onset of diabetes due to defects in glucose metabolism and cellular signalling mechanism. Over the past few years, many plant derived bioactive compounds have been recorded with increased efficacy and fewer side-effects against variety of diseases.Methods:In the current study, molecular docking and molecular dynamics simulation approaches were employed to evaluate the tetrapeptides devised from AdMc1 protein of Momordica charantia. Due to unavailability of appropriate template for modelling of 3D structure of AdMc1 protein, I-TASSER server was employed for prediction of good quality tertiary structure. Predicted model was refined by GalaxyRefine Web and evaluated by Verify 3D, ERRAT and Ramachandran plot analysis. Next, a ready-to-dock library of fifty tetrapeptides as potent inhibitors was prepared and docked against aldose reductase (AR), protein tyrosine phosphatase 1B (PTP1B), α-glucosidase, α-amylase and glycogen synthase kinase 3-beta as receptor proteins. Molecular dynamics (MD) simulation was performed on Schrodinger’s Desmond Module to check stability of the best docking complex.Results:Top five ligands were selected against each receptor protein based on their binding pattern and docking scores. Among selected ligands (i.e. VEID, TVEV, AYAY, EEIA, ITTV, TTIT, LPSM, RGIE, TTVE and EIAR) followed all parameters in drug scanning and ADMET screening tests. The MD simulations confirmed that the best selected peptide (i.e. VEID) docked with AR and PTP1B was structurally stable.Conclusion:In the light of overall results of all analyses employed in this study, the selected ligands could be further processed as potential hypoglycaemic drug candidates.