DOCSLIB.ORG

Hypoglycemia Unawareness in the Geriatric Patient: a Safety Concern

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
Hypoglycemia Unawareness in the Geriatric Patient: a Safety Concern 7/28/17 Hypoglycemia Unawareness in the Geriatric Patient: A Safety Concern 29TH ANNUAL TNP CONFERENCE TRANSFORMING HEALTHCARE IN TEXAS SEPTEMBER 8, 2017 AUSTIN, TEXAS Kenneth Lowrance, DNP, APRN, CNS, FNP-BC, NEA-BC, FAANP Associate Professor of Professional Practice Director, Post-Master’s DNP and CNS Programs Texas Christian University Disclaimer: The presenter has no conflicts of interest to declare. Objectives: • Describe the concept of hypoglycemia unawareness • Articulate and identify physiologic, sensory, and cognitive changes associated with aging that contribute to hypoglycemia unawareness • Analyze the relationship of hypoglycemia to frailty and dementia • Formulate implementation strategies to mitigate hypoglycemic episodes in the elderly 1 7/28/17 Definition of Hypoglycemia Unawareness Onset of neuroglycopenia before the appearance of autonomic warning symptoms (palpitations, sweating, hunger, anxiety, tremors, etc.) Impairment or inability of an individual to recognize the presence of hypoglycemia (Elliott & Heller, 2011) Definition of Neuroglycopenia Neuroglycopenia refers to a shortage of glucose in the brain. (Martin-Timon & Canizo-Gomez, 2015) The brain uses glucose as an exclusive energy source, using up to 25% of the total glucose in the body. (Cryer, 2012) Diabetes Facts: • 29.1 million people in the US have diabetes (1 of 11 people) • 1 of 4 do not know they have it • 86 million people have prediabetes • 9 of 10 do not know they have it • 5% of people with diabetes have Type 1; 95% have Type 2 • Annual cost of care of diabetes in 2012: $245 billion (CDC, 2017) 2 7/28/17 Classification of Hypoglycemia vSEVERE: an event requiring assistance of another person (glucose levels may not be available) vDOCUMENTED HYPOGLYCEMIA: symptoms are present and confirmed with a glucose of ≤ 70 mg/dL vASYMPTOMATIC HYPOGLYCEMIA: no symptoms present, but glucose < 70 mg/dL vPROBABLE SYMPTOMATIC HYPOGLYCEMIA: typical symptoms but not confirmed with glucose readings vPSEUDOHYPOGLYCEMIA: typical symptoms with glucose readings > 70 mg/dL (American Diabetes Association Workgroup on Hypoglycemia, 2013) Incidence and Prevalence of Hypoglycemia Unawareness More likely in Type 1 Diabetes, but also occurs in Type 2, particularly those on insulin. Type 1: 20-40% Type 2: 10-20% The literature varies widely in this regard. (Martin-Timon & Canizo-Gomez, 2015) Regulation of Glucose Levels Hypoglycemia generally results from excess insulin or the inability to raise blood glucose through endogenous or exogenous methods. Regulation is a complex interaction between the liver, kidneys, muscles, pancreas, and neuroendocrine system. 3 7/28/17 Regulation of Glucose Levels The liver is responsible for about 80% of endogenous glucose release. Kidneys are responsible for about 20%. (Kreider, Padilla, & Pereira, 2017) Physiology of Hypoglycemia Glucose approaches ~80-85 mg/dL Body attempts to restore glucose control First counter-regulatory measure is halting insulin production Physiology of Hypoglycemia Glucose approaches 65-70 mg/dL Second counter-regulatory measure occurs as alpha cells of pancreas begin to release glucagon. Body releases epinephrine, cortisol, and growth hormone. 4 7/28/17 Physiology of Hypoglycemia All of these mechanisms are dependent upon proper functioning of pancreatic alpha cells, the liver, and the kidneys. Impairment of any of these elements effect glucose control. (Kreider, Padilla, & Pereira, 2016) In individuals with repeated episodes of hypoglycemia, normal protective mechanisms sometimes will not be triggered at normal thresholds, but at lower numbers before recognizable autonomic symptoms occur (palpitations, sweating, hunger, anxiety, tremors, etc.) resulting in hypoglycemia unawareness. This is referred to as Hypoglycemia-associated Autonomic Failure (HAAF). (Kreider, Padilla, & Pereira, 2016) Contributing Factors to Hypoglycemia Unawareness • Long duration of diabetes • Sleep • Antecedent hypoglycemia • Polypharmacy (some drugs in particular) • Alcohol—inhibits counter • Multiple comorbidities regulation through effects on liver; reduces peripheral • Under nutrition autonomic responses such as • Obsession over tight control tremor and cognitive function • Increasing age • Antecedent exercise (Elliott & Heller, 2011) 5 7/28/17 Factors Affecting Recognition of Hypoglycemia in Older People • Symptoms may be nonspecific • Easily misdiagnosed: stroke, vertigo, or visual disturbance • Misinterpreted as dementia with related Sx of agitation/behavior changes • Atypical presentation: confusion or passive delirium • Little warning or awareness of autonomic symptoms • Patients with dementia are unable to communicate feelings or Sx (Abdelhafiz, Rodriguez-Manas, Morley, & Sinclair, 2015) Chronic Consequences Associated with Hypoglycemia in Older People Aging modifies cognitive, symptomatic, and counter- regulatory responses to hypoglycemia. Chronic Consequences Associated with Hypoglycemia in Older People • General physical functional decline • Increased risk of dementia • Reduced ability to perform ADLs • Increased fear & anxiety • Complete dependence • Increased social isolation • Frequent falls • Behavioral changes • Increased risk of Fx, (hip, etc.) • Increased panic attacks • Frequent hospitalizations • Increased risk of frailty • Increased risk of vascular disease • Increased risk of disability • Impaired cognitive function • Increased risk of mortality (Abdelhafiz et al., 2015) 6 7/28/17 Prevention and Management of Hypoglycemia Unawareness Some authorities speculate that if hypoglycemia could be prevented that this might lead to recovery of counter-regulatory measures and symptomatic awareness. (Elliott & Heller, 2011) Prevention and Management of Hypoglycemia Unawareness • Work with patients individually and use insulin therapy flexibility to match to eating and other activities • Education regarding insulin self-management (CDE) • Insulin pumps • Continuous Glucose Monitoring • Islet Cell Transplantation (Elliott & Heller, 2011) Prevention and Management of Hypoglycemic Unawareness Because of increased potential of hypoglycemia in older people with limited life expectancy or multiple comorbidities, the ADA recommends a higher A1C goal of <8%. (ADA, 2017) European Diabetes Working Group for Older People recommends A1C goals of 7.5%-9% for frail elders which includes those with multi-system disease or dementia or those in skilled nursing facilities. (Sinclair, Paolisso, Castro, Fourdel-Marchasson, Gadsby, & Manas, 2011) 7 7/28/17 Questions? References Abdelhariz, A., Rodriguez-Manas, L., Morley, J., & Sinclair, A. (2015). Hypoglycemia in older people—A less well recognized risk factor for frailty. Aging & Disease, 6(2), 156-167. American Diabetes Association. (2017). Standards of medical care in diabetes. Retrieved from https://doi.org/10.2337/dc17- 5003 Centers for Disease Control and Prevention (CDC). (2017). A snapshot of diabetes in the United States. Retrieved from https://www.cdc.gov/diabetes/pubs/statsreport14/diabetes-infographic.pdf Cryer, P. (2012). Hypoglycemia in diabetes: Pathophysiology, prevalence, and prevention. Alexandria, VA: American Diabetes Association. Elliott, J., & Heller, S. (2011). Hypoglycemia unawareness. Practical Diabetes, 28(5), 227-232. Kreider, K., Padilla, B., & Pereira, K. (2017). Hypoglycemia in diabetes: Challenges and opportunities in care. JNP, 13(3), 228- 234. Martin-Timon, I., & Canizo-Gomez, F. (2015). Mechanisms of hypoglycemia unawareness and implications in diabetic patients. World J Diabetes, 6(7), 912-926. Sinclair, A., Paolissa, G., Castro, M., Bourdel-Marchasson, I., Gadsby, R., & Manas, L. (2011). European diabetes working party for older people 2011 clinical guidelines for type 2 diabetes mellitus. Executive summary. Diabetes metabolism, 37(S27-38). 8.
Load more

Recommended publications
  • Acid-Base Disorders in Critical Care
    Update in Anaesthesia Acid-base disorders in critical care Alex Grice Correspondence Email: [email protected] INTRODUCTION assess severity (and likely outcome) and allow the Metabolic acidosis is a common component of critical clinician to determine whether current treatments are cid-base disorders illness. Evaluation of this component can aid diagnosis, working. A CASE EXAMPLES was dehydrated and hypotensive. Admission bloods revealed Na+ 134, K+ 2.5, Cl- 122, urea 15.4, creatinine Case 1 280, and blood gas analysis revealed: Summary A known diabetic patient presented with severe diabetic ketoacidosis. He was drowsy, exhibited pH 7.21 Disorders in acid-base balance are commonly classical Kussmaul respiration and proceeded to PaCO 2.9 kPa have a respiratory arrest whilst being admitted to 2 found in critically ill patients. Clinicians responsible for the ICU. After immediate intubation the trainee PaO 19.5 kPa 2 these patients need a clear ventilated the patient with the ventilator’s default HCO - 6.4mmol.L-1 understanding of acid-base settings (rate 12, tidal volume 500ml, PEEP 5, FiO 0.5) 3 2 pathophysiology in order to and attempted to secure arterial and central venous • Describe the acid-base disorder present. What provide effective treatment access. Shortly after intubation the patient became is the likely cause? for these disorders. This asystolic and could not be resuscitated. • Is her compensation adequate? article concentrates on • Why did this patient have a respiratory arrest? aspects of metabolic acidosis often seen in intensive care, Case 4 • Why did he deteriorate after intubation? including poisoning with the A man was brought in to the emergency room heavily alcohols (ethanol, methanol Case 2 intoxicated.
    [Show full text]
  • First Do No Harm…Hypoglycemia Or Hyperglycemia? Dr
    First do no harm…Hypoglycemia or hyperglycemia? Dr. Van den Berghe has received a research grant from Novo Nordisk to the University of Leuven. Copyright © 2006 by the Society of Critical Care Medicine and Lippincott Williams & Wilkins DOI: 10.1097/01.CCM.0000242913.88721.6E 2843 Crit Care Med 2006 Vol. 34, No. 11 Hyperglycemia is common in intensive care unit (ICU) patients, and severity of hyperglycemia has been repeatedly associated with adverse outcome of a variety of illnesses including critical illness (1). Traditionally, insulin was not administered until blood glucose exceeded 180–200 mg/dL based on the rationale that such mild increases were not deleterious and tighter control might be complicated by life- threatening hypoglycemia. In 2001, our large, randomized, controlled study revealed that intensive insulin therapy to maintain normal blood glucose levels (<110 mg/dL) saves lives and prevents debilitating and expensive complications in a predominantly surgical ICU population (2). The level of blood glucose control rather than the insulin dose explained the benefits (3). This study was followed by a publication by Krinsley (4), who reported that when intensive insulin therapy is implemented in real life intensive care, the benefits on morbidity and mortality can be largely reproduced. Our subsequent randomized, controlled study of intensive insulin therapy in a very ill medical ICU population, with a high co-morbidity and a high risk of death, confirmed the morbidity benefits and, when blood glucose control is continued for at least a third day, also the reduced mortality (5). Furthermore, analysis of healthcare resource utilization clearly revealed substantial cost savings (6, 7).
    [Show full text]
  • Syncope and Hypoglycemia
    International Journal of Clinical Medicine, 2011, 2, 129-132 doi:10.4236/ijcm.2011.22023 Published Online May 2011 (http://www.SciRP.org/journal/ijcm) Syncope and Hypoglycemia Alfonso Lagi Emergency Department, Ospedale Santa Maria Nuova, Florence, Italy. Email: [email protected] Received February 8th, 2011; revised March 10th, 2011; accepted March 28th, 2011. ABSTRACT Objective: This review focuses on syncope in diabetic patients who suffer from hypoglycemia. Clinically, transient loss of consciousness during hypoglycemia appears similar to vasovagal syncope. Research Design and Methods: Current understanding of this problem is based on physicians’ personal experiences as well as on published case reports. It is difficult to explain a temporary loss of consciousness as a result of hypoglycemia. Demonstration that hypoglycemia can be transient, with the patient suffering from neuroglycopenia without autonomic symptoms due to delayed counter- regulation, might be a first step in confirming that a diabetic patient suffered from a transient loss of consciousness with spontaneous recovery. Results: Hypoglycemic syncope is uncommon, affecting 1.9% of diabetic patients using insulin therapy. It is characterized clinically by brief periods of unconsciousness with slow recovery and without loss of postural muscle tone. The difficulty in correlating loss of consciousness to hypoglycemia arises from mismatching symptoms, that is, there may be mental symptoms such as confusion, loss of memory or consciousness, in the absence of autonomic manifestations such as sweating or blurred vision. There are currently no established glucose values that define the level of hypoglycemia that causes loss of consciousness. Conclusion: Hypoglycemic syncope should be sus- pected in older diabetic patients with preserved postural tone, usually but not always using insulin therapy, who show a slow recovery from transient loss of consciousness with persisting neurological impairment and low blood glucose lev- els.
    [Show full text]
  • Paroxysmal Dyskinesia Associated with Hypoglycemia
    LE JOURNAL CANADIEN DES SCIENCES NEUROLOGIQUES Paroxysmal Dyskinesia Associated with Hypoglycemia Brian J. Schmidt and Neelan Pillay ABSTRACT: The association of movement disorders with hypoglycemia has been rarely noted in the past. We recently observed 2 patients with documented hypoglycemia and paroxysmal dyskinesias. One patient had evidence of an insulin-secreting tumor. The other patient had insulin-dependent diabetes, and also experienced recurrent episodes of hypoglycemic hemiparesis. Classical adrenergic symptoms of hypoglycemia were absent in both patients. Our observa­ tions support the concept that the development of neuroglycopenie symptoms cannot be predicted from blood glucose measurements alone, but must depend on other factors controlling the availability or metabolism of glucose in the brain. RESUME: Dyskinesies paroxystiques associees a I'hypoglycemic L'association de desordres du mouvement avec I'hypoglycemie a rarement ete notee dans le passe. Nous avons recemment observe 2 patients avec une hypoglycemic documented et des dyskinesies paroxistiques. Un patient avait des manifestations cliniques associees a une tumeur secretant de l'insuline. L'autre patient avait un diabete insulino-dependant accompagne d'episodes recurrents d'hemi- paresie hypoglycemique. Les symptomes adrenergiques classiques d'hypoglycemie etaient absents chez ces deux patients. Nos observations appuient la notion que I'apparition de symptomes de neuroglycopenie ne peut etre predite sur la base de la glycemie seulement mais depend d'autres facteurs controlant la disponibilite ou le metabolisme du glucose dans le cerveau. Can../. Neurol. Sci. 1993; 20:151-153 In 1937 Golden described the occurrence of a variety of movements. The attacks usually began with a sudden "restless sensa­ involuntary movements in psychiatric patients undergoing tion" in his lower limbs, followed by chaotic thrashing of his legs and insulin-induced hypoglycemic shock treatment.1 During deeper sometimes arms.
    [Show full text]
  • Relationships Between Hyperglycemia and Cognitive Performance Among Adults with Type 1 and Type 2 Diabetes
    Epidemiology/Health Services/Psychosocial Research ORIGINAL ARTICLE Relationships Between Hyperglycemia and Cognitive Performance Among Adults With Type 1 and Type 2 Diabetes DANIEL J. COX, PHD ANTHONY MCCALL, MD, PHD test cognitive functioning at 14.5 and 16 BORIS P. KOVATCHEV, PHD KEVIN J. GRIMM, MA mmol/l in adults with type 2 diabetes. LINDA A. GONDER-FREDERICK, PHD WILLIAM L. CLARKE, MD During hyperglycemia, significant dis- KENT H. SUMMERS, PHD ruptions occurred in the performance of complex tests of cognitive functioning, such as four-choice reaction time. How- ever, other investigators (5,6) were un- OBJECTIVE — Hyperglycemia is a common event among patients with type 1 and type 2 able to detect decay in cognitive-motor diabetes. While the cognitive-motor slowing associated with hypoglycemia is well documented, the acute effects of hyperglycemia have not been studied extensively, despite patients’ reports of performance on selected neuropsycho- negative effects. This study prospectively and objectively assessed the effects of hyperglycemia on logical tests during hyperglycemia. cognitive-motor functioning in subjects’ natural environment. Contrary to hypoglycemia and its associated neuroglycopenia, a major RESEARCH DESIGN AND METHODS — Study 1 investigated 105 adults with type 1 barrier to the investigation of the effects of diabetes (mean age 37 years and mean duration of diabetes 20 years), study 2 investigated 36 hyperglycemia on cognitive-motor per- adults with type 2 diabetes (mean age 50 years and mean duration of diabetes 10 years), and formance is the absence of a clear physi- study 3 investigated 91 adults with type 1 diabetes (mean age 39 years and mean duration of ological mechanism that explains how diabetes 20 years).
    [Show full text]
  • A Case Report of Neuroglycopenic Coma with Diffuse Cortical Involvement
    Open Access Austin Journal of Clinical Neurology Case Report A Case Report of Neuroglycopenic Coma with Diffuse Cortical Involvement Phani Kumar P*, Divya Latha Y, Ramadevi M and Jaya Bhaskar C Abstract Department of General Medicine, Sri Venkateswara Hypoglycemia is a metabolic abnormality that triggers a series Medical College, India of physiological, psychological and behavioral responses. Prolonged *Corresponding author: Phani Kumar P, Department hypoglycemia can result in neuronal dysfunction and death. A 31year old male of General Medicine, Sri Venkateswara Medical College, patient presented with hypoglycemia and altered sensorium. MRI brain showed Tirupati, Andhra Pradesh, India bilateral hyper intense areas with gyral edema in fronto parietal cortex with sparing of deep grey nuclei, viz, cerebellum, brainstem, basal ganglia, capsular Received: June 09, 2017; Accepted: July 10, 2017; tracts and thalami, suggestive of neuroglycopenic coma. With early identification Published: July 26, 2017 and prompt treatment, hypoglycemia can be reversed, otherwise is associated with poor prognosis. Keywords: Neuroglycopenia; Hypoglycemia Abbreviations state to causality on the same day. CVS: Cardiovascular System; RS: Respiratory System; GIT: At the time of presentation GCS is 3/15. Vitals: pulse rate: 96 Gastrointestinal System; CSF: Cerebrospinal Fluid; GCS: Glasgow bpm, blood pressure: 90/60 mm of Hg, Spo 2:88% with room air Coma Scale; FLAIR: Fluid Attenuated Inversion Recovery; DTR: and 96% with 4L of oxygen. On examination, CVS and GIT: normal, Deep Tendon Reflexes RS: Coarse crepitations present, CNS: Bilateral pin point pupils, not reacting to light, hypotonia with absent DTR in alllimbs. Planter’s Introduction bilateral no response. Investigations: Random blood sugar: 39 mg/dl, Hypoglycemia is a metabolic abnormality that triggers a series Total counts: 7,500 cells/mm3, differential counts: polymorphs 78%, of physiological, psychological and behavioral responses.
    [Show full text]
  • Pathogenesis and Management of Hypoglycemia
    177:1 N E Kittah and A Vella Pathogenesis and management 177:1 R37–R47 Review of hypoglycemia MANAGEMENT OF ENDOCRINE DISEASE Pathogenesis and management of hypoglycemia Correspondence Nana Esi Kittah and Adrian Vella should be addressed to A Vella Division of Endocrinology, Diabetes, Metabolism and Nutrition, Mayo Clinic, Rochester, Minnesota, USA Email [email protected] Abstract Glucose is the main substrate utilized by the brain and as such multiple regulatory mechanisms exist to maintain glucose concentrations. When these mechanisms fail or are defective, hypoglycemia ensues. Due to these robust mechanisms, hypoglycemia is uncommon and usually occurs in the setting of the treatment of diabetes using glucose-lowering agents such as sulfonylureas or insulin. The symptoms of hypoglycemia are non-specific and as such it is important to confirm hypoglycemia by establishing the presence of Whipple’s triad before embarking on an evaluation for hypoglycemia. When possible, evaluation of hypoglycemia should be carried out at the time of spontaneous occurrence of symptoms. If this is not possible then one would want to create the circumstances under which symptoms occur. In cases where symptoms occur in the post absorptive state, a 72-h fast should be performed. Likewise, if symptoms occur after a meal then a mixed meal study may be the test of choice. The causes of endogenous hyperinsulinemic hypoglycemia include insulinoma, post-bariatric hypoglycemia and noninsulinoma pancreatogenous hypoglycemia syndrome. Autoimmune hypoglycemia syndrome is clinically and biochemically similar to insulinoma but associated with high levels of insulin antibodies and plasma insulin. Other important causes of hypoglycemia include medications, non-islet cell tumors, hormonal deficiencies, critical illness and factitious hypoglycemia.
    [Show full text]
  • Drugs and Hypoglycemia
    9 Drugs and Hypoglycemia Marek Pytliak, Viola Vargová and Viola Mechírová Medical Faculty of the University of P.J. Safarik, Košice, Slovakia 1. Introduction Manifested hypoglycemia is relatively frequent cause of out-patient office visit at general practitioner, diabetologist and in severe cases represents emergent situation requiring transport to hospital and hospitalization. Severe and untreated hypoglycemia can even lead to death. The aetiology of hypoglycemia is variable, and includes drugs, insulinoma, liver failure, renal failure, hormonal deficiencies, alcohol abuse and reactive hypoglycemia. The medication history is an integral part in the evaluation of a patient with hypoglycemia. A variety of medications have been associated with hypoglycemia, and the list of these medications is expanding (Comi, 1993). The common causes of acute hypoglycemia are related to therapy for diabetes mellitus – insulin and its analogues or oral antidiabetic drugs (OAD). Determining the aetiology of hypoglycemia poses little difficulty in patients known to be taking parenteral or oral hypoglycaemic agents. Severe hypoglycemia, associated with coma or requiring assistance of another person for reversal occurs at least once a year in 10% of patients treated with insulin, with a mortality of 2-4%. There is difficulty assessing the absolute rates but the frequency of iatrogenic hypoglycemia is substantially lower in type 2 than in type 1 diabetes. Thus, the rates of severe hypoglycemia in type 2 diabetes are approximately 10% of those in type 1 diabetes even during aggressive insulin therapy (Marks, 1981). Episodes of hypoglycemia may occur also in patients without diabetes mellitus, insulin or OAD therapy. In these patients, hypoglycemia absents often among diagnostic concerns what might worsen subsequently their prognosis.
    [Show full text]
  • The Ketogenic Diet and Its Clinical Applications in Type I and II Diabetes
    ISSN: 2377-3634 Pilla. Int J Diabetes Clin Res 2018, 5:092 DOI: 10.23937/2377-3634/1410092 Volume 5 | Issue 3 International Journal of Open Access Diabetes and Clinical Research Review ARticle The Ketogenic Diet and its Clinical Applications in Type I and II Diabetes * Check for Raffaele Pilla updates External Pharmacy, St. John of God - Fatebenefratelli Hospital, Benevento, Italy *Corresponding author: Raffaele Pilla, Pharm.D, PhD, External Pharmacy, St. John of God - Fatebenefratelli Hospital, Benevento, Italy, E-mail: [email protected] Introduction across the blood-brain barrier by monocarboxylic acid transporters to fuel brain function. Starvation or nutri- It has been shown that metabolic-based therapies, tional ketosis is an essential survival mechanism that such as nutritional ketosis, are effective to contrast sei- ensures metabolic flexibility during prolonged fasting or zure disorders and various acute and chronic neurolo- lack of carbohydrate ingestion [1]. Therapeutic ketosis gical disorders [1-4]. From a physiological perspective, leads to metabolic adaptations that may improve brain glucose is the primary metabolic fuel for cells. However, metabolism, restore mitochondrial ATP production, many neurodegenerative disorders have been recent- decrease reactive oxygen species production, reduce ly associated with impaired glucose transport and me- inflammation, and increase neurotrophic factors’ fun- tabolism and with mitochondrial dysfunction causing ction [12]. It has been shown that KD mimics the effects energy deficits, such as in Alzheimer’s disease, Parkin- of fasting and the lack of [13] glucose/insulin signaling, son’s disease, general seizure disorders, and traumatic which promotes a metabolic shift towards fatty acid uti- brain injury [5-9].
    [Show full text]
  • Diabetic Ketoacidosis (DKA)
    LECTURE 8 : Diabetic ketoacidosis (DKA) Objectives: •Ketone bodies ( ketogenesis & ketolysis). •Diabe5c ketoacidosis. •Hyperosmolar hyperglycemic state. •Hypoglycemia. Acetoacetate Ketone bodies Acetone β-Hydroxybutyrate § They are produced by the liver (ketogenesis) and u5lized for energy produc5on by peripheral 5ssues(ketolysis). § Normally, glucose is the primary fuel for the brain, It can penetrate the blood brain barrier. § The brain’s GLUT is insulin-independent. § If glucose is not available for the brain, the brain can u5lize plasma ketone bodies, that can penetrate the blood brain barrier and serve as fuel molecules. #Eang diets extremely high in fat and low in carbohydrates or starving or suffering from a severe lack of insulin (Type I diabetes mellitus) therefore, increase the synthesis and u5lizaon of ketone bodies. # Occurs in the hepatocyte mitochondria only . # In uncontrolled DM: there is ↑ lipolysis in adipose 5ssue à ↑ FFA mobilizaon to liver à ↑hepac FA oxidaon à↑acetyl CoA which will be channeled into KB synthesis. # ↑ Acetyl CoA produc5on ac5vates pyruvate carboxylase that converts pyruvic acid into OAA. # OAA is used for gluconeogenesis rather than Krebs cycle (in Krebs cycleà Acetyl CoA + OAA) #HMG CoA synthase is the rate limi;ng enzyme. #The first KB to be synthesized is acetoacetate. Reduced to β-Hydroxybutyrate Acetoacetate can be: *FFA=Free faAy acid Or spontaneously decarboxylated to acetone *OAA=Oxaloacetate *KB= Ketone bodies 1 3 2 4 5 #Ketone bodies are synthesized in the liver(mitocondria) from acetyl-CoA. 1-First enzyme in the ketone body synthesis pathway is thiolase that catalyzes the condensaon of two acetyl-CoA molecules to form acetoacetyl-CoA.
    [Show full text]
  • Hyperinsulinemic Hypoglycemia – the Molecular Mechanisms
    View metadata, citation and similar papers at core.ac.uk brought to you by CORE provided by Frontiers - Publisher Connector REVIEW published: 31 March 2016 doi: 10.3389/fendo.2016.00029 Hyperinsulinemic Hypoglycemia – The Molecular Mechanisms Azizun Nessa , Sofia A. Rahman and Khalid Hussain* Genetics and Genomic Medicine Programme, Department of Paediatric Endocrinology, UCL Institute of Child Health, Great Ormond Street Hospital for Children NHS, London, UK Under normal physiological conditions, pancreatic β-cells secrete insulin to maintain fasting blood glucose levels in the range 3.5–5.5 mmol/L. In hyperinsulinemic hypoglyce- mia (HH), this precise regulation of insulin secretion is perturbed so that insulin continues to be secreted in the presence of hypoglycemia. HH may be due to genetic causes (congenital) or secondary to certain risk factors. The molecular mechanisms leading to HH involve defects in the key genes regulating insulin secretion from the β-cells. At this moment, in time genetic abnormalities in nine genes (ABCC8, KCNJ11, GCK, SCHAD, GLUD1, SLC16A1, HNF1A, HNF4A, and UCP2) have been described that lead to the congenital forms of HH. Perinatal stress, intrauterine growth retardation, maternal diabe- tes mellitus, and a large number of developmental syndromes are also associated with Edited by: José C. Moreno, HH in the neonatal period. In older children and adult’s insulinoma, non-insulinoma pan- Institute for Medical and Molecular creatogenous hypoglycemia syndrome and post bariatric surgery are recognized causes Genetics-INGEMM,
    [Show full text]
  • 214231Orig1s000
    CENTER FOR DRUG EVALUATION AND RESEARCH APPLICATION NUMBER: 214231Orig1s000 SUMMARY REVIEW Dasiglucagon NDA 214231 Summary Basis for Regulatory Action Date electronic stamp NDA # NDA 214231 Applicant Zealand Pharma Date of Submission March 27, 2020 PDUFA Goal Date March 27, 2021 Proprietary Name ZEGALOGUE Established or Proper Name Dasiglucagon injection Dosage Form(s) Subcutaneous injection Applicant Proposed Treatment of severe hypoglycemia in patients Indication(s)/Population(s) with diabetes ages six years and above Applicant Proposed Dosing Regimen(s) 0.6 mg/0.6 mL Recommendation on Regulatory Action Approval Treatment of severe hypoglycemia in pediatric Recommended Indication(s)/Population(s) and adult patients with diabetes ages six years and above Recommended Dosing Regimen(s) 0.6 mg/0.6 mL Office of New Drugs (OND) Action Package Names of discipline reviewers; Material Reviewed/Consulted: Dates of review Clinical Reviewer Kristen Pluchino 3/10/21 Biostatistics Yoonhee Kim 11/09/20 Center for Device and Radiologic Health David Wolloscheck/Rumi Young 2/2/21 Pharmacology Toxicology Patricia Brundage 12/18/20; 11/23/20 Office of Pharmaceutical Quality Technical Lead: Muthukumar Ramaswamy 11/27/20, 2/5/21, and 2/23/21 Clinical Pharmacology and Pharmacometrics SJ Lau/Manoj Khurana 12/10/21 and 3/4/21 Interdisciplinary Review Team for Cardiac Girish Bende 2/13/20 and 7/28/20 Safety Studies Clinical Cardiology, Division of Cardiology Preston Dunnmon 10/29/20 and Nephrology Office of Biotechnology Products­ Faruk Sheikh 12/04/20 immunogenicity
    [Show full text]