Few data are available on the association between serum lipids and insulin secretion (ISEC) in children. We evaluated the association of triglycerides (TG), HDL cholesterol (HDL-C) and LDL cholesterol (LDL-C) with ISEC in 1150 non-diabetic obese children and adolescents using multivariable robust median regression. The following models were employed: (1) IGI or incAUCR as the ISEC response variable; (2) QUICKI, OGIS, the Stumvoll index or the Matsuda insulin sensitivity index as the insulin sensitivity (ISEN) predictor; (3) TG, HDL-C and LDL-C as the predictors of interest; (4) 120-min glucose, age, sex and body mass index as confounders. LDL-C and TG were not associated with ISEC in any model. In three out of four IGI models, an increase of 1 interquartile range (IQR) of HDL-C was associated with a decrease of median incAUCR ranging from −9 (robust 95% CI −17 to −2) to −8 (−14 to −1) pmol/mmol. In two out of four incAUCR models, an increase of 1 IQR of HDL-C was associated with a decrease of median IGI ranging from −8 (−15 to −1) to −7 (−11 to −2) pmol/mmol. TG and LDL-C are not associated and HDL-C is inversely associated with ISEC in obese children and adolescents.
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Giorgio Bedogni, Andrea Mari, Alessandra De Col, Sofia Tamini, Amalia Gastaldelli and Alessandro Sartorio
Amalie R Lanng, Lærke S Gasbjerg, Natasha C Bergmann, Sigrid Bergmann, Mads M Helsted, Matthew P Gillum, Bolette Hartmann, Jens J Holst, Tina Vilsbøll and Filip K Knop
Ingestion of the calorically dense compound alcohol may cause metabolic disturbances including hypoglycaemia, hepatic steatosis and insulin resistance, but the underlying mechanisms are uncertain. The gastrointestinal tract is well recognised as a major influencer on glucose, protein and lipid metabolism, but its role in alcohol metabolism remains unclear.
To examine the effects of oral and intravenous alcohol, respectively, on plasma concentrations of several gluco-regulatory hormones including serum/plasma insulin, C-peptide, glucagon, glucose-dependent insulinotropic polypeptide (GIP), glucagon-like peptide 1 (GLP-1) and fibroblast growth factor 21 (FGF21).
Design and methods
In a double-blinded, randomised, crossover design, we subjected 12 healthy men to intragastric ethanol infusion (IGEI) and an isoethanolaemic intravenous ethanol infusion (IVEI) (0.7 g alcohol per kg body weight), respectively, on two separate experimental days.
Isoethanolaemia during the two alcohol administration forms was obtained (P = 0.38). During both interventions, plasma glucose peaked after ~30 min and thereafter fell below baseline concentrations. GIP and GLP-1 concentrations were unaffected by the two interventions. Insulin concentrations were unaffected by IGEI but decreased during IVEI. C-peptide, insulin secretion rate and glucagon concentrations were lowered similarly during IGEI and IVEI. FGF21 concentrations increased dramatically (nine-fold) and similarly during IGEI and IVEI.
Alcohol does not seem to affect the secretion of incretin hormones but decreased insulin and glucagon secretion independently of gut-derived factors. IGEI as well as IVEI potently stimulate FGF21 secretion indicating a gut-independent effect of alcohol on FGF21 secretion in humans.
Patricia Iozzo and Maria Angela Guzzardi
The prevalence of obesity has reached epidemic proportions and keeps growing. Obesity seems implicated in the pathogenesis of cognitive dysfunction, Alzheimer’s disease and dementia, and vice versa. Growing scientific efforts are being devoted to the identification of central mechanisms underlying the frequent association between obesity and cognitive dysfunction. Glucose brain handling undergoes dynamic changes during the life-course, suggesting that its alterations might precede and contribute to degenerative changes or signaling abnormalities. Imaging of the glucose analogue 18F-labelled fluorodeoxyglucose (18FDG) by positron emission tomography (PET) is the gold-standard for the assessment of cerebral glucose metabolism in vivo. This review summarizes the current literature addressing brain glucose uptake measured by PET imaging, and the effect of insulin on brain metabolism, trying to embrace a life-course vision in the identification of patterns that may explain (and contribute to) the frequent association between obesity and cognitive dysfunction. The current evidence supports that brain hypermetabolism and brain insulin resistance occur in selected high-risk conditions as a transient phenomenon, eventually evolving towards normal or low values during life or disease progression. Associative studies suggest that brain hypermetabolism predicts low BDNF levels, hepatic and whole body insulin resistance, food desire and an unfavorable balance between anticipated reward from food and cognitive inhibitory control. Emerging mechanistic links involve the microbiota and the metabolome, which correlate with brain metabolism and cognition, deserving attention as potential future prevention targets.
Kaisu Luiro, Kristiina Aittomäki, Pekka Jousilahti and Juha S Tapanainen
To study the use of hormone therapy (HT), morbidity and reproductive outcomes of women with primary ovarian insufficiency (POI) due to FSH-resistant ovaries (FSHRO).
A prospective follow-up study in a university-based tertiary clinic setting.
Twenty-six women with an inactivating A189V FSH receptor mutation were investigated by means of a health questionnaire and clinical examination. Twenty-two returned the health questionnaire and 14 were clinically examined. Main outcome measures in the health questionnaire were reported as HT, morbidity, medication and infertility treatment outcomes. In the clinical study, risk factors for cardiovascular disease (CVD) and metabolic syndrome (MetS) were compared to age-matched controls from a national population survey (FINRISK). Average number of controls was 326 per FSHRO subject (range 178–430). Bone mineral density and whole-body composition were analyzed with DXA. Psychological and sexual well-being was assessed with Beck Depression Inventory (BDI21), Generalized Anxiety Disorder 7 (GAD-7) and Female Sexual Function Index (FSFI) questionnaires.
HT was initiated late (median 18 years of age) compared with normal puberty and the median time of use was shorter (20–22 years) than the normal fertile period. Osteopenia was detected in 9/14 of the FSHRO women despite HT. No major risk factors for CVD or diabetes were found.
HT of 20 years seems to be associated with a similar cardiovascular and metabolic risk factor profile as in the population control group. However, optimal bone health may require an early-onset and longer period of HT, which would better correspond to the natural fertile period.
Lian Hollander-Cohen, Benjamin Bohm, Krist Hausken and Berta Levavi-Sivan
The pituitary gonadotropins, luteinizing hormone (LH) and follicle stimulating hormone (FSH), are the principle endocrine drivers of reproductive processes in the gonads of jawed vertebrates. Canonically, FSH recruits and maintains selected ovarian follicles for maturation and LH induces the stages of germinal vesicle breakdown and ovulation. In mammals, LH and FSH specifically activate cognate G-protein coupled receptors that affect the proteins involved in steroidogenesis, protein hormone synthesis, and gametogenesis. This dual-gonadotropin model also exists in some fish species, but not in all. In fact, due to their diverse number of species, extended number of ecological niches, and remarkably flexible reproductive strategies, fish are appropriate as models to understand the co-evolution of gonadotropins and their receptors. In this study, we cloned and characterized the expression profile over the final stages of ovarian maturation of carp (Cyprinus carpio) LHCGR and FSHR. Expression of both gonadotropin receptors increased in the later stage of early vitellogenesis, suggesting that both LH and FSH play a role in the development of mature follicles. We additionally tested the activation of cLHCGR and cFSHR using homologous and heterologous recombinant gonadotropins in order to gain insight into an evolutionary model of permissive gonadotropin receptor function. These data suggest that carp (Cyprinus carpio) gonad development and maturation depends on a specific gonadotropin profile that does not reflect the temporally distinct dual-gonadotropin model observed in salmonids or mammals, and that permissive gonadotropin receptor activation is a specific feature of Ostariophysii, not all teleosts.
Hélène Lasolle, Amandine Ferriere, Alexandre Vasiljevic, Sandrine Eimer, Marie-Laure Nunes and Antoine Tabarin
Little data are available regarding the safety and efficacy of switching to Pasireotide-LAR monotherapy in acromegaly patients with partial resistance to first-generation somatostatin agonists (1gSRL) who require combination treatment with cabergoline or pegvisomant.
In this monocentric prospective study within a tertiary university hospital, 15 consecutive acromegalic adults partially resistant to 1gSRL treated with octreotide LAR or lanreotide SR, and cabergoline (n = 4, 3.5 mg/week) or pegvisomant (n = 11, median dose 100 mg/week), were switched to Pasireotide-LAR (8 with 40 mg/month; 7 with 60 mg/month). Immunohistochemical expression level of SSTR5 and the granulation pattern of nine somatotroph adenomas were retrospectively determined to test for a correlation with the therapeutic efficacy of Pasireotide-LAR.
Median IGF-1 concentration at the first evaluation (median 3 months) was similar to baseline (1.0 vs 1.1 ULN). 11/15 patients had IGF-1 levels ≤1.3 ULN before and after the switch but individual changes were variable. Hyperglycemia was frequent and greater in diabetic patients. 7/15 patients stopped Pasireotide-LAR due to lack of control of IGF-1 or intolerance. 8/15 patients received Pasireotide-LAR for a median of 29 months with IGF-1 levels ≤1.3 ULN and acceptable glucose tolerance (median HbA1c 6.1%). Two patients required initiation of oral antidiabetic treatment. The intensity of SSTR5 expression and the granulation pattern of adenomas were of limited value for the prediction of Pasireotide-LAR effectiveness.
Pasireotide-LAR may represent a suitable therapeutic alternative in a subset of acromegalic patients requiring combination therapy involving a 1gSRL
Cornelia Then, Holger Then, Andreas Lechner, Cornelia Huth, Christa Meisinger, Margit Heier, Annette Peters, Wolfgang Koenig, Wolfgang Rathmann, Christian Herder, Michael Roden, Jürgen Scherberich and Jochen Seissler
Metabolic syndrome and obesity are risk factors for chronic kidney disease. However, early kidney alterations may escape diagnosis in these conditions due to glomerular hyperfiltration. Uromodulin, a glycoprotein exclusively synthesized in tubular cells of the thick ascending limb of Henle's loop, is a novel tissue-specific biomarker for kidney function. In contrast to the commonly used markers creatinine and cystatin C, serum uromodulin does not primarily depend on glomerular filtration. We hypothesized that serum uromodulin is a marker for metabolic syndrome and related components.
The analyses included 1088 participants of the population-based KORA F4 study aged 62–81 years. Metabolic syndrome was present in 554 participants. After a mean follow-up time of 6.5 years, 621 participants were reevaluated, of which 92 had developed incident metabolic syndrome.
The association of serum uromodulin with metabolic syndrome and its components were assessed using multivariable logistic regression models.
Serum uromodulin was inversely associated with metabolic syndrome after adjustment for sex, age, estimated glomerular filtration rate, physical activity, smoking, alcohol consumption and high-sensitivity C-reactive protein (OR 0.65; 95% CI 0.56–0.76 per standard deviation uromodulin; P < 0.001). Serum uromodulin was inversely associated with all single components of metabolic syndrome. However, serum uromodulin was not associated with new-onset metabolic syndrome after the follow-up period of 6.5 ± 0.3 years (OR 1.18; 95% CI 0.86–1.60).
Serum uromodulin is independently associated with prevalent, but not with incident metabolic syndrome. Low serum uromodulin may indicate a decreased renal reserve in the metabolic syndrome.
Stephen A Martin, Kenneth Philbrick, Carmen P Wong, Dawn A Olson, Adam J Branscum, Donald Jump, Charles Marik, Jonathan DenHerder, Jennifer Sargent, Russell T Turner and Urszula T Iwaniec
Mice are a commonly-used model to investigate aging-related bone loss but, in contrast to humans, mice exhibit cancellous bone loss prior to skeletal maturity. The mechanisms mediating premature bone loss are not well established. However, our previous work in female mice suggests housing temperature is a critical factor. Premature cancellous bone loss was prevented in female C57BL/6J mice by housing the animals at thermoneutral temperature (where basal rate of energy production is at equilibrium with heat loss). In the present study, we determined if the protective effects of thermoneutral housing extend to males. Male C57BL/6J mice were housed at standard room temperature (22°C) or thermoneutral (32°C) from 5 (rapidly growing) to 16 (slowly growing) weeks of age. Mice housed at room temperature exhibited reductions in cancellous bone volume fraction in distal femur metaphysis and 5th lumbar vertebra; these effects were abolished at thermoneutral conditions. Mice housed at thermoneutral temperature had higher levels of bone formation in distal femur (based on histomorphometry) and globally (serum osteocalcin), and lower global levels of bone resorption (serum C-terminal telopeptide of type I collagen) compared to mice housed at room temperature. Thermoneutral housing had no impact on bone marrow adiposity but resulted in higher abdominal white adipose tissue and serum leptin. The overall magnitude of room temperature housing-induced cancellous bone loss did not differ between male (current study) and female (published data) mice. These findings highlight housing temperature as a critical experimental variable in studies using mice of either sex to investigate aging-related changes in bone metabolism.
Ravikumar Shah, Anurag R Lila, Ramteke-Swati Jadhav, Virendra Patil, Abhishek Mahajan, Sushil Sonawane, Puja Thadani, Anil Dcruz, Prathamesh Pai, Munita Bal, Subhada Kane, Nalini Shah and Tushar Bandgar
Tumor-induced osteomalacia in the head and neck region remains a challenging diagnosis to manage. Literature pertaining to management and outcome details remains sparse. We describe two cohorts: cohort 1 included seven patients from a single center in Western India with tumors located in paranasal sinuses (n = 3), intracranial (n = 2) and maxilla (n = 2). The unique features from our series is the management of persistent disease with radiation therapy (n = 2) and peptide receptor radionuclide therapy (PRRT) (n = 1). Cohort two has 163 patients identified from 109 publications for systematic review. Paranasal sinuses, mandible, intracranial disease, maxilla and oral cavity, in descending order, are reportedly common tumor sites. Within this cohort, mean age was 46 ± 14 years at presentation with 44.1% having local symptoms. Duration of symptoms varied from 1 to 240 months. Pre-surgery mean serum phosphorus was 1.4 ± 0.4 mg/dL and median FGF-23 levels were 3.6 (IQR:1.8–6.8) times of normal upper limit of normal. Majority (97.5%) were managed primarily with surgical excision; however, primary radiotherapy (n = 2) and surgery combined with radiotherapy (n = 2) were also reported. Twenty patients had persistent disease while nine patients had recurrence, more commonly noted with intracranial and oral cavity tumors. Surgery was the most common second mode of treatment employed succeeded by radiotherapy. Four patients had metastatic disease. The most common histopathological diagnosis reported is PMT mixed connective tissue, while the newer terminology ‘PMT mixed epithelial and connective tissue type’ has been described in 15 patients.
Mauricio Alvarez, Oswaldo Rincón Sierra, Ginna Saavedra and Sergio Moreno
Vitamin B12 deficiency resulting from metformin use has been demonstrated in multiple studies. In this study, we aimed to evaluate the prevalence of vitamin B12 deficiency in patients with chronic metformin use and the relationship between vitamin B12 deficiency and diabetic neuropathy.
A cross-sectional study was conducted with 162 patients. Vitamin B12 levels were measured by chemiluminescence immunoassay. Diabetic neuropathy was evaluated by patient record, nerve conduction and Michigan test for the diagnosis of diabetic neuropathy. Additional data, including demographic characteristics were collected. A linear regression model was used to evaluate variables that correlated with vitamin B12 levels and diabetic neuropathy.
Low vitamin B12 levels were found in 7.3% (95% CI: 4.0–12%) of patients. In those with diabetic neuropathy, altered (low and borderline) vitamin B12 level was 64% (95% CI: 47–78%) compared to 17% (95% CI: 10–26%) in patients without diabetic neuropathy (coefficient: −110.8; CI 95%: −165.8, −59.7). Those taking a higher metformin dose had lower levels of vitamin B12 (coefficient: −0.061; CI 95%: −0.09, −0.024). In addition, female patients had higher levels of vitamin B12 compared to men (coefficient: 49.1; CI 95%: 2.3–95).
Vitamin B12 deficiency is highly prevalent, especially in patients with diabetic neuropathy. In this study an inverse correlation was found between diabetic neuropathy and the plasma level of vitamin B12. Higher doses of metformin and male sex were factors related to lower levels of vitamin B12.