RESUMO
Insulin resistance is the primary contributor to the disruption in glucose homeostasis in the body, playing a significant causative role in many metabolic diseases. Insulin resistance is characterized by compensatory insulin secretion and reduced insulin responsiveness in target organs. Dysregulation of the interaction between insulin-secreting cells and insulin-responsive target organs is an important factor driving the progression of insulin resistance. Circulating endocrine hormones are important mediators mediating the interaction between insulin-secreting cells and insulin-responsive target organs. In addition to the classical hormones secreted by endocrine glands and organ-specific hormones secreted by metabolism-related organs (adipose tissue, muscle, liver, etc.), extracellular vesicles have been recognized as a novel class of endocrine hormones with a complex composition. Extracellular vesicles can transport signaling molecules, such as miRNAs and LncRNAs, to vital organs related to insulin resistance, in a manner akin to conventional hormones. The significant role in regulating the development of insulin resistance underscores the increasing interest in extracellular vesicles as essential contributors to this process. In this review, we summarize the three types of hormones (classical hormones, organokines and extracellular vesicles) that play a regulatory role in insulin resistance, and focus on the novel endocrine hormones, extracellular vesicles, to elaborate the mechanism of extracellular vesicles' regulation of insulin resistance progress from two aspects: the impact on insulin-secreting cells and the influence on insulin-responsive target organs. In addition, this paper outlines the clinical applications of extracellular vesicles in insulin resistance. A comprehensive understanding of the regulatory mechanisms and diagnostic status of the inter-organ network in insulin resistance has great potential to advance targeted therapeutic interventions and diagnostic markers, thereby benefiting both the prevention and treatment of insulin resistance.
Assuntos
Vesículas Extracelulares , Resistência à Insulina , Humanos , Vesículas Extracelulares/metabolismo , Células Secretoras de Insulina/metabolismo , Células Secretoras de Insulina/fisiologia , Insulina/metabolismo , Hormônios/metabolismo , Animais , Tecido Adiposo/metabolismo , MicroRNAs/metabolismo , MicroRNAs/genéticaRESUMO
The existence of functionally diverse and plastic ß cells in islets of Langerhans has been reported since the 1980s. Recently, high-resolution technologies have advanced our understanding of ß-cell heterogeneity and plasticity. Here, we define plasticity broadly as dynamic changes in cellular phenotypes and heterogeneity as differences in cellular behaviors. Individual ß cells react differently to environmental challenges and act together to maintain ß-cell mass and glucose homeostasis within a narrow range of 70-140 mg/dL. During the progress of diabetes, this elaborate balance is disrupted, and a lack of ß-cell compensation leads to dysregulated blood glucose. In this chapter, we assess ß-cell stress that instigates increased ß-cell heterogeneity and adaptive ß-cell responses such as proliferation, dedifferentiation, maturity, and insulin secretion. We also discuss the maturity, electrical activity, and insulin secretion of well-characterized ß-cell subgroups. Finally, we touch upon the plasticity of other non-ß pancreatic cells and their cooperation with ß cells to maintain homeostasis.
Assuntos
Plasticidade Celular , Células Secretoras de Insulina , Células Secretoras de Insulina/fisiologia , Células Secretoras de Insulina/metabolismo , Humanos , Animais , Secreção de Insulina , Insulina/metabolismo , HomeostaseRESUMO
The pancreas has been considered a non-regenerative organ. ß cells lost in diabetes are not replaced due to the inability of the pancreas to regenerate. However, ample evidence generated in the last few decades using murine models has demonstrated that the pancreas has a remarkable plasticity wherein differentiated cells can change cell fate toward a ß-like cell phenotype. Although this process is observed after using rather artificial stimuli and the conversion efficiency is very limited, these findings have shed some light on novel pathways for ß-cell regeneration. In this chapter, we will summarize the different cellular interconversion processes described to date, the experimental details and molecular regulation of such interconversions, and the genomic technologies that have allowed the identification of potential new ways to generate ß cells.
Assuntos
Plasticidade Celular , Células Secretoras de Insulina , Regeneração , Animais , Células Secretoras de Insulina/fisiologia , Células Secretoras de Insulina/citologia , Regeneração/fisiologia , Humanos , Plasticidade Celular/fisiologia , Pâncreas/fisiologia , Pâncreas/citologia , Diferenciação Celular , CamundongosRESUMO
Pancreatic δ cells act locally to repress both insulin and glucagon secretion. Because they are a rare cell type, experimentation examining δ-cell function and control has lagged that of the more abundant α and ß cells. Emerging evidence, enabled partly by developing single-cell technology, demonstrates that δ-cell function is, in part, directed by δ cells but that δ cells also have intrinsic control. The contribution of these cells to overall glucose homeostasis and diabetes onset and progression is still unclear. However, they regulate both α and ß cells, both of which are dysfunctional in diabetes, and their numbers are disrupted in humans with diabetes and in multiple animal models of diabetes, suggesting δ cells are a pivotal character in both health and disease.
Assuntos
Células Secretoras de Insulina , Humanos , Animais , Células Secretoras de Insulina/fisiologia , Diabetes Mellitus , Células Secretoras de Somatostatina/metabolismo , Insulina/metabolismo , Células Secretoras de Glucagon/metabolismo , Glucagon/metabolismoRESUMO
Previous studies suggested that pyrethroid exposure was associated with elevated type 2 diabetes (T2D) risk, while it remains uncertain whether genetic predisposition modifies this association. A nested case-control study within the prospective Dongfeng-Tongji cohort comprised 1832 T2D cases, age- (±5 years) and sex-matched controls with qualified genotyping data. Serum pyrethroids were measured by gas chromatography-tandem mass spectrometry. Overall diabetes-related genetic risk score (GRS) or pathway-specific GRS, including unweighted GRSs (uGRS) and weighted GRSs (wGRS), was developed by genetic variants identified in Asian populations. Higher overall diabetes-related GRS and GRS specific to the pathway of impaired beta cell function (Beta-cell GRS) were associated with a higher incident T2D risk. Beta-cell uGRS significantly modified the association of serum permethrin (Pinteraction=0.04) and deltamethrin (Pinteraction=0.01) with T2D. Specifically, for each doubling increase in serum deltamethrin, the odds ratios (ORs) (95â¯% confidence intervals [CIs]) for T2D were 1.23 (0.98-1.56) and 0.91 (0.77-1.07) in the highest and lowest Beta-cell uGRS group, as well as 1.23 (1.02-1.47) and 0.95 (0.78-1.15) for Beta-cell wGRS group, respectively. When considering jointly, those with the highest deltamethrin levels and highest Beta-cell GRS had a substantially higher T2D risk, compared with the reference group (OR for uGRS: 3.79 [95â¯% CI: 2.03-7.07], Pinteraction=0.03 and 3.23 [95â¯% CI: 1.78-5.87], Pinteraction=0.05 for wGRS). Our findings suggested that genetic susceptibility to impaired beta-cell function should be considered for T2D prevention targeting pyrethroid exposure, particularly deltamethrin.
Assuntos
Diabetes Mellitus Tipo 2 , Interação Gene-Ambiente , Predisposição Genética para Doença , Células Secretoras de Insulina , Piretrinas , Diabetes Mellitus Tipo 2/genética , Piretrinas/sangue , Piretrinas/toxicidade , Humanos , Feminino , Pessoa de Meia-Idade , Estudos de Casos e Controles , Masculino , Células Secretoras de Insulina/efeitos dos fármacos , Células Secretoras de Insulina/fisiologia , Estudos Prospectivos , Inseticidas/sangue , Inseticidas/toxicidade , Adulto , Nitrilas , China , Idoso , Fatores de RiscoRESUMO
OBJECTIVES: To explore parameters that may determine the improvement in C-peptide levels in patients with type 2 diabetes (T2D) receiving continuous subcutaneous insulin infusion (CSII) therapy. METHODS: The trial included a lead-in period for collecting baseline parameters and correcting hyperglycemia, a 4-day CGM period, and a 2-3 weeks treatment period. After screening, patients were hospitalized and randomized to the metformin add-on NovoRapid group or the Prandilin group. Once the glycemic target was reached, all patients underwent a 4-day CGM, with treatments maintained for 2-3 weeks. OGTTs were performed at baseline and endpoint. The primary endpoint was identifying factors contributing to better ß-cell function recovery after CSII therapy. RESULTS: A total of 99 recruited patients were admitted as inpatients and achieved glycemic control within 3.8 ± 1.1 days. Of these, 83 (84 %) patients showed improvement in C-peptide levels, while 16 (16 %) did not show any change in C-peptide levels at the endpoint. Pearson analysis showed a negative correlation between the incremental AUC of glucose concentration (from 0700 to 1000) and the increase in incremental AUC of C-peptide levels (r = -0.199, P < 0.05). CONCLUSIONS: Drug-naïve T2D patients with lower postprandial glucose concentration during CSII therapy exhibit better ß-cell function recovery.
Assuntos
Glicemia , Peptídeo C , Diabetes Mellitus Tipo 2 , Hipoglicemiantes , Células Secretoras de Insulina , Insulina , Período Pós-Prandial , Humanos , Diabetes Mellitus Tipo 2/tratamento farmacológico , Diabetes Mellitus Tipo 2/sangue , Masculino , Feminino , Pessoa de Meia-Idade , Células Secretoras de Insulina/fisiologia , Células Secretoras de Insulina/efeitos dos fármacos , Células Secretoras de Insulina/metabolismo , Glicemia/metabolismo , Glicemia/análise , Insulina/administração & dosagem , Insulina/uso terapêutico , Hipoglicemiantes/uso terapêutico , Hipoglicemiantes/administração & dosagem , Período Pós-Prandial/fisiologia , Peptídeo C/sangue , Idoso , Sistemas de Infusão de Insulina , Metformina/uso terapêuticoRESUMO
AIMS: To evaluate whether treatment with insulin is advantageous compared with oral anti-diabetic drugs (OAD) for patients newly diagnosed with type 2 diabetes with moderate hyperglycemia. METHODS: Patients newly diagnosed with type 2 diabetes with moderate hyperglycemia were recruited and randomized to receive insulin, metformin or sitagliptin treatment. The oral glucose tolerance test (OGTT) was performed before treatment and 6 months thereafter. The primary outcome was the glycohemoglobin (HbA1c) level change. For the secondary efficacy analysis, the ß-cell function and insulin sensitivity were calculated from the OGTT, as was the proportion of subjects who reached the treatment target (HbA1c level < 7.0 % or < 6.5 %) at 6 months. RESULTS: We randomized 50 patients to the three groups and 32 patients who received the allocated treatment were analyzed. The change of HbA1c level in the insulin, metformin, and sitagliptin groups was - 2.06 ± 1.37 %, -0.43 ± 0.32 %, and - 1.62 ± 0.92 %, respectively. This change was smallest in the metformin group. There was no significant difference in the changes or final HbA1c levels between the insulin and sitagliptin groups. The treat-to-target (HbA1c level < 7.0 %) rates in the insulin, metformin and sitagliptin were 75 %, 50 % and 100 %, respectively. The treat-to-target rates were not significantly different among the three groups. The insulin secretion indices, including the Matsuda index and HOMA-IR, indicated that the groups did not differ after 6 months of therapy. CONCLUSION: A 6-month course of basal insulin therapy did not benefit patients newly diagnosed with diabetes with moderate hyperglycemia in terms of insulin sensitivity or insulin secretion.
Assuntos
Glicemia , Diabetes Mellitus Tipo 2 , Hemoglobinas Glicadas , Hiperglicemia , Hipoglicemiantes , Células Secretoras de Insulina , Insulina , Metformina , Fosfato de Sitagliptina , Humanos , Diabetes Mellitus Tipo 2/tratamento farmacológico , Diabetes Mellitus Tipo 2/sangue , Masculino , Feminino , Pessoa de Meia-Idade , Hipoglicemiantes/uso terapêutico , Células Secretoras de Insulina/efeitos dos fármacos , Células Secretoras de Insulina/metabolismo , Células Secretoras de Insulina/fisiologia , Insulina/uso terapêutico , Metformina/uso terapêutico , Fosfato de Sitagliptina/uso terapêutico , Hemoglobinas Glicadas/metabolismo , Hemoglobinas Glicadas/análise , Glicemia/metabolismo , Glicemia/efeitos dos fármacos , Glicemia/análise , Idoso , Controle Glicêmico , Teste de Tolerância a GlucoseRESUMO
Youth-onset type 2 diabetes (T2D) is increasing around the globe. The mounting disease burden of youth-onset T2D portends substantial consequences for the health outcomes of young people and for health care systems. The pathophysiology of this condition is characterized by insulin resistance and initial insulin hypersecretion ± an inherent insulin secretory defect, with progressive loss of stimulated insulin secretion leading to pancreatic ß-cell failure. Research studies focusing on youth-onset T2D have illuminated key differences for youth- vs adult-onset T2D, with youth having more profound insulin resistance and quicker progression to loss of sufficient insulin secretion to maintain euglycemia. There is a need for therapies that are targeted to improve both insulin resistance and, importantly, maintain sufficient insulin secretory function over the lifespan in youth-onset T2D.
Assuntos
Diabetes Mellitus Tipo 2 , Insulina , Adolescente , Humanos , Idade de Início , Diabetes Mellitus Tipo 2/fisiopatologia , Diabetes Mellitus Tipo 2/metabolismo , Diabetes Mellitus Tipo 2/epidemiologia , Insulina/metabolismo , Resistência à Insulina , Secreção de Insulina , Células Secretoras de Insulina/fisiologia , Células Secretoras de Insulina/metabolismoRESUMO
Obesity has increased dramatically worldwide. Being overweight or obese can lead to various conditions, including dyslipidaemia, hypertension, glucose intolerance and metabolic syndrome (MetS), which may further lead to type 2 diabetes mellitus (T2DM). Previous studies have identified a link between ß-cell dysfunction and the severity of MetS, with multiple organs and tissues affected. Identifying the associations between pancreatic ß-cell dysfunction and organs is critical. Research has focused on the interaction between the liver, gut and pancreatic ß-cells. However, the mechanisms and related core targets are still not perfectly elucidated. The aims of this review were to summarize the mechanisms of ß-cell dysfunction and to explore the potential pathogenic pathways and targets that connect the liver, gut, adipose tissue, muscle, and brain to pancreatic ß-cell dysfunction.
Assuntos
Tecido Adiposo , Diabetes Mellitus Tipo 2 , Células Secretoras de Insulina , Fígado , Obesidade , Humanos , Células Secretoras de Insulina/fisiologia , Células Secretoras de Insulina/metabolismo , Diabetes Mellitus Tipo 2/fisiopatologia , Diabetes Mellitus Tipo 2/metabolismo , Tecido Adiposo/metabolismo , Tecido Adiposo/fisiopatologia , Obesidade/fisiopatologia , Obesidade/metabolismo , Obesidade/complicações , Fígado/metabolismo , Síndrome Metabólica/fisiopatologia , Síndrome Metabólica/metabolismo , Encéfalo/fisiopatologia , Encéfalo/metabolismo , Animais , Músculo Esquelético/metabolismo , Músculo Esquelético/fisiopatologiaRESUMO
The pancreatic islet is the functional and structural unit of the pancreatic endocrine portion. Islet remodeling occurs in both normal development and pathogenesis of type 1 (T1D) and type 2 diabetes (T2D). However, accurately quantifying changes in islet cellular makeup and hormone expressions poses significant challenges due to large intra- and inter-donor heterogeneity and the limited scalability of traditional methods such as immunostaining. The cytometry by time-of-flight (CyTOF) technology enables simultaneous quantification of more than 30 protein markers at single-cell resolution in a high-throughput fashion. Moreover, with distinct DNA and viability markers, single live cells can be explicitly selected in CyTOF. Here, leveraging the CyTOF data generated by the Human Pancreas Analysis Program, we characterized more than 12 million islet cells from 71 donors. Our data revealed continued age-related changes in islet endocrine cell compositions, but the maturity of endocrine cells is reached by 3 years of age. We also observed significant changes in beta cell numbers and key protein expressions, along with a significant increase in bihormonal cells in T1D donors. In contrast, T2D donors exhibited minimal islet remodeling events. Our data shine a light on the islet dynamics during development and diabetes pathogenesis and suggest divergent pathogenesis processes of T1D and T2D. Our comprehensive approach not only elucidates islet plasticity but also establishes a foundation for integrated CyTOF analysis in islet biology and beyond.
Assuntos
Diabetes Mellitus Tipo 1 , Diabetes Mellitus Tipo 2 , Ilhotas Pancreáticas , Humanos , Ilhotas Pancreáticas/patologia , Ilhotas Pancreáticas/metabolismo , Diabetes Mellitus Tipo 2/patologia , Diabetes Mellitus Tipo 2/metabolismo , Adulto , Diabetes Mellitus Tipo 1/patologia , Diabetes Mellitus Tipo 1/metabolismo , Masculino , Feminino , Adolescente , Pessoa de Meia-Idade , Criança , Adulto Jovem , Pré-Escolar , Citometria de Fluxo/métodos , Lactente , Células Secretoras de Insulina/patologia , Células Secretoras de Insulina/metabolismo , Células Secretoras de Insulina/fisiologia , Células Secretoras de Insulina/citologia , Idoso , Análise de Célula Única/métodosRESUMO
Accurate measurements of glycaemic control and the underpinning regulatory mechanisms are vital in human physiology research. Glycaemic control is the maintenance of blood glucose concentrations within optimal levels and is governed by physiological variables including insulin sensitivity, glucose tolerance and ß-cell function. These can be measured with a plethora of methods, all with their own benefits and limitations. Deciding on the best method to use is challenging and depends on the specific research question(s). This review therefore discusses the theory and procedure, validity and reliability and any special considerations of a range common methods used to measure glycaemic control, insulin sensitivity, glucose tolerance and ß-cell function. Methods reviewed include glycosylated haemoglobin, continuous glucose monitors, the oral glucose tolerance test, mixed meal tolerance test, hyperinsulinaemic euglycaemic clamp, hyperglycaemic clamp, intravenous glucose tolerance test and indices derived from both fasting concentrations and the oral glucose tolerance test. This review aims to help direct understanding, assessment and decisions regarding which method to use based on specific physiology-related research questions.
Assuntos
Glicemia , Técnica Clamp de Glucose , Teste de Tolerância a Glucose , Controle Glicêmico , Resistência à Insulina , Humanos , Glicemia/metabolismo , Teste de Tolerância a Glucose/métodos , Resistência à Insulina/fisiologia , Controle Glicêmico/métodos , Técnica Clamp de Glucose/métodos , Hemoglobinas Glicadas/metabolismo , Células Secretoras de Insulina/metabolismo , Células Secretoras de Insulina/fisiologia , Insulina/metabolismo , Insulina/sangue , Reprodutibilidade dos TestesRESUMO
Inducible pluripotent stem cell-derived human ß-like cells (BLCs) hold promise for both therapy and disease modeling, but their generation remains challenging and their functional analyses beyond transcriptomic and morphological assessments remain limited. Here, we validate an approach using multicellular and single-cell electrophysiological tools to evaluate function of BLCs from pioneer protocols that can be easily adapted to more differentiated BLCs. The multi-electrode arrays (MEAs) measuring the extracellular electrical activity revealed that BLCs, like primary ß-cells, are electrically coupled and produce slow potential (SP) signals that are closely linked to insulin secretion. We also used high-resolution single-cell patch clamp measurements to capture the exocytotic properties, and characterize voltage-gated sodium and calcium currents, and found that they were comparable with those in primary ß- and EndoC-ßH1 cells. The KATP channel conductance is greater than in human primary ß-cells, which may account for the limited glucose responsiveness observed with MEA. We used MEAs to study the impact of the type 2 diabetes-protective SLC30A8 allele (p.Lys34Serfs50*) and found that BLCs with this allele have stronger electrical coupling activity. Our data suggest that BLCs can be used to evaluate the functional impact of genetic variants on ß-cell function and coupling.
Assuntos
Células-Tronco Pluripotentes Induzidas , Células Secretoras de Insulina , Transportador 8 de Zinco , Humanos , Células-Tronco Pluripotentes Induzidas/metabolismo , Células Secretoras de Insulina/metabolismo , Células Secretoras de Insulina/fisiologia , Transportador 8 de Zinco/genética , Transportador 8 de Zinco/metabolismo , Diferenciação Celular , Diabetes Mellitus Tipo 2/metabolismo , Diabetes Mellitus Tipo 2/genética , Técnicas de Patch-Clamp , Fenômenos EletrofisiológicosRESUMO
Regeneration, the ability to replace injured tissues and organs, is a phenomenon commonly associated with lower vertebrates but is also observed in mammals, in specific tissues. In this study, we investigated the regenerative potential of pancreatic islets following moderate beta-cell loss in mice. Using a rapid model of moderate ablation, we observed a compensatory response characterized by transient inflammation and proliferation signatures, ultimately leading to the recovery of beta-cell identity and function. Interestingly, this proliferative response occurred independently of inflammation, as demonstrated in ablated immunodeficient mice. Furthermore, exposure to high-fat diet stimulated beta-cell proliferation but negatively impacted beta-cell function. In contrast, an equivalent slower ablation model revealed a delayed but similar proliferative response, suggesting proliferation as a common regenerative response. However, high-fat diet failed to promote proliferation in this model, indicating a differential response to metabolic stressors. Overall, our findings shed light on the complex interplay between beta-cell loss, inflammation, and stress in modulating pancreatic islet regeneration. Understanding these mechanisms could pave the way for novel therapeutic strategies based on beta-cell proliferation.
Assuntos
Proliferação de Células , Dieta Hiperlipídica , Células Secretoras de Insulina , Regeneração , Animais , Células Secretoras de Insulina/metabolismo , Células Secretoras de Insulina/fisiologia , Camundongos , Dieta Hiperlipídica/efeitos adversos , Masculino , Camundongos Endogâmicos C57BL , Inflamação/metabolismo , Inflamação/patologiaRESUMO
The T allele at rs7903146 in TCF7L2 increases the rate of conversion from prediabetes to type 2 diabetes. This has been associated with impaired ß-cell function and with defective suppression of α-cell secretion by glucose. However, the temporal relationship of these abnormalities is uncertain. To study the longitudinal changes in islet function, we recruited 128 subjects, with 67 homozygous for the diabetes-associated allele (TT) at rs7903146 and 61 homozygous for the protective allele. Subjects were studied on two occasions, 3 years apart, using an oral 75-g glucose challenge. The oral minimal model was used to quantitate ß-cell function; the glucagon secretion rate was estimated from deconvolution of glucagon concentrations. Glucose tolerance worsened in subjects with the TT genotype. This was accompanied by impaired postchallenge glucagon suppression but appropriate ß-cell responsivity to rising glucose concentrations. These data suggest that α-cell abnormalities associated with the TT genotype (rs7903146) occur early and may precede ß-cell dysfunction in people as they develop glucose intolerance and type 2 diabetes.
Assuntos
Diabetes Mellitus Tipo 2 , Glucagon , Teste de Tolerância a Glucose , Células Secretoras de Insulina , Proteína 2 Semelhante ao Fator 7 de Transcrição , Humanos , Proteína 2 Semelhante ao Fator 7 de Transcrição/genética , Proteína 2 Semelhante ao Fator 7 de Transcrição/metabolismo , Diabetes Mellitus Tipo 2/genética , Diabetes Mellitus Tipo 2/metabolismo , Glucagon/metabolismo , Masculino , Feminino , Adulto , Pessoa de Meia-Idade , Células Secretoras de Insulina/metabolismo , Células Secretoras de Insulina/fisiologia , Estudos Longitudinais , Células Secretoras de Glucagon/metabolismo , Ilhotas Pancreáticas/metabolismo , Genótipo , Glicemia/metabolismo , Intolerância à Glucose/genética , Intolerância à Glucose/metabolismo , AlelosRESUMO
CF-related diabetes (CFRD) is a prevalent comorbidity in people with Cystic Fibrosis (CF), significantly impacting morbidity and mortality rates. This review article critically evaluates the current understanding of CFRD molecular mechanisms, including the role of CFTR protein, oxidative stress, unfolded protein response (UPR) and intracellular communication. CFRD manifests from a complex interplay between exocrine pancreatic damage and intrinsic endocrine dysfunction, further complicated by the deleterious effects of misfolded CFTR protein on insulin secretion and action. Studies indicate that ER stress and subsequent UPR activation play critical roles in both exocrine and endocrine pancreatic cell dysfunction, contributing to ß-cell loss and insulin insufficiency. Additionally, oxidative stress and altered calcium flux, exacerbated by CFTR dysfunction, impair ß-cell survival and function, highlighting the significance of antioxidant pathways in CFRD pathogenesis. Emerging evidence underscores the importance of exosomal microRNAs (miRNAs) in mediating inflammatory and stress responses, offering novel insights into CFRD's molecular landscape. Despite insulin therapy remaining the cornerstone of CFRD management, the variability in response to CFTR modulators underscores the need for personalized treatment approaches. The review advocates for further research into non-CFTR therapeutic targets, emphasizing the need to address the multifaceted pathophysiology of CFRD. Understanding the intricate mechanisms underlying CFRD will pave the way for innovative treatments, moving beyond insulin therapy to target the disease's root causes and improve the quality of life for individuals with CF.
Assuntos
Regulador de Condutância Transmembrana em Fibrose Cística , Fibrose Cística , Diabetes Mellitus , Estresse do Retículo Endoplasmático , Estresse Oxidativo , Humanos , Fibrose Cística/metabolismo , Estresse do Retículo Endoplasmático/fisiologia , Regulador de Condutância Transmembrana em Fibrose Cística/metabolismo , Regulador de Condutância Transmembrana em Fibrose Cística/genética , Diabetes Mellitus/metabolismo , Insulina/metabolismo , Resposta a Proteínas não Dobradas/fisiologia , Células Secretoras de Insulina/metabolismo , Células Secretoras de Insulina/fisiologiaRESUMO
ß-Cell death contributes to ß-cell loss and insulin insufficiency in type 1 diabetes (T1D), and this ß-cell demise has been attributed to apoptosis and necrosis. Apoptosis has been viewed as the lone form of programmed ß-cell death, and evidence indicates that ß-cells also undergo necrosis, regarded as an unregulated or accidental form of cell demise. More recently, studies in non-islet cell types have identified and characterized novel forms of cell death that are biochemically and morphologically distinct from apoptosis and necrosis. Several of these mechanisms of cell death have been categorized as forms of regulated necrosis and linked to inflammation and disease pathogenesis. In this review, we revisit discoveries of ß-cell death in humans with diabetes and describe studies characterizing ß-cell apoptosis and necrosis. We explore literature on mechanisms of regulated necrosis including necroptosis, ferroptosis and pyroptosis, review emerging literature on the significance of these mechanisms in ß-cells, and discuss experimental approaches to differentiate between various mechanisms of ß-cell death. Our review of the literature leads us to conclude that more detailed experimental characterization of the mechanisms of ß-cell death is warranted, along with studies to better understand the impact of various forms of ß-cell demise on islet inflammation and ß-cell autoimmunity in pathophysiologically relevant models. Such studies will provide insight into the mechanisms of ß-cell loss in T1D and may shed light on new therapeutic approaches to protect ß-cells in this disease.
Assuntos
Apoptose , Morte Celular , Diabetes Mellitus Tipo 1 , Células Secretoras de Insulina , Necrose , Humanos , Células Secretoras de Insulina/patologia , Células Secretoras de Insulina/fisiologia , Diabetes Mellitus Tipo 1/patologia , Diabetes Mellitus Tipo 1/imunologia , Animais , Morte Celular/fisiologia , Apoptose/fisiologia , Necroptose/fisiologia , Piroptose/fisiologia , Ferroptose/fisiologiaRESUMO
Type 2 diabetes (T2D) is a polygenic metabolic disorder characterized by insulin resistance in peripheral tissues and impaired insulin secretion by the pancreas. While the decline in insulin production and secretion was previously attributed to apoptosis of insulin-producing ß-cells, recent studies indicate that ß-cell apoptosis rates are relatively low in diabetes. Instead, ß-cells primarily undergo dedifferentiation, a process where they lose their specialized identity and transition into non-functional endocrine progenitor-like cells, ultimately leading to ß-cell failure. The underlying mechanisms driving ß-cell dedifferentiation remain elusive due to the intricate interplay of genetic factors and cellular stress. Understanding these mechanisms holds the potential to inform innovative therapeutic approaches aimed at reversing ß-cell dedifferentiation in T2D. This review explores the proposed drivers of ß-cell dedifferentiation leading to ß-cell failure, and discusses current interventions capable of reversing this process, thus restoring ß-cell identity and function.
Assuntos
Desdiferenciação Celular , Diabetes Mellitus Tipo 2 , Células Secretoras de Insulina , Humanos , Células Secretoras de Insulina/metabolismo , Células Secretoras de Insulina/fisiologia , Células Secretoras de Insulina/citologia , Desdiferenciação Celular/fisiologia , Diabetes Mellitus Tipo 2/metabolismo , Diabetes Mellitus Tipo 2/patologia , Animais , Diferenciação Celular/fisiologia , Apoptose/fisiologia , Secreção de Insulina/fisiologiaRESUMO
The pathogeneses of type 1 and type 2 diabetes involve the progressive loss of functional beta cell mass, primarily attributed to cellular demise and/or dedifferentiation. While the scientific community has devoted significant attention to unraveling beta cell dedifferentiation in type 2 diabetes, its significance in type 1 diabetes remains relatively unexplored. This perspective article critically analyzes the existing evidence for beta cell dedifferentiation in type 1 diabetes, emphasizing its potential to reduce beta cell autoimmunity. Drawing from recent advancements in both human studies and animal models, we present beta cell identity as a promising target for managing type 1 diabetes. We posit that a better understanding of the mechanisms of beta cell dedifferentiation in type 1 diabetes is key to pioneering interventions that balance beta cell function and immunogenicity.
Assuntos
Desdiferenciação Celular , Diabetes Mellitus Tipo 1 , Células Secretoras de Insulina , Animais , Humanos , Autoimunidade , Desdiferenciação Celular/fisiologia , Diabetes Mellitus Tipo 1/patologia , Células Secretoras de Insulina/patologia , Células Secretoras de Insulina/fisiologiaRESUMO
OBJECTIVE: While most genetic variants of type 2 diabetes (T2D) are suggested to be associated with ß-cell dysfunction cross sectionally, their association with the longitudinal change of ß-cell function remains largely unknown. RESEARCH DESIGN AND METHODS: We analyzed data from 6,311 participants without T2D at baseline (mean [SD] age 51.6 [8.7] years) from a community-based prospective cohort in Korea. Participants underwent biennial 2-h 75-g oral glucose tolerance tests (OGTTs) during 14 years of follow-up, and the OGTT-derived disposition index (DI) was used as a marker for ß-cell function. Genetic risk was quantified using the genome-wide polygenic risk score (PRS) and was stratified into low (1st quintile), intermediate (2nd-4th quintiles), and high (5th quintile) genetic risk. Lifestyle was assessed according to Life's Essential 8. RESULTS: During a mean follow-up of 10.9 years, 374 (29.6%), 851 (22.5%), and 188 (14.9%) participants developed T2D in the high, intermediate, and low genetic risk groups, respectively. Compared with the low genetic risk group, participants in the high genetic risk group had a 25% lower DI at baseline. Furthermore, in longitudinal analysis, we observed a 1.83-fold faster decline in log2-transformed DI per year (-0.034 vs. -0.019, P = 2.1 × 10-3; per 1-SD increase in T2D PRS, P = 1.2 × 10-4). Healthy lifestyle attenuated the rate of decline in DI across all genetic risk groups. CONCLUSIONS: Individuals with a higher genetic risk for T2D exhibited not only a lower OGTT-derived ß-cell function at baseline but also a notably more rapid decline during follow-up. This information could be used to enable a focused precision prevention with lifestyle intervention.
Assuntos
Diabetes Mellitus Tipo 2 , Células Secretoras de Insulina , Humanos , Diabetes Mellitus Tipo 2/genética , Diabetes Mellitus Tipo 2/epidemiologia , Células Secretoras de Insulina/fisiologia , Pessoa de Meia-Idade , Masculino , Feminino , Adulto , Teste de Tolerância a Glucose , Povo Asiático/genética , Predisposição Genética para Doença , Estudos Prospectivos , Fatores de Risco , População do Leste AsiáticoRESUMO
This study investigates the metabolic parallels between stimulated pancreatic beta cells and cancer cells, focusing on glucose and glutamine metabolism. Addressing the significant public health challenges of Type 2 Diabetes (T2D) and cancer, we aim to deepen our understanding of the mechanisms driving insulin secretion and cellular proliferation. Our analysis of anaplerotic cycles and the role of NADPH in biosynthesis elucidates their vital functions in both processes. Additionally, we point out that both cell types share an antioxidative response mediated by the Nrf2 signaling pathway, glutathione synthesis, and UCP2 upregulation. Notably, UCP2 facilitates the transfer of C4 metabolites, enhancing reductive TCA cycle metabolism. Furthermore, we observe that hypoxic responses are transient in beta cells post-stimulation but persistent in cancer cells. By synthesizing these insights, the research may suggest novel therapeutic targets for T2D, highlighting the shared metabolic strategies of stimulated beta cells and cancer cells. This comparative analysis not only illuminates the metabolic complexity of these conditions but also emphasizes the crucial role of metabolic pathways in cell function and survival, offering fresh perspectives for tackling T2D and cancer challenges.