CME Sohag | internal medicine | Diabetes mellitus

Internal medicine
training session (1)
Dr. Ahmed Othman
Assistant lecturer of internal medicine,
Sohag university

Case Study
• 55 year old, obese man, routinely
avoid medical care presented to
the clinic with a fasting blood sugar
of 108 mg/ml and a 2 hours post-
prandial of 186 mg/ml.

Diagnosing Diabetes
 Casual plasma glucose ≥ 200mg/dl
AND symptoms
– Polyuria, polydispia, unexplained weight
loss
 Fasting plasma glucose of ≥ 126mg/dl
AND symptoms
2 RBS or 2 FPG without symptoms

Oral Glucose Tolerance Test
Fasting
• Oral glucose load of 75g anhydrous glucose dissolved in water
• Plasma glucose testing at 2 hours

Oral Glucose Tolerance Test in pregnancy
Fasting more than 95
• Oral glucose load of 100g glucose dissolved in water
• Plasma glucose testing at 3 hours
 1 h more than 180
 2 h more than 155
 3 h more than140

When to screen…
• Screening for T1DM involves the measurement of
autoantibody markers (antibodies to islet cells, insulin,
glutamic acid decarboxylase, and tyrosine
phosphatase).
• Every 3 years for all individuals >45yo T2DM
• More frequently or at a younger age if…
 BMI >25 - Hypertension
 Inactive - HDL<35
 First degree relative with DM -TG >250
 h/o glucose intolerance - PCOS
 High risk ethnic group - Vascular disease
 h/o gestational DM -Have delivered a baby weighing 4kg

Targets for Treatment
HbA1c <6.5% (Check q 3months until stable and <7,
then q 6months)
Premeal Glucose 90-130mg/dl
Peak Postprandial G <180mg/dl
Systolic <130
Diastolic <80
LDL <100
HDL >40
Triglycerides <150

Annual Monitoring Tests
• Dilated eye exam
• Foot exam
– more often if neuropathy present
• Lipid profile
• Microalbumin measurement

Nutritional Recommendation
• Provide individualized meal planning
guidelines
• Carbohydrate training
• Caloric balancing
• Exercise

Diet
Multiple Insulin Injection Therapy
I
N
S
U
L
I
N
I
N
J
E
C
T
I
O
N
30
25
20
35
30
25
40
35
30
Physical activity
Bodyweight
25 years male IBW 60 kgm
Carbohydrate (65%)390
Protein (10%)60
Fat (25%)150
Carbohydrate 100 gm
Protein (10%) 15 gm
Fat (25%) 17 gm
Diet Carbohy. Protein Fat _
Arabian bread 30 gm --- ---
Cheese 5 gm 10 gm 10 gm
Honey 50 gm 2 gm 3 gm
Glass of milk 10 gm 5 gm 5 gm_
Total 95 gm 17 gm 18 gm
Protein (10%)80
Fat (25%)200
Carbohydrate 130 gm
Protein (10%) 20 gm
Fat (25%) 22 gm
Rice 80 gm --- 6 gm
chicken 5 gm 15 gm 12 gm
Salad 30 gm 4 gm 4 gm
Orange 10 gm --- ---___
Protein (10%)40
Fat (25%)100
Carbohydrate 65 gm
Protein (10%) 10 gm
Fat (25%) 11 gm
Tuna sandwich 45 gm 12 gm 10 gm
Apple 15 gm --- ---
Tea --- --- --- _
60 Kg X 30 kcal = 1800 kcal
Breakfast600 kcal Lunch800 kcal Dinner400 kcal
The total calories intake depends on patients age and activity but have to
related to the desirable body weight.
Total daily calories = IBW X Estimated daily energy
Add 300 kcal/day during pregnancy.
Add 500 kcal/day during lactation.
Fibers, sweeteners, vitamins, and minerals.

Meglitinide Analogs
Sulphonylureas
Thiazolindinediones
Metformin
(Biguanides)
Alpha
Glucosidase
Inhibitors
Oral
Hypoglycemic
drugs

•Metformin (Biguanides)
•Glybenclemide, Glicliazide
Glipizide, Glimepiride
• Acarbose , Miglitol, Voglibose
• Repaglinide, Nateglinide
• Rosiglitazone , Pioglitazone
• Sitagliptin, Vildagliptin,
Saxagliptin
Spectrum of Oral Hypoglycaemic Agents
• Biguanides
•Sulphonylureas
•-Glucosidase
inhibitors
•Meglitinide analogues
•Thiazolidinediones
DPPV-4 Inhibitors

Oral Therapy
Typically reduces HbA1c by 2-3 points
maximum
 Choosing an Oral Therapy
• Glucophage (Metformin)
– Increases sensitivity to endogenous insulin
– Decreases hepatic glucose production
– First line for obese patients
• Acarbose (Precose)
– Delays glucose absorption
• Sulfonylureas
– Increases release of endogenous insulin
– First line for non-obese patients
• Thiozolindinediones
– Increases insulin sensitivity

Glucophage
Advantages
– Minimal weight gain
– No added risk of hypoglycemia
 Adverse Effects
– GI upset common
– Lactic acidosis (uncommon but 50% mortality)
Starting Dose
– 500mg PO BID or 850mg PO QD
– Increase by 500mg Q Week

Glucophage
Contraindications
– Renal impairment: Creatinine > 1.5 for men and > 1.4
for women; (caution is warranted in elderly patients)
– Cardiac or respiratory insufficiency that is likely to
cause hypoxia or reduced tissue perfusion
– CHF
– History of lactic acidosis
– Surgery
– Severe infection that can lead to decreased tissue
perfusion
– Alcohol abuse sufficient to cause acute hepatic toxicity
– Use of IV radiocontrast agents

Glucophage
Others
Cidophage 500- Retard 850
Glucophage 500- 1000

Sulfonylureas
Includes:
– glipizide (Glucotrol/ minidiab 5),
– glimepiride (Amaryl /Dolcy),
– glyburide (Diabeta/Micronase)
- Glibenclamid (Daonil5 - Diaben 5)up to 3
- glicazid( Diamicron80 -MR30-60) antiplatles
Adverse Effects
– Hypoglycemia
–Weight gain

Thiozolindinediones
Includes:
– rosiglitazone (Avandia)
– pioglitazone (Actos / actozon 30- 45) 15:45
- Repaglinide (Diarol 0.5-1-2)
Contraindications
– Class III or IV CHF
– Baseline ALT > 2.5x normal
Adverse Effects
– Edema
– Weight Gain

Alpha Glucosidase inhbitors
Work on the brush border of the intestine
cause carbohydrate malabsorption
Advantages:
• Selective for postprandial hyperglycaemia
• No hypoglycaemic symptoms
Disadvantages:
• Abdominal Distension and flatus
• Only effective in mild hyperglycaemia

Alpha Glucosidase inhbitors
• Acarbose- 25 mg to 50mg thrice a day
• Miglitol- 25mg to 100mg thrice a day
• Voglibose- 0.2 to 0.3 mg thrice a day

Contraindications
• an inflammatory bowel disease, such as
ulcerative colitis or Crohn's disease; or any
other disease of the stomach or intestines
• ulcers of the colon
• Intestinal Obstruction
• kidney disease.

Sulphonylurea + Metformin
Includes:
– Glibenclamid+met500 (glucovance)
– Glyburid (Diavance 1.25-2.5-5)

Incretin concept
• Insulin secretion dynamics is dependent on
the method of administration of glucose
• Intravenous glucose gives a marked first and
second phase response
• Oral glucose gives less marked first and
second phase insulin response, but a
prolonged and higher insulin
concentration

Insulin secretion profilesInsulinconcentration
0 10 20 30 40 50 60 70 80 90
minutes
Glucose given orally
Glucose given intravenously

Iso-glycaemic profilesInsulinconcentration
0 10 20 30 40 50 60 70 80 90
minutes
Glucose given orally
Glucose given intravenously to
achieve the same profile
Incretin effect

What are the incretins?
• GIP: Glucose-dependent insulinotrophic polypeptide
Small effect in Type 2 diabetes.
• GLP-1(glucagon-like peptide 1)
augmented in the presence of hyperglycaemia.
Action less at euglycaemia and in normal subjects.
• Pituitary Adenylate Cyclase Activating Peptide (PACAP)

GLP-1 Modes of Action in Humans
GLP-1 is secreted
from the L-cells
in the intestine
This in turn…
•Stimulates glucose-dependent
insulin secretion
•Suppresses glucagon secretion
•Slows gastric emptying
Long term effects
demonstrated in animals…
•Increases beta-cell mass and
maintains beta-cell efficiency
•Reduces food intake
Upon ingestion of food…

Now for the bad News…………..

GLP-1 is short-acting
Modified from J Larsen et al: Diabetes Care 2001; 24:1416-1421
After 7 days
Control
Blood glucose
profiles
24-h/day GLP-1 s.c. infusion
16-h/day GLP-1 s.c. infusion
100
200
300
400
04 06 08 10 12 14 16 18 20 22 00 02 04 06
BloodGlucose
(mg/dl)
Time
400
100
200
300
04 06 08 10 12 14 16 18 20 22 00 02 04 06
BloodGlucose
(mg/dl)
Time

Dipeptyl- peptidase inhibitors
Sitagliptin
Vildagliptin
Saxagliptin
Septagliptin
Allogliptin

DPP-4 Inhibitors
• Sitagliptin (Januvia)
• Saxagliptin (Onglyza)
• Linagliptin ( Tradjenta)
Take once a day at the same time each day
Improves insulin level after a meal and lowers the
amount of glucose made by your body
Side effect
Stomach discomfort, diarrhea, sore throat, stuffy
nose, upper respiratory infection.

Comparing the Gliptins
Sitagliptin Vildagliptin Saxagliptin
Dosing OD BD OD
Renal Failure Approved Not Approved Approved
Hepatic Failure No info No info Safe
With Insulin Not Approved Approved Studies Pending
On Bone Improved BMD? Unknown Unknown
Infections Slight increase Neutral Neutral
UTI, URI
Cardiac Impact Reduced Neutral ?reduced CV mortality
post ischaemic stunning

Which is the appropriate oral hypoglycaemic agent to
use and when?

Mechanism of Action of Sitagliptin
Incretin hormones GLP-1 and GIP are released by the intestine
throughout the day, and their levels increase in response to a meal.
Concentrations of the active intact hormones are increased by sitagliptin, thereby increasing and
prolonging the actions of these hormones.
Release of
active incretins
GLP-1 and GIP  Blood glucose in
fasting and
postprandial states
Ingestion of
food
 Glucagon
(GLP-1)
 Hepatic
glucose
production
GI tract
DPP-4
enzyme
Inactive
GLP-1
XSitagliptin
(DPP-4
inhibitor)
 Insulin
(GLP-1 and
GIP)
Glucose-
dependent
Glucose
dependent
Pancreas
Inactive
GIP
β cells
α cells
 Glucose
uptake by
peripheral
tissues
30

Determinants of OAD usage
1)Body Mass Index : Metformin, Gliptins
BMI> 22kg/m2
2)Presence of GI symptoms: Sulpha, Gliptins, Glitazones
3)Renal Dysfunction: Gliptins,Glitazones(+/-),Sulpha (variable)
4) Aging Meglitinides, Gliptins(?)
5) Hepatic Dysfunction Nateglinide, Saxagliptin(?)
6) Compliance Gliptins, Glitazones,
7) Cost Metformin, Sulphas, Glitazones

Back to our patient
• During the next five years he was not compliant to
his medications despite
• having laser treatment for his left eye twice. And in
the last few months
• he noticed edema of his lower limbs.

Internal medicine
training session (2)
Dr. Ahmed Othman
Assistant lecturer of internal medicine,
Sohag university

Case study (2)
• A 32-year-old male with type 1 diabetes since the
age of 14 years was taken to the emergency room
because of drowsiness, fever, cough, diffuse
abdominal pain, and vomiting.
• Fever and cough started 2 days ago and the patient
could not eat or drink water.
• He has been treated with an intensive insulin
regimen (insulin glargine 24 IU at bedtime and a
rapid-acting insulin analog before each meal )

Case study (2)
• On examination he was tachypneic.
• His temperature was 39° C.
• pulse rate 104 beats per minute,
• respiratory rate 24 breaths per minute,
• supine blood pressure 100/70 mmHg;
• he also had dry mucous membranes, poor skin
turgor, and rales in the right lower chest. He was
slightly confused

Case study (2)
• Investigations:
• hemoglobin 14.3 g/dl ,
• white blood cell count 18,000/ μ l,
• glucose 450 mg/dl,
• creatinine 1.2 mg/dl ,
Na+ 152 mEq/L, PO 2 95 mmHg
K+ 5.3 mEq/L PCO 2 28 mmHg,
Cl- 110 mmol/L. HCO3 9 mEq/L
Arterial
pH
6.9 O2 sat 98%..

DKA Definition
DKA = 3 letters= triad of D K A
Diabetic
glucose >250 mg/dL (usually 500-800)
Keto
ketones produced
ketones – both in urine and in serum
acetoacetate, acetone, betahydroxybutyrate
fruity smell, not often encountered in real life)
consider that if these criteria aren’t met, it may not be DKA
Acidosis
Increased anion gap, metabolic acidosis; HCO3- <15, pH<7.30

Pathophysiology
Insulin
Counterregulatory hormones
Glucagon, Epinephrine, Cortisol,
Growth hormone
Normal

Pathophysiology
Excess
counterregulatory
hormones
Insulin deficiency
DKA

Etiology
• Insulin deficiency
Insulin missed dose
Pancreatitis
Heavy meal
• Excess Counterregulatory
hormones
• Infection i.e. Pneumonia
• MI
• Stroke
• Trauma
• Emotional
• Pregnancy
• Iatrogenic

Insulin Deficiency
Glucose uptake
Proteolysis
Lipolysis
Amino Acids
Glycerol Free Fatty Acids
Gluconeogenesis
Glycogenolysis
Hyperglycemia Ketogenesis
Acidosis
Osmotic diuresis
Polyuria
Polydipsia
Fruity breath (acetone smell)
Kussmaul breathing (acidotic)
Mental status changes
Dehydration
Dry tongue Tachycardia Hypotension Abd pain
Electrolyte imbalance
Clinical manifestations

Clinical manifestations
• Special notes
• Abdominal pain
It is more common in children than in adults
It is multifactorial
 dehydration of muscle tissue
 Delayed gastric emptying
 Ileus from electrolyte disturbances
 Metabolic acidosis;
It sometimes mimicks acute abdomen
It is classically periumbilical

Differential Diagnosis
• DD of acidotic breathing
– Renal failure
– Amonia increase in HCF
– Hysterical
• DD of diabetic coma
– Lactic acidosis
– Hyperosmolar non-ketotic coma
– Hypoglycemia
• DD of coma in general
• DD of acute abdomen

DKA vs. HHS
HHSDKA
More in elderlyMore in childrenAge
More in type IIMore in type IDM type
> 600> 250Glucose
+ or -+++++Ketonuria/emia
>7.3<7.3pH
>15<15HCO3
HyperosmolarityVariableS osmolarity
Sensitive to small
dose
VariableSensitivity to insulin

DKA vs. HYPOGLYCEMIA
HypoglycemiaDKA
Insulin overdose or
hyperinsulinemia
Insulin deficiency or increased
counter-reg hormones
Etiology
AcuteGradualOnset
-S of Brain glucopenia
- S of sympathetic overactivity
S of hyperglycemia
S of dehydration
S of acidosis
Symptoms and signs
hypoglycemiahyperglycemiaRBS
NoYesKetonuria
NoYesKetonemia
Rapidly recover if earlyNo effectIV glucose
Golden rule
Any diabetic patient with DKA versus hypoglycemia, give glucose
even before glucose measuring

Investigations
For diagnosis
Triad for diagnosis
1. RBS  Hyperglycemia > 250 mg/dl
2. Ketonemia and ketonuria
3. Blood gas metabolic acidosis
– pH < 7.35, anion gap (Na + K) – (Cl + Bicarb) > 10, and Bicarbonate <15
mEq/L

Investigations
For diagnosis
• Other findings
– Electrolyte serum level
• Hyperkalemia (rarely Hypokalemia), Hyponatremia (rarely
Hypernatremia )
– Investigation for the cause such as
• Urine Analysis, AMI panel and ECG, Chest x-ray
– Hyperosmolarity
• Normal = 285-295 milli-osmoles per kilogram (mOsmol/kg)
• [Glucose] and [BUN] are measured in mg/dL

Investigations
For Monitoring
• RBS
– Every 1 hour till RBS reaches 200 mg/dL or less,
then every 6 hours
• Urine ketones
– Every 8h
• Blood gas after fluid replacement
• Electrolyte serum level every 4 hours till correction

Treatment of DKA
• Treatment of predisposing factors
• Initial hospital management
– Care of comatosed patients
– Fluid and electrolytes replacement
– Insulin replacement and glucose administration
when needed
– Treatment of complications
• Once resolved
– Convert to home insulin regimen
– Prevent recurrence

Fluids and Electrolytes
• Fluid replacement
– Restores perfusion of the tissues
– Average fluid deficit 3-6 liters
• Initial resuscitation with saline
– 1 L of normal saline over the first ½ hour then
– 1 L of normal saline over ½ hour then
– ½ L of normal saline over 1 hour then
– ½ L of normal saline over 2 hours
– Then the rate will depend on clinical judge
(BP, CVP, basal lung crepitation)

• K+ level (check at 0,2,6,10,24 hr).
– If Hyperkalemia (> 5.5 meqlL)
• initially present
• No treatment as it resolves quickly with insulin drip
– If normal level (3.5-5.5 meqlL)
• Add 20-30 meql for each Liter of infused fluid
– If Hypokalemia (<3.5 meqlL)
• Add 40 meq for each Liter of infused fluid

• Phosphate deficit
– May want to use potassium phosphate
• Bicarbonate
– Not given unless pH <7 or bicarbonate <5 mmol/L or unresolved acidosis
after fluid replacement
– Dose (mmol of NaHco3) = -------------------------------------------
– Dose (No of ampoules of NaHco3) = ----------------------------------------
BW x Becar deficit
6
BW x Becar deficit
150

• Na level:
– Calculate the corrected Sodium (for each 100
mg/dL glucose above 100, add 1.6 meq/l to Na
level)
• If corrected Na is High or Normal  use Half NS
(250-1000 ml/hr)
• If corrected Na is Low  use NS, rate depends on
severity of volume depletion

Insulin Therapy
• Initial dose
– IV bolus of 0.1-0.2 units/kg (~ 10 units) regular insulin
– Infusion insulin at 0.1 units/kg/hr (max 8 units/hr).
• Maintenance dose (Check BG Q1hour, goal is 50-80
mg/dl/hr)
– If falling too rapidly, decrease the rate
– If falling too slowly increase the rate by 50-100%
• Continue IV insulin until urine is free of
ketones and RBS reaches 250-300 mg/dl

Insulin Therapy
• When RBS reaches 250-300 mg/dl
– Decrease the rate of insulin infusion to 0.05-0.1
IU/kg/hr (goal is to keep RBS in this range until the
gap closes (normal gap 7-8 mEq/l)
– then start home maintenance SC insulin
under umbrella of infused insulin for 2
hours, then continue on SC insulin only .

Glucose Administration
• Supplemental glucose
– Hypoglycemia occurs
• Insulin has restored glucose uptake
• Suppressed glucagon
– Prevents rapid decline in plasma osmolality
• Rapid decrease in insulin could lead to cerebral edema
• Glucose decreases before ketone levels decrease
• Start glucose when plasma glucose < 300
mg/dl

Insulin-Glucose Infusion for DKA
Blood glucose Insulin Infusion D5W Infusion
<70 0.5 units/hr 150 ml/hr
70-100 1.0 125
101-150 2.0 100
151-200 3.0 100
201-250 4.0 75
251-300 6.0 50
301-350 8.0 0
351-400 10.0 0
401-450 12.0 0
451-500 15.0 0
>500 20.0 0

Complications of DKA
• Infection
– Precipitates DKA
– Leukocytosis can be secondary to
acidosis
• Shock
– If not improving with fluids r/o MI
• Vascular thrombosis
– Severe dehydration
– Cerebral vessels
– Occurs hours to days after DKA
• Pulmonary Edema
– Result of aggressive fluid
resuscitation
• Cerebral Edema
– First 24 hours due to aggressive
correction of hypoglycemia or
administration of hypotonic
solution
– c/p: Mental status changes
– Tx: Mannitol
– May require intubation with
hyperventilation

Causes of Cerebral Edema
Mechanism:
• The brain adapts by producing intracellular osmoles (idiogenic
osmoles) which stabilize the brain cells from shrinking while the
DKA was developing.
• When the hyperosmolarity is rapidly corrected, the extracellular
fluids is corrected faster than brain cells
– The brain becomes more hypertonic than the extracellular fluids
 water flows into the cells  cerebral edema

Causes of Cerebral Edema
The many factors have been implicated:
 Rapid and/or sharp decline in serum osmolality with treatment.
 High initial corrected serum Na concentration.
 High initial serum glucose concentration.
 Failure of serum Na to raise as serum glucose falls during
treatment.
Glucose

Presentations of Cerebral Edema
Cerebral Edema Presentations include:
 Deterioration of level of consciousness.
 Headache and blurring of vision
 Vomiting
 Convulsion.

Treatment of Cerebral Edema
• Reduce IV fluids
• Raise foot of Bed
• IV Mannitol
• Elective Ventilation
• Dialysis if associated with fluid overload or renal
failure.
• Use of IV dexamethasone is not recommended.

Prevention of DKA
• Never omit insulin
– Cut long acting in half
• Prevent dehydration and hypoglycemia
• Monitor blood sugars frequently
• Monitor for ketosis
• Provide supplemental fast acting insulin
• Treat underlying triggers
• Maintain contact with medical team

Pitfalls in DKA
• Plasma glucose is usually high but not always
– DKA can be present with RBS < 300 due to
• Impaired gluconeogenesis
– Liver disease
– Acute alcohol ingestion
– Prolonged fasting
– Insulin-independent glucose is high (pregnancy)
• Chronic poor control but taking insulin
• Ketone in urine may be –ve in DKA, but always +ve in
blood
– Due to measurement of acetoacetic acid in urine
not, betahydroxybuteric acid
– Acetone in blood should be done in this case

Pitfalls in DKA
• High WBC may be present without infection
• Infection may be present without fever
• High Creatinine may be present without true renal
function: it may cross react with ketone bodies.
• Blood urea may be elevated with prerenal azotemia
secondary to dehydration.
• Serum amylase is often raised even in the
absence of pancreatitis

Case study (3)
A 82-year-old male patient was taken to the
emergency room in the afternoon for loss of
consciousness in the previous hour.
The patient had hypertension, chronic
ischemic heart disease, and mild diabetes
treated with glibenclamide daily.
On examination the patient had coma
(Glasgow scale 5) and right hemiplegia.

RBS of this patient is 30 mg/dl

Hypoglycemia or low blood glucose is a
clinical state associated with <55mg/dl or
low plasma glucose with typical
symptoms.

Whipples triad
1) Symptoms consistent with hypoglycemia
2) Low plasma glucose concentration
3) Relief of those symptoms after the plasma
glucose level is raised

Risk factors
insulin doses are excessive, ill-timed, or of the
wrong type
influx of exogenous glucose 
insulin-independent glucose utilization 
sensitivity to insulin 
endogenous glucose production 
insulin clearance 
The Journal of Clinical Endocrinology & Metabolism
March 1, 2009 vol. 94 no. 3 709-728

Clinical features
MILD HYPOGLYCEMIA
- mainly adrenergic or cholinergic symptoms
 Pallor
 Diaphoresis
 Tachycardia
 Palpitations
 Hunger
 Paresthesias

Clinical features
MODERATE HYPOGLYCEMIA (<40 mg/dL)
- mainly neuroglycopenic symptoms
 Inability to concentrate  Confusion
 Slurred speech  Irrational behaviour
 Slower reaction time  Blurred vision
 Somnolence  Extreme fatigue

Clinical features
SEVERE HYPOGLYCEMIA (<20 mg/dL )
 Associated with severe impairment of
neurologic function
 Completely disoriented behavior
 LOC
 Coma
 Seizures

Treatment
MILD HYPOGLYCEMIA
 Oral carbohydrates (at least 15gm)
 Sources include
• Three glucose tablets (5g each)
• 2 ½ cups of fruit juice
• ½ to ¾ cup regular soda
• 1 cup of milk
 If patient is unable to take orally give IV dextrose

Treatment
MODERATE TO SEVERE HYPOGLYCEMIA
 Dextrose - 50mL of 50% dextrose IV bolus followed by
10% dextrose
 Glucagon – 1mg IM or SC can be given
 Effective in treating hypoglycemia only if sufficient
liver glycogen present
 These measures raise blood glucose only transiently
 Patient is urged to eat as soon as possible

Prevention
 Patient education
 Knowing signs and symptoms of hypoglycemia
 Take meals on a regular schedule
 Carry a source of carbohydrate
 Self monitoring of blood glucose
 Take regular insulin at least 30 min before eating

First step into insulin
therapy
(How to start insulin in a patient not controlled on OADs)

Basal insulins
NPH
• Humulin N (Eli Lilly)
• Insulatard (Novo)
(also available as insulatard Novolet pen)
• Dongsulin N (Highnoon)
• Insuget N (Getz)
===========================================
Analogs
Glargine (Lantus)
Lantus Solostar Pen (Sanofi Aventis)
Detemir (Levimir) by Novo

Basal Insulins
Insulin Type Onset of
action
Peak of
action
Duration
of action
NPH Intermediate
acting
1-2 hours 5-7 hours 13-18
hours
Glargine
(Lantus)
Aventis
Long
acting
1-2 hours Relatively
flat
Upto 24
hours
Detemir
(Levimir)Novo
Long
acting
2-4 hours 8-12 hours 16-20
hours
The time course of action of any insulin may vary in different individuals, or at different times in
the same individual. Because of this variation, time periods indicated here should be considered
general guidelines only.

Bolous insulins
(Mealtime or prandial)
Human Regular
• Humulin R (Eli Lilly)
• Actrapid (Novo)
(Also available as Actrapid novolet pen)
• Dongsulin R (Highnoon)
• Insuget R (Getz)
==========================================
Analogs
• Lispro (Humolog) by Eli Lilly
• Novorapid by Novo
• Aspart
• Glulisine (Apidra) by Sanofi Aventis

Bolous insulins
(Mealtime or prandial)
Insulin Type Onset of
action
Peak of
action
Duration of
action
Human
regular
Short acting 30-60 minutes 2-4 hours 8-10 hours
Insulin
analogs
(Lispro,Aspart,
Glulisine)
Rapid acting 5-15 minutes 1-2 hours 4-5 hours
The time course of action of any insulin may vary in different individuals, or at
different times in the same individual. Because of this variation, time periods
indicated here should be considered general guidelines only.

Pre mixed
70/30 (70% N,30% R)
• Humulin 70/30 (Eli Lilly)
• Mixtard 30 (Novo)
(Also available as Mixtard 30 Novolet Pen)
• Dongsulin 70/30 (Highnoon)
• Insuget 70/30 (Getz)
===================================
Analogs
• Novomix 30 (Novo)
• Humolog Mix 25(Lilly)
• Humolog Mix 50(Lilly)

Types of Insulin
1. Rapid-acting
2. Short-acting
3. Intermediate-acting
4. Premixed
5. Long-acting
6. Extended long-acting
(Analogs)
(Regular)
(NPH)
(70/30)
(Lantus)

Indications for Insulin Use in Type 2 Diabetes
Pregnancy (preferably prior to pregnancy)
Acute illness requiring hospitalization
Perioperative/intensive care unit setting
Postmyocardial infarction
High-dose glucocorticoid therapy
Inability to tolerate or contraindication to oral antiglycemic agents
Newly diagnosed type 2 diabetes with significantly elevated blood
glucose levels (pts with severe symptoms or DKA)
Patient no longer achieving therapeutic goals on combination
antiglycemic therapy

Inadequate
Non pharmacological
therapy
1oral agent
2 oral
agents
3 oral
agents
Add Insulin Earlier in the Algorithm
•Severe symptoms
•Severe
hyperglycaemia
•Ketosis
•pregnancy
Proposed Algorithm of therapy for Type 2
Diabetes

First step into
Insulin therapy

Advantages of Insulin Therapy
• Oldest of the currently available
medications, has the most clinical
experience
• Most effective of the diabetes medications
in lowering glycemia
– Can decrease any level of elevated HbA1c
– No maximum dose of insulin beyond which a
therapeutic effect will not occur
• Beneficial effects on triglyceride and HDL
cholesterol levels
Nathan DM et al. Diabetes Care 2006;29(8):1963-72.

Disadvantages of Insulin Therapy
• Weight gain ~ 2-4 kg
– May adversely affect cardiovascular health
• Hypoglycemia
– However, rates of severe hypoglycemia in patients
with type 2 diabetes are low…
 Type 1 DM: 61 events per 100 patient-years
 Type 2 DM: 1-3 events per 100 patient-years

The ADA Treatment
Algorithm for the Initiation
and Adjustment of Insulin

Initiating and Adjusting Insulin
Continue regimen; check
HbA1c every 3 months
If fasting BG in target range, check BG before lunch, dinner, and bed.
Depending on BG results, add second injection
(can usually begin with ~4 units and adjust by 2 units every 3 days until BG in range)
Recheck pre-meal BG levels and if out of range, may need to add another
injection; if HbA1c continues to be out of range, check 2-hr postprandial levels
and adjust preprandial rapid-acting insulin
If HbA1c ≤7%...
Bedtime intermediate-acting insulin, or
bedtime or morning long-acting insulin
(initiate with 10 units or 0.2 units per kg)
Check FG and increase dose until in target range.
If HbA1c 7%...
Hypoglycemia
or FG >3.89 mmol/l (70 mg/dl):
Reduce bedtime dose by ≥4 units
(or 10% if dose >60 units)
Pre-lunch BG out of range: add
rapid-acting insulin at breakfast
Pre-dinner BG out of range: add NPH insulin at
breakfast or rapid-acting insulin at lunch
Pre-bed BG out of range: add
rapid-acting insulin at dinner
Target range:
3.89-7.22 mmol/L
(70-130 mg/dL)
Nathan DM et al. Diabetes Care. 2006;29(8):1963-72.
If HbA1c ≤7%... If HbA1c 7%...

Step One…
If HbA1c ≤7%...
If HbA1c 7%...
Hypoglycemia
Target range:
3.89-7.22 mmol/L
(70-130 mg/dL)
If HbA1c ≤7%... If HbA1c 7%...

Step One: Initiating Insulin
• Start with either…
– Bedtime intermediate-acting insulin or
– Bedtime or morning long-acting insulin
Insulin regimens should be designed taking
lifestyle and meal schedules into account

Step One: Initiating Insulin, cont’d
• Check fasting glucose and increase dose until
in target range
– Target range: 3.89-7.22 mmol/l (70-130 mg/dl)
– Typical dose increase is 2 units every 3 days, but if
fasting glucose >10 mmol/l (>180 mg/dl), can
increase by large increments (e.g., 4 units every 3
days)

• If hypoglycemia occurs or if fasting glucose <
3.89 mmol/l (70 mg/dl)…
– Reduce bedtime dose by ≥4 units or 10%
if dose >60 units
Step One: Initiating Insulin, cont’d
Reduction in overnight and fasting glucose levels achieved
by adding basal insulin may be sufficient to reduce
postprandial elevations in glucose during the day and
facilitate the achievement of target A1C concentrations.
While using basal insulin alone,never stop or reduce ongoing oral
therapy

• If HbA1c is <7%...
– Continue regimen and check HbA1c every 3
months
• If HbA1c is ≥7%...
– Move to Step Two…
After 2-3 Months…

With the addition of basal insulin and titration
to target FBG levels, only about 60% of
patients with type 2 diabetes are able to achieve
A1C goals < 7%.[36] In the remaining patients
with A1C levels above goal regardless of
adequate fasting glucose levels, postprandial
blood glucose levels are likely elevated.

If HbA1c ≤7%...
If HbA1c 7%...
Hypoglycemia
Target range:
3.89-7.22 mmol/L
(70-130 mg/dL)
If HbA1c ≤7%... If HbA1c 7%...
Step Two…

Step Two: Intensifying Insulin
If fasting blood glucose levels are in target range but
HbA1c ≥7%, check blood glucose before lunch, dinner, and
bed and add a second injection:
• If pre-lunch blood glucose is out of range,
add rapid-acting insulin at breakfast
• If pre-dinner blood glucose is out of range,
add NPH insulin at breakfast or rapid-acting insulin at
lunch
• If pre-bed blood glucose is out of range,
add rapid-acting insulin at dinner

Making Adjustments
• Can usually begin with ~4 units and
adjust by 2 units every 3 days until blood
glucose is in range
When number of insulin Injections increase from
1-2………..Stop or taper of insulin secretagogues
(sulfonylureas).

• If HbA1c is <7%...
– Continue regimen and check HbA1c every
3 months
• If HbA1c is ≥7%...
– Move to Step Three…
After 2-3 Months…

If HbA1c ≤7%...
If HbA1c 7%...
Hypoglycemia
Target range:
3.89-7.22 mmol/L
(70-130 mg/dL)
If HbA1c ≤7%... If HbA1c 7%...
Step Three…

Step Three:
Further Intensifying Insulin
• Recheck pre-meal blood glucose and if out of
range, may need to add a third injection
• If HbA1c is still ≥ 7%
– Check 2-hr postprandial levels
– Adjust preprandial rapid-acting insulin

Premixed Insulin
• Not recommended during dose adjustment
• Can be used before breakfast and/or dinner if the
proportion of rapid- and intermediate-acting
insulin is similar to the fixed proportions
available

Key Take-Home Messages
• Insulin is the oldest, most studied, and most effective
antihyperglycemic agent, but can cause weight gain
(2-4 kg) and hypoglycemia
• Insulin analogues with longer, non-peaking profiles
may decrease the risk of hypoglycemia compared with
NPH insulin
• Premixed insulin is not recommended during dose
adjustment

Key Take-Home Messages, cont’d
• When initiating insulin, start with bedtime intermediate-acting
insulin, or bedtime or morning long-acting insulin
• After 2-3 months, if FBG levels are in target range but HbA1c
≥7%, check BG before lunch, dinner, and bed,and, depending on
the results, add 2nd injection (stop sulfonylureas here)
• After 2-3 months, if pre-meal BG out of range, may
need to add a 3rd injection; if HbA1c is still ≥7% check 2-hr
postprandial levels and adjust preprandial rapid-
acting insulin.

First calculate total
daily dose of insulin
Body weight in kgs / 2
•e.g; an 80 kg person will require roughly about
40 units / day.

Dose calculation……..contd
Split the total calculated dose into 4 (four) equal s/c
injections.
–¼ of total dose as regular insulin s/c half-hour
( ½ hr ) before the three main meals with 6 hrs
gap in between.
–¼ total calculated dose as NPH insulin s/c at
11:00 p.m. with no food to follow.

Dose calculation: example
For example in an 80-kg diabetic requiring 40 units per day,
start with:
•08:00 a.m. --- 10 units regular insulin s/c ½ hr before
breakfast.
•02:00 p.m. --- 10 units regular insulin s/c ½ hr before lunch.
•08:00 p.m. --- 10 units regular insulin s/c ½ hr before dinner.
•11:00 p.m. --- 10 units NPH/ lantus insulin s/c

Dose adjustment
•For adjustment of dosage, check fasting
blood sugar the next day and adjust the
dose of night time NPH Insulin
accordingly i.e. keep on increasing the
dose of NPH by approximately 2 units
daily until you achieve a normal fasting
blood glucose level of 80-110 mg/dl.

Control BSF by adjusting
the prior the dose of NPH

Dose adjustment…contd.
• Once the fasting blood glucose has been
controlled, check 6-Point blood sugar as
follows:
– Fasting.
– 2 hours after breakfast.
– Before lunch (and noon insulin)
– 2 hours after lunch.
– Before dinner (AND EVENING INSULIN)
– 2 hours after dinner

Dose adjustment…contd.
• Now control any raised random reading by
adjusting the dose of previously
administered regular insulin.
• For example: a high post lunch reading will
NOT be controlled by increasing the dose
of next insulin (as in sliding scale), rather
adjustment of the pre-lunch regular insulin
on the next day will bring down raised
reading to the required levels.

Examples
•For the following profile:
–Blood sugar fasting = 180
mg/dl
–Blood sugar after breakfast =
250 mg/dl.
–Blood sugar pre lunch = 190
mg/dl
–Blood sugar post lunch 270 =
mg/dl
–Blood sugar pre dinner = 200
mg/dl
–Blood sugar post dinner 260 =
mg/dl
•We need to increase the dose
of NPH at night to bring
down baseline sugar level
(BSF) to around 100 mg/dl
after which the profile should
automatically adjust as
follows:
–Blood sugar fasting = 100
mg/dl
–Blood sugar 02 hrs after
breakfast = 170 mg/dl
–Blood sugar pre-lunch =
110
mg/dl
–Blood sugar 2 hrs. after
lunch = 190 mg/dl
–Blood sugar pre-dinner =
120 mg/dl
–Blood sugar 2 hrs. post
dinner = 180 mg/dl

Examples……contd.
•Blood sugar fasting = 130 mg/dl
•Blood sugar after breakfast = 160 mg/dl
•Blood sugar pre-lunch = 130 mg/dl
•Blood sugar post lunch = 240 mg/dl
•Blood sugar pre-dinner = 180 mg/dl
•Blood sugar 2 hrs. post dinner = 200 mg/dl
•This patient needs adjustment of pre-lunch regular
Insulin which will bring down post lunch and pre dinner
readings within normal limits.
•2 hrs post dinner blood sugar(200 mg/dl) will be
brought down by adjusting pre dinner regular insulin.

Combinations
•In types 2 subjects, once the blood
sugar profile is normalized and the
patient is not under any stress, the
total daily dose (morning + noon +
night + NPH at 11 p.m) may be
divided into two 12 hourly injections
of premixed Insulin

Examples….contd.
•e.g-1; If a patient is
stabilized on
•10U R + 12U R +
10U R + 12U NPH;
•then he may be
shifted to
•44/2 = 22 units of
70/30 Insulin 12
hourly s/c ½ hr before
meal.
•e.g-2; If the
adjusted Insulin is
•14U R+16U R+12U
R+8U NPH,
•then split the total
dose:
30 U 70/30 before
breakfast and 20U
70/30 before dinner
to compensate for the
high morning and lunch
Insulin.

Combinations………contd.
•Problem: Remember that BD dosing usually fails to
cover lunch, especially if it is heavy. So:
•Always check for post lunch hyperglycemia when using
this regimen.
•Solution:
.1Patients can be advised to take their lunch (heavier
meal) at breakfast; and breakfast (lighter meal) at
lunch.
.2Adding Glucobay with lunch some times provides a
reasonable control.
.3An alternate combination to overcome the problem is
regular insulin for morning and noon, with premixed
insulin at night.

Example
•10U R before breakfast + 12U R
before lunch + 22U 70/30 before
dinner.
•Insulin will be injected exactly 6 hrs
apart as in the QID regimen.

Choice of regimens
.1R+ R+ R+ L****
.2R+ R+ R+ N ***
.3R+ R+ premixed insulin**
.4BD premixed insulins*

How to start pre mixed (70/30)
Insulin

For pre mixed insulins(70/30 preparations)
Step1:First calculate the total daily starting requirement
of insulin;
body weight(kg)/2
eg, For a 60kg patient,total daily dose =30 units
Step 2:Then devide this dose into 3 equal parts;
10+10+10
Step 3:Give 2 parts in the morning and 1 part in the
evening;
Morning=20U Evening=10 U

Dose titration of Pre-mixed(70/30)
preparations

You can increase or decrease the dose of
pre-mixed insulin by 10 % i.e
If the patients is using,
1-10 units…………….+/- 1 unit
11-20 units……………+/- 2 units
21-30 units……………+/- 3 units
31-40 units……………+/- 4 units…………………..

Advantages and disadvantages of
premixed insulins

Advantages:
Easy to administer for the
physician.
Easy to fill and inject by the
patient.
Provides both basal and bolus
coverage with fewer number of
injections.

Disadvantage:
No dose flexability
If u increase/decrease the dose of one
component ,the dose of other
component is also changed un
desirably

How to solve the problem of
nocturnal hypoglycemia

Somogyi phenomenon
• Due to
– excess dose of night time insulin, or
– Night insulin taken early
• Peaks at 3:00 a.m: hypoglycemia
• Counter regulatory hormones released in excess:
• Resulting in over correction of hypoglycemia:
• Fasting hyperglycemia
• Solution:
– Check BSL AT 3 :00 a.m
– Give long acting at 11:00 p.m so peak comes
later
– Reduce dose of night time insulin

Dawn phenomenon
• Growth hormone surge at dawn raises insulin
requirement.
• Night time insulin taken early, fades out before
dawn.
• Fasting hyperglycemia
Solution
• Give long acting insulin not before 11 :00 p.m
• May need to increase dose of night time insulin

Sites of injection
•Arms 
•Legs 
•Buttocks 
•Abdomen 

Sites of injection…….contd.
• Preferred site of injection is the
abdominal wall due to
• Easy access
– Ample subcutaneous tissue
• Absorption is not affected by exercise.

Technique
• Tight skin fold
• Spirit…. X
• Appropriate needle size
• 90 degree angle
• Change site to avoid lipodystrophy

Injection
technique…….contd.
INSTRUCTIONS:
Keep the needle perpendicular to skin in order to
avoid variability in absorption (fig-A)
Insert needle upto the hilt (fig-A)
Distribute daily injections over a wide area to avoid
lipodystrophy and other local complications (fig-B)

Storage
• Injections: refrigerate
• Pens: do not refrigerate

Shelf life
•One month
once opened

Thank you all
For
Sparing your valuable time
&
Patient listening

CME Sohag | internal medicine | Diabetes mellitus

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