Updated for

Diabetes
Mellitus
Krairat Komdee, MD.
Department of Internal Medicine
Phayao Hospital

Outline
Classification
Screening
Diagnosis
Evaluation
Management

Diabetes mellitus
A group of metabolic diseases characterized by
hyperglycemia
Resulting from defects
in insulin secretion, insulin action, or both

The chronic hyperglycemia of diabetes is ass.

with dysfunction, and failure of various organs,
especially the eyes, kidneys, nerves, heart, and
blood vessels

Classification
Type 1 diabetes mellitus (5-10%)
-cell destruction, usually leading to
absolute insulin deficiency; immune
mediated, idiopathic
Juvenile onset, IDDM, type I
Auto-immune disease
Pancreas is unable to produce insulin
Generally diagnosed from birth to age 30,
highest incidence between 12-18 years of
age

Classification
Type 2 diabetes mellitus (90-95%)
may range from predominantly insulin
resistance with relative insulin deficiency
to a predominantly secretory defect with
insulin resistance
Adult onset, NIDDM, type II
Disorder ass. with obese and aging process
Generally diagnosed after age 40

Classification
Other specific type ( <1%)
Genetic defects of B-cell funtion; MODY
Genetic defects in insulin action
Disease of the exocrine pancreas
Endocrinopathies
Drug- or chemical-induced
Infections
Other genetic syndrome sometimes ass. With diabetes;
Downs syndrome, Klinefelters syndrome, Turners
syndrome, Wolfrans syndrome
Gestational diabetes mellitus (GDM)
Hyperglycemia 1st diagnosed in pregnancy
Diagnosis made by OGTT

Risk Factors of Developing

Diabetes
Family history; 1st degree relative with diabetes
Physical inactivity
Previous IGT or IFG = Impaired glucose
homeostasis
Previous GDM or baby > 4 kg
Hypertension ; BP 140/90 mm.Hg
HDL 35mg/dl, TG 250mg/dl
Overweight or obese
Polycystic ovary syndrome; PCOS
Acanthosis nigricans
History of vascular disease
Sedentary lifestyle

Screening of Diabetes in
adult
Indication:
1. Age 45 years old esp. BMI 25kg/m2
(if normal, then repeat q 3 years)
2. Asymptomatic and BMI 25kg/m2 with
risks of having diabetes (if normal, then
repeat q 1-2 years)

Criteria for diagnosis of diabetes

FPG 126 mg/dl.
Fasting is defined as no caloric intake for at least 8 h
Symptoms of hyperglycemia and a casual plasma glucose
200 mg/dl.
Casual is defined as any time of day without regard to
time since last meal
The classic symptoms of hyperglycemia include
polyuria, polydipsia, and unexplained weight loss.
2-h plasma glucose 200 mg/dl during an OGTT
Using a glucose load containing the equivalent of 75 g
anhydrous glucose dissolved in water

Diagnosis of Diabetes
Fasting

2-hour
(after 75-glucose)

Normal

< 100

< 140

IGT

< 126

140-199

IFG

100 - 125

<140

DM

126

200

2 or more abnormal values are required for diagnosis

AACE Diabetes Mellitus Guidelines, Endocr Pract.
2007;13(Suppl 1) 2007

IGT VS IFG
Impaired glucose tolerance
Impaired fasting glucose

Impaired Fasting Glucose

FPG 100 mg/dl
Normal fasting glucose

FPG 100125 mg/dl

IFG

FPG 126 mg/dl

Provisional diagnosis of diabetes
For diagnosis must be confirmed

Oral Glucose Tolerance Test

2-h postload glucose 140 mg/dl
Normal glucose tolerance

2-h postload glucose 140199 mg/dl

IGT ; impaired glucose tolerance

2-h postload glucose 200mg/dl

Type 1 and 2 DM : Clinical

comparison

Features

Type 1

Type 2

Age of onset

< 20

30

Onset

Sudden

Gradual

Structure

Thin

Obese

Others

DKA

Diabetes in family

Lab : C-peptide testing with glucagon or

mixed meal test

Gestational Diabetes Mellitus;

GDM
Recommendations from the ADA use
Carpenter/Coustan diagnostic criteria as well as
the alternative use of a diagnostic 75-g 2-h OGTT
Human placentral lactogen increase insulin
resistance
May normal after delivery or turn to DM type 2

Risk Factors for Gestational Diabetes

Mellitus
>25 years of age
Overweight or obese state
Family history of diabetes mellitus (ie, in a irstdegree relative)
History of abnormal glucose metabolism
History of poor obstetric outcome
History of delivery of infant with a birth weight
>4kg
History of polycystic ovary syndrome
Latino/Hispanic, nonHispanic black, Asian
American, Native American, or Paciic Islander
ethnicity
Fasting (no energy intake for at least 8 hours)
plasma glucose concentration >85 mg/dL or 2hour
Postprandial glucose concentration >140 mg/dL

I/C for screening at 1st ANC

Family history of DM
Obese
Hx of baby > 4000 gm
Age > 35 yrs
Hx of perinatal death
Glucosuria
Hypertension
Multiparity
Hx of GDM
Hx of recurrent abortion
Hx of congenital deformity

Screening
GCT
50 gms of glucose then CBG at 1hr if >
140mg/dl OGTT

OGTT
NPO 10-12 hrs
100 gms of glucose
Plasma glucose before 1hr then q 1 hr after
glucose ingestion x 3 times
Positive more than 2 Dx

Diagnosis of GDM
State at plasma glucose
measurement

Plasma glucose
concentration; mg/dl

Fasting

> 95 mg/dl

1-hour

> 180

2-hour

> 155

Two or more of the listed venous plasma glucose concentrations must be met
or exceeded for a positive diagnosis.
The test should be performed after an overnight fast of 8 to 14 hours and after
at least 3 days of unrestricted diet (ie,
150 g carbohydrate per day) and unlimited physical activity

GDM vs DM before Pregnancy

20 wks of pregnancy
Post-pandial
hyperglycemia
No chronic
complication

Fasting hyperglycemia
or pre-pandial
hyperglycemia
Chronic complication

Maturity-Onset Diabetes of the

Young; MODY
Age < 25
AD; 3 generation
No sign or clinical of autoimmune
No obesity
Insulin secretion impairment
No insulin resistance

Distinctive features of MODY

Transcription factor

Extrapancreatic features

HNF1A (MODY 3)

Glycosuria
Raised HDL

HNF1B (MODY 5)

Renal cysts
PKD
Renal impairment
Uterine and genital
abnormalities
Hyperuricemia
Short stature

IPF-1 (MODY 4)

Pancreatic agenesis with

homozygous mutation

Correlation between A1C and

mean plasma glucose levels
HbA1C
6

Mean plasma glucose

(mg/dl)
135

170

205

240

10

275

11

310

12

345

Prevention of Type 2 Diabetes

Mellitus
Initiate interventions include lifestyle
modiications :

Weight reduction goal: 5% to 10% of total

body weight
Nutrition goals:
reduce fat intake to less than 30% of total
energy intake
reduce saturated fat intake to less than
10% of total energy intake
increase fiber intake to 15 g/1000 kcal

Prescribe regular physical activity (approx

150 min per wk)
Counsel patients with prediabetes mellitus
about CV risk factors such as tobacco use,
hypertension, and dyslipidemia

Management of
Diabetes Mellitus

Standard of care for people with

diabetes
Goal
Pre-prandial plasma glucose (mg/dl)

< 110

Post-prandial plasma glucose

< 140

HbA1C

< 6.5 - 7%

Blood Pressure (mmHg)

< 130/80

Lipids
LDL-cholesterol (mg/dl)

< 100

Triglycerides

< 150

HDL

> 40

Anti-Diabetic Drug

Major Classes of Antidiabetic

Drugs
1.Drugs that stimulate
pancreas to make more
insulin

Sulfonylureas
Meglitinides

2.Drugs that sensitize

insulin action

Thiazolidinediones
Biguanides

3.Drugs that slow the

absorption of starches

Alpha-glucosidase
inhibitors

4.Drugs that enhance

incretin effects

GLP-1 R agonists
DPP-IV inhibitor

5.Insulin
6.New drug atc at ECS

Ribonamont

At Diagnosis

HbA1C < 8% and/or

FPG < 200 mg/dL

Lifestyle Modification (Medical Nutrition and

Exercise)
If blood glucose targets not achieved within 3
months, move to Oral Agent Stage
Potential cumulative benefit: ~1 percentage point
reduction in HbA1c

Oral hypoglycemic agent

Metformin
Insulin resistance (BMI >23,
central obesity, BP >130/85 or on
antiHTN, elevated TG, low HDL-C)

FPG 200-300 mg/dL

Sulfonylurea
Insulin deficiency (BMI <23,
severe hyperglycemia,
postprandial hyperglycemia)

Alternative drugs; TZD or repaglinide or -GI or DPP-4 inhibitor

Potential cumulative benefit: ~2 percentage point reduction inHbA1c
Any individual may have both insulin deficiency and insulin
resistance

FPG 250-350 mg/dL

HbA1c > 9%

.. 2551

Combination Oral Agent Stage

Current therapy: Add Oral Agent:
Sulfonylurea:
Metformin, TZD, or basal insulin
Metformin:
Sulfonylurea, Repaglinide, TZD, or
basal insulin
Alternative drugs:
-GI or DPP-4 inhibitor
Consider triple combination therapy (SU +
Metformin + Thaizolidenedione)
Combination Oral Agent and insulin Stage
Morning FPG >300 mg/dL: Continue OAS; add BT G
or N
Potential cumulative benefit: 2-4 percentage point
reduction in HbA1c

HbA1C >11% and/or

FPG >300 mg/dL +
symptomatic
hyperglycemia

.. 2551
Combination Oral Agent and insulin Stage

Treat to Target
1. Target of treatment is HbA1c <7%
2. Monthly improvement is SMBG of
15-30 mg/dl and/or HbA1c of 0.5-1.0
% is considered significant
improvement.
3. Continue with lifestyle
modification throughout all stages
of therapy.
4. This Decision path is bidirectional; patients move in either
direction between therapies.
5. Consider insulin sensitizers when
insulin dose is > 0.7 U/kg.

Abbreviation for Insulin

RA=Rapid Acting
(Lispro or Aspart)
N=NPH

R=Regular
G=Glargine
O=None

Dose Schedule: AM-Midday-PM-hs

RA RA RA G

Morning FPG >300 mg/dL: Continue OAS; add BT G

or N
Potentialc umulative benefit: 2-4 percentage point
reduction in HbA1c

Physiologic Insulin (4 Injections)

Or refer to endocrinologist
RA RA RA - G or N
Optional R R R G or N
Begin single injection of G at bed time (alternatively at
breakfast) or N at bedtime; and RA or R before meals as
needed based on patterns of elevated post-meal
glucose values
Potential cumulative benefit: >4 percentage point
reduction in HbA1c

Insulin Therapy (2
Injections)
RA/N 0-RA/N-0
R/N-0-R/N-0
If persistent AM
hyperglycemia or
nocturnal hypoglycemia,
start insulin therapy (3
injections); if need more
flexibility or intensified
regimen, start physiologic
insulin
Potential cumulative
benefit: >4 percentage
point reduction in HbA1c

Insulin Therapy (3
Injections) or refer to
endocrinologist
If persistent
midafternoon
hyperglycemia , need
more flexibility and/or
intensified insulin
regimen, start
physiologic insulin
Potentialc umulative
benefit: >4 percentage
point reduction in HbA1c

Algorithm for the metabolic management of type 2 DM

At
diagnosis:
Lifestyle
+
Metformin

STEP 1

Lifestyle + Metformin
+
Basal insulin

Lifestyle +
Metformin
+
Intensive insulin

Lifestyle + Metformin
+
sulfonylurea
STEP 2

STEP 3

Lifestyle + Metformin
+
Pioglitazone
No hypoglycemia
Edema/CHF
Bone loss

Lifestyle +
Metformin
+
Pioglitazone
+
sulfonylurea

Lifestyle + Metformin
+
GLP-1 agonist
No hypoglycemia
Weight loss
Nausea/vomiting

Lifestyle +
Metformin
+
Basal insulin

Consensus statement of ADA and EASD. Diabetes Care 2008;31:1-1

Pharmacologic Targets of Current

Drugs Used in the Treatment of
T2DM

GLP-1 analogs
Improve pancreatic islet glucose
sensing, slow gastric emptying,
improve satiety

DPP-4 inhibitors
Prolong GLP-1 action leading to
improved pancreatic islet glucose
sensing, increase glucose uptake

Thiazolidinediones
Decrease lipolysis in
adipose tissue, increase
glucose uptake in
skeletal muscle,
decrease glucose
production in liver

Biguanides
Increase glucose
uptake
and decrease hepatic
glucose production

Sulfonylureas
Increase insulin
secretion from
pancreatic -cells
Glinides
Increase insulin secretion
from pancreatic -cells

-glucosidase inhibitors
Delay intestinal
carbohydrate absorption

DDP-4=dipeptidyl peptidase-4; GLP-1=glucagon-like peptide-1; T2DM=type 2 diabetes mellitus

Adapted from Cheng AY, Fantus IG. CMAJ. 2005; 172: 213226.
Ahrn B, Foley JE. Int J Clin Pract. 2008; 62: 814.

Oral Hypoglycemic Agents

Sulfonylurea
Glyburide/
Glibenclamide

1.23 5 mg od

20 mg divided to
twice daily

Administer once daily

doses with breakfast or
first main meal
Doses >10 mg/d should
be divided and given
twice daily

Glipizide

5 mg once daily;
2.5 mg once daily in
elderly patients

40 mg in 2
divided doses

Administer once daily

doses 30 min before
breakfast or after first
main meal
Doses >15 mg/d should
be divided and given
twice daily

Glimepiride
(Amaryl)

1 to 2 mg once daily

8 mg once daily

Administer with breakfast

or first main meal

Action of Sulfonylureas

Oral Hypoglycemic Agent

Glinides (Short-Acting Secretagogues)

Repaglinide

Elderly patients and patients

not previously treated with
hypoglycemic agents or
patients with HbA1c
<8%:Give 0.5 mg three times
daily
Patients previously treated
with hypoglycemic agents or
those with HbA1c >8%: Give
1 to 2 mg three times daily

16 mg/d

Administer 15 to
30 min before
each meal

Oral Hypoglycemic Agent

-Glucosidase Inhibitors
Acarbose
(Precose)

25 mg three 100 mg
times daily
three times
daily

Administer with first

bite of each main
meal
Dosage should be
gradually increased
as tolerated over
several weeks

Biguanides
Metformin 500 mg
2550 mg in 3 Administer with
twice daily
divided
meals
or 850 mg
doses
once daily in
Maximum effective
the morning
dose is 2000 mg/d

Oral Hypoglycemic Agent

Thiazolidinediones
Pioglitazone
(Actos)

15 or 30 mg 45 mg once
once daily
daily

Rosiglitazone 4 mg once
(Avandia)
daily or 2
mg twice
daily

8 mg once daily
or 4 mg twice
daily

Administer with or
without food
Administer with or
without food

New drugs for Treat DM

Considration for Oral Therapy in

Patients with Type2 DM

Considration for Oral Therapy in

Patients with Type2 DM

Effect of Oral Therapies on HbA1C

Levels in Patients with DM

Anti-diabetic agents
Agent

Advantages

Disadvantages

Sulfonylureas

Inexpensive, extensive
experience

Weight gain, hypoglycemia

Repaglinide

Reduce postprandial blood

Expensive, multiple daily
glucose, Lifestyle flexibility
dose, weight gain, long-tern
usable in renal failure; mild to efficacy/safety data lacking
moderate

Metformin

CV benefit, improved multiple

cardiovascular risk ,weight
loss, low risk of hypoglycemia
,inexpensive

GI side effects, rare lactic

acidosis

Glitazones

More sustained glucose

control, reduced
macrovascular
risk(pioglitazone only) , low
risk of hypoglycemia,
reduced atherosclerosis
progression(PROACTIVE
study), improve multiple CV
risk, reduced
microalbuminuria, Usable in

Expensive, weight gain, heart

failure, peripheral edema,
increase risk of distal
fractures in women

Anti-diabetic agents
Agent

Advantages

Disadvantages

glucosidase
inhibitor

Weight neutral, low risk of

hypoglycemia

GI side effects,multiple
daily dose

Insulin

Most effective

Inconvenience,
hypoglycemia

DDP-IV
inhibitor

Weight neutral to weight

loss, no hypoglycemia,
usable for CKD

Expensive, possible link to

pancreatitis

GLP-1 analog Weight loss, low risk of

hypoglycemia

Expensive, subcutneous
form inconvenience,
possible link to
pancreatitis

ECS
blockage

Expensive, problem with

psychiatric patient

Effect on multiple organ,

improve CMR factor; no
hypoglycemia, increase
HDL, decrease LDL

Starting and adjustment of insulin

Start with bedtime
intermediate-acting insulin
or bedtime or morning
long-acting insulin 10U or
0.2U/kg
Increase dose by 2U every 3
days
Target FBG 70-130 mg/dl
If FBG 70-130 and HbA1C > 7%
Check premeal and bedtime Blood glucose

High pre-lunch BG
Add rapid-acting
insulin at
breakfast

High pre-dinner BG
Add NPH at
breakfast
Or rapid-acting
insulin at lunch

High pre-bedtime
BG
Add rapid-acting
insulin at dinner

Endocannabinoid system
is a modulatory system
Endocannabinoids:
Synthesized on demand
from lipid precursors in
postsynaptic cell
Activate CB1 receptors
presynaptically, then
degraded immediately
Act as retrograde
messengers
Inhibit neurotransmitter
release

CB1 receptors:
Play a key role in energy
balance and lipid and
glucose metabolism
Di Marzo V et al, 2005; Di Marzo V et al, 1998;
Wilson R et al, 2002

Sites of CB1 receptors and potential effects of

CB1 receptor blockade
Site of action

Mechanism(s)

Addresses

Hypothalamus /
Nucleus accumbens

Food intake

Body weight
Intra-abdominal adiposity

Adipose tissue

Adiponectin
Lipogenesis

Dyslipidaemia
Insulin resistance

Muscle

Glucose uptake

Insulin resistance

Lipogenesis

Dyslipidaemia
Insulin resistance

Satiety signals

Body weight
Intra-abdominal adiposity

Liver
GI tract