DIABETES

MELLITUS
Dr. Indika Karunamuni
MBBS (Colombo)

DEFINITION
a syndrome of disordered metabolism and inappropriate hyperglycemia
secondary to an absolute/ relative deficiency of insulin, or a reduction
in biological effectiveness of insulin, or both.

INTRODUCTION
World pandemic with a trend of declining age of onset
Prevalence in Sri Lanka is 20.3% in men and 19.8% in women in urban
setting in 2013.
Around 1.5 million Sri Lankan adults suffer from diabetes ; the number
expected to rise up to 2.1 million by the year 2030
Leading cause for myocardial infarction , stroke, chronic kidney
disease, blindness and amputations in adults

TASK
Evidence based multiple risk
factor approach
Patient centered self
management approach
Multidisciplinary support

Early intensive glycemic control

- Decreases microvascular
complications
- Improves cardiovascular
outcomes

GLUCOSE
REGULATION

PHYSIOLOGICAL GLUCOSE SECRETION

In healthy subjects , insulin release is exact to meet the metabolic
demands.
Capillaries surrounding islets, show a remarkable number of fenestrae
that allows for a greater nutrient exchange.
This structure enhances permeability, so that - cells can sense the
nutritional state quickly.

PHYSIOLOGICAL GLUCOSE SECRETION

- cells respond to many nutrients in
the blood circulation, including glucose,
other monosaccharides, amino acids
and fatty acids but amplitude of insulin
secretion is much larger by glucose.
Oral ingestion of 75 g of glucose will
cause plasma insulin to rise from a
basal level of 2030 pmol/L to 250300
pmol/L in 30 min, while intake of a
similar amount of fat or a fat plus
protein diet will only increase plasma
insulin levels to 50 and 60 pmol/L

MEAL TIME INSULIN

In addition to the 24 hour background insulin secretion, there is a
burst of insulin at every meal- often called the bolus.
Whenever glucose is released to the blood stream from food, a
matching release of insulin is required for up to two hours in order to
move glucose into cells.
How long this increased insulin level is needed depends on the type of
carbohydrate, its glycaemic index, and the fat content of the meal

PHASES OF INSULIN SECRETION

Insulin secretion shows a characteristic biphasic pattern

a transient first phase (In response to a meal,

there is a rapid and sizable release of preformed
insulin from storage granules within the beta
cell)
a sustained second phase ( basal)

PHASES OF INSULIN SECRETION

The second phase secretion provides the 50% of the total daily
insulin and maintains basal level.
This basal insulin suppresses lipolysis, proteolysis, and glycogenolysis.
The "first phase" of insulin secretion promotes peripheral utilization of
the prandial nutrient load, suppresses hepatic glucose production, and
limits postprandial glucose elevation

 First-phase insulin secretion begins within 2 minutes of nutrient

ingestion and continues for 10 to 15 minutes.
The second phase of prandial insulin secretion follows, and is sustained
until normoglycemia is restored.

INCRETINS
Incretinsare a group of metabolic hormonesthat stimulate a decrease
in blood glucose levels. Incretins do so by causing an increase in the
amount of inslinreleased from pancreaticbeta cellsof the islets of
Langerhans after eating, beforeblood glucoselevels become elevated.
They also slow the rate of absorption of nutrients into the blood stream
by reducing gastric emptying and may directly reduce food intake.
They also inhibit glucagon release from the alphaof the islets of
Langerhans.

The two main candidate

molecules that fulfill criteria
for an incretin are the
intestinalpeptides glucagonlike peptide-I (GLP-1)
andgastric inhibitory peptide.
Both GLP-1 and GIP are rapidly
inactivated by the enzyme
dipeptidyl peptidase- 4 (DPP-4)

GIP and GLP-1 secreted,

respectively, by K and L cells in
the gut

When the extracellular

glucose concentration
is in the normal fasting
range (lower than 4 m
mol/L), GLP-1 is inactive
in stimulating insulin
secretion.
Such glucosedependent action of
GLP-1 is very important
in preventing
hypoglycemia

ETIOLOGIC CLASSIFICATION OF DM

TYPE 2 DIABETES
It is characterized by insulin resistance and a progressive loss of betacell function.
The ability to secrete adequate amounts of insulin is determined by the
functional integrity of beta-cells and their overall mass
Glucose, the main regulator of insulin secretion and production, exerts
negative effects on beta-cell function when present in excessive
amounts over a prolonged period

TYPE 1 DIABETES
In addition to progressive beta cell destruction, there is abnormal alpha cell
function with excess glucagon secretion
HLA DR-DQ genotypes can be used at birth to predict risk for islet
autoimmunity and type1 diabetes
GAD 65, IA-2 or Zn T8 predict type 1 diabetes- 90% (glutamic acid
decarboxylase (GAA or GAD) and protein tyrosine phosphatase (IA2 or ICA512)
Triggers for formation of antibodies is unknown
There are environmental factors viruses, cows milk
Rapid gastric emptying is a feature

MODY( MATURITY ONSET DIABETES OF

YOUNG )
2 -4 % of all the diabetes
Is an disorder with diabetes mellitus , classically characterized by:
Age of onset les than 25 years
Three generation family history with sibblilng involvement
Generally Non- insulin requiring initially
Generally thought to be monogenic
Usually associated with a non- obese state

BETA-CELL DESTRUCTION
Both T1D and T2D are characterized by progressive -cell destruction
Apoptosis is the main form of cell destruction.
Hyperglycemia may negatively affect beta-cell mass by inducing
apoptosis without a compensatory increase in beta-cell proliferation and
neogenesis
In T1D, -cell loss is caused by an autoimmune reaction
A decrease in both mass and insulin secretary function of -cells is the
common characteristic shared in both type 1 and type 2 diabetic patients

BETA-CELL DESTRUCTION
Both T1D and T2D are characterized by progressive -cell destruction
Apoptosis is the main form of cell destruction.
Hyperglycemia may negatively affect beta-cell mass by inducing
apoptosis without a compensatory increase in beta-cell proliferation and
neogenesis
In T1D, -cell loss is caused by an autoimmune reaction
A decrease in both mass and insulin secretary function of -cells is the
common characteristic shared in both type 1 and type 2 diabetic patients

GLUCOTOXICITY & LIPOTOXICITY

Glucotoxicity refers to the structural and functional damage in the beta
cells and target tissues of insulin, caused by chronic hyperglycemia.
These alterations cause a lower hormonal secretion and action (insulin
resistance).
Lipotoxicity refers to the damage caused by persistently high free fatty
acid levels, as a consequence of triacylglycerol catabolism

INSULIN RESISTANCE
Obesity is a leading pathogenic factor for developing insulin resistance
Always associated with impairment in energy metabolism, causing
increased intracellular fat content in skeletal muscle, liver and fat, as
well as pancreatic islets
Chronic insulin resistance will progress to T2D when -cells are unable
to secret adequate amounts of insulin to compensate for decreased
insulin sensitivity

INSULIN RESISTANCE

CONT

Insulin resistance is observed in a variety of conditions including

gestational diabetes, obesity, impaired glucose tolerance (IGT) and
polycystic ovarian syndrome.
Although obesity is associated with T2D, most obese people dont
develop the disease
Increased insulin secretion due to enhanced function of pre-existing cells or expansion of -cell mass compensates and restores blood
glucose levels

DIABETES MELLITUS
TYPE 1 AND II COMPARISON

Type I

Type
Type III

DIABETES MELLITUS
TYPE 1 AND II
Comparison

DIAGNOSTIC
CRITERIA
American Diabetes
Association
2016

SCREENING
American Diabetes
Association
2016

GLYCEMIC CONTROL GLYCEMIC TARGETS

More stringent HbA1c targets (6
6.5%) might be considered in
selected patients.

HbA1c

<7.0 %

Pre-prandial
capillary
Plasma glucose

70 130 mg/dl
(3.9 7.2 mmol/L)

Peak post
prandial capillary
plasma glucose

< 180 mg/dl

(< 10 mmol/L)

- Short disease duration

- Long life expectancy
- No significant CVD
- Before conception in women

Diabetes Mellitus : Glucose Control, Sri

Lanka Journal of Diabetes, Endocrinology
and Metabolism 2013;3:45-57

GLYCEMIC CONTROL GLYCEMIC TARGETS

Less stringent HbA1c targets
( 7.5 8.0%) is appropriate for
patients with

HbA1c

<7.0 %

Pre-prandial
capillary
Plasma glucose

70 130 mg/dl
(3.9 7.2 mmol/L)

Peak post
prandial capillary
plasma glucose

< 180 mg/dl

(< 10 mmol/L)

- Severe hypoglycemia
- Limited life expectancy
- Advanced complications
- Extensive co-morbid conditions

Diabetes Mellitus : Glucose Control, Sri

Lanka Journal of Diabetes, Endocrinology
and Metabolism 2013;3:45-57

Self Monitoring of Blood Glucose

(SMBG)
MONITORING OF
CONTROL
Ideally a combination of
HbA1c and self monitoring
with capillary glucose will give
optimal results.

Monitoring by the patient using a

glucometer
Recommended for pts on multiple insulin
doses or insulin pump therapy
The practice of monitoring glucose control
with a monthly FBG is suboptimal and has
many limitations

HbA1c
MONITORING OF
CONTROL

HbA1c should be measured by a NGSP

certified method

Ideally a combination of
HbA1c and self monitoring
with capillary glucose will give
optimal results.

(NGSP National Glycohaemoglobin

Standardization Programm)

HbA1c : Frequency
Stable every 6 months

MONITORING OF
CONTROL
Ideally a combination of
HbA1c and self monitoring
with capillary glucose will give
optimal results.

Inadequate 3 monthly

HbA1c can be used to check accuracy of

SMBG results & adequacy of testing schedule

HbA1c : Limitations
MONITORING OF
CONTROL
Ideally a combination of
HbA1c and self monitoring
with capillary glucose will give
optimal results.

In pts with haemoglobinopathy or high red

cell turnover, values may be discordant with
clinical status

Self monitoring is recommended in pts who

have high glycemic

TREATMENT OF TYPE 2 DIABETES

Nonpharmacological

Life Style Modifications

- Changing dietary habits
- Physical activity
- Cessation of smoking

Pharmacological

Pharmacotherapy

MEDICAL NUTRITION THERAPY

Should be individualized and ideally given by a trained health professional
Weight loss is recommended (at least 5 10%) for all overweight or obese
individuals
Calorie restricted diet is recommended for weight loss
Routine supplementation with antioxidants and vitamins is not
recommended
Alcohol is best avoided (If taking < 2 units for men , < 1 unit for women)

PLATE PLANNER

Diabetic Diet ?

PHYSICAL ACTIVITY
Moderate intensity aerobic physical activity
At least 150 min/week

30 minutes x 5 days

- spread over at least 3 days per week

- With no more than 2 consecutive days without exercise
For obese at least 60 minutes a day is recommended

Resistance training is recommended at least twice a week

PATIENT EDUCATION
Offer structured education to every person and/or their carer at and
around the time of diagnosis, with annual reinforcement and review.
Offer group education programmes as the preferred option.
Ensure the patient-education programmes available meet the cultural,
linguistic, cognitive and literacy needs in the locality .

INITIATION OF PHARMACOTHERAPY
Metformin is the preferred first line oral therapy unless contraindicated.
- Long standing evidence base for efficacy, safety and cardiovascular risk prediction
At diagnosis, monotherapy with metformin along with life style interventions is the preferred
choice as most patients can not achieve recommended targets on life style interventions alone
If FPG > 200 mg/dl at diagnosis consider starting with two drugs
In the presence of severe hyperglycemia (> 300 mg/dl) consider treatment with dual/triple
therapy or with insulin
Consider insulin therapy if there are severe symptoms or complications
Early combination therapy is preferred than prolonged monotherapy in achieving glycemic
targets

Healthy eating, weight control, increased physical activity & diabetes education

Monotherapy

Metformin

Efcacy*

high
low risk
neutral/loss
GI / lactic acidosis
low

Hypo risk
Weight
Side effects
Costs

If HbA1c target not achieved after ~3 months of monotherapy, proceed to 2-drug combination (order not meant to denote
any specific preference - choice dependent on a variety of patient- & disease-specific factors):

Dual
therapy
Efcacy*
Hypo risk
Weight
Side effects
Costs

Metformin

Metformin

Sulfonylurea

Thiazolidinedione

DPP-4
inhibitor

SGLT2
inhibitor

GLP-1 receptor
agonist

Insulin (basal)

high
moderate risk
gain
hypoglycemia
low

high
low risk
gain
edema, HF, fxs
low

intermediate
low risk
neutral
rare
high

intermediate
low risk
loss
GU, dehydration
high

high
low risk
loss
GI
high

highest
high risk
gain
hypoglycemia
variable

Metformin

Metformin

Metformin

Metformin

If HbA1c target not achieved after ~3 months of dual therapy, proceed to 3-drug combination (order not meant to denote
any specific preference - choice dependent on a variety of patient- & disease-specific factors):

Metformin

Triple
therapy

Sulfonylurea

+
TZD

Metformin

Thiazolidinedione

SU

Metformin

Metformin

DPP-4
Inhibitor

SGLT-2
Inhibitor

SU

SU

Metformin

GLP-1 receptor
agonist

Metformin

Insulin (basal)

+
TZD

SU

or

DPP-4-i

or

DPP-4-i

or

TZD

or

TZD

or

TZD

or

DPP-4-i

or

SGLT2-i

or

SGLT2-i

or

SGLT2-i

or

DPP-4-i

or

Insulin

or

SGLT2-i

or

Insulin

or

Insulin

or GLP-1-RA

or GLP-1-RA

or

or

Insulin

or GLP-1-RA

Insulin

If HbA1c target not achieved after ~3 months of triple therapy and patient (1) on oral combination, move to injectables, (2) on GLP-1 RA, add
basal insulin, or (3) on optimally titrated basal insulin, add GLP-1-RA or mealtime insulin. In refractory patients consider adding TZD or SGL T2-i:

Metformin

Combination
injectable
therapy

Basal Insulin +

Mealtime Insulin or

GLP-1-RA

BENEFICIAL EFFECTS OF INCRETINS

Decrease glucagon secretion
Decrease gastric emptying
Increased satiety due to delayed gastric emptying
Lower blood pressure and favorable lipid profile
Well tolerated
No hypoglycemia
Weight neutral

INCRETIN BASED THERAPIES REGISTERED IN

SRI LANKA
GLP-1 Receptor agonists (subcutaneous injections)
- Liraglutide
DPP-4 Inhibitors (oral)
- Sitagliptin
- Saxagliptin
- vildagliptin

SGLT 2 INHIBITORS( SODIUM GLUCOSE CO

TRANSPORTER 2 INHIBITORS)
Reduces glucose reabsorption in the proximal tubule leading to urinary
glucose excretion and osmotic diuresis
Demonstrated reduction in body weight and visceral obesity as add on
benefit
Demonstrated reduction in blood pressure as add on benefit
Reduction of renal hyperfiltration (potential nephron-protective effect)

SGLT 2 : KETOACIDOSIS

INTIATION OF INSULIN THERAPY :

BENEFITS OF INSULIN BEYOND GLYCEMIC
CONTROL

Reduces glucotoxicity

Improves lipid profile

Reduces lipotoxicity

Correct endothelial dysfunction

Reverses insulin resistance

Has anti-inflammatory effects

Preserves beta cell function

Posses anti-platelet effect

Improves quality of life

PREDICTORS OF EARLY INSULIN USE

High A1C
Younger age
Lower BMI
High serum creatinine
Short duration of disease at time of 2nd OHA addition
smoking

INDICATIONS FOR INSULIN THERAPY

Type 1 diabetes
Pregnancy/ lactation
T2DM in special situations- renal and hepatic diseases, pancreatitis,
during surgery, infections etc.
In T2DM, inadequately controlled on OHAs ,after using of optimal doses
of 2 -3 drugs

TYPES OF AVAILABLE INSULIN

Short / rapid acting insulins:
- Regular Human Insulin
- Analogues ( Lispro, Aspart, Glulisine)
- Inhaled insulin

Basal Insulins:
- Intermediate human : NPH
- long acting Analogues : Glargine, Detemir, Degludec

Premix:
- Regular + NPH
- Analogue pre mix ( protamine added)
- Analogue pure pre mix - RYZODEG

SHORT ACTING INSULIN - REGULAR

Regular insulin because of its slow rate of absorption is unable to mimic
physiological insulin secretion following a meal.

INTERMEDIATE ACTING INSULIN: NPH

NPH is modified into a suspension to delay its absorption from
subcutaneous sites, thereby prolonging its action.
When given at appropriate time, it is effective in lowering fasting
plasma glucose and pre- dinner glucose levels.

LONG ACTING INSULIN ANALOGUES: DETEMIR

AND GLARGINE
With virtually constant insulin action for upto 24 hours, these insulins
provide the closet to an ideal basal insulin supply
Have minimal activity peak

PREMIX INSULIN THERAPY

Consists of premix human insulin or premix insulin analogue in ratio of
30: 70 and 50:50
Rapid / short acting component ( 30% or 50%) augments background
insulin levels.
This may take care of fasting ,prandial & HbA1c with a single insulin

INSULIN PREPARATION - TIMELINE

WHAT DO THE GUIDELINES STATE ABOUT

WHEN TO START INSULIN THERAPY?
All guidelines suggest insulin as an option for initial therapy in those
with very high A1c
(> 9 10%), especially with symptoms.

INITIATION OF INSULIN THERAPY

Start with Basal insulin day time Sulphonylurea regimen (BIDS)
Keep the oral agents and add bed time basal Insulin (isophane or long
acting insulin analogues- Glargine, Detemir, Degludec
Starting dose is 6-10 units ( 0.1-0.2U /kg) . But higher doses can be used in
severe hyperglycemia ( 0.3-0.4U/kg)
Adjust doses by 1-2 U to the daily dose, once or twicea week until target
FPG is achieved

INITIATION OF INSULIN THERAPY

Basal insulin will counteract hepatic glucose output between meals and
overnight

Most individuals with type 2 diabetes will achieve adequate control with
the addition of basal insulin alone

 In-range fasting plasma glucose with one or both:

Persistently elevated post-prandial glucose(>180 mg/dL).
A1c above target.
Average type 2 DM patient requires 0.5 units/kg basal insulin.
Higher doses (>0.5 units/kg) strongly suggest need for mealtime
insulins.
Further increases in basal insulin cause daytime or nighttime
hypoglycemia.

PRACTICAL TIPS HOW TO USE MEALTIME

INSULIN
Use rapid-acting analogs, not regular insulin:

Less postprandial hypoglycemia

Can be taken up to 15-20 minutes after start eating

Start with 1 shot, at the largest meal:

4 units, and uptitrate.

Titrate to:

<160-180 mg/dL 2 hours post-prandial OR

<130 mg/dL next meal or bedtime

Add a second and third prandial insulin injection if needed for

complete daytime BG control.

SIMPLER TITRATION ALGORITHMS

Algorithm 1: 1 IU increase once daily, if fasting plasma glucose [FPG] >
target
Algorithm 2: 2 IU increase every 3 days, if FPG > target
Algorithm 3: treat-to-target, generally 28 IU increase weekly based on
2-day mean FPG levels
Target FPG 100 mg/dL
Lower incidence of hypoglycemia

RECOMMENDATIONS FOR STARTING AND

ADJUSTING PRANDIAL INSULIN THERAPY
4 units short-acting insulin OR
10% basal dose before largest meal

Maximum PPG (<180 mg/dL)

or premeal/bedtime (<130 mg/dL)
Increase dose 1-2 units or 10-15%
once-twice weekly BG target met.

Hypoglycemia: address
cause and lower dose 2-4
units or 10-20%.

Consider reducing the basal insulin dose by 0.1 unit/kg if A1c <8.
A common recommendation is a lower postprandial glucose target (<160 mg/dL)
Inzucchi SE et al. Diabetes Care 2015;38:140-149.

SPILT-MIXED INSULIN
Twice a day or thrice a day (thrice a day if analogue insulin is used)
Dosed according to patients need
15 minutes before meals

PRE MIXED INSULINS - EXAMPLES

Mixtard 30
Humulin
Aalogues : - Humalog Mix, Novomix 30

BARRIERS FOR INSULIN USE

PATIENT RESISTANCE

PHYSICIAN RESISTANCE

Compliance issues

Lack of resources

Fear of scars

Time to plan and follow up

intensive therapy

Administration difficulties

Perceived and real ADR

-Weight gain
-Hypoglycemia

OVERVIEW OF INSULIN PRODUCTS

http://www.slideshare.net/abahnassi/a-quick-review-of-available-insulinproducts/5

INSULIN PENS

ACUTE COMPLICATIONS
Hyperglycemic comatose status
- Diabetic Ketoacidosis (DKA)
- Hyperosmolar Hyperglycemic state (HHS)

MACROVASCUCLAR COMPLICATIONS
Increased risk of CAD, ischemic strokes and peripheral arterial disease
secondary to accelerated atherosclerosis.

- CAD is the leading cause of death in type 2 diabetes

MICROVASCULAR COMPLICATIONS
Diabetic retinopathy
Diabetic nephropathy
Diabetic neuropathy

CLINICAL PRESENTATION OF DIABETIC

NEUROPATHY

OTHER COMPLICATIONS
Dermatology
- Diabetic dermopathy : atrophic brown spots in pretibial region, known as shin spots.
secondary to increased glycosylation of tissue proteins and vasculopathy
- Eruptive xanthomas
- Necrobiosis lipodica diabeticorum thinning of skin over the shin allowing visualization of
subcutaneous vessles
Bone and joint disease : Dupuytrens contractures , Adhesive capsulitis, juvenile
cheiroarthropathy, bone demineralization
Cataracts
Infections

SPECIAL TOPICS
Diabetes in pregnancy
Diabetes in Children
Diabetes in Older Adults
Diabetes and CKD
Diabetes Management in Hospital Settings

Metabolic Syndrome
Pre Diabetes

ALSO KNOW
Statins and anti platelet use in diabetes patients
Hypoglycemia

THANK YOU