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Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Context: Hypoglycemia in people with diabetes is common, especially in those taking medications such as insulin and sulfonylureas (SU) that place them at higher risk. Hypoglycemia is associated with distress in those with diabetes and their families, medication nonadherence, and disruption of life and work, and it leads to costly emergency department visits and hospitalizations, morbidity, and mortality., Objective: To review and update the diabetes-specific parts of the 2009 Evaluation and Management of Adult Hypoglycemic Disorders: Endocrine Society Clinical Practice Guideline and to address developing issues surrounding hypoglycemia in both adults and children living with diabetes. The overriding objectives are to reduce and prevent hypoglycemia., Methods: A multidisciplinary panel of clinician experts, together with a patient representative, and methodologists with expertise in evidence synthesis and guideline development, identified and prioritized 10 clinical questions related to hypoglycemia in people living with diabetes. Systematic reviews were conducted to address all the questions. The Grading of Recommendations Assessment, Development and Evaluation (GRADE) methodology was used to assess the certainty of evidence and make recommendations., Results: The panel agreed on 10 questions specific to hypoglycemia risk and prevention in people with diabetes for which 10 recommendations were made. The guideline includes conditional recommendations for use of real-time continuous glucose monitoring (CGM) and algorithm-driven insulin pumps in people with type 1 diabetes (T1D), use of CGM for outpatients with type 2 diabetes at high risk for hypoglycemia, use of long-acting and rapid-acting insulin analogs, and initiation of and continuation of CGM for select inpatient populations at high risk for hypoglycemia. Strong recommendations were made for structured diabetes education programs for those at high risk for hypoglycemia, use of glucagon preparations that do not require reconstitution vs those that do for managing severe outpatient hypoglycemia for adults and children, use of real-time CGM for individuals with T1D receiving multiple daily injections, and the use of inpatient glycemic management programs leveraging electronic health record data to reduce the risk of hypoglycemia., Conclusion: The recommendations are based on the consideration of critical outcomes as well as implementation factors such as feasibility and values and preferences of people with diabetes. These recommendations can be used to inform clinical practice and health care system improvement for this important complication for people living with diabetes., (© The Author(s) 2022. Published by Oxford University Press on behalf of the Endocrine Society. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Context: Interventions targeting hypoglycemia in people with diabetes are important for improving quality of life and reducing morbidity and mortality., Objective: To support development of the Endocrine Society Clinical Practice Guideline for management of individuals with diabetes at high risk for hypoglycemia., Methods: We searched several databases for studies addressing 10 questions provided by a guideline panel from the Endocrine Society. Meta-analysis was conducted when feasible. The Grading of Recommendations Assessment, Development and Evaluation (GRADE) methodology was used to assess certainty of evidence., Results: We included 149 studies reporting on 43 344 patients. Continuous glucose monitoring (CGM) reduced episodes of severe hypoglycemia in patients with type 1 diabetes (T1D) and reduced the proportion of patients with hypoglycemia (blood glucose [BG] levels <54 mg/dL). There were no data on use of real-time CGM with algorithm-driven insulin pumps vs multiple daily injections with BG testing in people with T1D. CGM in outpatients with type 2 diabetes taking insulin and/or sulfonylureas reduced time spent with BG levels under 70 mg/dL. Initiation of CGM in hospitalized patients at high risk for hypoglycemia reduced episodes of hypoglycemia with BG levels lower than 54 mg/dL and time spent under 54 mg/dL. The proportion of patients with hypoglycemia with BG levels lower than 70 mg/dL and lower than 54 mg/dL detected by CGM was significantly higher than point-of-care BG testing. We found no data evaluating continuation of personal CGM in the hospital. Use of an inpatient computerized glycemic management program utilizing electronic health record data was associated with fewer patients with and episodes of hypoglycemia with BG levels lower than 70 mg/dL and fewer patients with severe hypoglycemia compared with standard care. Long-acting basal insulin analogs were associated with less hypoglycemia. Rapid-acting insulin analogs were associated with reduced severe hypoglycemia, though there were more patients with mild to moderate hypoglycemia. Structured diabetes education programs reduced episodes of severe hypoglycemia and time below 54 mg/dL in outpatients taking insulin. Glucagon formulations not requiring reconstitution were associated with longer times to recovery from hypoglycemia, although the proportion of patients who recovered completely from hypoglycemia was not different between the 2 groups., Conclusion: This systematic review summarized the best available evidence about several interventions addressing hypoglycemia in people with diabetes. This evidence base will facilitate development of clinical practice guidelines by the Endocrine Society., (© The Author(s) 2022. Published by Oxford University Press on behalf of the Endocrine Society. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

In an effort to enhance the trustworthiness of its clinical practice guidelines, the Endocrine Society has recently adopted new policies and more rigorous methodologies for its guideline program. In this Clinical Practice Guideline Communication, we describe these recent enhancements-many of which reflect greater adherence to the Grading of Recommendations, Assessment, Development and Evaluation (GRADE) approach to guideline development-in addition to the rationale for such changes. Improvements to the Society's guideline development practices include, but are not limited to, enhanced inclusion of nonendocrinologist experts, including patient representatives, on guideline development panels; implementation of a more rigorous conflict/duality of interest policy; a requirement that all formal recommendations must be demonstrably underpinned by systematic evidence review; the explicit use of GRADE Evidence-to-Decision frameworks; greater use and explanation of standardized guideline language; and a more intentional approach to guideline updating. Lastly, we describe some of the experiential differences our guideline readers are most likely to notice., (© The Author(s) 2022. Published by Oxford University Press on behalf of the Endocrine Society. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Spinocerebellar ataxia type 7 (SCA7) is an autosomal-dominant neurodegenerative disorder caused by a CAG repeat expansion in the coding region of the ataxin-7 gene. Infantile-onset SCA7 patients display extremely large repeat expansions (>200 CAGs) and exhibit progressive ataxia, dysarthria, dysphagia and retinal degeneration. Severe hypotonia, aspiration pneumonia and respiratory failure often contribute to death in affected infants. To better understand the features of respiratory and upper airway dysfunction in SCA7, we examined breathing and putative phrenic and hypoglossal neuropathology in a knock-in mouse model of early-onset SCA7 carrying an expanded allele with 266 CAG repeats. Whole-body plethysmography was used to measure awake spontaneously breathing SCA7-266Q knock-in mice at baseline in normoxia and during a hypercapnic/hypoxic respiratory challenge at 4 and 8 weeks, before and after the onset of disease. Postmortem studies included quantification of putative phrenic and hypoglossal motor neurons and microglia, and analysis of ataxin-7 aggregation at end stage. SCA7-266Q mice had profound breathing deficits during a respiratory challenge, exhibiting reduced respiratory output and a greater percentage of time in apnea. Histologically, putative phrenic and hypoglossal motor neurons of SCA7 mice exhibited a reduction in number accompanied by increased microglial activation, indicating neurodegeneration and neuroinflammation. Furthermore, intranuclear ataxin-7 accumulation was observed in cells neighboring putative phrenic and hypoglossal motor neurons in SCA7 mice. These findings reveal the importance of phrenic and hypoglossal motor neuron pathology associated with respiratory failure and upper airway dysfunction, which are observed in infantile-onset SCA7 patients and likely contribute to their early death., Competing Interests: Competing interests The authors declare no competing or financial interests., (© 2021. Published by The Company of Biologists Ltd.)

Pompe disease is a lysosomal storage disease caused by mutations within the GAA gene, which encodes acid α-glucosidase (GAA)-an enzyme necessary for lysosomal glycogen degradation. A lack of GAA results in an accumulation of glycogen in cardiac and skeletal muscle, as well as in motor neurons. The only FDA approved treatment for Pompe disease-an enzyme replacement therapy (ERT)-increases survival of patients, but has unmasked previously unrecognized clinical manifestations of Pompe disease. These clinical signs and symptoms include tracheo-bronchomalacia, vascular aneurysms, and gastro-intestinal discomfort. Together, these previously unrecognized pathologies indicate that GAA-deficiency impacts smooth muscle in addition to skeletal and cardiac muscle. Thus, we sought to characterize smooth muscle pathology in the airway, vascular, gastrointestinal, and genitourinary in the Gaa -/- mouse model. Increased levels of glycogen were present in smooth muscle cells of the aorta, trachea, esophagus, stomach, and bladder of Gaa -/- mice, compared to wild type mice. In addition, there was an increased abundance of both lysosome membrane protein (LAMP1) and autophagosome membrane protein (LC3) indicating vacuolar accumulation in several tissues. Taken together, we show that GAA deficiency results in subsequent pathology in smooth muscle cells, which may lead to life-threatening complications if not properly treated.

Amyotrophic Lateral Sclerosis (ALS) is a devastating neurodegenerative disorder that results in death due to respiratory failure. Many genetic defects are associated with ALS; one such defect is a mutation in the gene encoding optineurin (OPTN). Using an optineurin null mouse (Optn -/- ), we sought to characterize the impact of optineurin deficiency on respiratory neurodegeneration. Respiratory function was assessed at 6 and 12 mo of age using whole body plethysmography at baseline during normoxia (FiO 2 : 0.21; N 2 balance) and during a respiratory challenge with hypoxia and hypercapnia (FiCO 2 : 0.07, FiO 2 : 0.10; N 2 balance). Histological analyses to assess motor neuron viability and respiratory nerve integrity were performed in the medulla, cervical spinal cord, hypoglossal nerve, and phrenic nerve. Minute ventilation, peak inspiratory flow, and peak expiratory flow are significantly reduced during a respiratory challenge in 6 mo Optn -/- mice. By 12 mo, tidal volume is also significantly reduced in Optn -/- mice. Furthermore, 12mo Optn -/- mice exhibit hypoglossal motor neuron loss, phrenic and hypoglossal dysmyelination, and accumulated mitochondria in the hypoglossal nerve axons. Overall, these data indicate that Optn -/- mice display neurodegenerative respiratory dysfunction and are a useful model to study the impact of novel therapies on respiratory function for optineurin-deficient ALS patients., (Copyright © 2020 Elsevier B.V. All rights reserved.)

This study aimed to compare conventional medication management of type 2 diabetes (T2D) to medication management in conjunction with a lifestyle intervention using continuous glucose monitoring to minimize glucose excursions. Thirty adults (63% female; mean age, 53.3 years) who were diagnosed with T2D for less than 11 years (mean, 5.6 years), had glycated A 1c (HbA 1c ) ≥ 7.0% (51 mmol/mol) (mean 8.8%, [73 mmol/mol]), and were not using insulin, were randomly assigned in a 1:2 ratio to routine care (RC) or 4 group sessions of glycemic excursion minimization plus real-time CGM (GEM CGM ). Assessments at baseline and 5 months included a physical exam, metabolic and lipid panels, a review of diabetes medications, and psychological questionnaires. For the week following assessments, participants wore a blinded activity monitor and completed 3 days of 24-hour dietary recall. A subgroup also wore a blinded CGM. GEM CGM participants significantly improved HbA 1c (from 8.9% to 7.6% [74-60 mmol/mol] compared with 8.8% to 8.7% [73-72 mmol/mol] for RC ( P  = .03). Additionally, GEM CGM reduced the need for diabetes medication ( P  = .01), reduced carbohydrate consumption ( P  = .009), and improved diabetes knowledge ( P  = .001), quality of life ( P  = .01) and diabetes distress ( P  = .02), and trended to more empowerment ( P  = .05) without increasing dietary fat, lipids, or hypoglycemia. Confirming our prior research, GEM CGM appears to be a safe, effective lifestyle intervention option for adults with suboptimally controlled T2D who do not take insulin., (© The Author(s) 2020. Published by Oxford University Press on behalf of the Endocrine Society.)

Amyotrophic lateral sclerosis (ALS) is a fatal disease characterized by degeneration of motor neurons and muscles, and death is usually a result of impaired respiratory function due to loss of motor neurons that control upper airway muscles and/or the diaphragm. Currently, no cure for ALS exists and treatments to date do not significantly improve respiratory or swallowing function. One cause of ALS is a mutation in the superoxide dismutase-1 ( SOD1 ) gene; thus, reducing expression of the mutated gene may slow the progression of the disease. Our group has been studying the SOD1 G93A transgenic mouse model of ALS that develops progressive respiratory deficits and dysphagia. We hypothesize that solely treating the tongue in SOD1 mice will preserve respiratory and swallowing function, and it will prolong survival. At 6 weeks of age, 11 SOD1 G93A mice (both sexes) received a single intralingual injection of gene therapy (AAVrh10-miR SOD1 ). Another 29 mice (both sexes) were divided into two control groups: (1) 12 SOD1 G93A mice that received a single intralingual vehicle injection (saline); and (2) 17 non-transgenic littermates. Starting at 13 weeks of age, plethysmography (respiratory parameters) at baseline and in response to hypoxia (11% O 2 ) + hypercapnia (7% CO 2 ) were recorded and videofluoroscopic swallow study testing were performed twice monthly until end-stage disease. Minute ventilation during hypoxia + hypercapnia and mean inspiratory flow at baseline were significantly reduced ( p  < 0.05) in vehicle-injected, but not AAVrh10-miR SOD1 -injected SOD1 G93A mice as compared with wild-type mice. In contrast, swallowing function was unchanged by AAVrh10-miR SOD1 treatment ( p  > 0.05). AAVrh10-miR SOD1 injections also significantly extended survival in females by ∼1 week. In conclusion, this study indicates that intralingual AAVrh10-miR SOD1 treatment preserved respiratory (but not swallowing) function potentially via increasing upper airway patency, and it is worthy of further exploration as a possible therapy to preserve respiratory capacity in ALS patients.

Duchenne muscular dystrophy (DMD) is a fatal neuromuscular disease caused by deleterious mutations in the DMD gene which encodes the dystrophin protein. Skeletal muscle weakness and eventual muscle degradation due to loss of dystrophin are well-documented pathological hallmarks of DMD. In contrast, the neuropathology of this disease remains understudied despite the emerging evidence of neurological abnormalities induced by dystrophin loss. Using quantitative morphological analysis of nerve sections, we characterize axonopathies in the phrenic and hypoglossal (XII) nerves of mdx mice. We observe dysfunction in these nerves - which innervate the diaphragm and genioglossus respectively - that we propose contributes to respiratory failure, the most common cause of death in DMD. These observations highlight the importance in the further characterization of the neuropathology of DMD. Additionally, these observations underscore the necessity in correcting both the nervous system pathology in addition to skeletal muscle deficits to ameliorate this disease.

Pompe disease is a glycogen storage disease caused by a deficiency in acid α-glucosidase (GAA), a hydrolase necessary for the degradation of lysosomal glycogen. This deficiency in GAA results in muscle and neuronal glycogen accumulation, which causes respiratory insufficiency. Pompe disease mouse models provide a means of assessing respiratory pathology and are important for pre-clinical studies of novel therapies that aim to treat respiratory dysfunction and improve quality of life. This review aims to compile and summarize existing manuscripts that characterize the respiratory phenotype of Pompe mouse models. Manuscripts included in this review were selected utilizing specific search terms and exclusion criteria. Analysis of these findings demonstrate that Pompe disease mouse models have respiratory physiological defects as well as pathologies in the diaphragm, tongue, higher-order respiratory control centers, phrenic and hypoglossal motor nuclei, phrenic and hypoglossal nerves, neuromuscular junctions, and airway smooth muscle. Overall, the culmination of these pathologies contributes to severe respiratory dysfunction, underscoring the importance of characterizing the respiratory phenotype while developing effective therapies for patients.

Faster-acting insulins, new noninsulin drug classes, more flexible insulin-delivery systems, and improved continuous glucose monitoring devices offer unprecedented opportunities to improve postprandial glucose (PPG) management and overall care for adults with insulin-treated diabetes. These developments led the Endocrine Society to convene a working panel of diabetes experts in December 2018 to assess the current state of PPG management, identify innovative ways to improve self-management and quality of life, and align best practices to current and emerging treatment and monitoring options. Drawing on current research and collective clinical experience, we considered the following issues for the ∼200 million adults worldwide with type 1 and insulin-requiring type 2 diabetes: (i) the role of PPG management in reducing the risk of diabetes complications; (ii) barriers preventing effective PPG management; (iii) strategies to reduce PPG excursions and improve patient quality of life; and (iv) education and clinical tools to support endocrinologists in improving PPG management. We concluded that managing PPG to minimize or prevent diabetes-related complications will require elucidating fundamental questions about optimal ways to quantify and clinically assess the metabolic dysregulation and consequences of the abnormal postprandial state in diabetes and recommend research strategies to address these questions. We also identified practical strategies and tools that are already available to reduce barriers to effective PPG management, optimize use of new and emerging clinical tools, and improve patient self-management and quality of life., (Copyright © 2019 Endocrine Society.)

Introduction: Efforts to lower glycosylated hemoglobin (A1c) in patients with type 2 diabetes (T2D) are intended to reduce the risk of diabetic complications, but A1c is not the only factor contributing to this risk. Consequently, we re-analyzed published data from a broad-spectrum lifestyle intervention that lowered A1c to assess its effectiveness in lowering the overall risk of two complications of T2D, namely, coronary heart disease (CHD) and stroke., Methods: Data from 37 adults who participated in a randomized clinical trial of a lifestyle intervention intended to reduce postprandial glucose (PPG) were re-analyzed for their pre- and post-treatment risk of CHD and stroke using the T2D-specific UK Prospective Diabetes Study (UKPDS) v2.0 risk algorithm., Results: Compared to participants who received routine care, those using the lifestyle intervention had a significantly greater reduction in 10-year risk for CHD, but not for stroke., Conclusion: These secondary analyses suggest that broad-spectrum lifestyle interventions that focus on lowering PPG may lower the risk of future CHD, which could guide future research., Trial Registration: ClinicalTrials.gov ID: NCT02432391.

Pompe disease is an autosomal recessive glycogen storage disorder caused by deficiency of the lysosomal enzyme acid alpha-glucosidase (GAA). GAA deficiency results in systemic lysosomal glycogen accumulation and cellular disruption in muscle and the central nervous system (CNS). Adeno-associated virus (AAV) gene therapy is ideal for Pompe disease, since a single systemic injection may correct both muscle and CNS pathologies. Using the Pompe mouse (B6;129-Gaa Tm1Rabn /J), this study sought to explore if AAVB1, a newly engineered vector with a high affinity for muscle and CNS, reduces systemic weakness and improves survival in adult mice. Three-month-old Gaa -/- animals were injected with either AAVB1 or AAV9 vectors expressing GAA and tissues were harvested 6 months later. Both AAV vectors prolonged survival. AAVB1-treated animals had a robust weight gain compared to the AAV9-treated group. Vector genome levels, GAA enzyme activity, and histological analysis indicated that both vectors transduced the heart efficiently, leading to glycogen clearance, and transduced the diaphragm and CNS at comparable levels. AAVB1-treated mice had higher GAA activity and greater glycogen clearance in the tongue. Finally, AAVB1-treated animals showed improved respiratory function comparable to wild-type animals. In conclusion, AAVB1-GAA offers a promising therapeutic option for the treatment of muscle and CNS in Pompe disease.

Amyotrophic lateral sclerosis (ALS) and spinocerebellar ataxia (SCA) are neurodegenerative disorders that result in progressive motor dysfunction and ultimately lead to respiratory failure. Rodent models of neurodegenerative disorders provide a means to study the respiratory motor unit pathology that results in respiratory failure. In addition, they are important for pre-clinical studies of novel therapies that improve breathing, quality of life, and survival. The goal of this review is to compare the respiratory phenotype of two neurodegenerative disorders that have different pathological origins, but similar physiological outcomes. Manuscripts reviewed were identified using specific search terms and exclusion criteria. We excluded manuscripts that investigated novel therapeutics and only included those manuscripts that describe the respiratory pathology. The ALS manuscripts describe pathology in respiratory physiology, the phrenic and hypoglossal motor units, respiratory neural control centers, and accessory respiratory muscles. The SCA rodent model manuscripts characterized pathology in overall respiratory function, phrenic motor units and hypoglossal motor neurons. Overall, a combination of pathology in the respiratory motor units and control centers contribute to devastating respiratory dysfunction.

Background: Pompe disease is a fatal neuromuscular disorder caused by a deficiency in acid α-glucosidase, an enzyme responsible for glycogen degradation in the lysosome. Currently, the only approved treatment for Pompe disease is enzyme replacement therapy (ERT), which increases patient survival, but does not fully correct the skeletal muscle pathology. Skeletal muscle pathology is not corrected with ERT because low cation-independent mannose-6-phosphate receptor abundance and autophagic accumulation inhibits the enzyme from reaching the lysosome. Thus, a therapy that more efficiently targets skeletal muscle pathology, such as adeno-associated virus (AAV), is needed for Pompe disease., Objective: The goal of this project was to deliver a rAAV9-coGAA vector driven by a tissue restrictive promoter will efficiently transduce skeletal muscle and correct autophagic accumulation., Methods: Thus, rAAV9-coGAA was intravenously delivered at three doses to 12-week old Gaa-/- mice. 1 month after injection, skeletal muscles were biochemically and histologically analyzed for autophagy-related markers., Results: At the highest dose, GAA enzyme activity and vacuolization scores achieved therapeutic levels. In addition, resolution of autophagosome (AP) accumulation was seen by immunofluorescence and western blot analysis of autophagy-related proteins. Finally, mice treated at birth demonstrated persistence of GAA expression and resolution of lysosomes and APs compared to those treated at 3 months., Conclusion: In conclusion, a single systemic injection of rAAV9-coGAA ameliorates vacuolar accumulation and prevents autophagic dysregulation., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Pompe disease (OMIM 232300) is an autosomal recessive disorder caused by mutations in the gene encoding acid α-glucosidase (GAA) (EC 3.2.1.20), the enzyme responsible for hydrolyzing lysosomal glycogen. The primary cellular pathology is lysosomal glycogen accumulation in cardiac muscle, skeletal muscle, and motor neurons, which ultimately results in cardiorespiratory failure. However, the severity of pathology and its impact on clinical outcomes are poorly described in smooth muscle. The advent of enzyme replacement therapy (ERT) in 2006 has improved clinical outcomes in infantile-onset Pompe disease patients. Although ERT increases patient life expectancy and ventilator free survival, it is not entirely curative. Persistent motor neuron pathology and weakness of respiratory muscles, including airway smooth muscles, contribute to the need for mechanical ventilation by some patients on ERT. Some patients on ERT continue to experience life-threatening pathology to vascular smooth muscle, such as aneurysms or dissections within the aorta and cerebral arteries. Better characterization of the disease impact on smooth muscle will inform treatment development and help anticipate later complications. This review summarizes the published knowledge of smooth muscle pathology associated with Pompe disease in animal models and in patients.

Background: Hypoglycemia is a known risk of intensive postoperative glucose control in patients undergoing cardiac operations. However, neither the consequences of hypoglycemia relative to hyperglycemia, nor the possible interaction effects, have been well described. We examined the effects of postoperative hypoglycemia, hyperglycemia, and their interaction on short-term morbidity and mortality., Methods: Single-institution Society of Thoracic Surgeons (STS) database patient records from 2010 to 2014 were merged with clinical data, including blood glucose values measured in the intensive care unit (ICU). Exclusion criteria included fewer than three glucose measurements and absence of an STS predicted risk of morbidity or mortality score. Primary outcomes were operative mortality and composite major morbidity (permanent stroke, renal failure, prolonged ventilation, pneumonia, or myocardial infarction). Secondary outcomes included ICU and postoperative length of stay. Hypoglycemia was defined as below 70 mg/dL, and hyperglycemia as above 180 mg/dL. Simple and multivariable regression models were used to evaluate the outcomes., Results: A total of 2,285 patient records met the selection criteria for analysis. The mean postoperative glucose level was 140.8 ± 18.8 mg/dL. Overall, 21.4% of patients experienced a hypoglycemic episode (n = 488), and 1.05% (n = 24) had a severe hypoglycemic episode (<40 mg/dL). The unadjusted odds ratio (UOR) for operative mortality for patients with any hypoglycemic episode compared with those without was 5.47 (95% confidence interval [CI] 3.14 to 9.54), and the UOR for major morbidity was 4.66 (95% CI 3.55 to 6.11). After adjustment for predicted risk of morbidity or mortality and other significant covariates, the adjusted odds (AOR) of operative mortality were significant for patients with any hypoglycemia (AOR 4.88, 95% CI 2.67 to 8.92) and patients with both events (AOR 8.29, 95% CI 1.83 to 37.5) but not hyperglycemia alone (AOR 1.62, 95% CI 0.56 to 4.69). The AOR of major morbidity for patients with both hypoglycemic and hyperglycemic events was 14.3 (95% CI 6.50 to 31.4)., Conclusions: Postoperative hypoglycemia is associated with both mortality and major morbidity after cardiac operations. The combination of both hyperglycemia and hypoglycemia represents a substantial increase in risk. Although it remains unclear whether hypoglycemia is a cause, an early warning sign, or a result of adverse events, this study suggests that hypoglycemia may be an important event in the postoperative period after cardiac operations., (Copyright © 2017 The Society of Thoracic Surgeons. Published by Elsevier Inc. All rights reserved.)

Aims: This preliminary RCT investigated whether an integrated lifestyle modification program that focuses on reducing postprandial blood glucose through replacing high with low glycemic load foods and increasing routine physical activities guided by systematic self-monitoring of blood glucose (GEM) could improve metabolic control of adults with type 2 diabetes mellitus, without compromising other physiological parameters., Methods: Forty-seven adults (mean age 55.3 years) who were diagnosed with type 2 diabetes mellitus for less than 5 years (mean 2.1 years), had HbA1c ≥ 7% (mean 8.4%) and were not taking blood glucose lowering medications, were randomized to routine care or five 1-h instructional sessions of GEM. Assessments at baseline and 6 months included a physical exam, metabolic and lipid panels, and psychological questionnaires., Results: The GEM intervention led to significant improvements in HbA1c (decreasing from 8.4 to 7.4% [69-57 mmol/mol] compared with 8.3 to 8.3% [68-68 mmol/mol] for routine care; Interaction p<.01) and psychological functioning without compromising other physiological parameters., Conclusions: Consistent with a patient-centered approach, GEM appears to be an effective lifestyle modification option for adults recently diagnosed with type 2 diabetes mellitus., (Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.)

Purpose of Review: Autoimmune destruction of the β cells is considered the key abnormality in type 1 diabetes mellitus and insulin replacement the primary therapeutic strategy. However, a lack of insulin is accompanied by disturbances in glucagon release, which is excessive postprandially, but insufficient during hypoglycaemia. In addition, replacing insulin alone appears insufficient for adequate glucose control. This review focuses on the growing body of evidence that glucagon abnormalities contribute significantly to the pathophysiology of diabetes and on recent efforts to target the glucagon axis as adjunctive therapy to insulin replacement., Recent Findings: This review discusses recent (since 2013) advances in abnormalities of glucagon regulation and their link to the pathophysiology of diabetes; new mechanisms of glucagon action and regulation; manipulation of glucagon in diabetes treatment; and analytical and systems biology tools to study glucagon regulation., Summary: Recent efforts 'resurrected' glucagon as a key hormone in the pathophysiology of diabetes. New studies target its abnormal regulation and action that is key for improving diabetes treatment. The progress is promising, but major questions remain, including unravelling the mechanism of loss of glucagon counterregulation in type 1 diabetes mellitus and how best to manipulate glucagon to achieve more efficient and safer glycaemic control.

Type 1 diabetes is a disorder where slow destruction of pancreatic β-cells occurs through autoimmune mechanisms. The result is a progressive and ultimately complete lack of endogenous insulin. Due to β-cell lack, secondary abnormalities in glucagon and likely in incretins occur. These multiple hormonal abnormalities cause metabolic instability and extreme glycemic variability, which is the primary phenotype. As the disease progresses patients often develop hypoglycemia unawareness and defects in their counterregulatory defenses. Intensive insulin therapy may thus lead to 3-fold excess of severe hypoglycemia and severely hinder the effective and safe control of hyperglycemia. The main goal of the therapy for type 1 diabetes has long been physiological mimicry of normal insulin secretion based on monitoring which requires considerable effort and understanding of the underlying physiology. Attainment of this goal is challenged by the nature of the disease and our current lack of means to fully repair the abnormal endocrine pancreas interactive functions. As a result, various insulin preparations have been developed to partially compensate for the inability to deliver timely exogenous insulin directly to the portal/intrapancreatic circulation. It remains an ongoing task to identify the ideal routes and regimens of their delivery and potentially that of other hormones to restore the deficient and disordered hormonal environment of the pancreas to achieve a near normal metabolic state. Several recent technological advances help addressing these goals, including the rapid progress in insulin pumps, continuous glucose sensors, and ultimately the artificial pancreas closed-loop technology and the recent start of dual-hormone therapies.

Hypoglycemia is the most important and common side effect of insulin therapy. It is also the rate limiting factor in safely achieving excellent glycemic control. A three-fold increased risk of severe hypoglycemia occurs in both type 1 and type 2 diabetes with tight glucose control. This dictates a need to individualize therapy and glycemia goals to minimize this risk. Several ways to reduce hypoglycemia risk are recognized and discussed. They include frequent monitoring of blood sugars with home blood glucose tests and sometimes continuous glucose monitoring (CGM) in order to identify hypoglycemia particularly in hypoglycemia unawareness. Considerations include prompt measured hypoglycemia treatment, attempts to reduce glycemic variability, balancing basal and meal insulin therapy, a pattern therapy approach and use of a physiological mimicry with insulin analogues in a flexible manner. Methods to achieve adequate control while focusing on minimizing the risk of hypoglycemia are delineated in this article., (Copyright © 2012 Elsevier Inc. All rights reserved.)

Glucagon counterregulation (GCR) protects against hypoglycemia, but is impaired in type 1 diabetes (T1DM). A model-based analysis of in vivo animal data predicts that the GCR defects are linked to basal hyperglucagonemia. To test this hypothesis we studied the relationship between basal glucagon (BasG) and the GCR response to hypoglycemia in 29 hyperinsulinemic clamps in T1DM patients. Glucose levels were stabilized in euglycemia and then steadily lowered to 50 mg/dL. Glucagon was measured before induction of hypoglycemia and at 10 min intervals after glucose reached levels below 70 mg/dL. GCR was assessed by CumG, the cumulative glucagon levels above basal; MaxG, the maximum glucagon response; and RIG, the relative increase in glucagon over basal. Analysis of the results was performed with our mathematical model of GCR. The model describes interactions between islet peptides and glucose, reproduces the normal GCR axis and its impairment in diabetes. It was used to identify a control mechanism consistent with the observed link between BasG and GCR. Analysis of the clinical data showed that higher BasG was associated with lower GCR response. In particular, CumG and RIG correlated negatively with BasG (r = -0.46, p = 0.012 and r = -0.74, p < 0.0001 respectively) and MaxG increased linearly with BasG at a rate less than unity (p < 0.001). Consistent with these results was a model of GCR in which the secretion of glucagon has two components. The first is under (auto) feedback control and drives a pulsatile GCR and the second is feedback independent (basal secretion) and its increase suppresses the GCR. Our simulations showed that this model explains the observed relationships between BasG and GCR during a three-fold simulated increase in BasG. Our findings support the hypothesis that basal hyperglucagonemia contributes to the GCR impairment in T1DM and show that the predictive power of our GCR animal model applies to human pathophysiology in T1DM.

In health, the pancreatic islet cells work as a network with highly co-ordinated signals over time to balance glycaemia within a narrow range. In type 1 diabetes (T1DM), with autoimmune destruction of the β-cells, lack of insulin is considered the primary abnormality and is the primary therapy target. However, replacing insulin alone does not achieve adequate glucose control and recent studies have focused on controlling the endogenous glucagon release as well. In T1DM, glucagon secretion is disordered but not absolutely deficient; it may be excessive postprandially yet it is characteristically insufficient and delayed in response to hypoglycaemia. We review our system-level analysis of the pancreatic endocrine network mechanisms of glucagon counterregulation (GCR) and their dysregulation in T1DM and focus on possible use of α-cell inhibitors (ACIs) to manipulate the glucagon axis to repair the defective GCR. Our results indicate that the GCR abnormalities are of 'network origin'. The lack of β-cell signalling is the primary deficiency that contributes to two separate network abnormalities: (i) absence of a β-cell switch-off trigger and (ii) increased intraislet basal glucagon. A strategy to repair these abnormalities with ACI is proposed, which could achieve better control of glycaemia with reduced hypoglycaemia risk., (© 2011 Blackwell Publishing Ltd.)

This review analyzes an interdisciplinary approach to the pancreatic endocrine network-like relationships that control glucagon secretion and glucagon counterregulation (GCR). Using in silico studies, we show that a pancreatic feedback network that brings together several explicit interactions between islet peptides and blood glucose reproduces the normal GCR axis and explains its impairment in diabetes. An α-cell auto-feedback loop drives glucagon pulsatility and mediates triggering of GCR by hypoglycemia by a rapid switch-off of β-cell signals. The auto-feedback explains the enhancement of defective GCR in β-cell deficiency by a switch-off of signals in the pancreas that suppress α cells. Our models also predict that reduced β-cell activity decreases and delays the GCR. A key application of our models is the in silico simulation and testing of possible scenarios to repair defective GCR in β-cell deficiency. In particular, we predict that partial suppression of hyperglucagonemia may repair the impaired GCR. We also outline how the models can be extended and tested using human data to become a part of a larger construct including the regulation of the hepatic glucose output by the pancreas, circulating glucose, and incretins. In conclusion, a model of the normal GCR control mechanisms and their dysregulation in insulin-deficient diabetes is proposed and partially validated. The model components are clinically measurable, which permits its application to the study of the abnormalities of the human endocrine pancreas and their role in the progression of many diseases, including diabetes, metabolic syndrome, polycystic ovary syndrome, and others. It may also be used to examine therapeutic responses., (© 2010 Diabetes Technology Society.)

Diabetic patients are at increased risk for developing cardiovascular disease, and they constitute a large proportion of the global cardiovascular disease burden. Although multiple drugs exist for treating the hyperglycemia associated with diabetes, few have been shown to reduce cardiovascular risk. Great hope surrounded the arrival of the thiazolidinediones-drugs that favorably affect insulin sensitivity, inflammation, and some aspects of lipid profiles in diabetic patients. However, the cardiovascular effects of these agents are varied, and studies have suggested that they may be associated with increases in ischemic heart disease and heart failure, as well as with an increased risk for bone fracture. The following article provides a summary of important studies that have been published regarding the safety profiles of these agents. Findings from two recently published trials, RECORD and BARI 2D, are emphasized in this paper.

Background: Conventional methods describing daily glycemic variability (i.e., standard deviation and coefficient of variation) do not express risk. Low and High Blood Glucose Indices (LBGI and HBGI, respectively) and Average Daily Risk Range (ADRR) are parameters derived from self-monitored blood glucose (SMBG) data that quantify risk of glycemic excursions and temporal aspects of variability. In the present study, variability parameters were used to assess effects of exenatide and insulin glargine on risk of acute blood glucose extremes., Methods: New (LBGI, HBGI, and ADRR) and conventional variability analyses were applied retrospectively to SMBG data from patients with type 2 diabetes suboptimally controlled with metformin and a sulfonylurea plus exenatide or insulin glargine as a next therapeutic step. Exenatide- (n = 282) and insulin glargine-treated (n = 267) patients were well matched., Results: Exenatide treatment reduced ADRR overall (exenatide, mean +/- SEM, 16.33 +/- 0.45; insulin glargine, 18.54 +/- 0.49; P = 0.001). Seventy-seven percent of exenatide-treated patients were at low risk for glucose variability compared with 62% of glargine-treated patients (P = 0.00023). LBGI for exenatide remained minimal for all categories and significantly lower than glargine for all comparisons, and HBGI for exenatide remained low or moderate for all categories and significantly lower than glargine after the morning and evening meals. Reduced variability in exenatide-treated patients was shown by conventional methods but provided no indications of risk., Conclusions: Average glycemic control was similar for both treatment groups. However, exenatide treatment minimized risk for glycemic variability and extremes to a greater degree than insulin glargine treatment.

Hemoglobin A1c (HbA1c), a long-term, integrated average of tissue exposure to hyperglycemia, is the best reflection of average glucose concentrations and the best proven predictor of microvascular complications of diabetes mellitus. However, HbA1c fails to capture glycemic variability and the risks associated with extremes of hypoglycemia and hyperglycemia. These risks are the primary barrier to achieving the level of average glucose control that will minimize both the microvascular and the long-term macrovascular complications of type 1 diabetes. High blood glucose levels largely due to prandial excursions produce oxidative and inflammatory stress with potential acceleration of preexisting atherosclerosis and increased cardiovascular risk. Moreover, some temporal aspects of glycemic variation, including the rates of rise and fall of glucose, are associated with adverse cognitive and mood symptoms in those with diabetes. Methods to quantify the risk of glycemic extremes, both high and low, and the variability including its temporal aspects are now more precise than ever. These important endpoints should be included for use in clinical trials as useful metrics and recognized by regulatory agencies, which has not been the case in the past. Precise evaluation of glycemic variability and its attendant risks are essential in the design of optimal therapies; for these reasons, inclusion of these metrics and the pulsatile hormone patterns in mathematical models may be essential. For the clinician, the incursion of mathematical models that simulate normal and pathophysiological mechanisms of glycemic control is a reality and should be also gradually incorporated into clinical practice., (© Diabetes Technology Society)

Background: Glucagon counterregulation (GCR) is a key protection against hypoglycemia that is compromised in diabetes. In β-cell-deficient rats, GCR pulsatility can be amplified if insulin (INS) or somatostatin (SS) are infused in the pancreatic artery and then switched off during hypoglycemia. The data indicate that these signals act by different mechanisms, and here we analyze the differences between the two switch offs (SOs) and predict the GCR-amplifying effect of their individual or combined application., Methods: A minimal control network (MCN) of α/δ-cell interactions is approximated by differential equations to explain the GCR response to a SO and test in silico the hypotheses: (i) INS SO suppresses basal and pulsatile, while SS SO blocks only pulsatile glucagon release and (ii) simultaneous application of the two switch offs will augment the individual GCR response., Results: The mechanism postulated in (i) explains the differences in the GCR responses between the SOs. The MCN predicts that simultaneous application of INS and SS decreases basal glucagon but increases post-SO amplitude, thus doubling the response of GCR achieved by each of the individual signals., Conclusion: The current analyses predict that INS and SS SOs improve defective GCR in β-cell deficiency through different but complementary mechanisms and suggest SO strategies to maximally enhance GCR in type 1 diabetes by simultaneous manipulation of the network control. These results are clinically relevant, as they could have application to design of an artificial pancreas by providing ways to augment GCR that would not require glucagon infusion., (© Diabetes Technology Society)

Glucagon counterregulation (GCR) is a key protection against hypoglycemia compromised in insulinopenic diabetes by an unknown mechanism. In this work, we present an interdisciplinary approach to the analysis of the GCR control mechanisms. Our results indicate that a pancreatic network which unifies a few explicit interactions between the major islet peptides and blood glucose (BG) can replicate the normal GCR axis and explain its impairment in diabetes. A key and novel component of this network is an alpha-cell auto-feedback, which drives glucagon pulsatility and mediates triggering of pulsatile GCR by hypoglycemia via a switch-off of the beta-cell suppression of the alpha-cells. We have performed simulations based on our models of the endocrine pancreas which explain the in vivo GCR response to hypoglycemia of the normal pancreas and the enhancement of defective pulsatile GCR in beta-cell deficiency by switch-off of intrapancreatic alpha-cell suppressing signals. The models also predicted that reduced insulin secretion decreases and delays the GCR. In conclusion, based on experimental data we have developed and validated a model of the normal GCR control mechanisms and their dysregulation in insulin deficient diabetes. One advantage of this construct is that all model components are clinically measurable, thereby permitting its transfer, validation, and application to the study of the GCR abnormalities of the human endocrine pancreas in vivo.

Glucagon counterregulation (GCR) is a key protection against hypoglycemia that is compromised in diabetes via an unknown mechanism. To test the hypothesis that alpha-cell-inhibiting signals that are switched off during hypoglycemia amplify GCR, we studied streptozotocin (STZ)-treated male Wistar rats and estimated the effect on GCR of intrapancreatic infusion and termination during hypoglycemia of saline, insulin, and somatostatin. Times 10 min before and 45 min after the switch-off were analyzed. Insulin and somatostatin, but not saline, switch-off significantly increased the glucagon levels (P = 0.03), and the fold increases relative to baseline were significantly higher (P < 0.05) in the insulin and somatostatin groups vs. the saline group. The peak concentrations were also higher in the insulin (368 pg/ml) and somatostatin (228 pg/ml) groups vs. the saline (114 pg/ml) group (P < 0.05). GCR was pulsatile in most animals, indicating a feedback regulation. After the switch-off, the number of secretory events and the total pulsatile production were lower in the saline group vs. the insulin and somatostatin groups (P < 0.05), indicating enhancement of glucagon pulsatile activity by insulin and somatostatin compared with saline. Network modeling analysis demonstrates that reciprocal interactions between alpha- and delta-cells can explain the amplification by interpreting the GCR as a rebound response to the switch-off. The model justifies experimental designs to further study the intrapancreatic network in relation to the switch-off phenomenon. The results of this proof-of-concept interdisciplinary study support the hypothesis that GCR develops as a rebound pulsatile response of the intrapancreatic endocrine feedback network to switch-off of alpha-cell-inhibiting islet signals.

Although type 1 diabetes cannot be prevented or reversed, replacement of insulin production by transplantation of the pancreas or pancreatic islets represents a definitive solution. At present, transplantation can restore euglycemia, but this restoration is short-lived, requires islets from multiple donors, and necessitates lifelong immunosuppression. An emerging paradigm in transplantation and autoimmunity indicates that systemic inflammation contributes to tissue injury while disrupting immune tolerance. We identify multiple barriers to successful islet transplantation, each of which either contributes to the inflammatory state or is augmented by it. To optimize islet transplantation for diabetes reversal, we suggest that targeting these interacting barriers and the accompanying inflammation may represent an improved approach to achieve successful clinical islet transplantation by enhancing islet survival, regeneration or neogenesis potential, and tolerance induction. Overall, we consider the proinflammatory effects of important technical, immunological, and metabolic barriers including: 1) islet isolation and transplantation, including selection of implantation site; 2) recurrent autoimmunity, alloimmune rejection, and unique features of the autoimmune-prone immune system; and 3) the deranged metabolism of the islet transplant recipient. Consideration of these themes reveals that each is interrelated to and exacerbated by the other and that this connection is mediated by a systemic inflammatory state. This inflammatory state may form the central barrier to successful islet transplantation. Overall, there remains substantial promise in islet transplantation with several avenues of ongoing promising research. This review focuses on interactions between the technical, immunological, and metabolic barriers that must be overcome to optimize the success of this important therapeutic approach.

Hyperglycemia characterizes diabetes mellitus and is linked to its chronic and acute complications. Cognitive dysfunction in diabetes occurs especially in longstanding disease and with poor glycemic control. Recent data in humans suggests that hyperglycemia causes acute cognitive dysfunction. The underlying mechanisms are unknown but deserve further research as diabetes is becoming epidemic and will likely contribute increasingly to premature cognitive decline. The primary side effect of diabetes treatment is hypoglycemia, particularly resulting from insulin treatment. CNS adaptations to acute and chronic hypoglycemia underlie the inability of some people to promptly recognize and defend against the risk of serious hypoglycemia. Data from human and animal models may help explain how altered glycemia affects brain function both acutely and chronically. Improved mechanistic understanding of altered glycemia's effects could prevent the adverse impact of diabetes upon the CNS and give new insights into effects that may exist in normal aging.

Treatment of hypertension, to reverse and delay proteinuria progression and kidney failure, is the primary focus of medical management in patients with diabetic nephropathy. The initial choice for hypertension treatment in those with early nephropathy involves agents that block the renin-angiotensin system. However, it is not clear what the best choices for further drug therapy management are, because there are few data concerning the impact that antihypertensive drug combinations have on hard clinical outcomes, such as preventing the need for dialysis, and death. Patients usually require several drugs for controlling hypertension, which becomes harder to control as nephropathy progresses. In this review, it is suggested that quantitatively tracking proteinuria to guide therapy and a broad focus on the cardiovascular and renal end points are important for best outcomes in patients. Strategies may vary based on stage of disease, comorbidities, and age. Therapies not directed specifically at hypertension may also significantly aid hypertension management in prevention of progressive nephropathy, comorbidities, and mortality.

The brain uses glucose as its primary fuel. Cerebral metabolism of glucose requires transport through the blood-brain barrier, glycolytic conversion to pyruvate, metabolism via the tricarboxylic acid cycle and ultimately oxidation to carbon dioxide and water for full provision of adenosine triphosphate (ATP) and its high-energy equivalents. When deprived of glucose, the brain becomes dysfunctional or can be even permanently damaged. Glucose is stored as glycogen within astrocytes with potential importance for tolerance of hypoglycemia. Glycogen may also be important for the metabolic response to somatosensory stimulation and coupling of blood flow and cellular metabolism. Uncontrolled diabetes has a variety of adverse effects upon brain metabolism and function. Many aspects of function that affect the brain may be indirectly linked to cerebral glucose metabolism. Neurotransmitter metabolism, cerebral blood flow, blood-brain barrier and microvascular function may all be affected to varying degrees by either hypoglycemia or uncontrolled diabetes mellitus.

Fluorescence immunohistochemistry was performed to characterize the distribution and phenotype of GLUT8-positive neurons in rat brain and to compare the cellular distribution of GLUT8 with GLUT3 in the hippocampus. Based upon the absence of co-localization with the non-neuronal markers GFAP (astroglial) and OX42 (microglial), it appears that GLUT8 is expressed exclusively in neurons. At the cellular level, GLUT8 immunofluorescence was localized to neuronal cell bodies and the most proximal dendrites of inhibitory and excitatory neurons while GLUT3 immunofluorescence was localized to the neuropil in the hippocampus. These results demonstrate that GLUT8 is a neuron-specific glucose transporter expressed in the neuronal cell bodies of excitatory and inhibitory neurons in the rat hippocampus.