A disease of ancient Greeks and
modern men
Namita Jayaprakash MB BcH BAO, MCEM
 The history of Diabetes
 The pathophysiology behind diabetes
 Definitions
 Management
 Diabetic emergencies
Diabetes mellitus is a syndrome of chronic hyperglycemia
due to relative insulin deficiency, resistance, or both
 Ebers papyrus
 1550 B.C
 Galen and Arateus further delineated the disease
 130 – 201 A.D
 Arateus coined the term diabetes
 150 A.D
 Diabetes = ‘siphon’
 ‘liquefaction of the flesh and bone into urine’
 Lavoisier’s legacy
 Late 18th century
 established the concept of the respiratory quotient
 Baron Justus von Liebig
 Identified protein, carbohydrates and fats
 Claude Bernard
 Questioned role of pancreas in diabetes
 Apollinaire Bouchardat and E. Lancereaux
 Identified two forms of diabetes
 1921 Banting and Best
worked on ‘isletin’
extraction
 1922 ‘insulin’ Leonard
Thompson first human
recipient
 1923 Nobel Prize in
Medicine awarded for
discovery of insulin
 Sulfonylurea
 Introduced in 1955
 Biguanide
 Phenformin, metformin
 α – glucosidase inhibitors
 1980’s
 Thiazolidinediones
 1990’s
 Nonsulfonylureas
 Key hormone involved in storage and controlled release
of chemical energy
 Coded for on chromosome 11
 Synthesized in β – cells of pancreatic islets
Pre - proinsulin
Proinsulin
Insulin
C-peptide
Insulin
α – subunit
β – subunit
 Increases glucose uptake into cells and glycogen
formation
 Decreases glycogenolysis and gluconeogenesis
 Increases fat deposition and decreases lipolysis
 Increases protein synthesis
 Increases potassium (K+) uptake into cells
 Decrease [glucose]
 Decrease [amino acid]
 Decrease [fatty acid]
 Decrease [ketoacid]
 Hypokalemia
 Carbohydrate metabolism
 Normal blood glucose = 63 – 144 mg/dL
 Liver is principal organ of glucose homeostasis
 Glycogenolysis
 Gluconeogenesis
Carbohydrate
Glycemia
Glucose
Insulin
Cell
Glucose
Glycogen
Glucose – 6 – phosphate
Fructose
Fructose 6 – P
Ribose 5 – P
Fructose 1,6 – P
Uric acid
Pyruvate
Lactate
Mobilization of
substrates for
gluconeogenesis and
ketogenesis
Impaired
removal by
insulin
responsive
tissues
Accelerated
production of
glucose and
ketones
Overwhelmed
excretory
mechanisms
 Insulin deficiency
 Glucose cannot enter cells
 Alternatives for cellular energy
 Lipolysis -> glycerol and free fatty acids
 Glycerol -> glucose
 Free fatty acids -> ketones
 Peripheral resistance to insulin
 Increased production of glucose by the liver
 Altered pancreatic insulin secretion
 Secondary Diabetes
 Genetic defects in β – cell function
 Genetic defects in insulin action
 Disease of exocrine pancreas
 Drug or chemical induced diabetes
 Gestational Diabetes
s
o
e
e
A
SGLT2 inhibitors
Bromocriptine
Colesevelam
DPP4 inhibitors
Inhaled insulin
2008
Pramlintide
GLP-1 receptor agonists
Glinides
Thiazolidinedione antidiabetics
Insulin analogues
α-glucosidase inhibitors
Human insulin
15
Classes of glucose-lowering drugs
e
r
s
e
e
t
e
h
d
10
5
Metformin
Animal insulin Sulfonylurea antidiabetics
0
0
B
1920
1930
1940
1950
1960
Year
Classic
1970
1980
1990
2000
2010
2002
Lessclassic
Sulfonylurea antidiabetics
Glinides
Bromocriptine
 Primary focus is insulin replacement
 Healthy lifestyle
 Prevent long term complications
Category
Rapid acting
Name
Insulin lispro (Humalog)
Insulin aspart (Novolog)
Insulin glulisine (Apidra)
Short acting
Regular insulin (Humulin R, Novolin R)
Intermediate acting
NPH (Humulin N, Novolin N)
Insulin detemir (Levemir)
Long acting
Insulin glargine (Lantus)
Mixtures
70/30 Humulin/Novolin (70% NPH, 30% regular)
50/50 Humulin/Novolin (50% NPH, 50% regular)
75/25 Humalog (75% NPL, 25% lispro)
50/50 Humalog (50% NPL, 50% lispro)
70/30 NovoLog Neutral (70% protamine aspart, 30%
aspart)
 Intervention at time of diagnosis
 Metformin
 Lifestyle changes
 Aim to achieve and maintain recommended levels of
glycemic control
 Continuing timely augmentation of therapy
Class
s
has
s to
hese
cose
ible
vent
pies
s or
well
for
3).
ffer
ture
The
have
(eg,
ics,
ator-
Human insulin
Metformin
Animal insulin Sulfonylurea antidiabetics
0
0
B
1920
1930
1940
1950
1960
Year
Classic
1970
1980
1990
2000
2010
Lessclassic
Bromocriptine
Sulfonylurea antidiabetics
Glinides
GLP-1 receptor agonists
DPP4 inhibitors
Insulin
Lifestyle modification
Metformin
Thiazolidinedione antidiabetics
α-glucosidase inhibitors
Pramlintide
Colesevelam
SGLT2 inhibitors
Figure3: Drugsto treat type 2 diabetes
(A) The rate of introduction of new classes of drugs has accelerated during the past 20 years. Two classes (animal
insulin and inhaled insulin; red) are essentially no longer available as therapeutics. (B) Di fferent classes of drugs act
on different organ systems. Insulin is a replacement for the natural product of islet β cells. Classic organ systems
that have been targeted for decades comprise the pancreatic islet, liver, muscle, and adipose tissue. Non-classic
targets have been focused on recently, and include the intestine, kidneys, and brain. DPP4=dipeptidyl peptidase 4.
 Metformin
 Reduces hepatic glucose production
 Improves peripheral glucose utilzation
 Reduces plasma glucose and insulin levels
 Improves lipid profile
 Promotes moderate weight loss
 Pioglitazone, rosiglitazone
 Binds to PPAR – γ
 Reduces insulin resistance
 Promote redistribution of fat from central to peripheral
 Stimulate insulin secretion
 Act on ATP – sensitive potassium channel on the β – cell
 Most effective in Type II diabetics onset < 5 years
 Sulfonylureas
 Reduce fasting and post prandial glucose
 Increase insulin acutely
 Hypoglycemia can be related to delayed meals, increased
physical activity, alcohol intake, renal insufficiency
 Incretins
 Amplify glucose – stimulated insulin secretion
 Mimic or augment the action of GLP – 1 and GIP
 GLP – 1 analogue or GLP – 1 receptor agonist
 Exanatide
 Gila monster saliva
 Liraglutide
 DPP – IV inhibitors
 Inhibit degradation of native GLP – 1
 Promote insulin secretion
 Absence of weight gain and hypoglycemia
 Have preferential effect on post prandial glucose
 α – glucosidase inhibitors
 Slow glucose absorption
 Delay degradation of complex carbohydrates
 Pramlintide
 Slows gastric emptying
 Colesevelam
 Lowers cholesterols
 Modifies release of GI peptides that reduce plasma
[glucose]
 Inhibitors of Sodium – glucose co transporter 2
 Increases urinary glucose excretion
 Inhibits SGLT 2 reabsorption of glucose
 Dapagliflozin and canagliflozin available
 Reduce plasma glucose, body weight and BP
Parameter
Normal
Target
Pre – prandial plasma glucose (mg/dL)
< 100
90 – 130
2 –hr post – prandial plasma glucose
(mg/dL)
< 140
< 160 – 180
Bedtime plasma glucose (mg/dL)
< 120
110 – 150
Hemoglobin A1c (%)
<6
<7
LDL cholesterol (mg/dL)
< 130
< 100
HDL cholesterol (mg/dL)
> 40 (m), > 50 (w) > 45 (m), > 55 (w)
Fasting triglycerides (mg/dL)
< 150
< 150
Blood pressure (mmHg)
< 140/90
< 130/80
Sugar = 28.8g
Sugar = 14.8g
Sugar = 21.7g
 Diabetic Ketoacidosis (DKA)
 Hyperosmolar Hyperglycemic state (HHS)
 Insulin deficiency
 Increased counter – regulatory mechanisms
 Glucagon
 Catecholamines
 Cortisol
 Growth hormone
 Triad of hyperglycemia, ketosis and acidemia
 Mortality is < 5% but remains most common cause of
death in young people
Blood glucose
> 250 mg/dL (13.8 mmol/L)
pH
< 7.30
Serum bicarbonate
< 18 mmol/L
Anion gap
> 10
Ketonemia
 DKA forms rapidly
 Symptoms may be present for several days before
ketoacidosis forms
 Presenting symptoms
 Polyuria, polydipsia, weight loss
 Vomiting and abdominal pain
 Physical signs
 Increased respiratory rate
 Kussmaul breathing
 Fruity breath
 Evidence of dehydration with hypotension
 Fluid depletion of 5 – 8 L
 Diagnostic criteria
 [Glucose], pH, [bicarbonate], ketones, osmolality
 Electrolyte abnormalities
 Sodium
 Pseudohyponatremia
 Glucose and triglyceride elevation
 Potassium
 Loss and cellular shifts
 Magnesium
 Phosphate
 High levels at presentation with decreases with DKA treatment
 Correct fluid depletion
 Decrease blood glucose levels
 Correct electrolyte imbalance
 Treat precipitating causes
 Isotonic saline (0.9% normal saline)
 First hour aim to restore renal perfusion
 Rate of fluid infusion depends on clinical status
 Corrects blood glucose and plasma osmolality
Severe hypovolemia
Mild dehydration
Administer 0.9%
normal saline at
1L/hour
Evaluate corrected
Sodium (Na+)
Serum Na+ high
Sodium Na+ normal
0.45% NaCl (250 – 500
ml/hr) depending on
hydration status
Cardiogenic shock
Hemodynamic
monitoring/pressors
Sodium Na+ low
0.9% NaCl (250 – 500
ml/hr) depending on
hydration status
When glucose reaches 200 mg/dL, change to 5% dextrose with 0.45% NaCl at
150 – 250 ml/hr
 Lowers blood glucose
 Increases peripheral glucose utilization
 Decreases hepatic glucose production
 Lowers ketones
Corrects acidosis
 Inhibits release of free fatty acids
 Dose of insulin
 Intravenous
 Bolus 0.1 U/kg
 Infusion at 0.1 U/kg/hr
If serum glucose does not fall by 50 – 70 mg/dL in first hour, double dose
of insulin
 Subcutaneous
 Rapid acting insulin
 0.3 U/kg, then 0.2 U/kg one hour later
 0.2 U/kg subcutaneous every two hours
 Alternatives
 Low dose infusions as effective as standard
 Randomized controlled trial
 Compared load with infusion, no load, and no load with twice
the infusion dose
 0.14 U/kg/hr
 Longer time to reach peak free insulin levels
 No differences in times to reach glucose < 250 mg/dL, pH = 7.3,
and HCO3 > 15 mmol/L
 Aim to correct glucose to 200 mg/dL
 Reduce insulin infusion to 0.02 – 0.05 U/kg/hr
 Give rapid acting insulin at 0.1 U/kg sc every 2 hours
 Keep serum glucose at 150 – 200 mg/dL until DKA resolves
 Start after 1st liter of fluid
 Aim to maintain concentration at 4 – 5 mmol/L
 K+ < 3.3 mmol/L
 Hold insulin
 Give 20 – 30 mEq/hr until K+ > 3.3 mmol/L
 K+ > 5.3 mmol/L
 Do not give K+, check serum K+ every 2 hours
 Rarely need > 20 mEq K+/500 mls of fluid
 If serum K+ > 3.3 and < 5.3
 Give 20 – 30 mEq K+ in each liter of IV fluid
 Replacement remains controversial
 RCT’s have not shown clear benefit
 Experts advise use if pH < 7
 Worsens hypokalemia
 NaHCO3 (100 mmol) in 400 ml H2O with 20 mEq KCL over
2 hours
 No clear benefit from iv replacement
 Can be harmful
 If needed replace with oral forms
 Caused by an inadequacy of insulin
 High mortality
 As high as 15%
 Higher in elderly
Blood glucose
> 600 mg/dL (> 33.3 mmol/L)
pH
> 7.30
Bicarbonate
> 15 mmol/L
Serum osmolality
> 320 mOsm/kg
Small amount of ketones may be
present
 Correct fluid depletion
 Decrease blood glucose levels
 Correct electrolyte imbalance
 Treat precipitating causes
Severe hypovolemia
Mild dehydration
Administer 0.9%
normal saline at
1L/hour
Evaluate corrected
Sodium (Na+)
Serum Na+ high
Sodium Na+ normal
0.45% NaCl (250 – 500
ml/hr) depending on
hydration status
Cardiogenic shock
Hemodynamic
monitoring/pressors
Sodium Na+ low
0.9% NaCl (250 – 500
ml/hr) depending on
hydration status
When glucose reaches 300 mg/dL, change to 5% dextrose with 0.45% NaCl at
150 – 250 ml/hr
 Regular insulin
When serum glucose reaches 300 mg/dL, reduce insulin infusion to
 Bolus dose of 0.1 U/kg
0.02 – 0.05 U/kg/hr.
Aim to keep serum glucose 250 – 300 mg/dL until patient is mentally alert
 Intravenous infusion of 0.1 U/kg/hr
 If serum glucose does not fall by 50 – 75 mg/dL in the first
hour, double the infusion dose
 Glucose every hour until stable
 Serum electrolytes, BUN, serum creatinine, pH (venous),
osmolality every 2 – 4 hours depending on severity of
illness
 Hypoglycemia
 Hypokalemia
 Cerebral edema
 Non cardiogenic pulmonary edema
 Lower limit of normal plasma glucose
 70 mg/dL (3.9 mmol/L)
 Hypoglycemia occurs at < 50 – 55 mg/dL
 Diabetic
 Hypoglycemia occurs at < 63 mg/dL
 Neurogenic
 Tremor
 Neuroglycopenic
 Palpitations
 Cognitive impairment
 Anxiety/arousal
 Behavioral changes
 Sweating
 Psychomotor
 Hunger
abnormalities
 Seizure
 Coma
 Paresthesias
 Pallor
 Diaphoresis
 Rise in heart rate and systolic blood pressure
 Transient neurological deficits
 Glucose
 Oral carbohydrate
 Fruit juice, dextrose drink
 Simple sugars
 Buccal absorption from honey, chewable toffees or candy
 Complex carbohydrates
 Meal substitutes, biscuits, bread
 Parenteral glucose
 IV dextrose 50%, 25%, 10%, 5%
 Glucagon
 1 – 2 mg IM or sc
 IV Hydrocortisone
 SC adrenaline
 SC terbutaline
 Primarily disease of children treated for DKA
 Associated mortality rate of 20 – 40%
 Clinical features
 Headache, lethargy, decreased arousal
 Rapid neurological deterioration
 Seizures, incontinence, bradycardia, respiratory arrest
 Avoiding cerebral edema
 Gradual replacement of sodium and water deficits
 Addition of glucose to the solution once serum levels reach
200 mg/dL in DKA or 250 – 300 mg/dL in HHS
 Maintain serum glucose in HHS at 250 – 300 mg/dL until
hyperosmolality and mental status improve
 Treatment with mannitol (0.2 – 1.0 g/kg) or 3%
hypertonic saline (5 – 10 ml/kg over 30 mins.)
 Rare complication of DKA treatment
 Hypoxemia
 Reduced colloid oncotic pressure
 Increased lung water content and decreased lung compliance
 Pulmonary edema
 Higher risk if widened alveolar – arterial gradient noted on initial
ABG
 DKA resolution
 Serum glucose < 200 mg/dL
 Serum anion gap < 12
 Serum bicarbonate > 18 mmol/L
 Venous pH > 7.30
 HHS
 Serum glucose 250 – 300 mg/dL
 Mentally alert
 Plasma osmolality < 315 mOsm/kg
 If known diabetic, give previous insulin dose
 Insulin naïve patients
 Multi – dose insulin regimen
 0.5 – 0.8 U/kg/day
 Timing of switch
 Rapid acting sc insulins 15 – 30 mins
 Regular insulin 1 – 2 hours
 Intermediate and long acting longer with a gradual taper of
infusion
 Before breakfast
 2/3 of total daily dose
 1/3 as rapid acting insulin
 2/3 as intermediate acting insulin
 Before dinner
 1/3 of total daily dose
 1/3 as rapid acting insulin
 2/3 as intermediate acting insulin
 Diabetes Mellitus treatment goal to reduce
hyperglycemia and prevent long term complications
 Diabetic emergencies: DKA and HHS
 Treatment goals in DKA and HHS correct fluid depletion
and electrolyte losses, reduce hyperglycemia, treat
underlying precipitants
 During treatment watch for complications including
hypoglycemia
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