Lec 9: Glucose regulation, Diabetes

what do endocrine organs do

synthesize & secrete hormones

• endocrine=hormones released into bloodstream

• paracrine=into adjacent tissue only ex histamine

• many have a long half life (=> kinetics: likely highly PPB, ex T4 hormone)

what is endocrine secretion triggered by

• concentration of specific substances ex glucose

• neural stimulation ex SNS & epinephrine

• endocrine sequences ex epinephrine => aldosterone

what is endocrine secretion regulated by

negative feedback mechanism

how can we test endocrine fx

hormone level or the affector-substance level

• ex glucose (indirect test of insulin function), T4 (direct hormone level test)

what are the 2 diff dysfunctions of the endocrine system, why do they exist

hyposecretion or hypersecretion

• d/t primary endocrine disorder, signaling disorder, sequence disorder

• s&s will be directly related to excess or deficit of the expected hormone level

hyposecretion causes

• congenital defect

• disease/infection/inflammation

• hypoperfusion

• ageing

hypersecretion causes

• genetic

• tumours (hypo or hyper)

• environmental stimuli

what are the primary energy sources of the body

• glucose (readily distributed)

• fatty acids (fat)

what is the most needy system for glucose

CNS (brain)

• requires constant supply of glucose (broken down: CO2 & H2O)

• cannot store it for later

what is extra glucose stored as

as glycogen (liver, muscles) & triglycerides (adipose cell)

if there is a fall in blood glucose (BG), what happens aka what are names of the processes of glucose formation/breakdown

• => glycogen breakdown via glycogenolysis (triggered by glucagon hormone)

• formation of more glucose from other sources gluconeogenesis, released PRN

how are fatty acids distributed, who cant use it and what is it stored as

via lymph to circulation

• CNS & RBCs cannot use fatty acids

• extra FAs=stored as triglycerides

what are fatty acids broken down into

3 fatty acids & glycerol

• glycerol can be broken down via glycolytic pathway into glucose

• fatty acids are NOT converted into glucose - cant be used by the brain for energy

• fatty acid metabolism in liver => ketone metabolites

what is insulin def

• pancreatic hormone (endocrine)

• synthesized in beta cells (Langerhans)

• main action is to move glucose

what are the fxs of insulin

• glucose cellular uptake

• promotes storage formation (glycogen/triglyceride/protein synthesis)

• prevents glycogen & fat lysis (in order to 1st use glucose) & protein lysis (to preserve tissues)

• amino acid cellular uptake; triglyceride adipose cell uptake

where is glucagon synthesized

synthesized in alpha cells = opposite of Insulin

what are the fxs of glucagon

promotes mobilization of stores:

• glycogenolysis (glycogen breakdown)

• gluconeogenesis (amino acid conversion into glucose)

• lipolysis (triglyceride breakdown)

what is glucagon triggered by

low plasma glucose levels (between meals, hypoglycemia)

• => mobilize stores and replenish blood glucose for cellular use

glycemic regulation for low BG and high BG

• high BG=pancreas releases insulin, liver produces glycogen/cells take up glucose from blood=low BG

• low BG=pancreas releases glucagon, liver breaks down glycogen=high BG

what is the simulant of insulin synthesis

high serum glucose

what is the pathophysiology pathway of insulin release

1. glucose enters pancreatic beta cell via glucose transporter => metabolized via glucokinase into ATP => closes K channels (on Beta cell) => depolarization => insulin secretion (from pancreas)

2. => insulin from pancreas enters hepatic circulation => 50% 1st pass metabolized => metabolites re renally excreted

what is insulins action/what does it bind to

binds to cellular membrane receptor (tyrosine kinase) => activates kinase enzyme within cell => stimulates glucose transporter channels to open to glucose

what is insulins inhibition

somatostatin (D cell produced)

what are the immediate effects of beta cell destruction

disabled transport of glucose into cells => dysfunction of glucose, fat, and protein metabolism

Pathophysiology sequelae of beta cell destruction aka pathway

• increased glucose in plasma (hyperglycemia) =>

• high solute concentration (polydipsia/thirst stimulated) =>

• osmotic shift of fluid into circulation (increased osmotic pressure)= cellular dehydration

• high solute concentration in renal tubules

• => osmotic shift into filtrate = high urine production (polyuria stimulated)

therefore=hyperglycemia, polydipsia, polyuria, glycosuria (glucose in urine)

after hyperglycemia; polydipsia; polyuria; glycosuria (glucose in urine) happens from beta cell destruction, what happens next

• => metabolic shift to use fat for energy = breakdown of triglycerides & glycerol

• => hepatic metabolism of fatty acids => ketones (ketone bodies) produced as byproduct

• therefore=ketonuria, changes in LOC, acetone breath (sweet), metabolic acidosis, coma, death

ketones consequences

• are acidic => accumulation causes metabolic acidosis + metabolism produces acetone

• =high blood glucose, drops pH of blood

what are the energy subsitutes when glucose uptake is reduces (consequences)

• lipolysis (fatty acid breakdown)

  • liver metabolism fatty acids (fatty acid oxidation)= ketones & ketonuria

• proteolysis (next phase)= weight loss & muscle wasting

what are all the altered cellular functions from reduced glucose uptake (consequences)

• insulin resistance (when insulin given=no immediate results, takes a few hrs)

• altered cellular repair

• endothelial dysfunction + decreased angiogenesis

• increased oxidative stress => inflammatory consequences, risk for clotting

• organ injury=retinopathy, neuropathy, nephropathy (kidneys), CV

how do we diagnose diabetes mellituse, what is the normal range

• fasting glucose

• >7 mmol/L (normal <6)

• dx usually pre-30 yrs of age (toddlers, teens)

what are the diff types of diabetes mellitus

• type 1A

• type 1B

type 1A diabetes mellitus causes

genetic predisposition + triggering event (ex infection, trauma) => immune reaction to beta cell antigens = autoimmune

• most common

type 1B diabetes Mellitus causes

idiopathic (familial), rare

DM tx and ultimate effect

total destruction of beta cells: IDDM (insulin dependent), pt wont be able to make glucose

• tx=insulin

• if no tx=diabetic ketoacidosis = death

what is insulin always measured in

units (IU/ml)

Endogenous insulin levels

• basal level = 5-15 IU/mL aka cruise control

• peak level = 60-90 IU/mL, booster at meals

• clinically BG is measured, normal level = 4-8 mmol/L

• tx with exogenous insulin focuses on mimicking basal & peak

Tx with Insulin goal

restore normal glucose patterns

• mimic basal & peak endogenous levels

• minimize risk of hypoglycemia

what are the 4 diff preparation categories for insulin

1. rapid acting

2. long acting

3. short acting (regular)

4. intermediate acting (NPH)

insulin administration methods

• SC (into hypodermis)

  • SC needle injections

  • portable pen injectors (usually for pt, we dont use it)

  • insulin pumps – basal & bolus delivery

• IV=utilized in critically ill patients

rapid acting insulin qualities

• onset=10-15 mins

• peak=1-2 hr

• duration=3-5 hrs

rapid acting insulin, who is it used for

• meal-time bolus, pt eats right away! (food tray ready); the insulin for insulin pumps

• not given IV

• dose per carbohydrate content + BG pre-meal

• check BG 1-2 hr post (to check peak)

• give glucose IV if pt cant eat

list drugs of the rapid acting insulin

• humalog (Lispro)

• novorapid (Aspart)

• apidra (Glulisine)

• fiasp (Aspart) more fast acting/4 min

‘Rapid acting’ insulin in pumps: meal time boluses requirements

• per carbohydrate content

• check BG pre-meal

• check BG 1-2 hr post

‘Rapid acting’ insulin in pumps: basal insulin requirements

• continuous, slow infusion of rapid acting insulin over 24 hrs

• check bedtime BG (usually tells us if too much or little)

• IF BG rises too much overnight => risk of nighttime hypoglycaemia= adjust basal insulin dose

Long acting Insulin qualities and use

• onset 90 min

• plateaus for up to 24 hrs

• ideal for background, admin, 1-2 x daily (consistency is important)

• never IV

• adjust dose according to bedtime BG level

list long acting insulin drugs

• levemir (Detemir)

• lantus (Glargine)

• tresiba (Degludec) ultra-long acting, 30hrs

Short acting Insulin (‘regular’) qualities

• onset 30 minutes

• peak 2-3 hr

• duration 6.5 hrs (dose dependent!)

short acting insulin use

• ideal for meals (must be 30-45 min pre-meal!) BUT issues with hypoglycemia & balancing dose w intake (peak is later)=ensure pt eats (proteins and fats)

• used IV if ketoacidosis, new dx, stabilizing pt in hospital

list short acting insulin drugs

• novolin ge Toronto

• Humulin R

• Entuzity (KwikPen) 5x more concentrated

intermediate acting insulin qualities

• onset 1-3 hrs

• peak 5-8 hrs

• duration up to 18 hrs (dose dependent!)

intermediate acting insulin use

• ideal for background replacement, admin, 1-2x daily, if pt on steroids

• can match sugar peaks, monitor for night hypoglycemia!!! (evening snack important)

• never IV

list intermediate acting insulin drugs

• humulin N

• novolin ge NPH

intensive insulin Tx requirements, general guide: for Insulin Therapy & Insulin dosing for DM I: (what is the daily insulin requirements)

estimated daily insulin req (U) = 0.55 (U) x pt wt (kg)

• estimate=does not factor in BMR, activity/stress, food, is a starting point only

• approx 40% of estimate=basal

• other 60% estimate=boluses (meal time)

what is the bolus insulin dosage based on when treating DM

• BG (pre-meal level)

• carbohydrate content/meal

what is the basal insulin dosage based on when treating DM

• estimate

• bedtime BG level

• am administration preferred, avoids nighttime hypoglycaemia

• similar amount each day, as long as the bedtime BG is normal

• given even if pt NPO

• IF pt on insulin pump, the basal dose is continuously delivered (fast acting insulin)

Daily routine: BG monitoring & Insulin administration, what does BBIT stand for

• B=basal (long acting insulin) in am

• B=bolus (short/rapid acting insulin) @ meals

• I=insulin correction (short/rapid acting) if necessary (based on BG post-meal)

• T=titrate doses to achieve glucose levels 4-8 mmol/L (monitor glucose throughout the day)

what times do we check blood glucose levels

• pre-each MEAL

• post-meals 1-2 hrs (new dx!)

• at bedtime

• 4x per day is minimum requirement

• 8x for newly diagnosed pts (pre+post meals; bedtime; nighttime)

Diet in DM matters for accurate bolus dosing, what do we measure

carbohydrate intake counting:

• carb counting, average 45-60 g/meal

• carb total - fibre = total count (fibre isnt absorbed=no glucose)

• 15 g of carbohydrate=1 unit rapid acting insulin (on average across lifespan)

Regular meals & snacks are key to steady BG, what are the recommended strategies/foods

• low GI foods, balanced diet with protein intake

• bedtime snack to avoid night time hypoglycaemia

• regular activity/exercise

insulin bolus recommendations pre meal

rapid or short acting insulin pre-meals (3x per day)

• know the approx estimate from original calculation

• pre-meal BG level

• carb-count for this meal

• BOLUS in IU (units) - administer before eating

what is the important rule for pre meals insulin bolus,

• 1 IU Insulin decreases BG by approx 2-5 mmol/L

• on average by 2.5 mmol/L

• used to decrease high BG, give at same time as normal dose

what do we do after administering insulin for a meal

• check BG 1-2 hrs post-meal (at peak action), goal=4-8 mmol/L = normal

• insulin correction & titrate:

  • 10 mmol/L = require additional insulin

  • <4 = too much insulin, require additional sugar

Rx of Insulin: the ‘Sliding scale’

• frequently used in hospitals, rural settings

• an outline of BG level results & Insulin dose based on it

• in pt’s chart

what results in high ketones

insufficient insulin-glucose transport = fatty acid breakdown into ketones for energy

• if rising ketones = intervention!

• high ketones seen in ketoacidosis (diabetic ketoacidosis = DKA)

how do we monitor ketones

measured in urine

• urine ketone strip

• monitor levels

hyperglycemia onset of symptoms (most telling signs of trouble)

takes a while for S&S, dangerous longterm

• thirst

• fatigue

hypoglycemia onset of symptoms (most telling signs of trouble)

rapid onset of S&S

• loss of focus

• nervousness

• shakiness

• if your pt seems off= check BG level

hyperglycemia pathophysiology

• high BG (high osmolality) => cellular dehydration & polyuria=overall dehydration

• shift of potassium out of cells => ECF => excreted

• low cellular function

• metabolic shift & ketone accumulation

• progression to => DKA

s&s of hyperglycemia

• high BG, high urine ketones + glucose in urine, high serum lactate (metabolic acidosis),

• changes in LOC, N&V, kussmaul respirations, acetone (fruity) breath

• eventually hypokalemia

tx of hyperglycemia

regular Insulin IV, IV fluids, KCl, close monitoring ex BG q1h

• neutralize metabolic acidosis=sodium bicarbonate

• correction of fluids is 1st

management of adults with DKS pic

using NS or RL to restore fluids back into cells, IV

hypogylcemia causes and s&s

• diet change, activity (higher than anticipated), insulin (too much)

• S&S=BG <4 mmol/L

Hypoglycemia protocol: 15-15 rule (tx)

conscious or unconscious?

• conscious=glucose PO; 15 g, ex glucose tablets, honey, apple juice

• unconscious= glucagon IM, D50W IV

• reassess q 15 min

what does BG balance influence

• illness

• exercise

how does illness influence BG balance… require more monitoring

• increased BG d/t cortisol release

• increased BG d/t SNS stimulation (epi, norepi)

• increased BMR => demand on resources d/t fever, processes ex inflammation, repair

• decreased appetite, may include N&V

how does exercise influence BG balance… require more monitoring

decreases BG

DM I other tx choices

tx=beta cell transplant + immunosuppressant drugs forever ex tacrolimus (T-cell suppression)

• 2-3 infusions of islet cells required (over time)

• challenges=donor numbers, chronic immunosuppression

Keeping blood glucose levels even in daily life, what tests can we use

glycohemoglobin (A1c hemoglobin)

• serum test of glucose bound hgb

• assessment of longterm glucose control (ex over 3 months)

• a tool to monitor DM pts & dx pts at risk for DM