Top PDF Obesity, insulin resistance and type 2 diabetes mellitus in adolescents

Introducción. La obesidad está considerada como un problema de salud pública. Su presencia a edades tempranas implica una obligación de identificar la aparición de complicaciones como resistencia a la insulina y diabetes mellitus (DM). Métodos. Estudio observacional, descriptivo y transversal. Participaron 1206 mujeres adolescentes. Se definió la obesidad con valores de IMC ≥ 95p según la OMS. Se determinó niveles séricos de insulina, glucosa y perfil lipídico. Se usó el Homeostasis Model of Assesmente Index (HOMA-I), mediante la ecuación de Matthews con el valor ≥ 3,16 para definir resistencia a la insulina (RI). Para las dislipidemias: hipercolesterolemia ≥ 200 mg/dL, bajo C-HDL ≤ 40 mg/dL, alto C-LDL ≥ 130 mg/dL e hipetrigliceridemia ≥ 130 mg/dL. A las adolescentes obesas con RI se les hizo una prueba de tolerancia oral a la glucosa (PTG): glicemia de 140 a 199 mg/dL intolerantes a la glucosa y ≥ 200 mg/dL diabéticas. Resultados. El 25,1% (303) de la población fue obesa; 246 adolescentes obesas participaron de la evaluación bioquímica, 28,1% (69) de ellas presentaron RI. En las adolescentes obesas con y sin RI, el promedio de las variables bioquímicas en las primeras fueron mayores, siendo estas diferencias significativas estadísticamente, salvo el C-HDL. Diferencias entre la prevalencia de dislipidemias fueron significativas a excepción del C-HDL. La RI presentó un OR de 10,9 (IC 5,4-26,6), 12,1 (IC 4,9-30,1), y 7,6 (IC 3-19,5) con la hipertrigliceridemia, hipercolesterolemia y C-LDL alto. La PTG mostró un 3,3% de intolerantes y ninguna diabética. Conclusiones. El 28,1% (69) de adolescentes obesas presentaron RI; ninguna participante del estudio presentó DM. Palabras clave: Obesidad; Resistencia a la insulina; Diabetes mellitus; Adolescente; Dislipidemias Abstract

There is now strong evidence that type 2 diabetes and the metabolic syndrome are associated with a low-grade in- fl ammatory state associated with an unbalanced innate immune system. This low-grade infl ammatory state is triggered by a continuous exposure to external insults such as reactive oxygen species (ROS), fatty acids, AG- Es and LPS. Metabolic concentrations of plasma LPS are associated with insulin resistance and obesity in ani- mal models, and this increase in plasma LPS could be caused by intestinal translocation of LPS from Gram- negative bacteria present in gut fl ora. High fat diet could contribute to this increased LPS translocation from in- testine into the bloodstream.

highest non-severe hypoglycemia rates. The three scenarios all give cost-effective results and contemplate hypoglycemia rates. It must be considered that the non-severe hypoglycemia rate of these studies was assumed to correspond to treatment with NPH, although insulin type information was not available and most probably included different insulin types. However, this is a conservative assumption in that NPH is known to be associated to higher hypoglycemia rates than more modern insulin analogs [34]. In addition, the use of an overall hypoglycemia RR for IDet versus NPH, instead of a specific RR for non-severe hypoglycemia episodes, due to the lack of a robust source for this datum in the literature, may be considered a limitation of the model. Anyway, the approximated values that are maintained from the original models by Valentine et al. [10] and Ridderstra˚le et al. [22] give conservative estimations of the non-severe hypoglycemia RR, as already discussed by Valentine et al. [10], and offer the advantage of integrating data from a very controlled setting (RCTs [20, 21]), with a setting that is closer to the ‘‘real-world’’ data (observational study [23]), as explained by Ridderstra˚le et al. [22].

(fi gure 6), it appears to be far from mimicking the fl at, peakless, physiological basal insulin (fi gure 2). NPH insulin has a peak 5-6 hours after injection and wanes a few hours later (fi gure 6). Thus, when injected during the evening, the peak action of NPH insulin in- creases the risk of hypoglycaemia after midnight. On the other hand, the relatively short duration of the action of NPH insulin makes it very diffi cult to achieve near-nor- moglycaemia in the fasting state without increasing the risk for nocturnal hypoglycaemia. Finally, since NPH in- sulin is an insoluble preparation that needs to be resus- pended prior to s.c. injection, its absorption is quite vari- able, resulting in different fasting blood glucose from day to day. For these reasons, NPH insulin should no longer be used in T1DM. Only long-acting insulin ana- logues (glargine, detemir) or CSII should be used to re- place basal insulin in T1DM.

In humans, muscle FNDC5 gene expression increased with obesity (11, 12). Huh et al (12) speculated that this association might be a compensatory mechanism. Reinforc- ing this hypothesis, we found that muscle FNDC5 gene ex- pression was positively associated with BMI (r ⫽ 0.42, P ⫽ .02) but negatively associated with age (r ⫽ ⫺ 0.44, P ⫽ .01). In fact, age ( ␤ ⫽ ⫺ .43, P ⫽ .02) contributed independently to the FNDC5 gene expression variance in muscle after controlling for gender and BMI. Timmons et al (11) de- tected an exercise-induced increase of FNDC5 mRNA in human muscle biopsies from old (precisely the subjects with the lowest FNDC5 levels in our study) but not from young subjects. These data are not comparable with our data because FNDC5 gene expression in our study was measured only in the basal state. In addition, we also found that muscle FNDC5 mRNA was significantly de- creased in subjects with type 2 diabetes. Whether this is pathophysiologically linked to type 2 diabetes should be explored more in depth in future studies.

Rusinek, H., Ha, J., Yau, P. L., Storey, P., Tirsi, A., Tsui, W. H., Frosch, O., Azova, S., y Convit, A. (2015). Cerebral perfusion in insulin resistance and type 2 diabetes. Journal of Cerebral Blood Flow & Metabolism, 35(1), 95–102. doi.org/10.1038/jcbfm.2014.173. Salinas-Contreras, R. M., Hiriart-Urdanivia, M., Acosta-Castillo, I., y Sosa-Ortiz, A. L. (2013). Diabetes mellitus y su asociación con demencia y deterioro cognitivo leve en adultos mayores mexicanos de población urbana y rural. Arch Neurocien (Mex), 18, Supl-I, 1-7. Soriguer, F., Goday, A., Bosch-Comas, A., Bordiu, E., Calle-Pascual, A., Carmena, R., et al.

In chronic hepatitis C, insulin resistance (IR) and type 2 diabetes mellitus (DM) are more prevalent than in healthy controls or in chronic hepatitis B patients. HCV infection promotes IR mainly through increased TNF- α and cytokine suppressor (SOCS-3) production. Both events inhibit insulin receptor and IRS-1 (insulin receptor substrate) tyrosine phosphorylation. Hepatic steatosis is also 2.5 fold more frequent in hepatitis C vi- rus (HCV) infected patients as compared to the general population. Metabolic factors play a crucial role in the etiology of hepatic steatosis genotype non-3 related, which are also the genotypes with a greater association to IR. However, genotype 3, and particularly 3a, has a greater direct steatogenic capacity, and consequently, in those patients, the association with metabolic factors is weaker. Instead, in genotype 3, steatosis associates with viral factors like viral load. Those metabolic fac- tors influence not only the natural history of HCV in- fection, as well as associate to an accelerated hepatic fi- brosis progression, to a worse prognosis when hepatic cirrhosis is present, namely an increased risk of hepa- tocellular carcinoma, and to a lower sustained viral re- sponse rate. On the other hand, in patients who achieve viral eradication, IR and hepatic steatosis may re- gress, and return if viral infection recurs, which once again indicates an intrinsic steatosis and IR promoter action by HCV.

Among all the polymorphisms which have been tested for their relationship with obesity and type 2 diabetes within the FABP1 gene, the functional mutation rs2241883 (p.Thr94Ala) has been the most studied. According to our results while there was no association with the p.Thr94Ala in our populations, haplotypes containing the allele T (wild allele) were significantly associated with the risk of type 2 diabetes in both populations and in the pooled analysis. The p.Thr94Ala polymorphism induces an amino- acid change that is located within the N-terminal region of the protein which is a component of the fatty acid binding site and therefore the binding capacity might be reduced in patients with the 94Ala variant [24]. In the study carried out by Brouillette et al, they found that carriers of the 94Ala allele had higher baseline FFA, lower BMI and waist circumference than homozygotes Thr94Thr [6]. In our associated haplotypes, the direction of the association was driven by alleles of the rs2197076 and not by alleles of the functional mutation. Our results suggest that the most strongly associated SNP (rs2197076), because of its location in the 3 prime UTR site and its association with a potential functional variant in one risk haplotype, could regulate the functional activity of the protein individually or in haplotypes. It is likely that the A allele of the rs2197076 might therefore reduce FABP1 gene expression thereby contributing to enhance that situation of IR- lipotoxicity, IR and DM2.

Much evidence now exists concerning an important change in our microbiota over recent decades, with some species increasing and others decreasing, though one of the most striking findings is that in developed countries there is a loss in the diversity of our microbiota. One of the most important factors that can dis- turb microbiota composition is the increased use of antibiotic treatment. There is evidence of important alterations in micro- biota after antibiotic treatment (Sullivan et al., 2001; Jernberg et al., 2007; Dethlefsen et al., 2008). Although affected taxons vary among subjects, some taxons are not recovered even sev- eral months after treatment, and in general, there is a long-term reduction in bacterial diversity after the use of antibiotics (Jern- berg et al., 2010; Dethlefsen and Relman, 2011). A correlation has recently been proposed between the increasing global use of antibi- otics and weight gain or obesity in humans (Thuny et al., 2010). Several studies have indicated that some antibiotics are associated with weight gain in malnourished children, neonates, and adults (Ajslev et al., 2011; Trehan et al., 2013), but the precise mechanisms by which antibiotics improve weight are not well characterized. It has been suggested that antibiotics, such as avoparcin (a glycopep- tide structurally related to vancomycin), exert selective pressure on Gram-positive bacteria and that gut colonization by Lactobacillus spp., which are known to be resistant to glycopeptides, used as a growth promoter in animals and found at a high concentration in the feces of obese patients, could be responsible for the weight

Obesity is associated with a low-grade chronic inflammation state. As a consequence, adipose tissue expresses pro- inflammatory cytokines that propagate inflammatory responses systemically elsewhere, promoting whole-body insulin resistance and consequential islet b-cell exhaustation. Thus, insulin resistance is considered the early stage of type 2 diabetes. However, there is evidence of obese individuals that never develop diabetes indicating that the mechanisms governing the association between the increase of inflammatory factors and type 2 diabetes are much more complex and deserve further investigation. We studied for the first time the differences in insulin signalling and inflammatory pathways in blood and visceral adipose tissue (VAT) of 20 lean healthy donors and 40 equal morbidly obese (MO) patients classified in high insulin resistance (high IR) degree and diabetes state. We studied the changes in proinflammatory markers and lipid content from serum; macrophage infiltration, mRNA expression of inflammatory cytokines and transcription factors, activation of kinases involved in inflammation and expression of insulin signalling molecules in VAT. VAT comparison of these experimental groups revealed that type 2 diabetic-MO subjects exhibit the same pro-inflammatory profile than the high IR-MO patients, characterized by elevated levels of IL-1b, IL-6, TNFa, JNK1/2, ERK1/2, STAT3 and NFkB. Our work rules out the assumption that the inflammation should be increased in obese people with type 2 diabetes compared to high IR obese. These findings indicate that some mechanisms, other than systemic and VAT inflammation must be involved in the development of type 2 diabetes in obesity.

As we know, WC is one of the best anthropometric indicators of abdominal visceral fat. Although the cause- and-effect association has not been definitively established, the available evidence indicates that visceral fat is an important link between the many facets of the metabolic syndrome: obesity, glucose intolerance, hypertension, dys- lipidemia, insulin resistance, decreased HDL cholesterol concentrations and atherosclerotic cardiovascular disease (Wajchenberg, 2000). For this reason, it is relevant to point out the high percentage of participants without diabetes who fell in the high risk category according to their WC. Between them 76.1% are females and 23% are males in which other significant correlations were found with DEB (binge eating, food and weight concern and dietary restraint). These findings allow to propose that, if these subjects did not modify their eating behaviors, lose weight, and in gen- eral change their lifestyle they would soon be patients with type 2 diabetes, not only because the excess of visceral abdominal fat and high BMI are associated with this disease,

GIPR expression in the sc adipose depot, an inverse rela- tionship to insulin resistance, and a GIP-resistant pheno- type in obese-derived adipocytes. Interestingly, although there is a clear link established between VAT and meta- bolic complications such as T2D, dyslipidemia, and hy- pertension, the fact that our major findings were detected in the SAT depot would be in agreement with the hypoth- esis that a primary defect in sc fat might be considered as a causal link between obesity and insulin resistance (29). Although circulating levels of GIP are usually increased in patients with T2D, the insulinotropic activity of GIP is blunted under these conditions (3). Other findings suggest that alterations in GIPR expression in SAT might be as- sociated with signs of insulin resistance in nondiabetic women with central obesity (18). Also, a recent report indicates that GIPR expression in SAT is inversely asso- ciated with BMI (30). Our findings, in 3 independent co- horts, confirm and extend this recent analysis by providing a detailed analysis of clinical variables associated with an insulin-resistant metabolic profile including BMI, SBP, waist circumference, and glucose levels. It is worth noting that although pooling results from all cohorts might in- crease the power and sensitivity of our study, the inclusion of cohorts phenotypically different might be more reflec- tive of real populations. In this regard, cohort 1 included a high percentage of overweight subjects (44%), whereas the cohort 2 comprised morbidly obese patients (40%). Furthermore, our results complement the observation that hyperglycemia leads to a downregulation of GIPR expres- sion in pancreatic ␤ -cells, and normalization of glucose levels in patients with poorly controlled T2D enhances the incretin response of GIP (31). Interestingly, we found that with obese subjects, insulin resistance persists as an im- portant determinant of GIPR expression in sc fat, inde- pendent of BMI. Thus, obese patients with the highest degree of insulin resistance exhibit the lowest levels of GIPR. Taken together, these observations support a link between GIP and insulin sensitivity in adipose tissue. In- deed, our results indicate that the relationship between obesity and GIPR expression might be mediated through the degree of insulin resistance. Accordingly, there are no significant differences in the expression of GIPR mRNA between lean and obese patients with low insulin resis- tance (data not shown), suggesting that low levels of GIPR

According to the American Diabetes Association (ADA) and the Diabetes medical attention standards of 2014, the goal for HbA1c in type 1 diabetic patients varies depend- ing on age. Concerning values <8% in the 6---12 years-of-age range, because it is not possible to have more strict goals due to the risk of developing hypoglycemia, even in this age range we can demand goals of <7.5% in specific cases where patients do not present severe hypoglycemia. In the 13---19 years-of-age range, values of <7.5% are considered and in specific cases even <7%. In children under 6 years of age, goals of <8% are too strict, so up to <8.5% is accept- able, because these children have a greater vulnerability for hypoglycemia, a greater sensitivity to insulin, and are unpredictable in their intake and physical activity. 10

important determinants of many of the metabolic disturbances seen in this disorder. Therefore, HIV lipodystrophy is an interesting model to elucidate the molecular mechanisms regulating fatty acid trapping and adipose tissue distribution. Recent studies have clearly shown that components of the complement system play an important role in lipoprotein metabolism and fatty acid regulation. Especial attention has been drawn to the complement component 3 (C3) which is also a strong predictor of the metabolic syndrome. C3 is synthesized by adipose tissue during lipolysis of triglyceride rich lipoproteins. This process seems to be disturbed in different situations of insulin resistance like the metabolic syndrome, type 2 diabetes and familial combined hyperlipidemia. C3 may be a potential link between inflammation and lipoprotein dysmetabolism. Surprisingly, C3 concentrations are also modulated by several interventions designed to treat the me metabolic syndrome, like statins. Other inflammatory markers like leukocyte count and activation behave similar to C3 concentrations, especially during the postprandial phase. In this overview we will discuss several metabolic aspects of two examples of the insulin resistance syndrome, type 2 diabetes and HIV lipodystrophy.

In developed countries, type 2 diabetes mellitus (T2DM) represents a major public health problem mainly by its relationship with different cardiovascular diseases (CVD) [1]. Long-term hyperglycemia results in the synthesis of a number of molecules like advanced glycation end products (AGEs), advanced oxidation protein products (AOPPs), and low-density lipoprotein susceptibility to oxidation (oxLDL). Besides chronic hyperglycemia, other factors such as insulin resistance, dyslipidemia and states of inflammation and oxidation are related to vascular injury in diabetes through several underlying processes [2]. However, only some diabetic patients develop cardiovascular disease while others do not develop these complications despite having the same common risk factors. The etiologic pathway linking impaired glucose tolerance and cardiovascular disease remains to be clarified. Many factors, including genetic components may be involved and not all are well established. Currently, multiple areas of research are open to explain this complex phenomenon [3] and the precise role of the different disturbed metabolic pathways is not well established. In this context, the identification of new molecules that take part in the development of these vascular complications in T2DM may be of great importance for improving the outcomes of this population or to design new therapeutic targets. Thus, the underlying factors that may lead to the development of CVD require further in-depth research. The proteomic analysis is a hypothesis-free approach integrating genetic and epigenetic influences by examining the protein expression profiles and is not limited by the above knowledge.

Estudio del consumo de alimentos. Se realizaron cuestionarios recordatorio por espacio de 1 mes llevados a cabo por la nutricionista del grupo de investigación, acerca del consumo frecuente (por sujeto de estudio) de 87 productos que forman parte de la alimentación habitual de Mallorca, considerando en los cuestionarios como: no consumo (punto 1), consumo ocasional (punto 2 cuando se consumen una vez a la semana), consumo frecuente y estacional (punto 3 cuando es diario o al menos 3 veces en la semana). Se propusieron dos variantes para la valoración del consumo de alimentos: La variante 1 se refirió a la valoración del Índice de Alimentación Saludable (IAS o HIN), de acuerdo a lo sugerido y contrastado por Norte y Ortiz 9 (IAS: rango saludable >80; dieta necesita

Probiotics are live microorganisms that confer a health benefit on the host when administered in adequate amounts [19], although dead bacteria and their components can also show probiotic properties. Bifidobacterium and Lactobacillus strains are the most widely used bacteria exhibiting probiotic properties and are included in many functional foods and dietary supplements [20]. Major mechanisms underlying the antagonistic effects of probiotics include improvement of the gut barrier function, increased competitive adherence to the mucosa and epithelium, gut microbiota modification, and regulation of the gut associated lymphoid immune system. In this sense, probiotics communicate with the host through intestinal cell pattern recognition receptors, such as toll-like receptors and nucleotide-binding oligomerization domain-containing protein-like receptors, which modulate important key signaling pathways, such as nuclear factor- κ B and mitogen-activated protein kinase, to enhance or suppress activation and influence downstream pathways [21–25].

29. Klein DJ, Aronson Friedman L, Harlan WR, Barton BA, Schreiber GB, Cohen RM, et al. Obesity and the development of insulin resistance and impaired fasting glucose in black and white adolescent girls. Diabetes Care. 2004;27:378-83. 30. Goran M, Bergman R, Cruz M, Watanabe R. Insulin resistance and associated compensatory responses in African- American and Hispanic children. Diabetes Care. 2002;25:2184-90.

precast polyacrylamide gel (Criterion Tris-HCl protein gel, Bio Rad, USA) and electro-transferred onto polyvinylidene difluoride filters (PVDF; Millipore, USA) for immunoblotting by conventional means. Electro-transferred PVDF membranes were blocked for 1 h at room temperature using blocking buffer (1X PBS, 0.1% Tween-20 with 5% w/v non-fat dry milk). After being probed with specific antibodies, the membranes were stripped using stripping buffer (2% SDS, 62.5mM Tris-HCl, pH 6.8 and 100mM β-mercaptoethanol) for 30 min at 50 ºC and then washed and reprobed with other antibodies. Signals were detected by chemiluminescence (Clarity Western ECL Substrate kit; Bio Rad, USA) and band densitometry was quantified with Image J software (National Institutes of Health, USA).

desaturation of fatty acids, at least in mice, may occur predominantly in the liver rather than in adipose tissue. In our study we were able to compare liver lipid and mRNA profiles to scWAT profiles for the wild-type and ob/ob mouse groups. It was notable that even in wild-type mice liver TG was predominantly derived from DNL and then elongated and desaturated to a greater extent than the TG found in scWAT or diet. Adipose tissue appeared to have a profile in terms of Elovl6, SCD1 and DNL indices that fell between the diet and liver, suggesting a mechanism by which the majority of dietary lipid is directed to adipose tissue in the fed state when insulin is high. In addition to lipid from the diet itself, the liver generates fatty acids through DNL and exports these for storage in WAT. The net result is that WAT FFA composition is a hybrid of diet and DNL. In the ob/ob mouse, which is hyperphagic and hyperinsulinaemic, the profiles observed suggest an exaggerated version of this model. Consistent with previous reports ob/ob mice had a lipid profile in liver representative of greater rates of DNL compared to controls 22,23 . In