Diabetes Type 1

Contents: Pathogenesis, Risk factors, DKA,Hx Physical complications, treatment (incomplete)

Pathogenesis

History

Genetic, environmental and immunologic factorsresulting in

1. Pancreatic beta cell destruction
2. Insulin deficiency

Symptoms polyuria/polydipsia, fatigue,

fainting, weight loss, blurry vision, nausea
vomiting, tachypnea
When is glucose tested, what medication is
used, how often is there hypo/hyper,
hospitalization

Autoimmune process resulting in beta cell

destruction. 70-80% destruction required before
Physical examination
diabetes become clinically present.
- BMI
- Retinal examination
- Blood pressure (orthostatic) <130/80mmHG
considered hypertension in diabetic
- Foot examination- ulcers, peripheral pulses,
infections, nails, reflexes, sensory.
- Insulin injection
- Mouth examination teeth and gums
Investigations
-

HbA1c
Microalbuminuria
Dyslipidaemia
Thyroid dysfunction

Some individuals have residual function showing C

peptide production and insulin positive cells in
autopsy.
Immune response
-

Infiltration of T lymphocytes (mediated by

these more than antibodies)
Autoantibodies against islet cells
Cytokines causing insulitis

B cells are particularly susceptible to the toxic

effects of:
1. TNFa
2. IFNy
3. IL1

Risk factors
-

African American or Asian heritage

HLADR3 or DR4 gene
Low risk of first degree relative genetic
Environmental trigger can onset DM1 e.g.
Viruses (enterovirus), bovine milk proteins,
nitrosourea compounds

Diabetes type 2
Pathogenesis

Hepatic glucose and lipid production

Insulin resistance in liver is due to failure of the

Impaired insulin secretion, insulin
resistance, excessive hepatic glucosehigh insulin to suppress gluconeogenesis. This
results in fasting hyperglycaemia and decrease
production and abnormal fat metabolism
- Central obesity is common
glycogen storage by liver. Increased hepatic
glucose occurs early in diabetes.
Pancreatic islets
Insulin resistance in adipose tissue leads to
- Unable to sustain the hyperinsulinaemic
lipolysis and FFA increase. Increase VLVL and
state and lead to further decline in insulin
triglyceride synthesis in hepatocytes.
secretion
- Ultimately beta cell failure.
Risk factors
Insulin resistance
- Strong genetic component
- Parents with DM2 = increased risk of
- Genetic susceptibility and obesity
- Insulin dose-response curve have a
diabetes
- Insuline resistance present in first degree
rightward shift
o Reduced sensitivity and reduced
relatives of DM2
- Metabolic syndrome (metabolic
maximal response = overall
derangement in insulin resistance,
decrease in maximum glucose
hypertension, duslipideamia, central
utilization
obesity, DM2 and CV disease)
- Insulin resistance imapires glucose itlization
- Polycystic ovary syndrome can have insulin
and this increases hepatic glucose output =
hyperglycaemia.
- Glucose metabolism in insulin independent
issues is not altered
-

Central obesity
-

Increased adipocyte mass with increased

circulating FFA and other fat cell products.
FFA impaire glucose utilization in skeletal
muscles.
Adipokines modulate insulin sensitivity
insulin resistance in skeletal muscles and
liver
Reduced adiponectin (insulin-sensitizing
peptide) in obesity and contribute to
hepatic insulin resistance
Adipocyte products create an inflammatory
state (IL 6 and CRP raised)

Impaired insulin secretion

Relationship between insulin secretion and

sensitivity.Beta cell mass decreased by 50% in long
standing DM2. Amyloid fibrillary deposits in islet
due to amyloid/amylin secretion by beta cells.
Hyperglycaemia and dietary fat also impairs islet

Complications of diabetes (combined with

DM2)

Vitreous haemorrhage, fibrosis and retinal

detachment can occur.
Macular oedema can occur only when NPDR is
present. Fluorescein angiography is useful for
detecting macular oedema.
Treatment
-

Glycaemic control
Comprehensive eye examinations

Renal complications
-

Smoking accelerates the decline in renal

function
Family history is a risk factor

Disease progression
-

Coronary and mortality 2-4x in DM2

Important to have good glycaemic control

Glomerular hyperperfusion > renal

hypertrophy (increase in GFR)
Thickening of glomerular basement
membrane, glomerular hypertrophy,
mesangial volume expansion
Albumin excretion (micralbuminuria
macroalbuminuria) This is also risk factor for
CVD
Once macro, end stage renal disease in 7-10
years

Type 2
-

In addition to above, hypertension and

microalbuminuria progression is less
predictive

Treatment
Screening of microalbuminuria

Ophthalmic
-

Non proliferative diabetic retinopathy. Late

first decade of disease presentation with
marked retinal vascular microaneurysms, blot
haemorrhage and cottonwool spots
Proliferative diabetic retinopathy. Response to
hypoxemia there is neovascularization.
Vessels appear near optic nerve and macula
which can rupture easily.

Renal testing
-

Microalbuminuria
Serum creatinine
Estimate GFR

Strict blood pressure control (ACEi, ARB)

Dyslipiedmia treatment
Diet restriction of protein with patients at the
micro/macroalbuminuria phase.

Neuropathy
50% of individuals is as with other complications it is
related to duration and glycaemic control, BMI and
smoking.
Polyneuropathy/mononeuropathy
-

Distal sensory loss, hyperesthesia,

paresthesia, dysesthesia.
Numbness, tingling, sharpness or burning in
feet moving up proximally

Mononeuropathy in CNIII is more common presenting

with diplopia. Other cranial nerve can occur
Autonomic neuropathy
-

Can involve many organ systems such as

Cardiovascular Resting tachycardia,
orthostatic hypotension
Gastro gastroparesis and bladder emptying
abnormalities
Sympathetic hyperhidrosis in upper
extremities and anhidrosis in lower
extremities
o Dry skin and root ulcer risk

Treatment
Avoidance of neurotoxins such as alcohol and
smoking.
Supplementation with B12 and folate.
Pain management
-

Antidepressants
Anticonvulsants
Tricyclic antidepressant

Diagnosisketoacidosis
Diabetic
Management
of Type
1 Diabetes
diabetic
ketoacidosis
Gastrointestinal/genitourinary
is
to control
blood
glucose
concentration
and
Mainly
occurs
in DM1
but
can occur
in nonglucose,
Confirm
diagnosis
with
Increased
plasma
- Target
Gastroparesis,
constipation,
diarrhea
complications.
immunological
features
of typeacidosis
1 + obese
serum
ketones
and metabolic
+ GCS
- minimize
Anorexia,
nausea,
vomiting,
early
satiety
and
individuals
with
DM2 of Hispanic and African
abdominal
bloating
assessment
of
American
descent.
Management
is similar.
- Ongoing
Cystopathy,
erectile
dysfunction,
female
sexual
dysfunction
1. Serum
electrolytes K, Na, Mg, CL,
- Symptoms
Urinary
hesitancy,
voiding
bicarbondate, decrease
phosphate
frequency,
incontinence,
recurrent
urinary
2. Acid base
state pH Bicarb,
PCO2
and ketones
tract(B-hydroxybutyrate)
infection
3. Renal function (Creatinine and output)
Cardiovascular
Treatment
Treatment
Control
risk factors
Replace
fluids:
23 Lbackground
of 0.9% saline
1. Basal
insulin
insulinover first
- Dysplipidemia,
hypertension, obesity,
13 h (1520
mL/kg of
per
hour); subsequently,
0.45%
independent
carbohydrate
intake. 40-50%
physical
activity,mL/h;
smoking
saline
at
change
5% glucose
and
of250500
total daily
insulin
dose to
through
once or
0.45%(see
saline
at 150250
mL/h when acting
plasmainsulin
twice
daily
long/intermediate
Treatment
cardio)
glucose
reaches
200 mg/dL (11.2 mmol/L)
2. Bolus
insulin
Prandial
insulin
cover carohybdrate
- GPIIb.IIIaa.platelet
inhibit
hastoimproved
GIVE POTASSIUM
IF REQUIRED
using
short or very short
outcomes inintake
diabetic
patients
acting
insulin
- Short
Use acting
of B blockers,
ACE
inhibitors or ARB
insulin
b.
Correction
doses of insulin to return
- Antiplatelet therapy (aspirin)
- IVLDL
0.1units/kg
increasing
if no response
high
blood
glucose2-3x
to acceptable
- Lower
as
a focus
Serum
glucose
can initially
but only
- by
Nausea
and
vomiting
most common
2-4 hours
levels
- Hypertension
treatment
choice
Abdominal
pain
=
DDx
pancreatitis?
- oEnsure
serum
K isacute
<3.3mmol/L
= do
minimally
elevated
ACEi initial
that
are
glucose/lipid
beneficial
Typical
starting
islow
0.3-0/4
units/kg
per is
day
administer
insulin
until
- onot
Bicarb
isdose
often
(below
10mmol)
Ruptured
viscus?
Calcium
channel
blockers,
B this
blockers
pHand
can
vary
with the
acidosis
- corrected
Cerebral
oedema
= are
serious
vasodilators
lipid complication
and glucose of
Treatment
types
- If
initial
serum
K
is
>5.2mmol/l
do not
Dehydration
results
in
DKA
and
frequently
seen
in
children
neutral
supplement
K+
until
potassium
isCl,
corrected.
o
Inaccurate
reading
of
Na,
K and
Multiple
daily
injection
regime
o B blockers and thiazide diuretics
can
PrecipitatorsMg
of which
DKA are decreased
increase
insulin+
resistance
= not60%
good.
Secondary
assessment
- Basal
(once)
bolusand
(meals)
o 40%
Increased
in BUN
creatinine
Sympathetic
inhibits
and
a-adrenergic
- oInfection
(patients
should
increase
their
Based on carbohydrate intake, expected
- precipitated
Leukocytosis
What
the
episode
blockers
= worsen
orthostatic
insulin
illness)
level
ofduring
physical
activity,
blood glucose
- Hypertrigylceridemia
-- concentration
Tissue
hypotension
ischaemia
(brain
or heart)
at
that
time
Noncompliances,
infection
trauma, infarction
- Hyperlipoproteinaemi
Monitor
potassium
and renal.
- oOmission
ofserum
insulin
due to eating
disorder
cocaine
use
Mixed
insulininfusion
regimen
Insulin
device
mechanical
failure
Ketones
can bestate
detected via capillary ketone,
- Mental
Dermatology
Cultures,
urinary
or serum.
- Mixture
ofCXR,
shortECG
acting and intermediate
Pathophysiology
acting
to
be
given
- On-going
Poor wound
healing andtwice
skin daily
ulceration.
assessment
Differentials
Minimal
role
in
type
1 diabetes
decrease
glucagon/catecholeamines
- Insulin
Diabetic
skin spots
(pigmented
pretibial
increase
promotes
papules)
1.
Capillary
glucose
1-2
hours
If
hyperamylasemia
+
abdominal
pain
can suggest
Continuous subcutaneous insulin infusions
- pancreatis
Acanthosis
nigricans
hyperpigementation
2. Measure
electrolytes
(K+, bicarbondate,
-- Gluconeogenesis
phosphate
and
anion
gap).
K+axilla
repletion
velvety
plaques
seen
on the
neck,
or as
Pump
therapy
(high
cost)
-- Glycogenolysis
soonsurfaces.
as
urine output
and
normal
Need
to adequate
monitor
and count
extensor
regularly
severe
insulin
resistance
- Ketone
body formation
liverinsulin doses
serumannulare
K+.
carbohydrates
to
selectin
bolus
- Grauloma
is erythematous
plaques
3.
Continue
replacement
of
treatment
until
on
extremities
or
trunk
Ketosis
is dueoftoblood
increase
in FFA release from
Monitoring
glucose
patient
is
stable
- adipocytes
Sclerodema
thinkinginsulin
on back
or neck
dueskin
to reduced
levels.
These are
4. Long acting insulin as soon as patient is
- and
Performed
4-6 times each
day, usually
acidic
are
physiologically
decreased
by
eating
before and
after main meals,
before
bicarbonates.
As bicarbonate
decreases
exercise, when hypo is suspected and before
Extra notes:
Infection
driving.
SC insulin
can
be usedand
in mild
DKAof
- Periods
ofcolonization
unwell
Hyperglycaemia
aids
growth
Acidosis
and
ketosis
resolves
slower
than
After
treatment
of
hypoglycaemia
organisms. But they also have impaired white cell
hyperglycaemia
During
times
of
increased
activity
function. Watch for
Potassiuminisinsulin
decreased
due to insulin,
- Changes
regimen
- Skin resolution
infections of acidosis and urinary loss.
should should
also bebe
monitored
if symptoms
- Glucose
ADDED when
plasma or
- Ketones
Otitis
externa
low
blood
glucose
or
acute
illness
- UTI glucose hit 8.3-13.9 mmol/L and insulin
infusion continued (possibly decreased
slightly)
- Ketones improve slower and as it improves B
hydroxybutyrate is converted to
acetoactetate

Treatment of HHS
Choice of therapyHyperglycaemic hyperosmolar state
Similar patient
to DKA in
that
there
is need
for careful
Elderly
with
Type
2 DM
and history
of
Generally a HbA1c of less than 53 or 7% is Metformin is first choice
of antihyperglycaemic
drug
monitoring
of
patients
polyuria,
weight
loss
and
decreased
oral
intake
+
recommended but glycaemic target should be
in type 2.
mental
confusion
leathgy
or
coma.
individualized to ensure hypoglycemia is avoided.
- Fluid state
No lifestyle changes met + max metformin dose =
6.5% in a younger person. 8% in an older if they
Laboratory
This- is due
to drug values
add second antihyperglycaemic
(Sulfonylurea).
have risk of hypoglycaemia
- Insulin infusion rate
Basal insulin or incretin- based
therapies
are new
Profound dehydration
second line treatment
HHS-approaches.
has
more pronouched fluid loss and
Hyperosmoalility
dehydration
due to longer duration of illness
- Hypotension
Sulfonylureas can cause
hypoglycaemia. The
Tachycardia
other medication when
used
with
sulfonylureas
Mental
state
and
changes should also be noted.
Altered mental state
have increased riskHHS
of -hypoglycaemia.
has higher moratlity rate than DKA
This is NOT DKA = no nausea, vomiting, abdominal
1. Fluid replacement 1-3L 0.9% saline over first
pain or KLussmaul respiration.
2-3 hours
2. Ensure there
isnt too rapid repletion as it
Precipitating
factors
can worsen neurological function
-3. Concurrent
illness
(sepsis, pneumonia)
Serum sodium
> 150mmo/L
= usue 0.45%
- Myocardial
infarction
saline
-4. Stroke
Free water deficit
- Social
stroke or dementia
causes
a. situation
After haemodynamically
stable
decreased
water
intake
b. 0.45%
saline
c. Then 5% dextrose in water
Pathology
5. Potassium repletion usually necessary
6. deficiency
Insulin bolus then constant infusion rate. If
Insulin
glucose does not fall increase 2x
-7. Hepatic
production
Glucose glucose
should be
added when plasma
- Impaired
glucose
utilization
in and
skeletal
glucose fall 13.9-16.7
mmol/L
insulin
Diet
muscles
decreased.
Management of Type 2 DIabetes

Low GI food recommended and avoid foods rich in

fat and refined carbohydrate. Sweeteners can
interfere with satiety mechanisms. Fructose can
also promote triglyceride synthesis, exacerbate
insulin resistance and interfere with satiety.
Exercise 150m per week
Antihyperglycaemic therapy
1. Metformin reduces hepatic
gluconeogenesis and thus insulin
requirements
2. Sulfonylureas increase insulin secretion
3. Incretin-based therapy
a. DDP-4 inhibitors increase
concentration of GLP and GIP. GLP1
stimulates insulin release and
reduces glucagon
b. GLP1 receptor agonists increase
insulin secretion and reduce glucagon
secretion and reduce appetite
4. Acarbose reduce breakdown of complex
carbohydrate in gut thus absorption
5. Insulin
6. Thiazolidinediones reduced peripheral
insulin resistance
7. Sodium glucose co-transporter 2
inhibitors Reduced glucose reabsorption
in kidneys

Dehydration
-

Hyperglycaemia causing osmotic diuresis

Inadequate fluid replacement

(Why not ketones? Possibly insulin deficiency is only

relative and less severe than DM1- insulin/glucagon
ratio)
Laboratory diagnosis
-

Hyperglycaemia ( >55.5mmol/L)
Hyperosmolality (>350mosmol/L)
Prerenal azotaemia

No acidosis and keotnaemia (small anion gap

metabolic acidosis may be present)

Pharmacology of type 2 medication

Metformin
Reduces hepatic
glucose production.
Does not cause
weight gain

Gastrointestinal intolerance
Lactic acidosis (rare and adverse)
Kidney excretion (dose reduction in those with
poor kidney function)

Sulfonylureas (eg glibenclamide, gliclazide, glimepiride, glipizide)

Oral dose glibenclamide (Once Increase insulin
- Hypoglycaemia
- Longer acting(glibenclamide and glimepriride)
or twice)
secretion via
should be avoided in elderly due to severe
Immediate release oral
pancreatic
prolonged hypogylcaemia. Gliclazide and
gliclazide (once or twice)
sulonylurea
glipizide liver metabolism and thus shorter
Modified release gliclazide
receptor. Start at low
acting
(once daily)
dose
- Weight gain
Oral glimepiride (once)
Oral glipizide (once or twice)
Incretin based therapies( GLP1 and GIP related, these produced in gut and stimulate insulin release and inhibit
glucagon. Has effect on appetite)
Dipeptidyl peptidase-4 DDP4 inhibitors (linagliptin, saxagliptin, stagliptin, vildaglitin)
Orally once daily except
Enzyme that rapidly
Pancreatitis is a rare side effect and thus should not
vildaglitin which is once or
breaks down GLP1
be used when there is previous pancreatitis and
twice daily
GIP. Well tolerated
cease if pancreatitis occurs.
and no associated
Dose adjustment for kidney impairement (creatinine
with weight gain and clearance <50Mml/minute) recommended except
hypoglycaemia
lingliptin
Glucagon like peptide 1 (GLP1) receptor agonist (exenatide, liraglutide)
Subcutaneous injection
More potente that
Inhibition fo gastric emptying thus can cause nausea
DPP4 inhibitors and
but improves as treatment continues.
may improve satiety Pancreatitis is a rare side effect and thus should not
thus weight loss.
be used when there is previous pancreatitis and
cease if pancreatitis occurs.
Acarbose
Oral 3 times daily

Insulin
Basal insulin with metformin/
+sulfonylurea
Combination insulin with
metform

Inhibits alphaglucosidase and

delayes
carbohydrate
digestion, glucose
absorption and thus
decrease in
postprandial glucose
peaks. Taken with
food and treatment
started at low dose

Gastrointestinal
- Flatulence
- Bloating
- diarrhoea

Used when
glycaemic targets
are not met.
Eventually require

Hypoglycaemia

Basal + bolus insulin

insulin due to
progressive beta cell
failure.
Thiazolidinediones (pioglitazone, rosiglitazone)
Peroxisome
- Heart failure due to fluid retention
- Fracture risk in postmenopausal women
proliferator- Bladder cancer with pioglitazone
activated receptor
- Macular oedema
gamma agonists.
Only
used in those with severe insulin resistance or
Promotes glucose
hypoglycaemia
avoidance is paramount
utlisation in
peripheral tissues,
suppress
gluconeogenesis in
liver and reduce
adipocyte lipolysis.
Sodium glucose cotransporter 2 inhibitor (Dapagliflozin)
New drug
Increases urine
output of glucose

Other considerations
Alcohol intake
-

Increases risk of hypoglycaemia as it reduces gluconeogenesis particularly in those using insulin or

sulfonylureas
Limit to 2 standard drinks

High risk behavior

-

Recreational drugs impaired ability to recognize hypoglycaemia

Travel
-

Carry a letter of introduction with their diabetes history and letter for customs (syringes, blood testing
equipment, insulin vails and other drugs)

Take twice as much medication in separate bags

Short acting and long acting carbohydrates
Exercise to prevent DVT and maintain glycaemic control

Driving
-

Test BGL

DM 1 Summary

PBL case Brief

Mary 23rd year old women brought in by ambulance from a music festival presenting with drowsiness,
slurred speech, dyspnea and has vomited three time on a background of poorly controlled Type 1
diabetes. She had missed her last two insulin dosage and had some food intake during the day. DKA
was suspected and was later confirmed with glucometer and urinalysis showing a hyperglycaemia and
presence of ketones. Her blood results showed metabolic acidosis with ph of 7.12 and bicarbonate at
15. She had some electrolyte and dehydration but was not hypokalaemic. Therefore, she was
immediate managed with 2000mls of 0.9% saline IV, quick acting insulin infusion of 5 units per hour.
When Mary was stable maintenance IV fluid with potassium was provided at 100mls per hour.
Precipitating factors include atypical pneumonia (confirmed by CXR) with right base crackles and a
candida vaginal infection confirmed by swab. IV azithromycin and fluconazole treatment was
provided.
Diabetic history
Regarding Marys diabetic history she was diagnosed with Type 1 DM at 19 presenting with increased
urinary frequency. Her initial and current treatment consist of twice daily insulin. Although seen by a
dietician, there is poor dietary compliance due to concerns with friends and colleagues finding out her
diagnosis and weight gain.
She has had multiple hypoglycaemia attacks with one requiring IV glucose from paramedics but was
not admitted into hospital. Due to hypoglycaemic attack she had stopped insulin and had symptoms
including polyuria,polydipsia, blurred vision and vaginal irritation. Her insulin dose was lowered.
She admits to poor insulin use and often forgets to test her BGL.
Social history
Mary has not told anyone of her diabetes except for her boyfriend. She is a drama teacher and fears
impact of diabetes on her job and her ability to maintain her drivers license.
She is currently on OCP and hopes to have children in the future.
Summary
In summary, 23 year old female with Type 1 diabetes presenting with DKA due to missed insulin dose,
poor diabetic control and possibly precipitated by atypical pneumonia and vaginal candidal infection.
She was stablised with insulin and fluids and treated for the infections. Her medication compliances,
diet and social support will need to be addressed. Education on this as well as diabetes control for
pregnancy planning should be discussed.
DM 2 summary