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1.
Acta Diabetol ; 2024 Apr 17.
Artigo em Inglês | MEDLINE | ID: mdl-38627282

RESUMO

AIMS: Aim of this study was to investigate in type 2 diabetes whether expression level of GALNT2, a positive modulator of insulin sensitivity, is associated with a metabolic signature. METHODS: Five different metabolite families, including acylcarnitines, aminoacids, biogenic amines, phospholipids and sphingolipids were investigated in fasting serum of 70 patients with type 2 diabetes, by targeted metabolomics. GALNT2 expression levels were measured in peripheral white blood cells by RT-PCR. The association between GALNT2 expression and serum metabolites was assessed using false discovery rate followed by stepwise selection and, finally, multivariate model including several clinical parameters as confounders. The association between GALNT2 expression and the same clinical parameters was also investigated. RESULTS: GALNT2 expression was independently correlated with HbA1c levels (P value = 0.0052), a finding that is the likely consequence of the role of GALNT2 on insulin sensitivity. GALNT2 expression was also independently associated with serum levels of the aminoacid glycine (P value = 0.014) and two biogenic amines phenylethylamine (P value = 0.0065) and taurine (P value = 0.0011). The association of GALNT2 expression with HbA1c was not mediated by these three metabolites. CONCLUSIONS: Our data indicate that in type 2 diabetes the expression of GALNT2 is associated with several serum metabolites. This association needs to be further investigated to understand in depth its role in mediating the effect of GALNT2 on insulin sensitivity, glucose control and other clinical features in people with diabetes.

2.
Adv Biol (Weinh) ; 7(9): e2200319, 2023 09.
Artigo em Inglês | MEDLINE | ID: mdl-36861373

RESUMO

Several studies have shown that downregulation of GALNT2 (Polypeptide N-Acetylgalactosaminyltransferase 2), encoding polypeptide N-acetylgalactosaminyltransferase 2, decreases high-density lipoprotein cholesterol (HDL-C) and increases triglycerides levels by glycosylating key enzymes of lipid metabolism, such as angiopoietin like 3, apolipoprotein C-III, and phospholipid transfer protein. GALNT2 is also a positive modulator of insulin signaling and action, associated with in vivo insulin sensitivity and during adipogenesis strongly upregulates adiponectin. Thus, the hypothesis that GALNT2 affects HDL-C and triglycerides levels also through insulin sensitivity and/or circulating adiponectin, is tested. In 881 normoglycemic individuals the G allele of rs4846914 SNP at the GALNT2 locus, known to associate with GALNT2 downregulation, is associated with low HDL-C and high values of triglycerides, triglycerides/HDL-C ratio, and theHomeostatic Model Assessment of insulin resistance HOMAIR (p-values = 0.01, 0.027, 0.002, and 0.016, respectively). Conversely, no association is observed with serum adiponectin levels (p = 0.091). Importantly, HOMAIR significantly mediates a proportion of the genetic association with HDL-C (21%, 95% CI: 7-35%, p = 0.004) and triglyceride levels (32%, 95% CI: 4-59%, p = 0.023). The results are compatible with the hypothesis that, besides the effect on key lipid metabolism enzymes, GALNT2 alters HDL-C and triglyceride levels also indirectly through a positive effect on insulin sensitivity.


Assuntos
Aterosclerose , Dislipidemias , Resistência à Insulina , Humanos , Adiponectina , Aterosclerose/genética , Aterosclerose/complicações , HDL-Colesterol/genética , Dislipidemias/genética , Dislipidemias/complicações , Resistência à Insulina/genética , Triglicerídeos , Polipeptídeo N-Acetilgalactosaminiltransferase
5.
Artigo em Inglês | MEDLINE | ID: mdl-36078750

RESUMO

We describe early-onset diabetes in a 6-month-old patient carrying an LRBA gene mutation. Mutations in this gene cause primary immunodeficiency with autoimmune disorders in infancy. At admission, he was in diabetic ketoacidosis, and treatment with fluid infusion rehydration and then i.v. insulin was required. He was discharged with a hybrid closed-loop system for insulin infusion and prevention of hypoglycemia (Minimed Medtronic 670G). He underwent a next-generation sequencing analysis for monogenic diabetes genes, which showed that he was compound heterozygous for two mutations in the LRBA gene. In the following months, he developed arthritis of hands and feet, chronic diarrhea, and growth failure. He underwent bone marrow transplantation with remission of diarrhea and arthritis, but not of diabetes and growth failure. The blood glucose control has always been at target (last HbA1c 6%) without any severe hypoglycemia. LRBA gene mutations are a very rare cause of autoimmune diabetes. This report describes the clinical course in a very young patient. The hybrid closed-loop system was safe and efficient in the management of blood glucose. This report describes the clinical course of diabetes in a patient with a novel LRBA gene mutation.


Assuntos
Artrite , Diabetes Mellitus Tipo 1 , Hipoglicemia , Proteínas Adaptadoras de Transdução de Sinal/genética , Glicemia , Diabetes Mellitus Tipo 1/tratamento farmacológico , Diarreia , Mutação da Fase de Leitura , Humanos , Hipoglicemiantes/uso terapêutico , Lactente , Insulina/genética , Insulina/uso terapêutico , Masculino , Mutação
8.
Genes (Basel) ; 13(1)2022 01 09.
Artigo em Inglês | MEDLINE | ID: mdl-35052457

RESUMO

Monogenic diabetes is a genetic disorder caused by one or more variations in a single gene. It encompasses a broad spectrum of heterogeneous conditions, including neonatal diabetes, maturity onset diabetes of the young (MODY) and syndromic diabetes, affecting 1-5% of patients with diabetes. Some of these variants are harbored by genes whose altered function can be tackled by specific actions ("actionable genes"). In suspected patients, molecular diagnosis allows the implementation of effective approaches of precision medicine so as to allow individual interventions aimed to prevent, mitigate or delay clinical outcomes. This review will almost exclusively concentrate on the clinical strategy that can be specifically pursued in carriers of mutations in "actionable genes", including ABCC8, KCNJ11, GCK, HNF1A, HNF4A, HNF1B, PPARG, GATA4 and GATA6. For each of them we will provide a short background on what is known about gene function and dysfunction. Then, we will discuss how the identification of their mutations in individuals with this form of diabetes, can be used in daily clinical practice to implement specific monitoring and treatments. We hope this article will help clinical diabetologists carefully consider who of their patients deserves timely genetic testing for monogenic diabetes.


Assuntos
Diabetes Mellitus Tipo 2/diagnóstico , Diabetes Mellitus Tipo 2/genética , Genes , Mutação , Medicina de Precisão , Testes Genéticos , Humanos
9.
Int J Mol Sci ; 23(2)2022 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-35055114

RESUMO

O-linked glycosylation, the greatest form of post-translational modifications, plays a key role in regulating the majority of physiological processes. It is, therefore, not surprising that abnormal O-linked glycosylation has been related to several human diseases. Recently, GALNT2, which encodes the GalNAc-transferase 2 involved in the first step of O-linked glycosylation, has attracted great attention as a possible player in many highly prevalent human metabolic diseases, including atherogenic dyslipidemia, type 2 diabetes and obesity, all clustered on the common ground of insulin resistance. Data available both in human and animal models point to GALNT2 as a molecule that shapes the risk of the aforementioned abnormalities affecting diverse protein functions, which eventually cause clinically distinct phenotypes (a typical example of pleiotropism). Pathways linking GALNT2 to dyslipidemia and insulin resistance have been partly identified, while those for type 2 diabetes and obesity are yet to be understood. Here, we will provide a brief overview on the present knowledge on GALNT2 function and dysfunction and propose novel insights on the complex pathogenesis of the aforementioned metabolic diseases, which all impose a heavy burden for patients, their families and the entire society.


Assuntos
Dislipidemias/metabolismo , Resistência à Insulina/fisiologia , N-Acetilgalactosaminiltransferases/metabolismo , Animais , Glicosilação , Homeostase , Humanos , Metabolismo dos Lipídeos , Polipeptídeo N-Acetilgalactosaminiltransferase
10.
J Clin Endocrinol Metab ; 107(3): 668-684, 2022 02 17.
Artigo em Inglês | MEDLINE | ID: mdl-34718610

RESUMO

CONTEXT: Genes causing familial forms of diabetes mellitus are only partially known. OBJECTIVE: We set out to identify the genetic cause of hyperglycemia in multigenerational families with an apparent autosomal dominant form of adult-onset diabetes not due to mutations in known monogenic diabetes genes. METHODS: Existing whole-exome sequencing (WES) data were used to identify exonic variants segregating with diabetes in 60 families from the United States and Italy. Functional studies were carried out in vitro (transduced MIN6-K8 cells) and in vivo (Caenorhabditis elegans) to assess the diabetogenic potential of 2 variants in the malate dehydrogenase 2 (MDH2) gene linked with hyperglycemia in 2 of the families. RESULTS: A very rare mutation (p.Arg52Cys) in MDH2 strongly segregated with hyperglycemia in 1 family from the United States. An infrequent MDH2 missense variant (p.Val160Met) also showed disease cosegregation in a family from Italy, although with reduced penetrance. In silico, both Arg52Cys and Val160Met were shown to affect MDH2 protein structure and function. In transfected HepG2 cells, both variants significantly increased MDH2 enzymatic activity, thereby decreasing the NAD+/NADH ratio-a change known to affect insulin signaling and secretion. Stable expression of human wild-type MDH2 in MIN6-K8 cell lines enhanced glucose- and GLP-1-stimulated insulin secretion. This effect was blunted by the Cys52 or Met160 substitutions. Nematodes carrying equivalent changes at the orthologous positions of the mdh-2 gene showed impaired glucose-stimulated insulin secretion. CONCLUSION: Our findings suggest a central role of MDH2 in human glucose homeostasis and indicate that gain of function variants in this gene may be involved in the etiology of familial forms of diabetes.


Assuntos
Glicemia/metabolismo , Hiperglicemia/genética , Malato Desidrogenase/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Animais , Animais Geneticamente Modificados , Glicemia/análise , Caenorhabditis elegans , Proteínas de Caenorhabditis elegans/genética , Proteínas de Caenorhabditis elegans/metabolismo , Estudos de Casos e Controles , Linhagem Celular Tumoral , Análise Mutacional de DNA , Feminino , Mutação com Ganho de Função , Humanos , Hiperglicemia/sangue , Insulina/análise , Insulina/metabolismo , Secreção de Insulina/genética , Ilhotas Pancreáticas , Malato Desidrogenase/metabolismo , Masculino , Camundongos , Pessoa de Meia-Idade , Modelos Animais , Cultura Primária de Células , Proteínas Recombinantes/genética , Proteínas Recombinantes/metabolismo , Sequenciamento do Exoma
11.
Int J Obes (Lond) ; 45(6): 1362-1366, 2021 06.
Artigo em Inglês | MEDLINE | ID: mdl-33658684

RESUMO

3T3L1 mouse pre-adipocytes develop into adipocytes differently in response to GALNT2 overexpression or to stimulation with rosiglitazone, a reference inducer of adipogenesis. To investigate the biology of alternative pathways of adipogenesis, we studied lipid droplets (LD) morphology, chromatin organization, and gene expression in GALNT2- versus rosiglitazone-induced 3T3L1 adipogenesis. 3T3L1 overexpressing either GALNT2 (GALNT2) or GFP and treated with rosiglitazone (GFPR) were differentiated into adipocytes. LD and nuclei were profiled measuring their morphological features. The expression of adipogenesis-related genes was measured by RT-PCR. As compared to GFPR, GALNT2 showed smaller and more clustered LD, more nuclei with condensed chromatin and several gene expression changes (P < 0.001 for all). As compared to those stimulated by rosiglitazone, GALNT2 overexpressing cells show differences in the most established readouts of adipogenesis. Characterizing alternative pathways of adipogenesis may help tackle those diseases which are secondary to increased dysfunctional mass of adipose tissue.


Assuntos
Adipogenia , N-Acetilgalactosaminiltransferases , Células 3T3-L1 , Adipócitos/metabolismo , Adipogenia/genética , Adipogenia/fisiologia , Animais , Camundongos , N-Acetilgalactosaminiltransferases/genética , N-Acetilgalactosaminiltransferases/metabolismo , Transcriptoma/genética , Polipeptídeo N-Acetilgalactosaminiltransferase
12.
Eur J Endocrinol ; 184(4): 575-585, 2021 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-33606663

RESUMO

OBJECTIVE: Transient neonatal diabetes mellitus (TNDM) is caused by activating mutations in ABCC8 and KCNJ11 genes (KATP/TNDM) or by chromosome 6q24 abnormalities (6q24/TNDM). We wanted to assess whether these different genetic aetiologies result in distinct clinical features. DESIGN: Retrospective analysis of the Italian data set of patients with TNDM. METHODS: Clinical features and treatment of 22 KATP/TNDM patients and 12 6q24/TNDM patients were compared. RESULTS: Fourteen KATP/TNDM probands had a carrier parent with abnormal glucose values, four patients with 6q24 showed macroglossia and/or umbilical hernia. Median age at diabetes onset and birth weight were lower in patients with 6q24 (1 week; -2.27 SD) than those with KATP mutations (4.0 weeks; -1.04 SD) (P = 0.009 and P = 0.007, respectively). Median time to remission was longer in KATP/TNDM than 6q24/TNDM (21.5 weeks vs 12 weeks) (P = 0.002). Two KATP/TNDM patients entered diabetes remission without pharmacological therapy. A proband with the ABCC8/L225P variant previously associated with permanent neonatal diabetes entered 7-year long remission after 1 year of sulfonylurea therapy. Seven diabetic individuals with KATP mutations were successfully treated with sulfonylurea monotherapy; four cases with relapsing 6q24/TNDM were treated with insulin, metformin or combination therapy. CONCLUSIONS: If TNDM is suspected, KATP genes should be analyzed first with the exception of patients with macroglossia and/or umbilical hernia. Remission of diabetes without pharmacological therapy should not preclude genetic analysis. Early treatment with sulfonylurea may induce long-lasting remission of diabetes in patients with KATP mutations associated with PNDM. Adult patients carrying KATP/TNDM mutations respond favourably to sulfonylurea monotherapy.


Assuntos
Diabetes Mellitus , Doenças do Recém-Nascido , Conjuntos de Dados como Assunto , Diabetes Mellitus/classificação , Diabetes Mellitus/congênito , Diabetes Mellitus/diagnóstico , Diabetes Mellitus/genética , Diabetes Mellitus/terapia , Diagnóstico Diferencial , Técnicas de Diagnóstico Endócrino/normas , Feminino , Humanos , Lactente , Recém-Nascido , Doenças do Recém-Nascido/classificação , Doenças do Recém-Nascido/diagnóstico , Doenças do Recém-Nascido/genética , Doenças do Recém-Nascido/terapia , Itália , Masculino , Mutação , Canais de Potássio Corretores do Fluxo de Internalização/genética , Indução de Remissão/métodos , Estudos Retrospectivos , Receptores de Sulfonilureias/genética
13.
Mol Genet Genomic Med ; 7(7): e00728, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-31197960

RESUMO

BACKGROUND: Homozygous inactivating GCK mutations have been repeatedly reported to cause severe hyperglycemia, presenting as permanent neonatal diabetes mellitus (PNDM). Conversely, only two cases of GCK homozygous mutations causing mild hyperglycemia have been so far described. We here report a novel GCK mutation (c.1116G>C, p.E372D), in a family with one homozygous member showing mild hyperglycemia. METHODS: GCK mutational screening was carried out by Sanger sequencing. Computational analyses to investigate pathogenicity and molecular dynamics (MD) were performed for GCK-E372D and for previously described homozygous mutations associated with mild (n = 2) or severe (n = 1) hyperglycemia, used as references. RESULTS: Of four mildly hyperglycemic family-members, three were heterozygous and one, diagnosed in the adulthood, was homozygous for GCK-E372D. Two nondiabetic family members carried no mutations. Fasting glucose (p = 0.016) and HbA1c (p = 0.035) correlated with the number of mutated alleles (0-2). In-silico predicted pathogenicity was not correlated with the four mutations' severity. At MD, GCK-E372D conferred protein structure flexibility intermediate between mild and severe GCK mutations. CONCLUSIONS: We present the third case of homozygous GCK mutations associated with mild hyperglycemia, rather than PNDM. Our in-silico analyses support previous evidences suggesting that protein stability plays a role in determining clinical severity of GCK mutations.


Assuntos
Diabetes Mellitus/genética , Quinases do Centro Germinativo/genética , Adulto , Pré-Escolar , Diabetes Mellitus/metabolismo , Família , Feminino , Quinases do Centro Germinativo/metabolismo , Homozigoto , Humanos , Hiperglicemia/genética , Hiperglicemia/metabolismo , Masculino , Pessoa de Meia-Idade , Mutação , Mutação de Sentido Incorreto , Linhagem , Polimorfismo de Nucleotídeo Único/genética
14.
Int J Obes (Lond) ; 43(12): 2448-2457, 2019 12.
Artigo em Inglês | MEDLINE | ID: mdl-31040393

RESUMO

BACKGROUND/OBJECTIVES: A better understanding of adipose tissue biology is crucial to tackle insulin resistance and eventually coronary heart disease and diabetes, leading causes of morbidity and mortality worldwide. GALNT2, a GalNAc-transferase, positively modulates insulin signaling in human liver cells by down-regulating ENPP1, an insulin signaling inhibitor. GALNT2 expression is increased in adipose tissue of obese as compared to that of non-obese individuals. Whether this association is secondary to a GALNT2-insulin sensitizing effect exerted also in adipocytes is unknown. We then investigated in mouse 3T3-L1 adipocytes the GALNT2 effect on adipogenesis, insulin signaling and expression levels of both Enpp1 and 72 adipogenesis-related genes. METHODS: Stable over-expressing GALNT2 and GFP preadipocytes (T0) were generated. Adipogenesis was induced with (R+) or without (R-) rosiglitazone and investigated after 15 days (T15). Lipid accumulation (by Oil Red-O staining) and intracellular triglycerides (by fluorimetric assay) were measured. Lipid droplets (LD) measures were analyzed at confocal microscope. Gene expression was assessed by RT-PCR and insulin-induced insulin receptor (IR), IRS1, JNK and AKT phosphorylation by Western blot. RESULTS: Lipid accumulation, triglycerides and LD measures progressively increased from T0 to T15R- and furthermore to T15R+. Such increases were significantly higher in GALNT2 than in GFP cells so that, as compared to T15R+GFP, T15R- GALNT2 cells showed similar (intracellular lipid and triglycerides accumulation) or even higher (LD measures, p < 0.01) values. In GALNT2 preadipocytes, insulin-induced IR, IRS1 and AKT activation was higher than that in GFP cells. GALNT2 effect was totally abolished during adipocyte maturation and completely reversed at late stage maturation. Such GALNT2 effect trajectory was paralleled by coordinated changes in the expression of Enpp1 and adipocyte-maturation key genes. CONCLUSIONS: GALNT2 is a novel modulator of adipogenesis and related cellular phenotypes, thus becoming a potential target for tackling the obesity epidemics and its devastating sequelae.


Assuntos
Adipócitos , Adipogenia , Insulina/metabolismo , N-Acetilgalactosaminiltransferases , Transdução de Sinais/fisiologia , Células 3T3-L1 , Adipócitos/química , Adipócitos/metabolismo , Adipogenia/genética , Adipogenia/fisiologia , Animais , Camundongos , N-Acetilgalactosaminiltransferases/genética , N-Acetilgalactosaminiltransferases/metabolismo , Polipeptídeo N-Acetilgalactosaminiltransferase
15.
Sci Rep ; 7: 44337, 2017 03 14.
Artigo em Inglês | MEDLINE | ID: mdl-28290549

RESUMO

In cells and tissues resistin affects IL-1ß, IL-6, IL-8, IL-12 and TNF-α expression, thus suggesting the existence of a multi-cytokine "resistin pathway". We investigated whether such pathway does exist in humans and, if so, if it is associated with cardiovascular risk factors and with major adverse cardiovascular events (MACE). Serum cytokines were measured in 280 healthy subjects from the Gargano Study 2 (GS2) whose BMI, waist circumference, HOMAIR, triglycerides, HDL-cholesterol, systolic and diastolic blood pressure data were available and in 353 patients with type 2 diabetes and coronary artery disease from the Gargano Heart Study (GHS)-prospective design (follow-up 5.4 ± 2.5 years; 71 MACE). In GS2, cytokines mRNA levels in white blood cells were also measured. In GS2, resistin mRNA was correlated with all cytokines expression (all p < 0.001), but IL-12B. Consistently, serum resistin was correlated with all serum cytokines (all p < 0.001), but IL-12. Expression (eRPS) and serum (sRPS) resistin pathway scores (excluding IL-12) were each other correlated (p < 0.001) and both associated with cardiovascular risk factors (all p < 0.01). In GHS, sRPS was independently associated with MACE (HR = 1.44, 95% CI = 1.10-1.90). Our data indicate the existence of a resistin pathway, which is associated with cardiovascular risk factors and which strongly and independently predicts MACE.


Assuntos
Doença da Artéria Coronariana/genética , Diabetes Mellitus Tipo 2/genética , Resistência à Insulina , Resistina/genética , Adulto , Idoso , Pressão Sanguínea , Índice de Massa Corporal , Estudos de Casos e Controles , HDL-Colesterol/sangue , LDL-Colesterol/sangue , Doença da Artéria Coronariana/sangue , Doença da Artéria Coronariana/diagnóstico , Doença da Artéria Coronariana/patologia , Diabetes Mellitus Tipo 2/sangue , Diabetes Mellitus Tipo 2/diagnóstico , Diabetes Mellitus Tipo 2/patologia , Feminino , Regulação da Expressão Gênica , Humanos , Interleucina-12/sangue , Interleucina-12/genética , Interleucina-1beta/sangue , Interleucina-1beta/genética , Interleucina-6/sangue , Interleucina-6/genética , Interleucina-8/sangue , Interleucina-8/genética , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Resistina/sangue , Fatores de Risco , Transdução de Sinais , Triglicerídeos/sangue , Fator de Necrose Tumoral alfa/sangue , Fator de Necrose Tumoral alfa/genética , Circunferência da Cintura
16.
Endocrine ; 54(1): 38-46, 2016 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-26956846

RESUMO

The high mortality risk of patients with type 2 diabetes mellitus may well be explained by the several comorbidities and/or complications. Also the intrinsic genetic component predisposing to diabetes might have a role in shaping the risk of diabetes-related mortality. Among type 2 diabetes mellitus SNPs, rs1801282 is of particular interest because (i) it is harbored by peroxisome proliferator-activated receptor-γ2 (PPARγ2), which is the target for thiazolidinediones which are used as antidiabetic drugs, decreasing all-cause mortality in type 2 diabetes mellitus, and (ii) it is associated with insulin resistance and related traits, risk factors for overall mortality in type 2 diabetes mellitus. We investigated the role of PPARγ2 P12A, according to a dominant model (PA + AA vs. PP individuals) on incident all-cause mortality in three cohorts of type 2 diabetes mellitus, comprising a total of 1672 patients (462 deaths) and then performed a meta-analysis of ours and all available published data. In the three cohorts pooled and analyzed together, no association between PPARγ2 P12A and all-cause mortality was observed (HR 1.02, 95 % CI 0.79-1.33). Similar results were observed after adjusting for age, sex, smoking habits, and BMI (HR 1.09, 95 % CI 0.83-1.43). In a meta-analysis of ours and all studies previously published (n = 3241 individuals; 666 events), no association was observed between PPARγ2 P12A and all-cause mortality (HR 1.07, 95 % CI 0.85-1.33). Results from our individual samples as well as from our meta-analysis suggest that the PPARγ2 P12A does not significantly affect all-cause mortality in patients with type 2 diabetes mellitus.


Assuntos
Diabetes Mellitus Tipo 2/genética , Resistência à Insulina/genética , PPAR gama/genética , Polimorfismo de Nucleotídeo Único , Diabetes Mellitus Tipo 2/mortalidade , Estudos de Associação Genética , Predisposição Genética para Doença , Genótipo , Humanos , Fenótipo
18.
Acta Diabetol ; 52(5): 991-8, 2015 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-26302880

RESUMO

AIMS: Our aims were to investigate in several large samples, with a wide range of adiposity, whether: (1) the effect of BMI on insulin sensitivity is different between sexes; (2) also waist circumference plays a sex-specific role on insulin sensitivity; and (3) serum adiponectin and resistin are mediators of such sex-dimorphic effect. METHODS: Samples used were: Gargano study 1 (GS1), GS2 and Catania study (CS) comprising 3274 individuals. Adiponectin and resistin were measured by ELISA. Associations between variables were tested by linear models. RESULTS: In all samples, relationship between BMI and HOMAIR was steeper in males than in females (BMI-by-sex interaction p = 0.04-0.0007). No interaction was observed on serum adiponectin and resistin (p = 0.40-059), which are therefore unlikely to mediate the sex-dimorphic effect of BMI on insulin resistance. Relationship between waist circumference and HOMAIR was similar between sexes in GS1 and GS2 but not in CS (waist-by-sex interaction p = 0.01), comprising much heavier individuals. This suggests that a sex-dimorphic effect of abdominal adiposity on insulin resistance is observable only in the context of high BMI. CONCLUSIONS: Our findings represent a proof of concept that BMI and insulin sensitivity are associated in a sex-specific manner. This may explain why females are protected from diabetes and cardiovascular disease, compared to males of similar BMI.


Assuntos
Adiposidade , Resistência à Insulina , Sobrepeso/fisiopatologia , Gordura Abdominal , Adiponectina/sangue , Idoso , Índice de Massa Corporal , Estudos de Coortes , Feminino , Humanos , Itália , Masculino , Pessoa de Meia-Idade , Resistina/sangue , Caracteres Sexuais , Circunferência da Cintura
19.
Am J Hum Genet ; 97(1): 177-85, 2015 Jul 02.
Artigo em Inglês | MEDLINE | ID: mdl-26073777

RESUMO

Diabetes mellitus is a highly heterogeneous disorder encompassing several distinct forms with different clinical manifestations including a wide spectrum of age at onset. Despite many advances, the causal genetic defect remains unknown for many subtypes of the disease, including some of those forms with an apparent Mendelian mode of inheritance. Here we report two loss-of-function mutations (c.1655T>A [p.Leu552(∗)] and c.280G>A [p.Asp94Asn]) in the gene for the Adaptor Protein, Phosphotyrosine Interaction, PH domain, and leucine zipper containing 1 (APPL1) that were identified by means of whole-exome sequencing in two large families with a high prevalence of diabetes not due to mutations in known genes involved in maturity onset diabetes of the young (MODY). APPL1 binds to AKT2, a key molecule in the insulin signaling pathway, thereby enhancing insulin-induced AKT2 activation and downstream signaling leading to insulin action and secretion. Both mutations cause APPL1 loss of function. The p.Leu552(∗) alteration totally abolishes APPL1 protein expression in HepG2 transfected cells and the p.Asp94Asn alteration causes significant reduction in the enhancement of the insulin-stimulated AKT2 and GSK3ß phosphorylation that is observed after wild-type APPL1 transfection. These findings-linking APPL1 mutations to familial forms of diabetes-reaffirm the critical role of APPL1 in glucose homeostasis.


Assuntos
Proteínas Adaptadoras de Transdução de Sinal/genética , Diabetes Mellitus/genética , Modelos Moleculares , Mutação de Sentido Incorreto/genética , Proteínas Adaptadoras de Transdução de Sinal/química , Adulto , Idoso , Feminino , Células Hep G2 , Humanos , Immunoblotting , Insulina/metabolismo , Itália , Masculino , Pessoa de Meia-Idade , Linhagem , Proteínas Proto-Oncogênicas c-akt/metabolismo , Estados Unidos
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