Consensus statement from 2nd International Conference on Controversies in Vitamin D.

The 2nd International Conference on Controversies in Vitamin D was held in Monteriggioni (Siena), Italy, September 11-14, 2018. The aim of this meeting was to address ongoing controversies and timely topics in vitamin D research, to review available data related to these topics and controversies, to promote discussion to help resolve lingering issues and ultimately to suggest a research agenda to clarify areas of uncertainty. Several issues from the first conference, held in 2017, were revisited, such as assays used to determine serum 25-hydroxyvitamin D [25(OH)D] concentration, which remains a critical and controversial issue for defining vitamin D status. Definitions of vitamin D nutritional status (i.e. sufficiency, insufficiency and deficiency) were also revisited. New areas were reviewed, including vitamin D threshold values and how they should be defined in the context of specific diseases, sources of vitamin D and risk factors associated with vitamin D deficiency. Non-skeletal aspects related to vitamin D were also discussed, including the reproductive system, neurology, chronic kidney disease and falls. The therapeutic role of vitamin D and findings from recent clinical trials were also addressed. The topics were considered by 3 focus groups and divided into three main areas: 1) "Laboratory": assays and threshold values to define vitamin D status; 2) "Clinical": sources of vitamin D and risk factors and role of vitamin D in non-skeletal disease and 3) "Therapeutics": controversial issues on observational studies and recent randomized controlled trials. In this report, we present a summary of our findings.

Invited Review: Pathology of pituitary neuroendocrine tumours: present status, modern diagnostic approach, controversies and future perspectives from a neuropathological and clinical standpoint.

Neuroendocrine tumours of the adenohypophysis have traditionally been designated as pituitary adenomas to underline their usually indolent growth and lack of metastatic potential. However, they may demonstrate a huge spectrum of growth patterns and endocrine disturbances, some of them significantly affecting health and quality of life. To predict tumour growth, risk of postoperative recurrence and response to medical therapy in patients with pituitary neuroendocrine tumours is challenging. A thorough histopathological and immunohistochemical diagnostic work-up is an obligatory part of a multidisciplinary effort to precisely define the tumour type and assess prognostic and predictive factors on an individual basis. In this review, we have summarized the current status in the pathology in pituitary neuroendocrine tumours based on the selection of references from the PubMed database. We have presented possible diagnostic approaches according to the current pituitary cell lineage-based classification. The importance of recognizing histological subtypes with potentially aggressive behaviour and identification of prognostic and predictive tissue biomarkers have been highlighted. Controversies related to particular subtypes of pituitary tumours and a still limited prognostic impact of the current classification indicate the need for further refinement. Multidisciplinary approach including clinical, pathological and molecular genetic characterization will be essential for improved personalized therapy and the search for novel therapeutic targets in patients with pituitary neuroendocrine tumours.

The role of delayed bone age in the evaluation of stature and bone health in glucocorticoid treated patients with Duchenne muscular dystrophy.

BACKGROUND: Low bone mineral density and an increased risk of appendicular and vertebral fractures are well-established consequences of Duchenne muscular dystrophy (DMD) and the risk of fractures is exacerbated by long-term glucocorticoid treatment. Monitoring of endocrine and skeletal health and timely intervention in at-risk patients is important in the management of children with DMD. METHODS: As part of the Norwegian Duchenne muscular dystrophy cohort study, we examined the skeletal maturation of 62 boys less than 18 years old, both currently glucocorticoid treated (n = 44), previously treated (n = 6) and naïve (n = 12). The relationship between bone age, height and bone mineral density (BMD) Z-scores was explored. RESULTS: The participants in the glucocorticoid treated group were short in stature and puberty was delayed. Bone age was significantly delayed, and the delay increased with age and duration of treatment. The difference in height between glucocorticoid treated and naïve boys was no longer significant when height was corrected for delayed skeletal maturation. Mean BMD Z-scores fell below - 2 before 12 years of age in the glucocorticoid treated group, with scores significantly correlated with age, duration of treatment and pubertal development. When BMD Z-scores were corrected for by retarded bone age, the increase in BMD Z-scores was significant for all age groups. CONCLUSION: Our results suggest that skeletal maturation should be assessed in the evaluation of short stature and bone health in GC treated boys with DMD, as failing to consider delayed bone age leads to underestimation of BMD Z-scores and potentially overestimation of fracture risk.

Is there a need for an emergency card in hypoparathyroidism?

BACKGROUND: Patients with hypoparathyroidism are at risk of both hypocalcemic and hypercalcemic crisis. Patients report that health professionals do not always respond adequately in an acute situation. The extent and handling of severe hypo- and hypercalcemia in hypoparathyroidism is unknown. AIMS: To outline the need for a medical emergency card for primary hypoparathyroidism. METHOD: Postal survey amongst Norwegian and Swedish patients with chronic hypoparathyroidism of all causes. Altogether 455 invitations were sent (333 from Norway and 122 from Sweden). RESULTS: Three hundred and thirty-six of 455 (74%) patients responded (253 from Norway and 83 from Sweden). The majority were women (79%), and the main cause was postsurgical hypoparathyroidism (66%). Overall 44% and 16% had been hospitalized at least once for hypo- or hypercalcemia, respectively. Eighty-seven per cent felt that an emergency card would be highly needed or useful. Amongst those hospitalized for hypocalcemia, 95% felt a card was needed compared to 90% amongst those hospitalized for hypercalcemia. Five per cent believed that a card would not be useful. CONCLUSIONS: The majority answered that an acute card is highly needed or useful. Hospitalization for acute hypocalcemia was more common (44%) than for acute hypercalcemia (16%). As a result of this survey, an emergency card will be distributed in three European countries to test its utility.

Primary hyperparathyroidism: review and recommendations on evaluation, diagnosis, and management. A Canadian and international consensus.

The purpose of this review is to assess the most recent evidence in the management of primary hyperparathyroidism (PHPT) and provide updated recommendations for its evaluation, diagnosis and treatment. A Medline search of "Hyperparathyroidism. Primary" was conducted and the literature with the highest levels of evidence were reviewed and used to formulate recommendations. PHPT is a common endocrine disorder usually discovered by routine biochemical screening. PHPT is defined as hypercalcemia with increased or inappropriately normal plasma parathyroid hormone (PTH). It is most commonly seen after the age of 50 years, with women predominating by three to fourfold. In countries with routine multichannel screening, PHPT is identified earlier and may be asymptomatic. Where biochemical testing is not routine, PHPT is more likely to present with skeletal complications, or nephrolithiasis. Parathyroidectomy (PTx) is indicated for those with symptomatic disease. For asymptomatic patients, recent guidelines have recommended criteria for surgery, however PTx can also be considered in those who do not meet criteria, and prefer surgery. Non-surgical therapies are available when surgery is not appropriate. This review presents the current state of the art in the diagnosis and management of PHPT and updates the Canadian Position paper on PHPT. An overview of the impact of PHPT on the skeleton and other target organs is presented with international consensus. Differences in the international presentation of this condition are also summarized.

Preoperative octreotide therapy and surgery in acromegaly: associations between glucose homeostasis and treatment response.

In acromegaly, high GH/IGF-1 levels associate with abnormal glucose metabolism. Somatostatin analogs (SSAs) reduce GH and IGF-1 but inhibit insulin secretion. We studied glucose homeostasis in de novo patients with acromegaly and changes in glucose metabolism after treatment with SSA and surgery. In this post hoc analysis from a randomized controlled trial, 55 de novo patients with acromegaly, not using antidiabetic medication, were included. Before surgery, 26 patients received SSAs for 6 months. HbA1c, fasting glucose, and oral glucose tolerance test were performed at baseline, after SSA pretreatment and at 3 months postoperative. Area under curve of glucose (AUC-G) was calculated. Glucose homeostasis was compared to baseline levels of GH and IGF-1, change after SSA pretreatment, and remission both after SSA pretreatment and 3 months postoperative. In de novo patients, IGF-1/GH levels did not associate with baseline glucose parameters. After SSA pretreatment, changes in GH/IGF-1 correlated positively to change in HbA1c levels (both p < 0.03). HbA1c, fasting glucose, and AUC-G increased significantly during SSA pretreatment in patients not achieving hormonal control (all p < 0.05) but did not change significantly in patients with normalized hormone levels. At 3 months postoperative, HbA1c, fasting glucose, and AUC-G were significantly reduced in both cured and not cured patients (all p < 0.05). To conclude, in de novo patients with acromegaly, disease activity did not correlate with glucose homeostasis. Surgical treatment of acromegaly improved glucose metabolism in both cured and not cured patients, while SSA pretreatment led to deterioration in glucose homeostasis in patients not achieving biochemical control.

European Society of Endocrinology: European Society of Endocrinology Clinical Guideline: treatment of chronic hypoparathyroidism in adults

Hypoparathyroidism (HypoPT) is a rare (orphan) endocrine disease with low calcium and inappropriately low (insufficient) circulating parathyroid hormone levels, most often in adults secondary to thyroid surgery. Standard treatment is activated vitamin D analogues and calcium supplementation and not replacement of the lacking hormone, as in other hormonal deficiency states. The purpose of this guideline is to provide clinicians with guidance on the treatment and monitoring of chronic HypoPT in adults who do not have end-stage renal disease. We intend to draft a practical guideline, focusing on operationalized recommendations deemed to be useful in the daily management of patients. This guideline was developed and solely sponsored by The European Society of Endocrinology, supported by CBO (Dutch Institute for Health Care Improvement) and based on the Grading of Recommendations Assessment, Development and Evaluation (GRADE) principles as a methodological base. The clinical question on which the systematic literature search was based and for which available evidence was synthesized was: what is the best treatment for adult patients with chronic HypoPT? This systematic search found 1100 articles, which was reduced to 312 based on title and abstract. The working group assessed these for eligibility in more detail, and 32 full-text articles were assessed. For the final recommendations, other literature was also taken into account. Little evidence is available on how best to treat HypoPT. Data on quality of life and the risk of complications have just started to emerge, and clinical trials on how to optimize therapy are essentially non-existent. Most studies are of limited sample size, hampering firm conclusions. No studies are available relating target calcium levels with clinically relevant endpoints. Hence it is not possible to formulate recommendations based on strict evidence. This guideline is therefore mainly based on how patients are managed in clinical practice, as reported in small case series and based on the experiences of the authors.(AU)

Preoperative octreotide treatment of acromegaly: long-term results of a randomised controlled trial.

OBJECTIVE: Randomised studies have demonstrated a beneficial effect of pre-surgical treatment with somatostatin analogues (SSA) in acromegaly when evaluated early postoperatively. The objective of this study was to evaluate the long-term surgical cure rates. METHODS: Newly diagnosed patients were randomised to direct surgery (n=30) or 6-month pretreatment with octreotide LAR (n=32). The patients were evaluated 1 and 5 years postoperatively. Cure was defined as normal IGF1 levels and by normal IGF1 level combined with nadir GH <2 mU/l in an oral glucose tolerance test, all without additional post-operative treatment. A meta-analysis using the other published randomised study with long-term analyses on preoperative SSA treatment was performed. RESULTS: The proportion of patients receiving post-operative acromegaly treatment was equal in the two groups. When using the combined criteria for cure, 10/26 (38%) macroadenomas were cured in the pretreatment group compared with 6/25 (24%) in the direct surgery group 1 year postoperatively (P=0.27), and 9/22 (41%) vs 6/22 (27%) macroadenomas, respectively, 5 years postoperatively (P=0.34). In the meta-analysis, 16/45 (36%) macroadenomas were cured using combined criteria in the pretreatment group vs 8/45 (18%) in the direct surgery group after 6-12 months (P=0.06), and 15/41 (37%) vs 8/42 (19%), respectively, in the long-term (P=0.08). CONCLUSION: This study does not prove a beneficial effect of SSA pre-surgical treatment, but in the meta-analysis a trend towards significance can be claimed. A potential favourable, clinically relevant response cannot be excluded.

Celiac disease and risk of fracture in adults--a review.

Patients with celiac disease (CD) have low bone mineral density. Evidence of increased fracture risk in these patients is conflicting, and the indication for bone mineral density screening of all adult CD patients is debated. Our aim was to review current published data on fractures in CD. Cross-sectional cohort studies and one case study were identified by searching Medline and Embase. Although the identified studies are heterogeneous and difficult to compare, the overall findings indicate a positive association between CD and risk of fracture. Adult patients with CD should be considered for bone densitometry in order to estimate fracture risk.

Two years of growth hormone treatment in adults with Prader-Willi syndrome do not improve the low BMD.

BACKGROUND: Bone mineral density (BMD) in adult patients with Prader-Willi syndrome (PWS) might be low due to high bone turnover. OBJECTIVES: The objective of the study was to investigate bone mass in a group of adult PWS subjects and study the effects of GH treatment on BMD and markers of bone turnover. DESIGN: Forty-six adults with genetically verified PWS were randomized to GH or placebo for 12 months, followed by open prospective GH for 24 additional months. BMD at the lumbar spine (LS) L1-4, the total hip, and the total body was assessed by dual-energy x-ray absorptiometry at baseline and every 12th month thereafter. Markers of bone turnover were measured at baseline and at the end of the controlled study. RESULTS: In this cohort of adult subjects with PWS, baseline BMD was reduced in all compartments compared with the reference (Z-scores). Men had lower Z-scores BMD than women in LS and total body (P < .05). With 12 months of GH, LS-BMD was significantly reduced compared with placebo. No changes in BMD were observed with continuous GH treatment for 24 months. The bone formation markers increased with GH therapy compared with placebo, whereas the resorption marker did not change. CONCLUSIONS: Adult PWS subjects, especially the men, have low bone mass that was not improved with GH treatment for 2 years. Because PWS subjects are short, BMD might be underestimated and should be adjusted for. Further studies, with adequate GH and sex hormone replacement throughout puberty and early adult life, are needed to better characterize PWS.

A 1-year randomized, double-blind, placebo-controlled study of intravenous ibandronate on bone loss following renal transplantation.

The clinical profile of ibandronate as add-on to calcitriol and calcium was studied in this double-blind, placebo-controlled trial of 129 renal transplant recipients with early stable renal function (≤ 28 days posttransplantation, GFR ≥ 30 mL/min). Patients were randomized to receive i.v. ibandronate 3 mg or i.v. placebo every 3 months for 12 months on top of oral calcitriol 0.25 mcg/day and calcium 500 mg b.i.d. At baseline, 10 weeks and 12 months bone mineral density (BMD) and biochemical markers of bone turnover were measured. The primary endpoint, relative change in BMD for the lumbar spine from baseline to 12 months was not different, +1.5% for ibandronate versus +0.5% for placebo (p = 0.28). Ibandronate demonstrated a significant improvement of BMD in total femur, +1.3% versus -0.5% (p = 0.01) and in the ultradistal radius, +0.6% versus -1.9% (p = 0.039). Bone formation markers were reduced by ibandronate, whereas the bone resorption marker, NTX, was reduced in both groups. Calcium and calcitriol supplementation alone showed an excellent efficacy and safety profile, virtually maintaining BMD without any loss over 12 months after renal transplantation, whereas adding ibandronate significantly improved BMD in total femur and ultradistal radius, and also suppressed biomarkers of bone turnover. Ibandronate was also well tolerated.

Correction of an unexpected increasing trend in glucose measurements during 7 years recruitment to a cohort study.

OBJECTIVES: To study an unexpected, significant increase in glucose measurements during 7 year recruitment to a cohort study. DESIGN AND METHODS: Measurements of quality control solutions and blood glucose in pregnant women were done by Accu-Chek Sensor glucometer. Time-trends were analysed by regression models and control charts. RESULTS: Cohort measurements were de-trended by weighted linear regressions based on independent control values. CONCLUSIONS: Biologically implausible trends in data can be corrected by using independent control values.

Increased serum and bone matrix levels of transforming growth factor {beta}1 in patients with GH deficiency in response to GH treatment.

OBJECTIVE: Patients with adult onset GH deficiency (aoGHD) have secondary osteoporosis, which is reversed by long-term GH substitution. Transforming growth factor ß1 (TGFß1 or TGFB1) is abundant in bone tissue and could mediate some effects of GH/IGFs on bone. We investigated its regulation by GH/IGF1 in vivo and in vitro. DESIGN AND METHODS: The effects of GH substitution (9-12 months, placebo controlled) on circulating and cortical bone matrix contents of TGFß1 were investigated in patients with aoGHD. The effects of GH/IGF1 on TGFß1 secretion in osteoblasts (hFOB), adipocytes, and THP-1 macrophages as well as the effects on release from platelets were investigated in vitro. RESULTS: In vivo GH substitution increased TGFß1 protein levels in cortical bone and serum. In vitro, GH/IGF1 stimulation induced a significant increase in TGFß1 secretion in hFOB. In contrast, no major effect of GH/IGF1 on TGFß1 was found in adipocytes and THP-1 macrophages. Finally, a minor modifying effect on SFLLRN-stimulated platelet release of TGFß1 was observed in the presence of IGF1. CONCLUSION: GH substitution increases TGFß1 in vivo and in vitro, and this effect could contribute to improved bone metabolism during such therapy, potentially reflecting direct effect of GH/IGF1 on bone cells.

The importance of body composition and dry weight assessments in patients with chronic kidney disease.

Chronic volume overload is the major cause of hypertension and other cardiovascular morbidity in dialysis patients. One of the most important goals of physicians who take care of patients with chronic renal failure is to obtain near euvolemia or "dry body weight" in order to maintain or normalize blood pressure and prevent further cardiovascular events. In clinical practice, exact estimation of dry weight in hemodialysis patients remains a major challenge. Alterations in body composition, particularly malnutrition, are common in patients receiving long-term hemodialysis and contribute to a high mortality rate. In contrast, obesity - a known risk factor for cardiovascular morbidity and mortality - is prevalent amongst kidney allograft recipients in - long term after renal transplantation. Several technological tools and biochemical markers for estimation of plasma volume and body composition are available for clinical use. Our aim was to highlight the importance of control of body fluid volume and body composition in patients with chronic kidney disease and to describe the different methods available for such measurements.

Favorable long-term effects of growth hormone replacement therapy on quality of life, bone metabolism, body composition and lipid levels in patients with adult-onset growth hormone deficiency.

OBJECTIVE: The goal of growth hormone (GH) replacement is to improve quality of life (QoL) and prevent the long-term complications of GH deficiency (GHD). Thirty-nine patients with adult-onset GH deficiency (AOGHD) who had originally participated in a randomized placebo-controlled crossover study involving treatment with either GH or placebo for nine months were enrolled in an open, 33-month follow-up study of the effects on QoL as well as bone and metabolic parameters. METHODS: GH replacement was dosed individually to obtain IGF-I concentrations that were within the upper part of the normal range for age (mean+1SD). The variables were assessed on five occasions during the study. RESULTS: QoL, as assessed by the sum scores of HSCL-58, AGHDA, physical activity (KIMS question 11) and the dimension vitality in SF-36, improved. Markers of bone formation and resorption remained increased throughout the study period. Bone mineral area (BMA), bone mineral content (BMC) and bone mineral density (BMD) increased in both the lumbar (L2-L4) spine and total body. BMC and BMD increased in the femur. Hypogonadal women however, showed reduced bone mass during the study period. The changes in body fat mass (BFM) and lean body mass (LBM) were sustained throughout the long-term treatment (BFM -2.18 (+/-4.87) kg LBM by 2.01(+/-3.25) kg). Low-density lipoprotein cholesterol (LDL-C) levels were reduced by 0.6 (+/-1.1) mmol/l, and high-density lipoprotein cholesterol (HDL-C) levels increased by 0.2 (+/-0.3) mmol/l. No changes were observed in body weight, fasting total cholesterol, triglycerides, HbA1c and plasma glucose. Mean fasting insulin levels increased significantly from 110 pmol/l to 159 pmol/l, p<0.02. CONCLUSION: Long-term replacement of growth hormone in patients with AOGHD induces favorable effects on QoL as well as bone and metabolic parameters. An increase in insulin levels is also noteworthy.

Osteoclast activity and subtypes as a function of physiology and pathology--implications for future treatments of osteoporosis.

Osteoclasts have traditionally been associated exclusively with catabolic functions that are a prerequisite for bone resorption. However, emerging data suggest that osteoclasts also carry out functions that are important for optimal bone formation and bone quality. Moreover, recent findings indicate that osteoclasts have different subtypes depending on their location, genotype, and possibly in response to drug intervention. The aim of the current review is to describe the subtypes of osteoclasts in four different settings: 1) physiological, in relation to turnover of different bone types; 2) pathological, as exemplified by monogenomic disorders; 3) pathological, as identified by different disorders; and 4) in drug-induced situations. The profiles of these subtypes strongly suggest that these osteoclasts belong to a heterogeneous cell population, namely, a diverse macrophage-associated cell type with bone catabolic and anabolic functions that are dependent on both local and systemic parameters. Further insight into these osteoclast subtypes may be important for understanding cell-cell communication in the bone microenvironment, treatment effects, and ultimately bone quality.

Beta cell function after weight loss: a clinical trial comparing gastric bypass surgery and intensive lifestyle intervention.

OBJECTIVE: The effects of various weight loss strategies on pancreatic beta cell function remain unclear. We aimed to compare the effect of intensive lifestyle intervention (ILI) and Roux-en-Y gastric bypass surgery (RYGB) on beta cell function. DESIGN: One year controlled clinical trial (ClinicalTrials.gov identifier NCT00273104). METHODS: One hundred and nineteen morbidly obese participants without known diabetes from the MOBIL study (mean (s.d.) age 43.6 (10.8) years, body mass index (BMI) 45.5 (5.6) kg/m², 84 women) were allocated to RYGB (n = 64) or ILI (n = 55). The patients underwent repeated oral glucose tolerance tests (OGTTs) and were categorised as having either normal (NGT) or abnormal glucose tolerance (AGT). Twenty-nine normal-weight subjects with NGT (age 42.6 (8.7) years, BMI 22.6 (1.5) kg/m², 19 women) served as controls. OGTT-based indices of beta cell function were calculated. RESULTS: One year weight reduction was 30% (8) after RYGB and 9% (10) after ILI (P < 0.001). Disposition index (DI) increased in all treatment groups (all P<0.05), although more in the surgery groups (both P < 0.001). Stimulated proinsulin-to-insulin (PI/I) ratio decreased in both surgery groups (both P < 0.001), but to a greater extent in the surgery group with AGT at baseline (P < 0.001). Post surgery, patients with NGT at baseline had higher DI and lower stimulated PI/I ratio than controls (both P < 0.027). CONCLUSIONS: Gastric bypass surgery improved beta cell function to a significantly greater extent than ILI. Supra-physiological insulin secretion and proinsulin processing may indicate excessive beta cell function after gastric bypass surgery.

Obesity-related cardiovascular risk factors after weight loss: a clinical trial comparing gastric bypass surgery and intensive lifestyle intervention.

OBJECTIVE: Weight reduction improves several obesity-related health conditions. We aimed to compare the effect of bariatric surgery and comprehensive lifestyle intervention on type 2 diabetes and obesity-related cardiovascular risk factors. DESIGN: One-year controlled clinical trial (ClinicalTrials.gov identifier NCT00273104). METHODS: Morbidly obese subjects (19-66 years, mean (s.d.) body mass index 45.1 kg/m(2) (5.6), 103 women) were treated with either Roux-en-Y gastric bypass surgery (n=80) or intensive lifestyle intervention at a rehabilitation centre (n=66). The dropout rate within both groups was 5%. RESULTS: Among the 76 completers in the surgery group and the 63 completers in the lifestyle group, mean (s.d.) 1-year weight loss was 30% (8) and 8% (9) respectively. Beneficial effects on glucose metabolism, blood pressure, lipids and low-grade inflammation were observed in both groups. Remission rates of type 2 diabetes and hypertension were significantly higher in the surgery group than the lifestyle intervention group; 70 vs 33%, P=0.027, and 49 vs 23%, P=0.016. The improvements in glycaemic control and blood pressure were mediated by weight reduction. The surgery group experienced a significantly greater reduction in the prevalence of metabolic syndrome, albuminuria and electrocardiographic left ventricular hypertrophy than the lifestyle group. Gastrointestinal symptoms and symptomatic postprandial hypoglycaemia developed more frequently after gastric bypass surgery than after lifestyle intervention. There were no deaths. CONCLUSIONS: Type 2 diabetes and obesity-related cardiovascular risk factors were improved after both treatment strategies. However, the improvements were greatest in those patients treated with gastric bypass surgery.

The interleukins IL-6 and IL-1Ra: a mediating role in the associations between BMI and birth weight?

The biological mechanisms in the association between maternal body mass index (BMI) and birth weight are not well understood, but are likely to involve maternal plasma glucose levels and nutrient transport across the placenta, both important modulators of fetal growth. Adipose tissue contributes to circulating levels of interleukins that may affect glucose metabolism and possibly also placental transport of nutrients. We investigated possible mediating roles of Interleukin 6 (IL-6) and Interleukin 1 Receptor antagonist (IL-1Ra) in 208 pregnant women. Known and hypothesized dependencies between BMI in early pregnancy and fasting glucose, IL-1Ra and IL-6 at gestational weeks 30-32, and birth weight were specified in a path diagram. Standardized regression coefficients, expressing direct, indirect and total effects, were estimated by Bayesian path analysis. Mean (s.d.) BMI was 24.9 kg/m2 (4.2) and mean (s.d.) birth weight 3748 g (454). The total effect of BMI on birth weight was 0.24 (95% credibility interval (CrI) [0.12, 0.36]). The direct effect of IL-1Ra on birth weight was not statistically significant, but significant effects of BMI on IL-1Ra (0.61, 95% CrI [0.51, 0.72]), of IL-1Ra on fasting glucose (0.17, 95% CrI [0.01, 0.34]) and of fasting glucose on birth weight (0.14, 95% CrI [0.01, 0.27]) implied an indirect pathway from BMI via IL-1Ra on birth weight. Approximately 20% of the effect of BMI on birth weight was mediated through IL-1Ra. For IL-6, no such effects were found. Our results indicate that IL-1Ra may be a mediator in the association between BMI and birth weight.

Overweight is associated with impaired beta-cell function during pregnancy: a longitudinal study of 553 normal pregnancies.

OBJECTIVE: To monitor beta-cell function and insulin sensitivity longitudinally in a large cohort of pregnant women to elucidate mechanisms that influence glycemic control in pregnancy. DESIGN AND METHODS: Five hundred and fifty-three pregnant Scandinavian women underwent 75 g oral glucose tolerance test (OGTT) at weeks 14-16 and 30-32. Insulin sensitivity (Matsuda index) and beta-cell function (ratio of AUC(insulin) to AUC(glucose), AUC(ins/glc)) were calculated from 520 complete tests, and subsequently beta-cell function was adjusted for insulin sensitivity, rendering an oral disposition index (DI(o)). RESULTS: Eleven women (2.1%) had gestational diabetes mellitus (GDM1) at weeks 14-16, and 49 (9.4%) at weeks 30-32 (GDM2), which is higher than that previously reported in this region. In the subdivision of OGTT, more overweight (body mass index>25) was found in glucose-intolerant groups (glucose-tolerant women (normal glucose tolerance, NGT) 38 versus GDM2 women 58 and GDM1 women 82%, P<0.005). In early pregnancy, insulin sensitivity was lowest in GDM1, intermediate in GDM2, and highest in NGT. In late pregnancy, insulin sensitivity decreased in all groups, most in gestational diabetes. beta-cell function demonstrated minor shifts during pregnancy, but when adjusted for decreasing insulin sensitivity, DI(o) levels fell by 40% (P<0.001). DI(o) was significantly attenuated relative to glucose intolerance (GDM1 25% and GDM2 53%) during pregnancy. In overweight women, DI(o) levels were lower throughout pregnancy (P<0.001 versus normal weight women), this reduction was significant (P<0.01) in both NGT (21-25%) and GDM2 subjects (26-49%). CONCLUSION: beta-cell function adjusted for insulin sensitivity (DI(o)) deteriorated during pregnancy in both glucose-tolerant and glucose-intolerant women. The failure to compensate the decrease in insulin sensitivity was accentuated in overweight women.