Disturbed Glucose Research Articles

Assessment of disturbed glucose metabolism and surrogate measures of insulin sensitivity in obese children and adolescents

BackgroundWith the rising prevalence of obesity and type 2 diabetes (T2D) in obese children, it is becoming imperative to detect disturbed glucose metabolism as early as possible in order to prevent T2D development.Subjects/MethodsCross-sectional study of 92 obese children (median age 11.7 years, 51% female) and 7 lean children (median age 11.4 years, 57% female) who underwent an oral glucose tolerance test (OGTT) in a tertiary pediatric care center. Glucose tolerance was assessed and different indices for β-cell function, insulin sensitivity and insulin secretion were calculated.ResultsNineteen obese children were identified with prediabetes (PD, 12 impaired glucose tolerance, 4 increased fasting glucose and 3 combined). Compared with the 73 obese children with normal glucose tolerance (nGT), subjects with PD had higher insulin resistance, but lower insulin sensitivity and β-cell function, although their glycated hemoglobin (HbA1c) levels were comparable. The Whole Body Insulin Sensitivity Index (WBISI) and β-cell function by Insulin Secretion-Sensitivity Index-2 (ISSI-2) strongly correlated with the OGTT glucose area under the curve 0–120 min (r = 0.392, p < 0.0002; r = 0.547, p < 0.0001, respectively). When testing the relation between early insulin response during OGTT by insulinogenic index and insulin sensitivity assessed by WBISI, a hyperbolic relationship between insulin secretion and insulin sensitivity was found. The calculated disposition index was lower in subjects with PD vs. nGT (median 459 vs. 792, p = 0.004). We identified the OGTT 30-min/120-min insulin ratio as a simple marker, which is significantly lower in obese children with vs. without PD (median 0.87 vs. 1.29, p = 0.021) and which has a better sensitivity and specificity for detecting PD than HbA1c among obese children.ConclusionsChildren with identified PD had changes of several markers for β-cell function, insulin sensitivity and resistance before changes in HbA1c occurred. The lower disposition index indicates that these children have already inadequate β-cell compensation for the degree of insulin resistance.

Investigation of Naturally Occurring Single-Nucleotide Variants in Human TAAR1.

Activation of trace amine-associated receptor 1 (TAAR1) in endocrine pancreas is involved in weight regulation and glucose homeostasis. The purpose of this study was the identification and characterization of potential TAAR1 variants in patients with overweight/obesity and disturbed glucose homeostasis. Screening for TAAR1 variants was performed in 314 obese or overweight patients with impaired insulin secretion. The detected variants were functionally characterized concerning TAAR1 cell surface expression and signaling properties and their allele frequencies were determined in the population-based Study of Health in Pomerania (SHIP). Three heterozygous carriers of the single nucleotide missense variants p.Arg23Cys (R23C, rs8192618), p.Ser49Leu (S49L, rs140960896), and p.Ille171Leu (I171L, rs200795344) were detected in the patient cohort. While p.Ser49Leu and p.Ille171Leu were found in obese/overweight patients with slightly impaired glucose homeostasis, p.Arg23Cys was identified in a patient with a complete loss of insulin production. Functional in vitro characterization revealed a like wild-type function for I171L, partial loss of function for S49L and a complete loss of function for R23C. The frequency of the R23C variant in 2018 non-diabetic control individuals aged 60 years and older in the general population-based SHIP cohort was lower than in the analyzed patient sample. Both variants are rare in the general population indicating a recent origin in the general gene pool and/or the consequence of pronounced purifying selection, in line with the obvious detrimental effect of the mutations. In conclusion, our study provides hints for the existence of naturally occurring TAAR1 variants with potential relevance for weight regulation and glucose homeostasis.

Role of Glucagon in Catabolism and Muscle Wasting of Critical Illness and Modulation by Nutrition.

Critical illness is hallmarked by muscle wasting and disturbances in glucose, lipid, and amino acid homeostasis. Circulating concentrations of glucagon, a catabolic hormone that affects these metabolic pathways, are elevated during critical illness. Insight in the nutritional regulation of glucagon and its metabolic role during critical illness is lacking. To evaluate whether macronutrient infusion can suppress plasma glucagon during critical illness and study the role of illness-induced glucagon abundance in the disturbed glucose, lipid, and amino acid homeostasis and in muscle wasting during critical illness. In human and mouse studies, we infused macronutrients and manipulated glucagon availability up and down to investigate its acute and chronic metabolic role during critical illness. In critically ill patients, infusing glucose with insulin did not lower glucagon, whereas parenteral nutrition containing amino acids increased glucagon. In critically ill mice, infusion of amino acids increased glucagon and up-regulated markers of hepatic amino acid catabolism without affecting muscle wasting. Immunoneutralizing glucagon in critically ill mice only transiently affected glucose and lipid metabolism, did not affect muscle wasting, but drastically suppressed markers of hepatic amino acid catabolism and reversed the illness-induced hypoaminoacidemia. These data suggest that elevated glucagon availability during critical illness increases hepatic amino acid catabolism, explaining the illness-induced hypoaminoacidemia, without affecting muscle wasting and without a sustained impact on blood glucose. Furthermore, amino acid infusion likely results in a further breakdown of amino acids in the liver, mediated by increased glucagon, without preventing muscle wasting. Clinical trial registered with www.clinicaltrials.gov (NCT 00512122).

Role of Probiotics in Diabetes: A Review of Their Rationale and Efficacy

The commensal bacteria that are present in our body since infancy are known to play a role in metabolism, in health as well as disease. Diabetes is a growing epidemic, and a long-term solution that targets the disease at the molecular level is yet to be developed. In this article, we have reviewed the link between the body’s microbiota and disturbed glucose metabolism, as well as the reasons for bacterial dysbiosis and the mechanisms by which it causes inflammation. The link between dysbiosis and diabetes is convincing, particularly since probiotics have been shown to be of some benefit in normalising disturbed metabolism in diabetes patients. Probiotics have recently been found to have a wide application in diseases such as autoimmune, inflammatory, and allergic conditions. The efficacy of probiotics in diabetes has been proven by their ability to lower fasting glucose and insulin levels in a preclinical setting as well as in human trials. However, there is heterogeneity in these studies, including the species used, probiotic dosage, and the magnitude of efficacy. Based on the robust understanding of the benefits of probiotics in diabetes at the cellular level, in both animal studies and clinical trials, combined with their excellent tolerability, probiotics should be explored for their application in clinics.

Nuclear Magnetic Resonance-Assisted Metabolic Analysis of Plasma for Mild Gestational Diabetes Mellitus Patients.

This study aimed at detecting the difference of metabolic profile in mild gestational diabetes mellitus (GDM) patients, and at identifying the correlation between the disturbed metabolites and insulin resistance pathway induced by the inflammation factors secreted by the placenta and adipocytes. Blood samples were collected from 36 pregnant women diagnosed with mild GDM and 36 normal glucose-tolerant (NGT) pregnant women. Metabolic profiles were acquired by using proton nuclear magnetic resonance (1H-NMR) spectroscopy, and the data were analyzed by multivariate statistical data analysis. The messenger RNA (mRNA) expression of CX3CL1, CD14, and CD86 in placenta and omental adipose tissues was detected by quantitative real-time polymerase chain reaction. (1) Weight and body mass index in GDM group were remarkably higher at both pre-pregnancy and delivery than those in the NGT group. The levels of fasting blood glucose, insulin, and homeostasis model assessment-2 for insulin resistance in GDM group were also significantly higher than those in the NGT group. (2) The expression of mRNA of CD86 was significantly higher in placenta of GDM patients. However, the gene expression of CX3CL1 and CD86 in omental adipose tissues of GDM was markedly lower as compared with the control group. (3) The GDM group exhibited severely perturbed glucose metabolism, fatty acid metabolism, amino acid metabolism, and activated inflammatory response. The 1H-NMR-based metabonomics approach together with biochemical assay and the mRNA expression analysis provided metabolic information about mild GDM, which indicated disturbed glucose metabolism, fatty acid metabolism, amino acid metabolism, and activated inflammatory response in mild GDM patients. This integrated study provides a new idea and methods to understand underlying mechanisms of mild GDM in clinics.

Associations between Liver Enzyme Levels and Parameters of the Metabolic Syndrome in Obese Children

Background: Obesity is strongly associated with insulin resistance, hypertension, dyslipidemia, and therefore risk for metabolic syndrome (MetS), which is an increasing problem in youth. The potential role of elevated liver enzyme levels in this context needs to be further investigated. Methods: This paper provides a post hoc analysis of a cross-sectional study of 77 obese nondiabetic children (51% female; median age 11.7 years; BMI >97th percentile) enrolled at the University of Bonn, Bonn, Germany. Anthropometric parameters, lipid profiles, glycemic control, and liver enzyme levels were evaluated. Glucose and insulin levels were determined during an oral glucose tolerance test (OGTT). Gender- and age-specific cutoff values were used to assess MetS. Results: A high prevalence of hypertension (51%), dyslipidemia (52%), elevated liver enzyme levels (51%), and hyperglycemia (24%) was found. There was considerable overlap between the presence of different MetS risk factors in individuals, and 40% of the participants had ≥3 of a maximum of 5 MetS risk factors. Elevated liver enzyme levels were significantly associated with reduced insulin sensitivity, as the OGTT-insulin response was significantly higher in participants with elevated transaminases (p = 0.01). This association was independent of hyperglycemia and dyslipidemia (p = 0.03). Conclusions: We conclude that liver enzyme levels are related to insulin sensitivity in obese children and could therefore be an indirect indicator for MetS. Testing for disturbed glucose metabolism should be considered for obese children with elevated liver enzymes.

Effect of Magnesium Supplements on Insulin Secretion After Kidney Transplantation: A Randomized Controlled Trial.

BACKGROUND Hypomagnesemia is associated with a disturbed glucose metabolism. Insulin hypo-secretion predicts diabetes in the general population and in transplant recipients. We aimed to assess whether magnesium improves insulin secretion and glycemic control after transplantation in prevalent hypomagnesemic kidney transplant recipients. MATERIAL AND METHODS We conducted an open-label, randomized, parallel-group study. Eligible participants were adults more than 4 months after kidney transplantation on tacrolimus with persisting serum magnesium concentrations <1.8 mg/dL randomized to magnesium oxide supplementation up to a maximum of 3 times 450 mg daily (N=26) or no supplements (N=26). Insulin secretion was assessed by OGTT-derived, first-phase insulin secretion (FPIR). The primary endpoint was the mean difference in FPIR between baseline and 6 months after randomization. Secondary endpoints were differences in HbA1c and insulin resistance, measured by HOMA. Dietary magnesium was assessed by a food-frequency questionnaire. All analyses were done on an intention-to-treat basis. RESULTS Magnesium with a mean daily dose of 688±237mg in the treatment group failed to lead to significant differences between the 2 groups in FPIR, fasting glucose, HbA1c, or HOMA-IR. Persisting hypomagnesemia was very common and associated with more insulin hypo-secretion, glucose intolerance, and lower dietary magnesium intake (142±56 versus 202±90 mg; p=0.015) as compared to patients with a rise in serum magnesium over 6 months. CONCLUSIONS Magnesium supplementation does not improve insulin secretion in stable hypomagnesemic kidney transplant recipients on tacrolimus. Persisting hypomagnesemia is associated with impaired glucose tolerance, insulin hypo-secretion, and dietary factors.

Glucose metabolism disorders in patients with non-functioning adrenal adenomas - single-centre experience.

The presence of glucose metabolism disorders and their possible correlation with degree of cortisol secretion were evaluated in patients with non-functioning adrenal incidentalomas (NFAIs). The study group consisted of 131 patients with hormonally inactive adrenal incidentalomas. In each patient, besides hormonal and radiological evaluation, was assessed for fasting glucose and insulin concentrations, and the oral glucose tolerance test (OGTT) was performed in all participants without previous history of glucose disturbances. The HOMA-IR, QUICKI, and TyG indices were calculated. Diabetes was diagnosed in 30.5% of the studied group. Among glucose tolerance abnormalities, impaired fasting glucose (IFG) was found in 23.7%, impaired glucose tolerance (IGT) in 4.6%, and combined IFG and IGT in 11.5%. Normoglycaemia was recognised in 29.8% of NFAIs patients. The occurrence rate of glucose aberrations increased with age. There was a significant difference in all insulin resistance indices shown between normoglycaemic patients and those with impairments in glucose tolerance. There was no significant correlation between fasting glucose, insulin resistance indices, and adrenal tumour size or degree of cortisol secretion. The prevalence of diabetes and impaired fasting glucose among NFAIs patients is much higher than in the general population. Therefore, patients with incidentally discovered adrenal tumours should be tested for glucose tolerance.

New indexes of body fat distribution, visceral adiposity index, body adiposity index, waist-to-height ratio, and metabolic disturbances in the obese.

The aim of this study was to examine the relationship between new obesity-related indexes, anthropometric and biochemical parameters, and body composition in individuals with obesity. The study group consisted of 72 women and 34 men, aged 39.0 ± 5.9 years, with a mean body mass index (BMI) of 32.6 ± 2.4 kg/m², admitted for body weight reduction. In all participants body weight (BW), height, waist circumference (WC), hip circumference (HC), BMI, waist-to-hip-ratio (WHR), visceral adiposity index (VAI), body adiposity index (BAI), and waist-to-height ratio (WHtR) were assessed. Using bioelectrical impedance (BIA, TANITA MC 180M) the following parameters were obtained: the level of visceral adipose tissue (VAT) and body fat percentage (FM%). Serum concentrations of total cholesterol (TC), high-density lipoprotein cholesterol (HDL), low-density lipoprotein cholesterol (LDL), triglycerides (TG), glucose, insulin, and insulin resistance (HOMA-IR) were determined. It was observed that almost all the studied indicators: WC, WHtR, BAI, VAI, and BMI, positively correlated with VAT estimated by bioimpedance, but only VAI, WC, and WHtR were strongly associated with glucose and lipid disturbances in the obese. BAI and BMI correlated with total FM%, while WC, WHtR, and VAI correlated with total body weight. The results indicate that VAI, WC, and WHtR can be useful in the assessment of increased VAT accumulation associated with disturbances in glucose and lipid metabolism. BAI should be calculated separately for each sex, then it could be also useful for the prediction of disturbances in glucose metabolism. However, further studies are needed to recognise cut-off values for BAI, as a marker of body fatness, associated with adverse health effects.

OP 10 Longitudinal assessment of cardiovascular risk factors after hypertensive disorders of pregnancy – Towards identifying a window of opportunity for screening and prevention

Introduction Accumulating evidence consistently demonstrates an increased risk and accelerated development of cardiovascular disease (CVD) risk in women with a history of a hypertensive disorder of pregnancy (HDP). Guidelines emphasize the emerging need for the prevention of CVD in these women, but fail to provide uniform recommendations on commencement and time interval in screening these patients. Objective The aim of this study is to investigate development of blood pressure, lipids and fasting glucose levels over time in women with a history of HDP in order to identify a window of opportunity for screening and prevention. Methods We identified women with self-reported normotensive pregnancy and HDP (NP, n = 1811; HDP, n = 1005) within the PREVEND study, a Dutch population-based cohort with a follow-up of maximum of 5 visits with 3-year intervals. Development of blood pressure, lipids, fasting glucose and Framingham 10-years CVD scores was longitudinally assed using generalized estimating equations. Results HDP”s present with overall higher and faster increasing prevalence of hypertension (p = 0.005), dyslipidemia (p = 0.009) and glucose disturbances (p = 0.002), reflecting in the use of medication (p Conclusion Women with a history of HDP show early development of hypertension, dyslipidemia and glucose homeostasis disturbances. Based on this cohort study, calculated 10-years CVD risk and NNS indicate commencing CVRM screening in these women at age 45 would be feasible. Download : Download high-res image (385KB) Download : Download full-size image

Identification of urine metabolites associated with 5-year changes in biomarkers of glucose homoeostasis

AimMetabolomics provides information on pathogenetic mechanisms and targets for interventions, and may improve risk stratification. During the last decade, metabolomics studies were used to gain deeper insight into the pathogenesis of diabetes mellitus. However, longitudinal metabolomics studies of possible subclinical states of disturbed glucose metabolism are limited. Therefore, the aim of this study was to analyze the associations between baseline urinary metabolites and 5-year changes in continuous markers of glucose homoeostasis, including fasting glucose, HbA1c and homoeostasis model assessment of insulin resistance (HOMA-IR) index values. MethodsUrine metabolites in 3986 participants at both baseline and 5-year follow-up of the population-based Inter99 study were analyzed by 1H-NMR spectroscopy. Linear regression and analyses of covariance models were used to detect associations between urine metabolites and 5-year changes in markers of glucose homoeostasis. ResultsHigher baseline levels of urinary alanine, betaine, N,N-dimethylglycine (DMG), creatinine and trimethylamine were associated with an increase in HbA1c from baseline to follow-up. In contrast, formic acid and trigonelline levels were associated with a decrease in HbA1c over time. Analyses of 5-year changes in fasting glucose and HOMA-IR index showed similar findings, with high baseline levels of lactic acid, beta-d-glucose, creatinine, alanine and 1-methylnicotinamide associated with increases in both parameters. ConclusionSeveral urine metabolites were found to be associated with detrimental longitudinal changes in biomarkers of glucose homoeostasis. The identified metabolites point to mechanisms involving betaine and coffee metabolism as well as the possible influence of the gut microbiome.

Insulin resistance in endocrine disorders - treatment options.

Changes in sensitivity to insulin occur in the course of a number of endocrine disorders. Most of the hormones through their antagonistic action to insulin lead to increased hepatic glucose output and its decreased utilisation in peripheral tissues. Carbohydrate disorders observed in endocrine diseases result from the phenomenon of insulin resistance, and in some cases also a reduction in insulin secretion is present. Abnormalities of glucose metabolism are observed in acromegaly, but also in growth hormone deficiency, hypercortisolism in the course of Cushing's syndrome, hyper- or hypothyroidism, primary hyperparathyroidism, aldosteronism, pheochromocytoma, congenital hypertrophy of the adrenal glands, polycystic ovaries syndrome, hypogonadism, or other hormonally active neuroendocrine tumours. They are of a secondary nature in relation to impaired hormonal balance. Hyperglycaemia is therefore often reversible, and the most effective method of treatment of impaired insulin sensitivity is successful therapy of specific endocrinopathies. Insulin sensitisers, also with a good effect, are used. Most experiences to date can be attributed to metformin therapy. Attempts have been made at treatment with other agents that are also effective in reducing insulin resistance as incretins or glitazones. In the presented paper, the authors reviewed endocrine diseases in which there is a clinically significant change in insulin sensitivity. Moreover, methods of therapy of concomitant disturbed glucose metabolism were presented.

The use of metabolic profiling to identify insulin resistance in veal calves.

Heavy veal calves (4–6 months old) are at risk of developing insulin resistance and disturbed glucose homeostasis. Prolonged insulin resistance could lead to metabolic disorders and impaired growth performance. Recently, we discovered that heavy Holstein-Friesian calves raised on a high-lactose or high-fat diet did not differ in insulin sensitivity, that insulin sensitivity was low and 50% of the calves could be considered insulin resistant. Understanding the patho-physiological mechanisms underlying insulin resistance and discovering biomarkers for early diagnosis would be useful for developing prevention strategies. Therefore, we explored plasma metabolic profiling techniques to build models and discover potential biomarkers and pathways that can distinguish between insulin resistant and moderately insulin sensitive veal calves. The calves (n = 14) were classified as insulin resistant (IR) or moderately insulin sensitive (MIS) based on results from a euglycemic-hyperinsulinemic clamp, using a cut-off value (M/I-value <4.4) to identify insulin resistance. Metabolic profiles of fasting plasma samples were analyzed using reversed phase (RP) and hydrophilic interaction (HILIC) liquid chromatography–mass spectrometry (LC-MS). Orthogonal partial least square discriminant analysis was performed to compare metabolic profiles. Insulin sensitivity was on average 2.3x higher (P <0.001) in MIS than IR group. For both RP-LC-MS and HILIC-LC-MS satisfactory models were build (R2Y >90% and Q2Y >66%), which allowed discrimination between MIS and IR calves. A total of 7 and 20 metabolic features (for RP-LC-MS and HILIC-LC-MS respectively) were most responsible for group separation. Of these, 7 metabolites could putatively be identified that differed (P <0.05) between groups (potential biomarkers). Pathway analysis indicated disturbances in glycerophospholipid and sphingolipid metabolism, the glycine, serine and threonine metabolism, and primary bile acid biosynthesis. These results demonstrate that plasma metabolic profiling can be used to identify insulin resistance in veal calves and can lead to underlying mechanisms.

Extensive phenotypic characterization of a new transgenic mouse reveals pleiotropic perturbations in physiology due to mesenchymal hGH minigene expression

The human growth hormone (hGH) minigene used for transgene stabilization in mice has been recently identified to be locally expressed in the tissues where transgenes are active and associated with phenotypic alterations. Here we extend these findings by analyzing the effect of the hGH minigene in TgC6hp55 transgenic mice which express the human TNFR1 under the control of the mesenchymal cell-specific CollagenVI promoter. These mice displayed a fully penetrant phenotype characterized by growth enhancement accompanied by perturbations in metabolic, skeletal, histological and other physiological parameters. Notably, this phenotype was independent of TNF-TNFR1 signaling since the genetic ablation of either Tnf or Tradd did not rescue the phenotype. Further analyses showed that the hGH minigene was expressed in several tissues, also leading to increased hGH protein levels in the serum. Pharmacological blockade of GH signaling prevented the development of the phenotype. Our results indicate that the unplanned expression of the hGH minigene in CollagenVI expressing mesenchymal cells can lead through local and/or systemic mechanisms to enhanced somatic growth followed by a plethora of primary and/or secondary effects such as hyperphagia, hypermetabolism, disturbed glucose homeostasis, altered hematological parameters, increased bone formation and lipid accumulation in metabolically critical tissues.

Impact of Muscarinic M3 Receptor Antagonism on the Risk of Type 2 Diabetes in Antidepressant-Treated Patients: A Case-Controlled Study.

BackgroundM3 muscarinic receptor antagonism has been associated with glucose intolerance and disturbance of insulin secretion.ObjectiveOur objective was to examine the risk of type 2 diabetes mellitus (T2DM) in patients using antidepressants with and without M3 muscarinic receptor antagonism (AD_antaM3 and AD_nonantaM3, respectively).MethodsWe designed a case–control study using a pharmacy prescription database. We selected a cohort of patients who initiated antidepressant use between the ages of 20 and 40 years and who did not receive any anti-diabetic prescriptions at baseline. Cases were defined as those who developed T2DM [i.e., receiving oral anti-diabetic medication, Anatomical Therapeutic Chemical (ATC) code A10B] during the follow-up period (1994–2014), and ten random controls were picked for each case from the cohort of patients who did not develop T2DM.ResultsA total of 530 cases with incident T2DM and 5300 controls were included. Compared with no use of antidepressants during the previous 2 years, recent (within the last 6 months) exposure to AD_antaM3 was associated with a moderately increased risk of T2DM: adjusted odds ratio 1.55 (95% confidence interval 1.18–2.02). In the stratified analyses, this association was dose dependent (>365 defined daily doses) and significant for patients who were in the younger age group (<45 years at the end of follow-up), were female and had no co-morbidity. On the other hand, recent exposure to AD_nonantaM3 was not associated with a risk for T2DM in any of our analyses.ConclusionOur results suggest that exposure to AD_antaM3 was associated with the development of T2DM among antidepressant users.Electronic supplementary materialThe online version of this article (doi:10.1007/s40263-017-0436-x) contains supplementary material, which is available to authorized users.

Asymptotic tracking and disturbance rejection of the blood glucose regulation system

Type 1 diabetes patients need external insulin to maintain blood glucose within a narrow range from 65 to 108 mg/dl (3.6 to 6.0 mmol/l). A mathematical model for the blood glucose regulation is required for integrating a glucose monitoring system into insulin pump technology to form a closed-loop insulin delivery system on the feedback of the blood glucose, the so-called “artificial pancreas”. The objective of this paper is to treat the exogenous glucose from food as a glucose disturbance and then develop a closed-loop feedback and feedforward control system for the blood glucose regulation system subject to the exogenous glucose disturbance. For this, a mathematical model for the glucose disturbance is proposed on the basis of experimental data, and then incorporated into an existing blood glucose regulation model. Because all the eigenvalues of the disturbance model have zero real parts, the center manifold theory is used to establish blood glucose regulator equations. We then use their solutions to synthesize a required feedback and feedforward controller to reject the disturbance and asymptotically track a constant glucose reference of 90 mg/dl. Since the regulator equations are nonlinear partial differential equations and usually impossible to solve analytically, a linear approximation solution is obtained. Our numerical simulations show that, under the linear approximate feedback and feedforward controller, the blood glucose asymptotically tracks its desired level of 90 mg/dl approximately.

Patients With Long-QT Syndrome Caused by Impaired hERG-Encoded Kv11.1 Potassium Channel Have Exaggerated Endocrine Pancreatic and Incretin Function Associated With Reactive Hypoglycemia.

Loss-of-function mutations in hERG (encoding the Kv11.1 voltage-gated potassium channel) cause long-QT syndrome type 2 (LQT2) because of prolonged cardiac repolarization. However, Kv11.1 is also present in pancreatic α and β cells and intestinal L and K cells, secreting glucagon, insulin, and the incretins glucagon-like peptide-1 (GLP-1) and GIP (glucose-dependent insulinotropic polypeptide), respectively. These hormones are crucial for glucose regulation, and long-QT syndrome may cause disturbed glucose regulation. We measured secretion of these hormones and cardiac repolarization in response to glucose ingestion in LQT2 patients with functional mutations in hERG and matched healthy participants, testing the hypothesis that LQT2 patients have increased incretin and β-cell function and decreased α-cell function, and thus lower glucose levels. Eleven patients with LQT2 and 22 sex-, age-, and body mass index-matched control participants underwent a 6-hour 75-g oral glucose tolerance test with ECG recording and blood sampling for measurements of glucose, insulin, C-peptide, glucagon, GLP-1, and GIP. In comparison with matched control participants, LQT2 patients had 56% to 78% increased serum insulin, serum C-peptide, plasma GLP-1, and plasma GIP responses (P=0.03-0.001) and decreased plasma glucose levels after glucose ingestion (P=0.02) with more symptoms of hypoglycemia (P=0.04). Sixty-three percent of LQT2 patients developed hypoglycemic plasma glucose levels (<70 mg/dL) versus 36% control participants (P=0.16), and 18% patients developed serious hypoglycemia (<50 mg/dL) versus none of the controls. LQT2 patients had defective glucagon responses to low glucose, P=0.008. β-Cell function (Insulin Secretion Sensitivity Index-2) was 2-fold higher in LQT2 patients than in controls (4398 [95% confidence interval, 2259-8562] versus 2156 [1961-3201], P=0.03). Pharmacological Kv11.1 blockade (dofetilide) in rats had similar effect, and small interfering RNA inhibition of hERG in β and L cells increased insulin and GLP-1 secretion up to 50%. Glucose ingestion caused cardiac repolarization disturbances with increased QTc intervals in both patients and controls, but with a 122% greater increase in QTcF interval in LQT2 patients (P=0.004). Besides a prolonged cardiac repolarization phase, LQT2 patients display increased GLP-1, GIP, and insulin secretion and defective glucagon secretion, causing decreased plasma glucose and thus increased risk of hypoglycemia. Furthermore, glucose ingestion increased QT interval and aggravated the cardiac repolarization disturbances in LQT2 patients. URL: http://clinicaltrials.gov. Unique identifier: NCT02775513.

Early Mitochondrial Adaptations in Skeletal Muscle to Obesity and Obesity Resistance Differentially Regulated by High-Fat Diet.

The mechanism for different susceptibilities to obesity after short-term high-fat diet (HFD) feeding is largely unknown. Given the close association between obesity occurrence and mitochondrial dysfunction, the early events in skeletal muscle mitochondrial adaptations between HFD-induced obesity (DIO) and HFD-induced obesity resistant (DIO-R) lean phenotype under excess nutritional environment were explored.ICR/JCL male mice were randomly divided into 2 groups, as follows: low-fat diet (LFD) and HFD groups. After 6 weeks on HFD, HFD-fed mice were classified as DIO or DIO-R according to their body weight gain. Serum parameters, oxidative stress biomarkers, the activation of AMPK/ACC axis, and the expression profiles of mitochondrial biogenesis were measured by using corresponding methods among the LFD control, DIO, and DIO-R groups. Serum glucose, total cholesterol, low-density lipoprotein, and high-density lipoprotein levels were significantly increased in DIO and DIO-R mice compared with LFD controls. However, DIO-R mice had significantly higher MDA levels and exhibited a significantly higher level of AMP-activated protein kinase (AMPK) activation and acetyl-CoA carboxylase (ACC) inactivation than DIO mice. Furthermore, the transcript and protein levels of transcriptional coactivator peroxisome proliferator-activated receptor γ (PPARγ) coactivator 1α (PGC-1α) and estrogen-related receptor-α (ERRα) in DIO-R mice were significantly up-regulated compared with the DIO mice. Although the body weight gain differed, the DIO and DIO-R mice had similar metabolic disturbance of glucose and lipids after short-term HFD consumption. The diverse alterations on fatty acid oxidation and mitochondrial biogenesis pathway induced by AMPK activation might be involved in different susceptibilities to obesity when consuming HFD.

Impact of risperidone on leptin and insulin in children and adolescents with autistic spectrum disorders

ObjectiveTo evaluate the influence of dose and duration of risperidone treatment on cardiovascular and diabetes risk biomarkers in children and adolescents with autistic spectrum disorders (ASDs). Design and methodsIn this cross-sectional analysis, a total of 168 ASDs patients (89% male) treated with a risperidone-based regimen for ≥12months were included. Blood samples were analyzed for glucose and lipid metabolic markers, adiponectin, leptin, prolactin, cortisol and high sensitive C-reactive protein. ResultsThe mean concentrations of glucose, insulin, prolactin and leptin and HOMA-IR significantly rose with risperidone dosage (all P<0.025), but those of adiponectin and cortisol did not. Using regression analysis, insulin, leptin, prolactin and glucose concentrations and HOMA-IR show significant association with dosage. None of the markers except adiponectin showed dependence on duration of treatment. However, insulin and leptin concentrations and HOMA-IR clearly increased with increasing both dosage and duration. Dosage and duration of treatment had minimal effect on standard lipid profile and lipoprotein subclasses. ConclusionsRisperidone treatment disturbed glucose homeostasis and endocrine regulation (particularly leptin) in children and adolescents with ASDs, in a dose- and duration-dependent manner, being suggestive of leptin and insulin resistance mechanisms. Metabolic adverse effects, especially development of type 2 diabetes mellitus should be closely monitored, particularly in individuals receiving high doses and/or long-term risperidone treatment.

Copeptin in patients with acute myocardial infarction and newly detected glucose abnormalities – A marker of increased stress susceptibility? A report from the Glucose in Acute Myocardial Infarction cohort

To characterize copeptin levels and to explore its prognostic importance in patients with acute myocardial infarction with newly detected glucose abnormalities. Copeptin was measured in 166 patients with acute myocardial infarction without known diabetes and in 168 age- and gender-matched controls. Participants were classified as having normal glucose tolerance or abnormal glucose tolerance (impaired glucose tolerance + type 2 diabetes mellitus) by oral glucose tolerance test. Study participants were followed over a decade for major cardiovascular event (acute myocardial infarction/stroke/congestive heart failure/cardiovascular death), cardiovascular and total death. Median copeptin level was higher in patients (10.5 pmol/L) than controls (5.9 pmol/L; p < 0.01). Patients with abnormal glucose tolerance had higher copeptin (12.2 pmol/L) than those with normal glucose tolerance (7.9 pmol/L; p < 0.01) but levels of copeptin did not differ in controls with abnormal glucose tolerance or normal glucose tolerance. Copeptin predicted major cardiovascular events [ n = 64; hazard ratio = 1.15 (1.01-1.32; p = 0.04)], cardiovascular mortality [ n = 29; hazard ratio = 1.24 (1.06-1.46; p = 0.01)] and total death [ n = 51; hazard ratio = 1.21 (1.05-1.40; p = 0.01)] in unadjusted Cox regression analyses in the patient cohort. In controls, copeptin predicted major cardiovascular events [ n = 26; hazard ratio = 1.17 (1.01-1.36; p = 0.03)]. Copeptin levels are highest among acute myocardial infarction patients with glucose disturbances and predict an adverse prognosis in unadjusted analyses. These findings imply that raised copeptin reflects stress rather than acting as a pathogenic factor for glucose abnormalities.