Non-fasting Glucose Research Articles

Use of metformin and outcome of patients with newly diagnosed glioblastoma: Pooled analysis.

Metformin has been linked to improve survival of patients with various cancers. There is little information on survival of glioblastoma patients after use of metformin. We assessed the association between metformin use and survival in a pooled analysis of patient data from 1,731 individuals from the randomized AVAglio, CENTRIC and CORE trials. We performed multivariate Cox analyses for overall survival (OS) and progression-free survival (PFS) comparing patients' use of metformin at baseline and/or during concomitant radiochemotherapy (TMZ/RT). Further exploratory analyses investigated the effect of metformin with a history of diabetes and nonfasting glucose levels in relation to OS or PFS of glioblastoma patients. Metformin alone or in any combination was not significantly associated with OS or PFS (at baseline, hazard ratio [HR] for OS = 0.87; 95% confidence interval [CI] = 0.65-1.16; HR for PFS = 0.84; 95% CI = 0.64-1.10; during TMZ/RT HR for OS = 0.97; 95% CI = 0.68-1.38; HR for PFS = 1.02; 95% CI = 0.74-1.41). We found a statistically nonsignificant association of metformin monotherapy with glioblastoma survival at baseline (HR for OS = 0.68; 95% CI = 0.42-1.10; HR for PFS = 0.57; 95% CI = 0.36-0.91), but not during the TMZ/RT period (HR for OS = 0.90; 95% CI = 0.51-1.56; HR for PFS = 1.05; 95% CI = 0.64-1.73). Diabetes mellitus or increased nonfasting glucose levels were not associated with a difference in OS or PFS in our selected study population. Metformin did not prolong survival of patients with newly diagnosed glioblastoma in our analysis. Additional studies may identify patients with specific tumor characteristics that are associated with potential benefit from treatment with metformin, possibly due to metabolic vulnerabilities.

The chinchilla as a novel animal model of gestational diabetes

BackgroundGestational diabetes occurs in 3–4% of all pregnancies, thereby being one of the leading pregnancy diseases in developed countries. The disease poses important health implications for both mother and child. Several animal models exist in this field, but with significant limitations. Consequently we want to introduce the pregnant chinchilla as a novel animal model of gestational diabetes. The chinchilla is excelled for various reasons; it gives birth to one or two cubs, is pregnant for 115 day and has a histological similar placenta barrier as compared with the human one. Since the chinchilla has never been used in diabetic studies, we aimed to show that it is possible to make it diabetic, before making a gestational model.Streptozotocin is by far the most applied method to induce diabetes in animal models, mimicking the ethology of diabetes type 1. However, since gestational diabetes is due to insulin resistance, we wanted to use high fructose feed as a method to induce diabetes.MethodsTwelve chinchillas were included in the study, six of which received high fructose diet to induce diabetes and six who received control diets. Blood glucose was monitored using Abbott Libre Freestyle glucometer. After 19 weeks the animals were euthanized and organs and blood withdrawn for analysis.Preliminary resultsNon‐fasting plasma glucose levels in chinchillas fed with high fructose diet was 19.3 ± 6.9 mmol/l, compared to controls 11.1 ± 2.2 mmol/l, p=0.056. Furthermore, DXA scans showed significant higher body fat percentage among fructose animals, p=0.043 compared to controls. HBA1C was, however, not affected in any of the groups.ConclusionWe have proven it possible to induce high blood glucose levels in the chinchilla by using high fructose diet. Because of the low sample size the blood glucose levels were, however, not statistically significant between groups. In spite of this, we consider the chinchilla a promising option for a future model of gestational diabetes.This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Prevalence of prediabetes and type 2 diabetes in two non-random populations aged 44–77 years in the Faroe Islands

AimsThe prevalence of type 2 diabetes is increasing worldwide but little known about the status in the Faroe Islands. The aim was therefore to determine the prevalence of type 2 diabetes mellitus and prediabetes in two non-random populations aged 44–77 years. MethodsThis cross-sectional survey was conducted between 2011 and 2012 and included two sub-populations, namely 518 Septuagenarians aged 74–77 years (84% of the invited) and 401 Mark aged 44–73 years (87% of the invited). Subjects were screened for glycosylated haemoglobin, type A1c, non-fasting random plasma glucose, fasting plasma glucose followed by an oral glucose tolerance test. The screening was based on a diagnostic algorithm that included screening, diagnostic and confirmatory steps. ResultsEach group was analysed separately. In the Septuagenarian group 20.4% had type 2 diabetes, with 5.2% being newly detected and a total of 59% had prediabetes. In the Mark group 4.1% had diabetes, with 2.1% being newly detected and 22.3% had prediabetes. Diabetes increased with age and was significantly more prevalent among men. Women had lower mean fasting plasma glucose concentrations and men had lower values for 2-hours plasma glucose. Significant predictors associated with diabetes mellitus included obesity (BMI ≥ 30, abnormal waist/hip ratio and vegetable consumption. ConclusionsAmong the Faroese populations studied, the prevalence of type 2 diabetes increased with age and was more prevalent among men. The detected prevalence was comparable to other Nordic countries for all age-groups.

PREVALENCE OF GESTATIONAL DIABETES MELLITUS IN AN URBAN INDIAN COHORT USING DIABETES IN PREGNANCY STUDY GROUP IN INDIA (DIPSI) CRITERIA – VALIDATING ONE-STEP APPROACH

Background. India is the “World’s Diabetes capital”, with half the diabetic population being women. Early detection of glucose intolerance during pregnancy offers a timely opportunity for screening, management and prevention of gestational diabetes mellitus (GDM) and prevents fetal complications.
 Objective. The study assessed the prevalence of GDM in an Indian cohort using the Diabetes in Pregnancy Study group of India (DIPSI) criteria.
 Methods. 200 pregnant women underwent two-phase testing with non-fasting 75-gram glucose challenge under Diabetes in Pregnancy Study group of India (DIPSI) criteria at <20 weeks and between 24-28 weeks period of gestation. A 3-hour 100-gm oral glucose tolerance test (OGTT) was used for confirmation. Repeat testing was done for women negative during the first-phase.
 Results. Mean age was 24.26±3.75 years with 52.5% multigravidas. Mean Body Mass Index (BMI) was 20.7±3.07 kg/m2. The prevalence of GDM in study cohort was found to be 15.5% using the DIPSI criteria while the prevalence of GDM after 100 g OGTT was 13.0%. GDM was mostly seen to occur in women of 26-30-year age group. Statistically significant associations for age and GDM, and BMI and GDM were evidenced.
 Conclusions. Maternal age of ≥25 years should be adopted as a risk factor for the development of GDM. The DIPSI criteria offer a cost-effective and an evidence-based protocol for a single-step definitive glucose test for both screening and diagnosis of pregnant patients belonging to any socio-economic strata; furthering its implementation for public health obstetrics.

Low to moderate toenail arsenic levels in young adulthood and incidence of diabetes later in life: findings from the CARDIA Trace Element study

Some studies suggest a positive association between arsenic exposure and risk of diabetes. However, the findings are inconsistent and inconclusive, particularly at a low to moderate arsenic exposure level, and longitudinal data are lacking. We examined toenail arsenic at low to moderate level in young adulthood in relation to incidence of diabetes later in life. This study included 4102 black and white participants aged 20–32 at baseline (1987–88) who completed up to 7 follow-up exams through 2015–16. Toenail arsenic was measured by collision-cell inductively-coupled-plasma mass-spectrometry. Incident diabetes was defined as fasting glucose ≥ 126 mg/dL, non-fasting glucose ≥ 200 mg/dL, 2-h postchallenge glucose ≥ 200 mg/dL, hemoglobin A1c ≥ 6.5%, or use of glucose-lowering medications. Cox proportional hazards model and generalized estimating equations (GEEs) were used to determine the associations of quintiles of toenail arsenic with incident diabetes and other metabolic parameters. The median (inter-quartile range) toenail arsenic level was 0.097 (0.065–0.150) ppm in this study. During the follow-up period, 599 incident cases of diabetes were identified. After adjustment for potential confounders, the hazards ratio (95% confidence interval) was 0.96 (0.73, 1.27) (P for linear trend= 0.85) comparing the highest to the lowest quintile of toenail arsenic levels. No significant association was observed between toenail arsenic and levels of fasting glucose, insulin, homeostatic model assessment of insulin resistance, homeostatic model assessment of beta cell function, or C-reactive protein. The null associations persisted across subgroups of age, sex, race, and body mass index. Findings from this longitudinal study do not support the hypothesis that low to moderate toenail arsenic levels in young adulthood is associated with diabetes risk later in life.

Significance of serum uric acid level in prediabetic and diabetic patients

Introduction: Diabetes is a group of metabolic disorder characterized by hyperglycemia resulting from defects in insulin secretion, insulin action, or both. Research has shown strong links between uric acid (UA) levels and medical conditions that are related to insulin resistance, which increases the chance of acquiring diabetes, though discrepancies in result have also been reported. Aim: This study aims to investigate the role of UA in diabetic and prediabetic subjects and compare them with euglycemic control. Methods: In this hospital-based comparative cross-section study, 220 subjects were enrolled, out of which 76 were diabetic, 74 prediabetic, and 70 euglycemic control. The male and female ratio was almost the same in the three groups. Diabetes mellitus was defined as fasting glucose ≥126mg/dl, non-fasting glucose ≥200mg/dl, or use of oral hypoglycemic medication or insulin. Around 3 ml of fasting blood samples were collected and analyzed for fasting blood glucose (FBG), and UA. Two-hour post-meal blood was collected for postprandial glucose (PPG) estimation. For comparison of variables among the group’s chi-square for categorical and student’s t-test, Mann Whitney U and analysis of variance for continuous data were applied. Pearson’s correlation coefficients were used to determine the relationships between variables. The p-value <0.05 was considered significant. Results: Mean age of the diabetic, prediabetic, and euglycemic control was 56.16 ± 12.58 years, 53.69 ± 14.92 years, and 48.97 ± 14.74 years, respectively, and the difference was statistically significant (p = 0.009). The mean UA level was also statistically different in the three groups (p = 0.010), the highest level (7.50 ± 2.24 mg/dl) in diabetic patients and lowest level (6.44 ± 2.06 mg/dl) in euglycemic control. There was a positive and significant correlation between UA and FBG, PPG (r = 0.253, p =0.002; r = 0.134, p = 0.048) in the participants. Conclusion: We observed a significant association of UA in diabetic, prediabetic, and euglycemic control; however, it is not associated with the outcome of diabetes.

Antidiabetic effect of bitter melon/Kerala (Momordica charantia) in alloxan induced diabetic rat

This study aims at investigating the effect of Momordica charantia extract on glucose tolerance and some biochemical parameters in alloxan induced diabetes rat. A total of 150 rats (50 normal rats and 100 alloxan induced diabetic rats) were used for five trials. The rats were divided into three groups for each trial, each containing 10 individuals as follows: Group A: is the control group, Group B as diabetic control group and group C were diabetic rat received bitter melon (Momordica charantia). Then alloxan injection was injected at a dose rate of 150 mg/kg body weight through intra-peritoneal route to each rat to induce diabetes in groups B and C. Aqueous extract of bitter melon (Momordica charantia) were fed by gavage at a dose of 300 mg/kg body weight daily for 21 days in group C. On 15th day blood glucose level and the body weights, biochemical parameters were measured for the first time to ensure diabetic induction. Then all the rats of this group were kept for more 21 days for the treatment of diabetic condition. Alloxan produced a significant increase in serum glucose, triglyceride (TG), total cholesterol (TC), low density lipoprotein cholesterol (LDL-C), Alanine aminotransaminase (ALT) and Aspartate aminotransaminase (AST) and significant decrease in body weight and high density lipoprotein cholesterol (HDLC). Bitter melon treatment reduced non-fasting and fasting glucose level (p<0.05). In addition, administration of bitter melon juice was associated with a reduction in the serum levels of Alanine aminotransaminase (ALT) and Aspartate aminotransaminase (AST), Triglyceride (TG), Total Cholesterol (TC) and Low Density Lipoprotein Cholesterol (LDL-C) when compared with positive diabetic control (p<0.05). High density lipoprotein cholesterol (HDLC) and body weight level significantly increased in bitter melon treated group C compare to Group B (p<0.05).
 Res. Agric., Livest. Fish.5(3): 373-379, December 2018

Exendin-4(Lys27 PAL)/gastrin/xenin-8-Gln: A novel acylated GLP-1/gastrin/xenin hybrid peptide that improves metabolic status in obese-diabetic (ob/ob) mice.

Therapeutic benefits of peptide-based drugs is limited by rapid renal elimination. Therefore, to prolong the biological action profile of the recently characterized triple-acting hybrid peptide, exendin-4/gastrin/xenin-8-Gln, a fatty acid (C-16) has been covalently attached, creating exendin-4(Lys27 PAL)/gastrin/xenin-8-Gln. Exendin-4/gastrin and liraglutide/gastrin/xenin-8-Gln were also synthesized as direct comparator peptides. All hybrid peptides evoked significant concentration-dependent increases of insulin secretion from isolated murine islets and BRIN-BD11 cells. Following administration of peptides with glucose to mice, all hybrids significantly reduced the overall glycaemic excursion and increased insulin concentrations. In contrast to other treatments, exendin-4(Lys27 PAL)/gastrin/xenin-8-Gln displayed impressive antihyperglycaemic actions even 12hours after administration, highlighting protracted duration of effects. Exendin-4/gastrin/xenin-8-Gln, exendin-4/gastrin, and exendin-4(Lys27 PAL)/gastrin/xenin-8-Gln were then progressed to a 31-day twice-daily treatment regimen in obese-diabetic ob/ob mice. All treatments decreased nonfasting glucose and HbA1c concentrations, as well as enhancing circulating and pancreatic insulin levels. Exendin-4/gastrin and exendin-4/gastrin/xenin-8-Gln also decreased food intake. Glucose tolerance was improved by all treatments, but only exendin-4(Lys27 PAL)/gastrin/xenin-8-Gln augmented glucose-induced insulin secretion. Interestingly, treatment regimens that included a xenin component induced clear advantages on the metabolic response to glucose-dependent insulinotropic polypeptide (GIP) and the glucose-lowering actions of insulin. This study emphasizes the therapeutic promise of long-acting, multi-targeting hybrid gut peptides for type 2 diabetes.

Cross-Sectional and Longitudinal Association between Glycemic Status and Body Composition in Men: A Population-Based Study.

This study sought to evaluate the associations between changes in glycemic status and changes in total body (TB), trunk, and appendicular fat (FM) and lean mass (LM) in men. A population-based study of men aged 20–66 years at baseline were included in cross-sectional (n = 430) and three-year longitudinal (n = 411) analyses. Prediabetes was defined as fasting glucose 100–125 mg/dL. Type 2 diabetes (T2D) was determined by: self-reported diabetes, current anti-diabetic drug use (insulin/oral hypoglycemic agents), fasting glucose (≥126 mg/dL), or non-fasting glucose (≥200 mg/dL). Body composition was evaluated by dual-energy X-ray absorptiometry. Longitudinal analyses showed that changes in TB FM and LM, and appendicular LM differed among glycemic groups. Normoglycemic men who converted to prediabetes lost more TB and appendicular LM than men who remained normoglycemic (all, p < 0.05). Normoglycemic or prediabetic men who developed T2D had a greater loss of TB and appendicular LM than men who remained normoglycemic (both, p < 0.05). T2D men had greater gains in TB FM and greater losses in TB and appendicular LM than men who remained normoglycemic (all, p < 0.05). Dysglycemia is associated with adverse changes in TB and appendicular LM.

2-Acyl-3-carboxyl-tetrahydroisoquinoline Derivatives: Mixed-Type PTP1B Inhibitors without PPARγ Activation.

A novel series of 2-acyl-3-carboxyl-tetrahydroisoquinoline derivatives were synthesized and biologically evaluated. Among them, (S)-2-{(E)-3-furan-2-ylacryloyl}-7-[(2E,4E)-5-(2,4,6-trifluorophenyl)penta-2,4-dienyloxy]-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid (compound 17u) was identified as a potent protein tyrosine phosphatase 1B (PTP1B) inhibitor without peroxisome proliferator-activated receptor (PPAR) γ activation: PTP1B inhibition IC50=0.19 µM and PPARγ ΕC50>10 µM. Compound 17u exhibited mixed-type inhibition for PTP1B, and this mode of inhibition was rationalized by computational ligand docking into the catalytic and allosteric sites of PTP1B. Compound 17u also showed high oral absorption at 10 mg/kg (per os (p.o.), Cmax=4.67 µM) in rats, significantly reduced non-fasting plasma glucose and triglyceride levels with no side effects at 30 mg/kg/d (p.o.) for 4 weeks, and attenuated elevations in plasma glucose levels in the oral glucose tolerance test performed 24 h after its final administration in db/db mice. In conclusion, the substituted 2-acyl-3-carboxyl-tetrahydroisoquinoline is a novel scaffold of mixed-type PTP1B inhibitors without PPARγ activation, and compound 17u has potential as an efficacious and safe anti-diabetic drug as well as a useful tool for investigations on the physiological and pathophysiological effects of mixed-type PTP1B inhibition.

The Association between Circulating Inflammatory Markers and Metabolic Syndrome: A General Population Study

INTRODUCTIONChronic inflammation has recently been proposed as the driving force for the development of the Philadelphia chromosome-negative myeloproliferative neoplasms (MPNs). Chronic inflammation is associated with various metabolic disturbances and may also contribute to the massive comorbidity burden in MPNs, which include e.g. inflammatory bowel diseases (Crohn's disease and ulcerative colitis) and polymyalgia rheumatica. Accordingly, MPNs have also been described as “inflammatory diseases”. The metabolic syndrome has so far not been shown to be prevalent in patients with MPNs although the chronic inflammatory state might induce insulin resistance as in other chronic inflammatory diseases. If MPNs indeed are preceded by a chronic inflammatory drive eliciting persistent leukocytosis, monocytosis and thrombocytosis, and ultimately clonal myeloproliferation it is intriguing to consider if MPNs and metabolic syndrome share common pathways. If so, an MPN-phenotype might be expected to be associated with metabolic syndrome in the background population. Therefore, in this study, we tested the association between circulating inflammatory markers (CIMs), a phenotypical presentation of MPNs (e.g. erythrocytosis, leukocytosis, and thrombocytosis), and the metabolic syndrome in a general population study.METHODSData sourcesIn this cross-sectional study, we used data from 20,872 individuals from the Danish General Suburban Population Study (GESUS). Individuals were invited between January 2010 and October 2013 and data were collected through questionnaires, health examinations, and biochemical measurements.AnalysesWe analyzed eight CIMs (leukocytes, neutrophils, monocytes, thrombocytes, erythrocytes, hematocrit, hemoglobin, and high-sensitive CRP) and their linear association with indicators of the metabolic syndrome (according to a modified version of the US National Cholesterol Education Program Adult Treatment Panel III): HbA1c, non-fasting plasma glucose, body mass index, blood pressure, cholesterol, low-density lipoprotein, high-density lipoprotein, and triglycerides. With logistic regression, we calculated odds ratios (ORs) of metabolic syndrome in individuals with increased levels of CIMs compared to individuals with normal levels based on current Danish reference ranges.RESULTSIn general, there was a positive correlation between most CIMs and indicators of the metabolic syndrome both in the age-sex-adjusted and multivariable linear regression analyses. In the age-sex-adjusted logistic regression analyses, increased levels of all CIMs were associated with increased prevalence of dyslipidemia (OR: 1.4-2.2), hypertension (OR: 1.3-3.1), diabetes mellitus (OR: 1.5-3.4), obesity (1.4-4.6), and the metabolic syndrome (OR: 1.4-2.8). However, neutrophils and thrombocytes were not significant when it came to hypertension and diabetes mellitus, respectively (Table 1).DISCUSSION & CONCLUSIONIn this study we examined the association between different CIMs and a wide variety of metabolic changes. To our knowledge it is the first comprehensive epidemiological study linking the phenotypical presentation of MPNs in a general population of more than 20.000 individuals with a broad spectrum of metabolic disturbances.With chronic inflammation being proposed as a trigger and consequence of both MPNs and metabolic syndrome and considering the results in the present study it is intriguing to postulate chronic inflammation as the common denominator in both metabolic syndrome leading to MPNs and MPNs leading to metabolic syndrome(Figure 1). It is of great clinical interest to investigate if an increased risk of metabolic syndrome exists in e.g. a cohort of MPN patients and whether people with incident metabolic syndrome have increased risk of MPNs and second cancer.An increased prevalence of a wide variety of metabolic disturbances following increased CIMs could potentially, if similar results are found in the MPN population, support a future change in the MPN-risk stratification. Amongst the tested CIMs only thrombocytes (> 1500 Mia/L) are currently used as a risk factor.In conclusion, elevated levels of CIMs were associated with an increased prevalence of metabolic disturbances. Our results substantiate the need for similar studies in MPN patients, being characterized by chronic inflammation and elevated cell counts. [Display omitted] DisclosuresHasselbalch:Novartis: Research Funding.

Mitochondrial dysfunction and inhibition of myoblast differentiation in mice with high-fat-diet-induced pre-diabetes.

Pre-diabetes is characterized by impaired glucose tolerance (IGT) and/or impaired fasting glucose. Impairment of skeletal muscle function is closely associated with the progression of diabetes. However, the entire pathological characteristics and mechanisms of pre-diabetes in skeletal muscle remain fully unknown. Here, we established a mouse model of pre-diabetes, in which 6-week-old male C57BL6/J mice were fed either normal diet or high-fat diet (HFD) for 8 or 16 weeks. Both non-fasting and fasting glucose levels and the results of glucose and insulin tolerance tests showed that mice fed an 8-week HFD developed pre-diabetes with IGT; whereas mice fed a 16-week HFD presented with impaired fasting glucose and impaired glucose tolerance (IFG-IGT). Mice at both stages of pre-diabetes displayed decreased numbers of mitochondria in skeletal muscle. Moreover, IFG-IGT mice exhibited decreased mitochondrial membrane potential and ATP production in skeletal muscle and muscle degeneration characterized by a shift in muscle fibers from predominantly oxidative type I to glycolytic type II. Western blotting and histological analysis confirmed that myoblast differentiation was only inhibited in IFG-IGT mice. For primary skeletal muscle satellite cells, inhibition of differentiation was observed in palmitic acid-induced insulin resistance model. Moreover, enhanced myoblast differentiation increased glucose uptake and insulin sensitivity. These findings indicate that pre-diabetes result in mitochondrial dysfunction and inhibition of myoblast differentiation in skeletal muscle. Therefore, interventions that enhance myoblast differentiation may improve insulin resistance of diabetes at the earlier stage.

Individuals Fulfilling Criteria for Type 2 Diabetes Rather Than LADA Display Transient Signs of Autoimmunity Preceding Diagnosis With Possible Clinical Implications: The HUNT Study

Latent autoimmune diabetes in adults (LADA) is classified as type 1 diabetes because of autoantibody positivity. In contrast, individuals classified as having type 2 diabetes are by definition autoantibody negative. However, autoantibodies may fluctuate (1). We therefore examined whether some individuals have transient evidence of autoimmunity preceding a diagnosis of type 2 diabetes and whether their clinical characteristics differ from those of other individuals classified as having type 2 diabetes. The study was performed among participants of the second (HUNT2, 1995–1997) and third (HUNT3, 2006–2008) surveys of the Nord-Trondelag Health Study (HUNT) in Norway. Details about HUNT are available elsewhere (2,3). Participants with self-reported diabetes in HUNT3 ( n = 2,264) were given a detailed diabetes-related questionnaire and invited to a follow-up clinical investigation that included measurements of hemoglobin A1c (HbA1c), fasting glucose, C-peptide, and the autoantibodies GADA and islet antigen-2 (IA-2A). We investigated participants with incident type 2 diabetes between HUNT2 and HUNT3 ( n = 965), defined as diabetes without GADA and IA-2A in HUNT3 and no insulin treatment within 1 year after diagnosis. Among them, 171 participants were excluded due to lack of serum samples or possible unknown diabetes at HUNT2, as indicated by nonfasting serum glucose >11.0 mmol/L in HUNT2. Serum samples that were collected during the HUNT2 …

Hepatology Basic Science

Hepatology Basic Science

‘Could my son have diabetes too?’

A 32-year-old man with type 1 diabetes brought his 23-month-old son in for evaluation. The father said that he had noticed his son had had increased numbers of wet diapers and increased thirst in the past week. He said that he could have tested the finger blood stick on his son using his own glucometer but he did not want to ‘make the diagnosis’. The system review of the toddler and his physical examination were both unremarkable. The family history was significant for the diagnosis of type 1 diabetes (T1DM) in the father at the age of six years. In the clinic, the non-fasting glucose level of the toddler was 29.082mmol/L (524mg/dL) and his HbA1c level was 53mmol/mol, confirming the diagnosis of diabetes. The father cried in the clinic feeling guilty that he had caused diabetes in his son. We provided positive reinforcement to the father, reassuring him that his good vigilance led to the early diagnosis. Further laboratory evaluation showed positive islet cell antibodies and positive anti-glutamic acid decarboxylase. A diabetes education session was held in the clinic; the father was able to check the glucose and give insulin to his son successfully. The incidence of T1DM varies according to age, ethnic background and geographical area. It is estimated that 24.5 per 100 000 children up to the age of 14 years in the UK are diagnosed with the condition every year.1 The children of patients with T1DM are at increased risk of developing the disease.2 The increased risk is around 6% if the father is affected while it is around 3% if the mother is affected.3, 4 Table 1 shows the increased risk if a parent or sibling has the disease. It is estimated that at diagnosis of T1DM 4–7% of children have a father with T1DM whereas only 1.5–3% have an affected mother.5 A study from Finland showed that the greatest increase of T1DM occurred in the youngest offspring, aged 0–4 years, when the father had T1DM.4 Since there is no typical Mendelian inheritance of T1DM, it is very important that physicians discuss with their T1DM patients this increased risk once it is known they are planning to have children. Understanding the risk of diabetes in offspring of affected parents is important not only in T1DM but also in type 2 diabetes due to the increased rate of childhood obesity related type 2 diabetes,6 as well as in rare forms of maturity-onset diabetes of the young.7 Parents with diabetes may be more vigilant in detecting early symptoms of diabetes, compared to those without diabetes. Early detection of T1DM can prevent life-threatening diabetic ketoacidosis (DKA), especially in very young children.8 Thus, identifying children at risk for diabetes even before the clinical onset can help both physicians and parents in preventing the dramatic course of DKA. The early detection and management of T1DM in children with parents who have diabetes may provide an easier course, faster education process, and better overall management of diabetes at home; nevertheless, parents may have a tremendous feeling of guilt about transmitting diabetes to their children. This emotional factor should be recognised and addressed appropriately by the health care team, stressing the positive benefits about parents’ diabetes knowledge.

Long-term treatment with acylated analogues of apelin-13 amide ameliorates diabetes and improves lipid profile of high-fat fed mice.

Previous studies have shown that modified apelin analogues exhibited enzyme resistance in plasma and improved circulating half-life compared to apelin-13. This study investigated the antidiabetic effects of chronic administration of stable long acting fatty acid modified apelin analogues, namely, (Lys8GluPAL)apelin-13 amide and pGlu(Lys8GluPAL)apelin-13 amide, in high-fat fed obese-diabetic mice. Male NIH Swiss mice (groups n = 8) were maintained either on a high-fat diet (45% fat) from 8 to 28 weeks old, or control mice were fed a normal diet (10% fat). When diet induced obesity-diabetes was established after high-fat feeding, mice were injected i.p. once daily with apelin analogues, liraglutide (25 nmol/kg) or saline (controls). Administration of (Lys8GluPAL)apelin-13 amide and pGlu(Lys8GluPAL)apelin-13 amide for 28 days significantly reduced food intake and decreased body weight. Non-fasting glucose was reduced (p<0.01 to p<0.001) and plasma insulin concentrations increased (p<0.01 to p<0.001). This was accompanied by enhanced insulin responses (p<0.01 to p<0.001) and significant reductions in glucose excursion after oral (p<0.01) or i.p. (p<0.01) glucose challenges and feeding. Apelin analogues also significantly improved HbA1c (p<0.01), enhanced insulin sensitivity (p<0.01), reduced triglycerides (p<0.001), increased HDL-cholesterol (p<0.01) and decreased LDL-cholesterol (p<0.01), compared to high-fat fed saline treated control mice. Cholesterol levels were decreased (p<0.01) by pGlu(Lys8GluPAL)apelin-13 amide and both apelin treated groups showed improved bone mineral content, reduced fat deposits and increased plasma GLP-1. Daily treatment with liraglutide mirrored many of these changes (not on bone or adipose tissue), but unlike apelin analogues increased plasma amylase. Consumption of O2, production of CO2, respiratory exchange ratio and energy expenditure were improved by apelin analogues. These results indicate that long-term treatment with acylated analogues (Lys8GluPAL)apelin-13 amide and particularly pGlu(Lys8GluPAL)apelin-13 amide resulted in similar or enhanced therapeutic responses to liraglutide in high-fat fed mice. Fatty acid derived apelin analogues represent a new and exciting development in the treatment of obesity-diabetes.

One-step versus two-step diagnostic testing for gestational diabetes: a randomized controlled trial

Objective: To evaluate the incidence of gestational diabetes mellitus (GDM) using the one-step as compared with the two-step approach.Study design: This was a parallel group nonblinded randomized trial conducted at Thomas Jefferson University Hospital (TJUH) in Philadelphia, Pennsylvania from June 2016 to December 2016. The primary outcome was GDM incidence in the one-step compared to the two-approach. Pregnant women without a history of pregestational diabetes were offered screening for GDM at gestational age 24–28 weeks. Obese women, defined as having a BMI ≥30 kg/m2, as well as those with a history of a pregnancy complicated by GDM, a history of a macrosomic baby (>4000 g), or with polycystic ovarian syndrome (PCOS), were offered early screening at their initial prenatal visit, and screening was repeated at 24–28 weeks if initially normal. Women were excluded if they had pre-existing diabetes or had a history of bariatric surgery. Women who were eligible were randomized in a 1:1 ratio to either the one-step or two-step approaches. A sample size of 142 women was planned per group. Women randomized to the one-step approach, after an overnight fast, were given a 2-h glucose tolerance test, which consisted of a 75-g glucose load. Blood glucose levels were measured fasting, at 1 h and 2 h after the glucose load. Diagnostic cutoffs for GDM diagnosis were one value of either fasting ≥92 mg/dL, 1 h ≥180 mg/dL, or 2 h ≥153 mg/dL, respectively. Women randomized to the two-step approach were given a nonfasting 50-g glucose load, and the blood glucose level was measured an hour after the glucose load. If that value was ≥135 mg/dL, the patient had a 3-h glucose tolerance test consisting of a 100-g glucose load. Diagnostic cutoffs for GDM diagnosis for this 3-h test were ≥2 abnormal values of fasting ≥95 mg/dL, 1 h ≥180 mg/dL, 2 h ≥155 mg/dL and 3 h ≥140 mg/dL, respectively. All analyses were done using an intention-to-treat approach, evaluating women according to the treatment group to which they were randomly allocated.Results: Two hundred eighty-four women agreed to take part in the study and underwent randomization from June 2015 to December 2015. Of them, 249 completed the screening and were followed up for the primary endpoint. Out of the 249 women who completed the screening, 123 were assigned to the one-step group and 126 to the two-step group. GDM occurred in 10 women (8.1%) in the one-step group, and 7 women (5.6%) in the two-step group (p = .42). Preeclampsia, preterm birth (PTB), induction of labor, mode of delivery and incidence of gestational age (OASIS) were not significantly different. Perinatal outcomes were similar as well.Conclusions: Screening for GDM with one-step, compared with the two-step approach, resulted in a similar incidence of GDM.

Liver-specific ablation of insulin-degrading enzyme causes hepatic insulin resistance and glucose intolerance, without affecting insulin clearance in mice

The role of insulin-degrading enzyme (IDE), a metalloprotease with high affinity for insulin, in insulin clearance remains poorly understood. OBJECTIVE: This study aimed to clarify whether IDE is a major mediator of insulin clearance, and to define its role in the etiology of hepatic insulin resistance. MethodsWe generated mice with liver-specific deletion of Ide (L-IDE-KO) and assessed insulin clearance and action. ResultsL-IDE-KO mice exhibited higher (~20%) fasting and non-fasting plasma glucose levels, glucose intolerance and insulin resistance. This phenotype was associated with ~30% lower plasma membrane insulin receptor levels in liver, as well as ~55% reduction in insulin-stimulated phosphorylation of the insulin receptor, and its downstream signaling molecules, AKT1 and AKT2 (reduced by ~40%). In addition, FoxO1 was aberrantly distributed in cellular nuclei, in parallel with up-regulation of the gluconeogenic genes Pck1 and G6pc. Surprisingly, L-IDE-KO mice showed similar plasma insulin levels and hepatic insulin clearance as control mice, despite reduced phosphorylation of the carcinoembryonic antigen-related cell adhesion molecule 1, which upon its insulin-stimulated phosphorylation, promotes receptor-mediated insulin uptake to be degraded. ConclusionIDE is not a rate-limiting regulator of plasma insulin levels in vivo.

Lupinus mutabilis Extract Exerts an Anti-Diabetic Effect by Improving Insulin Release in Type 2 Diabetic Goto-Kakizaki Rats.

Lupinus mutabilis (LM) is a legume part of Bolivian traditional diet that has a nutraceutical property reducing blood glucose levels. The prevalence of type 2 diabetes is increasing worldwide thus; the search for novel anti-diabetic drugs is needed. Based on its traditional use, we evaluated the anti-diabetic effect of LM in the spontaneously diabetic Goto-Kakizaki (GK) rat, a model of type 2 diabetes and in Wistar (W) rats as healthy control. LM seeds hydroethanolic extract, analyzed by gas chromatography-mass spectrometry and high-performance liquid chromatography-high resolution mass spectrometry, is a complex mixture of volatile and non-volatile components. A single oral administration of LM extract (2000 mg/kg b.w.) improved glucose tolerance during the oral glucose tolerance test (OGTT) (30–120 min) in GK and W rats (p < 0.0001). The long-term treatment with LM (1000 mg/kg b.w.), for 21 days, improved the area under the curve (AUC) of glucose during OGTT at day 20, in both GK (p < 0.01) and W rats (p < 0.01). The HbA1c (GK rats, p < 0.05 and W rats, p < 0.0001) and the non-fasting glucose (GK rats, p < 0.05) were also reduced. LM increased both serum insulin levels (2.4-fold in GK rats and 2.5-fold W rats), and the glucose-induced (16.7 mM glucose) insulin release in isolated islets from treated animals (6.7-fold in GK rats, and 6.6-fold in W rats). Moreover, LM (10 mg/mL) stimulated in vitro glucose induced (16.7 mM glucose) insulin release in batch incubated GK and W rat islets (p < 0.0001). In perifused GK rat islets, insulin release in 16.7 mM glucose was increased 95.3-fold compared to untreated islets (p < 0.0001), while no significant differences were found in perifused W rat islets. The LM mechanism of action, evaluated using inhibitory compounds of the insulin secretion pathway, showed that LM-dependent insulin secretion was reduced 42% by diazoxide (p < 0.001), 70% by nifedipine (p < 0.001), 86.7% by H89 (p < 0.0001), 70.8% by calphostine-C (p < 0.0001) and 93% by pertussis toxin (p < 0.0001). A similar effect was observed in W rats islets. Our findings provide evidence that LM has an anti-diabetic effect through stimulation of insulin release. The effect is-dependent on L-type calcium channel, protein kinase A and C systems, and G protein-coupled exocytosis and is partially mediated by K-ATP channels.

Risk factors for cardiovascular disease in children and young adults with haemophilia.

The origins of cardiovascular disease (CVD) begin in childhood. The primary objective of this cross-sectional cohort study was to determine the prevalence of cardiovascular risk factors in patients with congenital haemophilia A or B followed at Rady Children's Hospital San Diego Hemophilia and Thrombosis Treatment Center (HTC). We hypothesized that cardiovascular risk factors could be identified as part of a comprehensive clinic visit. Standardized measurement of weight, height, waist circumference and blood pressure plus non-fasting glucose and lipid panel were performed. Participants and/or caregivers completed questionnaires about family history, medical history and lifestyle. Clinical data were abstracted from the medical record. Descriptive statistics, Student's t test, correlation, Mann-Whitney U test and chi-square test were performed to analyse the data. Forty-three males (mean 12years, range 5-20years) enrolled. High rates of overweight and obesity, (pre)hypertension and abnormal lipids were identified. Subjects with normal weight had more days of >60minutes of physical activity compared with those with overweight or obesity (5.2±2.4 vs. 3.8±2.5day; P=0.07). Higher weight was correlated with higher factor consumption (cor=0.88; P<0.001). There was no difference in target joints based on weight category (30% in normal weight vs. 25% in overweight or obese, χ2 = 0.11, P=0.74), which may be attributed to high rates of prophylaxis. Modifiable risk factors for CVD were identified as part of the study during comprehensive clinic visits. The HTC team may develop behavioural interventions to target cardiovascular risk reduction as part of the comprehensive care model.