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PubMed2025

Exploring the therapeutic potential of extract in targeting localized adiposity.

OBJECTIVE: To determine direct targeting of localized adiposity through Morus alba Linne bark injection based on pharmacology network analysis. METHODS: Male C57BL/6J mice were fed a high-fat diet (HFD) to induce obesity. After 6 weeks on HFD, the water extract of Morus alba L.bark (MAB, 2 mg/mL) was locally injected into one inguinal fat pad, while saline was injected into the other side, 3 times/week for 6 weeks (n = 6/group). The water extract of MAB was freeze-dried and then diluted in saline before use. RESULTS: HFD-fed mice treated with local MAB topical injection showed reduced adipocyte weight and size in inguinal fat pads by dual-energy X-ray absorptiometry. No toxicity changes seen in liver, spleen, kidney tissue, or alanine aminotransferase / aspartate aminotransferase levels in serum by MAB injection. Protein levels of phosphorylated insulin receptor substrate-1 and glucose transporter type 4, and mRNA expression of adiponectin, were increased in inguinal adipose tissue injected with MAB locally. Locally MAB injection led to a decrease in glucose-6-phosphatase and phosphoenolpyruvate carboxykinase, linked to gluconeogenesis, while forkhead box protein O1, which regulates these factors, was increased. Moreover, there was an increase in adenosine 5'-monophosphate-activated protein kinase, related to lipogenesis, as well as elevated levels of hormone-sensitive lipase and fatty acid synthase, both associated with lipolysis. These results support the 'insulin signaling pathway' and 'regulation of lipolysis in adipocytes' identified in the Kyoto Encyclopedia of Genes and Genomes pathway through network analysis. CONCLUSION: This study suggests that MAB topical injection exhibits localized fat reduction by inhibiting insulin resistance, gluconeogenesis and lipogenesis mediator, while activating lipolysis enzymes within targeted adipose site.

Animals↗
PubMed2025

Two-Step Loss of GLUTs in the High-Metabolism Passerines.

Glucose transporters (GLUTs) play vital roles in cellular metabolism. Understanding their evolutionary dynamics in birds is essential for elucidating avian physiology and adaptation. However, the choice of gene detection method in gene family analysis may affect the conclusion. Here, we present a comprehensive investigation of methodologies and GLUT gene loss events in avian lineages, focusing on the loss of GLUT4 and GLUT8. To illustrate the effects of these methods, we first employed BUSCO-based homolog identification, calculated pairwise evolutionary distances between different species, and performed separate blastn and blastp searches to identify homologs in two groups of animals. Our analyses revealed a significant decline in blastn accuracy with increasing evolutionary distance, represented by relative divergence times. Through a more robust blastp-based gene detection pipeline, we provide evidence for the loss of GLUT genes in birds based on 58 vertebrate genomes, including 47 bird species. Our results support the reported early loss of GLUT4 in Aves. We also newly emphasize the absence of GLUT8 in passerines, potentially due to adaptation to high-sugar diets in their ancestors. These findings enhance our knowledge of avian metabolism and the evolution of GLUT genes.

Animals↗
PubMed1976

Electron transport components of the MnO2 reductase system and the location of the terminal reductase in a marine Bacillus.

The response of MnO2 reduction by uninduced and induced whole cells and cell extracts of Bacillus 29 to several electron transport inhibitors was compared. MnO2 reduction with glucose by uninduced whole cells and cell extracts was strongly inhibited at 0.1 mM dicumarol, 100 mM azide, and 8 mM cyanide but not by atebrine or carbon monoxide, suggesting the involvement of a vitamin K--type quinone and a metalloenzyme in the electron transport chain. MnO2 reduction with ferrocyanide by uninduced cell extracts was inhibited by 5 mM cyanide and 100 mM azide but not by atebrine, dicumarol, or carbon monoxide, suggesting that the metalloenzyme was associated with the terminal oxidase activity. MnO2 reduction with glucose by induced whole cells and cell extracts, was inhibited by 1 mM atebrine, 0.1 mM dicumarol, and 10 mM cyanide but not by antimycin A, 2n-nonyl-4-hydroxyguinoline-N-oxide) (NOQNO), 4,4,4-trifluoro-1-(2-thienyl),1,3-butanedione, or carbon monoxide. Induced cell extract was also inhibited by 100 mM azide, but stimulated by 1 mM and 10 mM azide. Induced whole cells were stimulated by 10 mM and 100 mM azide. These results suggested that electron transport from glucose to MnO2 in induced cells involved such components as flavoprotein, a vitamin K-type quinone, and metalloenzyme. The stimulatory effect of azide on induced cells was explained on the basis of a branching in the terminal part of the electron transport chain, one branch involving a metalloenzyme for the reduction of MnO2 and the other involving a metalloenzyme for the reduction of oxygen. The latter was assumed to be the more azide sensitive. Spectral studies showed the presence of a-, b-, and c-type cytochromes in membrane but not in soluble fractions. Of these cytochromes, only the c type may be involved in electron transport of MnO2, owing to the lack of inhibition by antimycin A or 2n-nonyl-4-hydroxyquinoline-N-oxide. The terminal MnO2 reductase appears to be loosely attached to the cell membrane of Bacillus 29 because of cell fractionation it is found associated with both particulate and soluble fractions. Electron photomicrographs of bacilli attached to synthetic Fe-Mn oxide revealed an intimate contact of the cell walls with the oxide particles.

Antimycin A↗
PubMed1976

Differences in neutral amino acid and glucose transport between brush border and basolateral plasma membrane of intestinal epithelial cells.

A comparison of L-valine and D-glucose transport was carried out with vesicles of plasma membrane isolated either from the luminal (brush border) or from the contra-luminal (basolateral) region of small intestinal epithelial cells. The existence of transport systems for both non-electrolytes was demonstrated by stereospecificity and saturability of uptake, as well as tracer coupling. Transport of L-valine and D-glucose differs markedly in the two types of plasma membrane with respect to stimulation by Na+. The presence of Na+ stimulated initial L-valine and D-glucose uptake in brush border, but not in basolateral membrane. Moreover, an electro-chemical Na+ gradient, oriented with the lower potential on the inside, supported accumulation of the non-electrolytes above medium concentration only in the brush border membrane. L-Valine and D-glucose transport also were saturated at lower concentrations in brush border (10-20 mM) than in basolateral plasma membranes (30-50 mM). A third difference between the two membranes was found in the effectiveness of known inhibitors of D-glucose transport. In brush border membranes phlorizin was more potent than phloretin and 2', 3', 4'-trihydroxy-4-methoxy chalcone and cytochalasin B did not inhibit at all. In contrast, with the basolateral plasma membranes the order of potency was changed to phloretin = 2',3',4'-trihydroxy-4-methoxy chalcone greater than cytochalasin B greater than phlorizin. These results indicate the presence of different types of transport systems for monosaccharides and neutral amino acids in the luminal and contra-luminal region of the plasma membrane. Active transepithelial transport can be explained on the basis of the different properties of the non-electrolyte transport systems in the two cellular regions and an electro-chemical Na+ gradient that is dependent on cellular metabolism.

Animals↗
PubMed1979

Effect of sulphated glycopeptides on kinetics of 3-O-methyl glucose and 2-deoxyglucose transport by epithelial cells isolated from rabbit small intestine.

Suspensions of cells isolated from rabbit small intestine were prepared which showed a considerable rate of respiration after 4 h of their isolation. Rabbit intestinal cells accumulated 3-O-methyl-glucose by an active transport mechanism which was Na+-dependent whereas 2-deoxyglucose was transported by a saturable pathway. Analysis of the initial transport data indicated that the uptake of both sugars by cells followed Michaelis-Menten-type kinetics. These cells also showed a considerable degree of 2-deoxyglucose phosphorylation and the transport of the sugar into the cells appeared to be a rate-limiting factor for its phosphorylation. Sulphated glycopeptide had no effect on the respiration rate of these cells but it increased the transport of 3-O-methyl-glucose and 2-deoxyglucose into cells by many fold compared with untreated cells. Kinetic analysis of the data indicated that the increase in the transport was due to increased V while the Km remained unchanged. Presence of sulphated glycopeptide had no effect on the kinetics of phosphorylation of 2-deoxyglucose. These effects of sulphated glycopeptide on the transport activity of the cells have been discussed as a result of an increase in the number of sugar sites in the cell membrane due to unmasking or activation of preexisting sites owing to the interaction between the cell membrane components and highly polyanionic sulphated glycopeptides.

Animals↗
PubMed1977

Glucose effect in tgl mutant of Escherichia col K12 defective in methyl-alpha-D-glucoside transport.

1. The dependence of the rate of accumulation of methyl-alpha-D-glucoside on its extracellular concentration was studied in the tgl mutant of Escherichia coli K12, isolated earlier. It has been shown that the kinetics of methyl-alpha-D-glucoside transport differ sharply from those in wild-type bacteria. 2. The beta-galactosidase synthesis in tgl strain is much less sensitive both to permanent and transient glucose catabolite repression. The level of cyclic AMP in mutant cells under the conditions of glucose catabolite repression is several times higher than in the parent strain. 3. The tgl mutation does not affect the manifestation of catabolite inhibition and inducer exclusion with glucose. 4. The data obtained are discussed in the light of a hypothesis concerning the existence of two sites, binding and pecific enzyme II of the phosphoenolpyruvate-dependent phosphotransferase system. The tgl mutation alters the first site, and the second one is damaged by the pgt mutation. 5. It is suggested that the products of the tgl and gpt genes are necessary for the manifestation of the phenomena of glucose permanent and transient repression. The effects of catabolite inhibition and inducer exclusion are realized irrespective of the existence or absence of the tgl product.

Amino Acids↗
PubMed1975

On the regulation of adenosine 3', 5'-monophosphate synthesis in bacteria. I. Effect of carbon source variation on cyclic AMP synthesis in Escherichia coli B/r.

1. The effect of carbon source variation in bacterial growth media on their growth rate, inducible enzyme and cyclic AMP synthesis was examined: an inverse relationship between the culture's growth rate and its differential rate of inducible enzyme (tryptophanase and beta-galactosidase), and cyclic AMP synthesis was found. 2. The effect of the culture's growth phase on its sensitivity or resistance to glucose catabolite repression was determined in the wild type and a catabolite insensitive mutant (ABDROI): the wild type's sensitivity to glucose repression was not affected, whereas the insensitivity of the mutant was found to be limited to its early logarithmic phase of growth. At late log, or stationary phase, the mutant was found to be sensitive to glucose repression. 3. Examination of the kinetics of glucose uptake by the mutant, using alpha-[1 4-C] methyl-glucoside showed evidence for two transport systems each with a different affinity to glucose. A low affinity transport system (apparent Km of 3.4-10-minus 5 M) which appears mostly at the early logarithmic phase of growth. A high affinity transport system (apparent Km of 1.2-10-minus 5 M) which appears mostly at the late log and stationary phases of growth. 4. The effect of the culture density variation on its sensitivity to glucose repression showed that sensitivity to glucose catabolic repression is primarily a reflection of the formation of an allosteric effector molecule between glucose and its specific transport molecule which in turn regulates the activity of the adenylate cyclase.

Allosteric Regulation↗
PubMed1976

Pig reticulocytes: I. Transitory glucose permeability and metabolism.

Glucose permeability and metabolism were examined in the reticulocytes of pigs made anemic by daily administration of phenylhydrazine for 5-7 days. Blood samples containing 70-90% reticulocytes were fractionated according to their density by centrifugation. The most immature reticulocytes obtained from the top centrifugal fractions possessed a glucose permeation mechanism. The salient features of glucose transport include a) saturable kinetics with Vm ranging from 0.1 to 0.4 mumol/ml cell X min and with Km ranging from 6.6 to 12 mM, b) inhibition by phloretin, and c) countertransport characteristics suggesting that the glucose entry was mediated by a mechanism involving membrane carrier-type transport. In the course of reticulocyte maturation leading to mature red cells, the glucose carrier mechanism was discarded or rendered ineffective, resulting in nonglycolytic mature red cells. Glucose and ribose consumptions in the most immature reticulocytes were 2.5 and 0.75 mumol/ml cell X h, respectively. Concomitant with the diminishing glycolytic ability, ribose consumption was enhanced slightly as the reticulocytes matured to red cells. Dihydroxyacetone, a potent metabolic substrate for the mature pig red cell, was utilized readily by the reticulocytes.

4-Chloromercuribenzenesulfonate↗
PubMed1975

A comparative study of inner membrane enzymes and transport systems in mitochondria from R3230AC mammary tumor and normal rat mammary gland.

Mitochondria from a rat mammary tumor (R3230AC) have been compared with mitochondria from pregnant and lactating rat mammary glands, with particular attention paid to inner membrane enzymes and Transport proteins. In the tumor the mitochondrial adenosine triphosphatase was not activated by 2,4-dinitrophenol, in contrast to the mammary mitochondria from lactating or pregnant rats. Translocation of adenosine diphosphate across the inner membrane was found to be more rapid in the tumor by virtue of lovered Km adenosine diphosphate and raised Vmax. Transport of phosphate and dicarboxylic acids occurred at similar rates in all three types of mitochondria. The inner membrane proteins were also examined directly by sodium dodecyl sulfate/polyacrylamide gel electrophoresis and some differences are noted. These results, although they indicate subtle differences between the inner mitochondrial membranes of tumor as compared with those of pregnant or lactating rat mammary glands, cannot form the basis of an explanation for enhanced glucose utilization and aerobic lactic acid production in this tumor.

Adenocarcinoma↗
PubMed1979

The permeability of rat liver lysosomes to sugars. Evidence for carrier-mediated facilitated diffusion.

1. By the osmotic-protection method, the penetration of sugars through the rat liver lysosomal membranes was studied with a view of determining whether sugar uptake was by facilitated diffusion. 2. The following criteria for this type of transport were established: sugar specificity, the order of uptake being 2-deoxy-D-glucose less than D-glucose less than D-mannose less than D-galactose less than D-ribose less than 2-deoxy-D-ribose; stereospecificity, the uptake of L-glucose and L-ribose being 50% slower than their D-stereoisomers; inhibition by 1 MM-phlorrhizin and 1 M-cytochalastin B; competition between sugars for uptake, and a Q10 (rate difference over a 10 degrees C temperature range) for uptake of approx. 2.8. 3. It is proposed that sugar uptake into lysosomes from rat liver is by facilitated diffusion.

4-Nitrophenylphosphatase↗
PubMed1977

Energy-dependent uptake of calcium by the yeast Schizosaccharomyces pombe.

1. In resting cells of the fission yeast Schizosaccharomyces pombe, the uptake of calcium is stimulated by the addition of 90 mM glucose in the presence as in the absence of respiration and inhibited by Antimycin A in the absence of exogenous carbon source. This uptake therefore requires fermentative or respiratory metabolic energy. 2. The calcium uptake by S. pombe exhibits saturation kinetics and high affinity for calcium. At external pH 4.5, the apparent Km is 45 muM ca2+ 400 muM of other divalent cations exert competitive inhibitions of calcium uptake in the following order of affinities: Sr2+ greater than Mn2+ greater than Co2+ greater than Mg2+. Inhibition by KCl is also observed but is of non-competitive type and requires high concentrations of the order of 40 mM. 3. At 30 degrees C, the uptake rate of calcium is about 10-times higher at pH 8925 than at pH 4.0. An extrusion of 45Ca2+, the rate of which is estimated to be lower than one-fifth of the uptake, is observed in the presence of glucose when the external pH is acid. 4. At external pH 4.5, low concentrations of lanthanum chloride, ruthenium red and hexamine cobaltichloride are inhibitory for the uptake of calcium by the yeast cells. 5. In presence of Antimycin A, the uncouplers: NaN3, dinitrophenol, and concentrations of crobonylcyanide m-chlorophenylhydrazone higher than 80 muM inhibit the calcium uptake by glycolysing cells. In the presence of glucose, the K+ ionophore Dio-9 dnhances severalfold the uptake of calcium even at 2 degrees C. 6. It is concluded that S. pombe possess an active transport system for low concentrations of calcium. This transport seems to be dependent on an electric potential (negative inside) across the cellular membrane.

Antimycin A↗
PubMed1976

The ammocoetes endostyle: its oxidative enzymes as an evidence of its homology with the thyroid of higher chordates.

Histochemical methods were used for the demonstration of activity of the following intracellular oxidative enzymes, unstudied hitherto, in the epithelial cells of the endostyle of the river lampre (Lampertr aluviatilis L.) ammocoetes: reduced NAD dehydrogenase (NADD), lactate dehydrogenase (LD), cytochrome oxidase (CO), succinate dehydrogenase (SD), alpha-glycerophosphate dehydrogenase (alphaGPD) and glucose-6-phosphate dehydrogenase (G6PD). The activities of NADD and LD in the iodophil and throidogenic cells of type 3, then of subtype 2c and partly types 4 and 5 of the endostylar epithelium and the hypobranchial duct-lining epithelium were particularly ithe larva proves the possibility of their participation in the formation of the thyroid gland in the period of metamorphosis. In type 1 cells of the ammocoetes, despite their fairly strong enzymatic reactivity, the oxidative activity does not change significantly during the ontogenetic stages examined. The data obtained make it possible to modify the present views on the genesis of the thyroid gland of the adult lamprey, namely, they indicate the participation of the type 6 cells of the hypobranchial duct-lining epithelium in the process of thyroidogenesis.

Animals↗
PubMed1977

Phosphohexosyl components of a lysosomal enzyme are recognized by pinocytosis receptors on human fibroblasts.

Human beta-glucuronidase (beta-D-glucuronide glucuronosohydrolase, EC 3.2.1.31), like many other glycoprotein lysosomal hydrolases, is specifically taken up from the culture medium by human fibroblasts. Prior work has indicated that the enzyme exhibits charge heterogeneity and that "high-uptake" forms, i.e., those rapidly internalized by human fibroblasts, are more acidic than slowly internalized forms. Here we present two lines of evidence that the acidic group required for the high-uptake property of certain forms of the enzyme is a phosphate on, or in proximity to, a D-mannose-type carbohydrate. The first line of evidence was obtained from analysis of inhibition of enzyme pinocytosis by yeast mannans, phosphorylated sugars, and sugars. Mannans that contained phosphate were more potent inhibitors than those that did not contain phosphate. D-Mannose 6-phosphate was a more potent inhibitor than either D-mannose 1 phosphate or 2-deoxy-D-glucose 6-phosphate. D-Mannose and certain related sugars were weak pinocytosis inhibitors, while 2- and 4-epimers of mannose were noninhibitory. Competitive inhibition was demonstrated and the apparent Kis estimated for the following compounds: Saccharomyces cerevisiae mannan from mutant X2180-mnnl, 3 X 10(-6) M; mannan from wild-type S. cerebisiae, 3 X 10(-5) M; D-mannose 6-phosphate, 6 X 10(-5) M; L-fucose, 4 X 10(-2) M; and D-mannose, 6 X 10(-2) M. The second line of evidence comes from the observation that alkaline phosphatase [orthophosphoric-monoester phosphohydrolase (alkaline optimum), EC 3.1.3.1] treatment of human platelet beta-glucuronidase abolished its "high-uptake" activity, without diminishing its catalytic activity, and converted some forms of the heterogeneous enzyme to less acidic forms.

Alkaline Phosphatase↗
PubMed1976

Mitogen receptors in chick embryo fibroblasts. Kinetics, specificity, unmasking, and synthesis of 125I-insulin binding sites.

Insulin, a mitogen for cultured chick embryo fibroblasts (Temin, H.M. (1968) Cancer 3, 771-787), has been employed to characterize the effects of mitogen/cell membrane interactions as it relates to growth. The specific binding of 125I-insulin to substratum-attached cells is time- and temperature dependent and is optimum at a pH of 7.0. Fetal calf and chicken sera, somatomedin "A/C mixed," and desalanine or native porcine insulin compete with 125I-insulin for membrane-binding sites. Proinsulin, although competing less effectively than native insulin for binding, is more effective than desoctapeptide insulin. Unrelated polypeptide hormones do not compete for 125I-insulin binding. The lowest concentration of insulin at which specific binding is detected is 0.1 nM. Scatchard plot analysis of the binding data indicates that there are two types of binding sites in confluent cultures of fibroblasts: one of high affinity (K1 = 2 to 6 X 10(8) M-1) and low capacity, the other of low affinity (K2 = 0.8 to 3.0 X 10(7) M-1) and high capacity. Approximately 1.9 and 7.1 X 10(3) molecules of insulin are bound at each site, respectively. A 10-min incubation at 24 degrees of the fibroblasts with 10 mug/ml of trypsin causes a 2-fold stimulation of specific 125I-insulin binding and a similar 2-fold increase in insulin-stimulated 2-deoxy-D-glucose uptake and thymidine incorporation. Neuraminidase treatment also produces a 37% increase in specific 125I-insulin binding but treatment with alpha-chymotrypsin or phospholipase C are without significant effect. The results of this and additional experiments support the hypothesis that trypsin treatment of chick embryo fibroblasts leads to an unmasking of 125I-insulin binding sites. Serum starvation of fibroblasts for 12 or 24 h produces a 2.5- to 5-fold increase in specific 125I-insulin binding. This increase is the result of an increase in the number of hormone-binding sites from 9 X 10(3) to 6 X 10(4) per cell which are predominantly of the low affinity type. There is no change in the affinity constants. The presence of camptothecin, or cordycepin, or cycloheximide in the incubation medium completely blocks the increase in number of 125I-insulin-binding sites resulting from serum starvation. The addition of native insulin to the medium of serum-starved cultures also blocks this increase. The magnitude of insulin-stimulated 2-deoxy-D-glucose uptake and thymidine incorporation correlates with the levels of occupancy of the low affinity 125I-insulin-binding sites in untreated fibroblasts. In fibroblasts cultured in the absence of serum, the marked increase in insulin-stimulated 2-deoxy-D-glucose uptake and thymidine incorporation parallels the increase in number of mitogen receptors. The concentration of insulin that produces a half-maximum stimulation of thymidine incorporation is calculated to be 5 X 10(-8) M. At this concentration of insulin, 42% of the receptor sites are occupied.

Animals↗
PubMed1978

Regulation of the galactose pathway in Saccharomyces cerevisiae: induction of uridyl transferase mRNA and dependency on GAL4 gene function.

In Saccharomyces cerevisiae, utilization of galactose requires four inducible enzyme activities. Three of these activities (galactose-1-phosphate uridyl transferase, EC 2.7.7.10; uridine diphosphogalactose 4-epimerase, EC 5.1.3.2; and galactokinase, EC 2.7.1.6) are specified by three tightly linked genes (GAL7, GAL10, and GAL1, respectively) on chromosome II, whereas the fourth, galactose transport, is specified by a gene (GAL2) located on chromosome XII. Although classic genetic analysis has revealed both positive and negative regulatory genes that coordinately affect the appearance of all four enzyme activities, neither the basic events leading to the appearance of enzyme activities nor the roles of the regulatory genes have yet been determined. Regulation of inducible enzyme activity could be mediated by events related to transcription, translation, or enzyme activation. For the purpose of studying galactose pathway induction and its regulation, we have developed an immunoprecipitation assay that enables us to detect the GAL7 specified uridyl transferase polypeptide in yeast extracts and among the polypeptides synthesized in an RNA-dependent in vitro translation system. Use of this immunoprecipitation assay in conjunction with in vivo labeling experiments demonstrates the presence of [(3)H]leucine-labeled transferase in extracts prepared from cells grown in galactose but not from cells grown in glucose. This galactose-specific induction of transferase polypeptide is mediated by the de novo appearance of a functional mRNA species whose synthetic capacity is detectable by the combination of in vitro translation and immunoprecipitation. The appearance of functional transferase mRNA depends on wild-type expression of the positive regulatory gene, GAL4. Cells carrying a nonsense (amber) mutation in the GAL4 gene fail to produce the transferase mRNA, whereas a nonsense suppressor of the GAL4 amber mutant regains the galactose-specific mRNA response. Our results establish that the induction of the GAL7 specified uridyl transferase activity is mediated by de novo appearance of a functional mRNA and that this galactose-specific response is dependent on a wild-type GAL4 gene product.

Cell-Free System↗
PubMed2026

Glycemic and Renal Effects of SGLT2 Inhibitors in Monogenic Diabetes: A Real-World National Study.

AIMS: Evidence regarding the efficacy and safety of sodium-glucose cotransporter 2 inhibitors (SGLT2i) in monogenic diabetes is limited. We evaluated real-world metabolic, renal, and safety outcomes of SGLT2i therapy in adults with monogenic diabetes. MATERIALS AND METHODS: This multicenter retrospective study included adults with genetically confirmed monogenic diabetes treated with SGLT2i. Clinical and biological data were collected at baseline and after approximately 1 and 2 years. Longitudinal changes were analysed using linear mixed-effects models adjusted for baseline value, age, and sex and treatment intensification. RESULTS: Forty patients (mean age 48.6 ± 15.2 years) with MIDD (n = 16), HNF1B-MODY (n = 9), HNF1A/HNF4A-MODY (n = 11), or other MODY subtypes (ABCC8, INS, RFX6; n = 4) were followed for 23.9 ± 5.9 months. HbA1c remained stable overall but decreased significantly in patients with baseline HbA1c ≥ 8% (9.6% ± 1.3% to 7.6% ± 0.7%; p = 0.001). UACR declined significantly (-35.6% at 1 year and -43.5% at 2 years; p = 0.004), particularly in those with baseline CKD (trend). Genotype-specific trends suggested greater glycemic improvement in HNF1A/HNF4A-MODY and greater UACR reduction in MIDD. eGFR declined modestly over time. Non-serious adverse events occurred in 15% of patients, 7.5% discontinued treatment, and no ketoacidosis, acute kidney injury, or deaths were reported. CONCLUSIONS: In this nationwide cohort of patients with monogenic diabetes-the largest reported to date-SGLT2i therapy was associated with improved glycemic control in individuals with baseline HbA1c ≥ 8%, reduced albuminuria, and showed a favourable safety profile. These findings support SGLT2i as a potential therapeutic option that warrants confirmation in larger controlled studies.

Humans↗
PubMed1977

Sodium efflux from voltage clamped squid giant axons.

1. The efflux of radioactive sodium was measured from squid axons during simultaneous voltage clamp experiments such that it was possible to determine the efflux of sodium associated with a measured voltage clamp current. 2. The extra efflux of sodium associated with voltage clamp pulses increased linearly with the magnitude of the depolarization above 40 mV. A 100 mV pulse of sufficient duration to produce all of the sodium current increased the rate constant of efflux by about 10(-6). 3. Application of 100 nM tetrodotoxin eliminated the sodium current and the extra efflux of radioactive sodium. 4. Cooling the axon increased the extra efflux/voltage clamp pulse slightly with a Q10 of 1/1-1. On the same axons cooling increased the integral of the sodium current with a Q10 of 1/1-4. 5. Replacing external sodium with Tris, dextrose or Mg-mannitol reduced the extra efflux of sodium by about 50%. The inward sodium current was replaced with an outward current as expected. 6. Replacing external sodium with lithium also reduced the extra efflux by about 50% but the currents seen in lithium were slightly larger than those in sodium. 7. The effect of replacing external sodium was not voltage dependent. Cooling reduced the effect so that there was less reduction of efflux on switching to Tris ASW in the cold than in the warm. 8. The extra efflux of sodium into sodium-free ASW is approximately the same as the integral of the sodium current. Adding external sodium produces a deviation from the independence principle such that there is more exchange of sodium than predicted. Such a deviation from prediction was noted by Hodgkin & Huxley (1952c). 9. Using the equations of Hodgkin & Huxley (1952c) modified to include the deviation from independence reported in this paper and its temperature dependence, one can predict the temperature dependence of the sodium efflux associated with action potentials and obtain much better agreement than is possibly without these phenomena. 10. This deviation from independence in the sodium fluxes is the type expected from some kind of mixing and binding of sodium within the membrane phase.

Animals↗
PubMed1978

Adenosine triphosphatases of rat pancreatic islets: comparison with those of rat kidney.

Electrolyte fluxes are fundamental to normal endocrine pancreatic function. Adenosine triphosphatases (ATPases) are enzyme systems believed to modulate electrolyte movements across membranes in a number of cell types. This study was undertaken to measure cation-dependent ATPases of rat pancreatic islets. In addition, we compared effects of substances which influence endocrine pancreatic function upon ATPases in homogenates of islets and kidney, the latter being a tissue which would not be expected to have a stimulus-secretion response to substances which activate islets. Both tissues were generally similar with respect to apparent Michaelis constant (ATP) of Na(+)K(+)ATPase, Mg(++)ATPase, and Ca(++)ATPase. In islets and kidney, Na(+)K(+)ATPase specific activity was increased when the Na:K ratio was lowered from 250:1 (175:0.7 mM) to 5:1 (100:20 mM). Inhibition of Na(+)K(+)ATPase at either Na:K ratio by ouabain, an activator of secretion, and enhancement of the high-ratio Na(+)K(+)ATPase by diphenylhydantoin, an islet secretory inhibitor, were also common to both tissues. Because both inhibition and enhancement of Na(+)K(+)ATPase could be studied at the high Na:K ratio, we examined the effect of regulators of secretion upon the activity of this enzyme. Like ouabain, substances which induce or support islet secretion, glucose 16 mM or 3.3 mM, arginine 14.2 mM (with 3.3 mM glucose), or Ca(++) 1 mM, inhibited high-ratio islet Na(+)K(+)ATPase. Like diphenylhydantoin, the inhibitors of insulin secretion, diazoxide 0.22 mM, or NH(4)Cl 16 mM, enhanced this islet ATPase. Neither valine, which is non-secretogenic, nor arginine without glucose, which is a weak secretagogue, had any effect upon islet Na(+)K(+)ATPase. We examined the effect of these substances upon other cation-dependent islet ATPases. Ca(++) inhibited Mg(++)ATPase, and glucose inhibited Ca(++)ATPase. Leucine, 22.9 mM, which induces insulin secretion in the absence of glucose, suppressed islet Ca(++)ATPase and had no effect upon high-ratio Na(+)K(+)ATPase. In contrast to the observations in the islets, most substances which influence islet function had no effect on kidney ATPases, or effects which were different from those seen in islets. Except for ouabain, none of these substances influenced the three kidney ATPases in a manner similar to that seen with islets. These findings support the hypothesis that cation-dependent ATPases are involved in specificity of islet response to substances which influence endocrine pancreatic activity.

Adenosine Triphosphatases↗