DIABETES MELLITUS

BY
K R A I R AT K O M D E E , M D .
D E PA R T M E N T O F I N T E R N A L M E D I C I N E
P H AYA O H O S P I TA L

T O P I C T O D AY
Classification
Screening
Diagnosis
Evaluation
Management

DIABETES MELLITUS
a group of metabolic disease characterised by

hyperglycemia

resulting from defects

in insulin secretion, insulin action, or both
chronic hyperglycemia of diabetes is ass. with

dysfunction, and failure of various organs, especially

the eyes, kidneys, nerves, heart, and blood vessels

C L A S S I F I C AT I O N
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

C L A S S I F I C AT I O N
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

C L A S S I F I C AT I O N
Other specific type ( <1%)
Genetic defects of B-cell function ; MODY (Maturity-Onset Diabetes of the Young)
Genetic defects in insulin action ; insulin receptor gene mutation, Rabson-Medenhall

syndrome, familial partial lipodystrophy

Pancreatic disorders ; pancreatectomy, chronic pancreatitis, fibrocalculous pancreatopathy,

hemochromatosis
Endocrinopathies ; ass with acromegaly, cushing syndrome, pheochomocytoma, PCOS,

hyperthyroidism
Drug- or chemical-induced ; glucocorticoids, thiazide, protease inhibitors, antipsychotic drugs
Infections
Other genetic syndrome sometimes ass. With diabetes; Downs syndrome, Klinefelters

syndrome, Turners syndrome, Wolfrans syndrome

C L A S S I F I C AT I O N
Gestational diabetes mellitus (GDM)
Hyperglycemia 1st diagnosed in pregnancy
Diagnosis made by OGTT

R I S K FA C T O R S O F D E V E L O P I N G D I A B E T E S
st

Family history; 1 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

S C R E E N I N G O F D I A B E T E S I N A D U LT
Indication:
1. Age 35 years old esp.
2. BMI 25kg/m2 with family history of DM2
3. HT, DLP
4. Hx of GDM or hx of giant baby
5. IGT or IFG
6. Hx of CVD

CRITERIA FOR DIAGNOSIS OF DIABETES

FPG 126 mg/dl.

Fasting is defined as no caloric intake for at least 8 hr
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
FA S T I N G
NORMAL

2-HR

(AFTER 75-GLUCOSE)

<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

T Y P E 1 A N D 2 D M : C L I N I C A L C O M PA R I S O N

F E AT U R E S

TYPE 1

TYPE 2

AGE OF ONSET

<20

>30

ONSET

SUDDEN

GRADUAL

STRUCTURE

THIN

OBESE

DKA

DIABETES IN
F A M I LY

OTHER

Lab : C-peptide testing with glucagon or mixed

meal test

G E S TAT I O N A L D I A B E T E S M E L L I T U S ; G D M
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 !

resistance

increase insulin

May normal after delivery or turn to DM type 2

R I S K F A C T O R S F O R G E S TAT I O N A L
DIABETES MELLITUS
>25 years of age
Overweight or obese state
Family history of diabetes mellitus (ie, in a irst-degree 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 2-hour
Postprandial glucose concentration >140 mg/dL (indicates need to perform a 75-g oral glucose

tolerance test)

I / C F O R S C R E E N I N G AT 1 S T A N C
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

Fasting hyperglycemia

or pre-pandial
hyperglycemia

Post-pandial

hyperglycemia

No chronic

complication

Chronic complication
!

M AT U R I T Y- O N S E T D I A B E T E S O F T H E
YOUNG; MODY
Age < 25
AD; 3 generation
No sign or clinical of autoimmune
No obesity
Insulin secretion impairment
No insulin resistance

D I S T I N C T I V E F E AT U R E S O F M O D Y
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

C O R R E L AT I O N B E T W E E N A 1 C A N D M E A N
PLASMA GLUCOSE LEVELS
HbA1C

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 modifications :
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

Major Pathophysiologic Defects in Type 2 Diabetes

Islet-Cell Dysfunction
Glucagon
( cell)

Pancreas

Insulin
( cell)

Hepatic
glucose
output

Insulin
resistance

Glucose uptake
Hyperglycemia
Muscle

Liver

Adipose
tissue

Kahn CR, Saltiel AR. In: Kahn CR et al, eds. Joslins Diabetes Mellitus. 14th ed. Lippincott Williams & Wilkins; 2005:145168.

Development and Progression of Type 2 Diabetes

and Related Complicationsa
Progression of Type 2 Diabetes Mellitus
Insulin resistance
Hepatic glucose
production
Insulin level
Beta-cell function
47 years

Postprandial
glucose
Fasting plasma glucose

Development of Microvascular Complications

Development of Macrovascular Complications
Impaired Glucose Tolerance

Frank Diabetes

Diabetes Diagnosis
Reprinted from Primary Care, 26, Ramlo-Halsted BA, Edelman SV, The natural history of type 2 diabetes.
Implications for clinical practice, 771789, 1999, with permission from Elsevier.

aConceptual

representation.

MANAGEMENT OF DIABETES
MELLITUS

S TA N D A R D O F C A R E F O R P E O P L E W I T H
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

P H A R M A C O L O G I C TA R G E T S O F C U R R E N T
D R U G S U S E D I N T H E T R E AT M E N T O F T 2 D M
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

Biguanides
Increase glucose uptake
and decrease hepatic
glucose production

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

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

-glucosidase inhibitors
Delay intestinal carbohydrate
absorption

Target Sites for Different Oral Drug Classes

Used in Type 2 Diabetes
Pancreatic -cells

Increase insulin secretion

SU (eg glimepiride)
Meglitinides/D-Phenylalanine derivatives
(eg, repaglinide, nateglinide)
Muscle and Adipose Tissue

Liver

Increase glucose uptake

Decrease glucose production

Ways to reduce
hyperglycemia
Biguanides (eg metformin)
TZDs (eg, rosiglitazone)

TZDs (eg rosiglitazone)

Biguanides (eg, metformin)

Gut

Delay intestinal
carbohydrate absorption

-glucosidase inhibitors
(eg, acarbose)

TZD = thiazolidinediones Adapted from Inzucchi SE. JAMA 2002;287:360372.

ANTI-DIABETIC AGENTS
Agent

Advantages

Sulfonylureas Inexpensive, extensive

experience
Reduce postprandial blood

Disadvantages
Weight gain, hypoglycemia

Repaglinide

Expensive, multiple daily dose,

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

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 renal
failure

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

SGLT2inhibitor

>>>

>>>

At Diagnosis

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

HbA1C < 8% and/or

FPG < 180 mg/dL

Oral hypoglycemic agent

Metformin

Sulfonylurea

Insulin resistance (BMI >23, central obesity, BP

>130/85 or on antiHTN, elevated TG, low HDLC) ,Elevated TG, low HDL-C, Acanthosis nigricans

Insulin deficiency (BMI <23, severe

hyperglycemia, postprandial hyperglycemia)

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

FPG 180-250 mg/dL

Potential cumulative benefit: ~2 percentage point reduction inHbA1c

Any individual may have both insulin deficiency and insulin resistance

COMBINE DRUG GUIDE

1ST DRUG

FPG 250-350 mg/dL

HbA1c > 9%

METFORMIN

SULFONYLUREA

A D D I T I O N D R U G 1. S U L F O N Y L U R E A 1. M E T F O R M I N
OR GLINIDE
2. T Z D
2. T Z D
3. D D P - 4
3. D D P - 4
INHIBITOR
INHIBITOR
4. B A S A L I N S U L I N
4. B A S A L I N S U L I N
A LT E R N AT I V E D R U G : A L P H A - G L U C O S I D A S E I N H I B I T O R

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Combination Oral Agent and insulin Stage

Morning FPG >300 mg/dL or A1C>11% and hyperglycaemic
symptom: Continue OAS; add BT G or N
Potential cumulative benefit: 2-4 percentage point reduction in
HbA1c

Combination Oral Agent and insulin Stage

Morning FPG >300 mg/dL or A1C>11% and hyperglycaemic
symptom: 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

Treat to Target

Physiologic Insulin (4 Injections)

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 bi-directional; patients move in
either direction between therapies.
5. Consider insulin sensitizers when insulin dose is >
0.7 U/kg.

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

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

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A L G O R I T H M F O R T H E M E TA B O L I C M A N A G E M E N T O F T Y P E 2 D M

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;31:1-11