Activation of the insulin receptor by insulin-like growth factor 2

Nature Communications, Journal Year: 2024, Volume and Issue: 15(1)

Published: March 23, 2024

Abstract Insulin receptor (IR) controls growth and metabolism. Insulin-like factor 2 (IGF2) has different binding properties on two IR isoforms, mimicking insulin’s function. However, the molecular mechanism underlying IGF2-induced activation remains unclear. Here, we present cryo-EM structures of full-length human long isoform (IR-B) in both inactive IGF2-bound active states, short (IR-A) state. Under saturated IGF2 concentrations, IR-A IR-B adopt predominantly asymmetric conformations with or three IGF2s bound at site-1 site-2, which differs from that insulin forms an exclusively T-shaped symmetric conformation. exhibits a relatively weak to site-2 compared insulin, making it less potent promoting full activation. Cell-based experiments validated functional importance distinct sites optimal signaling trafficking. In state, C-terminus α-CT contacts FnIII-2 domain same protomer, hindering its threading into C-loop IGF2, thus reducing association rate IR-B. Collectively, our studies demonstrate by reveal basis affinity

Language: Английский

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Insulin Resistance in Type 1 Diabetes: Pathophysiological, Clinical, and Therapeutic Relevance

Endocrine Reviews, Journal Year: 2025, Volume and Issue: unknown

Published: Feb. 25, 2025

People with type 1 diabetes (T1D) are usually considered to exclusively exhibit β-cell failure, but they frequently also feature insulin resistance. This review discusses the mechanisms, clinical features, and therapeutic relevance of resistance by focusing mainly on human studies using gold-standard techniques (euglycemic-hyperinsulinemic clamp). In T1D, tissue-specific can develop early sustain throughout disease progression. The underlying pathophysiology is complex, involving both metabolic- autoimmune-related factors operating synergistically. Insulin treatment may play an important pathogenic role in predisposing individuals T1D However, established lifestyle-related risk peripheral administration inducing glucolipotoxicity, hyperinsulinemia, hyperglucagonemia, inflammation, mitochondrial abnormalities, oxidative stress cannot always fully explain suggesting a phenotype distinct from 2 diabetes. mutual interaction between impaired endothelial function further contributes diabetes-related complications. should therefore be target T1D. Aside lifestyle modifications, continuous subcutaneous infusion ameliorate thereby improving glucose toxicity compared multiple injection treatment. Among other concepts, metformin, pioglitazone, incretin-based drugs such as GLP-1 receptor agonists, sodium-glucose cotransporter inhibitors, pramlintide improve resistance, either directly or indirectly. considering current issues high cost, side effects, limited efficacy, their off-label status, these agents people not widely used routine care at present.

Language: Английский

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Dysglycemia and liver lipid content determine the relationship of insulin resistance with hepatic OXPHOS capacity in obesity

Journal of Hepatology, Journal Year: 2024, Volume and Issue: unknown

Published: Aug. 1, 2024

Highlights•Glycemia and liver lipid content jointly affect the adaptation of hepatic oxidative capacity to insulin resistance•Prediabetes affects signaling, mitochondrial dynamics relates fibrosis prevalence•Fasting plasma glucose predicts decline plasticity more robustly than 2-hour OGTT glucoseAbstractBackground & AimsHepatic respiration is higher in steatosis, but lower overt type 2 diabetes. We hypothesized that OXPHOS increases with a greater degree resistance obesity, independent other metabolic diseases.MethodsWe analysed 65 humans without diabetes (BMI 50±7 kg/m2, HbA1c 5.5±0.4%) undergoing bariatric surgery. MASLD stages were assessed by histology, whole-body sensitivity (PREDIcted-M index) oral tolerance tests, maximal ADP-stimulated high-resolution respirometry samples.ResultsPrediabetes was present 30 participants, 46 participants. Thereof, 25 had dysfunction-associated steatohepatitis (MASH), seven F2-F3 fibrosis. While simple regression did not detect an association capacity, interaction analyses revealed coefficient depended on fasting (FPG) content. Interestingly, respective slopes negative for FPG ≤100 mg/dl, positive >100 mg/dl. Liver displayed similar behavior, threshold value 24%. Post-challenge glycemia affected between normalized citrate synthase activity. Presence prediabetes prevalence, while presence related biomarkers inflammation, cell damage peroxidation people normal tolerance.ConclusionsRising contents concentrations, even non-diabetic range, are associated progressive obesity resistance.ClinTrials.gov identifierNCT01477957Graphical abstract

Language: Английский

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Aberrant STING activation promotes macrophage senescence by suppressing autophagy in vascular aging from diabetes

iScience, Journal Year: 2024, Volume and Issue: 28(1), P. 111594 - 111594

Published: Dec. 13, 2024

Language: Английский

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Reduced insulin clearance in paediatric metabolic (dysfunction)‐associated fatty liver disease and its dual role in beta‐cell offload and diabetes risk

Diabetes Obesity and Metabolism, Journal Year: 2024, Volume and Issue: 26(11), P. 5390 - 5398

Published: Aug. 27, 2024

Diminished hepatic insulin clearance (HIC) is observed in obese adults and presumed to be mediated by fatty liver. However, few reports have examined HIC Chinese children with metabolic (dysfunction)-associated liver disease (MAFLD). This study aimed investigate the correlation between HIC, sensitivity β-cell function MAFLD.

Language: Английский

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Sex differences in pathogenesis and treatment of dyslipidemia in patients with type 2 diabetes and steatotic liver disease

Frontiers in Medicine, Journal Year: 2024, Volume and Issue: 11

Published: Sept. 23, 2024

Previously published studies have shown that women with type 2 diabetes a higher risk of atherosclerotic cardiovascular disease than men diabetes. The exact reason for this is not yet known. association between metabolic dysfunction-associated steatotic liver and appears to be bidirectional, meaning the onset one may increase progression other. Dyslipidemia common in both diseases. Our aim was therefore investigate whether there sex difference pathogenesis management dyslipidemia patients dysfunction. While majority date found no statin treatment, some reduced effectiveness compared men. Statin treatment under-prescribed diabetics disease. No differences were ezetimibe treatment. However, best our knowledge, such study fibrate Conflicting results on efficacy newer cholesterol-lowering PCSK9 inhibitors been reported Results from two real-world suggest up-titration dose improves women. Bempedoic acid has effective safe more lipid lowering men, based phase 3 date. Further research needed clarify plays role ASCVD

Language: Английский

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Cell-specific regulation of insulin action and hepatic fibrosis by CEACAM1

Metabolism and Target Organ Damage, Journal Year: 2024, Volume and Issue: 4(4)

Published: Sept. 26, 2024

The incidence of metabolic dysfunction-associated steatotic liver disease (MASLD) has reached an epidemic rise worldwide. is a constellation broad range and histopathologic abnormalities. It begins with hepatic steatosis progresses to steatohepatitis (MASH), including fibrosis, apoptosis, cell injury. Despite ample research effort, the pathogenesis not been fully delineated. Whereas insulin resistance implicated in early stages disease, its role fibrosis remains controversial. We have focused our studies on carcinoembryonic antigen-related adhesion molecule 1 (CEACAM1) hepatocytes endothelial cells histopathological dysregulation MASH. Patients MASH exhibit lower CEACAM1 progressive decline as stage advances. In mice, conditional deletion impairs clearance cause hyperinsulinemia-driven even when mice are fed regular chow diet. contrast, causes inflammation-driven without adversely affecting metabolism (mice remain insulin-sensitive do develop steatosis). Thus, this review provides vivo evidence that supports or discards injury fibrosis.

Language: Английский

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Hepatic glucose production rises with the histological severity of metabolic dysfunction-associated steatohepatitis

Cell Reports Medicine, Journal Year: 2024, Volume and Issue: 5(11), P. 101820 - 101820

Published: Nov. 1, 2024

Language: Английский

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The relationship of changes in insulin demand and insulin adequacy over the life course

Diabetologia, Journal Year: 2024, Volume and Issue: unknown

Published: Nov. 29, 2024

Abstract Aims/hypothesis Insulin requirements in the human body undergo continuous changes response to growth and development. We assessed life course relationships between insulin demand adequacy. Methods Three independent Chinese cohorts (204 children, aged [mean ± SD] 7.0 0.5 years; 214 adolescents, 15.0 1.8 605 adults, 41.5 9.3 years), recruited 1998 2013, underwent OGTT tests. Indices of sensitivity secretion were calculated based on paired glucose/insulin values during fasting, early phase late OGTT. adequacy by standardised major axis (SMA) regression from indices. derived natural logarithm ratio exponential functions (RAD) index for further evaluating relationship The risk abnormal glucose tolerance (AGT) was evaluated logistic analyses. Area under receiver-operating characteristic curve (AUC-ROC) analyses, net reclassification improvement (NRI) integrated discrimination (IDI) indices used demonstrate discriminative value RAD method model. Results Adolescents had lowest highest all phases (fasting, phase) OGTT, as compared with children adults each (all p <0.001). fasting ( In general, both >0.05) <0.001) negative irrespective overweight obesity, while, positive <0.001 age groups OGTT). Participants below 25th percentile a higher AGT those above (fasting-phase OR 1.86 [95% CI 1.18, 2.91]; early-phase 1.99 1.24, 3.19]; late-phase 2.49 1.57, 3.97]). best performance fasting- (late-phase AUC-ROC = 0.635 0.583, 0.687]; NRI 0.350 0.190, 0.510]; IDI 0.033 0.015, 0.050]). Conclusions/interpretation changed throughout course. an imbalanced adequacy, balanced relationship. is novel that efficiently describe this evaluate AGT. Graphical

Language: Английский

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Elevations in plasma glucagon are associated with reduced insulin clearance after ingestion of a mixed-macronutrient meal in people with and without type 2 diabetes

Diabetologia, Journal Year: 2024, Volume and Issue: 67(11), P. 2555 - 2567

Published: Aug. 13, 2024

Abstract Aims/hypothesis The temporal suppression of insulin clearance after glucose ingestion is a key determinant tolerance for people without type 2 diabetes. Whether similar adaptations are observed the mixed-macronutrient meal unclear. Methods In secondary analysis data derived from two randomised, controlled trials, we studied responses standardised breakfast consisting cereal and milk in lean normoglycaemic individuals ( n =12; Lean-NGT), with central obesity =11; Obese-NGT) diabetes =19). Pre-hepatic secretion rates were determined by deconvolution C-peptide, was calculated using single-pool model. Insulin sensitivity measured an oral minimal Results There divergent time course changes between groups. Lean-NGT group, there immediate post-meal increase compared pre-meal values p <0.05), whereas remained stable at baseline Obese-NGT or declined slightly group <0.05). mean AUC during test ~40% lower (1.3 ± 0.4 l min −1 m −2 ) (1.4 0.7 groups (1.9 0.5 ; <0.01), no difference HOMA-IR glucagon emerged as predictors AUC, independent BMI, age (adjusted R =0.670). Individuals increased had 40% reduction (~ −0.75 <0.001). Conclusions/interpretation augments differing profiles among diabetes, which associated glucagon. Further research investigating role hepatic signalling postprandial kinetics warranted. Trial registration ISRCTN17563146 ISRCTN95281775 Graphical

Language: Английский

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