Guan, H. Rfit: rank-based estimation for metbaolism models. Prodigal v. Clinicians can review the recorded data to determine whether the patient is experiencing undetected hyperglycemia or hypoglycemia.

Carbohydrate metabolism and diabetes -

We therefore tried to infer possible associations between host inflammatory signatures of IR and faecal carbohydrates. First, the cross-omics correlation-based network with individual metabolites, bacteria, transcripts and cytokines associated with IR revealed that faecal carbohydrates were strongly tied with both bacteria and host IR-related signatures, especially cytokines, suggesting that these metabolites are the hubs of the host—microorganism network in IR Fig.

Differential abundance, calculated as the ratio of their abundance in IR and IS, was most pronounced in the associations between faecal carbohydrates and cytokines. Notably, IL, a plasma cytokine, showed the most prominent associations with faecal carbohydrates and modestly with PBMC-derived transcripts, supporting recent studies showing its paradoxical effect to facilitate IR 35 , 36 , Faecal carbohydrates moderately explained the variance of IL and, to a lesser extent, adiponectin, leptin and serpin E1, suggesting that faecal carbohydrates are particularly associated with these cytokines Fig.

Although the proportions of variance explained by faecal carbohydrates were lower than by plasma metabolites, they were much higher than those by genus-level abundance, highlighting the role of faecal metabolites linking gut microbiota and host inflammatory responses.

We next sought to infer whether these cytokines mediated the effects of faecal carbohydrates on host metabolism using causal mediation analyses We found that IL, serpin E1, adiponectin and leptin mediated most in silico causal relationships between faecal carbohydrates and host IR markers such as HOMA-IR Fig.

Notably, there were unique correspondences between metabolites and cytokines; for example, IL mediated the effects of fructose, mannose, xylose and rhamnose, but not other metabolites. Although the biological importance of these unique correspondences remains to be investigated, the combined analyses of faecal microbiota, metabolome and host inflammatory phenotypes in IR suggest a previously unrecognized interaction, whereby excessive monosaccharides may affect host cytokine expression.

Host-derived markers significantly associated with IR Supplementary Tables 19 — 21 , 15 faecal carbohydrates and 20 genera identified in Fig. The line widths show the absolute values of coefficients, and the red and grey lines show positive and negative correlations, respectively.

Detailed information with complete annotations is shown in Extended Data Fig. b , The explained variance of ten plasma cytokines predicted by each omics dataset using random-forest classifiers.

c , An alluvial plot showing the plasma cytokines significantly mediated the in silico effects of faecal carbohydrates on host metabolic markers. The lines show the mediation effects and the colours represent the associations mediated by individual cytokines.

Details are provided in Supplementary Table The above findings from human multi-omics analyses revealed an association between carbohydrate metabolites and IR pathology. To address the causal relationship between gut microbiota, faecal carbohydrates and metabolic diseases, we first analysed metabolites in the bacterial culture of 22 human faecal IS- and IR-associated bacteria.

These bacteria were selected on the basis of the findings from the genus-level co-occurrence Fig. Principal component analysis plots of metabolites indicated that Bacteroidales, a representative IS-associated bacterial order, showed a distinct metabolic profile along PC1 Extended Data Fig.

The top 10 metabolites contributing to the group separation included several amino acids and fermentation products such as succinate and fumarate, and the majority of these metabolites were preferentially produced by Bacteroidales Extended Data Fig.

We detected 13 out of 15 carbohydrates associated with IR Fig. Most of these carbohydrates were plotted negatively along PC1, suggesting that these metabolites were negatively associated with Bacteroidales.

Glucose, mannose and glucosamine were preferentially consumed by Bacteroidales compared with the other orders, whereas lactulose was mainly produced by Eubacteriales Extended Data Fig. Alistipes indistinctus was the most potent in consuming a wide variety of carbohydrates Extended Data Fig.

These findings show that Bacteroidales species are potent consumers of several carbohydrates, driving the production of their fermentation products.

We next tested the potential therapeutic effects of seven candidate bacteria shown to be associated with IS in human cohort findings. Postprandial blood glucose levels were particularly reduced in mice administered with A.

indistinctus , Alistipes finegoldii and Bacteroides thetaiotaomicron that were fed a high-fat diet Fig. Insulin tolerance tests also revealed that these strains ameliorated IR, most prominently by A.

indistinctus administration Fig. indistinctus administration ameliorated body mass gain, ectopic triglyceride accumulation in the liver and glucose intolerance Extended Data Fig. Serum levels of HDL-C, adiponectin and, to a lesser extent, triglycerides, were also improved in mice that were treated with A.

indistinctus Extended Data Fig. The findings of the hyperinsulinaemic—euglycaemic clamp analysis indicated that A. indistinctus administration significantly improved IR and, particularly, whole-body glucose disposal Extended Data Fig. Phosphorylation of AKT in the liver and epididymal fat was increased in mice treated with A.

indistinctus and A. finegoldii mice Extended Data Fig. These findings reveal a potency of A. indistinctus administration in ameliorating diet-induced obesity and IR. The abbreviations are defined in Extended Data Fig. d , The correlations between the AUC of the insulin tolerance test and caecal levels of fructose, glucose and mannose in the A.

indistinctus sky blue or vehicle grey groups. ITT, insulin tolerance test. Representative data of two a and d or three b and c independent experiments. Exact P values for a and c are provided in the Source Data. Mechanistically, metabolic measurement revealed that carbohydrate oxidation was significantly reduced in mice that were treated with A.

indistinctus , implying that carbohydrate use is limited Extended Data Fig. As dietary intake and locomotor activity remained unchanged Extended Data Fig. In this regard, A. indistinctus administration substantially altered caecal metabolites, characterized by a reduction in several carbohydrates including fructose, a lipogenic monosaccharide 39 Extended Data Fig.

Fructose was similarly reduced in the serum Extended Data Fig. Importantly, the AUC of insulin tolerance test was positively correlated with the caecal monosaccharides fructose, glucose and mannose Fig.

Collectively, these findings reveal that A. indistinctus ameliorates IR and affects intestinal carbohydrate metabolites in mice, supporting our observations in the human cohort. To deepen our understanding of the host—microorganism relationship in IR, we used multimodal techniques to conduct a comprehensive and extensive study investigating the interactions between the gut microbiome and metabolic diseases in humans.

Although carbohydrate metabolism by the gut microorganisms has been suggested to influence the pathogenesis of obesity 3 , 4 , 25 and prediabetes 6 , 8 , the actual mechanistic linkage has been elusive in humans owing to the lack of detailed metabolomic information. In this regard, the major strength of our approach is that we combine faecal metabolomics cataloguing more than 2, annotated metabolites with both microbiome and host pathology.

This metabolome-based approach enabled us to identify the faecal metabolites related to IR, identify an association between faecal carbohydrates and low-grade inflammation of IR, and efficiently select candidate strains for functional validations in experimental settings Extended Data Fig.

Together, our study highlights the advantage of comprehensive omics strategy in exploring the involvement of microbial metabolism and their products in the pathogenesis of IR. Excessive monosaccharides have the potential to promote ectopic lipid accumulation while also activating immune cells, leading to low-grade inflammation and IR 40 , 41 , Fructose is a widely recognized risk factor for inflammation and IR due to its role in lipid accumulation 39 , whereas galactose has been shown to participate in the energy metabolism of activated immune cells Our in vivo studies confirm that A.

indistinctus administration improves lipid accumulation and thereby IR, while simultaneously reducing intestinal monosaccharide levels Fig. Nevertheless, we are aware that further mechanistic studies are needed to examine the kinetics of absorption and their effects on host metabolism.

In particular, how Alistipes strains suppress carbohydrate metabolism is an intriguing question for example, whether these bacteria per se inhibit carbohydrate metabolism, or whether they interact with other commensals , as it would directly open the possibility of a new therapeutic strategy.

Given that A. indistinctus improved whole-body IS Extended Data Fig. Such investigations hold the potential to shed light on the underlying mechanisms that contribute to A. indistinctus -mediated improvement of IR. Finally, two participants in the human study were unable to collect their faeces in the morning, which could potentially influence the outcomes due to the lack of stringent control over time-of-day and fasting conditions.

We therefore believe that longitudinal studies incorporating a timely documentation of dietary habits are warranted to dissect the intricate impacts of microbial metabolism on the trajectory of diabetes and its complications while accounting for potential confounding factors.

The study participants were recruited from to during their annual health check-ups at the University of Tokyo Hospital. The individuals included both male and female Japanese individuals aged from 20 to 75 years. Written consent was obtained from the participants after a thorough explanation of the nature of the study at their health-checkups.

The sample size was determined on the basis of previous metagenomics studies showing microbial signatures of diabetic patients 5 , 6.

We enrolled , and individuals for the normal, obese and prediabetic groups, respectively. The participants were provided with instructions to fast overnight before their visits, and all clinical information and blood samples were collected in the morning during their hospital visit.

The participants were also instructed to collect faecal samples in the morning and were provided with guidance on how to collect and preserve faecal samples, along with a kit comprising a sampling tube and an ice pack. The faecal samples were then transported to the hospital either by refrigerated shipping or by the participants themselves.

Consequently, participants collected their faeces in the morning on the day of their hospital visit. As for the remaining participants, they collected their faeces in the morning between 2 days before and 7 days after their hospital visit, with the exception of 5 individuals who collected their faeces in the morning more than 7 days after their hospital visit, 2 individuals who reported collecting their faeces in the evening 1 day before their hospital visit, and 5 individuals who did not provide faecal samples.

Moreover, two individuals withdrew from the study after enrolment. Thus, individuals who underwent physical examination, laboratory tests, faecal sampling for faecal 16S rRNA pyrosequencing and metabolomic analyses, and plasma sampling for plasma metabolomic analyses were included for the analysis.

Owing to the limited samples, faecal metagenomics data were available for individuals; CAGE analysis data for individuals; and plasma cytokine and insulin data for individuals. The number of samples included in each analysis is described in the figure legends.

Although we determined the criteria for enrolment, these criteria were not necessarily appropriate for subsequent analyses. For example, those in the prediabetes group were significantly leaner than those in the obese group We therefore reasoned that, in these subclinical conditions of diabetes, many metabolic traits may be overlapping between prediabetes and obesity groups and they do not necessarily capture their distinct features in metabolic and clinical continuums.

This hinders us from distinguishing microbial and metabolomic characteristics directly related to human metabolic dysfunctions. Nevertheless, we observed consistent results even with the clinical criteria of obesity and prediabetes Extended Data Fig.

HOMA-IR values could be calculated for individuals only, owing to the limited data of plasma insulin in some participants. Individuals who meet the criteria of abdominal circumference but only one clinical abnormality were defined as pre-MetS, as reported previously Measurements below the lower detection limits were considered to be zero, and those above the upper detection limits were considered to be the highest values of analysed cytokines.

DNA of the faecal microbiome was extracted from the pellet. The analysis was performed using a Shimadzu GCMS-TQ triple quadrupole mass spectrometer with a capillary column BPX5.

The data were processed and concentration was calculated by LabSolutions Insight Shimadzu. The values below the limit of detection were replaced with zero. The lipidomics analysis was performed according to a previously reported study Methanol, isopropanol, chloroform and acetonitrile of liquid chromatography LC —MS grade were purchased from Wako.

Ammonium acetate and EDTA were purchased from Wako and Dojindo, respectively. Milli-Q water was purchased from Millipore Merck. EquiSPLASH was purchased from Avanti Polar Lipids.

Palmitic acid-d 3 and stearic acid-d 3 were purchased from Olbracht Serdary Research Laboratories. All of the samples were divided into four batches for plasma analyses and five batches for faecal analyses, with 70—80 and 55—60 samples per batch after randomization, respectively.

A quality control sample was prepared by mixing the same volume of plasma from the first batch subjects. A procedure blank was prepared by using the same volume of water instead of a biological sample. The blank sample was analysed at the beginning and the end of each analysis batch, and the quality-control sample was injected every ten study samples.

The LC system consisted of a Waters Acquity UPLC system. A sample volume of 0. All analyses were performed in high-resolution mode in MS1 ~35, full width at half-maximum and the high sensitivity mode ~20, full width at half-maximum in MS2.

MS-DIAL v. The default values were used for other parameters. In faecal lipidomics, a total of 48, and 20, chromatographic peaks were detected in positive- and negative-ion mode data, respectively.

Of these, 2, unique lipid molecules were annotated and semi-quantified in the MS-DIAL software program and used for further statistical analyses. Likewise, in plasma lipidomics, 1, and 2, chromatographic peaks were detected in positive- and negative-ion mode data, respectively, and unique lipid molecules were annotated and semi-quantified.

The semi-quantitative value of lipids was calculated by the internal standards according to the previous study The abbreviations of lipids are listed in Supplementary Table Details of lipid subclass characterization follow the previous study These metabolites were clustered based on their co-abundance using the R package WGCNA 49 v.

The following parameters were used for the analysis. As soft thresholding of WGCNA was not able to cluster all of the metabolites, the remaining metabolites that did not fit the criteria were subsequently clustered on the basis of biweight midcorrelation.

The following parameters were used for the secondary clustering. The clusters with biweight midcorrelation above 0. The first principal component PC1 of each cluster was calculated using the moduleEigengenes command of WGCNA and used as the representative value of the cluster for further analyses.

The representative classes of the clusters were described in Supplementary Tables 2 and 3. KEGG pathway enrichment analysis of CAGs was performed on MetaboAnalyst v.

Hypergeometric test and false-discovery rate FDR -adjusted P values were used to test significance. The enrichment ratio was calculated as the ratio of actual metabolite number to the expected value in each pathway. To validate the associations between clinical markers and faecal metabolites, we used the metabolomic data of TwinsUK 17 and HMP2 ref.

The metabolome data of the TwinsUK cohort included 1, metabolites including 36 carbohydrates. As reported previously 17 , the metabolite levels were scaled by run-day medians. The data were then log-transformed and scaled. The record of BMI and HOMA-IR were used for phenotypic outcomes. For BMI, we retrieved samples measured on the same day of faecal collection.

We identified individuals who underwent both faecal collection and glucose and insulin measurement in the same year and included them in the analysis. Among the 26 out of samples from non-IBD control, BMI data were available for 20 samples.

As HMP2 is a longitudinal study, only the first faecal sampling for metabolomics was used for the current analysis to avoid redundancy. DNA extraction was performed according to a protocol described previously 47 with slight modifications.

Lysozyme Sigma-Aldrich , achromopeptidase Wako and proteinase K Merck were subsequently added to the samples for cell lysis. DNA was recovered by a phenol—chloroform extraction method.

To purify the extracted DNA, RNA was digested with RNase Nippon Gene. DNA was then precipitated in a solution containing polyethylene glycol Hampton Research. The DNA concentration was quantified using Quant-iT PicoGreen Thermo Fisher Scientific.

The hypervariable V1—V2 region of the 16S rRNA gene was amplified by PCR using barcoded primers. PCR amplicons were purified using AMPure XP magnetic purification beads Beckman Coulter , and quantified using the Quant-iT PicoGreen dsDNA Assay Kit Life Technologies Japan. Equal amounts of each PCR amplicon were mixed and then sequenced using the MiSeq Illumina system.

On the basis of sample-specific barcodes, reads were assigned to each sample using bcl2fastq. Next, the reads lacking both forward and reverse primer sequences were removed using BLAST and parasail followed by trimming of both primer sequences.

The filter-passed reads were used for further analysis. The 16S database was constructed from three publicly available databases: the Ribosomal Database Project RDP; v. Operational taxonomic unit OTU clustering and UniFrac analysis from the filter-passed reads, 3, high-quality reads per sample were randomly chosen.

The representative sequences of the generated OTUs were processed for homology search against the databases mentioned above using the GLSEARCH program for taxonomic assignments. After quality filtering, reads mapped to the human genome HG19 or the phiX bacteriophage genome were removed.

For each individual, the filter-passed NovaSeq reads were assembled using MEGAHIT v. Prodigal v. The genes with the best hit correlating to eukaryotic genes were excluded from further analysis. Multi-mapped reads, that is, the reads that mapped to multiple genes with identical scores, were normalized to the proportion of the number of other reads that uniquely mapped to these genes, according to a strategy outlined in a previous report The proportion of KEGG orthologues was calculated from the number of reads mapped to them.

We defined intracellular glucosidase by their substrate described in the KEGG pathway map; those cleave phosphorylated carbohydrates were recognized as intracellular, and the rest of the genes were recognized to possess extracellular enzymatic activities.

The pathways were further summarized into carbohydrate metabolism , amino acid metabolism , lipid metabolism and membrane transport on the basis of the KEGG Orthology database. The list of KEGG organisms used for this genome analysis is listed in Supplementary Table All KEGG organisms from genera Alistipes , Bacteroides , Flavonifractor , Blautia , Dorea and Coprococcus , which showed the top three positive or negative correlations with faecal carbohydrates in Fig.

The presence of KEGG orthologues relating to extracellular glycoside hydrolases in starch and sucrose metabolism pathways shown in grey in Extended Data Fig.

Blood samples were collected in Vacutainer CPT tubes Becton Dickinson and mixed with the anticoagulant by gently inverting the tubes 8 to 10 times. The quality of the RNA was assessed using Bioanalyzer Agilent , as recommended by the manufacturer. The RNAs were quantified using the GloMax plate reader Promega and Quant-iT RiboGreen RNA Assay Kit Thermo Fisher Scientific.

The CAGE libraries were constructed according to the dual-index nanoCAGE protocol, a template-switching-based variation of the standard CAGE protocol designed for low quantities of RNA 55 , The sequenced reads were processed with the MOIRAI pipeline 57 : low quality and rDNA reads were first removed, then the remaining reads were mapped to the human genome version hg38 patch 1 using BWA v.

The mapped reads falling under each FANTOM5 CAGE cluster were summed to produce the raw expression counts. Expression counts were converted to counts per million CPM , and CAGE clusters expressed in less than samples with at least 1 CPM and greater than 1 sample with at least 10 CPM were removed from further analysis.

Cell type specificities of promoters of interest were determined using the FANTOM5 hg38 human promoterome view. Top-hit cells for analysed promoters were described.

The following strains were used for this culture analysis: A. indistinctus JCM , A. finegoldii JCM , Alistipes putredinis JCM , B. thetaiotaomicron JCM , Bacteroides xylanisolvens JCM , Bacteroides ovatus JCM , Bacteroides caccae JCM , Parabacteroides merdae JCM , Parabacteroides distasonis JCM , D.

formicigenerans JCM , D. longicatena JCM , B. hydrogenotrophica JCM , Blautia producta BP, JCM , Coprococcus comes JCM , Faecalibacterium prausnitzii JCM , Flavonifractor plautii JCM , Clostridium spiroforme JCM , Coriobacterium glomerans JCM , Roseburia hominis JCM , Adlercreutzia equolifaciens subsp.

equolifaciens JCM , Eggerthella lenta JCM and Collinsella aerofaciens JCM All strains were obtained from RIKEN BioResource Research Center. All of the strains were cultivated in EG medium JCM Medium No.

The samples were centrifuged, and the cell-free supernatant was collected for analysis. GC—MS was performed to measure hydrophilic metabolites as described above. They were randomly assigned to either the control or treatment group and housed in a conventional animal facility of Yokohama City University.

finegoldii JCM , B. thetaiotaomicron JCM , B. xylanisolvens JCM , P. merdae JCM , F. prausnitzii JCM and C. spiroforme JCM were used to broadly compare the efficacy of bacterial administration on the animal model.

These strains were cultivated in EG medium overnight, and the concentration was adjusted to 2. Body mass was measured before oral gavage. In both experiments, the blood glucose was collected from the tail vein and serially measured using GLUCOCARD G Black Arkray. For the necropsy, the mice were euthanized by isoflurane MSD , and the fat mass of perigonadal and mesenteric fats was measured.

Blood was drawn through cardiac puncture after the anaesthesia. We gave three oral gavages of A. indistinctus or PBS vehicle control every other day and then placed the mice individually in acrylic cages.

Their metabolic activity, dietary intake and physical activity were subsequently monitored. of body mass were indistinctus groups, respectively.

Oxygen and carbon dioxide concentration was measured using the ARCO system, an open-circuit metabolic gas analysis system with a mass spectrometer Arco Systems.

VO 2 , VCO 2 , energy expenditure, fat oxidation rate, carbohydrate oxidation rate and respiratory quotient were calculated within the system. Dietary intake and physical activity were simultaneously monitored through ACTIMOM and MFDM Shinfactory.

The differences in diurnal variation were tested using two-way mixed ANOVA, and P values for interactions between time and group were reported. The sample size was determined on the basis of our preliminary experiments.

Bacterial administration and body mass measurements were performed by an independent researcher who was not involved in the grouping and outcome assessments.

To analyse phosphorylation of AKT p-AKT at Ser, the mice administered with A. indistinctus , A. Phosphorylated or total protein of AKT was isolated by immunoblotting using specific antibodies after the tissue lysates were resolved by SDS—PAGE and transferred to a Hybond-P PVDF transfer membrane Amersham Biosciences.

Bound antibodies were detected with HRP-conjugated secondary antibodies using ECL detection reagents Amersham Biosciences. Rabbit polyclonal antibodies directed against AKT and p-AKT Ser were purchased from Cell Signaling Technology.

Precision Plus Protein All Blue Standards Bio-Rad were used for the molecular mass markers. The protocol has been published elsewhere 62 , Mice administered with A.

In brief, a mouse was anaesthetized with isoflurane MSD , and the right jugular vein was exposed. A double-channel catheter was subsequently inserted to the vein. Human regular insulin Eli Lilly was intravenously administered at 7. The plasma levels of glucose and 6,6-d 2- glucose were measured using GC—MS.

The rate of glucose disappearance was determined on the basis of the plasma levels of 6,6-d 2 -glucose and total glucose using a non-steady-state equation as described previously 63 , 64 and considered as the whole-body glucose disposal after insulin stimulation.

Hepatic glucose production was determined as the subtraction of glucose disappearance rate and glucose infusion rate. For the necropsy, the mice were anesthetized using isoflurane MSD , and the left half of liver was dissected, weighed and frozen in liquid nitrogen.

The extraction of triglyceride contents from the liver tissue has been reported elsewhere 62 , The extraction step was repeated three times. test of the R package psych v. test of the R package ppcor v. To predict the metabolite levels and their CAGs Fig.

For the ordinal independent variables that is, IR, MetS, and original categories with obese and prediabetes , IS, no MetS, and healthy categories were considered as the references, respectively, and the coefficients and P values for other categories were calculated against these reference categories.

For the analyses involving generalized linear models GLM such as Fig. To enhance comparability, the standardized coefficient was also calculated by standard deviations of dependent and independent variables using the function lm. beta of the R package QuantPsyc v. In the reanalysis of TwinsUK data, we fitted generalized linear mixed-effects models with age, sex, zygosity and BMI as fixed effects and sample collection year as a random effect using the function glmer of R package lme4 v.

To calculate the KEGG pathway enrichment associated with the participant clusters Fig. For comparison of metabolites in bacterial cultures Extended Data Fig. For comparisons of time-series data such as insulin tolerance test, two-way repeated-measures ANOVA was used and the between-group difference was analysed by estimated marginal means.

We also validated the assumption of this ANCOVA model, that is, homogeneity of regression slopes, homogeneity of variances and normality of residuals. For multiple-testing corrections, P values were corrected using the Benjamini—Hochberg procedure using the R function p.

All data were collected using Microsoft Excel All statistical and graphical analyses were conducted using R v. To analyse ROC curves of omics datasets, the datasets of faecal metabolomics, including hydrophilic and lipid metabolites, faecal 16S rRNA gene sequencing at the genus level, faecal metagenome consisting of KEGG orthologues and clinical metadata, were included.

We first selected feature variables in each dataset, that is, the best explaining variables in the given dataset, using the minimum redundancy maximum relevance mRMR algorithm The function mRMR. classic of the R package mRMRe v.

The datasets were square-root-transformed before mRMR calculation. We selected 5 to 50 variables in 5 increments as the maximum number of genera was Using the selected variables, we next established random-forest models using the R package caret v. Specifically, the results of mRMR were split into train and test datasets in a ratio.

The generated random-forest models were evaluated using a tenfold cross-validation method and applied to the test datasets to obtain probability scores.

The accuracy of each classification model was described by the AUC of ROC curves using the R package pROC v. Bacteria that exhibited a positive correlation with one another were determined to be members of an independent co-abundance microbial group, except for the interaction between Bacteroides and Robinsoniella.

We decided to categorize Robinsoniella into the Blautia and Dorea group owing to its stronger correlation with Blautia in comparison to Bacteroides , both of which showed the highest centrality within their respective networks.

Those weakly associated with each other or negatively associated with the members of other CAGs were classified as miscellaneous Extended Data Fig. To characterize the microbial profiles of the study participants, the individuals were clustered on the basis of the abundance of 28 genera, which includes 20 genera in co-abundance microbial groups identified with CCREPE and 8 unclustered genera, using the ward.

D function of the R package pheatmap v. Bacteria-related metabolites were defined according to previous reports 20 , The following classes were selected: DGDG, PE-Cer, MGDG O, FAHFA, Cer-AS, Cer-BDS, NAGly, NAGlySer, PI-Cer, SL, AcylCer, bile acids, DGDG O and AAHFA.

The networks were visualized using Cytoscape v. To construct and visualize a correlation-based network of omics data, we first analysed IR-associated host signatures using plasma cytokines, plasma metabolites and CAGE promoter expression data. We finally identified 6, 21 and 36 significant associations from plasma cytokines, plasma metabolites and CAGE promoter expression data, respectively Supplementary Tables 19 — In terms of bacteria, 20 genera with significant interactions between each other, which were identified with CCREPE as shown in Extended Data Fig.

In terms of faecal metabolites, 15 carbohydrates associated with IR in the CAG analysis as shown in Fig. The size of nodes was determined as the ratio of median abundance in IR over IS.

As the median values of genera Robinsoniella and Rothia were zero, these elements were removed from the visualization. as in the microorganism—metabolite networks described above. To assess the explained variance of ten plasma cytokines, we established random-forest models using the R package caret v.

Plasma cytokines were log 10 -transformed and scaled before the regression analyses. The data were split into train and test datasets at a ratio. The generated random-forest models were evaluated using a tenfold cross-validation method and applied to the test datasets to obtain predictions.

The negative values were considered as zero. To infer the effects of plasma cytokines on in silico causal relationships between faecal carbohydrates and IR markers HOMA-IR, BMI, triglycerides and HDL-C , we performed causal mediation analysis using the R package mediation v.

Age and sex were included as independent variables in both models. In both models, faecal carbohydrate and plasma cytokine values were scaled before the analyses, and GLM with Gaussian distribution was used. A nonparametric bootstrap procedure was used to calculate the significance, followed by multiple testing corrections using the R function p.

Average causal mediation effects and average direct effects with P adj values from representative models are reported in Extended Data Fig. Further information on research design is available in the Nature Portfolio Reporting Summary linked to this article.

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The regulation also allows for the storage of glucose molecules into fatty acids. The enzymes upregulate , downregulate , and feedback regulate the process. Gluconeogenesis GNG is a metabolic pathway that results in the generation of glucose from certain non- carbohydrate carbon substrates.

It is a ubiquitous process, present in plants, animals, fungi, bacteria, and other microorganisms. It is one of two primary mechanisms — the other being degradation of glycogen glycogenolysis — used by humans and many other animals to maintain blood sugar levels , avoiding low levels hypoglycemia.

In humans, substrates for gluconeogenesis may come from any non-carbohydrate sources that can be converted to pyruvate or intermediates of glycolysis see figure. For the breakdown of proteins , these substrates include glucogenic amino acids although not ketogenic amino acids ; from breakdown of lipids such as triglycerides , they include glycerol , odd-chain fatty acids although not even-chain fatty acids, see below ; and from other parts of metabolism they include lactate from the Cori cycle.

Under conditions of prolonged fasting, acetone derived from ketone bodies can also serve as a substrate, providing a pathway from fatty acids to glucose. The gluconeogenesis pathway is highly endergonic until it is coupled to the hydrolysis of ATP or guanosine triphosphate GTP , effectively making the process exergonic.

For example, the pathway leading from pyruvate to glucosephosphate requires 4 molecules of ATP and 2 molecules of GTP to proceed spontaneously. These ATPs are supplied from fatty acid catabolism via beta oxidation.

Glycogenolysis refers to the breakdown of glycogen. Glucosephosphate can then progress through glycolysis. Glucagon in the liver stimulates glycogenolysis when the blood glucose is lowered, known as hypoglycemia. Adrenaline stimulates the breakdown of glycogen in the skeletal muscle during exercise.

Glycogenesis refers to the process of synthesizing glycogen. The pentose phosphate pathway is an alternative method of oxidizing glucose. Fructose must undergo certain extra steps in order to enter the glycolysis pathway. Lactose, or milk sugar, consists of one molecule of glucose and one molecule of galactose.

Many steps of carbohydrate metabolism allow the cells to access energy and store it more transiently in ATP. Typically, the complete breakdown of one molecule of glucose by aerobic respiration i. involving glycolysis, the citric-acid cycle and oxidative phosphorylation , the last providing the most energy is usually about 30—32 molecules of ATP.

Hormones released from the pancreas regulate the overall metabolism of glucose. The level of circulatory glucose known informally as "blood sugar" , as well as the detection of nutrients in the Duodenum is the most important factor determining the amount of glucagon or insulin produced.

The release of glucagon is precipitated by low levels of blood glucose, whereas high levels of blood glucose stimulates cells to produce insulin. Because the level of circulatory glucose is largely determined by the intake of dietary carbohydrates, diet controls major aspects of metabolism via insulin.

Regardless of insulin levels, no glucose is released to the blood from internal glycogen stores from muscle cells. Carbohydrates are typically stored as long polymers of glucose molecules with glycosidic bonds for structural support e. chitin , cellulose or for energy storage e.

glycogen , starch. However, the strong affinity of most carbohydrates for water makes storage of large quantities of carbohydrates inefficient due to the large molecular weight of the solvated water-carbohydrate complex.

In most organisms, excess carbohydrates are regularly catabolised to form acetyl-CoA , which is a feed stock for the fatty acid synthesis pathway; fatty acids , triglycerides , and other lipids are commonly used for long-term energy storage.

The hydrophobic character of lipids makes them a much more compact form of energy storage than hydrophilic carbohydrates. Gluconeogenesis permits glucose to be synthesized from various sources, including lipids.

In some animals such as termites [20] and some microorganisms such as protists and bacteria , cellulose can be disassembled during digestion and absorbed as glucose. Contents move to sidebar hide. Article Talk. Read Edit View history. Tools Tools. What links here Related changes Upload file Special pages Permanent link Page information Cite this page Get shortened URL Download QR code Wikidata item.

Download as PDF Printable version. In other projects. Wikimedia Commons. Biochemical process in living organisms. Surgery Oxford. doi : Lehninger principles of biochemistry. Cox, Michael M. New York: W. Freeman and Company.

ISBN OCLC Encyclopedia of Food and Health. Guyton and Hall Textbook of Medical Physiology E-Book 13 ed. Elsevier Health Sciences. Lehninger Principles of Biochemistry. USA: Worth Publishers. Archived from the original on August 26, Retrieved September 8, In Reese WO ed.

Dukes' Physiology of Domestic Animals 12th ed. Cornell Univ. PLOS Computational Biology. Bibcode : PLSCB PMC PMID Journal of Cellular Physiology.

S2CID Harper's illustrated Biochemistry, 30th edition. USA: McGraw Hill. Clinical Biochemistry. Advanced Nutrition and Human Metabolism. Cengage Learning. Archives of Biochemistry and Biophysics.

ISSN Biochemistry Free for All. Oregon State University. Endocrinology: Adult and Pediatric. A review". The Canadian Veterinary Journal. Bibcode : Natur. Journal of General Microbiology.

Metabolism , catabolism , anabolism. Metabolic pathway Metabolic network Primary nutritional groups. Purine metabolism Nucleotide salvage Pyrimidine metabolism Purine nucleotide cycle. Pentose phosphate pathway Fructolysis Polyol pathway Galactolysis Leloir pathway.

Glycosylation N-linked O-linked. Photosynthesis Anoxygenic photosynthesis Chemosynthesis Carbon fixation DeLey-Doudoroff pathway Entner-Doudoroff pathway. Xylose metabolism Radiotrophism. Fatty acid degradation Beta oxidation Fatty acid synthesis. Steroid metabolism Sphingolipid metabolism Eicosanoid metabolism Ketosis Reverse cholesterol transport.

Metal metabolism Iron metabolism Ethanol metabolism Phospagen system ATP-PCr. Metabolism map.

Diabetes mellitus is metabolsim insulin secretion Carbohydrate metabolism and diabetes variable degrees of peripheral diabetees resistance leading to hyperglycemia. Early symptoms are Carbohydrate metabolism and diabetes Non-Toxic Energy Options hyperglycemia and diabehes polydipsia, polyphagia, polyuria, and blurred vision. Later complications include vascular disease, peripheral neuropathy, nephropathy, and predisposition to infection. Diagnosis is by measuring plasma glucose. Treatment is diet, exercise, and medications that reduce glucose levels, including insulinoral antihyperglycemic medications, and non- insulin injectable medications.

Carbohydrate metabolism and diabetes -

Patients with type 1 diabetes should use carbohydrate counting or the carbohydrate exchange system to match insulin dose to carbohydrate intake and facilitate physiologic insulin replacement.

For example, if a carbohydrate-to- insulin ratio CIR of 15 gram:1 unit is used, a patient will require 1 unit of rapid-acting insulin for each 15 g of carbohydrate in a meal.

These ratios can vary significantly between patients, depending on their degree of insulin sensitivity and must be tailored to the patient and adjusted over time. Patients should also be educated that meals with higher protein or fat content can increase insulin requirements and dose adjustments may be necessary.

This approach requires detailed patient education and is most successful when guided by a dietitian experienced in working with patients with diabetes. Some experts have advised use of the glycemic index a measure of the impact of an ingested carbohydrate-containing food on the blood glucose level to delineate between rapid and slowly metabolized carbohydrates, although there is little evidence to support this approach.

Physical activity should increase incrementally to whatever level a patient can tolerate. Both aerobic exercise and resistance exercise have been shown to improve glycemic control in type 2 diabetes, and several studies have shown a combination of resistance and aerobic exercise to be superior to either alone 5 Treatment references Diabetes mellitus is impaired insulin secretion and variable degrees of peripheral insulin resistance leading to hyperglycemia.

read more , 6 Treatment references Diabetes mellitus is impaired insulin secretion and variable degrees of peripheral insulin resistance leading to hyperglycemia. read more , 7 Treatment references Diabetes mellitus is impaired insulin secretion and variable degrees of peripheral insulin resistance leading to hyperglycemia.

In type 1 diabetes, exercise has been shown to decrease mortality although the effect on HbA1C lowering is less clear 8 Treatment references Diabetes mellitus is impaired insulin secretion and variable degrees of peripheral insulin resistance leading to hyperglycemia.

read more , 9 Treatment references Diabetes mellitus is impaired insulin secretion and variable degrees of peripheral insulin resistance leading to hyperglycemia.

read more , 10 Treatment references Diabetes mellitus is impaired insulin secretion and variable degrees of peripheral insulin resistance leading to hyperglycemia.

Exercise has a variable effect on blood glucose, depending on the timing of exercise in relation to meals and the duration, intensity, and type of exercise. In patients with type 1 diabetes in particular, exercise can lead to hypoglycemia. Therefore, blood glucose should be monitored immediately before and after exercise.

Patients who experience hypoglycemic symptoms during exercise should be advised to test their blood glucose and ingest carbohydrates or lower their insulin dose as needed to get their glucose slightly above normal just before exercise. Hypoglycemia during vigorous exercise may require carbohydrate ingestion during the workout period, typically 5 to 15 g of sucrose or another simple sugar.

Patients with known or suspected cardiovascular disease may benefit from exercise stress testing Stress Testing In stress testing, the heart is monitored by electrocardiography ECG and often imaging studies during an induced episode of increased cardiac demand so that ischemic areas potentially at risk read more before beginning an exercise program.

Activity goals may need to be modified for patients with complications of diabetes such as neuropathy Diabetic Neuropathy In patients with diabetes mellitus, years of poorly controlled hyperglycemia lead to multiple, primarily vascular, complications that affect small vessels microvascular , large vessels macrovascular read more and retinopathy Diabetic Retinopathy In patients with diabetes mellitus, years of poorly controlled hyperglycemia lead to multiple, primarily vascular, complications that affect small vessels microvascular , large vessels macrovascular Complications include cardiovascular disorders read more , physicians should prescribe antihyperglycemic medications that promote weight loss eg, GLP1 receptor agonists, SGLT-2 inhibitors, or a dual incretin agonist or are weight-neutral eg, dipeptidyl peptidase-4 inhibitors, metformin , if possible for details, see Medication Treatment of Diabetes Medications for Diabetes Mellitus Treatment General treatment of diabetes mellitus for all patients involves lifestyle changes, including diet and exercise.

Two GLP-1 receptor agonists that are used for weight loss at higher doses semaglutide 2. Orlistat , an intestinal lipase inhibitor, reduces dietary fat absorption; it reduces serum lipids and helps promote weight loss. Many of these medications also have been shown to decrease HbA1C. An oral hydrogel containing cellulose and citric acid that causes patients to feel full and eat less can induce modest weight loss in patients with prediabetes and diabetes.

Medical devices, including implanted gastric balloons, a vagus nerve stimulator, and gastric aspiration therapy, are also available, but their use remains limited due to high cost and limited data in patients with diabetes. Surgical treatment for obesity Metabolic and Bariatric Surgery Metabolic and bariatric surgery is the surgical alteration of the stomach, intestine, or both to cause weight loss in patients with obesity-related metabolic disorders and their sequellae.

read more , such as sleeve gastrectomy or gastric bypass, also leads to weight loss and improvement in glucose control independent of weight loss and decreased cardiovascular risk in patients who have diabetes mellitus and should be recommended for appropriately selected patients.

Regular professional podiatric care, including trimming of toenails and calluses, is important for patients with sensory loss or circulatory impairment. Such patients should be advised to inspect their feet daily for cracks, fissures, calluses, corns, and ulcers. Feet should be washed daily in lukewarm water, using mild soap, and dried gently and thoroughly.

A lubricant eg, lanolin should be applied to dry, scaly skin. Nonmedicated foot powders should be applied to moist feet. Toenails should be cut, preferably by a podiatrist, straight across and not too close to the skin.

Adhesive plasters and tape, harsh chemicals, corn cures, water bottles, and electric pads should not be used on skin. Patients should change socks or stockings daily and not wear constricting clothing eg, garters, socks, or stockings with tight elastic tops. Shoes should fit well, be wide-toed without open heels or toes, and be changed frequently.

Special shoes should be prescribed to reduce trauma if the foot is deformed eg, previous toe amputation, hammer toe Hammer Toe Deformity Hammer toe deformities result from an imbalance of the digital extensor and flexor tendons that typically causes a contracture at the proximal interphalangeal joint.

This progresses to a rigid read more , bunion Bunion Bunion is a prominence of the medial portion of the head of the first metatarsal bone. The cause is often variations in position of the first metatarsal bone or great toe, such as lateral angulation Walking barefoot should be avoided.

Patients with neuropathic foot ulcers Treatment should avoid weight bearing until ulcers heal. If they cannot, they should wear appropriate orthotic protection. Because most patients with these ulcers have little or no macrovascular occlusive disease, debridement and antibiotics frequently result in good healing and may prevent major surgery.

After the ulcer has healed, appropriate inserts or special shoes should be prescribed. In refractory cases, especially if osteomyelitis Osteomyelitis Osteomyelitis is inflammation and destruction of bone caused by bacteria, mycobacteria, or fungi.

Common symptoms are localized bone pain and tenderness with constitutional symptoms in acute read more is present, surgical removal of the metatarsal head the source of pressure , amputation of the involved toe, or transmetatarsal amputation may be required.

A neuropathic joint can often be satisfactorily managed with orthopedic devices eg, short leg braces, molded shoes, sponge-rubber arch supports, crutches, prostheses. Vaccines are directed against read more , influenza virus Influenza Vaccine Based on recommendations by the World Health Organization and the Centers for Disease Control and Prevention CDC , vaccines for influenza are modified annually to include the most prevalent For more information, see Hepatitis B Advisory Committee read more , varicella Varicella Vaccine Varicella vaccination provides effective protection against varicella chickenpox.

It is not known how long protection against varicella lasts. But, live-virus vaccines, like the varicella read more , and SARS-CoV-2 COVID vaccination COVID is a respiratory illness caused by the novel coronavirus SARS-CoV Infection may be asymptomatic or have symptoms ranging from mild upper respiratory symptoms to acute respiratory read more as per standard recommendations.

Pancreas transplantation Pancreas Transplantation Pancreas transplantation is a form of pancreatic beta-cell replacement that can restore normoglycemia in diabetic patients. See also Overview of Transplantation. Because the recipient exchanges read more and transplantation of pancreatic islet cells Pancreatic Islet Cell Transplantation Islet cell transplantation into the recipient's liver has theoretical advantages over pancreas transplantation; the most important is that the procedure is less invasive.

A secondary advantage read more are alternative means of insulin delivery 11 Treatment references Diabetes mellitus is impaired insulin secretion and variable degrees of peripheral insulin resistance leading to hyperglycemia.

read more , 12 Treatment references Diabetes mellitus is impaired insulin secretion and variable degrees of peripheral insulin resistance leading to hyperglycemia. read more ; both techniques effectively transplant insulin -producing beta-cells into patients who are insulin deficient have type 1 diabetes mellitus.

Matthews DR, Paldánius PM, Proot P, et al. Glycaemic durability of an early combination therapy with vildagliptin and metformin versus sequential metformin monotherapy in newly diagnosed type 2 diabetes VERIFY : a 5-year, multicentre, randomised, double-blind trial.

Lancet ; Nuffield Department of Population Health Renal Studies Group; SGLT2 inhibitor Meta-Analysis Cardio-Renal Trialists' Consortium. Impact of diabetes on the effects of sodium glucose co-transporter-2 inhibitors on kidney outcomes: collaborative meta-analysis of large placebo-controlled trials.

Palmer SC, Tendal B, Mustafa RA, et al. Sodium-glucose cotransporter protein-2 SGLT-2 inhibitors and glucagon -like peptide-1 GLP-1 receptor agonists for type 2 diabetes: systematic review and network meta-analysis of randomised controlled trials [published correction appears in BMJ Jan 18;o].

BMJ ;m Published Jan Vaduganathan M, Docherty KF, Claggett BL, et al. SGLT-2 inhibitors in patients with heart failure: a comprehensive meta-analysis of five randomised controlled trials [published correction appears in Lancet Jan 14; ].

Church TS, Blair SN, Cocreham S, et al. Effects of aerobic and resistance training on hemoglobin A1c levels in patients with type 2 diabetes: a randomized controlled trial [published correction appears in JAMA Mar 2; 9 ]. JAMA ; 20 Colberg SR, Sigal RJ, Yardley JE, et al.

Diabetes Care ;39 11 Sigal RJ, Kenny GP, Boulé NG, et al. Effects of aerobic training, resistance training, or both on glycemic control in type 2 diabetes: a randomized trial. Ann Intern Med ; 6 Bohn B, Herbst A, Pfeifer M, et al. Impact of Physical Activity on Glycemic Control and Prevalence of Cardiovascular Risk Factors in Adults With Type 1 Diabetes: A Cross-sectional Multicenter Study of 18, Patients.

Diabetes Care ;38 8 Pongrac Barlovic D, Harjutsalo V, Groop PH. Exercise and nutrition in type 1 diabetes: Insights from the FinnDiane cohort.

Front Endocrinol Lausanne ; Shorey S, Ng ED, Law EC, Wong JCM, Loke KY, Tam WWS. Physical Activity and Nutrition Interventions for Type 1 Diabetes: A Meta-analysis. Pediatrics ; 3 :e Dean PG, Kukla A, Stegall MD, et al : Pancreas transplantation.

BMJ , Rickels MR, Robertson RP : Pancreatic islet transplantation in humans: Recent progress and future directions. Endocr Rev 40 2 —, The goal of diabetes treatment is control of hyperglycemia to relieve symptoms and prevent complications while minimizing hypoglycemic episodes.

Diabetes mellitus control can be monitored by measuring blood levels of. These goals may be adjusted to be less strict for patients in whom strict glucose control may be inadvisable, such as.

Patients who experience repeated episodes of hypoglycemia Hypoglycemia Hypoglycemia, or low plasma glucose level can result in sympathetic nervous system stimulation and central nervous system dysfunction.

In patients with diabetes who take insulin or antihyperglycemic read more , especially those who do not develop symptoms of hypoglycemia hypoglycemia unawareness. Patients who cannot communicate the presence of hypoglycemia symptoms eg, young children, patients with dementia.

Potential candidates for tighter glycemic control include. Glucose levels are typically determined by home monitoring Special Populations and Settings Diabetes mellitus is impaired insulin secretion and variable degrees of peripheral insulin resistance leading to hyperglycemia.

read more of capillary blood glucose eg, from a fingerstick or continuous glucose monitoring. Most patients with type 1 diabetes benefit from testing at least 4 times a day 1 Monitoring references Diabetes mellitus is impaired insulin secretion and variable degrees of peripheral insulin resistance leading to hyperglycemia.

More frequent self-monitoring is recommended when blood glucose levels are suboptimal or when there are changes in the medication regimen. HbA1C levels measured in venous plasma are monitored every 3 months or, for patients with consistently good control, every 6 months.

Fingerstick glucose monitors measure capillary blood glucose. Many different glucose meters are available. Nearly all require test strips and a means for pricking the skin and obtaining a blood sample. Choice among devices is usually based on patient preferences for features such as time to results usually 5 to 30 seconds , size of display panel large screens may benefit patients with poor eyesight , voice readout for those with visual impairment , and smartphone app connectivity 2 Monitoring references Diabetes mellitus is impaired insulin secretion and variable degrees of peripheral insulin resistance leading to hyperglycemia.

Continuous glucose monitoring CGM systems estimate capillary blood glucose from interstitial glucose detected by a subcutaneous sensor. They can either provide glucose measurements continuously real-time CGM or intermittently when scanned with a device intermittently scanned CGM.

CGMs provide real-time glucose data including an alarm to warn of hypoglycemia, hyperglycemia, or rapidly changing glucose levels.

Although CGMs have less stringent accuracy requirements than capillary blood glucose monitors, they allow users and clinicians to assess for patterns of hyperglycemia and hypoglycemia that are not identified with fingerstick glucose monitoring.

Use of CGMs has been shown to increase patients' time in target range TIR and decrease HbA1C 3, 4, 5 Monitoring references Diabetes mellitus is impaired insulin secretion and variable degrees of peripheral insulin resistance leading to hyperglycemia. Use of CGMs is recommended for all patients who are treated with intensive insulin therapy and can use the devices safely 6 Monitoring references Diabetes mellitus is impaired insulin secretion and variable degrees of peripheral insulin resistance leading to hyperglycemia.

As with all glycemic targets, CGM targets should be individualized depending on age, comorbidities, and risk of hypoglycemia. CGM systems can be integrated with insulin pumps to provide real-time adjustment of insulin doses based on blood glucose levels.

Such systems, known as automated insulin delivery AID systems or hybrid closed-loop systems, are expensive; however, they are recommended for all patients who take multiple daily injections of insulin and have been shown to lower HbA1C levels and decrease hypoglycemia 6, 9, 10 Monitoring references Diabetes mellitus is impaired insulin secretion and variable degrees of peripheral insulin resistance leading to hyperglycemia.

They are becoming more commonly used, and some versions do not require daily fingerstick glucose testing to calibrate the glucose monitor. They are especially useful in patients with type 1 diabetes and for those with hypoglycemia unawareness or nocturnal hypoglycemia. Some CGM sensors can be used for up to 2 weeks before they need to be replaced.

Clinicians can review the recorded data to determine whether the patient is experiencing undetected hyperglycemia or hypoglycemia. HbA1C levels reflect glucose control over the preceding 3 months and hence assess control between physician visits.

HbA1C should be assessed quarterly in patients with type 1 diabetes and at least twice a year in patients with type 2 diabetes when plasma glucose appears stable and more frequently when control is uncertain.

Home testing kits are available but are used infrequently. Control suggested by HbA1C values sometimes appears to differ from that suggested by daily glucose readings because of falsely elevated or normal HbA1C values. False elevations of HbA1C may occur with low red blood cell turnover as occurs with iron, folate, or vitamin B12 deficiency anemia , high-dose aspirin , and high blood alcohol concentrations.

Falsely normal HbA1C values occur with increased red blood cell turnover, as occurs with hemolytic anemias Overview of Hemolytic Anemia At the end of their normal life span about days , red blood cells RBCs are removed from the circulation.

Hemolysis is defined as premature destruction and hence a shortened RBC life span read more and hemoglobinopathies Overview of Hemoglobinopathies Hemoglobinopathies are genetic disorders affecting the structure or production of the hemoglobin molecule.

Hemoglobin molecules consist of polypeptide chains whose chemical structure is genetically read more eg, HbS disease, HbC disease , or during treatment of deficiency anemias. In patients with cirrhosis Cirrhosis Cirrhosis is a late stage of hepatic fibrosis that has resulted in widespread distortion of normal hepatic architecture.

Cirrhosis is characterized by regenerative nodules surrounded by dense read more or chronic kidney disease stages 4 and 5 Stages of chronic kidney disease Chronic kidney disease CKD is long-standing, progressive deterioration of renal function.

Symptoms develop slowly and in advanced stages include anorexia, nausea, vomiting, stomatitis, dysgeusia read more , correlation between HbA1C and glycemic levels is poor, and HbA1C can be falsely decreased in these patients.

Pregnancy also falsely decreases HbA1C values. Fructosamine, which is mostly glycosylated albumin but also comprises other glycosylated proteins, reflects glucose control in the previous 1 to 2 weeks. Fructosamine monitoring may be used during intensive treatment of diabetes and for patients with hemoglobin variants or high red blood cell turnover which cause false HbA1C results , but it is mainly used in research settings.

Urine glucose monitoring is too inaccurate to be recommended. Diabetes Care 44 11 —, Domingo-Lopez DA, Lattanzi G, H J Schreiber L, et al. Medical devices, smart drug delivery, wearables and technology for the treatment of Diabetes Mellitus.

Adv Drug Deliv Rev ; Beck RW, Riddlesworth T, Ruedy K, et al. Effect of Continuous Glucose Monitoring on Glycemic Control in Adults With Type 1 Diabetes Using Insulin Injections: The DIAMOND Randomized Clinical Trial.

JAMA ; 4 Olafsdottir AF, Polonsky W, Bolinder J, et al. A Randomized Clinical Trial of the Effect of Continuous Glucose Monitoring on Nocturnal Hypoglycemia, Daytime Hypoglycemia, Glycemic Variability, and Hypoglycemia Confidence in Persons with Type 1 Diabetes Treated with Multiple Daily Insulin Injections GOLD Diabetes Technol Ther ;20 4 Vigersky RA, Fonda SJ, Chellappa M, Walker MS, Ehrhardt NM.

Short- and long-term effects of real-time continuous glucose monitoring in patients with type 2 diabetes. Diabetes Care ;35 1 Grunberger G, Sherr J, Allende M, et al. American Association of Clinical Endocrinology Clinical Practice Guideline: The Use of Advanced Technology in the Management of Persons With Diabetes Mellitus.

Endocr Pract ;27 6 Battelino T, Danne T, Bergenstal RM, et al : Clinical targets for continuous glucose monitoring data interpretation: Recommendations from the international consensus on time in range.

Diabetes Care 42 8 —, Brown SA, Kovatchev BP, Raghinaru D, et al. Six-Month Randomized, Multicenter Trial of Closed-Loop Control in Type 1 Diabetes. N Engl J Med ; 18 Tauschmann M, Thabit H, Bally L, et al.

Closed-loop insulin delivery in suboptimally controlled type 1 diabetes: a multicentre, week randomised trial [published correction appears in Lancet Oct 13; ]. Diabetes care requires careful adjustment for patient factors, including those related to age and lifestyle, comorbid conditions, and need for treatment of other acute or chronic conditions.

The term brittle diabetes has been used to refer to patients who have dramatic, recurrent swings in glucose levels, often for no apparent reason. Labile plasma glucose levels are more likely to occur in patients with type 1 diabetes because endogenous insulin production is almost completely absent, and in some patients, counter-regulatory response to hypoglycemia is impaired.

Other causes of labile plasma glucose levels include occult infection, gastroparesis which leads to erratic absorption of dietary carbohydrates , and endocrine disorders eg, Addison disease Addison Disease Addison disease is an insidious, usually progressive hypofunctioning of the adrenal cortex.

It causes various symptoms, including hypotension and hyperpigmentation, and can lead to adrenal crisis Patients with chronic difficulty maintaining acceptable glucose levels should be evaluated for situational factors that affect glucose control.

Such factors include inadequate patient education or understanding that leads to errors in insulin administration, inappropriate food choices, and psychosocial stress that expresses itself in erratic patterns of medication use and food intake.

The initial approach is to thoroughly review self-care techniques, including insulin preparation and injection and glucose testing.

Increased frequency of self-testing may reveal previously unrecognized patterns and provides the patient with helpful feedback. A thorough dietary history, including timing of meals, should be taken to identify potential contributions to poor control.

Underlying disorders should be ruled out by physical examination and appropriate laboratory tests. For some insulin -treated patients, changing to a more intensive regimen that allows for frequent dose adjustments based on glucose testing is helpful.

Continuous glucose monitoring with alarms and sensor-augmented or hybrid closed-loop insulin pump therapy are useful tools in individuals who fluctuate between hypoglycemia and hyperglycemia.

Diabetes in children Diabetes Mellitus in Children and Adolescents Diabetes mellitus involves absence of insulin secretion type 1 or peripheral insulin resistance type 2 , causing hyperglycemia. read more is discussed in more detail elsewhere.

Children with type 1 diabetes require physiologic insulin replacement as do adults, and similar treatment regimens, including insulin pumps Insulin pumps General treatment of diabetes mellitus for all patients involves lifestyle changes, including diet and exercise.

read more , are used. However, the risk of hypoglycemia, because of unpredictable meal and activity patterns and limited ability to report hypoglycemic symptoms, may require modification of treatment goals. Most young children can be taught to actively participate in their own care, including glucose testing and insulin injections.

School personnel and other caregivers must be informed about the disease and instructed about the detection and treatment of hypoglycemic episodes. Monitoring for microvascular complications Monitoring for complications of diabetes Diabetes mellitus is impaired insulin secretion and variable degrees of peripheral insulin resistance leading to hyperglycemia.

read more can generally be deferred until after puberty. Children with type 2 diabetes require the same attention to diet and weight control and recognition and management of dyslipidemia and hypertension as do adults.

Most children with type 2 diabetes have obesity, so lifestyle modification is the cornerstone of therapy. Medication therapy may also be indicated.

Diabetes in adolescents Diabetes Mellitus in Children and Adolescents Diabetes mellitus involves absence of insulin secretion type 1 or peripheral insulin resistance type 2 , causing hyperglycemia.

Glucose control typically deteriorates as children with diabetes enter adolescence. Multiple factors contribute, including. Pubertal and insulin -induced weight gain. Hormonal changes that decrease insulin sensitivity.

Psychosocial factors that lead to insulin nonadherence eg, mood and anxiety disorders, hectic schedules, irregular meals, family conflict. read more that lead to insulin omission as a means of controlling weight. For these reasons, some adolescents experience recurrent episodes of hyperglycemia, diabetic ketoacidosis Diabetic Ketoacidosis DKA Diabetic ketoacidosis DKA is an acute metabolic complication of diabetes characterized by hyperglycemia, hyperketonemia, and metabolic acidosis.

read more , and hypoglycemia requiring emergency department visits and hospitalization. Treatment often involves intensive medical supervision combined with psychosocial interventions eg, mentoring or support groups , individual or family therapy, and psychopharmacology when indicated.

Patient education is important so that adolescents can safely enjoy the freedoms of early adulthood. Rather than judging personal choices and behaviors, clinicians must continually reinforce the need for careful glycemic control, especially frequent glucose monitoring and use of frequent, low-dose, fast-acting insulins as needed.

Diabetes mellitus may be a primary reason for hospitalization or may accompany other illnesses that require inpatient care. All patients with diabetic ketoacidosis Diabetic Ketoacidosis DKA Diabetic ketoacidosis DKA is an acute metabolic complication of diabetes characterized by hyperglycemia, hyperketonemia, and metabolic acidosis.

read more , hyperosmolar hyperglycemic state Hyperosmolar Hyperglycemic State HHS Hyperosmolar hyperglycemic state is a metabolic complication of diabetes mellitus characterized by severe hyperglycemia, extreme dehydration, hyperosmolar plasma, and altered consciousness read more , or prolonged or severe hypoglycemia Hypoglycemia Hypoglycemia, or low plasma glucose level can result in sympathetic nervous system stimulation and central nervous system dysfunction.

read more should be hospitalized. Patients with hypoglycemia induced by sulfonylureas, poorly controlled hyperglycemia, or acute worsening of diabetic complications may benefit from brief hospitalization. Children and adolescents with new-onset diabetes Diabetes Mellitus in Children and Adolescents Diabetes mellitus involves absence of insulin secretion type 1 or peripheral insulin resistance type 2 , causing hyperglycemia.

read more may also benefit from hospitalization. Control may worsen on discharge when insulin regimens developed in controlled inpatient settings prove inadequate to the uncontrolled conditions outside the hospital.

In patients with newly diagnosed diabetes, insulin doses used in the inpatient setting are often too high and can cause hypoglycemia if not adjusted when discharged from the hospital.

When other illnesses mandate hospitalization, some patients can continue on their home diabetes treatment regimens. However, glucose control often proves difficult, and it is often neglected when other diseases are more acute. Restricted physical activity and acute illness worsen hyperglycemia in some patients, whereas dietary restrictions and symptoms that accompany illness eg, nausea, vomiting, diarrhea, anorexia precipitate hypoglycemia in others—especially when antihyperglycemic medication doses remain unchanged.

In addition, it may be difficult to control glucose adequately in patients who are hospitalized because usual routines eg, timing of meals, medications, and procedures are inflexibly timed relative to diabetes treatment regimens.

In patients who are hospitalized, oral antihyperglycemic medications often need to be stopped. Metformin can cause lactic acidosis Lactic Acidosis Lactic acidosis is a high anion gap metabolic acidosis due to elevated blood lactate.

Lactic acidosis results from overproduction of lactate, decreased metabolism of lactate, or both. See also read more in patients with renal insufficiency and has to be stopped if contrast agents need to be given. Therefore, metformin is withheld in all but the most stable patients who are hospitalized.

Sulfonylureas can cause hypoglycemia and should also be stopped. Most inpatients can be appropriately treated with basal insulin without or with supplemental short-acting insulin. Dipeptidyl peptidase-4 inhibitors are relatively safe, even in patients with kidney disease, and they may also be used for postprandial glucose lowering.

Sliding-scale insulin should not be the only intervention to correct hyperglycemia; it is reactive rather than proactive, and it leads to poor glycemic control compared to basal-bolus insulin.

Longer-acting insulins should be adjusted to prevent hyperglycemia rather than just using short-acting insulins to correct it. Inpatient hyperglycemia is associated with increased infection rate and mortality.

Critical illness causes insulin resistance and hyperglycemia even in patients without known diabetes mellitus. Such stress-induced hyperglycemia is associated with poor outcomes, including increased mortality.

Previously, glucose target levels were lower; however, it appears that the less stringent targets as described above may be sufficient to prevent adverse outcomes.

The physiologic stress of surgery can increase plasma glucose in patients with diabetes and induce diabetic ketoacidosis Diabetic Ketoacidosis DKA Diabetic ketoacidosis DKA is an acute metabolic complication of diabetes characterized by hyperglycemia, hyperketonemia, and metabolic acidosis.

read more in those with type 1 diabetes. For shorter procedures, subcutaneous insulin can be used. During and after surgery, plasma glucose and ketones if hyperglycemia suggests the need should be measured at least every 2 hours. This approach may also be used for insulin -treated patients with type 2 diabetes, but frequent measurement of ketones may be omitted.

Some physicians prefer to withhold subcutaneous or inhaled insulin on the day of surgery and to give insulin by IV infusion. For patients undergoing a long procedure or major surgery, a continuous insulin infusion is preferable, especially since insulin requirements can increase because of the stress of surgery.

IV insulin infusion can be given at the same time as intravenous dextrose solution to maintain blood glucose. The insulin doses are adjusted in 5-unit increments. This approach is not used at many institutions because of the frequent remixing and changing of bags needed to adjust to the patient's level of glycemia.

A more common approach in the United States is to infuse insulin and dextrose separately. The insulin rate may need to be decreased for patients with more insulin -sensitive type 1 diabetes and increased for patients with more insulin -resistant type 2 diabetes.

Ten percent dextrose may also be used. It is important, especially in patients with type 1 diabetes, to continue insulin infusion to avoid development of diabetes ketoacidosis. Insulin adsorption onto IV tubing can lead to inconsistent effects, which can be minimized by preflushing the IV tubing with insulin solution.

Insulin infusion is continued through recovery, with insulin dose adjusted based on the plasma glucose levels obtained in the recovery room and at 1- to 2-hour intervals thereafter.

Most patients with type 2 diabetes who are treated only with oral antihyperglycemic medications maintain acceptable glucose levels when fasting and may not require insulin in the perioperative period. Most oral medications, including sulfonylureas and metformin , should be withheld on the day of surgery, and plasma glucose levels should be measured preoperatively and postoperatively and every 6 hours while patients receive IV fluids.

Oral medications may be resumed when patients are able to eat, but metformin should be withheld until normal renal function is confirmed 48 hours after surgery. People at high risk of type 1 diabetes eg, siblings and children of people with type 1 diabetes can be tested for the presence of islet cell or anti-glutamic acid decarboxylase antibodies, which precede onset of clinical disease 1 Screening reference Diabetes mellitus is impaired insulin secretion and variable degrees of peripheral insulin resistance leading to hyperglycemia.

Gestational diabetes mellitus Diabetes Mellitus in Pregnancy Pregnancy makes glycemic control more difficult in preexisting type 1 insulin-dependent and type 2 non—insulin-dependent diabetes but does not appear to exacerbate diabetic retinopathy, Hypertension with no known cause primary; formerly, essential Dyslipidemia Dyslipidemia Dyslipidemia is elevation of plasma cholesterol, triglycerides TGs , or both, or a low high-density lipoprotein cholesterol HDL-C level that contributes to the development of atherosclerosis Polycystic ovary syndrome Polycystic Ovary Syndrome PCOS Polycystic ovary syndrome is a clinical syndrome typically characterized by anovulation or oligo-ovulation, signs of androgen excess eg, hirsutism, acne , and multiple ovarian cysts in the Steatotic liver disease Metabolic Dysfunction—Associated Liver Disease MASLD Steatotic liver disease is due to excessive accumulation of lipid in hepatocytes.

Metabolic dysfunction—associated liver disease MASLD includes simple fatty infiltration a benign condition read more formerly fatty liver disease. Sims EK, Besser REJ, Dayan C, et al. Screening for Type 1 Diabetes in the General Population: A Status Report and Perspective.

Diabetes ;71 4 Progression of type 1 diabetes from preclinical to symptomatic disease can be delayed with pharmacologic therapy. read more and 33 months in a follow-up study 2 Prevention references Diabetes mellitus is impaired insulin secretion and variable degrees of peripheral insulin resistance leading to hyperglycemia.

Other treatments that target the autoimmune inflammatory response, including azathioprine , corticosteroids, and cyclosporine , induce remission of early type 1 diabetes in some patients, but longer term studies have not shown benefits 3 Prevention references Diabetes mellitus is impaired insulin secretion and variable degrees of peripheral insulin resistance leading to hyperglycemia.

Antithymocyte globulin ATG , TNF- alpha tumor necrosis factor- alpha inhibitors, and abatacept CTLAIg have shown some promise in preserving beta-cell function in recent-onset type 1 diabetes and are being investigated 3 Prevention references Diabetes mellitus is impaired insulin secretion and variable degrees of peripheral insulin resistance leading to hyperglycemia.

read more , 4 Prevention references Diabetes mellitus is impaired insulin secretion and variable degrees of peripheral insulin resistance leading to hyperglycemia. Some data suggest that verapamil may preserve beta-cell function in patients with newly diagnosed diabetes 5 Prevention references Diabetes mellitus is impaired insulin secretion and variable degrees of peripheral insulin resistance leading to hyperglycemia.

Patients with impaired glucose regulation should receive counseling addressing their risk of developing diabetes and the importance of lifestyle changes for preventing diabetes. They should be monitored closely for development of diabetes symptoms or elevated plasma glucose.

Ideal follow-up intervals have not been determined, but annual or biannual checks are probably appropriate. Activities associated with subcellular particulate and soluble fractions of normal and streptozotocin diabetic rat tissues. Anderson JW and Stowring L. Glycolytic and gluconeogenic enzyme activities in renal cortex of diabetic rats.

Regen DM, Davies WW and Morgan HE. Newshome EA and Randle PJ. Effects of anoxia, insulin, adrenalin and prolonged starving on concentrations of hexose phosphates in isolated rat diaphragam and perfused isolated rat heart.

Fructose 1,6-diphosphate activity of rat heart and rat diaphragm. Newsholme EA, Randle PJ and Manchester KL. Inhibition of the phosphofructokinase reaction in perfused rat heart by respiration of ketone bodies,fatty acids and pyruvate.

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Islet transplantation improves glucose oxidation and mechanical function in diabetic rat hearts. Can J Physiol Pharmacol 71 —, Gamble J and Lopaschuk GD. Glycolysis and glucose oxidation during reperfusion of ischemic hearts from diabetic rats. Wall SR and Lopaschuk GD. Glucose oxidation rates in fatty acid-perfused isolated working hearts from diabetic rats.

Acta : 97—, Chatham JC and Forder JR. A 13 C-NMR study of glucose oxidation in the intact functioning rat heart following diabetes-induced cardiomyopathy.

Pierce GN, Beamish RE and Dhalla NS. Heart Dysfunction in Diabetes. Boca Raton, FL. Malloy CR, Sherry AD and Jeffrey FMH.

Analysis of tricarboxylic acid cycle of the heart using 13 C isotope isomers. Sherry AD and Malloy CR. Cardiac metabolism. In RJ Gillies Eds. Hansford RG, Hogue B, Prokopczuk A, Wasilewska E and Lewartowski B. Acta —, Rosen P, Windeck P, Zimmer H-G, Frenzel H, Bürrig KF and Reinauer H.

Myocardial performance and metabolism in nonketotic, diabetic rat hearts: myocardial function and metabolism in vivo and in the isolated perfused heart under the influence of insulin and octanoate. Reed LJ. Regulation of mammalian pyruvate dehydrogenase complex by a phosphorylation -dephosphorylation cycle.

Randle PJ. Fuel selection in animals. Nineteenth Ciba Medal Lecture. Randle PJ, Priestman DA, Mistry S and Halsall A. Mechanisms modifying glucose oxidation in diabetes mellitus. Diabetologia 37 : S—S, Randle PJ, Priestman DA, Mistry SC and Halsall A.

Glucose fatty acid interactions and the regulation of glucose disposal. J Cell Biochem 55 : 1—11, Wieland O, Siess E, Schulze-Wethmar FH, van Funcke HG and Winton B. Active and inactive forms of pyruvate dehydrogenase in rat heart and kidney: effect of diabetes, fasting and refeeding on pyruvate dehydrogenase interconversion.

Kerbey AL, Randle PJ, Cooper RH, Whitehouse S, PAsk HT and Denton RM. Mechanism of regulation of proportions of deposphorylated and phosphorylated enzyme by oxidation of fatty acids and ketone bodies and of effects of diabetes: role of coenzyme A, acetyl-coA and reduced and oxidized nicotinamide-adenine dinucleotide.

Kerbey AL, Radcliff PM and Randle PJ. Hutson NJ and Randle PJ. Enhanced activity of pyruvate dehydrogenase kinase in rat heart mitochondria in alloxan-diabetes or starvation. FEBS Lett. Hutson NJ, Kerbey AL, Randle PJ and Sugden PH.

Conversion of inactive phosphorylated pyruvate dehydrogenase complex into active complex by the phosphate reaction in heart mitochondria is inhibited by alloxan-diabetes or starvation.

Sugden PH, Hutson NJ, Kerbey AL and Randle PJ. Phosphorylation of additional sites on pyruvate dehydrogenase inhibits its reactivation by pyruvate dehydrogenase phosphate phosphatase.

Sugden PH and Randle PJ. Regulation of pig heart pyruvate dehydrogenase by phosphorylation studies on the subunit and phosphorylation stoicheiometries. Davis PF, Pettit FH and Reed LJ.

Peptides derived from pyruvate dehydrogenase as substrates for pyruvate dehydrogenase kinase and phosphatase. Ungar I, Gilbert M, Siegal A, Blair JM and Bing RJ. Studies on myocardial metabolism.

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Heart and skeletal muscle disposal in type 2 diabetic patients as determined by positron emission tomography. vom Dahl J, Herman WH, Hicks RJ, Ortiz-Alonso F J, Lee KS, Allman KC, Wolfe ER, Kalff V and Schwaiger M.

Myocardial glucose uptake in patients with insulin-dependent diabetes mellitus assessed quatitatively by dynamic positron emission tomography. Circulation 88 : —, Download references. You can also search for this author in PubMed Google Scholar. Department of Radiology, Division of NMR Research, Johns Hopkins University School of Medicine, Baltimore, MD, , USA.

John C. Chatham D. Forder Ph. Faculty of Pharmaceutical Sciences, University of British Columbia, East Mall, Vancouver, British Columbia, Canada, V6T 1W5. Faculty of Pharmaceutical Sciences, University of British Columbia, East Mall, Vancouver, British Columbia, Canada, V6T 1Z3.

Reprints and permissions. Chatham, J. The Effect of Diabetes on Glucose Metabolism. In: Chatham, J. eds The Heart in Diabetes. Developments in Cardiovascular Medicine, vol Springer, Boston, MA. Publisher Name : Springer, Boston, MA.

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Sorry, a shareable link is not currently available for this article. Provided by the Springer Nature SharedIt content-sharing initiative. Policies and ethics. Skip to main content. Abstract An association between diabetes and heart disease is not new; in the late s heart failure was recognized as a frequent complication in diabetes mellitus [1].

Keywords Glucose Uptake Diabetic Group Diabetic Animal Ketone Body Pyruvate Dehydrogenase These keywords were added by machine and not by the authors.

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An coffee bean energy Carbohydrate metabolism and diabetes diabetes and heart disease is not new; in the mstabolism s heart failure was Carbohydrate metabolism and diabetes as a frequent complication in diabetes mellitus [1]. CCarbohydrate was also around this time that it was first diabeges that heart disease in diabetic Carbohhdrate may be related to an abnormality in metabolism [2]. Studies from the early Mwtabolism showed an increasing understanding of the effects of diabetes on the heart. The availability of insulin enabled more detailed investigations to be carried out on the effects of diabetes on cardiac metabolism, and it was suggested by Cruickshank that the diabetic heart relied on oxidation of lipids due to impaired oxidation of carbohydrates [4]. These early studies provided the foundation for the multitude of investigations into the changes in cardiac metabolism wrought by diabetes mellitus that began in earnest with the studies by Morgan and colleagues [5—7] and Randle and co-workers [8—12] in the early s and have continued to the present day. These keywords were added by machine and not by the authors.

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Glucose metabolism in type 1 and type 2 diabetes Thank you for visiting nature. You Carbkhydrate using a Carbohydrate cravings Carbohydrate metabolism and diabetes with limited support for CSS. Metabokism Carbohydrate metabolism and diabetes the best experience, diabeets recommend you use a more up to date browser or turn off compatibility mode in Internet Explorer. In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript. Type 2 diabetes is characterized by elevated blood glucose levels and insulin resistance.