Overview. o Limitations o Normal regulation of blood glucose o Definition o Symptoms o Clinical forms o Pathophysiology o Treatment.

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1 Pål R. Njølstad MD PhD KG Jebsen Center for Diabetes Research University of Bergen, Norway Depertment of Pediatrics Haukeland University Hospital Broad Institute of Harvard & MIT Cambridge, MA, USA Hypoglycemia Ped Endo course, 2016 Overview o Limitations o Normal regulation of blood glucose o Definition o Symptoms o Clinical forms o Pathophysiology o Treatment Limitations Transient hypoglycemia in newborns o Common Children with diabetes o Very defined etiology and treatment Other forms o Complex Structure o C 6 H 12 O 6 Impact o More or less universal energy substrate for all living organisms CNS o Of particular importance o Only energy substrate for the brain Phases in the glucose homeostasis Phase 1: Absorption o 3-4 hours after a meal o is stored as glycogen and fat under insulin stimulation Phase 2: post absorption o 4-12 hours after a meal o Liver glycogen release glucose and insulin turns off Phase 3: Early/intermediate fast o hours after a meal o Glycogen stores emptied, gluconeogenesis initiated Mitochondrial fatty acid oxidation Fat tissue (Triglycerides) Free fatty acids Mitochondrial oxidation Acetyl-CoA Krebs cyclus Ketons The glucose saving effect of the fatty acids 1

2 Metabolic regulation of glucose Hormonal regulation of blood glucose Definition Symptoms When is hypoglycemia? o Blood glucose 2.2 mmol/l o Corresponds to US 40 mg/dl o Arbitrary cut off! Low blood glucose without symptoms Symptoms of acute hypoglycemia Autonomous o Sweating o Tachycardia o Tremor o Hunger Symptoms without low blood glucose Symptoms progressing Neuro glucopenia o Drowsiness o Incoordination o Speech problems o Dizziness o Abnormal behavior Light symptoms Loss of conciousness Coma Permanent brain damage Death 2

3 Incretin effect What is incretin effect? o Po glucose results in a larger insulin response than iv glucose How strong is it? o The incretin effect is believed to be around 50-70% of the insulin response to glucose What are the most important incretins? o GLP1 (glucagon-like peptide-1) o GIP (glucose-dependent insulinotropic polypeptide) Incretin effect Pearson, Flechtner, Njølstad et al, NEJM, 2006 Fatty acid oxidation defects General characteristics o Occurs at catabolic situations (stress, surgery) o Hypo- or non-ketotic condition o Insulin secretion is turned off o Moderately liver enlargement (steatosis) o Cardiac symptoms: cardiomyopathy, arrhythmia o Sometimes Reye-like picture o Diagnosis: Mass spectroscopy of the urine, acylcarnitins in plasma, prolonged fast Fatty acid oxidation defects Why hypoglycemia? o Lack of energy from fat leads to increased demand for glucose o Lack of energy to run the gluconeogenesis o Lack of from ketons as alternative source of energy Hypoglycemia clinical approach Acute o Liver failure, Reye syndrome? o Ketoacidosis? Relapsing o Relation to meals and fasting o Enlarged liver? o Growth retardation? o Adrenal function? o Ketosis? Acidosis? o Hyperinsulinism? o Organic acids? Prolonged fasting test Fasting until 24 hours After 18 and 20 hours: o Blood glucose o Plasma insulin o Serum ketons, free fatty acids o (Urine organic acids) Glucagon test at the end: o Glucagon iv 0.03 mg/kg iv o Blood glucose at time 0, 5, 10, 15 and 20 minutes 3

4 The pancreatic beta cell Interpretation of fasting test Fatty acid oxidation defect o Ketons o Insulin Hyperinsulinism o Ketons o Insulin INSR MCT1 HNF4A Amino acids Fatty acids GDH SCHAD GCK Ca++In Insulin secretion -6-P α-kg UCP2 Glycolysis Ketotic hypoglycemia o Ketons o Insulin Ca++ SUR1/Kir6.2 K+ ++ Ca++ Imbalance Congenital hyperinsulinism Prevalence o 1-2 per year in Norway Balanced blood glucose Diagnosis For little insulin o Measurable insulin at hypoglycemia o Low ketones and free fatty acids Subtypes Too much insulin Hypoglycemia Hyperglycemia (diabetes) Diagnosis o Mutations in factors involved in insulin secretion o Diffuse and focal forms o 18-F DOPA-PET scan of pancreas (special centers) Histopathological subtyping No insulin o At hypoglycemia, insulin should not be detactable o Three sets serum glucose/insulin Supporting data o Elevated glucose requirement (>8 mg/kg/min) o No ketones, low free fatty acids o Good response to glucagon o Elevated birth weight Focal or diffuse form? Diffuse form Focal form o 18F L-DOPA PET scan 24 4

5 Genetic causes Affected beta cell protein Glucokinase Glutamate dehydrogenase Mechanism Inheritance Morphology Prevalence Sensitive for diazoxide? Too high production Too high production Dominant Diffuse Extremely rare Yes Dominant Diffuse Rare Yes SCHAD??? Recessive Diffuse Extremely rare Yes Sulfonylurea receptor Kir6.2 Sulfonylurea receptor/kir6.2 Recessive or dominant Diffuse Common No (partial) Recessive Diffuse Rare No (partial) Non-mendelian Focal Common No (partial) 25 Nutrition Regular food o Avoid long fasting Tube feeding o Through nose, PEG, MicKey o Milk/nutrition preparations o Additions of Semper or Resource Energy Content o Calculate calorie need o Avoid overweight and eating problems Medical treatment Diazoxide o Proglicem o Chlortiazide Somatostatin o Octreotide sc x3 or via pump o Somatostatin LAR o Ipstyl sc Glucagon o Surgery o Emergency Surgical treatment Focal form o Resection of the focus only o Peroperative biopsies Diffuse form o Subtotal pancreatectomy o Roux-en-Y o Secondary diabetes in all Where? o Special centers abroad 5