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BACKGROUND: Melatonin is increasingly used as a pharmacological sleep aid but it is also emerging as a regulator of glucose homoeostasis. Yet, previous research has been ambiguous with reports of both positive and negative effects of melatonin on glucose metabolism.OBJECTIVES: To assess the effect of daily treatment with melatonin on fasting glucose, insulin, insulin sensitivity and haemoglobin A1c (HbA1c) levels.DATA SOURCES: MEDLINE, EMBASE, CENTRAL, clinicaltrials.gov and clinicaltrialsregister.eu were systematically searched.ELIGIBILITY CRITERIA, PARTICIPANTS AND INTERVENTIONS: All randomized, placebo-controlled studies with melatonin treatment were assessed. We included studies with daily melatonin treatment (≥2 weeks) of healthy adults or patients with metabolic diseases.METHODS: Hedges' g differences were calculated for the metabolic parameters of the included studies, heterogeneity was assessed with χ2 and I2 tests and meta-analyses were performed with the random-effects model.RESULTS: Long-term treatment with melatonin did not change fasting glucose significantly compared with placebo (g: -0.07 [-0.22 to 0.08], n = 603) but it reduced fasting insulin levels slightly (g: -0.27 [-0.50 to -0.04], n = 278) and trended towards reduced insulin resistance (HOMA-IR) (g: -0.20 [-0.44 to 0.03], n = 278). HbA1c levels were largely unaffected by melatonin treatment compared with placebo (g: 0.14 [-0.19 to 0.46], n = 142).CONCLUSIONS: With the available literature, melatonin seems to be a glucose-metabolic safe sleep aid in patients with metabolic diseases and in healthy adults. It may even have beneficial glucose-metabolic effects as fasting insulin levels were reduced in this meta-analysis, but the confidence intervals of the meta-analyses are wide, underscoring the need for further research within this field.

The aim of this study was to explore how prepregnancy glycosylated hemoglobin (HbA1c) affects the course of HbA1c and insulin requirements during pregnancy, the gestational length, and birthweight.An observational cohort study was conducted consisting of 380 women with type 1 diabetes who gave birth 530 times from 2004 to 2014. The participants were divided into four groups according to prepregnancy HbA1c.HbA1c was significantly different between the groups at all time intervals from week 5 to 10 to week 33 to 36 (P ≤ .01). In group 1, with the lowest prepregnancy HbA1c (6.5% [48 mmol/mol]), HbA1c stayed at the same level throughout pregnancy. In the other groups (group 2: 6.5% [48 mmol/mol]-7.9% [63 mmol/mol], group 3: 8% [64 mmol/mol]-9.9% [86 mmol/mol], and group 4: 10% [86 mmol/mol]) a decrease in HbA1c was seen in early pregnancy but stabilized from midpregnancy onward. Group 1 had the lowest daily insulin requirements throughout pregnancy among the four groups (P = .001). The relationship between birthweight and prepregnancy HbA1c was found to be inversely U-shaped. Mean gestational length in group 4 was significantly shorter than in group 1 (P = .001).In this very large cohort, we found that a poor prepregnancy HbA1c is a predictor for poor glycemic control during pregnancy and that HbA1c decreases until midpregnancy and then plateaus. A very poor prepregnancy HbA1c is associated with shorter gestational length and lower birthweight, which is contrary to the common assumption that poor glycemic control leads to higher birthweight.背景: 本研究旨在探讨孕前糖化血红蛋白(HbA1c)对孕期HbA1c进程和胰岛素需求、孕周和出生体重的影响。 方法: 对2004年至2014年间总计生育530次的380例1型糖尿病妇女进行观察性队列研究。受试者根据孕前HbA1c水平分为四组。 结果: HbA1c在5~10周、33~36周各时间点组间差异均有统计学意义(P0.01); 第1组孕前HbA1c最低(6.5%[48 mmol/mol]), 整个孕期HbA1c维持在同一水平。其他各组(第2组:6.5%[48 mmol/mol]~7.9%[63 mmol/mol], 第3组:8%[64 mmol/mol]~9.9%[86 mmol/mol], 第4组:10%[86 mmol/mol]), 早孕时HbA1c下降, 但中期以后稳定。在四组中, 第一组在整个妊娠期间的每日胰岛素需求量最低(P=0.001)。出生体重与孕前HbA1c呈倒U型关系。第4组的平均孕长明显短于第1组(P=0.001)。 结论: 在这个较大的队列中, 我们发现孕前HbA1c较高是妊娠期血糖控制较差的预测因子, 而HbA1c在妊娠中期下降, 然后进入平台期。极高的孕前HbA1c与较短的孕长和较低的出生体重有关, 这与血糖控制不佳会导致较高出生体重的普遍假设相反。.

Context Glucose homeostasis is under circadian control through both endocrine and intracellular mechanisms, with several lines of evidence suggesting that melatonin affects glucose homeostasis. Objective To evaluate the acute in vivo and in situ effects of melatonin on secretion of the incretin hormones, glucagon-like-peptide 1 (GLP-1) and glucose-dependent insulinotropic peptide (GIP), and their impact on β-cell insulin secretion. Design A human randomized, double-blinded, placebo-controlled crossover study combined with a confirmatory in situ study of perfused rat intestines. Setting Aarhus University Hospital. Methods Fifteen healthy male participants were examined 2 × 2 times: an oral glucose tolerance test (OGTT) was performed on day 1 and an isoglycemic IV glucose infusion replicating the blood glucose profile of the OGTT day was performed on day 2. These pairs of study days were repeated on treatment with melatonin and placebo, respectively. For the in situ study, 6 rat intestines and 4 rat pancreases were perfused arterially with perfusion buffer ± melatonin. The intestines were concomitantly perfused with glucose through the luminal compartment. Results In humans, melatonin treatment resulted in reduced GIP secretion compared with placebo (ANOVA P = 0.003), an effect also observed in the perfused rat intestines (ANOVA P = 0.003), in which GLP-1 secretion also was impaired by arterial melatonin infusion (ANOVA P Conclusion Melatonin reduced GIP secretion during an oral glucose challenge in healthy young men but did not affect insulin secretion. Reduced GIP secretion was confirmed in an in situ model of the rat intestine.

Type 2 diabetes mellitus (T2DM) is associated with impaired skeletal muscle function and degeneration of the skeletal muscles. However, the mechanisms underlying the degeneration are not well described in human skeletal muscle. Here we show that skeletal muscle of T2DM patients exhibit degenerative remodeling of the extracellular matrix that is associated with a selective increase of a subpopulation of fibro-adipogenic progenitors (FAPs) marked by expression of THY1 (CD90)—the FAPCD90+. We identify platelet-derived growth factor (PDGF) as a key FAP regulator, as it promotes proliferation and collagen production at the expense of adipogenesis. FAPsCD90+ display a PDGF-mimetic phenotype, with high proliferative activity, clonogenicity, and production of extracellular matrix. FAPCD90+ proliferation was reduced by in vitro treatment with metformin. Furthermore, metformin treatment reduced FAP content in T2DM patients. These data identify a PDGF-driven conversion of a subpopulation of FAPs as a key event in the fibrosis development in T2DM muscle. Sin financiación 31.373 JCR (2021) Q1, 8/195 Cell Biology 9.297 SJR (2021) Q1, 9/293 Cell Biology No data IDR 2021 UEM

Background Women with prior gestational diabetes mellitus (GDM) are at high risk of developing type 2 diabetes; however, this risk can be reduced by engaging in positive health behaviours e.g. healthy diet and regular physical activity. As such behaviours are difficult to obtain and maintain there is a need to develop sustainable behavioural interventions following GDM. We aimed to report the process of systematically developing a health promotion intervention to increase quality of life and reduce diabetes risk among women with prior GDM and their families. We distil general lessons about developing complex interventions through co-production and discuss our extensions to intervention development frameworks. Methods The development process draws on the Medical Research Council UK Development of complex interventions in primary care framework and an adaptation of a three-stage framework proposed by Hawkins et al. From May 2017 to May 2019, we iteratively developed the Face-it intervention in four stages: 1) Evidence review, qualitative research and stakeholder consultations; 2) Co-production of the intervention content; 3) Prototyping, feasibility- and pilot-testing and 4) Core outcome development. In all stages, we involved stakeholders from three study sites. Results During stage 1, we identified the target areas for health promotion in families where the mother had prior GDM, including applying a broad understanding of health and a multilevel and multi-determinant approach. We pinpointed municipal health visitors as deliverers and the potential of using digital technology. In stage 2, we tested intervention content and delivery methods. A health pedagogic dialogue tool and a digital health app were co-adapted as the main intervention components. In stage 3, the intervention content and delivery were further adapted in the local context of the three study sites. Suggestions for intervention manuals were refined to optimise flexibility, delivery, sequencing of activities and from this, specific training manuals were developed. Finally, at stage 4, all stakeholders were involved in developing realistic and relevant evaluation outcomes. Conclusions This comprehensive description of the development of the Face-it intervention provides an example of how to co-produce and prototype a complex intervention balancing evidence and local conditions. The thorough, four-stage development is expected to create ownership and feasibility among intervention participants, deliverers and local stakeholders. Trial registration ClinicalTrials.gov NCT03997773, registered retrospectively on 25 June 2019.

Aims: This systematic review examines the association between maternal lifestyle, diet and physical activity, and epigenetic changes in the offspring. Methods: A literature search was conducted using multiple science databases: PubMed, Embase and Cochrane Library, on 10 March 2021. RCT and Cohort studies in English or Scandinavian languages were included. Exposure variables included diet, lifestyle, meal patterns or physical activity. Studies using dietary supplements as exposure variables were excluded. Outcome variables included were DNA methylation, microRNA or histone changes in placenta, cord blood or offspring. Two independent authors screened, read and extracted data from the included papers. The Cochrane risk-of-bias tool for randomized trials (RoB2) and The Critical Appraisal Skills Program (CASP) Cohort Study Checklist were used to assess risk of bias in the included studies. A qualitative approach was employed due to heterogeneity of exposures and results of the studies. Results: 16 studies and 3617 participants were included in the final analysis. The exposure variables included physical activity, carbohydrate, low glycemic index diet, added sugar, fat, Mediterranean diet and pro-inflammatory diet. The outcome variables identified were differences in DNA methylation and microRNA. Most studies described epigenetic changes in either placenta or cord blood. Genes reported to be methylated were GR, HSD2, IGF-2, PLAG1, MEG-3, H19 and RXRA. However, not all studies found epigenetic changes strong enough to pass multiple testing, and the study quality varied. Conclusion: Despite the variable quality of the included studies, the results in this review suggest that there may be an association between the mother’s lifestyle, diet and level of physical activity during pregnancy and epigenetic changes in the offspring.

Summary During pregnancy, maternal tissues become increasingly insensitive to insulin in order to liberate nutritional supply to the growing fetus, but occasionally insulin resistance in pregnancy becomes severe and the treatment challenging. We report a rare and clinically difficult case of extreme insulin resistance with daily insulin requirements of 1420 IU/day during pregnancy in an obese 36-year-old woman with type 2 diabetes (T2D) and polycystic ovary syndrome (PCOS). The woman was referred to the outpatient clinic at gestational week 12 + 2 with a hemoglobin A1c (HbA1c) at 59 mmol/mol. Insulin treatment was initiated immediately using Novomix 30, and the doses were progressively increased, peaking at 1420 units/day at week 34 + 4. At week 35 + 0, there was an abrupt fall in insulin requirements, but with no signs of placental insufficiency. At week 36 + 1 a, healthy baby with no hypoglycemia was delivered by cesarean section. Blood samples were taken late in pregnancy to search for causes of extreme insulin resistance and showed high levels of C-peptide, proinsulin, insulin-like growth factor (IGF-1), mannan-binding-lectin (MBL) and leptin. CRP was mildly elevated, but otherwise, levels of inflammatory markers were normal. Insulin antibodies were undetectable, and no mutations in the insulin receptor (INSR) gene were found. The explanation for the severe insulin resistance, in this case, can be ascribed to PCOS, obesity, profound weight gain, hyperleptinemia and inactivity. This is the first case of extreme insulin resistance during pregnancy, with insulin requirements close to 1500 IU/day with a successful outcome, illustrating the importance of a close interdisciplinary collaboration between patient, obstetricians and endocrinologists. Learning points This is the first case of extreme insulin resistance during pregnancy, with insulin requirements of up to 1420 IU/day with a successful outcome without significant fetal macrosomia and hypoglycemia. Obesity, PCOS, T2D and high levels of leptin and IGF-1 are predictors of severe insulin resistance in pregnancy. A close collaboration between patient, obstetricians and endocrinologists is crucial for tailoring the best possible treatment for pregnant women with diabetes, beneficial for both the mother and her child.

Melatonin regulates circadian rhythm, but may also have effects on glucose homeostasis. A common G-allele in the MTNR1B locus has been associated with an increased risk of type 2 diabetes (T2DM). We aimed to examine acute effects of high doses of melatonin on glucose metabolism with attention to MTNR1B genotype. Twenty men were examined in a double-blinded, randomized crossover study on two nonconsecutive days with four doses of 10 mg oral melatonin or placebo. Insulin sensitivity and insulin secretion were assessed by an intravenous glucose tolerance test (IVGTT) and a hyperinsulinaemic-euglycaemic clamp (HEC). Blood samples were drawn to determine the metabolic profile and MTNR1B rs10830963 genotype. Indirect calorimetry and blood pressure measurements were also performed. Insulin sensitivity index was significantly reduced on the melatonin day (P = .028) in the whole group and in homozygous carriers of the rs10830963 C-allele (P = .041). Glucose during the IVGTT was unaffected, but there was a tendency towards lower insulin and C-peptide levels in the first minutes after glucose administration in G-allele carriers. Systolic blood pressure decreased and lipid oxidation increased significantly on the melatonin day in rs10830963 G-allele carriers. Overall, our study reports that acute administration of melatonin in supra-physiological doses may have a negative impact on insulin sensitivity. Clinical trial registration number (clinicaltrial.gov): NCT03204877.

Background Gestational diabetes mellitus (GDM) is associated with an increased risk of future diabetes in both mother, father and offspring. More knowledge is needed about how to effectively reduce the risk of diabetes through sustained behavioural interventions in these families. The Face-it intervention is a complex health promotion intervention embedded in multi-level supportive environments. The aim of the intervention is to reduce type 2 diabetes risk and increase quality of life among families in the first year following a GDM-affected pregnancy by promoting physical activity, healthy dietary behaviours and breastfeeding through a focus on social support, motivation, self-efficacy, risk perception and health literacy. Methods This national multicentre study is a two-arm randomised controlled trial including 460 women with GDM in a ratio of 2 (intervention):1 (usual care). The Face-it intervention consists of three main components: 1) additional visits from municipal health visitors, 2) digital health coaching tailored to family needs and 3) a structured cross-sectoral communication system in the health care system. The intervention runs from 3 to 12 months after delivery. The primary outcome is maternal body mass index at 12 months after delivery as a proxy for diabetes risk. The women will be examined at baseline and at follow-up, and this examination will include blood tests, oral glucose tolerance test (OGTT), anthropometrics, blood pressure, self-reported diet and physical activity, breastfeeding, quality of life, health literacy, physical and mental health status, risk perception and social support. Aside from those data collected for OGTT and breastfeeding and offspring parameters, the same data will be collected for partners. Data on offspring anthropometry will also be collected. Information on pregnancy- and birth-related outcomes will be derived from the medical records of the woman and child. Discussion This randomised controlled trial seeks to demonstrate whether the Face-it intervention, addressing the individual, family and health care system levels, is superior to usual care in reducing diabetes risk for mothers and their families. Coupled with a process evaluation and an economic analysis, the study will provide evidence for policymakers and health services about health promotion among families affected by GDM and the potential for reducing risk of type 2 diabetes and associated conditions. Trial registration ClinicalTrials.gov NCT03997773. Registered June 25, 2019 – Retrospectively registered.

Carbohydrate is the macronutrient that has the greatest impact on blood glucose response. Limited data are available on how carbohydrate distribution throughout the day affects blood glucose in women with gestational diabetes mellitus (GDM). We aimed to assess how a high-carbohydrate morning-intake (HCM) versus a low-carbohydrate-morning-intake (LCM), affect glycemic variability and glucose control. In this randomized crossover study continuous glucose monitoring (CGM) was performed in 12 women with diet treated GDM (75 g, 2-h OGTT &ge, 8.5 mmol/L), who went through 2 &times, 3 days of HCM and LCM. A within-subject-analysis showed a significantly higher mean amplitude of glucose excursions (MAGE) (0.7 mmol/L, p = 0.004) and coefficient of variation (CV) (5.1%, p = 0.01) when comparing HCM with LCM, whereas a significantly lower mean glucose (MG) (&minus, 0.3 mmol/L, p = 0.002) and fasting blood glucose (FBG) were found (&minus, 0.4 mmol/L, p = 0.01) on the HCM diet compared to the LCM diet. In addition, insulin resistance, expressed as Homeostatic Model Assessment for Insulin Resistance (HOMA-IR), decreased significantly during HCM. Results indicate that a carbohydrate distribution of 50% in the morning favors lower blood glucose and improvement in insulin sensitivity in women with GDM, but in contrary gives a higher glycemic variability.

Hypoglycemia is the leading limiting factor in glycemic management of insulin-treated diabetes. Skeletal muscle is the predominant site of insulin-mediated glucose disposal. Our study used a crossover design to test to what extent insulin-induced hypoglycemia affects glucose uptake in skeletal muscle and whether hypoglycemia counterregulation modulates insulin and catecholamine signaling and glycogen synthase activity in skeletal muscle. Nine healthy volunteers were examined on three randomized study days: 1) hyperinsulinemic hypoglycemia (bolus insulin), 2) hyperinsulinemic euglycemia (bolus insulin and glucose infusion), and 3) saline control with skeletal muscle biopsies taken just before, 30 min after, and 75 min after insulin/saline injection. During hypoglycemia, glucose levels reached a nadir of ∼2.0 mmol/L, and epinephrine rose to ∼900 pg/mL. Hypoglycemia impaired insulin-stimulated glucose disposal and glucose clearance in skeletal muscle, whereas insulin signaling in glucose transport was unaffected by hypoglycemia. Insulin-stimulated glycogen synthase activity was completely ablated during hyperinsulinemic hypoglycemia, and catecholamine signaling via cAMP-dependent protein kinase and phosphorylation of inhibiting sites on glycogen synthase all increased.

Insulin resistance changes over time during pregnancy, and in the last half of the pregnancy, insulin resistance increases considerably and can become severe, especially in women with gestational diabetes and type 2 diabetes. Numerous factors such as placental hormones, obesity, inactivity, an unhealthy diet, and genetic and epigenetic contributions influence insulin resistance in pregnancy, but the causal mechanisms are complex and still not completely elucidated. In this review, we strive to give an overview of the many components that have been ascribed to contribute to the insulin resistance in pregnancy. Knowledge about the causes and consequences of insulin resistance is of extreme importance in order to establish the best possible treatment during pregnancy as severe insulin resistance can result in metabolic dysfunction in both mother and offspring on a short as well as long-term basis.

The aims of this study were to determine the role of lipolysis in hypoglycaemia and define the underlying intracellular mechanisms. Nine healthy volunteers were randomised to treatment order of three different treatments (crossover design). Treatments were: (1) saline control; (2) hyperinsulinaemic hypoglycaemia (HH; i.v. bolus of 0.1 U/kg insulin); and (3) hyperinsulinaemic euglycaemia (HE; i.v. bolus of 0.1 U/kg insulin and 20% glucose). Inclusion criteria were that volunteers were healthy, aged >18 years, had a BMI between 19 and 26 kg/m2, and provided both written and oral informed consent. Exclusion criteria were the presence of a known chronic disease (including diabetes mellitus, epilepsy, ischaemic heart disease and cardiac arrhythmias) and regular use of prescription medication. The data was collected at the medical research facilities at Aarhus University Hospital, Denmark. The primary outcome was palmitic acid flux. Participants were blinded to intervention order, but caregivers were not. Adrenaline (epinephrine) and glucagon concentrations were higher during HH than during both HE and control treatments. NEFA levels and lipid oxidation rates (determined by indirect calorimetry) returned to control levels after 105 min. Palmitate flux was increased to control levels during HH (p = NS) and was more than twofold higher than during HE (overall mean difference between HH vs HE, 114 [95% CI 64, 165 μmol/min]; p

Gestational diabetes mellitus (GDM) among pregnant women increases the risk of both short-term and long-term complications, such as birth complications, babies large for gestational age (LGA), and type 2 diabetes in both mother and offspring. Lifestyle changes are essential in the management of GDM. In this review, we seek to provide an overview of the lifestyle changes which can be recommended in the management of GDM. The diet recommended for women with GDM should contain sufficient macronutrients and micronutrients to support the growth of the foetus and, at the same time, limit postprandial glucose excursions and encourage appropriate maternal gestational weight gain. Blood glucose excursions and hyperglycaemic episodes depend on carbohydrate-intake. Therefore, nutritional counselling should focus on the type, amount, and distribution of carbohydrates in the diet. Further, physical activity has beneficial effects on glucose and insulin levels and it can contribute to a better glycaemic control.

IntroductionThe metabolic abnormalities underlying gestational diabetes mellitus (GDM) include increased insulin resistance and beta cell defects, but it is essential to clarify how insulin resistance and insulin secretion develop post partum in order to decide when and how to screen for type 2 diabetes. The purpose of the present study was to characterize and compare changes in insulin sensitivity, insulin secretion and hormonal status around parturition and 6 months post partum in women with gestational diabetes.Research design and methodsA longitudinal experimental study was performed at Aarhus University Hospital, Denmark. Eight women with GDM were examined at three identical visits: in late pregnancy (LP) between gestational age 34+0 and 36+6, early post partum (EPP) between 12 and 34 days post partum, and late post partum (LPP) 6 months post partum. An intravenous glucose tolerance test was performed, followed by a hyperinsulinemic euglycemic clamp. Blood samples were collected to assess metabolic, hormonal and inflammatory markers at each visit.ResultsFirst and second phase insulin secretion and C-peptide concentrations were higher in late pregnancy than post partum (pLP=0.03±0.004, ISIEPP=0.09±0.008 and ISILPP=0.07±0.008) (pConclusionsInsulin sensitivity improves immediately after delivery in women with GDM but seems to deteriorate within the first 6 months post partum. Our findings underline the importance of having an increased awareness of the profound risk of developing type 2 diabetes after GDM.Trial registration numberNCT02770079.

AIMS/HYPOTHESIS: Lack of insulin and infection/inflammation are the two most common causes of diabetic ketoacidosis (DKA). We used insulin withdrawal followed by insulin administration as a clinical model to define effects on substrate metabolism and to test whether increased levels of counter-regulatory hormones and cytokines and altered adipose tissue signalling participate in the early phases of DKA.METHODS: Nine individuals with type 1 diabetes, without complications, were randomly studied twice, in a crossover design, for 5 h followed by 2.5 h high-dose insulin clamp: (1) insulin-controlled euglycaemia (control) and (2) after 14 h of insulin withdrawal in a university hospital setting.RESULTS: Insulin withdrawal increased levels of glucose (6.1 ± 0.5 vs 18.6 ± 0.5 mmol/l), NEFA, 3-OHB (127 ± 18 vs 1837 ± 298 μmol/l), glucagon, cortisol and growth hormone and decreased HCO3- and pH, without affecting catecholamine or cytokine levels. Whole-body energy expenditure, endogenous glucose production (1.55 ± 0.13 vs 2.70 ± 0.31 mg kg-1 min-1), glucose turnover, non-oxidative glucose disposal, lipid oxidation, palmitate flux (73 [range 39-104] vs 239 [151-474] μmol/min), protein oxidation and phenylalanine flux all increased, whereas glucose oxidation decreased. In adipose tissue, Ser473 phosphorylation of Akt and mRNA levels of G0S2 decreased, whereas CGI-58 (also known as ABHD5) mRNA increased. Protein levels of adipose triglyceride lipase (ATGL) and hormone-sensitive lipase phosphorylations were unaltered. Insulin therapy decreased plasma glucose concentrations dramatically after insulin withdrawal, without any detectable effect on net forearm glucose uptake.CONCLUSIONS/INTERPRETATION: Release of counter-regulatory hormones and overall increased catabolism, including lipolysis, are prominent features of preacidotic ketosis induced by insulin withdrawal, and dampening of Akt insulin signalling and transcriptional modulation of ATGL activity are involved. The lack of any increase in net forearm glucose uptake during insulin therapy after insulin withdrawal indicates muscle insulin resistance.TRIAL REGISTRATION: ClinicalTrials.gov NCT02077348 FUNDING: This study was supported by Aarhus University and the KETO Study Group/Danish Agency for Science Technology and Innovation.

Context Tight glycemic control throughout pregnancy in women with type 1 diabetes is crucial, and knowledge about which factors that affect insulin sensitivity could improve the outcome for both mother and offspring. Objective To evaluate insulin requirements in women with type 1 diabetes during pregnancy and test whether parity affects insulin requirements. Design Observational cohort study consisting of women with type 1 diabetes who gave birth at Aarhus University Hospital, Denmark, from 2004 to 2014. Main Outcome Measure Daily insulin requirement (the hypothesis that parity could affect insulin resistance was formulated before data collection). Results A total of 380 women with a total of 536 pregnancies were included in the study. Mean age was 31.1 years, and prepregnancy hemoglobin A1c was 60 mmol/mol. Parity was as follows: P0, 43%; P1, 40%; P2, 14%; and P3+4, 3%. Insulin requirements from weeks 11 to 16 decreased significantly by 4% (P = 0.0004) and rose from week 19 to delivery with a peak of 70% (P < 0.0005) at weeks 33 to 36. Overall, insulin requirements increased significantly with parity. The unadjusted differences between P0 and P1, P2, and P3+4 were 9% (P < 0.0005), 12% (P < 0.0005), and 23% (P < 0.0011), respectively. After adjustment for confounders, differences were 13% (P < 0.0005), 20% (P < 0.0005), and 36% (P < 0.0005). We also observed an adjusted difference between P1 and P3+4 of 20% (P < 0.0012). Conclusions The data show changes in insulin requirements from week to week in pregnancy and indicate that insulin requirements increase with parity. This suggests that the patient's parity probably should be considered in choosing insulin dosages for pregnant women with type 1 diabetes.

AIMS: Insulin treatment in type 1 diabetes encompasses multiple daily insulin injections (MDI) or continuous subcutaneous insulin infusion (CSII). Both population-based studies and comparative studies regarding CSII use are sparse. The aim of the current study was to describe the prevalence and distribution of CSII use among adults with type 1 diabetes in the Central Denmark Region and to compare metabolic control in CSII-treated patients to those treated with MDI.METHODS: A database was constructed using the Danish Adult Diabetes Registry in 2014/2015 in combination with an audit of the patients' medical records.RESULTS: 3909 adults with type 1 diabetes patients were included. The proportion of patients treated with CSII differed significantly between the 8 regional hospitals from 12.0 % to 31.1 %. CSII users had a significantly lower HbA1c compared to MDI treated patients (7.6 % (60 mmol/mol) versus 8.0 % (64 mmol/mol)) in unadjusted analyses. After adjustment for clinically relevant characteristics the difference between CSII and MDI-treated patients was attenuated, but remained statistically significant.CONCLUSION: The distribution of CSII differed markedly between hospitals and CSII users had better glycemic control, even after adjustment for sex, age, BMI, diabetes duration, smoking, use of lipid-lowering and blood pressure-lowering medication.

Increased sympathetic activity is important in the pathogenesis of hypertension and insulin resistance. Afferent signaling from the kidneys elevates the central sympathetic drive. We investigated the effect of catheter-based renal sympathetic denervation (RDN) on glucose metabolism, inflammatory markers, and blood pressure in nondiabetic patients with treatment-resistant hypertension. Eight subjects were included in an open-labelled study. Each patient was studied before and 6 months after RDN. Endogenous glucose production was assessed by a 3-3H glucose tracer, insulin sensitivity was examined by hyperinsulinemic euglycemic clamp, hormones and inflammatory markers were analyzed, and blood pressure was measured by office blood pressure readings and 24-hour ambulatory blood pressure monitoring. Insulin sensitivity (M-value) increased nonsignificantly from 2.68 ± 0.28 to 3.07 ± 0.41 (p=0.12). A significant inverse correlation between the increase in M-value and BMI 6 months after RDN (p=0.03) was found, suggesting beneficial effects on leaner subjects. Blood pressure decreased significantly, but there were no changes in hormones, inflammatory markers, or endogenous glucose production. Our results indicate that RDN may improve insulin sensitivity in some patients with treatment-resistant hypertension, albeit confirmation of these indications of beneficial effects on leaner subjects awaits the outcome of larger randomized controlled studies.

OBJECTIVES: To investigate, whether renal denervation (RDN) improves arterial stiffness, central blood pressure (C-BP) and heart rate variability (HRV) in patients with treatment resistant hypertension.METHODS: ReSET was a randomized, sham-controlled, double-blinded trial (NCT01459900). RDN was performed by a single experienced operator using the Medtronic unipolar Symplicity Flex(TM) catheter. C-BP, carotid-femoral pulse wave velocity (PWV), and HRV were obtained at baseline and after six months with the SphygmoCor(®)-device.RESULTS: Fifty-three patients (77% of the ReSET-cohort) were included in this substudy. The groups were similar at baseline (SHAM/RDN): n = 27/n = 26; 78/65% males; age 59 ± 9/54 ± 8 years (mean ± SD); systolic brachial BP 158 ± 18/154 ± 17 mmHg; systolic 24-hour ambulatory BP 153 ± 14/151 ± 13 mmHg. Changes in PWV (0.1 ± 1.9 (SHAM) vs. -0.6 ± 1.3 (RDN) m/s), systolic C-BP (-2 ± 17 (SHAM) vs. -8 ± 16 (RDN) mmHg), diastolic C-BP (-2 ± 9 (SHAM) vs. -5 ± 9 (RDN) mmHg), and augmentation index (0.7 ± 7.0 (SHAM) vs. 1.0 ± 7.4 (RDN) %) were not significantly different after six months. Changes in HRV-parameters were also not significantly different. Baseline HRV or PWV did not predict BP-response after RDN.CONCLUSIONS: In a sham-controlled setting, there were no significant effects of RDN on arterial stiffness, C-BP and HRV. Thus, the idea of BP-independent effects of RDN on large arteries and cardiac autonomic activity is not supported.

AIMS/HYPOTHESIS: Diabetic ketoacidosis (DKA) is often caused by concomitant systemic inflammation and lack of insulin. Here we used an experimental human model to test whether and how metabolic responses to insulin are impaired in the early phases of DKA with a specific focus on skeletal muscle metabolism.METHODS: Nine individuals with type 1 diabetes from a previously published cohort were investigated twice at Aarhus University Hospital using a 120 min infusion of insulin (3.0/1.5 mU kg(-1) min(-1)) after an overnight fast under: (1) euglycaemic conditions (CTR) or (2) hyperglycaemic ketotic conditions (KET) induced by an i.v. bolus of lipopolysaccharide and 85% reduction in insulin dosage. The primary outcome was insulin resistance in skeletal muscle. Participants were randomly assigned to one of the two arms at the time of screening using www.randomizer.org . The study was not blinded.RESULTS: All nine volunteers completed the 2 days and are included in the analysis. Circulating concentrations of glucose and 3-hydroxybutyrate increased during KET (mean ± SEM 17.7 ± 0.6 mmol/l and 1.6 ± 0.2 mmol/l, respectively), then decreased after insulin treatment (6.6 ± 0.7 mmol/l and 0.1 ± 0.07 mmol/l, respectively). Prior to insulin infusion (KET vs CTR) isotopically determined endogenous glucose production rates were 17 ± 1.7 μmol kg(-1) min(-1) vs 8 ± 1.3 μmol kg(-1) min(-1) (p = 0.003), whole body phenylalanine fluxes were 2.9 ± 0.5 μmol kg(-1) min(-1) vs 3.1 ± 0.4 μmol kg(-1) min(-1) (p = 0.77) and urea excretion rates were 16.9 ± 2.4 g/day vs 7.3 ± 1.7 g/day (p = 0.01). Insulin failed to stimulate forearm glucose uptake and glucose oxidation in KET compared with CTR (p < 0.05). Glycogen synthase phosphorylation was impaired in skeletal muscle.CONCLUSIONS/INTERPRETATION: In KET, hyperglycaemia is primarily driven by increased endogenous glucose production. Insulin stimulation during early phases of DKA is associated with reduced glucose disposal in skeletal muscle, impaired glycogen synthase function and lower glucose oxidation. This underscores the presence of muscle insulin resistance in the pathogenesis of DKA. Trial registration www.clinicaltrials.gov (ID number: NCT02157155). Funding This work was funded by the Danish Council for Strategic Research (grant no. 0603-00479B).

Background— Circulating lipid levels and myocardial lipid content (MyLC) is increased in type 2 diabetes mellitus. This may cause a state of lipotoxicity that compromises left ventricular function and aggravate heart failure. We investigated the relationship among circulating lipid levels, MyLC, and cardiac function together with the acute cardiac effects of high as opposed to low circulating free fatty acid (FFA) and triglyceride levels in patients with type 2 diabetes mellitus and heart failure. Methods and Results— Eighteen patients underwent 8-hour intralipid/heparin-infusion (high FFA) and hyperinsulinemic-euglycemic clamping (low FFA) in a randomized crossover–designed study. We applied magnetic resonance proton spectroscopy to measure MyLC. Cardiac function was assessed by advanced echocardiography, cardiopulmonary exercise, and MRI. MyLC correlated positively with circulating triglyceride ( r =0.47; r 2 =0.22; P =0.003) and FFA ( r =0.45; r 2 =0.20; P =0.001) levels and inversely with left ventricular ejection fraction ( r =−0.54; r 2 =0.29; P =0.004). Circulating FFA concentrations differed between study arms (0.05±0.04 mmol/L [low FFA] versus 1.04±0.27 mmol/L [high FFA]; P P P =0.02). Peak exercise capacity and oxygen consumption did not differ between the study arms, and neither did postexercise measurements of left ventricular ejection fraction, global strain, and S′max. Conclusions— Our findings indicate that the failing heart of patients with type 2 diabetes mellitus can adapt to short-term extreme changes in circulating substrates and does not display features of acute myocardial lipotoxicity. Clinical Trial Registration— URL: http://www.clinicaltrials.gov . Unique identifier: NCT01192373.

Background: A recent sham-controlled trial (ReSET) showed no sustained effect of renal denervation (RDN) on 24-hour ambulatory blood pressure (24hA-BP) measurements in patients with treatment resistant hypertension.1 The aim of this substudy was to investigate, whether RDN affects central blood pressure (C-BP) and arterial stiffness independently of brachial artery BP-levels. Methods: ReSET was a randomized, sham-controlled, double-blinded single-center trial. Main inclusion criteria were: daytime systolic 24hA-BP ≥145mmHg following 1 month of stable medication and 2 weeks of compliance registration. RDN was performed by a single experienced operator using the unipolar Medtronic Flex catheter1. C-BP and carotid-femoral pulse wave velocity (PWV) were obtained at baseline and after 6 months with the SphygmoCor®-device. Results: Fifty-three patients (77% of the ReSET cohort) were included in this substudy. The groups were similar at baseline (SHAM/RDN): n=27/n=26; 78/65% males; age 59±9/54±8 years (mean±SD); systolic brachial BP 158±18/154±17 mmHg; systolic 24hA-BP 153±14/151±13 mmHg; systolic C-BP 146±20/143±17 mmHg; diastolic C-BP 92±14/94±10 mmHg; augmentation index (AIx) 26±9/28±13 %; PWV 10.7±2.1/10.1±2.2 m/s. Changes in systolic C-BP (−2±17 (SHAM) vs. −8±16 (RDN) mmHg), diastolic C-BP (−2±9 (SHAM) vs. −5±9 (RDN) mmHg), AIx (0.7±7.0 (SHAM) vs. 1.0±7.4 (RDN) %), and PWV (0.1±1.9 (SHAM) vs. −0.6±1.3 (RDN) m/s) were not significantly different after six months (P>0.13 in all tests). Changes in brachial BP and 24hA-BP were also not significantly different. Conclusions: In a sham-controlled setting, there were no significant effects of RDN on C-BP or arterial stiffness. Thus, the idea of BP-independent effects of RDN on large arteries is not supported.

Objective Increasing parity may be a risk factor for the development of type 2 diabetes mellitus and the metabolic alterations during a normal pregnancy induces a prediabetic state; thus, multiple pregnancies may act as a risk factor for development of type 2 diabetes if these physiological alterations in glucose homeostasis are not reversed postpartum. We hypothesize that multiple pregnancies may lead to β-cell exhaustion and that the insulin resistance that occurs during pregnancy may persist after multiple births. Research design and measures A total of 28 healthy premenopausal women were recruited: 15 high parity women (≥4 children) and 13 body mass index (BMI)-matched and age-matched low parity women (1 and 2 children). The study consisted of an intravenous glucose tolerance test for assessment of β-cell function followed by a hyperinsulinemic euglycemic clamp for assessment of insulin sensitivity. Dual-energy X-ray absorptiometry was performed to assess body composition. Results All anthropometric measures, measures of body composition and baseline blood samples were comparable between the 2 groups. Neither first phase insulin release (0–10 min, p=0.92) nor second phase insulin release (10–60 min, p=0.62), both measured as area under the curve, differed between the 2 groups. The M-value, calculated as the mean glucose infusion rate during the last 30 min of the clamp period, was 8.66 (7.70 to 9.63) mg/kg/min in the high parity group compared with 8.41 (7.43 to 9.39) mg/kg/min in the low parity group (p=0.69). Conclusions We did not detect any effects of increasing parity on insulin sensitivity or β-cell function.

BACKGROUND: Renal denervation (RDN), treating resistant hypertension, has, in open trial design, been shown to lower blood pressure (BP) dramatically, but this was primarily with respect to office BP.METHOD: We conducted a SHAM-controlled, double-blind, randomized, single-center trial to establish efficacy data based on 24-h ambulatory BP measurements (ABPM). Inclusion criteria were daytime systolic ABPM at least 145 mmHg following 1 month of stable medication and 2 weeks of compliance registration. All RDN procedures were carried out by an experienced operator using the unipolar Medtronic Flex catheter (Medtronic, Santa Rosa, California, USA).RESULTS: We randomized 69 patients with treatment-resistant hypertension to RDN (n = 36) or SHAM (n = 33). Groups were well balanced at baseline. Mean baseline daytime systolic ABPM was 159 ± 12 mmHg (RDN) and 159 ± 14 mmHg (SHAM). Groups had similar reductions in daytime systolic ABPM compared with baseline at 3 months [-6.2 ± 18.8 mmHg (RDN) vs. -6.0 ± 13.5 mmHg (SHAM)] and at 6 months [-6.1 ± 18.9 mmHg (RDN) vs. -4.3 ± 15.1 mmHg (SHAM)]. Mean usage of antihypertensive medication (daily defined doses) at 3 months was equal [6.8 ± 2.7 (RDN) vs. 7.0 ± 2.5 (SHAM)].RDN performed at a single center and by a high-volume operator reduced ABPM to the same level as SHAM treatment and thus confirms the result of the HTN3 trial.CONCLUSION: Further, clinical use of RDN for treatment of resistant hypertension should await positive results from double-blinded, SHAM-controlled trials with multipolar ablation catheters or novel denervation techniques.This is an open-access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 License, where it is permissible to download and share the work provided it is properly cited. The work cannot be changed in any way or used commercially. http://creativecommons.org/licenses/by-nc-nd/4.0.

Solitary sellar plasmacytomas are exceedingly rare and difficult to distinguish from other pituitary tumors. We report a case of a 62-year-old woman presenting with blurred vision of the right eye and tenderness of the right temporal region, which was interpreted as temporal arteritis. MRI revealed a pituitary mass lesion (20mm×14mm×17mm) without compression of the optic chiasm and her pituitary function was normal. Pituitary surgery was undertaken due to growth of the lesion, and histopathological examination showed a highly cellular neoplasm composed of mature monoclonal plasma cells. Subsequent examinations revealed no evidence of extrasellar myeloma. The patient received pituitary irradiation and has remained well and free of symptoms apart from iatrogenic central diabetes insipidus. Until now, only eight cases of solitary sellar plasmacytoma have been reported. Most frequent symptoms stem from compression of the cranial nerves in the cavernous sinus (III, IV, V), whereas the anterior pituitary function is mostly intact. Learning points A solitary plasmacytoma is a rare cause of a sellar mass lesion. The radiological and clinical features are nonspecific, but cranial nerve affection and intact pituitary function are usually present. The diagnosis is made histologically and has important therapeutic implications. Background Plasmacytomas are characterized by monoclonal plasma cell proliferation in a single lesion, whereas multiple myeloma is a multifocal plasma cell neoplasm characterized by elevated serum monoclonal protein levels and/or increased bone marrow clonal cells with related organ or tissue impairment (increased calcium levels, renal insufficiency, anemia, and bone lesions). Solitary plasmacytomas are uncommon and can either arise from bone or soft tissue (1). Solitary sellar plasmacytomas are exceedingly rare and to date there has only been eight reported cases without progression to multiple myeloma (2, 3, 4, 5, 6, 7). Clinically and radiologically, sellar plasmacytomas mimic benign pituitary tumors, which make the differential diagnosis difficult (3, 6). We present the ninth case of a solitary intrasellar plasmacytoma, which revealed several emblematic features.

Most often, diabetic ketoacidosis (DKA) in adults results from insufficient insulin administration and acute infection. DKA is assumed to release proinflammatory cytokines and stress hormones that stimulate lipolysis and ketogenesis. We tested whether this perception of DKA can be reproduced in an experimental human model by using combined insulin deficiency and acute inflammation and tested which intracellular mediators of lipolysis are affected in adipose tissue. Nine subjects with type 1 diabetes were studied twice: 1) insulin-controlled euglycemia and 2) insulin deprivation and endotoxin administration (KET). During KET, serum tumor necrosis factor-α, cortisol, glucagon, and growth hormone levels increased, and free fatty acids and 3-hydroxybutyrate concentrations and the rate of lipolysis rose markedly. Serum bicarbonate and pH decreased. Adipose tissue mRNA contents of comparative gene identification-58 (CGI-58) increased and G0/G1 switch 2 gene (G0S2) mRNA decreased robustly. Neither protein levels of adipose triglyceride lipase (ATGL) nor phosphorylations of hormone-sensitive lipase were altered. The clinical picture of incipient DKA in adults can be reproduced by combined insulin deficiency and endotoxin-induced acute inflammation. The precipitating steps involve the release of proinflammatory cytokines and stress hormones, increased lipolysis, and decreased G0S2 and increased CGI-58 mRNA contents in adipose tissue, compatible with latent ATGL stimulation.

Gestational diabetes mellitus (GDM) is increasing in prevalence in tandem with the dramatic increase in the prevalence of overweight and obesity in women of childbearing age. Much controversy surrounds the diagnosis and management of gestational diabetes, emphasizing the importance and relevance of clarity and consensus. If newly proposed criteria are adopted universally a significantly growing number of women will be diagnosed as having GDM, implying new therapeutic challenges to avoid foetal and maternal complications related to the hyperglycemia of gestational diabetes. This review provides an overview of clinical issues related to GDM, including the challenges of screening and diagnosis, the pathophysiology behind GDM, the treatment and prevention of GDM and the long and short term consequences of gestational diabetes for both mother and offspring.

ObjectiveGhrelin has glucoregulatory and orexigenic actions, but its role in acute hypoglycemia remains uncertain. We aimed to investigate circulating levels of acylghrelin (AG) and unacylated ghrelin (UAG) in response to hyperinsulinemia and to hypoglycemia.DesignA randomized, single-blind, placebo-controlled crossover study including 3 study days was performed at a university hospital clinical research center.MethodsNine healthy men completed 3 study days: i) saline control (CTR), ii) hyperinsulinemic euglycemia (HE) (bolus insulin 0.1 IE/kg i.v. and glucose 20% i.v. for 105 min, plasma glucose ≈5 mmol/l), and iii) hyperinsulinemic hypoglycemia (HH) (bolus insulin 0.1 IE/kg i.v.).ResultsHH and HE suppressed AG concentrations at t=45–60 min as compared with CTR (Pt=90 min, a rebound increase in AG was observed in response to HH as compared with both HE and CTR (Pt=45 min (PConclusionsThis study demonstrates that AG and UAG are directly suppressed by hyperinsulinemia and that AG concentrations increase after a latency of ≈1 h in response to hypoglycemia, suggesting a potential counterregulatory role of AG.

BACKGROUND: CD300LG rs72836561 (c.313C>T, p.Arg82Cys) has in genetic-epidemiological studies been associated with the lipoprotein abnormalities of the metabolic syndrome. CD300LG belongs to the CD300-family of membrane-bound molecules which have the ability to recognize and interact with extracellular lipids. We tested whether this specific polymorphism results in abnormal lipid accumulation in skeletal muscle and liver and other indices of metabolic dysfunction.METHODS: 40 healthy men with a mean age of 55 years were characterized metabolically including assessment of insulin sensitivity by the hyperinsulinemic euglycemic clamp, intrahepatic lipid content (IHLC) and intramyocellular lipid content (IMCL) by MR spectroscopy, and β-cell function by an intravenous glucose tolerance test. Changes in insulin signaling and CD300LG mRNA expression were determined by western blotting and quantitative PCR in muscle and adipose tissue.RESULTS: Compared with the 20 controls (CC carriers), the 20 CT carriers (polymorphism carriers) had higher IMCL (p=0.045), a reduced fasting forearm glucose uptake (p=0.011), a trend toward lower M-values during the clamp; 6.0 mg/kg/min vs 7.1 (p=0.10), and higher IHLC (p=0.10). CT carriers had lower CD300LG mRNA expression and CD300LG expression in muscle correlated with IMCL (β=-0.35, p=0.046), forearm glucose uptake (β=0.37, p=0.03), and tended to correlate with the M-value (β=0.33, p=0.06), independently of CD300LG genotype. β-cell function was unaffected.CONCLUSIONS: The CD300LG polymorphism was associated with decreased CD300LG mRNA expression in muscle and adipose tissue, increased IMCL, and abnormalities of glucose metabolism. CD300LG mRNA levels correlated with IMCL and forearm glucose uptake. These findings link a specific CD300LG polymorphism with features of the metabolic syndrome suggesting a role for CD300LG in the regulation of common metabolic traits.TRIAL REGISTRATION NUMBER: NCT01571609.

Objectives Vitamin D insufficiency is common in subjects with type 2 diabetes. Observational studies suggest that vitamin D plays a role in the pathogenesis of type 2 diabetes. However, results of intervention studies have been inconsistent. We investigated the effects of improving vitamin D status on insulin sensitivity, insulin secretion, and inflammatory markers in patients with type 2 diabetes. Materials/methods A double blind, randomized, placebo controlled trial was conducted. Sixteen patients with type 2 diabetes and hypovitaminosis D were recruited. Eight patients received colecalciferol and (280 μg daily for 2 weeks, 140 μg daily for 10 weeks) and 8 patients received identical placebo tablets for 12 weeks. Before and after intervention, patients underwent IVGTT, hyperinsulinemic euglycemic clamp, assessment of baseline high-frequency insulin pulsatility, glucose-entrained insulin pulsatility, DXA scans, 24-hour-ambulatory blood pressure monitorings, and fasting blood samples. Results Serum-25(OH) vitamin D and serum-1,25(OH)2 vitamin D increased significantly after 12 weeks in the intervention group (p = 0.01, p = 0.004). Serum-25(OH) vitamin D was also significantly higher in the vitamin D group compared to the placebo group (p = 0.02) after intervention. Although no significant changes in insulin sensitivity, inflammation, blood pressure, lipid profile, or HbA1c were found, we observed borderline (p between 0.05 and 0.10) improvements of insulin secretion, in terms of c-peptide levels, first phase incremental AUC insulin and insulin secretory burst mass. Conclusions Improvement in vitamin D status does not improve insulin resistance, blood pressure, inflammation or HbA1c, but might increase insulin secretion in patients with established type 2 diabetes.

Low plasma 25-hydroxy-vitamin D (25OHD) is associated with obesity. Vitamin D (VD) may be implicated in obesity and its complications such as insulin resistance, hypertension, and low-grade inflammation. We investigated the effects of VD supplementation on fat distribution and on obesity complications in obese adults with low plasma levels of 25OHD.In a double-blind design 52 subjects aged 18 to 50years with BMI30kg/m(2) and plasma 25OHD50nmol/l were randomized to 26weeks of treatment with 7000IU of VD daily or placebo. Body composition was assessed by DXA and subcutaneous (SAT) and visceral adipose tissue (VAT), intrahepatic (IHL) and intramyocellular lipids (IMCL) were evaluated by magnetic resonance imaging and magnetic resonance spectroscopy. Insulin resistance (HOMA-IR), blood pressure, plasma lipids, and circulating inflammatory markers were also investigated.VD treatment increased mean plasma levels of 25OHD from 33nmol/l to 110nmol/l (P0.0001) and decreased median parathyroid hormone levels from 5.3 to 4.5pmol/l (P0.01) in the intervention group. Treatment did not change body fat, SAT, VAT, IHL, or IMCL compared with placebo. Neither did treatment affect HOMA, blood pressure, plasma lipids or any of several inflammatory markers investigated including hsCRP.Increasing 25OHD levels by VD treatment for 26weeks have no effects on obesity complications in obese adults with low baseline plasma 25OHD.

Background It is unknown whether changes in circulating glucose levels due to short-term insulin discontinuation affect left ventricular contractile function in type 2 diabetic patients with (T2D-HF) and without (T2D-nonHF) heart failure. Materials and Methods In two randomized cross-over-designed trials, 18 insulin-treated type 2 diabetic patients with (Ejection Fraction (EF) 36±6%, n = 10) (trial 2) and without systolic heart failure (EF 60±3%, n = 8) (trial 1) were subjected to hyper- and normoglycemia for 9–12 hours on two different occasions. Advanced echocardiography, bicycle exercise tests and 6-minute hall walk distance were applied. Results Plasma glucose levels differed between study arms (6.5±0.8 mM vs 14.1±2.6 mM (T2D-HF), 5.8±0.4 mM vs 9.9±2.1 mM (T2D-nonHF), p

Aim: To combat diabetic complications strict glycaemic control is desirable in type 2 diabetes, but some patients are severely insulin resistant and it is not known whether high doses of insulin are effective. This study was designed to determine the acute dose–response effects of insulin in patients with type 2 diabetes and severe insulin resistance. Methods: We included eight insulin-resistant (mean insulin dose: 186 IU/day; body mass index: 35) subjects with type 2 diabetes in a single-blinded, randomized crossover study. Each subject was studied on two occasions. On each occasion, subjects underwent two 3-h hyperinsulinaemic euglycaemic clamps. The subjects were randomized to two low-dose insulin infusions (0.5 and 1.5 mU/kg/min in random order) on one occasion and to two high-dose insulin infusions (3.0 and 5.0 mU/kg/min in random order) on another occasion. Results: On all occasions, steady-state glucose infusion rates (SSGIRs) were accomplished and we observed a clear dose–response relationship with GIR values of 0.4 ± 0.2 (s.e.), 2.6 ± 0.6, 3.7 ± 0.8 and 4.9 ± 0.9 mg/kg/min during the 0.5, 1.5, 3.0 and 5.0 mU/kg/min insulin infusions, respectively (p < 0.001). Likewise, there was a dose-dependent suppression of endogenous glucose production (EGP) (p < 0.009), plasma free fatty acids (FFAs) (p < 0.001) and plasma glucagon (p = 0.001). Conclusions: Our results show that the insulin dose response in terms of GIR and EGP is preserved for insulin doses corresponding to >800 IU/day, suggesting effectiveness of very high insulin doses in severely insulin-resistant subjects.

We report a case of life-threatening myxoedema presenting with hypothermia, hypotension, bradycardia, pericardial effusion and deep coma. The condition was complicated by prolonged status epilepticus. The optimal treatment strategy has been debated over the years and the literature is briefly reviewed. Treatment with l-thyroxine (LT4) monotherapy without initial loading dose and with no l-triiodothyronine (LT3) treatment was successful with full recovery after hospitalisation for more than a month. Myxoedema coma is a rare, reversible condition with a high mortality and should be considered as a differential diagnosis in medical emergencies.

UNLABELLED: The genetics of hypertension has been scrutinized in large-scale genome-wide association studies (GWAS) with a large number of common genetic variants identified, each exerting subtle effects on disease susceptibility. An amino acid polymorphism, p.Arg82Cys, in CD300LG was recently found to be associated with fasting HDL-cholesterol and triglyceride levels. The polymorphism has not been detected in hypertension GWAS potentially due to its low frequency, but CD300LG has been linked to blood pressure as CD300LG knockout mice have changes in blood pressure. Twenty-four-hour ambulatory blood pressure was obtained in human CD300LG CT-carriers to follow up on these observations.METHODS: Twenty healthy male CD300LG rs72836561 CT-carriers matched for age and BMI with 20 healthy male CC-carriers. Office blood pressure, 24-hour ambulatory blood pressure, carotid intima-media thickness (CIMT), and fasting blood samples were evaluated. The clinical study was combined with a genetic-epidemiological study to replicate the association between blood pressure and CD300LG Arg82Cys in 2,637 men and 3,249 women.RESULTS: CT-carriers had a higher 24-hour ambulatory systolic blood pressure (122 mmHg versus 115; p = 0.01) and diastolic blood pressure (77 mmHg versus 72; pCONCLUSIONS: Although 24-hour blood pressure, measured with a sensitive method, in a small sample of CD300LG rs72836561 CT-carriers was higher than in CC-carriers, this did not translate into significant differences in office blood pressure in a larger cohort. This discrepancy which may reflect differences in methodological approach, underlines the importance of performing replication studies in a larger clinical context, but a formal rejection of a relation between blood pressure and CD300LG requires measurement of 24-hour ambulatory blood pressure in a larger cohort.

Renal denervation (RDN) for the treatment of resistant hypertension has been shown in pilot studies to lower blood pressure (BP) without safety alerts. However, this was only shown in open la-belled study designs and has primarily addressed the effect on office BP. We therefore conducted a sham