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Introduction: Fetal hyperinsulinemia in gestational diabetes mellitus (GDM) not only is important during intrauterine life, a time when it can result in macrosomia, but also at delivery, since it can result in neonatal hypoglycemia and hyperbilirubinemia. The question is, how long before delivery does maternal glycemic control contribute to newborn insulinemia in GDM?, Methods: In 72 women with GDM, we calculated Spearman's rank (r s ) correlations between umbilical cord blood C-peptide at birth (a biomarker of insulin secretion), and both maternal glycosylated hemoglobin (HbA1c) and mean blood glucose (MBG) recorded in the last two visits prior to delivery. Iterative correlations were done between umbilical cord blood C-peptide at birth, and maternal glucose control, at 0, 1, 2, 3, 4, and 5 weeks before delivery., Results: At an early visit (32.95 ± 1.8 weeks), r s  = 0.353 (P = 0.07) between HbA1c and C-peptide, whereas r s  = 0.244 (P = 0.186) between MBG and C-peptide. At the latest visit (35.04 ± 1.6 weeks), r s  = 0.456 (P = 0.004) between HbA1c versus C-peptide, and r s  = 0.359 (P = 0.023) between MBG versus C-peptide. Iterative correlations between MBG and C-peptide became significant at 2 weeks before delivery., Conclusion: To further reduce the risk of hypoglycemia and hyperbilirubinemia in infants born to women with GDM, besides applying a strict in-patient glucose control protocol at delivery, it is necessary to improve even more the quality of maternal glucose control during the last 2 weeks prior to delivery., (Copyright © 2018 Society of Obstetricians and Gynaecologists of Canada. Published by Elsevier Inc. All rights reserved.)

Recurrent aspiration of gastric contents has been associated with several interstitial lung diseases. Despite this association, the pathogenic role of aspiration in these diseases has been poorly studied and little is known about extracellular matrix (ECM) changes in animal models of repetitive events of aspiration. Our aim was to study the repair phase of lung injury induced by each of several instillations of gastric fluid in Sprague-Dawley rats to evaluate changes in ECM and their reversibility. Anesthetized animals received weekly orotracheal instillations of gastric fluid for 1, 2, 3, and 4 wk and were euthanized at day 7 after last instillation. For reversibility studies, another group received 7 weekly instillations and was euthanized at day 7 or 60 after last instillation. Biochemical and histological measurements were used to evaluate ECM changes. Lung hydroxyproline content increased progressively and hematoxylin and eosin, Masson's trichrome, and alpha-SMA stains showed that after a single instillation, intra-alveolar fibrosis predominated, whereas with repetitive instillations this fibrosis pattern became less prominent and interstitial fibrosis progressively became evident. Both type I and III collagen increased in intra-alveolar and interstitial fibrosis. Imbalance between matrix metalloproteinase-2 (MMP-2) activity and tissue inhibitor of metalloproteinase-2 (TIMP-2) expression was observed, favoring either collagen degradation or accumulation depending on the number of instillations. Caspase-3 activation was also dose dependent. ECM changes were partially reversible at long-term evaluation, since Masson bodies, granulomas, and foreign body giant cells disappeared, whereas interstitial collagen accumulated. In conclusion, repetitive lung instillations of gastric fluid induce progressive fibrotic changes in rat lung ECM that persist at long-term evaluation.

Aim: Macrosomia in the offspring of overweight/obese mothers with glucose-controlled gestational diabetes mellitus (GDM) is due to excessive rise of maternal triglycerides (TG). We aimed to ascertain whether basal-bolus insulin therapy (BBIT), or other components of the treatment, could reduce TG in GDM., Methods: We studied the records of 131 singleton pregnancies with GDM, using stepwise multiple linear regression, Mann-Whitney, χ 2 , and Jonckheere-Terpstra tests. As maternal TG increased steadily during normal pregnancy, these were transformed as z-scores. The atherogenic index of plasma (AIP) was calculated as a measure of cholesteryl ester transfer protein activity., Results: Multiple regression showed that only BBIT (but neither limitation of weight gain nor metformin) reduced maternal TG z-scores (P = 0.011). When the 131 pregnancies were split into two groups - without BBIT (n = 58; HbA1c = 5.3 ± 0.3%) and with BBIT (n = 73; HbA1c = 5.4 ± 0.6; P = 0.2005) - we observed that BBIT (n = 73) reduced maternal TG z-scores in a dose-related fashion (Jonckheere-Terpstra P = 0.03817). The atherogenic index of plasma remained within normal range in both groups., Conclusion: BBIT (but not weight gain control nor metformin) reduced maternal TG in mothers with glucose-controlled GDM. This beneficial effect of BBIT was not related to changes in the cholesteryl ester transfer protein activity., (© 2017 Japan Society of Obstetrics and Gynecology.)

To measure the impact of a "Preventive Letter" designed to encourage the return of gestational diabetes mellitus (GDM) mothers to follow up visit after delivery, in the context of a worldwide concern about low return rates after delivery of these patients. Mothers with GDM require medical evaluation and an oral glucose tolerance test (OGTT) 6 weeks after delivery, in order to: [a] confirm remission of GDM and [b] provide advice on the prevention of type 2 diabetes. In the year 2003 we developed a "Preventive Letter", containing three aspects: [a] current treatment, [b] suggested management during labor, and [c] a stapled laboratory order for OGTT to be performed 6 weeks after delivery. The return rate after delivery was assessed in two groups of GDM mothers: [a] "Without Preventive Letter" (n = 253), and "With Preventive Letter" (n = 215). Both groups, similar with respect to age (33.0 ± 5.4 and 32.3 ± 4.9 years respectively, p = 0.166) and education time (14.9 ± 1.8 and 15.0 ± 1.8 years respectively, p = 0.494), showed a significant difference in the 1-year return rate after delivery, as assessed by the Kaplan-Meier test: 32.0 % for the group "Without Preventive Letter", and 76.0 % for the group "With Preventive Letter" (p < 0.001). The 1-year return rate after delivery of GDM mothers was 2.4 times higher in the group "With Preventive Letter" than in the group without it. We believe that this low-cost approach could be useful in other institutions caring for pregnant women with diabetes.

Objective: Infants born from overweight and obese mothers with glucose-controlled gestational diabetes (GDM) tend to be large-for-gestational age (LGA). It is hypothesized that this is due to an excessive rise in maternal triglyceride levels., Methods: Two-hundred and seventy nine singleton GDM pregnancies were divided into three groups according to prepregnancy BMI: normal weight (BMI = 20-24.9; n = 128), overweight (BMI = 25-29.9; n = 105), and obese (BMI ≥ 30; n = 46). Individual z-scores (ZS) of maternal triglycerides and of newborn weight (NWZS) were calculated as deviations from published 50th percentiles. Mean z-scores (MZS) were the average of triglyceride ZSs. MZS of triglycerides, HbA1c and NWZS were compared. Variables are expressed as mean ± SD., Results: In the three groups respectively: LGA (%) = 10.1%, 19.0% and 30.4% (P = 0.015). Birth weight (g) = 3274.2 ± 501.3, 3342.4 ± 620.2 and 3366.3±644.7 (RSPEARMAN  = 0.111, P = 0.027). HbA1c (%) = 5.2 ± 0.39, 5.3 ± 0.50 and 5.4 ± 0.47 (P = NS). Triglyceride MZS = 1.20 ± 1.13, 1.52 ± 1.37 and 1.62 ± 1.42 (RSPEARMAN = 0.116, P = 0.024). Correlations between triglyceride MZS and NWZS were, respectively: r = 0.12 (P = NS), r = 0.42 (P <0.001), and r = 0.47 (P < 0.001)., Conclusions: In overweight and obese GDM mothers, maternal triglycerides are partially responsible for LGA infants despite good maternal glucose control during pregnancy., (Copyright © 2014 The Obesity Society.)

The most studied roles of serotonin (5-hydroxytryptamine, 5HT) have been related to its action in the Central Nervous System (CNS). However, most of 5HT is produced outside the CNS, mainly in the enterochromaffin cells of the gut. Additionally, other tissues such as the endocrine pancreas, particularly β-cells, have its own serotonin system able to synthesize, secrete and respond to extracellular 5HT through cell surface receptors subtypes that have been grouped in 7 families (HTR1-7). Interestingly, 5HT is stored in granules and released together with insulin from β-cells and its biological significance is likely a combination of intra and extracellular actions. The expression of enzymes involved in 5HT synthesis and their receptors varied markedly in β-pancreatic cells during pregnancy, in parallel with an increase in their insulin secretion potential (probably through the action of Htr3a) and an increase in β-cell mass (through the action of Htr2b and Htr1d). In addition, it has been suggested that gut-derived 5HT may promote hepatic gluconeogenesis during prolonged fasting through Htr2b receptor. Taken together, these findings suggest that peripheral 5HT plays an important role in the regulation of glucose homeostasis through the differential expression and activation of 5-HT membrane receptors on the surface of hepatocytes, adipocytes and pancreatic β-cells., (Copyright AULA MEDICA EDICIONES 2014. Published by AULA MEDICA. All rights reserved.)

Nowadays, Diabetic Neuropathy (DN) is considered the most common cause of peripheral neuropathy in clinical practice. It can affect sensitive, motor or autonomic nerve fibers, with symmetric, asymmetric, acute or chronic presentations. Due to this variability, with multiple physiopathologic mechanisms involved, a complex clinical classification has been used until recently. The aim of this review is to present a new classification of diabetic neuropathy, based on its physiopathology. It is divided in metabolic microvascular and hypoxic, autoimmune and inflammatory, compressive, secondary to complications of diabetes and related to treatment. It must be understood that DN is not just a functional disease, but a complication of diabetes with molecular and pathological substrates caused by hyperglycemia. Therefore, normalization of blood glucose is a fundamental step towards the successful prevention and treatment of DN.

Aim: Good glycemic control in gestational diabetes mellitus (GDM) seems not to be enough to prevent macrosomia (large-for-gestational-age newborns). In GDM pregnancies we studied the effects of glycemic control (as glycosylated hemoglobin [HbA1c]), pre-pregnancy body mass index (PP-BMI) and gestational weight gain per week (GWG-W) on the frequency of macrosomia., Methods:   We studied 251 GDM pregnancies, divided into two groups: PP-BMI<25.0kg/m(2) (the non-overweight group; n=125), and PP-BMI≥25.0kg/m(2) (the overweight group; n=126). A newborn weight Z-score>1.28 was considered large-for-gestational-age. Statistical analysis was carried out using the Student's t-test and χ(2) -test, receiver-operator characteristic curves and linear and binary logistic regressions., Results: Prevalence of macrosomia was 14.9% among GDM (n=202/251, 88.4%) with good glycemic control (mean HbA1c<6.0%), and 28.1% in those with mean HbA1c≥6.0% (n=49/251, P<0.025). Macrosomia rates were 10.4% in the non-overweight group and 24.6% in the overweight group (P=0.00308), notwithstanding both having similar mean HbA1c (5.48±0.065 and 5.65±0.079%, P=0.269), and similar GWG-W (0.292±0.017 and 0.240±0.021kg/week, P=0.077). Binary logistic regressions showed that PP-BMI (P=0.012) and mean HbA1c (P=0.048), but not GWG-W (P=0.477), explained macrosomia., Conclusions: Good glycemic control in GDM patients was not enough to reduce macrosomia to acceptable limits (<10% of newborns). PP-BMI and mean HbA1c (but not GWG-W) were significant predictors of macrosomia. Thus, without ceasing in our efforts to improve glycemic control during GDM pregnancies, patients with overweight/obesity need to be treated prior to becoming pregnant., (© 2011 The Authors. Journal of Obstetrics and Gynaecology Research © 2011 Japan Society of Obstetrics and Gynecology.)

Objective: Some patients with the syndrome of mitochondrial diabetes and deafness (MIDD) have a m.3243A>G mutation of the MTTL1 gene encoding transfer ribonucleic acid for the amino acid leucine (tRNALeu(UUR)). One of our MIDD patients inspired us to propose an integrated view on how a single mutation of the mitochondrial deoxyribonucleic acid (DNA) affects both the glucose metabolism and the inner ear physiology., Design: (a) Study of mitochondrial DNA in a patient with MIDD. (b) REVIEW OF THE LITERATURE on the impact of the m.3243A>G mutation on glucose metabolism and on the physiology of the hearing process., Settings: Outpatient diabetes and nutrition department and molecular nutrition laboratory., Methods: (a) Polymerase chain reaction followed by restriction fragment analysis identified the m.3243A>G mutation. (b) REVIEW OF THE LITERATURE from 1994 to 2009., Results: (a) Molecular study: the m.3243A>G mutation was detected with an appreciable level of heteroplasmy. (b), Review of the Literature: the strial marginal cells located near the organ of Corti fulfill two characteristics: they are rich in mitochondria, and their dysfunction may produce neurosensorial deafness by means of a reduction in the potassium ion concentration of the endolymph., Conclusions: The m.3243A>G mutation not only underlies a dysfunction of the insulin-producing beta cell of the pancreas but also results in a reduction in adenosine triphosphate production of the strial marginal cells of the inner ear, thus diminishing the energy (in the form of potassium ion gradient) needed for the outer hair cells of the organ of Corti to amplify the soundwaves, particularly at high frequencies.

Background: It is known that tight control of glucose in the Intensive Care Unit reduces morbidity and mortality not only in diabetic patients but also in those non-diabetics who become transiently hyperglycemic. Taking advantage of a recently marketed subcutaneous glucose sensor we designed an Automatic Insulin Infusion System (AIIS) for inpatient treatment, and tested its stability under simulated clinical conditions., Methods: The system included: reference glucose, glucose sensor, insulin and glucose infusion controllers and emergency infusion logic. We carried out computer simulations using Matlab/Simulink, in both common and worst-case conditions., Results: The system was capable of controlling glucose levels without entering in a phase of catastrophic instability, even under severe simulated challenges. Care was taken to include in all simulations the 5-10 minute delay of the subcutaneous glucose signal when compared to the real-time serum glucose signal, a well-known characteristic of all subcutaneous glucose sensors., Conclusions: When tested in-Silico, a commercially available subcutaneous glucose sensor allowed the stable functioning of a proportional-derivative Automatic Insulin Infusion System, which was able to maintain glucose within acceptable limits when using a well-established glucose response model simulating a patient. Testing of the system in vivo using animal models is now warranted.

Unlabelled: After a 10-year program intending to improve glycemic control in diabetic pregnancies, we evaluated whether factors underlying macrosomia are similar for type-1 and -2 pregestational diabetic women., Patients and Methods: Twenty-three pregnancies in type-1 diabetics (PDM1, age 28.3+/-1.1 years) and 51 pregnancies in type-2 diabetics (PDM2, age 32.8+/-0.6 years) were followed and treated with intensified insulin therapy. Several factors potentially influencing macrosomia were evaluated., Statistics: chi-square, Fisher's exact, Student's "t" and Mann-Whitney "U" tests, and ROC analysis., Results: In PDM1 and PDM2, respectively, large-for-gestational-age (LGA) frequencies were 26.08% and 37.25% (NS), antepartum HbA1c values were 6.5+/-0.32 and 6.1+/-0.16 (NS), and pre-pregnancy body mass indexes (BMI) were 23.03+/-0.66 and 30.01+/-0.89 (p<0.0001). In PDM1 the main predictor of LGA was an antepartum HbA1c> or =6.8% (p=0.046), whereas in PDM2 pregestational BMI> or =24 the variable associated (p=0.032) with LGA newborns., Conclusions: PDM1 and PDM2 differ in the underlying factors related to macrosomia. Whereas in PDM1 the antepartum HbA1c emerged as the most significant variable, suggesting that glycemic control largely determines macrosomia, in PDM2 with near-optimal glycemic control, macrosomia related to pregestational BMI.

Syrian Golden hamsters develop more severe emphysema than Sprague-Dawley rats after intratracheal instillation of the same dose of elastase/body weight. Although species variations in antielastase defenses may largely explain these results, other variables, such as differences in lung antioxidants, cannot be overlooked since oxidative stress modulates antiprotease activity. We propose that elastase instillation might affect lung glutathione (GSH) metabolism differently in these species. Our aim was to study in hamsters and rats, lung glutathione metabolism at different times, from the stage of diffuse alveolar damage to advanced emphysema. We measured total and oxidized glutathione content as well as activity and expression of enzymes related to GSH synthesis and redox cycling: gamma-glutamylcysteine synthetase, glutathione peroxidase, and glutathione reductase. Whereas rats showed no significant changes in these measurements, hamsters showed significant derangement in GSH metabolism early after elastase instillation: 25% fall in total GSH (P < 0.05) with no increase in oxidized glutathione associated with reduced enzyme activities 24 h after elastase [60% for gamma-glutamylcysteine synthetase (P < 0.01), 30% for glutathione peroxidase (P < 0.01), and 75% for glutathione reductase (P < 0.001)]. GSH homeostasis was restored at the end of the first week, involving transient increased expression of these enzymes. We conclude that elastase induces significant alterations in GSH metabolism of hamster lungs and no overall change in rat lungs. Although differences in disease severity may account for our findings, the hamster becomes vulnerable to functional inhibition of alpha(1)-antitrypsin by oxidants and thus, even more susceptible to injury than it would be, considering only its low alpha(1)-antitrypsin level.

Multiple endocrine neoplasia type 1 (MEN 1) is a syndrome characterized by tumors of the parathyroid glands, pancreatic islet cells, duodenum, and pituitary gland. We report a case of cervical metastases of glucagonoma with MEN 1. The patient was a 34-year-old woman admitted to our hospital with epigastric pain. Her medical history included two resections of prolactinoma and two upper GI hemorrhages secondary to duodenal ulcers. Computed tomography (CT) showed two hypervascular lesions in the tail of the pancreas and cervical ultrasound showed multiple hypoechogenic ovoid images in the neck. A cervical CT scan confirmed two 15-mm lymph nodes in the left cervical region and 111In-DOTATOC imaging showed focal abnormal somatostatin expression in the pancreatic tail and the cervical nodes. The patient had asymptomatic hypoglycemic episodes, with blood sugar levels as low as 30 mg/dl, which raised our suspicion of MEN 1 associated with pancreatic insulinoma. Thus, we performed a distal pancreatectomy with bilateral cervical dissection and parathyroid gland resection. Histopathological examination revealed 12 pancreatic tumors as well as metastases in four cervical lymph nodes. The resected parathyroid glands had normal structure, suggesting parathyroid hyperplasia. A follow-up CT scan, 18 months after surgery, showed new tumors in the head of the pancreas and in the duodenal wall. A pancreatoduodenectomy was performed and histopathological examination revealed nine nonfunctioning endocrine tumors in the pancreas, one tumor in the duodenal wall, and metastases in two peripancreatic lymph nodes. The patient recovered well and remains asymptomatic.

Background: After a study of ICA prevalence among relatives of Type-1 diabetics (DM1) in Santiago, Chile, parents of those who tested positive asked us to go on forward with an intervention study., Methods: We had screened 1021 relatives, of which 30 had shown ICA > or = 20 JDF units (2.9%). Among the 26/30 who participated in the intervention study, the baseline screening showed normal glucose tolerance in all, and the first-phase insulin response (FPIR) was normal in 24/26 individuals, which were randomized into Nicotinamide (n = 12; oral Nicotinamide, 1200 mg m(-2) day(-1)) and Placebo (n = 12) groups. The FPIRs and ICAs were monitored yearly. Compliance was monitored by urine Nicotinamide., Results: The 1.5, 3.0 and 5-year life-table estimates of keeping the FPIR > or = 10th centile were, for Nicotinamide group 100% in all time points, and for Placebo these were 90.0% (c.i. = 100-71.4), 72.0% (c.i. = 100-37.1) and 0.0% (c.i. = 0.0-0.0) (p = 0.0091). The 5-year life-table estimates of remaining diabetes-free were 100% for Nicotinamide and 62.5% for Placebo (p = 0.0483). No adverse effects were observed., Conclusions: Oral Nicotinamide protected beta-cell function and prevented clinical disease in ICA-positive first-degree relatives of type-1 diabetes.

The objective was to evaluate the Semmes-Weinstein monofilament as a potential predictor of foot ulceration. A case-control study was carried out in a teaching hospital clinic specializing in diabetes and hyperlipidemic disorders. Two groups of patients with noninsulin-dependent diabetes mellitus were studied: 168 with no history of foot lesions (No-Ulcer group, aged 58.1 +/- 9.7 years, duration 11.5 +/- 7.8 years) and 14 who had at least one foot ulceration during the last year (foot ulcer group, aged 60.8 +/- 7.8 years', duration 17.1 +/- 10.5 years). The authors defined and measured a "monofilament index" using a size 5.07 Semmes-Weinstein monofilament on three locations on each foot and then measured peroneal nerve current perception thresholds using the Neurometer at three frequencies: 5 Hz, 250 Hz, and 2,000 Hz. The monofilament index score was lower in patients in the foot ulcer group than in patients in the No-Ulcer group (1.71 +/- 2.36 vs 5.21 +/- 1.81, P < 0.001). A cutoff point at an index of 5 out of 6 yielded a sensitivity rate of 85.71% and a false-positive rate of 16.07%. The peroneal nerve current perception threshold was higher (P < 0.005) in patients in the foot ulcer group than in patients in the No-Ulcer group for all frequencies (605.8 +/- 414.6 vs 181.5 +/- 272.3 for 5 Hz; 743.2 +/- 361.7 vs 251.6 +/- 283.7 for 250 Hz; 859.4 +/- 220.2 vs 423.3 +/- 252.6 for 2,000 Hz). (ABSTRACT TRUNCATED AT 250 WORDS)

We present an unusual patient with a medical history of a fibrosing pseudotumor of the left orbit that had been stable for 8 years who presented with acute anterior hypophyseal failure. During the next 10-month period, sequential magnetic resonance scans showed a rapid growth of a plaque-like sellar and parasellar mass extending into the right cavernous sinus, right Meckel's cave, along the dural surfaces of the clivus, dens, and body of the second cervical vertebra. A transsphenoidal biopsy revealed sphenoid and intrasellar pseudotumor that invaded the adenohypophysis and had microscopic features identical to those of the previously excised orbital pseudotumor. Rapid growth of the pseudotumor continued despite a course of radiotherapy. Palsies of cranial nerves V and VI and of the sensory root of the cranial nerve VII developed on the right side. Steroid therapy was associated with improvement of the cranial nerve palsies. This is the first report of the sellar fibrosing pseudotumor producing not only anterior hypophyseal failure, but also cranial nerve dysfunction secondary to plaque-like extension into the cavernous sinus, Meckel's cave, and cranial base dura. This intracranial plaque-like extension of a fibrous pseudotumor corresponds to a hypertrophic intracranial pachymeningitis, which is a rare, previously described phenomenon associated to the syndrome of multifocal fibrosclerosis.