To Örebro University

Context: Polycystic ovary syndrome (PCOS) is a heterogeneous condition affecting women of reproductive age. It is associated with dyslipidaemia and elevated plasma C-reactive protein (CRP), which increase the risks of cardiovascular disease (CVD).

Objective: To review the existing evidence on the effects of different pharmacological interventions on lipid profiles and CRP of women with PCOS.

Data Sources: We searched PubMed, MEDLINE, Scopus, Embase, Cochrane Library, and Web of Science in April 2020 and updated the results in March 2021.

Study Selection: The study included randomized controlled trials (RCTs) and follows the 2020 Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA).

Data Extraction: Two independent researchers extracted data and assessed for risk of bias using the Cochrane risk of bias tool. Covidence systematic review software were used for blinded screening and study selection.

Data Synthesis: In 29 RCTs, there were significant reductions in triglycerides with atorvastatin versus placebo [mean difference (MD): -0.21 mmol/L; 95% confidence interval (CI): -0.39, -0.03, I-2 = 0%, moderate grade evidence]. Significant reductions were seen for low-density lipoprotein cholesterol (LDL-C) with metformin versus placebo [standardized mean difference (SMD): -0.41; 95% CI: -0.85, 0.02, I-2 = 59%, low grade evidence]. Significant reductions were also seen for total cholesterol with saxagliptin versus metformin (MD: -0.15 mmol/L; 95% CI: -0.23, -0.08, I-2 = 0%, very low grade evidence). Significant reductions in C-reactive protein (CRP) were seen for atorvastatin versus placebo (MD: -1.51 mmol/L; 95% CI: -3.26 to 0.24, I-2 = 75%, very low-grade evidence).

Conclusion: There were significant reductions in the lipid parameters when metformin, atorvastatin, saxagliptin, rosiglitazone and pioglitazone were compared with placebo or other agents. There was also a significant reduction of CRP with atorvastatin.

Context: Polycystic ovary syndrome (PCOS) is a heterogeneous condition affecting women of reproductive age and is associated with increased body weight.

Objective: To review the literature on the effect of different pharmacological interventions on the anthropometric indices in women with PCOS.

Data sources: We searched PubMed, MEDLINE, Scopus, Embase, Cochrane library, and the Web of Science in April 2020 with an update in PubMed in March 2021.

Study selection: The study followed the Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA)2020.

Data extraction: Reviewers extracted data and assessed the risk of bias using the Cochrane risk of bias tool.

Results: 80 RCTs were included in the meta-analysis. Metformin vs placebo showed significant reduction in the mean body weight (MD: -3.13 kg; 95% confidence interval [CI]: -5.33 to -0.93, I-2 = 5%) and the mean body mass index (BMI) (MD: -0.75 kg/m(2); 95% CI: -1.15 to -0.36, I-2 = 0%). There was a significant reduction in the mean BMI with orlistat versus placebo (MD: -1.33 kg/m(2); 95% CI: -2.16 to -0.66, I-2 = 0.0%), acarbose versus metformin (MD: -1.26 kg/m(2); 95% CI: -2.13 to -0.38, I-2 = 0%), and metformin versus pioglitazone (MD: -0.91 kg/m(2); 95% CI: -1.62 to -0.19, I-2 = 0%). A significant increase in the mean BMI was also observed in pioglitazone versus placebo (MD: + 2.59 kg/m(2); 95% CI: 1.78-3.38, I-2 = 0%) and in rosiglitazone versus metformin (MD: + 0.80 kg/m(2); 95% CI: 0.32-1.27, I-2 = 3%). There was a significant reduction in the mean waist circumference (WC) with metformin versus placebo (MD: -1.21 cm; 95% CI: -3.71 to 1.29, I-2 = 0%) while a significant increase in the mean WC with pioglitazone versus placebo (MD: + 5.45 cm; 95% CI: 2.18-8.71, I-2 = 0%).

Conclusion: Pharmacological interventions including metformin, sitagliptin, pioglitazone, rosiglitazone orlistat, and acarbose have significant effects on the anthropometric indices in women with PCOS.

Objective: Polycystic ovary syndrome (PCOS) is a complex endocrine condition affecting women of reproductive age. It is characterized by insulin resistance and is a major risk factor for type 2 diabetes mellitus (T2DM). The objective was to review the literature on the effect of different pharmacological interventions on insulin resistance in women with PCOS.

Design: We searched PubMed, MEDLINE, Scopus, Embase, Cochrane library and the Web of Science in April 2020 and updated in March 2021. The study follows the 2020 Preferred Reporting Items for Systematic reviews and Meta-ana. Reviwers extracted data and assessed the risk of bias using the Cochrane risk of bias tool.

Results: In 58 randomized controlled trials there were significant reductions in the fasting blood glucose (FBG) with metformin versus placebo (standardized mean difference [SMD]: -0.23; 95% confidence interval [CI]: -0.40, -0.06; I-2 = 0%, low-grade evidence), and acarbose versus metformin (mean difference [MD]: -10.50 mg/dl; 95% CI: -15.76, -5.24; I-2 = 0%, low-grade evidence). Significant reductions in fasting insulin (FI) with pioglitazone versus placebo (SMD: -0.55; 95% CI: -1.03, -0.07; I-2 = 37%; p = .02, very-low-grade evidence). A significant reduction in homoeostatic model assessment of insulin resistance (HOMA-IR) was seen with exenatide versus metformin (MD: -0.34; 95% CI: -0.65, -0.03; I-2 = 0%, low-grade evidence). No effect on homoeostatic model assessment of beta cells (HOMA-B) was observed.

Conclusions: Pharmacological interventions, including metformin, acarbose, pioglitazone and exenatide have significant effects on FBG, FI, HOMA-IR but not on HOMA-B.

Context: Polycystic ovary syndrome (PCOS) is one of the commonest endocrine disorders affecting women of reproductive age, and metformin is a widely used medication in managing this condition.

Aim: To review the available literature comprehensively on the therapeutic impact of metformin on the clinical and metabolic parameters of women with PCOS.

Data source: We searched PubMed, MEDLINE, Scopus, Embase, Cochrane Library and the Web of Science and selected sources for grey literature from their inception to April 2020. An updated search in PubMed was performed in June 2022.

Data synthesis: Two reviewers selected eligible studies and extracted data, and the review is reported following the 2020 Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA).

Results: In 24 eligible randomised controlled trials (RCTs) involving 564 participants who received metformin therapy, metformin was associated with significant reduction in body weight by 3.13 kg (95% CI: -5.33, -0.93), body mass index (BMI) by 0.82 kg/m(2) (95% CI: -1.22, -0.41), fasting blood glucose [standardised mean difference (SMD): -0.23; 95% CI: -0.40, -0.06], low-density lipoprotein cholesterol (LDL-C) (SMD: -0.41; 95% CI: -0.85, 0.03), total testosterone (SMD: -0.33; 95% CI: -0.49, -0.17), androstenedione (SMD: -0.45; 95% CI: -0.70, -0.20), 17-hydroxyprogesterone (17-OHP) (SMD: -0.58; 95% CI: -1.16, 0.00) and increase the likelihood of clinical pregnancy rate [odds ratio (OR): 3.00; 95% CI: 1.95, 4.59] compared with placebo.

Conclusion: In women with PCOS, metformin use has shown a positive impact in reducing body weight, BMI, total testosterone, androstenedione, 17-OHP, LDL-C, fasting blood glucose and increasing the likelihood of pregnancy in women with PCOS.

This narrative review assesses the use of automated insulin delivery (AID) systems in managing persons with type 1 diabetes (PWD) in the pediatric population. It outlines current research, the differences between various AID systems currently on the market and the challenges faced, and discusses potential opportunities for further advancements within this field. Furthermore, the narrative review includes various expert opinions on how different AID systems can be used in the event of challenges with rapidly changing insulin requirements. These include examples, such as during illness with increased or decreased insulin requirements and during physical activity of different intensities or durations. Case descriptions give examples of scenarios with added user-initiated actions depending on the type of AID system used. The authors also discuss how another AID system could have been used in these situations.

Background: There is a need for reliable methods of glucose measurement in different environmental conditions. The objective of this in vitro study was to evaluate the performance of the Enlite® Sensor when connected to either the iPro™ Continuous Glucose Monitor recording device or the Guardian® REAL-Time transmitting device, in hypobaric and hyperbaric conditions.

Methods: Sixteen sensors connected to eight iPro devices and eight Guardian REAL-Time devices were immersed in three beakers containing separate glucose concentrations: 52, 88, and 207 mg/dl (2.9, 4.9, and 11.3 mmol/liter). Two different pressure tests were conducted: a hypobaric test, corresponding to maximum 18000 ft/5500 m height, and a hyperbaric test, corresponding to maximum 100 ft/30 m depth. The linearity of the sensor signals in the different conditions was evaluated.

Results: The sensors worked continuously, and the sensor signals were collected without interruption at all pressures tested. When comparing the input signals for glucose (ISIGs) and the different glucose concentrations during altered pressure, linearity (R(2)) of 0.98 was found. During the hypobaric test, significant differences (p < .005) were seen when comparing the ISIGs during varying pressure at two of the glucose concentrations (52 and 207 mg/dl), whereas no difference was seen at the 88 mg/dl glucose concentration. During the hyperbaric test, no differences were found.

Conclusions: The Enlite Sensors connected to either the iPro or the Guardian REAL-Time device provided values continuously. In hyperbaric conditions, no significant differences were seen during changes in ambient pressure; however, during hypobaric conditions, the ISIG was significantly different in the low and high glucose concentrations.

Background: Physical activity is advocated in all individuals with diabetes. However, good glycemic control can be difficult to achieve due to exercise induced glucose excursions.

Objective: To evaluate the impact on glucose control of a structured diabetes education concerning physical activity, delivered via the web/internet together with telemedical care (individualized feedback by phone).

Methods: Eighty-two individuals with type 1 (T1D) were included in the pre-race intervention and randomized into two groups: intervention (I) (n=48) and control (C) (n=48). Both groups received web-based training of sports and nutrition in relation to diabetes. The intervention group also received structured and individualized feedback on two different occasions. HbA1c was measured at baseline, after 3 and 6 months when a 45 km cross-country skiing race (the HalvVasa) was performed. Only the individuals attending the skiing race were eligible to be included in the study. Level of Physical Activity (LPA), Multidimensional Health Locus of Control (MHLC) and Confidence In Diabetes Self-care (CIDS) were assessed at baseline and after 7 months.

Results: HbA1c at start was 58.5 ± 10.0 (I) respectively 60.7 ± 9.5 (C) mmol/mol. At 3 months 56.7 ± 8.7 (I) respectively 61.0 ± 9.6 (C) mmol/mol and at 6 months 55.7 ± 8.1 (I) respectively 60.3 ± 9.7 (C) mmol/mol. A significant in (I) at 3 months: 2.2 ± 3.8 mmol/mol (0.7-3.7, 95% CI), (p<0.05) and after 6 months: 2.8 ± 5.5 mmol/mol (0.5-5.0, 95% CI), (p<0.05). No reduction was seen in (C). However between the two groups no difference was noted. The LPA was increased in 52% of the participants in (I) respectively 7% in (C), a significant difference, p<0.05. No differences were seen regarding HbA1c or LPA in the control group.

Conclusion: Education and individualized feedback, delivered via telemedicine, to physical active individuals with T1D resulted in improvements in glycemic control within the intervention group and improved level of physical activity and locus of control when compared to the control group(12) (PDF) Education and individualized support regarding exercise and diabetes improves glucose control and level of physical activity in type 1 diabetes individuals.

Background: The performance and accuracy of the Enlite(™) (Medtronic, Inc., Northridge, CA) sensor may be affected by microbubble formation at the electrode surface during hypo- and hyperbaric conditions. The effects of acute pressure changes and of prewetting of sensors were investigated.

Materials and Methods: On Day 1, 24 sensors were inserted on the right side of the abdomen and back in one healthy individual; 12 were prewetted with saline solution, and 12 were inserted dry. On Day 2, this procedure was repeated on the left side. All sensors were attached to an iPro continuous glucose monitoring (CGM) recorder. Hypobaric and hyperbaric tests were conducted in a pressure chamber, with each test lasting 105 min. Plasma glucose values were obtained at 5-min intervals with a HemoCue(®) (Ängelholm, Sweden) model 201 glucose analyzer for comparison with sensor glucose values.

Results: Ninety percent of the CGM systems operated during the tests. The mean absolute relative difference was lower during hyperbaric than hypobaric conditions (6.7% vs. 14.9%, P<0.001). Sensor sensitivity was slightly decreased (P<0.05) during hypobaric but not during hyperbaric conditions. Clarke Error Grid Analysis showed that 100% of the values were found in the A+B region. No differences were found between prewetted and dry sensors.

Conclusions: The Enlite sensor performed adequately during acute pressure changes and was more accurate during hyperbaric than hypobaric conditions. Prewetting the sensors did not improve accuracy. Further studies on type 1 diabetes subjects are needed under various pressure conditions.

BACKGROUND: This study evaluated the accuracy and function of the Continuous Glucose Monitoring System (CGMS, Minneapolis, MN) during recreational scuba diving in individuals with type 1 diabetes.

METHODS: Twenty-four adults, 12 with type 1 diabetes and 12 healthy controls, were studied during five recreational scuba dives performed on three consecutive days. All the participants used the CGMS on all the days and during all the dives. Comparisons were made between plasma glucose at specific time intervals and the CGMS.

RESULTS: The recording by the CGMS was robust, with few sensor problems. The mean sensor survival time was >48 h. Eighty-five percent of the individuals used one sensor during the entire length of the trial. The overall mean absolute difference (MAD) within the group with diabetes was 14.4 +/- 6%, and the corresponding daily figures were 23.2 +/- 19.3% on day 1, 11.6 +/- 4.5% on day 2, and 11.2 +/- 5.7% on day 3. A significant improvement regarding MAD when day 1 was compared with day 2 and 3 (P < 0.05). With a limit set at 70 mg/dL, hypoglycemia pre- and post-dive was detected with a positive predictive value of 0.39, negative predictive value of 0.98, sensitivity of 0.64, and specificity of 0.94.

CONCLUSIONS: We demonstrate that the CGMS was used with accuracy in such difficult conditions as scuba diving and provided robust information on glucose variations.

BACKGROUND: Our objective is to evaluate the Medtronic CGMS continuous glucose monitoring system and plasma glucose (PG) measurement performed in a monitoring schedule as tools to identify individuals with type 1 diabetes at risk when diving.

METHODS: We studied 24 adults, 12 type 1 diabetes subjects and 12 controls, during 5 recreational scuba dives performed on 3 consecutive days. The CGMS was used by all participants on all the days and all the dives. Comparisons were made between PG performed in a monitoring schedule during the days of diving, self-monitored blood glucose (SMBG) performed 2 weeks prior to diving, and the CGMS during the study.

RESULTS: One hundred seventeen dives were performed. Hypoglycemia (<70 mg/dl) was found in six individuals and on nine occasions. However, no symptoms of hypoglycemia were present during or immediately postdiving. In one case, repetitive hypoglycemia prediving gave rise to a decision not to dive. None of the dives were aborted. The number of hypoglycemic episodes, 10 min prediving or immediately postdiving, were related to the duration of diabetes, r = 0.83 and p =0.01, and the percentage of SMBG values below target (<72 mg/dl), r = 0.65 and p =0.02. Moreover, the number of hypoglycemic episodes was also related to the total duration below low limit (<70 mg/dl), measured by the CGMS, r =0.74 and p =0.006.

CONCLUSION: Safe dives are possible to achieve by well-informed, well-controlled individuals with type 1 diabetes. Using downloaded SMBG, CGMS, and repetitive PG in a monitoring schedule, it is possible to identify those subjects who are suitable for diving.

Överviktskirurgi diskuteras nu som ett behandlingsalternativ även för patienter med typ 2-diabetes där BMI inte överstiger nuvarande indikationsgräns 35 kg/m2. Artikelförfattarna vill varna för en sådan utveckling i avvaktan på kritisk värdering av denna typ av kirurgi.

Obesity is associated with adverse health outcomes, but the metabolic effects have not yet been fully elucidated. We aimed to investigate the association between adiposity with circulating metabolites and to address causality with Mendelian randomization (MR). Metabolomics data was generated by non-targeted ultra-performance liquid-chromatography coupled to time-of-flight mass-spectrometry in plasma and serum from three population-based Swedish cohorts: ULSAM (N=1,135), PIVUS (N=970), and TwinGene (N=2,059). We assessed associations between general adiposity measured as body mass index (BMI) and central body fat distribution measured as waist-to-hip ratio adjusted for BMI (WHRadjBMI) with 210 annotated metabolites. We employed MR analysis to assess causal effects. Lastly, we attempted to replicate the MR findings in the KORA and TwinsUK cohorts (N=7,373), the CHARGE consortium (N=8,631), the Framingham Heart Study (N=2,076) and the DIRECT consortium (N=3,029). BMI was associated with 77 metabolites, while WHRadjBMI was associated with 11 and 3 metabolites in women and men, respectively. The MR analyses in the Swedish cohorts suggested a causal association (p-value <0.05) of increased general adiposity and reduced levels of arachidonic acid, dodecanedioic acid and lysophosphatidylcholine (P-16:0) as well as with increased creatine levels. The replication effort provided support for a causal association of adiposity on reduced levels of arachidonic acid (p-value 0.03). Adiposity is associated with variation of large parts of the circulating metabolome, however causality needs further investigation in well-powered cohorts.

This dissertation includes three manuscripts focusing on health disparities between whites and Japanese with regard to measures of diabetes and subclinical atherosclerosis in the EBCT and Risk Factor Assessment among Japanese and U.S. Men in the Post World War II Birth Cohort (ERA JUMP) study. The first manuscript compares markers of insulin resistance and insulin secretion between white men in the United States and Japanese men in Japan, adjusting for visceral adipose tissue and other covariates. Whites had significantly higher HOMA-IR, HOMA-β%, and disposition index (DI) than Japanese in Japan. The better compensation of insulin resistance by increased insulin secretion in whites as shown by higher DI may partly explain lower susceptibility of whites to developing type 2 diabetes than Japanese in Japan at similar levels of body-mass index.The second manuscript compares progression of intima-media thickness of the carotid artery (CIMT) between middle-aged Japanese American men and white men, adjusting for baseline cardiovascular risk factors. Japanese Americans had greater progression of CIMT than whites. The third manuscript compares progression of coronary artery calcium (CAC) between Japanese American men and white men. Japanese Americans had similar progression of CAC as whites.This work contributes uniquely to public health significance. Future studies exploring reasons of poorer compensation of increasing insulin resistance by enhanced insulin secretion in Japanese in Japan may help to prevent earlier onset of type 2 diabetes in Japanese than whites at a given level of BMI. The second and third manuscripts identify increasing subclinical atherosclerosis in Japanese Americans that may translate into increased risk of CHD in Japanese Americans in the future. The second and third manuscripts identify Japanese American as a target group for prevention of CHD.

CONTEXT: The effect of GH therapy in short non-GH-deficient children, especially those with idiopathic short stature (ISS), has not been clearly established owing to the lack of controlled trials continuing until final height (FH).

OBJECTIVE: The aim of the study was to investigate the effect on growth to FH of two GH doses given to short children, mainly with ISS, compared with untreated controls.

DESIGN AND SETTING: A randomized, controlled, long-term multicenter trial was conducted in Sweden.

INTERVENTION: Two doses of GH (Genotropin) were administered, 33 or 67 microg/kg.d; control subjects were untreated.

SUBJECTS: A total of 177 subjects with short stature were enrolled. Of these, 151 were included in the intent to treat (AllITT) population, and 108 in the per protocol (AllPP) population. Analysis of ISS subjects included 126 children in the ITT (ISSITT) population and 68 subjects in the PP (ISSPP) population.

MAIN OUTCOME MEASURES: We measured FH sd score (SDS), difference in SDS to midparenteral height (diff MPHSDS), and gain in heightSDS.

RESULTS: After 5.9+/-1.1 yr on GH therapy, the FHSDS in the AllPP population treated with GH vs. controls was -1.5+/-0.81 (33 microg/kg.d, -1.7+/-0.70; and 67 microg/kg.d, -1.4+/-0.86; P<0.032), vs. -2.4+/-0.85 (P<0.001); the diff MPHSDS was -0.2+/-1.0 vs. -1.0+/-0.74 (P<0.001); and the gain in heightSDS was 1.3+/-0.78 vs. 0.2+/-0.69 (P<0.001). GH therapy was safe and had no impact on time to onset of puberty. A dose-response relationship identified after 1 yr remained to FH for all growth outcome variables in all four populations.

CONCLUSION: GH treatment significantly increased FH in ISS children in a dose-dependent manner, with a mean gain of 1.3 SDS (8 cm) and a broad range of response from no gain to 3 SDS compared to a mean gain of 0.2 SDS in the untreated controls. 

Background/Aims: Growth hormone (GH) treatment regimens do not account for the pubertal increase in endogenous GH secretion. This study assessed whether increasing the GH dose and/or frequency of administration improves pubertal height gain and adult height (AH) in children with low GH secretion during stimulation tests, i. e. idiopathic isolated GH deficiency.

Methods: A multicenter, randomized, clinical trial (No. 88-177) followed 111 children (96 boys) at study start from onset of puberty to AH who had received GH(33) mu g/kg/day for >= 1 year. They were randomized to receive 67 mu g/kg/day (GH(67)) given as one (GH(67x1); n = 35) or two daily injections (GH(33x2); n = 36), or to remain on a single 33 mu g/kg/day dose (GH(33x1); n = 40). Growth was assessed as height SDS gain for prepubertal, pubertal and total periods, as well as AH SDS versus the population and the midparental height.

Results: Pubertal height SDS gain was greater for patients receiving a high dose (GH(67), 0.73) than a low dose (GH(33x1), 0.41, p < 0.05). AH(SDS) was greater on GH(67) (GH(67x1), -0.84; GH(33x2), -0.83) than GH(33) (-1.25, p < 0.05), and height SDS gain was greater on GH(67) than GH(33) (2.04 and 1.56, respectively; p < 0.01). All groups reached their target height SDS.

Conclusion: Pubertal height SDS gain and AH SDS were dose dependent, with greater growth being observed for the GH(67) than the GH(33) randomization group; however, there were no differences between the once-and twice-daily GH(67) regimens. (C) 2014 S. Karger AG, Basel.

AIMS: The study aims were to determine autoantibodies associated with type 1 diabetes (T1D), celiac disease (CD) and autoimmune thyroid disease (AITD) in individuals living with type 2 diabetes (T2D) compared to T1D and matched controls.

METHODS: Individuals with T1D and T2D were randomly identified in health-care registers. Blood was collected through home-capillary sampling and autoantibodies associated with either T1D against glutamic acid decarboxylase (GADA), insulin (IAA), insulinoma antigen-2 (IA-2A), and zinc transporter 8 (ZnT8A), CD against tissue transglutaminase (tTGA) or AITD against thyroid peroxidase (TPOA) were determined in an automated, multiplex Antibody Detection by Agglutination-PCR (ADAP) assay.

RESULTS: GADA were detected in 46 % (88/191) of T1D and increased to 6.2 % (23/372) in T2D compared to 2.6 % (7/259) of controls (p = 0.0367). tTGA was low (1.1-2.6 %) and not different in between the study cohorts, nonetheless, in T1D tTGA was associated to islet autoantibodies. TPOA was more frequent in T1D, 27.1 % (53/191), compared to either T2D, 14.8 % (55/372; p = 0.0002) or controls, 14.3 % (37/259) (p = 0.0004). Overall, TPOA was more frequent in GADA positive (34.8 %; 8/23) than negative (13.5 %; 47/349; p = 0.0053) T2D individuals.

CONCLUSION: It's suggested that analyzing GADA and TPOA may refine the autoimmune landscape in individuals clinically classified as T2D.

The effect of the selective alpha 2 agonist Mivazerol on catecholamine levels in plasma, and on central hemodynamics and blood glucose levels developments during hemorrhagic stress in rats was investigated. The animals were randomly given either saline, low dose of Mivazerol (0.6 μg/ml) or high dose (2.0 μg/ml) at a rate of 30 μl/100 g/min, beginning the infusions intravenously 30 min before onset and throughout 60 min of hemorrhagic stress. Before hemorrhage, Mivazerol raised mean arterial pressure, and reduced heart rate, adrenaline and noradrenaline levels in a dose dependent fashion. High dose infusion also resulted in an elevation in blood glucose. During hemorrhage, the high dose effectively dampened the catecholamine response. Simultaneously, the same group maintained better mean arterial pressure in response to hemorrhage. Blood glucose levels were elevated to similar levels regardless of treatment. These data indicate that Mivazerol effectively reduced the catecholamine response to severe hemorrhagic stress, while central hemodynamic and blood glucose responses were maintained or improved.

Background: Therapeutic shoes can prevent diabetic foot reulcerations but their use is complicated by the fact that shoes have psychological and social meanings, which is believed to put a larger burden on women than men. The aim was to compare attitudes and attributes of women and men using therapeutic shoes for diabetic foot complications.

Methods: A questionnaire was posted to 1230 people with diabetes who had been fitted with therapeutic shoes. Women's and men's answers were compared using t-tests, Mann-Whitney U tests and chi-square tests with Fischer's exact tests. P-values < 0.05 were considered statistically significant.

Results: Questionnaires from 443 (36.0%) respondents (294 men, 149 women, mean age 69.2 years) were analyzed. More men than women (p < 0.05) had paid employment (20.4% vs 9.4%), had someone who reminded them to wear their therapeutic shoes (27.6% vs 10.0%), and had a history of foot ulcers (62.9% vs 46.3%) or minor amputation (17.7% vs 6.7%). More women than men received disability pension (18.8% vs 10.2%). Women reported worse general health, lower internal locus of control regarding ulcer prevention, and more negative attitudes to the appearance and price of therapeutic shoes and how they felt about wearing them in public. Other comparisons were non-significant: other shoe attributes, education, diabetes type, current foot ulcers, major amputations, satisfaction with shoe services, understanding of neuropathy as a risk factor, locus of control regarding ulcer healing, belief in the shoes' efficacy to prevent and heal ulcers, worries about ulcer healing and new ulcerations, self-efficacy, depression, shoe use/adherence, paying a fee for therapeutic shoes, and social support.

Conclusions: Men had worse foot complications. Women had worse general health, lower internal locus of control regarding ulcer prevention, and more negative attitudes toward therapeutic shoes. Clinicians should pay more attention to their female patients' concerns. Future research and development should focus on improving the weight and appearance of therapeutic shoes, particularly for women. Research is also needed on how to facilitate the adaption and reevaluation process where patients change from viewing shoes purely as items of clothing to also viewing them as medical interventions

Aim: There is some debate about laterality for diabetic foot complications, that is, whether the right and left limbs are unequally affected. Coxon and Gallen (1) found that more amputations were performed on the right limb and Evans et al. (2) interpreted this in the context of foot dominance: they found that most foot ulcers occured on the dominant limb (which for most people is the right one) and speculated that the dominant limb may be more exposed to mechanical stresses and injuries. However, Demetriou et al. (3) did not find any laterality in foot ulcer location. The aim was to investigate laterality for foot ulcers and amputations. Methods: A questionnaire was posted to 1245 people who had diabetes, experience of using therapeutic shoes, and who had attended one of two prosthetics and orthotics clinics during a 12 months’ period. The number of ulcers or amputations on the right and left limb were compared with a two-sided chi-square test. Results: 469 (37.7%) questionnaires were returned. 118 (25.2%) participants reported unilateral foot ulcers, 54 (11.5%) reported unilateral minor amputation, and 21 (4.5%) reported unilateral major amputation. There was no statistically significant right-left difference in foot ulcers, minor amputations or major amputations (Table 1, p-values 0.713-1.000). Conclusions: Our results do not support the hypothesis about laterality for foot ulcers and amputations.

OBJECTIVE: Data on pre- and postoperative pituitary function in nonfunctioning pituitary adenomas (NFPA) are not consistent. We aimed to investigate pituitary function before and up to five years after transsphenoidal surgery with emphasis on the hypothalamic-pituitary-adrenal axis (HPA).

DESIGN AND METHODS: Data from the Swedish Pituitary Register was used to analyze anterior pituitary function in 838 patients with NFPA diagnosed between 1991 and 2014. Patients who were reoperated or had received radiotherapy were excluded.

RESULTS: Preoperative ACTH, TSH, LH/FSH and GH deficiencies were reported in 31% (236/755), 39% (300/769), 51% (378/742) and 28% (170/604) of the patients, respectively. Preoperative median tumor volume was 5.0 (2.4-9.0) cm3. Amongst patients with preoperative, one year and five years postoperative data on the HPA axis (n=428), 125 (29%) were ACTH-deficient preoperatively. One year postoperatively, 26% (32/125) of them had recovered ACTH function while 23% (70/303) patients had developed new ACTH deficiency. Thus, one year postoperatively 163 (38%) patients were ACTH-deficient (P <0.001 vs. preoperatively). No further increase was seen five years postoperatively (36%, P=0.096). At one year postoperatively recoveries in the TSH- and LH/FSH-axes were reported in 14% (33/241) and 15% (46/310), respectively, and new deficiencies in 22% (88/403) and 29% (83/288), respectively.

CONCLUSIONS: ACTH deficiency increased significantly at one year postoperatively. Event though not significant, some patients recovered from or developed new deficiency between one and five years postoperatively. This pattern was seen in all axes. Our study emphasizes that continuous individual evaluations are needed during longer follow-up of patients operated for NFPA.

OBJECTIVE:

The menopausal transition is characterized by increased body fat accumulation, including redistribution from peripheral to central fat depots. This distribution is associated with an increased risk of type 2 diabetes and cardiovascular disease that are linked to low-grade inflammation. We determined whether postmenopausal women have higher levels of inflammatory markers, compared with premenopausal women. We also wanted to determine whether these markers are reduced by stable weight loss in obese women.

DESIGN AND METHODS:

Anthropometric data, blood samples and subcutaneous adipose tissue biopsies were collected from normal weight premenopausal and postmenopausal women and obese women before and 2 years after gastric bypass (GBP) surgery. Serum protein levels and adipose tissue gene expression of inflammatory markers were investigated.

RESULTS:

IL-8 expression in adipose tissue and circulating levels were higher in postmenopausal vs premenopausal women. IL-8 expression was associated with waist circumference, independent of menopausal status. IL-6 expression and serum levels of monocyte chemoattractant protein (MCP)-1 were higher in postmenopausal vs premenopausal women. Two years after GBP surgery, adipose expression of IL-8, tumour necrosis factor-α and MCP-1 decreased significantly. Serum insulin levels were associated with inflammation-related gene expression before GBP surgery, but these associations disappeared after surgery.

CONCLUSION:

Postmenopausal women have an increased inflammatory response in the subcutaneous fat and circulation. Inflammatory markers in adipose tissue decreased significantly after surgery-induced weight loss. This effect may be beneficial for metabolic control and reduced cardiovascular risk after weight loss.

The incidence of type 2 diabetes (T2D) is rapidly increasing worldwide and T2D is likely to affect 592 million people in 2035 if the current rate of progression is continued. Today, patients are diagnosed with T2D based on elevated blood glucose, either directly or indirectly (HbA1c). However, the information on disease progression is limited. Therefore, there is a need to identify novel early markers of glucose intolerance that reflect the underlying biology and the overall physiological, metabolic and clinical characteristics of progression towards diabetes. In the DEXLIFE study, several clinical cohorts provide the basis for a series of clinical, physiological and mechanistic investigations in combination with a range of--omic technologies to construct a detailed metabolic profile of high-risk individuals across multiple cohorts. In addition, an exercise and dietary intervention study is conducted, that will assess the impact on both plasma biomarkers and specific functional tissue-based markers. The DEXLIFE study will provide novel diagnostic and predictive biomarkers which may not only effectively detect the progression towards diabetes in high risk individuals but also predict responsiveness to lifestyle interventions known to be effective in the prevention of diabetes.

AIMS/HYPOTHESIS: The risk of complications and medical consequences of type 2 diabetes are well known. Hospital costs have been identified as a key driver of total costs in studies of the economic burden of type 2 diabetes. Less evidence has been generated on the impact of individual diabetic complications on the overall societal burden. The objective of this study was to analyse costs of hospital-based healthcare (inpatient and outpatient care) and work absence related to individual macrovascular and microvascular complications of type 2 diabetes in Sweden in 2016.

METHODS: Data for 2016 were retrieved from a Swedish national retrospective observational database cross-linking individual-level data for 1997-2016. The database contained information from population-based health, social insurance and socioeconomic registers for 392,200 people with type 2 diabetes and matched control participants (5:1). Presence of type 2 diabetes and of diabetes complications were derived using all years, 1997-2016. Costs of hospital-based care and of absence from work due to diabetes complications were estimated for the year 2016. Regression analysis was used for comparison with control participants to attribute absence from work to individual complications, and to account for joint presence of complications.

RESULTS: Use of hospital care for complications was higher in type 2 diabetes compared with control participants in 2016: 26% vs 12% had ≥1 hospital contact; there were 86,104 vs 24,608 outpatient visits per 100,000 people; and there were 9894 vs 2546 inpatient admissions per 100,000 people (all p < 0.001). The corresponding total costs of hospital-based care for complications were €919 vs €232 per person (p < 0.001), and 74.7% of costs were then directly attributed to diabetes (€687 per person). Regression analyses distributed the costs of days absent from work across diabetes complications per se, basic type 2 diabetes effect and unattributed causes. Diabetes complications amounted to €1317 per person in 2016, accounting for possible complex interactions (25% of total costs of days absent). Key drivers of costs were the macrovascular complications angina pectoris, heart failure and stroke; and the microvascular complications eye diseases, including retinopathy, kidney disease and neuropathy. Early mortality in working ages cost an additional €579 per person and medications used in risk-factor treatment amounted to €418 per person.

CONCLUSIONS/INTERPRETATION: The economic burden of complications in type 2 diabetes is substantial. Costs of absence from work in this study were found to be greater than of hospital-based care, highlighting the need for considering treatment consequences in a societal perspective in research and policy. Graphical abstract.

BACKGROUND: Diabetes is a growing threat to public health, and secondary diseases like foot complications are common. Foot ulcers affect the individual's quality of life and are a great cost to society. Regular foot examinations prevent foot ulcers and are a recommended approach both in Sweden and worldwide. Despite existing guidelines, there are differences in the execution of the foot examination, which results in care inequality. A structured foot examination form based on current guidelines was developed in this study as the first step toward digitalized support in the daily routine, and was validated by diabetes health care professionals.

OBJECTIVE: The study aimed to validate a structured foot examination form by assessing health care professionals' experiences of working with it "foot side" when examining patients with diabetes.

METHODS: Semistructured interviews were held in a focus group and individually with 8 informants from different diabetes professions, who were interviewed regarding their experiences of working with the form in clinical practice. The users' data were analyzed inductively using qualitative content analysis. The study is part of a larger project entitled "Optimised care of persons with diabetes and foot complications," with Västra Götaland Region as the responsible health care authority, where the results will be further developed.

RESULTS: Experiences of working with the form were that it simplified the foot examination by giving it an overview and a clear structure. Using the form made differences in work routines between individuals apparent. It was believed that implementing the form routinely would contribute to a more uniform execution. When patients had foot ulcers, the risk categories (established in guidelines) were perceived as contradictory. For example, there was uncertainty about the definition of chronic ulcers and callosities. The expectations were that the future digital format would simplify documentation and elucidate the foot examination, as well as contribute to the accessibility of updated and relevant data for all individuals concerned.

CONCLUSIONS: The foot examination form works well as a support tool during preventive foot examination, creates a basis for decision-making, and could contribute to a uniform and safer foot examination with more care equality in agreement with current guidelines.

TRIAL REGISTRATION: ClinicalTrials.gov NCT05692778; https://clinicaltrials.gov/ct2/show/NCT05692778.

Idiopathic short stature is a common condition with a heterogeneous etiology. Advances in genetic methods, including genome sequencing techniques and bioinformatics approaches, have emerged as important tools to identify the genetic defects in families with monogenic short stature. These findings have contributed to the understanding of growth regulation and indicate that growth plate chondrogenesis, and therefore linear growth, is governed by a large number of genes important for different signaling pathways and cellular functions, including genetic defects in hormonal regulation, paracrine signaling, cartilage matrix, and fundamental cellular processes. In addition, mutations in the same gene can cause a wide phenotypic spectrum depending on the severity and mode of inheritance of the mutation.

Roux-en-Y gastric bypass (RYGB) is an effective method to attain sustained weight loss and diabetes remission. We aimed to elucidate early changes in the plasma metabolome and lipidome after RYGB. Plasma samples from 16 insulin-resistant morbidly obese subjects, of whom 14 had diabetes, were subjected to global metabolomics and lipidomics analysis at pre-surgery and 4 and 42 days after RYGB. Metabolites and lipid species were compared between time points and between subjects who were in remission and not in remission from diabetes 2 years after surgery. We found that the variables that were most discriminatory between time points were decanoic acid and octanoic acid, which were elevated 42 days after surgery, and sphingomyelins (18:1/21:0 and 18:1/23:3), which were at their lowest level 42 days after surgery. Insulin levels were lower at 4 and 42 days after surgery compared with pre-surgery levels. At 4 days after surgery, insulin levels correlated positively with metabolites of branched chain and aromatic amino acid metabolism and negatively with triglycerides with long-chain fatty acids. Of the 14 subjects with diabetes prior to surgery, 7 were in remission 2 years after surgery. The subjects in remission displayed higher pre-surgery levels of tricarboxylic acid cycle intermediates and triglycerides with long-chain fatty acids compared with subjects not in remission. Thus, metabolic alterations are induced soon after surgery and subjects with diabetes remission differ in the metabolic profiles at pre- and early post-surgery time points compared to patients not in remission.

During the last decade, digital X-ray radiometry (DXR) has been used to measure bone mineral density (BMD) in the metacarpal bones. The aim of this study was to establish Swedish reference material for bone mass in women, measured in the metacarpal bones with DXR, and compare these data with the data from the manufacturer. A sample of 1440 women aged 20-79yr living in Örebro County was randomly assigned from the population register. Microdose mammography was used (Sectra MDM L30; Sectra Imtec AB, Linköping, Sweden) to measure BMD. Cole's LMS method was used to calculate DXR. Six hundred sixty-nine (48.3%) women participated. Peak bone mass occurred at the age of 43.4yr with a BMD of 0.597g/cm(2) (standard deviation: 0.050). Our Swedish data correlated well with the manufacturer's material. Only among women aged 50-59yr did BMD differ, where the Swedish sample had lower values. The LMS method can be used to describe the DXR data and provide a more detailed picture of bone density distribution. DXR-BMD in Swedish women aged 20-79yr is equivalent to findings from other studies, showing the same distribution of BMD in most age groups except for ages 50-59yr.

BACKGROUND: Endocrine-disrupting chemicals (EDCs) contribute to disease and dysfunction and incur high associated costs (>1% of the gross domestic product [GDP] in the European Union). Exposure to EDCs varies widely between the USA and Europe because of differences in regulations and, therefore, we aimed to quantify disease burdens and related economic costs to allow comparison.

METHODS: We used existing models for assessing epidemiological and toxicological studies to reach consensus on probabilities of causation for 15 exposure-response relations between substances and disorders. We used Monte Carlo methods to produce realistic probability ranges for costs across the exposure-response relation, taking into account uncertainties. Estimates were made based on population and costs in the USA in 2010. Costs for the European Union were converted to US$ (€1=$1·33).

FINDINGS: The disease costs of EDCs were much higher in the USA than in Europe ($340 billion [2·33% of GDP] vs $217 billion [1·28%]). The difference was driven mainly by intelligence quotient (IQ) points loss and intellectual disability due to polybrominated diphenyl ethers (11 million IQ points lost and 43 000 cases costing $266 billion in the USA vs 873 000 IQ points lost and 3290 cases costing $12·6 billion in the European Union). Accounting for probability of causation, in the European Union, organophosphate pesticides were the largest contributor to costs associated with EDC exposure ($121 billion), whereas in the USA costs due to pesticides were much lower ($42 billion).

INTERPRETATION: EDC exposure in the USA contributes to disease and dysfunction, with annual costs taking up more than 2% of the GDP. Differences from the European Union suggest the need for improved screening for chemical disruption to endocrine systems and proactive prevention.

Objectives: Gastric bypass surgery constitutes the most common and effective bariatric surgery to treat obesity. Gastric bypass leads to bone oss but fracture risk following surgery has been insufficiently studied. Our objective was to investigate if gastric bypass surgery in obese patients, with and without diabetes, was associated with fracture risk, and if the fracture risk was associated with post-surgery weight loss or insufficient calcium and vitamin D supplementation.

Methods: Using large databases, 38 971 obese patients undergoing gastric bypass were identified, 7758 with diabetes and 31 213 without. Through multivariable 1:1 propensity score matching, well-balanced controls were identified. The risk of fracture and fall injury was investigated using Cox proportional hazards and flexible parameter models. Fracture risk according to weight loss and degree of calcium and vitamin D supplementation one year post-surgery was investigated.

Results: 77 942 patients had a median and total follow-up time of 3.1 (IQR 1.7-4.6) and 251 310 person-years, respectively. Gastric bypass was associated with increased risk of any fracture, in patients with diabetes and without diabetes using a multivariable Cox model (HR 1.26, 95%CI 1.05-1.53 and HR 1.32, 95%CI 1.18-1.47, respectively). The risk of fall injury without fracture was also increased after gastric bypass, both in patients with (HR 1.26 95%CI 1.04-1.52) and without diabetes (HR 1.24 95%CI 1.12-1.38). Weight loss or degree of calcium and vitamin D supplementation after gastric bypass were not associated with fracture risk.

Conclusions: Gastric bypass was associated with an increased risk of fracture and fall injury. Weight loss or calcium and vitamin D supplementation following surgery were not associated with fracture risk. These findings indicate that gastric bypass increases fracture risk, which could at least partly be due to increased susceptibility to falls.

Gastric bypass surgery constitutes the most common and effective bariatric surgery to treat obesity. Gastric bypass leads to bone loss, but fracture risk following surgery has been insufficiently studied. Furthermore, the association between gastric bypass and fracture risk has not been studied in patients with diabetes, which is a risk factor for fracture and affected by surgery. In this retrospective cohort study using Swedish national databases, 38,971 obese patients undergoing gastric bypass were identified, 7758 with diabetes and 31,213 without. An equal amount of well-balanced controls were identified through multivariable 1:1 propensity score matching. The risk of fracture and fall injury was investigated using Cox proportional hazards and flexible parameter models. Fracture risk according to weight loss and degree of calcium and vitamin D supplementation 1-year postsurgery was investigated. During a median follow-up time of 3.1 (interquartile range [IQR], 1.7 to 4.6) years, gastric bypass was associated with increased risk of any fracture, in patients with and without diabetes using a multivariable Cox model (hazard ratio [HR] 1.26; 95% CI, 1.05 to 1.53; and HR 1.32; 95% CI, 1.18 to 1.47; respectively). Using flexible parameter models, the fracture risk appeared to increase with time. The risk of fall injury without fracture was also increased after gastric bypass. Larger weight loss or poor calcium and vitamin D supplementation after surgery were not associated with increased fracture risk. In conclusion, gastric bypass surgery is associated with an increased fracture risk, which appears to be increasing with time and not associated with degree of weight loss or calcium and vitamin D supplementation following surgery. An increased risk of fall injury was seen after surgery, which could contribute to the increased fracture risk.

OBJECTIVE: The aim of this study was to determine long-term changes in pharmacological treatment of type 2 diabetes after primary Roux-en-Y gastric bypass (RYGB) surgery, in patients with and without pharmacological treatment of diabetes preoperatively.

SUMMARY OF BACKGROUND DATA: Several studies have shown that gastric bypass has good effect on diabetes, at least in the short-term. This study is a nationwide cohort study using Swedish registers, with basically no patients lost to follow-up during up to 7 years after surgery.

METHODS: The effect of RYGB on type 2 diabetes drug treatment was evaluated in this nationwide matched cohort study. Participants were 22,047 adults with BMI ≥30 identified in the nationwide Scandinavian Surgical Obesity Registry, who underwent primary RYGB between 2007 and 2012. For each individual, up to 10 general population comparators were matched on birth year, sex, and place of residence. Prescription data were retrieved from the nationwide Swedish Prescribed Drug Register through September 2015. Incident use of pharmacological treatment was analyzed using Cox regression.

RESULTS: Sixty-seven percent of patients with pharmacological treatment of type 2 diabetes before surgery were not using diabetes drugs 2 years after surgery and 61% of patients were not pharmacologically treated up to 7 years after surgery. In patients not using diabetes drugs at baseline, there were 189 new cases of pharmacological treatment of type 2 diabetes in the surgery group and 2319 in the matched general population comparators during a median follow-up of 4.6 years (incidence: 21.4 vs 27.9 per 10,000 person-years; adjusted hazard ratio 0.77, 95% confidence interval 0.67-0.89; P < 0.001).

CONCLUSIONS: Gastric bypass surgery not only induces remission of pharmacological treatment of type 2 diabetes but also protects from new onset of pharmacological diabetes treatment. The effect seems to persist in most, but not all, patients over 7 years of follow-up.

Mixed muscle protein synthetic rate has been measured in humans. These measurements represent the average of synthetic rates of all muscle proteins with variable rates. We determined to what extent the synthesis rate of mixed muscle protein in humans reflects that of myosin heavy chain (MHC), the main contractile protein responsible for the conversion of ATP to mechanical energy as muscle contraction. Fractional synthetic rates of MHC and mixed muscle protein were measured from the increment of [C-13]leucine in these proteins in vastus lateralis biopsy samples taken at 5 and 10 h during a primed continuous infusion of L-[1-C-13]leucine in 10 young healthy subjects. Calculations were done by use of plasma [C-13]ketoisocaproate (KIC) and muscle tissue fluid [C-13]leucine as surrogate measures of leucyl-tRNA. Fractional synthetic rate of MHC with plasma KIC (0.0299 +/- 0.0043%/h) and tissue fluid leucine (0.0443 +/- 0.0056%/h) were only 72 +/- 3% of that of mixed muscle protein (0.0408 +/- 0.0032 and 0.0603 +/- 0.0059%/h, respectively, with KIC and tissue fluid leucine). Contribution of MHC (7 +/- 1 mg . kg(-1) . h(-1)) to synthetic rates of whole body mixed muscle protein (36 +/- 5 mg . kg(-1) . h(-1)) and whole body protein (127 +/- 4 mg . kg(-1) . h(-1)) is only 18 +/- 1 and 5 +/- 1%, respectively. This relatively low contribution of MHC to whole body and mixed muscle protein synthesis warrants direct measurement of synthesis rate of MHC in conditions involving abnormalities of muscle contractile function.

AIMS: We have evaluated long-term weighted mean HbA1c (wHbA1c), HbA1c variability, diabetes duration, and lipid profiles in relation to the development of diabetic peripheral neuropathy (DPN), nephropathy, and retinopathy in childhood-onset type 1 diabetes.

MATERIALS AND METHODS: In a longitudinal cohort study, 49 patients (21 women) with childhood-onset type 1 diabetes were investigated with neurophysiological measurements, blood tests, and clinical examinations after a diabetes duration of 7.7 (±3.3) years (baseline) and followed with repeated examinations for 30.6 (±5.2) years. We calculated wHbA1c by integrating the area under all HbA1c values since the diabetes diagnosis. Lipid profiles were analysed in relation to the presence of DPN. Long-term fluctuations of HbA1c variability were computed as the standard deviation of all HbA1c measurements. Data regarding the presence of other diabetes complications were retrieved from medical records.

RESULTS: In this follow-up study, 51% (25/49) of the patients fulfilled electrophysiological criteria for DPN. In nerve conduction studies, there was a deterioration in the amplitudes and conduction velocities for the median, peroneal, and sural nerves over time. Patients with DPN had a longer duration of diabetes, higher wHbA1c, and increased HbA1c variability. The lowest wHbA1c value associated with the development of DPN was 62 mmol/mol (7.8%). The presence of albuminuria and retinopathy was positively correlated with the presence of neuropathy.

CONCLUSIONS: More than half of the patients had developed DPN after 30 years. None of the patients who developed DPN had a wHbA1c of less than 62 mmol/mol (7.8%).

INTRODUCTION: To investigate whether circulating chemokines contribute to the development of diabetic peripheral neuropathy (DPN) in patients with type 1 diabetes (T1D).

METHODS: Fifty-two patients with childhood-onset T1D (mean age 28 ± 4 yrs.; diabetes duration 19.5 ± 5.5 yrs.) and 19 control subjects (mean age 26.5 ± 4.5 yrs.) were included in a cross-sectional analysis of this long-term longitudinal cohort study. A subgroup of 24 patients was followed prospectively for a further 10 yrs. Plasma levels of Th1- (CXCL9, CXCL10 and CXCL11), Th2- (CCL17 and CCL22) and Th17-associated (CXCL8 and CCL20) chemokines were assessed in all subjects. Additionally, the TID patients underwent clinical examination and electroneurography.

RESULTS: The frequency of neuropathy was 21% (11/52). Higher levels of CXCL9 levels were found in patients with DPN compared with control subjects (p = .019); by contrast, no difference between patients without DPN and control subjects was seen after adjustment for multiple comparisons. In patients with DPN, CXCL10 correlated negatively with suralis MCV and suralis SNAP (rho -0.966, p < .001 and rho -0.738, p < .001, respectively) and was positively correlated with the vibration perception threshold (rho 0.639, p = .034), while CXCL8 correlated negatively with the cold perception threshold (rho -0.645, p = .032). The frequency of neuropathy increased to 54% (13/24) in the subgroup of 23 TID patients, followed by an additional 10 yrs.

CONCLUSIONS: Changes in Th1- and Th17-associated chemokines were associated with impaired peripheral sensory nerve function and nerve conduction after long disease duration in childhood-onset T1D.

INTRODUCTION: This study aimed to investigate circulating biomarkers associated with the risk of developing diabetic peripheral neuropathy (DPN) and nephropathy in type 1 diabetes (T1D).

MATERIALS AND METHODS: Patients with childhood-onset T1D (n = 49, age 38.3 ± 3.8 yrs.) followed prospectively were evaluated after 30 years of diabetes duration. DPN was defined as an abnormality in nerve conduction tests. Matrix metalloproteinase-9 (MMP-9) and its tissue inhibitor TIMP-1, neutrophil gelatinase-associated lipocalin-2 (NGAL), soluble P-selectin (sP-selectin), estimated GFR (eGFR), micro/macroalbuminuria and routine biochemistry were assessed. For comparison, control subjects were included (n = 30, age 37.9 ± 5.5 yrs.).

RESULTS: In all, twenty-five patients (51 %) were diagnosed with DPN, and nine patients (18 %) had nephropathy (five microalbuminuria and four macroalbuminuria). Patients with DPN had higher levels of TIMP-1 (p = 0.036) and sP-selectin (p = 0.005) than controls. Patients with DPN also displayed higher levels of TIMP-1 compared to patients without DPN (p = 0.035). Patients with macroalbuminuria had kidney disease stage 3 with lower eGFR, higher levels of TIMP-1 (p = 0.038), and NGAL (p = 0.002). In all patients, we found only weak negative correlations between eGFR and TIMP-1 (rho = -0.304, p = 0.040) and NGAL (rho = -0.277, p = 0.062, ns), respectively. MMP-9 was higher in patients with microalbuminuria (p = 0.021) compared with normoalbuminuric patients.

CONCLUSIONS: Our findings indicate that TIMP-1 and MMP-9, as well as sP-selectin and NGAL, are involved in microvascular complications in T1D. Monitoring and targeting these biomarkers may be a potential strategy for treating diabetic nephropathy and neuropathy.

Increased serum insulin-like growth factor (IGF)-binding protein-3 (IGFBP-3) proteolytic activity (IGFBP-3-PA) has been demonstrated in a number of clinical states of insulin resistance, including severe illness, after surgery, and in noninsulin-dependent diabetes mellitus. In the present study we assessed the role of insulin sensitivity in expression of IGFBP-3-PA in serum. In 18 patients studied, a significant increase in IGFBP-3-PA (P < 0.005) was demonstrated after cole-rectal surgery. Eight patients receiving an oral glucose load before surgery demonstrated a significant greater relative increase in IGFBP-3-PA compared with 10 patients not receiving glucose (32.9 +/- 7.1% vs. 8.6 +/- 6.7%, respectively; P < 0.05). Both groups had reduced insulin sensitivity after surgery(-58 +/- 4%; P < 0.0001; n = 18), as determined by hyperinsulinemic, normoglycemic clamps; however, the group not receiving glucose displayed 18% less insulin sensitivity than the oral glucose load group (P < 0.05). Multiple regression analysis demonstrated that the relative changes in IGFBP-3-PA and C peptide levels were inversely correlated (P < 0.05), suggesting that increased IGFBP-3-PA, presumably increasing IGF bioavailability, may be associated with decreased insulin demands. Interestingly, insulin infusion during the 4-h hyperinsulinemic, normoglycemic clamp performed 24 h after surgery (post-op) resulted in a further increase in IGFBP-3-PA in both groups (P < 0.005), whereas no significant responses could be demonstrated during the pre-op clamp. The expression of increased IGFBP-3-PA was accompanied by conversion of endogenous intact 39/42-kDa IGFBP-3 into its 30-kDa fragmented form as determined by Western immunoblotting, and this conversion was virtually complete after the 4-h post-op clamp in patients displaying marked increases in IGFBP-3-PA. Characterization of the IGFBP-3-PA demonstrated that it was specific for IGFBP-3, as no degradation of IGFBP-1 and -2 was detected, and the use of various protease inhibitors demonstrated that serine proteases and possibly matrix metalloproteinases contribute to the increased IGFBP-3-PA level after surgery. We propose that IGF bioavailability may be increased by the induction of IGFBP-3-PA in insulin-resistant subjects, and that insulin regulates IGFBP-3-PA in this state.

Adipose tissue dysfunction is an important determinant of obesity-associated, lipid-induced metabolic complications. Ceramides are well-known mediators of lipid-induced insulin resistance in peripheral organs such as muscle. DEGS1 is the desaturase catalyzing the last step in the main ceramide biosynthetic pathway. Functional suppression of DEGS1 activity results in substantial changes in ceramide species likely to affect fundamental biological functions such as oxidative stress, cell survival, and proliferation. Here, we show that degs1 expression is specifically decreased in the adipose tissue of obese patients and murine models of genetic and nutritional obesity. Moreover, loss-of-function experiments using pharmacological or genetic ablation of DEGS1 in preadipocytes prevented adipogenesis and decreased lipid accumulation. This was associated with elevated oxidative stress, cellular death, and blockage of the cell cycle. These effects were coupled with increased dihydroceramide content. Finally, we validated in vivo that pharmacological inhibition of DEGS1 impairs adipocyte differentiation. These data identify DEGS1 as a new potential target to restore adipose tissue function and prevent obesity-associated metabolic disturbances.

Antigen-specific immunotherapy is an appealing strategy to preserve beta-cell function in type 1 diabetes, although the approach has yet to meet its therapeutic endpoint. Direct administration of autoantigen into lymph nodes has emerged as an alternative administration route that can improve the efficacy of the treatment. In the first open-label clinical trial in humans, injection of aluminum-formulated glutamic acid decarboxylase (GAD-alum) into an inguinal lymph node led to the promising preservation of C-peptide in patients with recent-onset type 1 diabetes. The treatment induced a distinct immunomodulatory effect, but the response at the cell level has not been fully characterized. Here we used mass cytometry to profile the immune landscape in peripheral blood mononuclear cells from 12 participants of the study before and after 15 months of treatment. The immunomodulatory effect of the therapy included reduction of naïve and unswitched memory B cells, increase in follicular helper T cells and expansion of PD-1+ CD69+ cells in both CD8+ and double negative T cells. In vitro stimulation with GAD65 only affected effector CD8+ T cells in samples collected before the treatment. However, the recall response to antigen after 15 months included induction of CXCR3+ and CD11c+Tbet+ B cells, PD-1+ follicular helper T cells and exhausted-like CD8+ T cells. This study provides a deeper insight into the immunological changes associated with GAD-alum administration directly into the lymph nodes. 

The skeletal research field develops rapidly and has produced several exciting findings in the last year and includes advances in the treatment of rare skeletal disorders and an ever deeper under-standing into the fundamental molecular mechanisms that control skeletal development, metabolism, growth, and mineralization.

The targeting of the C-type natriuretic peptide (CNP) pathway and options to directly antagonize the overactivity of the FGFR3 pathway in achondroplasia continues to be a subject of high inter-est and excitement and in the 2021 yearbook we highlight the dou-ble-blind, randomized placebo-controlled phase 3 study of a CNP analogue (vosoritide) in children with achondroplasia. We also highlight the identification of a novel gene for autosomal domi-nant hypophosphatemic rickets, publication of new growth charts for X-linked hypophosphatemia and two large well-designed pae-diatric vitamin D trials for the prevention of tuberculosis and asthma exacerbation, respectively.

Translational highlights include review on the recent advances of mineral metabolism and biomineralization, in vivo data sug-gesting that modification of the synovial microenvironment may allow endogenous skeletal stem cells to form hyalin cartilage and thereby heal articular cartilage injuries, as well as a study using gene targeting in zebra fish to reveal the pathogenic mechanism by which mutations in CRTAP and P3H1 causes osteogenesis imper-fecta type VII and VIII, respectively.

Advances in the understanding of skeletal biology a study by McDonald et al. that challenges the current dogma on the origin and fate of osteoclasts as they show evidence that multinucleated osteoclasts can fission into daughter cells, a.k.a. osteomorphs, that subsequently are recycled into bone resorbing osteoclasts via a RANKL-dependent process. Additional articles in this section directly and indirectly highlight the critical role of loading and mechanical stress on the growing skeleton. Several of these excit-ing findings will be highlighted in the presentation.

Objective: The Vitamin D receptor (VDR) has been positively associated with skeletal muscle mass, function and regeneration. Mechanistic studies have focused on the loss of the receptor, with in vivo whole-body knockout models demonstrating reduced myofibre size and function and impaired muscle development. To understand the mechanistic role upregulation of the VDR elicits in muscle mass/health, we studied the impact of VDR over-expression (OE) in vivo before exploring the importance of VDR expression upon muscle hypertrophy in humans.

Methods: Wistar rats underwent in vivo electrotransfer (IVE) to overexpress the VDR in the Tibialis anterior (TA) muscle for 10 days, before comprehensive physiological and metabolic profiling to characterise the influence of VDR-OE on muscle protein synthesis (MPS), anabolic signalling and satellite cell activity. Stable isotope tracer (D2O) techniques were used to assess sub-fraction protein synthesis, alongside RNA-Seq analysis. Finally, human participants underwent 20 wks of resistance exercise training, with body composition and transcriptomic analysis.

Results: Muscle VDR-OE yielded total protein and RNA accretion, manifesting in increased myofibre area, i.e., hypertrophy. The observed increases in MPS were associated with enhanced anabolic signalling, reflecting translational efficiency (e.g., mammalian target of rapamycin (mTOR-signalling), with no effects upon protein breakdown markers being observed. Additionally, RNA-Seq illustrated marked extracellular matrix (ECM) remodelling, while satellite cell content, markers of proliferation and associated cell-cycled related gene-sets were upregulated. Finally, induction of VDR mRNA correlated with muscle hypertrophy in humans following long-term resistance exercise type training.

Conclusion: VDR-OE stimulates muscle hypertrophy ostensibly via heightened protein synthesis, translational efficiency, ribosomal expansion and upregulation of ECM remodelling-related gene-sets. Furthermore, VDR expression is a robust marker of the hypertrophic response to resistance exercise in humans. The VDR is a viable target of muscle maintenance through testable Vitamin D molecules, as active molecules and analogues. (C) 2020 The Author(s). Published by Elsevier GmbH.

INTRODUCTION BACKGROUND TO METABOLOMICS: Metabolomics is the comprehensive study of the metabolome, the repertoire of biochemicals (or small molecules) present in cells, tissues, and body fluids. The study of metabolism at the global or "-omics" level is a rapidly growing field that has the potential to have a profound impact upon medical practice. At the center of metabolomics, is the concept that a person's metabolic state provides a close representation of that individual's overall health status. This metabolic state reflects what has been encoded by the genome, and modified by diet, environmental factors, and the gut microbiome. The metabolic profile provides a quantifiable readout of biochemical state from normal physiology to diverse pathophysiologies in a manner that is often not obvious from gene expression analyses. Today, clinicians capture only a very small part of the information contained in the metabolome, as they routinely measure only a narrow set of blood chemistry analytes to assess health and disease states. Examples include measuring glucose to monitor diabetes, measuring cholesterol and high density lipoprotein/low density lipoprotein ratio to assess cardiovascular health, BUN and creatinine for renal disorders, and measuring a panel of metabolites to diagnose potential inborn errors of metabolism in neonates.

OBJECTIVES OF WHITE PAPER—EXPECTED TREATMENT OUTCOMES AND METABOLOMICS ENABLING TOOL FOR PRECISION MEDICINE: We anticipate that the narrow range of chemical analyses in current use by the medical community today will be replaced in the future by analyses that reveal a far more comprehensive metabolic signature. This signature is expected to describe global biochemical aberrations that reflect patterns of variance in states of wellness, more accurately describe specific diseases and their progression, and greatly aid in differential diagnosis. Such future metabolic signatures will: (1) provide predictive, prognostic, diagnostic, and surrogate markers of diverse disease states; (2) inform on underlying molecular mechanisms of diseases; (3) allow for sub-classification of diseases, and stratification of patients based on metabolic pathways impacted; (4) reveal biomarkers for drug response phenotypes, providing an effective means to predict variation in a subject's response to treatment (pharmacometabolomics); (5) define a metabotype for each specific genotype, offering a functional read-out for genetic variants: (6) provide a means to monitor response and recurrence of diseases, such as cancers: (7) describe the molecular landscape in human performance applications and extreme environments. Importantly, sophisticated metabolomic analytical platforms and informatics tools have recently been developed that make it possible to measure thousands of metabolites in blood, other body fluids, and tissues. Such tools also enable more robust analysis of response to treatment. New insights have been gained about mechanisms of diseases, including neuropsychiatric disorders, cardiovascular disease, cancers, diabetes and a range of pathologies. A series of ground breaking studies supported by National Institute of Health (NIH) through the Pharmacometabolomics Research Network and its partnership with the Pharmacogenomics Research Network illustrate how a patient's metabotype at baseline, prior to treatment, during treatment, and post-treatment, can inform about treatment outcomes and variations in responsiveness to drugs (e.g., statins, antidepressants, antihypertensives and antiplatelet therapies). These studies along with several others also exemplify how metabolomics data can complement and inform genetic data in defining ethnic, sex, and gender basis for variation in responses to treatment, which illustrates how pharmacometabolomics and pharmacogenomics are complementary and powerful tools for precision medicine.

CONCLUSIONS KEY SCIENTIFIC CONCEPTS AND RECOMMENDATIONS FOR PRECISION MEDICINE: Our metabolomics community believes that inclusion of metabolomics data in precision medicine initiatives is timely and will provide an extremely valuable layer of data that compliments and informs other data obtained by these important initiatives. Our Metabolomics Society, through its "Precision Medicine and Pharmacometabolomics Task Group", with input from our metabolomics community at large, has developed this White Paper where we discuss the value and approaches for including metabolomics data in large precision medicine initiatives. This White Paper offers recommendations for the selection of state of-the-art metabolomics platforms and approaches that offer the widest biochemical coverage, considers critical sample collection and preservation, as well as standardization of measurements, among other important topics. We anticipate that our metabolomics community will have representation in large precision medicine initiatives to provide input with regard to sample acquisition/preservation, selection of optimal omics technologies, and key issues regarding data collection, interpretation, and dissemination. We strongly recommend the collection and biobanking of samples for precision medicine initiatives that will take into consideration needs for large-scale metabolic phenotyping studies.

The pyramidal neurons of the hippocampal CA1 region are essential for cognitive functions such as spatial learning and memory, and are selectively destroyed after cerebral ischemia. To analyze whether degenerated CA1 neurons are replaced by new neurons and whether such regeneration is associated with amelioration in learning and memory deficits, we have used a rat global ischemia model that provides an almost complete disappearance (to approximately 3% of control) of CA1 neurons associated with a robust impairment in spatial learning and memory at two weeks after ischemia. We found that transient cerebral ischemia can evoke a massive formation of new neurons in the CA1 region, reaching approximately 40% of the original number of neurons at 90 days after ischemia (DAI). Co-localization of the mature neuronal marker neuronal nuclei with 5-bromo-2'-deoxyuridine in CA1 confirmed that neurogenesis indeed had occurred after the ischemic insult. Furthermore, we found increased numbers of cells expressing the immature neuron marker polysialic acid neuronal cell adhesion molecule in the adjacent lateral periventricular region, suggesting that the newly formed neurons derive from this region. The reappearance of CA1 neurons was associated with a recovery of ischemia-induced impairments in spatial learning and memory at 90 DAI, suggesting that the newly formed CA1 neurons restore hippocampal CA1 function. In conclusion, these results show that the brain has an endogenous capacity to form new nerve cells after injury, which correlates with a restoration of cognitive functions of the brain.

Background: Heterozygous loss-of-function mutations in the aggrecan gene (ACAN) cause autosomal dominant short stature with advanced bone age, early-onset osteoarthritis and intervertebral disc disease (SSOAOD; OMIM#165800). ACAN mutations is a relatively common finding in idiopathic short stature (ISS) and has been reported to be the cause of growth failure in approximately 2% of children with ISS. However, the underlying cellular and molecular mechanisms by which ACAN mutations cause growth failure in SSOAOD have not been elucidated.

Objective: To investigate the underlying cellular and molecular mechanisms of growth failure using a mouse model of SSOAOD.

Methods: Cartilage matrix deficiency mouse (Acan cmd) has a naturally occurring 7 bp micro-deletion in aggrecan gene. Heterozygous Acancmd and wild-type (WT) male and female mice were assessed for skeletal and body growth at 1,3,6,12 and 24 weeks of age. Histomorphometric analysis was performed on Masson-Trichrome stained proximal tibial and distal femoral growth plates. Cell proliferation was assessed by EdU incorporation. Quantification of percentage matrix area was performed using Image J. Single-cell RNA sequencing was carried out on chondro-cytes isolated from 18 day old WT and Acan cmd female mice according to 3’ gene expression protocol (10X Genomics).

Results: Heterozygous Acancmd mice were born at a normal size and similar to humans with SSOAOD but showed decreased postnatal growth resulting in a gradually worsening dwarfism with reduced total body length and tibial and femoral lengths (p<0.0001). In the growth plates, chondrocytes were found to be more tightly packed with reduced matrix area (p<0.0001) and increased column density in Acan cmd mice compared to WT mice. Growth plate height (p<0.0001), heights of the individual zones (p<0.001), the number of resting zone chondrocytes (p<0.01), proliferative cells per column (p<0.0001), and the size of terminal hypertrophic chondrocytes (p<0.001) were slightly reduced in both male and female Acan cmd mice, especially at 1 week of age. Interestingly, chondrocyte proliferation was similar in Acan cmd and WT mice at all time-points assessed (p=0.90). Female Acan cmd mice exhibited a more pronounced phenotype than male mice.

Conclusions: Similar to children with heterozygous ACAN mutations, heterozygous Acancmd mice exhibit a growth pattern with postnatal growth failure resulting in adult short stature. The growth failure is primarily caused by decreased matrix production and hypertrophic cell size, whereas chondrocyte proliferation is normal. Single-cell RNA sequencing of growth plate chondrocytes is ongoing and will identify the underlying pathogenic mechanisms and might also identify compensatory mechanisms limiting the effects of aggrecan haploinsufficiency.

Background: Heterozygous Aggrecan (Acan) mutations cause autosomal short stature (ISS) with advanced bone age, early-onset osteoarthritis and intervertebral disc disease (OMIM#165800) in humans. Cartilage matrix deficiency mouse (Acancmd) has a naturally occurring 7 bp micro-deletion in aggrecan gene. Heterozygous Acancmd mice develop postnatal dwarfism with progressing age. However, the underlying cellular and molecular mechanisms causing the growth failure have not been characterized in detail.

Objective: To investigate the molecular mechanism of proportionate dwarfism in heterozygous Acan cmd mouse.

Methods: Heterozygous Acancmd and wild-type (WT) male and female mice were assessed for skeletal and body growth, at 1, 3, 6, 12 and 24 weeks of age. Histomorphometric analysis was performed on Masson-Trichrome stained proximal tibial and femoral growth plates. Cell proliferation was assessed by EdU incorpora-tion and assessed by confocal microscopy. Quantification of percentage matrix area was performed using Image J image analysis software.

Results: Heterozygous Acancmd mice were born with a normal body size. However, postnatal growth was reduced resulting in a gradually worsening dwarfism with reduced total body length (p <0.0001) as well as shorter tibial length (p<0.0001) and femoral length (p<0.0001) than their wild-type littermates. Histomorphometric analyses revealed that growth plate chondrocytes were more tightly packed with reduced matrix area (p<0.001) and increased proliferative column density in Acancmd mice compared to wild-type mice. Interestingly, the number of resting zone chondrocytes, proliferative cells per column and hypertropic cells per column were reduced at 1 week of age. In contrast, the size of terminal hypertrophic chondrocytes were normal during early postnatal growth, but reduced at 12 and 24 weeks of age. Despite the differences in growth plate morphology, chondrocyte proliferation was similar in Acan cmd and WT mice. Interestingly, female mice exhibited a more pronounced growth phenotype than the males.

Conclusions: Heterozygous Acan cmd mice have a growth disorder that is similar to that in children with heterozygous ACAN mutations in terms of progression with age as well as in magnitude (10-15% smaller). Histomorphometric analyses suggest that the growth failure of aggrecan deficient mice is due to a combination of reduced matrix production and decreased size of the terminal hypertrophic chondrocytes. Further studies will elucidate the pathogenic mechanisms as well as the effect of estrogen on growth in aggrecan haploinsufficiency.

Context: Whether biochemical remission normalizes life expectancy in Cushing's disease (CD) patients remains unclear. Previous studies evaluating mortality in CD are limited by using the expected number of deaths in the background population instead of the actual number in matched controls.

Objective and setting: To study mortality by time-to-event analysis in an unselected nationwide CD patient cohort.

Design and participants: Longitudinal data from the Swedish Pituitary Register of 371 patients diagnosed with CD from 1991 to 2018 and information from the Swedish Cause of Death Register were evaluated. Four controls per patient (n = 1484) matched at the diagnosis date by age, sex, and residential area were included.

Main outcome measures: Mortality and causes of death.

Results: The median diagnosis age was 44 years (interquartile range 32-56), and the median follow-up was 10.6 years (5.7-18.0). At the 1-, 5-, 10-, 15-, and 20-year follow-ups, the remission rates were 80%, 92%, 96%, 91%, and 97%, respectively. Overall mortality was increased in CD patients compared with matched controls [hazard ratio (HR) 2.1 (95% CI 1.5-2.8)]. The HRs were 1.5 (1.02-2.2) for patients in remission at the last follow-up (n = 303), 1.7 (1.03-2.8) for those in remission after a single pituitary surgery (n = 177), and 5.6 (2.7-11.6) for those not in remission (n = 31). Cardiovascular diseases (32/66) and infections (12/66) were overrepresented causes of death.

Conclusions: Mortality was increased in CD patients despite biochemical remission compared to matched controls. The study highlights the importance of careful comorbidity monitoring, regardless of remission status.