Search Medical Journals & Research Articles

Novel Approach for Assessing Outcomes of Type 1 Diabetes Prevention Trials Over a Fixed Time Interval

We evaluated whether a binary metabolic end point for change (Δ) from baseline to 1-year postrandomization could be useful in type 1 diabetes (T1D) prevention trials. Using 2-h oral glucose tolerance testing data from the stage 1 participants in the recent abatacept prevention trial and similar participants in the observational TrialNet Pathway to Prevention (PTP) study, we assessed Δmetabolic measures, plotted glucose and C-peptide response curves, and categorized vectors for Δ from baseline to 1 year as metabolic treatment failure versus success. Analyses were validated using the teplizumab prevention study. PTP participants with Δglucose >0 and ΔC-peptide <0 from baseline to 1 year were at substantially higher risk for stage 3 T1D than those with Δglucose <0 and ΔC-peptide >0 ( P < 0.0001). Based on this, we compared placebo versus treatment groups in both trials for failure (Δ glucose >0 with Δ C-peptide <0) versus success (Δ glucose <0 with ΔC-peptide >0) after 1 year. Using this end point, a favorable metabolic impact of abatacept was found after 12 months of treatment. An analytic approach using a binary metabolic end point of failure versus success at a fixed time interval appears to detect treatment effects at least as well as standard primary end points with shorter follow-up. Article Highlights Challenges in time to event type 1 diabetes (T1D) prevention trial design can yield negative results even for treatments that may actually improve disease pathology. We evaluated whether a binary metabolic end point for 12-month change from baseline to 1 year postrandomization could be useful in T1D prevention trials. This approach detected treatment effects at least as well as standard primary end points with shorter follow-up. Fixed interval metabolic end points should be used in combination with traditional T1D end points to better understand treatment effects of preventive agents.

Lipids Engage a Kidney-Brain GDF15 Axis to Suppress Food Intake

Growth differentiation factor 15 (GDF15) is an anorectic and weight loss–inducing hormone that responds to stimuli such as endoplasmic reticulum stress, exercise, metformin, and, more recently, dietary lipids. Given its potential as an antiobesogenic agent, we examined how endogenous GDF15 responds to an Intralipid infusion in different organs to regulate food intake in vivo. We found that an acute Intralipid infusion into the upper small intestine (USI) inhibited food intake and increased plasma GDF15, as well as kidney and hepatic Gdf15 expression in chow-fed but not high-fat (HF)–induced hyperphagic male rats. Kidney Gdf15 knockdown blunted Intralipid-induced increases in kidney and plasma GDF15 levels as well as its feeding-lowering effects, while hepatic Gdf15 expression remained unaffected. Lastly, we knocked down GDNF family receptor α-like (Gfral) in the area postrema, which negated the feeding-lowering effect of Intralipid despite a rise in plasma GDF15 levels in chow rats. In summary, we report that kidney GDF15 is necessary for USI intralipid sensing to trigger an area postrema axis to inhibit food intake. We propose that HF feeding impairs acute lipid sensing to lower feeding by negating the lipid-regulatory effect on kidney GDF15. Article Highlights Upper small intestine lipid infusion increases kidney, hepatic, and plasma growth differentiation factor 15 (GDF15) levels in chow but not high-fat rats. Upper small intestine lipid infusion lowers food intake in chow but not high-fat rats. Knockdown of kidney Gdf15 negates lipids to increase plasma GDF15 and lower feeding. Knockdown of GDNF family receptor α-like (Gfral) in the area postrema negates lipid anorectic effect.

Proinflammatory Stress Activates Neutral Sphingomyelinase 2–Based Generation of a Ceramide-Enriched β-Cell EV Subpopulation

β-Cell extracellular vesicles (EVs) play a role as paracrine effectors in islet health, yet mechanisms connecting β-cell stress to changes in EV cargo and potential impacts on diabetes remain poorly defined. We hypothesized that β-cell inflammatory stress engages neutral sphingomyelinase 2 (nSMase2)-dependent EV formation pathways, generating ceramide-enriched small EVs that could impact surrounding β-cells. Consistent with this, proinflammatory cytokine treatment of INS-1 β-cells and human islets concurrently increased β-cell nSMase2 and ceramide abundance, as well as small EV ceramide species. Direct chemical activation or genetic knockdown of nSMase2, chemical treatment to inhibit cell death pathways, or treatment with a glucagon-like peptide-1 (GLP-1) receptor agonist also modulated β-cell EV ceramide. RNA sequencing of ceramide-enriched EVs identified a distinct set of miRNAs linked to β-cell function and identity. EV treatment from cytokine-exposed parent cells inhibited peak glucose-stimulated insulin secretion in wild-type recipient cells; this effect was abrogated when using EVs from nSMase2 knockdown parent cells. Finally, plasma EVs in children with recent-onset type 1 diabetes showed increases in multiple ceramide species. These findings highlight nSMase2 as a regulator of β-cell EV cargo and identify ceramide-enriched EV populations as a contributor to EV-related paracrine signaling under conditions of β-cell inflammatory stress and death. Article Highlights Mechanisms connecting β-cell stress to extracellular vesicle (EV) cargo and diabetes are poorly defined. Does β-cell inflammatory stress engage neutral sphingomyelinase 2 (nSMase2)-dependent EV formation to generate ceramide-enriched small EVs? Proinflammatory cytokines increased β-cell small EV ceramide via increases in nSMase2. Ceramide-enriched EVs housed distinct cargo linked to insulin signaling, and ceramide species were enriched in plasma EVs from individuals with type 1 diabetes. Ceramide-enriched EV populations are a potential contributor to β-cell EV-related paracrine signaling.

Effects of Dorzagliatin, a Glucokinase Activator, on α- and β-Cell Function in Individuals With Impaired and Normal Glucose Tolerance

Dorzagliatin is a dual-acting allosteric activator of glucokinase (GCK). Dorzagliatin improved second-phase insulin secretion in individuals with type 2 diabetes and heterozygous carriers of GCK mutations. We investigated the effects of dorzagliatin on pancreatic insulin, glucagon, and glucagon-like-peptide 1 (GLP-1) secretion in individuals with impaired glucose tolerance (IGT) and normal glucose tolerance (NGT). In a double-blind, randomized, crossover, single-dose study, 9 participants with IGT and 10 with NGT underwent 2-h 12 mmol/L hyperglycemic clamp following a single dose of dorzagliatin 50 mg or matched placebo. Plasma insulin, C-peptide, glucagon, and total GLP-1 levels were measured at regular intervals. There were no differences in first-phase insulin after the dorzagliatin dose in either group. Dorzagliatin significantly increased second-phase insulin secretion rate and β-cell glucose sensitivity by 1.3-fold compared with placebo in IGT but remained similar in NGT. Dorzagliatin increased basal plasma insulin in the NGT group only. Glucagon (area under the curve 0–120 min = 161 ± 58 vs. 234 ± 70 pmol*min/L [mean ± SD]; P = 0.01) was suppressed after dorzagliatin in the NGT group but not the IGT group. Plasma glucagon was positively correlated with total GLP-1 levels. Dorzagliatin did not affect insulin sensitivity in either group. Dorzagliatin has different actions on β- and α-cells depending on glucose tolerance, increasing second-phase insulin secretion in IGT while enhancing glucose-suppression of glucagon secretion in NGT. Article Highlights Dorzagliatin is a dual-acting allosteric glucokinase (GCK) activator that increases β-cell glucose sensitivity and second-phase insulin in GCK monogenic diabetes of the young. Actions of dorzagliatin on α- and β-cell function in normal and impaired glucose tolerance are unknown. In this study, dorzagliatin increased second-phase insulin in individuals with impaired glucose tolerance while suppressing glucagon in participants with normal glucose tolerance during a hyperglycemic clamp. With increasing glucose, plasma glucagon and total GLP-1 levels declined progressively. A modest to moderate positive correlation between glucagon and total GLP-1 was observed under both dorzagliatin and placebo treatments.

Cell Type–Specific Expression of Long Noncoding RNAs in Human Diabetic Kidneys Identifies TARID as a Key Regulator of Podocyte Function

Long noncoding RNAs (lncRNAs) play essential roles in cellular processes, often exhibiting cell type–specific expression and influencing kidney function. While single-cell RNA sequencing (scRNA-seq) has advanced our understanding of cellular specificity, past studies focus solely on protein-coding genes. We hypothesize that lncRNAs, due to their cell-specific nature, have crucial functions within particular renal cells and thereby play essential roles in renal cell function and disease. Using single-nucleus RNA-seq (snRNA-seq) data from kidney samples of five healthy individuals and six patients with diabetic kidney disease (DKD), we explored the noncoding transcriptome. Cell type–specific lncRNAs were identified, and their differential expression in DKD was assessed. Integrative analyses included expression quantitative trait loci (eQTL), genome-wide association studies (GWAS) for estimated glomerular filtration rate (eGFR), and gene regulatory networks. Functional studies focused on TCF21 antisense RNA inducing promoter demethylation ( TARID ), a lncRNA with podocyte-specific expression, to elucidate its role in podocyte health. We identified 174 lncRNAs with cell type–specific expression across kidney cell types. Of these, 54 lncRNAs were differentially expressed in DKD. Integrative analyses, including eQTL data, GWAS results for eGFR, and gene regulatory networks, pinpointed TARID, a podocyte-specific lncRNA, as a key candidate upregulated in DKD. Functional studies confirmed TARID 's podocyte-specific expression and revealed its central role in actin cytoskeleton reorganization. Our study provides a comprehensive resource of single-cell lncRNA expression in the human kidney and highlights the importance of cell type–specific lncRNAs in kidney function and disease. Specifically, we demonstrate the functional relevance of TARID in podocyte health. Article Highlights This study provides a resource for kidney (cell type–specific) long noncoding (lnc)RNA expression and demonstrates the importance of lncRNAs in renal health. We identified 174 cell type–specific lncRNAs in the human kidney, with 54 showing altered expression in diabetic kidney disease. TCF21 antisense RNA inducing promoter demethylation (TARID ), a podocyte-specific lncRNA upregulated in diabetic kidney disease, is crucial for actin cytoskeleton reorganization in podocytes.

Application of Dental Pulp Stem Cell–Derived Intracellular Vesicles for Diabetic Wound Healing

Diabetic wounds represent a significant clinical and economic burden, affecting both patients and health care systems. While current therapeutic approaches, such as negative pressure wound therapy, offer benefits, their limitations necessitate alternative strategies. Newly discovered dental pulp stem cell–derived intracellular vesicles have emerged as a promising candidate in regenerative medicine due to their therapeutic potential. In vitro assessments using HUVECs, HaCaTs, and RAW264.7 cells revealed that intracellular vesicles enhance cell migration, angiogenesis, and proliferation while suppressing the cGAS-STING pathway. Additionally, intracellular vesicles promoted M2 macrophage polarization and maintained mitochondrial function. In a diabetic mouse wound model, both intracellular vesicles and negative pressure wound therapy individually improved wound healing, but their combination exhibited a synergistic effect, resulting in faster wound closure, enhanced angiogenesis, and reduced inflammation. The combined treatment also exhibited excellent biocompatibility. These findings highlight the therapeutic potential of intracellular vesicles as an adjunct to negative pressure wound therapy for diabetic wound treatment. Article Highlights Chronic diabetic wounds are difficult to heal, and current treatments, such as negative pressure wound therapy, have limited effectiveness. The potential of intracellular vesicles derived from dental pulp stem cell lysate for diabetic wound healing is well worth exploring. Intracellular vesicles promoted angiogenesis, cell proliferation, and M2 macrophage polarization by inhibiting cGAS-STING signaling and restoring mitochondrial function. Combined with negative pressure wound therapy, intracellular vesicles accelerated wound healing in diabetic mice. Intracellular vesicles offer a promising cell-free strategy to enhance negative pressure wound therapy outcomes and improve diabetic wound treatment.

Heterogeneity in Phenotype and Early Metabolic Response to Lifestyle Interventions in Type 2 Diabetes in China Using a Tree-Like Representation

Deciphering the heterogeneity of type 2 diabetes in prognosis and treatment effect is essential. We used a novel dimensionality reduction approach to describe the type 2 diabetes phenotype continuum and visualize the difference in lifestyle intervention efficacy in Chinese patients. Based on 17,816 participants with newly diagnosed type 2 diabetes (aged ≥40 years) from a nationwide cohort, 12 key phenotypes were residualized for age and sex to construct a two-dimensional tree structure. The tree demonstrated the continuous type 2 diabetes spectrum and region-specific characteristics, with a mixed phenotypic trunk and three extreme phenotypic branches. When mapping data from 325 participants with type 2 diabetes from a randomized controlled trial onto the original tree, lifestyle intervention induced a migration toward the left part of tree, indicating an overall metabolic improvement. Specifically, diet intervention was more effective for glycemic control in the upper part of the tree and featured moderate diabesity and elevated insulin, whereas exercise intervention was more effective for glycemic control in the left side of the tree and featured less adiposity and better overall metabolic status. In summary, this analysis depicted the tree structure representing the underlying pathophysiological features of patients with newly diagnosed type 2 diabetes and identified tree regions with different sensitivity to diet or exercise intervention. The results have the potential to aid lifestyle intervention selection. Article Highlights Deciphering the heterogeneity of diabetes is essential for prognosis prediction and treatment guidance, but current classifications are flawed because they lose continuous phenotypic information. We wanted to determine if the novel data reduction method, the data dimensionality reduction tree (DDRTree), is applicable to visualizing the phenotypic continuum, comorbid conditions, and lifestyle intervention effects in Chinese patients with type 2 diabetes. The DDRTree structure demonstrated the region-specific characteristics of type 2 diabetes. Diet intervention was more effective for glycemic control in the upper part of the tree, featuring moderate diabesity, whereas exercise intervention was more effective in the left side of the tree, featuring less adiposity and better overall metabolic status. The Chinese type 2 diabetes tree structure indicates individualized pathophysiology and guides the selection of lifestyle intervention.

Proinflammatory Cytokines Mediate Pancreatic β-Cell–Specific Alterations to Golgi Integrity via iNOS-Dependent Mitochondrial Inhibition

Type 1 diabetes (T1D) is caused by the selective autoimmune ablation of pancreatic β-cells. Emerging evidence reveals β-cell secretory dysfunction arises early in T1D development and may contribute to diseases etiology; however, the underlying mechanisms are not well understood. Our data reveal that proinflammatory cytokines elicit a complex change in the β-cell’s Golgi structure and function. The structural modifications include Golgi compaction and loss of the interconnecting ribbon resulting in Golgi fragmentation. We further show that Golgi structural alterations coincide with persistent altered cell surface glycoprotein composition. Our data demonstrate that inducible nitric oxide synthase (iNOS)–generated nitric oxide (NO) is necessary and sufficient for β-cell Golgi restructuring. Moreover, the unique sensitivity of the β-cell to NO-dependent mitochondrial inhibition results in β-cell–specific Golgi alterations that are absent in other cell types, including α-cells. Examination of human pancreas samples from autoantibody-positive and T1D donors with residual β-cells further revealed alterations in β-cell, but not α-cell, Golgi structure that correlate with T1D progression. Collectively, our studies provide critical clues as to how β-cell secretory functions are specifically impacted by cytokines and NO that may contribute to the development of β-cell autoantigens relevant to T1D. Article Highlights Proinflammatory cytokines drive disruptions in Golgi structure and function in human, mouse, and rat β-cells. Golgi alterations result from inducible nitric oxide synthase (iNOS)– and nitric oxide (NO)–dependent inhibition of mitochondrial metabolism. α-Cell Golgi structure is insensitive to cytokine- and NO-mediated metabolic inhibition. Analysis of human donor tissue shows early Golgi alteration in β-cells from autoantibody-positive donors, which persists in residual β-cells from T1D donors.

Mechanistic Insights Into Postprandial Insulin–Glucagon Interactions and Their Impact on Glucose Flux After Protein–Glucose Coingestion in Humans

Despite stimulating glucagon secretion, the mechanisms by which protein ingestion lowers glucose excursions remain unclear. We investigated this using the triple stable isotope glucose tracer technique to measure postprandial glucose fluxes. Eleven healthy adults completed three trials, ingesting 25 g glucose (25G; 100 kcal), 50 g glucose (50G; 200 kcal), or 25 g glucose plus 25 g whey protein (25WG; 200 kcal). Glucose excursions were lowest for 25WG. Glucagon increased approximately threefold with 25WG but was suppressed with 25G and 50G. Insulin and glucose-dependent insulinotropic polypeptide (GIP) were higher for 25WG versus 25G, whereas glucagon-like peptide 1 (GLP-1) was similar. Compared with 50G, 25WG produced a greater GIP but similar GLP-1 response, with a trend toward higher early-phase insulin. Endogenous glucose production (EGP) was less suppressed with 25WG (∼50%) versus 25G (∼70%) or 50G (∼80%). Compared with 25G, 25WG did not enhance glucose disposal (Rd) but reduced early-phase (30–60 min) glucose absorption. These findings confirm that protein–glucose coingestion robustly stimulates glucagon while enhancing GIP and insulin, leading to lower postprandial glucose excursions. Despite greater insulin secretion, the net glycemic benefit seems to stem from reduced early glucose absorption rather than increased Rd. This provides novel insights into the mechanisms by which protein improves postprandial glucose handling despite interfering with EGP suppression. Article Highlights Despite stimulating glucagon secretion, the addition of protein to carbohydrate typically lowers postprandial glucose excursions. The mechanisms underlying this phenomenon are incompletely understood. In healthy young adults, using the triple stable isotope glucose tracer technique, we investigated how whey protein and glucose coingestion modulates postprandial glucose fluxes. Despite stimulating glucagon secretion and impairing suppression of endogenous glucose production, whey protein–glucose coingestion significantly reduced glycemic excursions. Although whey protein–glucose coingestion strongly enhanced the insulin and glucose-dependent insulinotropic polypeptide (but not glucagon-like peptide 1) responses, whole-body glucose uptake was not enhanced; rather, the net glycemic benefit seemed to stem from reduced early-phase glucose absorption.

β-Cell Neogenesis From the Pancreatic Ductal Epithelium Revealed Dynamically by Long-term Intravital Imaging

Pancreatic β-cells can self-renew in the adult pancreas through replication, but the contribution of ductal progenitors to endocrine regeneration has been the subject of debate for two decades. While these mechanisms are not mutually exclusive, some lineage-tracing strategies suggest that intraductal endocrine cells cannot dynamically derive from ducts. Combining one such approach with a novel in vivo model in which live pancreatic slices are transplanted into the anterior chamber of the eye (ACE) of recipient mice, we show long-term growth of preexisting islets and real-time generation of neogenic insulin-expressing cells from ductal areas. Our results represent a departure from historical approaches to address these questions, which have been based on either static analyses of pancreatic tissue or “before and after” lineage-tracing designs. The slice-in-ACE model reveals the dynamic processes at play during regeneration and demonstrates the active formation of insulin-producing cells within the ductal network. Article Highlights The adult pancreas’ capacity to regenerate endocrine cells through ductal neogenesis has been disputed based on some pulse-chase lineage-tracing designs; however, no model described thus far has enabled the real-time study of regeneration in vivo. To facilitate long-term intravital imaging of pancreatic remodeling, we designed a novel system where pancreatic slices are transplanted into the anterior chamber of the eye of recipient mice. Using a transgenic mouse strain that enables the tracing of insulin-producing cells, we demonstrate that they arise dynamically from the ductal epithelium. Complementary work with human pancreatic slices suggests conservation of these mechanisms across species.

Serum Metabolomics Reveals Potential Differences in Gut Microbiota–Associated Metabolites in Twins Discordant for Type 1 Diabetes

We investigated serum metabolites in monozygotic (MZ) and dizygotic (DZ) twins discordant for type 1 diabetes (T1D) to explore potential environmental factors, with a focus on differences in gut microbiota–associated metabolites that may influence T1D. Serum samples from 39 twins discordant for T1D were analyzed using a semi-targeted metabolomics approach via liquid chromatography–high-resolution tandem mass spectrometry. Statistical analyses identified significant metabolites ( P < 0.1) within three groups: all twins (combined group [All]), MZ twins, and DZ twins. Thirteen metabolites exhibited significant differences between individuals with T1D and those without T1D. Across all groups, 3-indoxyl sulfate and 5-hydroxyindole were significantly reduced in individuals with T1D. Carnitine was reduced, and threonine, muramic acid, and 2-oxobutyric acid were significantly elevated in both All and MZ groups. Allantoin was significantly reduced and 3-methylhistidine was significantly elevated in All and DZ groups. These findings suggest metabolite dysregulation associated with gut dysbiosis was observed. However, further validation of our findings in a larger cohort is needed. Article Highlights We believed this cohort of twins discordant for type 1 diabetes (T1D) would allow for control over genetic variability to examine environmental factors. We aimed to identify differences in microbial and microbiota-associated metabolites in twins discordant for T1D to examine the effect of the gut microbiome on T1D. Thirteen metabolites were identified as significantly different. Our results show dysregulation of several microbial metabolites in twin pairs, suggesting the role of the gut microbiome in T1D pathogenesis.

Systems Biology and Functional Assessments of Human iPSC-Cardiomyocyte Models of Insulin Resistance Capture Key Hallmarks of Diabetic Cardiomyopathy

Human-centric models of diabetic cardiomyopathy (DbCM) are needed to provide mechanistic insights and translationally relevant therapeutic targets for patients with diabetes. A systems biology approach using insulin resistant (IR) two-dimensional (2D) human induced pluripotent stem cell–derived cardiomyocytes (hiPSC-CMs) and three-dimensional (3D) engineered heart tissue (EHT) provides a comprehensive evaluation of dysregulated pathways and determines suitability as a translationally relevant model of DbCM. Culturing hiPSC-CMs in 2D or 3D EHT in IR media induced insulin resistance and activated multiple pathways implicated in DbCM, including metabolic remodeling, mitochondrial dysfunction, extracellular matrix remodeling, endoplasmic reticulum stress, and blunted response to hypoxia, as assessed using transcriptomics and proteomics. Metabolic flux measurements in both IR 2D and 3D platforms demonstrated increased fatty acid oxidation and lipid storage, whereas glucose metabolism was downregulated. Modeling DbCM in 3D EHTs conferred additional metabolic and functional advantages over the 2D hiPSC-CM, demonstrating impaired contractility and muscle architecture. Metformin treatment improved both contractility and metabolic function, demonstrating the utility of IR EHT for drug assessment. In conclusion, IR 2D and 3D hiPSC-CM models effectively capture key DbCM features. However, 3D EHT provides additional insights into physiological and structural modifications. This highlights the potential of IR EHT for both mechanistic studies and drug screening in DbCM. Article Highlights Human-centric cardiac models are needed that recapitulate mechanistic and functional changes in the type 2 diabetic myocardium for understanding disease pathogenesis and developing new therapies. Using human induced pluripotent stem cell–derived cardiomyocytes (hiPSC-CM) in 2D and 3D as engineered heart tissue (EHT), we aimed to model diabetic cardiomyopathy in cellulo. Taking an unbiased systems biology approach, our cellular models recapitulated the dysregulated pathways and functional derangement of diabetic cardiomyopathy. Three-dimensional EHT models showed contractile dysfunction akin to that seen in patients, with mechanistic and functional changes reversed with metformin. It is possible to generate translationally relevant hiPSC-CM models that mimic diabetic cardiomyopathy.

Diabetes Spotlight: Kevin Williams, PhD—Mapping the Neural Networks of Metabolic Systems

Kevin Williams grew up in a household where he constantly learned the inner workings of everyday objects. “My father was an engineer and always tinkering,” he says. “He rebuilt TVs and radios. With my mother’s encouragement, we’d visit hardware stores then come home and build computers.” For his first car, Williams’ parents bought him an 1982 Pontiac Grand Prix—but it needed an engine rebuild. “I spent a lot of time with my father learning how to do that, and it took a lot longer than expected, but it gave me an understanding of how complex systems work,” he says. “Believe it or not, I think these foundational experiences have directly led to my current research interests and career.”

Metabolic Perturbations and Ectopic Fat Deposition in Men With Low Birth Weight: Effects of a 4-Week Carbohydrate Overfeeding Challenge

Low birth weight (LBW) is a risk factor for type 2 diabetes (T2D). We hypothesized that 4 weeks of carbohydrate overfeeding (COF) with +25% energy would unmask key T2D perturbations among 22 nonobese LBW men, including five with screen-detected metabolic dysfunction–associated steatotic liver disease (MASLD), compared with 21 healthy control participants with normal birth weight (NBW). Body weight, lean and fat mass, and hepatic fat content increased to the same extent in both groups during COF, whereas fasting glucose and insulin resistance increased significantly more in LBW compared with NBW participants. The differential COF responses were most pronounced in LBW participants without MASLD, including increased resting energy expenditure. Plasma adiponectin was lower, whereas fibroblast growth factor 21 levels increased more during COF in LBW participants. Subcutaneous adipose tissue (SAT) density was lower in LBW participants and decreased during COF in both groups. Serum alanine, phosphatidylcholines, and triglycerides increased significantly more in LBW participants during COF. Multiomics analysis of SAT RNA sequencing, serum lipidomics, and metabolomics uncovered impaired peroxisome proliferator–activated receptor signaling as well as aberrant collagen and extracellular matrix regulation in LBW participants. The results document differential and MASLD-independent metabolic perturbations in LBW participants during COF. Article Highlights Individuals with low birth weight (LBW) are at increased risk of type 2 diabetes. Four weeks of carbohydrate overfeeding (COF) was associated with differential elevations in fasting glucose, lipids, alanine, insulin resistance, and resting energy expenditure in LBW participants versus control participants. Multiomics analyses indicated reduced peroxisome proliferator–activated receptor signaling, as well as differential expression of genes involved in collagen and extracellular matrix metabolism in LBW participants during COF. Interestingly, the COF perturbations in LBW participants became more pronounced when excluding five LBW men with screen-detected metabolic dysfunction–associated steatotic liver disease. The findings support the notion of unhealthy subcutaneous adipose tissue expandability potentially underlying a reduced metabolic buffering capacity in nonobese LBW men.

Distributed Control of Muscle Glucose Uptake: A Tribute to the Late Dr. David H. Wasserman by Revisiting a 2004 Diabetes Classic by Fueger et al.

The control of muscle glucose uptake (MGU) is distributed across delivery, transport, and phosphorylation of glucose. These steps have been defined as control points of MGU in vivo due to the application of isotopic tracer techniques to transgenic mouse models. Using these techniques in a classic study published in Diabetes, Fueger et al. demonstrated that overexpression in skeletal muscle of hexokinase II (HKII), the enzyme responsible for intracellular glucose phosphorylation, enhanced MGU in insulin-sensitive but not in insulin-resistant mice. Conversely, HKII overexpression enhanced MGU in insulin-resistant mice in response to exercise. Since exercise reduces barriers of glucose delivery and transport, this suggested that these two processes contribute to the dysregulation of MGU in insulin-resistant states. These fundamental findings have spurred subsequent studies highlighting the contribution of glucose delivery and transport to the regulation of MGU in health and disease.