Endocrine Physiology – Glucose Control Bob Bing-You, MD, MEd, MBA Medical Director Maine Center for Endocrinology

Pancreas Two major types of tissues – acini: secrete digestive juices into duodenum – islets of Langerhans: empty insulin & glucagon directly into blood Islets of Langerhans – beta cells: insulin – alpha cells: glucagon – delta cells: somatostatin

Insulin Molecular weight of 5808 Two amino acid chains Binds to large receptor protein Subsequently activates cAMP Some effects occur without cAMP activation Quickly removed from blood by liver [<10 minutes in circulation]

cAMP causes a quicker response than steroids A. True B. False

Insulin Secreted in response to glucose absorbed from food Causes rapid uptake, storage, and use of glucose by all tissues, particularly liver, muscle, and fat tissues

Insulin & the Liver Inhibits phosphorylase [ie stops liver glycogen degradation] Enhanced glucose uptake by liver, by activating glucokinase – phosphorylates glucose trapping it in liver cells Increases phosphofructokinase which promotes glycogen synthesis [glycogen can  up to 5-6% of liver mass]

Fasting Pancreas decreases insulin outpt Phosphorylase splits glycogen Glucose phosphatase splits phosphate radical from glucose freeing glucose to diffuse out of liver

Other Insulin effects on Carbs Promotes conversion of liver glucose into fatty acids [transported to fat cells] Inhibits gluconeogenesis Decreases release of amino acids from muscles and extrahepatic tissues

Muscle In resting state rely on fatty acids Under exercise, becomes permeable to glucose After meals, with high insulin levels, facilitates uptake [“diffusion” via carrier proteins] and use < 1% of muscle mass glycogen

Brain Cells permeable to glucose without insulin Use glucose only for energy = reason important to maintain serum glucose levels “neuroglycopenic” sx’s –Irritability –Confusion –Coma, seizures

Adrenergic symptoms include A. Tachycardia B. Increased sweating C. Tremors D. A, B, and C

Insulin & Fat “spares” fat Promotes fatty acid synthesis [in liver] ~1/10 th of glucose transported into fat cells vs. liver Inhibits hormone-sensitive lipase [stops hydrolysis of triglycerides]

Insulin & Protein Causes active transport of amino acids into cells  rate of DNA transcription Inhibits protein catabolism Depresses gluconeogenesis All protein storage halted without insulin

Questions?

Control of Insulin Normal fasting state insulin secretion is not zero –~10 ng/min/kg – or….~1 unit/hour …..or 24 units/day After acute glucose elevation –1 st phase secretion: 10-fold secretion 5 mins after glucose; decreases 50% in 5-10 mins.

Insulin secretion 2 nd phase – after 1 st 15 mins, secretion rises 2 nd time reaching new plateau 2-3 hours – due to  insulin synthesis and then release Can reach times basal rate Turn-off of secretion as rapid

Good rules of thumb include all except A. Basal insulin is 1 unit/hour B. 2/3 of daily insulin is needed in the morning C. Insulin secretion falls to zero overnight D. Cortisol will cause hyperglycemia in days [vs minutes]

The Switch Glucose is key to determine switch between carbohydrates or fat for energy utilization Through insulin effects, body uses one or other “Counter-regulatory” hormones – catecholamines – growth hormone, cortisol

Glucagon Secreted by alpha cells Purpose is to  serum glucose levels  glycogenolysis in liver Works via cAMP Works within minutes Need glycogen stores for effect

Summary Glucose Regulation Liver serves as blood glucose-buffer system Insulin feedback mechanism more important than glucagon  glucose in hypothalamus  sympathetic output to  catecholamine secretion

Questions?

Hypoglycemia What is too low? – pathologic vs. normal excursions? Causes – too much insulin [endogenous or exogenous] – renal disease and insulin – adrenal insufficiency – liver disease

Hypoglycemia Rx D5 infusion Glucagon Stop offending medication [e.g., oral hypoglycemics] Glucocorticoids for adrenal insufficiency

Questions?

Too much sugar! Mental status changes Ketoacidosis Cellular dehydration due to osmotic pressure Osmotic diuresis causing intravascular fluid loss Diabetes!!

Diabetes Epidemic, with >2550 new cases diagnosed daily 30% of 60+ year olds have Type 2 DM or IGT Type 2’s eventually evolve into Type 1’s Post-prandial high glucose associated with  risk of death

Impaired glucose FBS 101 – 125 ….or ….2-hour BS 140 – 200 Associated with  macrovascular complications, risk of DM development

Goal? Normal blood sugars Both fasting and post-prandial throughout day Intensive medical Rx Combined with weight loss, exercise

DCCT Type 1 diabetics –32% reduction risk of retinopathy –25% reduction in risk of nephropathy –30% reduction in risk of neuropathy NEJM 2003;329;977

UKPDS Type 2 diabetics –10% reduction in risk diabetes-related death –6% reduction in all-cause mortality –16% reduction on myocardial infarction –25% reduction in risk of microvascular complications Lancet 1998;352;837.

Levemir insulin Most recent addition Long-acting Less of a peak than Glargine May require 2 shots a day Sometimes more of an insurance coverage

Peri-operative Issues Can decrease NPH 50% Hold Rapid- and Short-Acting in fasting state Can maintain glargine, Levemir doses Monitor frequently [I.e., hourly] Insulin drips

Sliding Scales “Does anyone know how to make insulin work backwards?” –Waiting for high glucose then giving insulin Try to anticipate what needs are High glucose causes – osmotic shifts – electrolyte disturbances – impaired white cell function – ?impaired wound healing

Questions??