Post-natal stress-induced endocrine and metabolic alterations in mice at adulthood involve different pro-opiomelanocortin-derived peptides.
ABSTRACT In previous investigations we added a physical stress (mild pain) to the "classical" post-natal psychological stress in male mice, and we found that this combination produced a series of dysmetabolic signs very similar to mild human type-2 diabetes. Here, for the first time we demonstrate that within this diabetes model at least two groups of signs depend on the unbalance of two different endogenous systems. Newborn male mice were daily exposed to stressful procedures for 21 days (brief mother separation plus sham injection). Other groups underwent the same procedure, and also received naloxone (Na) to block μ-δ endogenous receptors, or a phosphorothioate antisense oligonucleotide (AS) directed against pro-opiomelanocortin (POMC)-mRNA [to block adrenocorticotropin (ACTH)- and POMC-derived opioid peptides]. Adult mice which received only post-natal stress increased body weight (+7.5%), abdominal overweight (+74%), fasting glycemia (+43%), plasma corticosterone (+110%), plasma (+169%) and pituitary (+153%) ACTH levels. Conversely, hypothalamic ACTH and corticotropin-releasing hormone (CRH) were reduced (-70% and -75%, respectively). Neonatal AS administration reverted all parameters to control values. Neonatal naloxone had little or no influence on glucose, corticosterone, ACTH, CRH levels, whereas it prevented body overweight and abdominal overweight. We conclude that, within this type-2 diabetes model in male mice at least two endocrino-neurohumoral systems are damaged, one concerning the opioid system, and the other concerning HPA hormones. The use of the two drugs was of primary importance to demonstrate this statement, and to demonstrate that these two groups of signs could be defined as "separate entities" following our complex post-natal stress model.
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ABSTRACT: Gene expression in mammalian cells can be suppressed by oligonucleotides complementary to the target mRNA. This strategy was explored as a means of arresting translation of the prohormone precursor proopiomelanocortin (POMC), used as a model system of peptide messengers that are synthesized and released from endocrine and neuronal cells. The synthesis of the POMC-derived peptides adrenocorticotropin (ACTH) and beta-endorphin (beta-END) was markedly reduced by an oligodeoxynucleotide (ODN) complementary to a region of beta-END mRNA in AtT-20 cells, which retain many of the differentiated phenotypes of corticotrophs; this treatment did not affect the steady-state levels of POMC mRNA. Antisense ODN was stable in cell culture medium for 24 h, and cellular uptake was low (approximately 2.5% of the added ODN); however, the intracellular levels of the ODN were sufficient to form a ribonuclease-resistant duplex with complementary cellular mRNA. Addition of ODN to the cell culture did not affect the cellular levels of chromogranin A-(264-314)/pancreastatin or cell viability and proliferation, as evidenced by bromodeoxyuridine incorporation and ornithine decarboxylase activity. Microinfusion of the antisense ODN in the rat hypothalamic arcuate nucleus, where the majority of POMC-positive brain perikarya are located, significantly reduced ACTH- and beta-END-immunopositive neurons, and antisense ODN-treated rats showed substantially less of the grooming behavior usually observed in a novel environment.Proceedings of the National Academy of Sciences 09/1994; 91(17):8072-6. · 9.74 Impact Factor
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ABSTRACT: There is evidence of both hypothalamic-pituitary-adrenocortical (HPA) axis and cognitive dysfunction in type 2 diabetes mellitus (T2DM). However, the exact nature and the associations between these abnormalities remain unclear. The aim of the study was to characterize the nature of the HPA dysregulation in T2DM and ascertain whether impaired cognition in T2DM could be attributed to these abnormalities. A cross-sectional study was performed, contrasting matched groups on HPA axis function and cognition by using the combined dexamethasone (DEX)/CRH test and a neuropsychological battery assessing declarative and working memory, attention, and executive function. The study was conducted in a research clinic in an academic medical center. Participants were volunteers functioning in the cognitively normal range. We studied 30 middle-aged individuals with T2DM, on average 7.5 yr since diabetes diagnosis, and 30 age-, gender-, and education-matched controls. Basal cortisol levels, cortisol levels during the DEX/CRH test, and performance on neuropsychological tests were measured. Individuals with T2DM had elevated basal plasma cortisol levels, higher levels after DEX suppression, and a larger response to CRH (all P <or= 0.005). Among individuals with T2DM, cortisol levels during the DEX/CRH test were positively associated with glycosylated hemoglobin (P = 0.05), independent of age, body mass index, hypertension, and dyslipidemia. Diabetic subjects showed cognitive impairments restricted to declarative memory. Across all subjects, declarative memory was inversely associated with cortisol levels; however, these associations were subsumed by glycemic control (glycosylated hemoglobin). HPA hyperactivity and declarative memory deficits are present in T2DM. Both alterations may reflect the negative impact of poor glycemic control on the hippocampal formation.Journal of Clinical Endocrinology & Metabolism 07/2007; 92(7):2439-45. · 6.43 Impact Factor
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ABSTRACT: To determine the effects of lumbosacral transforaminal and caudal epidural betamethasone injections on blood glucose levels in diabetic subjects. The hypothesis is that epidural steroid injections result in transient elevation of blood glucose levels in diabetic subjects. This is a prospective, observational cohort. Twelve diabetic subjects (6 non-insulin-dependent and 6 insulin-dependent) receiving lumbosacral or caudal epidural betamethasone injections for neurogenic claudication or radicular pain were studied. Spinal level and approach were decided based on symptoms, pathology, and magnetic resonance imaging findings. Subjects recorded their finger stick blood glucose levels twice daily for 3 days before the injection, the day of the injection, and 3 days after the injection. A tertiary, university-based, spine center. Inclusion criteria included diabetic subjects (age 18 years) with the ability and willingness to monitor and report their blood glucose. Exclusion criteria included epidural steroid injections (ESIs) within the previous 2 months or peripheral corticosteroid injections within the previous 2 weeks. Nineteen subjects initially enrolled, and 12 successfully completed the study. After informed consent was obtained, subjects underwent fluoroscopically guided lumbosacral transforaminal ESIs (TFESIs) or caudal ESIs, using contrast to confirm targeted needle placement and to rule out vascular uptake. Subjects recorded morning and evening blood glucose (mg/dL) via glucometer. There was a 106 mg/dL average elevation in blood glucose level on the evening of the injection day. The blood glucose elevation remained statistically significant for 3 days after the injection (P < .002). Blood glucose remained elevated through postinjection day 2, though these elevations were not statistically significant. Lumbosacral transforaminal and caudal epidural betamethasone injections are associated with statistically significant elevations in blood glucose levels in diabetic subjects. This effect peaked on the day of the injection and lasted approximately 2 days.PM&R 05/2009; 1(4):340-5. · 1.37 Impact Factor