Predicting Insulin Resistance in a Pediatric Population With Obesity.

OBJECTIVES: Insulin resistance (IR) affects children and adolescents with obesity and early diagnosis is crucial to prevent long-term consequences. Our aim was to identify predictors of IR and develop a multivariate model to accurately predict IR. METHODS: We conducted a cross-sectional analysis of demographical, clinical, and biochemical data from a cohort of patients attending a specialized Paediatric Nutrition Unit in Portugal over a 20-year period. We developed multivariate regression models to predict IR. The participants were randomly divided into 2 groups: a model group for developing the predictive models and a validation group for cross-validation of the study. RESULTS: Our study included 1423 participants, aged 3-17 years old, randomly divided in the model (n = 879) and validation groups (n = 544). The predictive models, including uniquely demographic and clinical variables, demonstrated good discriminative ability [area under the curve (AUC): 0.834-0.868; sensitivity: 77.0%-83.7%; specificity: 77.0%-78.7%] and high negative predictive values (88.9%-91.6%). While the diagnostic ability of adding fasting glucose or triglycerides/high density lipoprotein cholesterol index to the models based on clinical parameters did not show significant improvement, fasting insulin appeared to enhance the discriminative power of the model (AUC: 0.996). During the validation, the model considering demographic and clinical variables along with insulin showed excellent IR discrimination (AUC: 0.978) and maintained high negative predictive values (90%-96.3%) for all models. CONCLUSION: Models based on demographic and clinical variables can be advantageously used to identify children and adolescents at moderate/high risk of IR, who would benefit from fasting insulin evaluation.

Changes in serotoninergic and noradrenergic descending pain pathways during painful diabetic neuropathy: the preventive action of IGF1.

Painful diabetic neuropathy (PDN) induces neuronal hyperactivity at the spinal cord and periaqueductal gray (PAG), a key area in descending nociceptive modulation. Since the PAG uses relay stations at serotoninergic and noradrenergic brainstem areas, we determined the serotonin and noradrenaline levels at the spinal cord of streptozotocin-diabetic rats and at those brainstem areas (serotoninergic rostroventromedial medulla and noradrenergic A(5) and A(7) cell groups). Since, during diabetes, the levels of insulin growth factor 1 (IGF1) decrease, reducing its neurotrophic effect in the brain, we also studied the effects of IGF1 treatment. One week after diabetes induction, subcutaneous injections of IGF1 (2.5mg/kg) were performed during 3 weeks. Body weights, glycemia, and mechanical nociception were weekly evaluated until the end of the study, the time when the animals were subjected to a modified formalin test to study chemical allodynia. Serotonin and noradrenaline levels were quantified by ELISA at the spinal cord, whereas at the brainstem, the quantification was performed by immunohistochemistry against, respectively, tryptophan hydroxylase (TpH) or tyrosine hydroxylase (TH). STZ-diabetic rats exhibited mechanical hyperalgesia and chemical allodynia, along with higher spinal levels of serotonin and noradrenaline and higher numbers of neurons expressing TpH at the RVM and TH at the A(5) noradrenergic cell group. Treatment with IGF1 prevented the behavioral signs of PDN and reversed the neuronal hyperactivity at the spinal cord and ventrolateral PAG and the neurochemical changes at the spinal cord and at the brainstem. Based on the facilitatory role of serotoninergic and noradrenergic descending modulation during chronic pain, the increased serotonin and noradrenaline innervation of the dorsal horn in STZ-diabetic rats may probably account for enhanced pain during PDN. The benefits of IGF1 in PDN are probably due to blockade of the increased peripheral input to the somatosensory system, but direct central actions cannot be discarded. The value of IGF1 in PDN treatment deserves further evaluation.

Transient gain of function of cannabinoid CB1 receptors in the control of frontocortical glucose consumption in a rat model of Type-1 diabetes.

Here we aimed to unify some previous controversial reports on changes in both cannabinoid CB1 receptor (CB1R) expression and glucose metabolism in the forebrain of rodent models of diabetes. We determined how glucose metabolism and its modulation by CB1R ligands evolve in the frontal cortex of young adult male Wistar rats, in the first 8 weeks of streptozotocin-induced type-1 diabetes (T1D). We report that frontocortical CB1R protein density was biphasically altered in the first month of T1D, which was accompanied with a reduction of resting glucose uptake ex vivo in acute frontocortical slices that was normalized after eight weeks in T1D. This early reduction of glucose uptake in slices was also restored by ex vivo treatment with both the non-selective CB1R agonists, WIN55212-2 (500 nM) and the CB1R-selective agonist, ACEA (3 µM) while it was exacerbated by the CB1R-selective antagonist, O-2050 (500 nM). These results suggest a gain-of-function for the cerebrocortical CB1Rs in the control of glucose uptake in diabetes. Although insulin and IGF-1 receptor protein densities remained unaffected, phosphorylated GSKα and GSKß levels showed different profiles 2 and 8 weeks after T1D induction in the frontal cortex. Altogether, the biphasic response in frontocortical CB1R density within a month after T1D induction resolves previous controversial reports on forebrain CB1R levels in T1D rodent models. Furthermore, this study also hints that cannabinoids may be useful to alleviate impaired glucoregulation in the diabetic cortex.

Diabetes affects the expression of GABA and potassium chloride cotransporter in the spinal cord: a study in streptozotocin diabetic rats.

Painful diabetic neuropathy is associated to hyperexcitability and spontaneous hyperactivity of spinal cord neurons. The underlying pathophysiological mechanisms are not clear. Increases in excitatory neurotransmission at the spinal cord, involving glutamate and SP, seem to account for the abnormal neuronal activity, but inhibitory influences were never evaluated. This study aims to analyse the expression of GABA, its synthesizing enzyme glutamic acid decarboxylase (GAD) and the potassium chloride cotransporter (KCC2), in the spinal dorsal horn of streptozotocin (STZ)-induced diabetic rats. Four weeks after saline or STZ (60mg/kg) injection, animals were sacrificed and the spinal segments L2-L3 were removed and immunoreacted for GABA, GAD and KCC2, or processed for western blotting for KCC2. Densitometric quantification was performed in the superficial dorsal horn (laminae I, II and III) of immunoreacted sections and in the immunoblots. STZ rats presented a significant increase of GABA expression in laminae II and III when compared with control animals, while no differences were detected in GAD expression. A significant decrease in KCC2 expression was detected by immunohistochemistry in laminae I and II, which was confirmed by immunoblotting. Increased GABA levels, along with decrease in KCC2 expression, may underlie the abnormal neuronal activity detected in the spinal cord of diabetic rats. Reduction in KCC2 expression was shown to lead to increases in intracellular chloride concentration and, in such condition, GABA binding to GABA(A) receptor induces membrane depolarization, provoking neuronal excitation rather than inhibition. Based on these findings, we propose that a loss of GABA-mediated inhibitory tone at the spinal cord may result in neuronal hyperexcitability and spontaneous hyperactivity during diabetes.

Neuronal hyperactivity at the spinal cord and periaqueductal grey during painful diabetic neuropathy: effects of gabapentin.

Painful diabetic neuropathy may be due to impairments in descending modulation of nociceptive transmission at the spinal cord. In the present study, streptozotocin diabetic rats (STZ rats) with neuropathic symptoms (mechanical hypersensitivity) were used to perform a time-course evaluation of neuronal activity at the spinal dorsal horn and at the periaqueductal grey matter (PAG), a major brainstem area of pain modulation. The expression of Fos protein, a marker of nociceptive activation, progressively increased at the spinal dorsal horn at 4 and 10 weeks. At the PAG, increases in Fos expression were detected until the 4th week, with a reversal to baseline values at 10 weeks in all areas except the ventrolateral PAG. Co-localisation of Fos with NeuN ascertained the neuronal nature of Fos-expressing cells at the spinal cord and PAG. Four weeks after diabetes induction, the effects of gabapentin (i.p. injection of 50mg/kg, daily during 3 days) were assessed. Gabapentin decreased Fos expression at the spinal cord and PAG and reversed mechanical hypersensitivity. The present study shows that diabetic neuropathy is accompanied by a progressive increase of the spontaneous neuronal activity at the spinal cord. Changes in descending modulation of nociceptive transmission from the PAG are likely to occur during diabetic neuropathy, probably with exacerbation of facilitatory actions. The effects of gabapentin in reversing the behavioural signs of diabetic neuropathy and neuronal hyperactivity in the spinal cord and PAG reinforce the central causes of diabetic neuropathy and point to the central targets of the drug.

Avaliação do bem-estar no transporte e nos currais de descanso pela ocorrência de lesões em carcaças de suínos abatidos em matadouro / Evaluation of welfare during transport and lairage through the occurrence of lesions in slaughtered pig carcasses

Bem-Estar Animal consiste no estado do animal em sua tentativa de adaptação ao meio ambiente envolvente, podendo ser medido e melhorado com a ação do ser humano. Nos últimos anos o tema “Bem-Estar Animal” tem adquirido importância, resultante das grandes preocupações com o manejo dos animais em vida e constatação da influência que este tem na qualidade da carne post mortem. Este trabalho teve como objetivo determinar o efeito do lote de suínos transportados, respectivo tamanho, tipo de trajeto e do tempo decorrido entre a origem e o abate na ocorrência de lesões, consideradas indicadores mínimos de bem-estar animal em matadouro. Nos matadouros de suínos da região norte de Portugal, foram monitorados 834 animais com relação à ocorrência de lesões compatíveis com lacerações, eritemas cutâneos, hematomas e fraturas, em cinco diferentes lotes. Pela análise global dos dados, verificou-se que as lacerações estavam presentes em 72 por cento dos animais e foi o tipo de lesão mais frequentemente observado. Seguiram-se os eritemas cutâneos em 20 por cento, os hematomas em 11 por cento e as fraturas em apenas 1 por cento dos animais. O tamanho do lote de animais transportados, a duração da viagem e o tempo de permanência no matadouro influenciaram significativamente a ocorrência das lesões monitoradas, nomeadamente lacerações, eritemas e hematomas.

Animal welfare is the state of the animal in its attempts to cope with its environment, and it can be measured and improved by the action of man. Recently, the topic “Animal Welfare” has become more important, resulting from the discovery that the management of animals in life has impact on the post mortem meat quality. This study aimed to determine the effect of transport batch number of pigs transported by batch, type of route and the time elapsed between the exploration and slaughter in the occurrence of lesions, considered as indicators of animal welfare at the slaughterhouse. At one slaughterhouse of pigs located in the northern of Portugal, 834 animals were monitored in order to check the occurrence of lesions consistent with lacerations, erythema, bruising and fractures, from a total of five different transport batches. The global analysis of the data showed that lacerations were present in 72 percent of animals and was the most common type of lesion, followed by erythema, bruises and broken bones presented in 20 percent percent and 1 percent respectively. The size of each batch, the duration of the journey and the time spent in the lairage significantly influenced the occurrence of observed lesions, particularly, lacerations, erythema and bruising.