Hybrid Closed Loop in Adults With Type 1 Diabetes and Severely Impaired Hypoglycemia Awareness.

BACKGROUND: Benefits of hybrid closed-loop (HCL) systems in a high-risk group with type 1 diabetes and impaired awareness of hypoglycemia (IAH) have not been well-explored. METHODS: Adults with Edmonton HYPO scores ≥1047 were randomized to 26-weeks HCL (MiniMed™ 670G) vs standard therapy (multiple daily injections or insulin pump) without continuous glucose monitoring (CGM) (control). Primary outcome was percentage CGM time-in-range (TIR; 70-180 mg/dL) at 23 to 26 weeks post-randomization. Major secondary endpoints included magnitude of change in counter-regulatory hormones and autonomic symptom responses to hypoglycemia at 26-weeks post-randomization. A post hoc analysis evaluated glycemia risk index (GRI) comparing HCL with control groups at 26 weeks post-randomization. RESULTS: Nine participants (median [interquartile range (IQR)] age 51 [41, 59] years; 44% male; enrolment HYPO score 1183 [1058, 1308]; Clarke score 6 [6, 6]; n = 5 [HCL]; n = 4 [control]) completed the study. Time-in-range was higher using HCL vs control (70% [68, 74%] vs 48% [44, 50%], P = .014). Time <70 mg/dL did not differ (HCL 3.8% [2.7, 3.9] vs control 6.5% [4.3, 8.6], P = .14) although hypoglycemia episode duration was shorter (30 vs 50 minutes, P < .001) with HCL. Glycemia risk index was lower with HCL vs control (38.1 [30.0, 39.2] vs 70.8 [58.5, 72.4], P = .014). Following 6 months of HCL use, greater dopamine (24.0 [12.3, 27.6] vs -18.5 [-36.5, -4.8], P = .014), and growth hormone (6.3 [4.6, 16.8] vs 0.5 [-0.8, 3.0], P = .050) responses to hypoglycemia were observed. CONCLUSIONS: Six months of HCL use in high-risk adults with severe IAH increased glucose TIR and improved GRI without increased hypoglycemia, and partially restored counter-regulatory responses. CLINICAL TRIAL REGISTRATION: ACTRN12617000520336.

High intensity interval training as a novel treatment for impaired awareness of hypoglycaemia in people with type 1 diabetes (HIT4HYPOS): a randomised parallel-group study.

AIMS/HYPOTHESIS: Impaired awareness of hypoglycaemia (IAH) in type 1 diabetes may develop through a process referred to as habituation. Consistent with this, a single bout of high intensity interval exercise as a novel stress stimulus improves counterregulatory responses (CRR) to next-day hypoglycaemia, referred to as dishabituation. This longitudinal pilot study investigated whether 4 weeks of high intensity interval training (HIIT) has sustained effects on counterregulatory and symptom responses to hypoglycaemia in adults with type 1 diabetes and IAH. METHODS: HIT4HYPOS was a single-centre, randomised, parallel-group study. Participants were identified using the Scottish Diabetes Research Network (SDRN) and from diabetes outpatient clinics in NHS Tayside, UK. The study took place at the Clinical Research Centre, Ninewells Hospital and Medical School, Dundee, UK. Participants were aged 18-55 years with type 1 diabetes of at least 5 years' duration and HbA1c levels <75 mmol/mol (<9%). They had IAH confirmed by a Gold score ≥4, modified Clarke score ≥4 or Dose Adjustment For Normal Eating [DAFNE] hypoglycaemia awareness rating of 2 or 3, and/or evidence of recurrent hypoglycaemia on flash glucose monitoring. Participants were randomly allocated using a web-based system to either 4 weeks of real-time continuous glucose monitoring (RT-CGM) or RT-CGM+HIIT. Participants and investigators were not masked to group assignment. The HIIT programme was performed for 20 min on a stationary exercise bike three times a week. Hyperinsulinaemic-hypoglycaemic (2.5 mmol/l) clamp studies with assessment of symptoms, hormones and cognitive function were performed at baseline and after 4 weeks of the study intervention. The predefined primary outcome was the difference in hypoglycaemia-induced adrenaline (epinephrine) responses from baseline following RT-CGM or RT-CGM+HIIT. RESULTS: Eighteen participants (nine men and nine women) with type 1 diabetes (median [IQR] duration 27 [18.75-32] years) and IAH were included, with nine participants randomised to each group. Data from all study participants were included in the analysis. During the 4 week intervention there were no significant mean (SEM) differences between RT-CGM and RT-CGM+HIIT in exposure to level 1 (28 [7] vs 22 [4] episodes, p=0.45) or level 2 (9 [3] vs 4 [1] episodes, p=0.29) hypoglycaemia. The CGM-derived mean glucose level, SD of glucose and glucose management indicator (GMI) did not differ between groups. During the hyperinsulinaemic-hypoglycaemic clamp studies, mean (SEM) change from baseline was greater for the noradrenergic responses (RT-CGM vs RT-CGM+HIIT: -988 [447] vs 514 [732] pmol/l, p=0.02) but not the adrenergic responses (-298 [687] vs 1130 [747] pmol/l, p=0.11) in those participants who had undergone RT-CGM+HIIT. There was a benefit of RT-CGM+HIIT for mean (SEM) change from baseline in the glucagon CRR to hypoglycaemia (RT-CGM vs RT-CGM+HIIT: 1 [4] vs 16 [6] ng/l, p=0.01). Consistent with the hormone response, the mean (SEM) symptomatic response to hypoglycaemia (adjusted for baseline) was greater following RT-CGM+HIIT (RT-CGM vs RT-CGM+HIIT: -4 [2] vs 0 [2], p<0.05). CONCLUSIONS/INTERPRETATION: In this pilot clinical trial in people with type 1 diabetes and IAH, we found continuing benefits of HIIT for overall hormonal and symptomatic CRR to subsequent hypoglycaemia. Our findings also suggest that HIIT may improve the glucagon response to insulin-induced hypoglycaemia. TRIAL REGISTRATION: ISRCTN15373978. FUNDING: Sir George Alberti Fellowship from Diabetes UK (CMF) and the Juvenile Diabetes Research Foundation.

Cure of Alzheimer's Dementia in Many Patients by Using Intranasal Insulin to Augment an Inadequate Counter-Reaction, Edaravone to Scavenge ROS, and 1 or 2 Other Drugs to Address Affected Brain Cells.

The goal of treatment for Alzheimer's dementia (AD) is the restoration of normal cognition. No drug regimen has ever achieved this. This article suggests that curing AD may be achieved by combination therapy as follows. First, with intranasal insulin to augment the body's natural counter-reaction to the changes in brain cell-types that produced the dementia. Second, with edaravone to decrease free radicals, which are increased and causal in AD. Third, as described elsewhere, with one or two drugs from among pioglitazone, fluoxetine, and lithium, which address the brain cell-types whose changed functions cause the dementia. Insulin restores cerebral glucose, which is the main nutrient for brain neurons whose depletion is responsible for the dementia; and edaravone decreases ROS, which are intrinsic causes of neuropathology in AD. This combination of drugs is a potential cure for many patients with AD, and should be tested in a clinical trial.

Arginine-vasopressin mediates counter-regulatory glucagon release and is diminished in type 1 diabetes.

Insulin-induced hypoglycemia is a major treatment barrier in type-1 diabetes (T1D). Accordingly, it is important that we understand the mechanisms regulating the circulating levels of glucagon. Varying glucose over the range of concentrations that occur physiologically between the fed and fuel-deprived states (8 to 4 mM) has no significant effect on glucagon secretion in the perfused mouse pancreas or in isolated mouse islets (in vitro), and yet associates with dramatic increases in plasma glucagon. The identity of the systemic factor(s) that elevates circulating glucagon remains unknown. Here, we show that arginine-vasopressin (AVP), secreted from the posterior pituitary, stimulates glucagon secretion. Alpha-cells express high levels of the vasopressin 1b receptor (V1bR) gene (Avpr1b). Activation of AVP neurons in vivo increased circulating copeptin (the C-terminal segment of the AVP precursor peptide) and increased blood glucose; effects blocked by pharmacological antagonism of either the glucagon receptor or V1bR. AVP also mediates the stimulatory effects of hypoglycemia produced by exogenous insulin and 2-deoxy-D-glucose on glucagon secretion. We show that the A1/C1 neurons of the medulla oblongata drive AVP neuron activation in response to insulin-induced hypoglycemia. AVP injection increased cytoplasmic Ca2+ in alpha-cells (implanted into the anterior chamber of the eye) and glucagon release. Hypoglycemia also increases circulating levels of AVP/copeptin in humans and this hormone stimulates glucagon secretion from human islets. In patients with T1D, hypoglycemia failed to increase both copeptin and glucagon. These findings suggest that AVP is a physiological systemic regulator of glucagon secretion and that this mechanism becomes impaired in T1D.

Acceleration of Gastric Emptying by Insulin-Induced Hypoglycemia is Dependent on the Degree of Hypoglycemia.

CONTEXT: Hypoglycemia is a major barrier to optimal glycemic control in insulin-treated diabetes. Recent guidelines from the American Diabetes Association have subcategorized "non-severe" hypoglycemia into level 1 (<3.9 mmol/L) and 2 (<3 mmol/L) hypoglycemia. Gastric emptying of carbohydrate is a major determinant of postprandial glycemia but its role in hypoglycemia counter-regulation remains underappreciated. "Marked" hypoglycemia (~2.6 mmol/L) accelerates gastric emptying and increases carbohydrate absorption in health and type 1 diabetes, but the impact of "mild" hypoglycemia (3.0-3.9 mmol/L) is unknown. OBJECTIVE: To determine the effects of 2 levels of hypoglycemia, 2.6 mmol/L ("marked") and 3.6 mmol/L ("mild"), on gastric emptying in health. DESIGN, SETTING, AND SUBJECTS: Fourteen healthy male participants (mean age: 32.9 ±â€…8.3 years; body mass index: 24.5 ±â€…3.4 kg/m2) from the general community underwent measurement of gastric emptying of a radiolabeled solid meal (100 g beef) by scintigraphy over 120 minutes on 3 separate occasions, while blood glucose was maintained at either ~2.6 mmol/L, ~3.6 mmol/L, or ~6 mmol/L in random order from 15 minutes before until 60 minutes after meal ingestion using glucose-insulin clamp. Blood glucose was then maintained at 6 mmol/L from 60 to 120 minutes on all days. RESULTS: Gastric emptying was accelerated during both mild (P = 0.011) and marked (P = 0.001) hypoglycemia when compared to euglycemia, and was more rapid during marked compared with mild hypoglycemia (P = 0.008). Hypoglycemia-induced gastric emptying acceleration during mild (r = 0.57, P = 0.030) and marked (r = 0.76, P = 0.0014) hypoglycemia was related to gastric emptying during euglycemia. CONCLUSION: In health, acceleration of gastric emptying by insulin-induced hypoglycemia is dependent on the degree of hypoglycemia and baseline rate of emptying.

Mood moderates the effect of aesthetic appeal on performance.

Aesthetically appealing stimuli can improve performance in demanding target localisation tasks compared to unappealing stimuli. Two search-and-localisation experiments were carried out to examine the possible underlying mechanism mediating the effects of appeal on performance. Participants (N = 95) were put in a positive or negative mood prior to carrying out a visual target localisation task with appealing and unappealing targets. In both experiments, positive mood initially led to faster localisation of appealing compared to unappealing stimuli, while an advantage for appealing over unappealing stimuli emerged over time in negative mood participants. The findings are compatible with the idea that appealing stimuli may be inherently rewarding, with aesthetic appeal overcoming the detrimental effects of negative mood on performance.

A Human Randomized Controlled Trial Comparing Metabolic Responses to Single and Repeated Hypoglycemia in Type 1 Diabetes.

AIMS: Hypoglycemia hinders optimal glycemic management in type 1 diabetes (T1D). Long diabetes duration and hypoglycemia impair hormonal counter-regulatory responses to hypoglycemia. Our study was designed to test whether (1) the metabolic responses and insulin sensitivity are impaired, and (2) whether they are affected by short-lived antecedent hypoglycemia in participants with T1D. MATERIALS AND METHODS: In a randomized, crossover, 2x2 factorial design, 9 male participants with T1D and 9 comparable control participants underwent 30 minutes of hypoglycemia (p-glucose < 2.9 mmol/L) followed by a euglycemic clamp on 2 separate interventions: with and without 30 minutes of hypoglycemia the day before the study day. RESULTS: During both interventions insulin sensitivity was consistently lower, while counter-regulatory hormones were reduced, with 75% lower glucagon and 50% lower epinephrine during hypoglycemia in participants with T1D, who also displayed 40% lower lactate and 5- to 10-fold increased ketone body concentrations following hypoglycemia, whereas palmitate and glucose turnover, forearm glucose uptake, and substrate oxidation did not differ between the groups. In participants with T1D, adipose tissue phosphatase and tensin homolog (PTEN) content, hormone-sensitive lipase (HSL) phosphorylation, and muscle glucose transporter type 4 (GLUT4) content were decreased compared with controls. And antecedent hypoglycemic episodes lasting 30 minutes did not affect counter-regulation or insulin sensitivity. CONCLUSIONS: Participants with T1D displayed insulin resistance and impaired hormonal counter-regulation during hypoglycemia, whereas glucose and fatty acid fluxes were intact and ketogenic responses were amplified. We observed subtle alterations of intracellular signaling and no effect of short-lived antecedent hypoglycemia on subsequent counter-regulation. This plausibly reflects the presence of insulin resistance and implies that T1D is a condition with defective hormonal but preserved metabolic responsiveness to short-lived hypoglycemia.

Evidence that hindbrain astrocytes in the rat detect low glucose with a glucose transporter 2-phospholipase C-calcium release mechanism.

Astrocytes generate robust cytoplasmic calcium signals in response to reductions in extracellular glucose. This calcium signal, in turn, drives purinergic gliotransmission, which controls the activity of catecholaminergic (CA) neurons in the hindbrain. These CA neurons are critical to triggering glucose counter-regulatory responses (CRRs) that, ultimately, restore glucose homeostasis via endocrine and behavioral means. Although the astrocyte low-glucose sensor involvement in CRR has been accepted, it is not clear how astrocytes produce an increase in intracellular calcium in response to a decrease in glucose. Our ex vivo calcium imaging studies of hindbrain astrocytes show that the glucose type 2 transporter (GLUT2) is an essential feature of the astrocyte glucosensor mechanism. Coimmunoprecipitation assays reveal that the recombinant GLUT2 binds directly with the recombinant Gq protein subunit that activates phospholipase C (PLC). Additional calcium imaging studies suggest that GLUT2 may be connected to a PLC-endoplasmic reticular-calcium release mechanism, which is amplified by calcium-induced calcium release (CICR). Collectively, these data help outline a potential mechanism used by astrocytes to convert information regarding low-glucose levels into intracellular changes that ultimately regulate the CRR.

Context Dependent Role of Type 2 Innate Lymphoid Cells in Allergic Skin Inflammation.

The discovery of innate lymphoid cells (ILC) has profoundly influenced the understanding of innate and adaptive immune crosstalk in health and disease. ILC and T cells share developmental and functional characteristics such as the lineage-specifying transcription factors and effector cytokines, but importantly ILC do not display rearranged antigen-specific receptors. Similar to T cells ILC are subdivided into 3 different helper-like subtypes, namely ILC1-3, and a killer-like subtype comprising natural killer (NK) cells. Increasing evidence supports the physiological relevance of ILC, e.g., in wound healing and defense against parasites, as well as their pathogenic role in allergy, inflammatory bowel diseases or psoriasis. Group 2 ILC have been attributed to the pathogenesis of allergic diseases like asthma and atopic dermatitis. Other inflammatory skin diseases such as allergic contact dermatitis are profoundly shaped by inflammatory NK cells. This article reviews the role of ILC in allergic skin diseases with a major focus on ILC2. While group 2 ILC are suggested to contribute to the pathogenesis of type 2 dominated inflammation as seen in atopic dermatitis, we have shown that lack of ILC2 in type 1 dominated contact hypersensitivity results in enhanced inflammation, suggesting a regulatory role of ILC2 in this context. We provide a concept of how ILC2 may influence context dependent the mutual counterbalance between type I and type II immune responses in allergic skin diseases.

Counter-regulation of regulatory T cells by autoreactive CD8+ T cells in rheumatoid arthritis.

The mechanisms whereby autoreactive T cells escape peripheral tolerance establishing thus autoimmune diseases in humans remain an unresolved question. Here, we demonstrate that autoreactive polyfunctional CD8+ T cells recognizing self-antigens (i.e., vimentin, actin cytoplasmic 1, or non-muscle myosin heavy chain 9 epitopes) with high avidity, counter-regulate Tregs by killing them, in a consistent percentage of rheumatoid arthritis (RA) patients. Indeed, these CD8+ T cells express a phenotype and gene profile of effector (eff) cells and, upon antigen-specific activation, kill Tregs indirectly in an NKG2D-dependent bystander fashion in vitro. This data provides a mechanistic basis for the finding showing that AE-specific (CD107a+) CD8+ T killer cells correlate, directly with the disease activity score, and inversely with the percentage of activated Tregs, in both steady state and follow-up studies in vivo. In addition, multiplex immunofluorescence imaging analyses of inflamed synovial tissues in vivo show that a remarkable number of CD8+ T cells express granzyme-B and selectively contact FOXP3+ Tregs, some of which are in an apoptotic state, validating hence the possibility that CD8+ Teff cells can counteract neighboring Tregs within inflamed tissues, by killing them. Alternatively, the disease activity score of a different subset of patients is correlated with the expansion of a peculiar subpopulation of autoreactive low avidity, partially-activated (pa)CD8+ T cells that, despite they conserve the conventional naïve (N) phenotype, produce high levels of tumor necrosis factor (TNF)-α and exhibit a gene expression signature of a progressive activation state. Tregs directly correlate with the expansion of this autoreactive (low avidity) paCD8+ TN cell subset in vivo, and efficiently control their differentiation rather their proliferation in vitro. Interestingly, autoreactive high avidity CD8+ Teff cells or low avidity paCD8+ TN cells are significantly expanded in RA patients who would become non-responders or patients who would become responders to TNF-α inhibitor therapy, respectively. These data provide evidence of a previously undescribed role of such mechanisms in the progression and therapy of RA.

Molecular reductions in glucokinase activity increase counter-regulatory responses to hypoglycemia in mice and humans with diabetes.

OBJECTIVE: Appropriate glucose levels are essential for survival; thus, the detection and correction of low blood glucose is of paramount importance. Hypoglycemia prompts an integrated response involving reduction in insulin release and secretion of key counter-regulatory hormones glucagon and epinephrine that together promote endogenous glucose production to restore normoglycemia. However, specifically how this response is orchestrated remains to be fully clarified. The low affinity hexokinase glucokinase is found in glucose-sensing cells involved in glucose homeostasis including pancreatic ß-cells and in certain brain areas. Here, we aimed to examine the role of glucokinase in triggering counter-regulatory hormonal responses to hypoglycemia, hypothesizing that reduced glucokinase activity would lead to increased and/or earlier triggering of responses. METHODS: Hyperinsulinemic glucose clamps were performed to examine counter-regulatory responses to controlled hypoglycemic challenges created in humans with monogenic diabetes resulting from heterozygous glucokinase mutations (GCK-MODY). To examine the relative importance of glucokinase in different sensing areas, we then examined responses to clamped hypoglycemia in mice with molecularly defined disruption of whole body and/or brain glucokinase. RESULTS: GCK-MODY patients displayed increased and earlier glucagon responses during hypoglycemia compared with a group of glycemia-matched patients with type 2 diabetes. Consistent with this, glucagon responses to hypoglycemia were also increased in I366F mice with mutated glucokinase and in streptozotocin-treated ß-cell ablated diabetic I366F mice. Glucagon responses were normal in conditional brain glucokinase-knockout mice, suggesting that glucagon release during hypoglycemia is controlled by glucokinase-mediated glucose sensing outside the brain but not in ß-cells. For epinephrine, we found increased responses in GCK-MODY patients, in ß-cell ablated diabetic I366F mice and in conditional (nestin lineage) brain glucokinase-knockout mice, supporting a role for brain glucokinase in triggering epinephrine release. CONCLUSIONS: Our data suggest that glucokinase in brain and other non ß-cell peripheral hypoglycemia sensors is important in glucose homeostasis, allowing the body to detect and respond to a falling blood glucose.

Insulin resistance depends on GH counter-regulation in two syndromes of short stature.

Specific phenotypic features of subjects affected with genetic syndromes depend on peculiarities of expression of each discrete mutation and on extent of its divergence from normal physiology. In this context, and when studying the GH/IGF-I axis of subjects with two different syndromes that include severe short stature (SSS), we noticed different metabolic phenotypes in each cohort. Subjects with Laron syndrome (LS), who have GH insensitivity (GHI), display obesity, increased body fat, enhanced insulin sensitivity and diminished incidence of diabetes mellitus. Subjects with a new syndrome (NS), who have normal GH signaling, display intrauterine growth retardation (IUGR), normal to slightly elevated body fat content, insulin resistance and early onset type 2 diabetes mellitus (T2DM). In consequence, we were able to observe the clinical consequences of different GH counter-regulation status on carbohydrate metabolism, especially considering that subjects with either syndrome most likely have diminished pancreatic reserve.

Effects of alcohol on plasma glucose and prevention of alcohol-induced hypoglycemia in type 1 diabetes-A systematic review with GRADE.

Because ethanol is thought to be a risk factor for severe hypoglycemia, patients with type 1 diabetes (T1D) are recommended to limit ethanol intake. However, little is known on how ethanol affects plasma glucose and how ethanol-induced hypoglycemia can be prevented. In this study, we systematically reviewed the literature for ethanol effects on plasma glucose and for prevention strategies on ethanol-induced hypoglycemia. Electronic searches on PubMed and Google were conducted in February 2017. Randomized clinical trials and observational studies were included. Studies involved patients with T1D with no history of ethanol abuse. The primary aims were changes in plasma glucose after ethanol intake and prevention strategies for ethanol-induced hypoglycemia. Quality of the studies was assessed by GRADE. Additionally, we searched for guidelines from diabetes associations on their suggested prevention strategies. We included 13 studies. Eight studies reported that ethanol, regardless of administration intravenously or orally, were associated with an increased risk of hypoglycemia due to decrease in plasma glucose, impaired counter-regulatory response, awareness of hypoglycemia, and cognitive function. Five studies did not report an increased risk of hypoglycemia. None of the studies investigated prevention strategies for ethanol-induced hypoglycemia. Recommendations from 13 diabetes associations were included. All associations recommend that ethanol should only be consumed with food intake. The majority of included studies showed that ethanol intake increased the risk of hypoglycemia in patients with T1D. However, the evidence for how to prevent ethanol-induced hypoglycemia is sparse, and further investigations are needed to establish evidence-based recommendations.

Counter-regulation in affective attentional biases: Evidence in the additional singleton paradigm.

We investigated motivational influences on affective processing biases; specifically, we were interested in whether anticipating positive versus negative future outcomes during goal pursuit affects attentional biases toward positive or negative stimuli. Attentional valence biases were assessed with the additional singleton task, with the task-irrelevant singleton colors being positive, negative or neutral. The motivational relevance of colors was established in a preceding task: In a balanced design, one color acquired positive valence by indicating the chance to win money, and a different color acquired negative valence by indicating the danger to lose money. Blocks of the additional singleton task were associated with either the chance of winning money (positive outcome focus) or the danger of losing money (negative outcome focus). We found an interaction of outcome focus and singleton valence in the accuracy rates, indicating an incongruency effect: Attentional capture was stronger for positive (negative) singletons in the negative (positive) outcome focus conditions. This result further corroborates the counter-regulation hypothesis, extending previous findings on the motivational top-down regulation of affective processing to the domain of early attentional processes.

Safeguarding of Fetal Growth by Mast Cells and Natural Killer Cells: Deficiency of One Is Counterbalanced by the Other.

Uterine natural killer cells (uNKs) and mast cells (uMCs) are of crucial importance for spiral artery (SA) remodeling and placentation. Mice deficient for both NKs and MCs including uNKs and uMCs show markedly impaired SA remodeling and their fetuses are growth-retarded. In contrast, the absence of either NKs or MCs results in only minor impairment. This suggests that uNKs can compensate for the effects of uMCs on SA remodeling and vice versa. To test this hypothesis, we assessed uNK numbers in uMC-deficient mice as well as uMC numbers in uNK-depleted mice. Notably, uMC-deficient C57BL/6J-Kit W-sh/W-sh (W-sh) mice showed markedly increased numbers of uNKs in contrast to wild type, and the transfer of bone marrow-derived MCs reverted this phenotype. Vice versa, uNK-deficient C57BL/6NTac-IL15 tm1Imx N5 (IL-15-/-) mice had significantly increased numbers of uMCs and MC-specific proteases. Our results suggest that uNKs and uMCs can counterbalance their effects at the feto-maternal interface and jointly promote SA remodeling and placentation.

Closed-Loop Insulin Delivery for Adults with Type 1 Diabetes Undertaking High-Intensity Interval Exercise Versus Moderate-Intensity Exercise: A Randomized, Crossover Study.

BACKGROUND: We aimed to compare closed-loop glucose control for people with type 1 diabetes undertaking high-intensity interval exercise (HIIE) versus moderate-intensity exercise (MIE). METHODS: Adults with type 1 diabetes established on insulin pumps undertook HIIE and MIE stages in random order during automated insulin delivery via a closed-loop system (Medtronic). Frequent venous sampling for glucose, lactate, ketones, insulin, catecholamines, cortisol, growth hormone, and glucagon levels was performed. The primary outcome was plasma glucose <4.0 mmol/L for ≥15 min, from exercise commencement to 120 min postexercise. Secondary outcomes included continuous glucose monitoring and biochemical parameters. RESULTS: Twelve adults (age mean ± standard deviation 40 ± 13 years) were recruited; all completed the study. Plasma glucose of one participant fell to 3.4 mmol/L following MIE completion; no glucose levels were <4.0 mmol/L for HIIE (primary outcome). There were no glucose excursions >15.0 mmol/L for either stage. Mean (±standard error) plasma glucose did not differ between stages pre-exercise; was higher during exercise in HIIE than MIE (11.3 ± 0.5 mmol/L vs. 9.7 ± 0.6 mmol/L, respectively; P < 0.001); and remained higher until 60 min postexercise. There were no differences in circulating free insulin before, during, or postexercise. During HIIE compared with MIE, there were greater increases in lactate (P < 0.001), catecholamines (all P < 0.05), and cortisol (P < 0.001). Ketones increased more with HIIE than MIE postexercise (P = 0.031). CONCLUSIONS: Preliminary findings suggest that closed-loop glucose control is safe for people undertaking HIIE and MIE. However, the management of the postexercise rise in ketones secondary to counter-regulatory hormone-induced insulin resistance observed with HIIE may represent a challenge for closed-loop systems.

Glutamine dipeptide and cortisol change the liver glucose metabolism and reduce the severity of insulin-induced hypoglycaemia in untreated T1DM Swiss mice.

CONTEXT: Glutamine is conditionally essential in type 1 diabetes mellitus, and might be useful to counteract hypoglycaemia. OBJECTIVE: To investigate the systemic and hepatic effects of counter-regulatory hormones and glutamine dipeptide (GDP) during hypoglycemic episodes. MATERIALS AND METHODS: Diabetic Swiss mice made hypoglycaemic by insulin injection (1 U/kg) were given counter-regulatory hormones and/or GDP. Sixty minutes later, liver histology, liver glucose metabolism and plasma were assessed. RESULTS: Combined, cortisol and GDP improved the hypoglycemic profile. During liver perfusion, gluconeogenesis was possibly the major pathway leading to glucose release. Perfusion with gluconeogenic precursors after glycogen depletion by adrenaline increased liver glucose and urea release. DISCUSSION: The less severe hypoglycaemia could result from cortisol stimulating periportal gluconeogenesis and GDP inhibiting pericentral glycogenolysis, both favouring liver glucose release. CONCLUSIONS: At least some benefits of GDP and cortisol during hypoglycaemia came from their hepatic actions, and their use in diabetic patients should be explored.

Automatic emotion regulation in response inhibition: The temporal dynamics of emotion counter-regulation during a go/no-go task.

Recent behavioral studies indicate that emotion counter-regulation automatically allocates attention to events that are opposite in the valence to the experienced emotional state. The present study explored the effect of emotion counter-regulation on response inhibition by using ERPs in a go/no-go paradigm. We recruited 58 subjects and randomly assigned them to either the angry priming group (watching Nanjing Massacre movie clips) or the neutral priming group (watching "mending a computer" movie clips). The behavioral results revealed that participants in the angry priming group responded significantly more accurately to go happy and no-go angry faces than go angry and no-go happy faces. The analyses of ERPs revealed that the amplitudes of the no-go N2 and no-go P3 were significantly larger for the happy faces than for the angry faces in the angry priming group. However, no such effects were found in the neutral priming group. These results suggest that highly aroused angry emotion could prompt a priority response to happy emotion stimuli and restrict the responses to angry emotion stimuli through emotion counter-regulation.

Managing hypoglycaemia.

Intensive glycaemic control reduces the diabetic microvascular disease burden but iatrogenic hypoglycaemia is a major barrier preventing tight glycaemic control because of the limitations of subcutaneous insulin preparations and insulin secretagogues. Severe hypoglycaemia is uncommon early in the disease as robust physiological defences, particularly glucagon and adrenaline release, limit falls in blood glucose whilst associated autonomic symptoms drive patients to take action by ingesting oral carbohydrate. With increasing diabetes duration, glucagon release is progressively impaired and sympatho-adrenal responses are activated at lower glucose levels. Repeated hypoglycaemic episodes contribute to impaired defences, increasing the risk of severe hypoglycaemia in a vicious downward spiral. Managing hypoglycaemia requires a systematic clinical approach with structured insulin self-management training and support of experienced diabetes educators. Judicious use of technologies includes insulin analogues, insulin pump therapy, continuous glucose monitoring, and in a few cases islet cell transplantation. Some individuals require specialist psychological support.

Hindbrain cytoglucopenia-induced increases in systemic blood glucose levels by 2-deoxyglucose depend on intact astrocytes and adenosine release.

The hindbrain contains critical neurocircuitry responsible for generating defensive physiological responses to hypoglycemia. This counter-regulatory response (CRR) is evoked by local hindbrain cytoglucopenia that causes an autonomically mediated increase in blood glucose, feeding behavior, and accelerated digestion; that is, actions that restore glucose homeostasis. Recent reports suggest that CRR may be initially triggered by astrocytes in the hindbrain. The present studies in thiobutabarbital-anesthetized rats show that exposure of the fourth ventricle (4V) to 2-deoxyglucose (2DG; 15 µmol) produced a 35% increase in circulating glucose relative to baseline levels. While the 4V application of the astrocytic signal blocker, fluorocitrate (FC; 5 nmol), alone, had no effect on blood glucose levels, 2DG-induced increases in glucose were blocked by 4V FC. The 4V effect of 2DG to increase glycemia was also blocked by the pretreatment with caffeine (nonselective adenosine antagonist) or a potent adenosine A1 antagonist (8-cyclopentyl-1,3-dipropylxanthine; DPCPX) but not the NMDA antagonist (MK-801). These results suggest that CNS detection of glucopenia is mediated by astrocytes and that astrocytic release of adenosine that occurs after hypoglycemia may cause the activation of downstream neural circuits that drive CRR.