Role of autophagy in β-cell function and mass

Type 2 diabetes (T2D) is characterized by decreased insulin secretion and action. Decreased insulin secretion results from a reduction in pancreatic β-cell mass and/or function. Apoptosis, oxidative stress, mitochondrial dysfunction and endoplasmic reticulum (ER) stress responses including JNK activation have been suggested as mechanisms for the changes of pancreatic β-cells in T2D; however, the underlying causes were not clearly elucidated. Autophagy is an intracellular process that plays crucial roles in cellular homeostasis through degradation and recycling of organelles. We have reported increased apoptosis and decreased proliferation of β-cells with resultant reduction in the β-cell mass in β-cell-specific autophagy-deficient mice. Morphological analysis of β-cells revealed accumulation of ubiquitinated proteins, swollen mitochondria and distended ER. Insulin secretory function ex vivo was also impaired. As a result, β-cell-specific autophagy-deficient mice showed hypoinsulinaemia and hyperglycaemia. These results suggested that autophagy is necessary to maintain the structure, mass and function of pancreatic β-cells. In addition, as autophagy may play a protective role against ER stress and rejuvenates organelle function, impaired autophagy may lead to mitochondrial dysfunction and ER stress, which have been implicated as potential causes of insulin resistance. Therefore, in addition to β-cell homeostasis, dysregulated autophagy may possibly be involved in diverse aspects of the pathogenesis of diabetes.     

Evaluation of muscle mass in obesity,prediabetes and diabetes mellitus by different equations used for the measurement of muscle mass

ObjectiveInsulin resistance is one of risk factors for sarcopenia and there is no specific equation for the measurement of muscle mass. The present study aimed to evaluate muscle mass in the patients with obesity, prediabetes (PDM) and type 2 diabetes mellitus (DM) by different equations for the measurement of muscle mass.MethodsObese patients aged 18–65 years old, who presented between 2013 and 2015 were reviewed and they were separated into three groups as obese, prediabetes (PDM) and diabetes mellitus (DM). Height, body weight, body mass index (BMI), sum of the appendicular lean masses (ALM) were measured in all participants. Body muscle mass ratio was calculated as the total muscle mass divided by the body weight, and skeletal muscle index was calculated as the total muscle mass divided by the square of the height. In addition, ALM/weight, ALM/height² and ALM/BMI ratios were also evaluated.ResultsA total of 1107 participants, of whom 666 (60.2%) were female, were enrolled into the study. Of the participants, 288 (%26.02) had obesity, 524 (%47.33) had PDM and 295 (26.65%) had DM. There was a significant difference in ALM/BMI ratio between the three groups for both genders (p = 0.003 for female and p = 0.003 for male). ALM/weight ratio and body muscle mass ratio were decreased between groups in female, whereas it was no difference in male (p = 0.003, p < 0.001 for females, respectively; p = 0.802, p = 0.840 for males, respectively).ConclusionsALM/BMI may be more accurate for the evaluation of muscle mass in middle-aged obese, PDM and DM subjects.     

Evaluation of beta-cell mass and function in the Göttingen minipig

Increased knowledge about beta-cell mass and function is important for our understanding of the pathophysiology of type 2 diabetes (T2DM). The relationship between the two is difficult to study in humans, whereas animal models allow studies of consequences of, for example, reduction of beta-cell mass and induction of obesity and procurement of the pancreas for histological examination. An overview of results obtained in the G?ttingen minipig in relation to beta-cell function, and mass is provided here. Effects of a primary reduction of beta-cell mass have indicated that not all of the defects of pulsatile insulin secretion in human T2DM can be explained by reduced beta-cell mass. Furthermore, induction of obesity has shown deterioration of beta-cell function and morphological changes in the pancreas. As in humans, obesity leads to an increased beta-cell volume in the minipig, and based on the increased number of islets, neogenesis of islets is an important factor in expansion of beta-cell mass in this species. Measurement of beta-cell function as an estimate of beta-cell mass is, at present, the only method possible in humans, and this approach has been validated using lean and obese minipigs with a range of beta-cell mass. The effects on beta-cell function and mass of obesity of longer duration and/or more pronounced hyperglycaemia remains to be determined, but the models developed so far represent a valuable tool for such investigations.     

Loss of beta-cell mass leads to a reduction of pulse mass with normal periodicity,regularity and entrainment of pulsatile insulin secretion in Göttingen minipigs

Aims/hypothesis Type 2 diabetes is associated with impaired insulin action and secretion, including disturbed pulsatile release. Impaired pulsatility has been related to impaired insulin action, thus providing a possible link between release and action of insulin. Furthermore, progressive loss of beta-cell mass has been implicated in the pathogenesis of Type 2 diabetes. The aim of this study was to evaluate a possible link between loss of beta-cell mass and impaired pulsatile insulin secretion with special focus on glucose responsiveness of insulin secretion.Methods The kinetic and dynamic profiles of insulin in Göttingen minipigs are favourable for studies on pulsatility and a model of diabetes with reduced beta-cell mass has recently been established. Pigs were studied before (n=14) and after (n=10) reduction of beta-cell mass by nicotinamide (67 mg/kg) and streptozotocin (125 mg/kg) from 17.7±4.7 (normal animals,n=5) to 6.1±2.0 mg/kg. Pulsatile insulin secretion was examined during basal (n=8 normal, n=6 beta-cell reduced) and glucose entrained (n=6 normal, n=4 beta-cell reduced) conditions. Insulin concentration time series were analysed by autocorrelation and spectral analyses for periodicities and regularity, and by deconvolution for pulse frequency, mass and amplitude.Results Reduction of beta-cell mass and secondary hyperglycaemia resulted in correspondingly (r=0.7421, p=0.0275) reduced pulse mass (42% of normal during basal and 31% during entrained conditions) with normal periodicity (6.6±2.2 vs 5.8±2.4 min, p=0.50), regularity and entrainability of insulin secretion.Conclusion/interpretation Neither beta-cell loss, nor 2 weeks of slight hyperglycaemia, as seen in the beta-cell-reduced minipig, probably accounts for the disturbed insulin pulsatility observed in human Type 2 diabetes.Abbreviations ApEn Approximate entropy - NIA nicotinamide - LADA late onset autoimmune diabetes of the adult - STZ streptozotocin An erratum to this article can be found at     

Persistence of onchocerciasis and associated dermatologic and ophthalmic pathologies after 27 years of ivermectin mass drug administration in the middle belt of Ghana

Objectives

There is a pressing need to regularly evaluate the progress of onchocerciasis elimination programmes to timely identify and mitigate potential risks hindering the reaching of the 2030 targets proposed by the World Health Organization (WHO) in its roadmap on neglected tropical diseases (NTDs). We determined the prevalence of onchocerciasis and associated dermatological and ophthalmological manifestations in six endemic communities in the Bono Region of Ghana after 27 years of ivermectin mass treatment.

Methods

In a cross-sectional study, 564 participants aged ≥5 years were enrolled (49.1% females), with a median age of 26 (range: 5–89) years. In 54% and 47%, skin-snip microscopy and Ov16 rapid diagnostic tests were performed, respectively. Skin disease was determined using the WHO Skin NTD App. Visual function assessments included tests of visual acuity.

Results

The overall microfilarial prevalence was 12.5% (38/305) and Ov16 seroprevalence was 24.2% (64/265). Severe itching was recorded in 24.3%, acute papular onchodermatitis in 52.8%, chronic papular onchodermatitis in 12.5%, lichenified onchodermatitis in 0.7%, skin atrophy in 11.3%, depigmentation in 1.7% and palpable nodules in 5.3%. Of the 301 persons in which visual acuity was examined, 17% were visually impaired and 5.3% were blind and 47.3% presented with cataract. Chronic papular onchodermatitis, lichenified onchodermatitis, depigmentation and visual impairment were significantly associated with the presence of skin microfilariae and Ov16 seropositivity.

Conclusions

The persistence of Onchocerca volvulus infection and onchocerciasis-associated dermatological and ophthalmological pathologies after prolonged treatment is of concern. There is a need to include morbidity management in onchocerciasis elimination programmes and understand better patterns of treatment coverage, adherence and actual intake of ivermectin.     

Accuracy of immunoassay and mass spectrometry urinary free cortisol in the diagnosis of Cushing’s syndrome

Purpose

Urinary free cortisol (UFC) determination by highly specific methods as mass spectrometry instead of commercially available antibody-based immunoassays is increasingly recommended. However, clinical comparisons of both analytical approaches in the screening of Cushing’s syndrome (CS) are not available. The aim of this study was to evaluate the diagnostic value of mass spectrometry versus immunoassay measurements of 24 h-UFC in the screening of CS.

Methods

Cross-sectional study of 33 histologically confirmed CS patients: 25 Cushing’s disease, 5 adrenal CS and 3 ectopic CS; 92 non-CS patients; and 35 healthy controls. UFC by immunoassay (UFCxIA) and mass spectrometry (UFCxMS), urinary free cortisone (UFCo) and UFC:UFCo ratio were measured, together with creatinine-corrected values. Sensitivity, specificity, AUC and Landis and Koch concordance index were determined.

Results

AUC for UFCxIA and UFCxMS were 0.77 (CI 0.68–0.87) and 0.77 (CI 0.67–0.87) respectively, with a kappa coefficient 0.60 and strong Landis and Koch concordance index. The best calculated cutoff values were 359 nmol/24 h for UFCxIA (78 % sensitivity, 62 % specificity) and 258.1 nmol/24 h for UCFxMS (53 % sensitivity, 86 % specificity). The upper limit of UFCxIA and UCFxMS reference ranges were 344.7 and 169.5 nmol/24 h respectively. Sensitivity and specificity for CS diagnosis at these cutpoints were 84 and 56 % for UFCxIA and 81 and 54 % for UFCxMS.

Conclusions

According to our data, both methods present a very similar diagnostic value. However, results suggest that lower cutoff points for mass spectrometry may be necessary in order to improve clinical sensitivity.

     

Differential effects of prenatal and postnatal nutritional environment on ß-cell mass development and turnover in male and female rats

Fetal nutrient and growth restriction is associated with development of type 2 diabetes. Although the exact mechanisms responsible for this association remain debated, intrauterine and/or postnatal maldevelopment of β-cell mass has been proposed as a potential mechanism. To address this hypothesis, β-cell mass development and turnover was assessed in rats exposed to either intrauterine and/or postnatal caloric/growth restriction. In total, four groups of male and female Sprague Dawley rats (n = 69) were developed and studied: 1) control rats, i.e. control mothers rearing control pups; 2) intrauterine calorically and growth-restricted rats, i.e. 50% prenatal calorically restricted pups cross-fostered to control mothers; 3) postnatal calorically and growth-restricted rats, i.e. 50% calorically restricted mothers rearing pups born to control mothers; and 4) prenatal and postnatal calorically and growth restricted rats, i.e. 50% calorically restricted mothers rearing intrauterine 50% calorically restricted pups. Intrauterine growth restriction resulted in approximately 45% reduction of postnatal β-cell fractional area and mass characterized by reduced rate of β-cell replication and decreased evidence of neogenesis. In contrast, β-cell fractional area and weight-adjusted β-cell mass in postnatal growth restriction was approximately 30% higher than in control rats. Rats exposed to both intrauterine and postnatal caloric and growth restriction demonstrated approximately 80% decrease in β-cell mass, reduction in β-cell replication, and decreased evidence of neogenesis compared with control. Neither intrauterine nor postnatal caloric restriction significantly affected the rate of β-cell apoptosis. These data support the hypothesis that intrauterine maldevelopment of β-cell mass may predict the increased risk of type 2 diabetes in adult life.     

Minireview: The link between fat and bone: does mass beget mass?

Osteoporosis is less common in individuals with high fat mass. This putative osteoprotection is likely an adaptive mechanism that allows obese individuals to better carry their increased body mass. Recent studies have focused on hormones that link fat to bone. Adipokines, such as leptin, modulate bone cells through both direct and indirect actions, whereas molecules activating peroxisome proliferator-activated receptor γ drive mesenchymal stem cell differentiation towards adipocytes away from the osteoblastic lineage. There is emerging evidence that bone-derived osteocalcin regulates insulin release and insulin sensitivity and, hence, might indirectly affect fat mass. Despite these molecular connections between fat and bone, animal and human studies call into question a primary role for body fat in determining bone mass. Mice devoid of fat do not have a skeletal phenotype, and in humans, the observed correlations between bone and body mass are not just due to adipose tissue. An improved understanding of the integrative physiology at the fat-bone interface should allow us develop therapies for both osteoporosis and obesity.     

Interventions to improve β-cell mass and function

Diabetes mellitus (T2DM) has become an epidemiologically important disease worldwide and is also becoming a great matter of concern due to the effects associated with it like: high morbidity, elevated health care cost and shortened life span. T2DM is a chronic metabolic disease characterized by insulin resistance as well as β-cell dysfunction. It is widely accepted that in the face of insulin resistance, euglycemia can be maintained by increase in pancreatic β-cell mass and insulin secretion. This compensation is largely due to enhanced secretion of insulin by the β-cell mass, which is present initially, and thereby subsequent increases in β-cell mass provide additional insulin secretion. However, the mechanism by which β-cell anatomical plasticity and functional plasticity for insulin secretion is coordinated and executed in different physiological and pathophysiological states is complex and has been poorly understood. As the incidence of T2DM continues to increase at an alarming rate, it is becoming imperative to shift the research focus towards the β-cell physiology where identification of novel pathways that influence the β-cell proliferation and/or contribute to increase insulin secretion has the potential to lead to new therapies for preventing or delaying onset of disease.     

Mediation of the APOE associations with Alzheimer’s and coronary heart diseases through body mass index and lipids

GeroScience - The APOE ε2/ε3/ε4 polymorphism is associated with multiple non-Mendelian traits, including high- (HDL-C) and low- (LDL-C) density lipoprotein cholesterol,...     

c-Myc directly induces both impaired insulin secretion and loss of β-cell mass, independently of hyperglycemia in vivo

c-Myc (Myc) is a mediator of glucotoxicity but could also independently compromise β-cell survival and function. We have shown that after Myc activation in adult β-cells in vivo, apoptosis is preceded by hyperglycemia, suggesting glucotoxicity might contribute to Myc-induced apoptosis. To address this question conditional Myc was activated in β-cells of adult pIns-c-MycER(TAM) mice in vivo in the presence or absence of various glucose-lowering treatments, including exogenous insulin and prior to transplantation with wild-type islets. Changes in blood glucose levels were subsequently correlated with changes in β-cell mass and markers of function/differentiation. Activation of c-Myc resulted in reduced insulin secretion, hyperglycemia and loss of β-cell differentiation, followed by reduction in mass. Glucose-lowering interventions did not prevent loss of β-cells. Therefore, Myc can cause diabetes by direct effects on β-cell apoptosis even in the absence of potentially confounding secondary hyperglycemia. Moreover, as loss of β-cell differentiation/function and hyperglycemia are not prevented by preventing β-cell apoptosis, we conclude that Myc might contribute to the pathogenesis of diabetes by directly coupling cell cycle entry and β-cell failure through two distinct pathways.     

c-Myc directly induces both impaired insulin secretion and loss of β-cell mass,independently of hyperglycemia in vivo

c-Myc (Myc) is a mediator of glucotoxicity but could also independently compromise β-cell survival and function. We have shown that after Myc activation in adult β-cells in vivo, apoptosis is preceded by hyperglycemia, suggesting glucotoxicity might contribute to Myc-induced apoptosis. To address this question conditional Myc was activated in β-cells of adult pIns-c-MycERTAM mice in vivo in the presence or absence of various glucose-lowering treatments, including exogenous insulin and prior to transplantation with wild-type islets. Changes in blood glucose levels were subsequently correlated with changes in β-cell mass and markers of function/differentiation. Activation of c-Myc resulted in reduced insulin secretion, hyperglycemia and loss of β-cell differentiation, followed by reduction in mass. Glucose-lowering interventions did not prevent loss of β-cells. Therefore, Myc can cause diabetes by direct effects on β-cell apoptosis even in the absence of potentially confounding secondary hyperglycemia. Moreover, as loss of β-cell differentiation/function and hyperglycemia are not prevented by preventing β-cell apoptosis, we conclude that Myc might contribute to the pathogenesis of diabetes by directly coupling cell cycle entry and β-cell failure through 2 distinct pathways.     

Should echocardiography be performed to assess effects of antihypertensive therapy? Test-retest reliability of echocardiography for measurement of left ventricular mass and function

Objectives. The purpose of this study was to determine the test-retest stability of echocardiography for the measurement of left ventricular mass and function in patients with hypertension.Background. Determination of changes in left ventricular mass may be impaired by study variability. The amount by which variables of mass and left ventricular function must change in an individual patient to exceed temporal variability has not been determined in a multicenter trial.Methods. Ninety-six patients with hypertension had two-demensional targeted, M-mode Doppler echocardiography repeated at 6 ± 8 days by the same technician utilizing the same machine. Left ventricular mass and variables of systolic and diastolic function were measured. Test-retest reliability and the width of the 95% confidence intervals of variable change, as well as the contributions of age, study quality and body size to measurement reliability, were determined.Results. Despite excellent reliability (intraclass coefficient of correlation 0.86), the 95% confidence interval width of a single replicate measurement of left ventricular mass was 59 g, exceeding usual decreases in mass during treatment. Study quality, which was dependent on age and weight, influenced test reliability. Although the confidence interval width for ejection fraction was narrow (5 U), those for peak early (E) and late (A) diastolic velocities were wide, resulting in a confidence interval width for the E/A ratio of 1.5.Conclusions. The temporal variability, particularly in obese or elderly patients, or both, of echocardiography for measurement of left ventricular mass precludes its use to measure changes in mass of the magnitude likely to occur with therapy. Measurement stability is affected by study quality, and age and body weight both influence study quality. Although ejection fraction shows little temporal variability, the large width of the confidence interval of the Doppler E/A ratio impairs its use to serially measure diastolic function.     

Repeated measures of blood pressure and correlations between systolic pressure,pulse pressure and LV mass: a circular debate?

This month's edition of the Journal contains an interesting contribution from Mule and colleagues from Palermo. The structure of the piece is very simple relating ambulatory blood pressure (ABP) measures for systolic, diastolic and pulse pressure to LV mass in hypertensive patients. The technique employed is linear correlation analysis. Pulse pressure is an area of interest of many of the readers, contributors and editorial board of the Journal. This is not a new area nor is this a new approach. The strategy of deriving biological inference from such data relevant to the individual by correlation analysis from a population sample deserves a closer and broader comment.