People with type 1 diabetes exhibit lower exercise capacity compared to a control population with similar physical activity levels.

AIMS: We aimed to assess physical activity (PA) levels, adherence to PA guidelines, and fitness capacity in individuals with type 1 diabetes (T1D) and control population. METHODS: This cross-sectional study included 232 T1D and 248 controls. PA levels (IPAQ-SF questionnaire), adherence to guidelines (>150 min/week of moderate-to-vigorous PA), fitness capacity (VO2max, maximal incremental test on a cycle ergometer and 1RM test) were assessed, along with other clinical variables. RESULTS: Total PA levels (T1D 2202 ± 1839 vs. controls 2357 ± 2189 METs/min/week), adherence (T1D 53.1 % vs controls 53.2 %), and sedentariness (T1D 27.3 % vs. controls 25.1 %) were similar between groups. However, participants with T1D exhibited significantly lower levels of VO2max (29.1 ± 10.5 vs. 32.5 ± 11.5 mlO2/kg/min, p < 0.001), work capacity (2.73 ± 1.03 vs. 3 ± 10 W/kg of body weight, p = 0.004) and strength capacity (2.29 ± 0.53 vs. 2.41 ± 0.79 kg/kg body weight in 1RM, p = 0.01) than controls, after adjusting for sex and age. CONCLUSIONS: Individuals with T1D exhibit lower fitness capacity compared to a control population, regardless of age and sex, even when presenting similar levels of total physical activity and adherence to guidelines.

Direct reprogramming of human fibroblasts into insulin-producing cells using transcription factors.

Direct lineage reprogramming of one somatic cell into another without transitioning through a progenitor stage has emerged as a strategy to generate clinically relevant cell types. One cell type of interest is the pancreatic insulin-producing ß cell whose loss and/or dysfunction leads to diabetes. To date it has been possible to create ß-like cells from related endodermal cell types by forcing the expression of developmental transcription factors, but not from more distant cell lineages like fibroblasts. In light of the therapeutic benefits of choosing an accessible cell type as the cell of origin, in this study we set out to analyze the feasibility of transforming human skin fibroblasts into ß-like cells. We describe how the timed-introduction of five developmental transcription factors (Neurog3, Pdx1, MafA, Pax4, and Nkx2-2) promotes conversion of fibroblasts toward a ß-cell fate. Reprogrammed cells exhibit ß-cell features including ß-cell gene expression and glucose-responsive intracellular calcium mobilization. Moreover, reprogrammed cells display glucose-induced insulin secretion in vitro and in vivo. This work provides proof-of-concept of the capacity to make insulin-producing cells from human fibroblasts via transcription factor-mediated direct reprogramming.

An Overview of Inter-Tissue and Inter-Kingdom Communication Mediated by Extracellular Vesicles in the Regulation of Mammalian Metabolism.

Obesity and type 2 diabetes are associated with defects of insulin action in different tissues or alterations in ß-cell secretory capacity that may be triggered by environmental challenges, inadequate lifestyle choices, or an underlying genetic predisposition. In addition, recent data shows that obesity may also be caused by perturbations of the gut microbiota, which then affect metabolic function and energy homeostasis in the host. Maintenance of metabolic homeostasis in complex organisms such as mammals requires organismal-level communication, including between the different organs and the gut microbiota. Extracellular vesicles (EVs) have been identified in all domains of life and have emerged as crucial players in inter-organ and inter-kingdom crosstalk. Interestingly, EVs found in edible vegetables or in milk have been shown to influence gut microbiota or tissue function in mammals. Moreover, there is a multidirectional crosstalk mediated by EVs derived from gut microbiota and body organs that has implications for host health. Untangling this complex signaling network may help implement novel therapies for the treatment of metabolic disease.

Treatment with EV-miRNAs Alleviates Obesity-Associated Metabolic Dysfunction in Mice.

Most cells release extracellular vesicles (EVs) that can be detected circulating in blood. We and others have shown that the microRNA contents of these vesicles induce transcriptomic changes in acceptor cells, contributing to the adjustment of metabolic homeostasis in response to environmental demands. Here, we explore the potential for modulating obesity- and exercise-derived EV-microRNAs to treat the metabolic dysfunction associated with obesity in mice. Treatment with EV-miRNAs alleviated glucose intolerance and insulin resistance in obese mice to an extent similar to that of high-intensity interval training, although only exercise improved cardiorespiratory fitness and decreased body weight. Mechanistically, EV-miRNAs decreased fatty acid and cholesterol biosynthesis pathways in the liver, reducing hepatic steatosis and increasing insulin sensitivity, resulting in decreased glycemia and triglyceridemia. Our data suggest that manipulation of EV-miRNAs may be a viable strategy to alleviate metabolic dysfunction in obese and diabetic patients who are unable to exercise, although actual physical activity is needed to improve cardiorespiratory fitness.

Remission of obesity and insulin resistance is not sufficient to restore mitochondrial homeostasis in visceral adipose tissue.

Metabolic plasticity is the ability of a biological system to adapt its metabolic phenotype to different environmental stressors. We used a whole-body and tissue-specific phenotypic, functional, proteomic, metabolomic and transcriptomic approach to systematically assess metabolic plasticity in diet-induced obese mice after a combined nutritional and exercise intervention. Although most obesity and overnutrition-related pathological features were successfully reverted, we observed a high degree of metabolic dysfunction in visceral white adipose tissue, characterized by abnormal mitochondrial morphology and functionality. Despite two sequential therapeutic interventions and an apparent global healthy phenotype, obesity triggered a cascade of events in visceral adipose tissue progressing from mitochondrial metabolic and proteostatic alterations to widespread cellular stress, which compromises its biosynthetic and recycling capacity. In humans, weight loss after bariatric surgery showed a transcriptional signature in visceral adipose tissue similar to our mouse model of obesity reversion. Overall, our data indicate that obesity prompts a lasting metabolic fingerprint that leads to a progressive breakdown of metabolic plasticity in visceral adipose tissue.

High Intensity Interval Training reduces hypoglycemic events compared with continuous aerobic training in individuals with type 1 diabetes: HIIT and hypoglycemia in type 1 diabetes.

AIMS: to investigate if a High Intensity Interval Training (HIIT) protocol improves glycemic control and fitness capacity, compared to traditional moderate Intensity Continuous Training (MICT) exercise. METHODS: 30 sedentary individuals with type 1 diabetes (T1D) and 26 healthy controls were assigned to a 3-week HIIT or MICT protocol. Blood glucose levels by continuous glucose monitoring system and fitness status were compared before and after the study period. RESULTS: During workouts, blood glucose levels remained stable in HIIT exercise (+3.2 ± 16.2 mg/dl (p = 0.43)), while decreased in MICT (-27.1 ± 17.5 mg/dl (p < 0.0001)) exercise. In addition, out of the 9 training sessions, HIIT volunteers needed to take carbohydrate supplements to avoid hypoglycemia in 0.56 ± 0.9 sessions, compared to 1.83 ± 0.5 sessions (p < 0.04) in MICT individuals. In the analysis of blood glucose levels between rest and training days (24h-period), training significantly reduced mean glycemic levels in both groups, but the MICT exercise results in an increase in the frequency of hypoglycemic episodes. The response to exercise seems to be attenuated in individuals with T1D, especially in HIIT group. CONCLUSION: HIIT training results in a greater glycemic stability, with reduction of hypoglycemic episodes.

Muscular carnosine is a marker for cardiorespiratory fitness and cardiometabolic risk factors in men with type 1 diabetes.

PURPOSE: Muscle is an essential organ for glucose metabolism and can be influenced by metabolic disorders and physical activity. Elevated muscle carnosine levels have been associated with insulin resistance and cardiometabolic risk factors. Little is known about muscle carnosine in type 1 diabetes (T1D) and how it is influenced by physical activity. The aim of this study was to characterize muscle carnosine in vivo by proton magnetic resonance spectroscopy (1H MRS) and evaluate the relationship with physical activity, clinical characteristics and lipoprotein subfractions. METHODS: 16 men with T1D (10 athletes/6 sedentary) and 14 controls without diabetes (9/5) were included. Body composition by DXA, cardiorespiratory capacity (VO2peak) and serum lipoprotein profile by proton nuclear magnetic resonance (1H NMR) were obtained. Muscle carnosine scaled to water (carnosineW) and to creatine (carnosineCR), creatine and intramyocellular lipids (IMCL) were quantified in vivo using 1H MRS in a 3T MR scanner in soleus muscle. RESULTS: Subjects with T1D presented higher carnosine CR levels compared to controls. T1D patients with a lower VO2peak presented higher carnosineCR levels compared to sedentary controls, but both T1D and control groups presented similar levels of carnosineCR at high VO2peak levels. CarnosineW followed the same trend. Integrated correlation networks in T1D demonstrated that carnosineW and carnosineCR were associated with cardiometabolic risk factors including total and abdominal fat, pro-atherogenic lipoproteins (very low-density lipoprotein subfractions), low VO2peak, and IMCL. CONCLUSIONS: Elevated muscle carnosine levels in persons with T1D and their effect on atherogenic lipoproteins can be modulated by physical activity.

Exosomes from Short-Term High-Fat or High-Sucrose Fed Mice Induce Hepatic Steatosis through Different Pathways.

Obesity and other closely associated diseases, such as metabolic-associated fatty liver disease (MAFLD) and type 2 diabetes, give rise to a common biometric and metabolic phenotype resulting from a different etiopathogenesis. To characterize the first stages of metabolic dysfunction induced by either obesity or hepatic steatosis, we compared two animal models of short-term feeding with either high-fat (HFD) or high-sucrose (SAC) diets. Using transcriptomic, metabolic, and calorimetric analyses, we determined that a short-term HFD leads to obesity and then hepatic steatosis through lipid storage, whereas SAC increases gluconeogenesis and de novo lipogenesis, resulting in hepatic steatosis followed later by obesity. Plasma exosomal miRNA profiles differed between HFD and SAC mice, and the injection of exosomes from HFD or SAC mice reproduced some transcriptomic and metabolic features of the donor mice. Finally, we exploited our data to identify circulating miR-22-3p as a candidate biomarker for MAFLD patient stratification. In conclusion, dietary challenges affecting adipose or hepatic metabolism regulate the abundance of exosomal miRNAs in plasma, which in turn modulate gene expression, helping the organism to adapt.

Clinical characteristics and management of type 1 diabetes in Spain. The SED1 study.

OBJECTIVES: To determine the sociodemographic and clinical profile of a representative sample of people with type 1 diabetes mellitus (DM1) in Spain and identify factors associated with glycemic control. MATERIAL AND METHODS: A cross-sectional observational study was carried out in adults and children with DM1 treated in 75 Spanish public hospitals, geographically distributed in order to be representative of the Spanish population. Within each center, the patients were included on a consecutive basis as they visited the clinic. They were interviewed, and their clinical histories were reviewed. A descriptive statistical analysis was made, and factors associated with HbA1c were analysed using multivariate linear regression analysis. RESULTS: A total of 647 patients were included: 55.3% females, aged 36.6 ±â€¯14.4 years, 97.2% Caucasians, BMI 24.7 ±â€¯4.4 kg/m2 (12.1% ≥ 30 kg/m2), and 74.0% had secondary / university education. A total of 20.2% were active smokers. The mean time from the diagnosis of DM1 was 17.9 ±â€¯12.0 years. A total of 48.7% presented comorbidities: 19.3% retinopathy and 16.4% hypothyroidism. As regards treatment for DM1, 76.5% received basal-bolus insulin therapy and 20.7% continuous subcutaneous insulin infusion (CSII); 51.0% of the patients used an insulin/carbohydrate ratio (ICR), with 4.6 ±â€¯1.6 self-monitored capillary blood glucose (SMCBG) measurements a day, and 24.8% used continuous glucose monitoring (CGM). The mean HbA1c value was 7.6 ±â€¯1.1% (30% below 7%). Metabolic control improved (lower HbA1c) with more daily SMCBG (B = -0.053; p = 0.009), a higher educational level (B = 0.461; P < 0.001), greater number of hypoglycemia episodes (B = -0.253; P = 0.018) and carbohydrate counting (B = -0.190; P = 0.048), and worsened the longer the duration of the disease (B = 0.010; P = 0.010), higher total dose of insulin (B = 0.010; P < 0.0001), poorer adherence to diet (B = 0.650; P < 0.0001) and a family history of DM (B = -0.233; P = 0.007). CONCLUSIONS: The management of patients with DM1 in Spain, as well as the treatment they receive, is similar to that seen in other Western countries. Blood glucose control is associated with educational level, disease duration, and the characteristics of treatment and self-care.

4-Phenylbutyrate (PBA) treatment reduces hyperglycemia and islet amyloid in a mouse model of type 2 diabetes and obesity.

Amyloid deposits in pancreatic islets, mainly formed by human islet amyloid polypeptide (hIAPP) aggregation, have been associated with loss of ß-cell mass and function, and are a pathological hallmark of type 2 diabetes (T2D). Treatment with chaperones has been associated with a decrease in endoplasmic reticulum stress leading to improved glucose metabolism. The aim of this work was to investigate whether the chemical chaperone 4-phenylbutyrate (PBA) prevents glucose metabolism abnormalities and amyloid deposition in obese agouti viable yellow (Avy) mice that overexpress hIAPP in ß cells (Avy hIAPP mice), which exhibit overt diabetes. Oral PBA treatment started at 8 weeks of age, when Avy hIAPP mice already presented fasting hyperglycemia, glucose intolerance, and impaired insulin secretion. PBA treatment strongly reduced the severe hyperglycemia observed in obese Avy hIAPP mice in fasting and fed conditions throughout the study. This effect was paralleled by a decrease in hyperinsulinemia. Importantly, PBA treatment reduced the prevalence and the severity of islet amyloid deposition in Avy hIAPP mice. Collectively, these results show that PBA treatment elicits a marked reduction of hyperglycemia and reduces amyloid deposits in obese and diabetic mice, highlighting the potential of chaperones for T2D treatment.

BACE2 suppression in mice aggravates the adverse metabolic consequences of an obesogenic diet.

OBJECTIVE: Pancreatic ß-cell dysfunction is a central feature in the pathogenesis of type 2 diabetes (T2D). Accumulating evidence indicates that ß-site APP-cleaving enzyme 2 (BACE2) inhibition exerts a beneficial effect on ß-cells in different models of T2D. Thus, targeting BACE2 may represent a potential therapeutic strategy for the treatment of this disease. Here, we aimed to investigate the effects of BACE2 suppression on glucose homeostasis in a model of diet-induced obesity. METHODS: BACE2 knock-out (BKO) and wild-type (WT) mice were fed with a high-fat diet (HFD) for 2 or 16 weeks. Body weight, food intake, respiratory exchange ratio, locomotor activity, and energy expenditure were determined. Glucose homeostasis was evaluated by glucose and insulin tolerance tests. ß-cell proliferation was assessed by Ki67-positive nuclei, and ß-cell function was determined by measuring glucose-stimulated insulin secretion. Leptin sensitivity was evaluated by quantifying food intake and body weight after an intraperitoneal leptin injection. Neuropeptide gene expression and insulin signaling in the mediobasal hypothalamus were determined by qPCR and Akt phosphorylation, respectively. RESULTS: After 16 weeks of HFD feeding, BKO mice exhibited an exacerbated body weight gain and hyperphagia, in comparison to WT littermates. Glucose tolerance was similar in both groups, whereas HFD-induced hyperinsulinemia, insulin resistance, and ß-cell expansion were more pronounced in BKO mice. In turn, leptin-induced food intake inhibition and hypothalamic insulin signaling were impaired in BKO mice, regardless of the diet, in accordance with deregulation of the expression of hypothalamic neuropeptide genes. Importantly, BKO mice already showed increased ß-cell proliferation and glucose-stimulated insulin secretion with respect to WT littermates after two weeks of HFD feeding, before the onset of obesity. CONCLUSIONS: Collectively, these results reveal that BACE2 suppression in an obesogenic setting leads to exacerbated body weight gain, hyperinsulinemia, and insulin resistance. Thus, we conclude that inhibition of BACE2 may aggravate the adverse metabolic effects associated with obesity.

In Situ LSPR Sensing of Secreted Insulin in Organ-on-Chip.

Organ-on-a-chip (OOC) devices offer new approaches for metabolic disease modeling and drug discovery by providing biologically relevant models of tissues and organs in vitro with a high degree of control over experimental variables for high-content screening applications. Yet, to fully exploit the potential of these platforms, there is a need to interface them with integrated non-labeled sensing modules, capable of monitoring, in situ, their biochemical response to external stimuli, such as stress or drugs. In order to meet this need, we aim here to develop an integrated technology based on coupling a localized surface plasmon resonance (LSPR) sensing module to an OOC device to monitor the insulin in situ secretion in pancreatic islets, a key physiological event that is usually perturbed in metabolic diseases such as type 2 diabetes (T2D). As a proof of concept, we developed a biomimetic islet-on-a-chip (IOC) device composed of mouse pancreatic islets hosted in a cellulose-based scaffold as a novel approach. The IOC was interfaced with a state-of-the-art on-chip LSPR sensing platform to monitor the in situ insulin secretion. The developed platform offers a powerful tool to enable the in situ response study of microtissues to external stimuli for applications such as a drug-screening platform for human models, bypassing animal testing.

Clinical characteristics and management of type 1 diabetes in Spain. The SED1 study. / Características clínicas y manejo de la diabetes tipo 1 en España. Estudio SED1.

OBJECTIVES: To determine the sociodemographic and clinical profile of a representative sample of people with type 1 diabetes mellitus (DM1) in Spain and identify factors associated with glycemic control. MATERIAL AND METHODS: A cross-sectional observational study was carried out in adults and children with DM1 treated in 75 Spanish public hospitals, geographically distributed in order to be representative of the Spanish population. Within each center, the patients were included on a consecutive basis as they visited the clinic. They were interviewed, and their clinical histories were reviewed. A descriptive statistical analysis was made, and factors associated with HbA1c were analyzed using multivariate linear regression analysis. RESULTS: A total of 647 patients were included: 55.3% females, aged 36.6±14.4 years, 97.2% Caucasians, BMI 24.7±4.4kg/m2 (12.1% ≥30kg/m2), and 74.0% had secondary / university education. A total of 20.2% were active smokers. The mean time from the diagnosis of DM1 was 17.9±12.0 years. A total of 48.7% presented comorbidities: 19.3% retinopathy and 16.4% hypothyroidism. As regards treatment for DM1, 76.5% received basal-bolus insulin therapy and 20.7% continuous subcutaneous insulin infusion (CSII); 51.0% of the patients used an insulin/carbohydrate ratio (ICR), with 4.6±1.6 self-monitored capillary blood glucose (SMCBG) measurements a day, and 24.8% used continuous glucose monitoring (CGM). The mean HbA1c value was 7.6±1.1% (30% below 7%). Metabolic control improved (lower HbA1c) with more daily SMCBG (B=-0.053; p=0.009), a higher educational level (B=0.461; P<0.001), greater number of hypoglycemia episodes (B=-0.253; P=0.018) and carbohydrate counting (B=-0.190; P=0.048), and worsened the longer the duration of the disease (B=0.010; P=0.010), higher total dose of insulin (B=0.010; P<0.0001), poorer adherence to diet (B=0.650; P<0.0001) and a family history of DM (B=-0.233; P=0.007). CONCLUSIONS: The management of patients with DM1 in Spain, as well as the treatment they receive, is similar to that seen in other Western countries. Blood glucose control is associated with educational level, disease duration, and the characteristics of treatment and self-care.

CD31+ Extracellular Vesicles From Patients With Type 2 Diabetes Shuttle a miRNA Signature Associated With Cardiovascular Complications.

Innovative biomarkers are needed to improve the management of patients with type 2 diabetes mellitus (T2DM). Blood circulating miRNAs have been proposed as a potential tool to detect T2DM complications, but the lack of tissue specificity, among other reasons, has hampered their translation to clinical settings. Extracellular vesicle (EV)-shuttled miRNAs have been proposed as an alternative approach. Here, we adapted an immunomagnetic bead-based method to isolate plasma CD31+ EVs to harvest vesicles deriving from tissues relevant for T2DM complications. Surface marker characterization showed that CD31+ EVs were also positive for a range of markers typical of both platelets and activated endothelial cells. After characterization, we quantified 11 candidate miRNAs associated with vascular performance and shuttled by CD31+ EVs in a large (n = 218) cross-sectional cohort of patients categorized as having T2DM without complications, having T2DM with complications, and control subjects. We found that 10 of the tested miRNAs are affected by T2DM, while the signature composed by miR-146a, -320a, -422a, and -451a efficiently identified T2DM patients with complications. Furthermore, another CD31+ EV-shuttled miRNA signature, i.e., miR-155, -320a, -342-3p, -376, and -422a, detected T2DM patients with a previous major adverse cardiovascular event. Many of these miRNAs significantly correlate with clinical variables held to play a key role in the development of complications. In addition, we show that CD31+ EVs from patients with T2DM are able to promote the expression of selected inflammatory mRNAs, i.e., CCL2, IL-1α, and TNFα, when administered to endothelial cells in vitro. Overall, these data suggest that the miRNA cargo of plasma CD31+ EVs is largely affected by T2DM and related complications, encouraging further research to explore the diagnostic potential and the functional role of these alterations.

Coxsackievirus B Type 4 Infection in ß Cells Downregulates the Chaperone Prefoldin URI to Induce a MODY4-like Diabetes via Pdx1 Silencing.

Enteroviruses are suspected to contribute to insulin-producing ß cell loss and hyperglycemia-induced diabetes. However, mechanisms are not fully defined. Here, we show that coxsackievirus B type 4 (CVB4) infection in human islet-engrafted mice and in rat insulinoma cells displays loss of unconventional prefoldin RPB5 interactor (URI) and PDX1, affecting ß cell function and identity. Genetic URI ablation in the mouse pancreas causes PDX1 depletion in ß cells. Importantly, diabetic PDX1 heterozygous mice overexpressing URI in ß cells are more glucose tolerant. Mechanistically, URI loss triggers estrogen receptor nuclear translocation leading to DNA methyltransferase 1 (DNMT1) expression, which induces Pdx1 promoter hypermethylation and silencing. Consequently, demethylating agent procainamide-mediated DNMT1 inhibition reinstates PDX1 expression and protects against diabetes in pancreatic URI-depleted mice . Finally, the ß cells of human diabetes patients show correlations between viral protein 1 and URI, PDX1, and DNMT1 levels. URI and DNMT1 expression and PDX1 silencing provide a causal link between enterovirus infection and diabetes.

Delivery of muscle-derived exosomal miRNAs induced by HIIT improves insulin sensitivity through down-regulation of hepatic FoxO1 in mice.

Implementation of regular physical activity helps in the maintenance of a healthy metabolic profile both in humans and mice through molecular mechanisms not yet completely defined. Here, we show that high-intensity interval training (HIIT) modifies the microRNA (miRNA) profile of circulating exosomes in mice, including significant increases in miR-133a and miR-133b Importantly, treatment of sedentary mice with exosomes isolated from the plasma of trained mice improves glucose tolerance, insulin sensitivity, and decreases plasma levels of triglycerides. Moreover, exosomes isolated from the muscle of trained mice display similar changes in miRNA content, and their administration to sedentary mice reproduces the improvement of glucose tolerance. Exosomal miRNAs up-regulated by HIIT target insulin-regulated transcription factor forkhead box O1 (FoxO1) and, accordingly, expression of FoxO1 is decreased in the liver of trained and exosome-treated mice. Treatment with exosomes transfected with a miR-133b mimic or with a specific siRNA targeting FoxO1 recapitulates the metabolic effects observed in trained mice. Overall, our data suggest that circulating exosomes released by the muscle carry a specific miRNA signature that is modified by exercise and induce expression changes in the liver that impact whole-body metabolic profile.

Peripheral insulin and amylin levels in Parkinson's disease.

BACKGROUND: Type-2-diabetes (T2D) has surfaced as a potential risk factor for Parkinson's disease (PD) in some epidemiological studies. Evidence of glucose metabolism alterations in PD from molecular studies remains conflicting. Amylin, the T2D amyloid protein, has been implicated in PD in pathological studies. We aimed to assess peripheral levels of amylin and insulin in PD patients and control subjects (Cs). METHODS: We conducted an observational cross-sectional study of 111 participants: 73 PD and 38 Cs, similar in age, sex and body mass index. All underwent motor (UPDRS-MDS-III), non-motor (NMSS) and cognitive (MDRS) scales as well as determination of four parameters: fasting glycaemia, glycated haemoglobin, fasting plasma insulin (FPI) and fasting plasma amylin (FPA). RESULTS: FPI was significantly lower in PD than Cs (p = 0.034). In participants with age above cohort-median-age, FPA was higher in PD than Cs (p = 0.046). The FPA/FPI ratio (FPAIR) was significantly higher in PD than Cs (p = 0.024). In PD, modest correlation was found between higher insulin-resistance and NMSS scores. CONCLUSIONS: PD patients had lower FPI and increased FPAIR. In older PD subgroup, FPA was increased. The more the insulin resistance, the higher the non-motor scores. These findings provide an additional link between pathophysiology of diabetes and PD. This might be related to a dissociated insulin and amylin secretion in PD, in line with recent evidence of endocrine pancreas role in PD pathogeny.

Management of Hypoglycemia in Adults with Type 1 Diabetes in Real-Life Condition.

INTRODUCTION: Hypoglycemia is the most common acute complication in individuals with type 1 diabetes (T1D). Episodes of mild or moderate hypoglycemia should be treated in adults with a dose of around 15-20 g fast-acting carbohydrates. However, this self-treatment of hypoglycemia in real-life condition is not well documented. OBJECTIVE: The aim of this study wasto determine the characteristics of hypoglycemia treatment in adults with T1D in a prospective study design. METHODS: Individuals with T1D were advised to record information related to hypoglycemia episodes for a period of 14 days. Quantity and quality (including glycemic index [GI] and glycemic load) of carbohydrates consumed in every hypoglycemia episode and others factors related with hypoglycemia such as physical activity, fear of hypoglycemia, or hypoglycemia awareness were analyzed. RESULTS: A total of 93 individuals (36.5 ± 16.2 years old, BMI of 24.9 ± 3.8 kg/m2, diabetes duration of 14.9 ± 10.4 years, and HbA1c levels of 7.3 ± 0.8%) were included in the study. A total of 483 episodes of mild or moderate hypoglycemia were reported, which supposed on average 2.7 ± 2.0 episodes a week. The quantity of carbohydrates consumed in all episodes of hypoglycemia was 25.9 ± 9.2 g. GI of food consumed in all episodes of hypoglycemia was classified as low (53.9 ± 8.3). Overtreatment of hypoglycemia, defined as ingestion of more than 20 g of carbohydrates, occurred in 50.3% of hypoglycemic episodes; even 22.3% of these episodes were treated with more than 30 g of carbohydrates. Fruit juice was the most popular option, chosen in almost 70% of the events. In addition, we observed other moderate or low GI foods such as milk, bread, cookies, and bakery products among the most consumed foods. CONCLUSION: A majority of the studied individuals with T1D does not manage hypoglycemia according to current American Diabetes Association guidelines, in most cases by overtreating, choosing foods with low glycemic effect, and not varying the dose of carbohydrates, depending on the physical activity performed.

Mitochondrial Dysfunction: A Common Hallmark Underlying Comorbidity between sIBM and Other Degenerative and Age-Related Diseases.

Sporadic inclusion body myositis (sIBM) is an inflammatory myopathy associated, among others, with mitochondrial dysfunction. Similar molecular features are found in Alzheimer's disease (AD) and Type 2 Diabetes Mellitus (T2DM), underlying potential comorbidity. This study aims to evaluate common clinical and molecular hallmarks among sIBM, AD, and T2DM. Comorbidity with AD was assessed in n = 14 sIBM patients by performing neuropsychological and cognitive tests, cranial magnetic resonance imaging, AD cerebrospinal fluid biomarkers (levels of amyloid beta, total tau, and phosphorylated tau at threonine-181), and genetic apolipoprotein E genotyping. In the same sIBM cohort, comorbidity with T2DM was assessed by collecting anthropometric measures and performing an oral glucose tolerance test and insulin determinations. Results were compared to the standard population and other myositis (n = 7 dermatomyositis and n = 7 polymyositis). Mitochondrial contribution into disease was tested by measurement of oxidative/anaerobic and oxidant/antioxidant balances, respiration fluxes, and enzymatic activities in sIBM fibroblasts subjected to different glucose levels. Comorbidity of sIBM with AD was not detected. Clinically, sIBM patients showed signs of misbalanced glucose homeostasis, similar to other myositis. Such misbalance was further confirmed at the molecular level by the metabolic inability of sIBM fibroblasts to adapt to different glucose conditions. Under the standard condition, sIBM fibroblasts showed decreased respiration (0.71 ± 0.08 vs. 1.06 ± 0.04 nmols O2/min; p = 0.024) and increased anaerobic metabolism (5.76 ± 0.52 vs. 3.79 ± 0.35 mM lactate; p = 0.052). Moreover, when glucose conditions were changed, sIBM fibroblasts presented decreased fold change in mitochondrial enzymatic activities (-12.13 ± 21.86 vs. 199.22 ± 62.52 cytochrome c oxidase/citrate synthase ratio; p = 0.017) and increased oxidative stress per mitochondrial activity (203.76 ± 82.77 vs. -69.55 ± 21.00; p = 0.047), underlying scarce metabolic plasticity. These findings do not demonstrate higher prevalence of AD in sIBM patients, but evidences of prediabetogenic conditions were found. Glucose deregulation in myositis suggests the contribution of lifestyle conditions, such as restricted mobility. Additionally, molecular evidences from sIBM fibroblasts confirm that mitochondrial dysfunction may play a role. Monitoring T2DM development and mitochondrial contribution to disease in myositis patients could set a path for novel therapeutic options.

Alpha1-antitrypsin ameliorates islet amyloid-induced glucose intolerance and ß-cell dysfunction.

OBJECTIVE: Pancreatic ß-cell failure is central to the development and progression of type 2 diabetes (T2D). The aggregation of human islet amyloid polypeptide (hIAPP) has been associated with pancreatic islet inflammation and dysfunction in T2D. Alpha1-antitrypsin (AAT) is a circulating protease inhibitor with anti-inflammatory properties. Here, we sought to investigate the potential therapeutic effect of AAT treatment in a mouse model characterized by hIAPP overexpression in pancreatic ß-cells. METHODS: Mice overexpressing hIAPP (hIAPP-Tg) in pancreatic ß-cells were used as a model of amyloid-induced ß-cell dysfunction. Glucose homeostasis was evaluated by glucose tolerance tests and insulin secretion assays. Apoptosis and amyloid formation was assessed in hIAPP-Tg mouse islets cultured at high glucose levels. Dissociated islet cells were cocultured with macrophages obtained from the peritoneal cavity. RESULTS: Nontreated hIAPP-Tg mice were glucose intolerant and exhibited impaired insulin secretion. Interestingly, AAT treatment improved glucose tolerance and restored the insulin secretory response to glucose in hIAPP-Tg mice. Moreover, AAT administration normalized the expression of the essential ß-cell genes MafA and Pdx1, which were downregulated in pancreatic islets from hIAPP-Tg mice. AAT prevented the formation of amyloid deposits and apoptosis in hIAPP-Tg islets cultured at high glucose concentrations. Since islet macrophages mediate hIAPP-induced ß-cell dysfunction, we investigated the effect of AAT in cocultures of macrophages and islet cells. AAT prevented hIAPP-induced ß-cell apoptosis in these cocultures without reducing the hIAPP-induced secretion of IL-1ß by macrophages. Remarkably, AAT protected ß-cells against the cytotoxic effects of conditioned medium from hIAPP-treated macrophages. Similarly, AAT also abrogated the cytotoxic effects of exogenous proinflammatory cytokines on pancreatic ß-cells. CONCLUSIONS: These results demonstrate that treatment with AAT improves glucose homeostasis in mice overexpressing hIAPP and protects pancreatic ß-cells from the cytotoxic actions of hIAPP mediated by macrophages. These results support the use of AAT-based therapies to recover pancreatic ß-cell function for the treatment of T2D.