D I A B E T E S M E L L I T U S

B Y 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

D I A B E T E S M E L L I T U S

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 (

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

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

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

C R I T E R I A F O R D I A G N O S I S O F D I A B E T E S

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

D I A G N O S I S O F D I A B E T E S

FA S T I N G 2 - H R ( A F T E R 7 5 - G L U C O S E )

N O R M A L < 1 0 0 < 1 4 0

I G T < 1 2 6 1 4 0 - 1 9 9

I F G 1 0 0 - 1 2 5 < 1 4 0

D M 1 2 6 2 0 0

2 or more abnormal values are required for diagnosis

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

I G T V S I F G

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

O R A L G L U C O S E T O L E R A N C E T E S T

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 T Y P E 1 T Y P E 2

A G E O F O N S E T < 2 0 > 3 0

O N S E T S U D D E N G R A D U A L

S T R U C T U R E T H I N O B E S E

O T H E R D K AD I A B E T E S I N

FA M I LY

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 ! increase insulin resistance

May normal after delivery or turn to DM type 2

R I S K FA C T O R S F O R 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

>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

S C R E E N I N G 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

D I A G N O S I S O F G D MState at plasma glucose measurement

Plasma glucose concentration; mg/dl

Fasting > 95 mg/dl

1-hour > 180

2-hour > 155Two 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

G D M V S D M B E F O R E P R E G N A N C Y

20 wks of pregnancy

Post-pandial hyperglycemia

No chronic complication

!

!

Fasting hyperglycemia or pre-pandial hyperglycemia

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 Y O U N G ; M O D Y 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 FeaturesHNF1A (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 P L A S M A G L U C O S E L E V E L S

HbA1C Mean plasma glucose (mg/dl)

6 135

7 170

8 205

9 240

10 275

11 310

12 345

P R E V E N T I O N O F T Y P E 2 D I A B E T E S M E L L I T U S 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

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

Hepatic glucose output

Insulin resistance

Glucagon ( cell)

Insulin ( cell)

Liver

Hyperglycemia

Islet-Cell Dysfunction

MuscleAdipose tissue

Pancreas

Glucose uptake

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.

Development and Progression of Type 2 Diabetes and Related Complicationsa

aConceptual representation.

Insulin level

Insulin resistance

Hepatic glucose production

Postprandial glucose

Fasting plasma glucose

Beta-cell function

Progression of Type 2 Diabetes Mellitus

Impaired Glucose Tolerance

Diabetes Diagnosis

Frank Diabetes

47 years

Development of Macrovascular ComplicationsDevelopment of Microvascular Complications

M A N A G E M E N T O F D I A B E T E S M E L L I T U S

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 D I A B E T E S

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

-glucosidase inhibitors Delay intestinal carbohydrate absorption

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

Sulfonylureas Increase insulin secretion from pancreatic -cells

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

Biguanides Increase glucose uptake and decrease hepatic glucose production

DDP-4=dipeptidyl peptidase-4; GLP-1=glucagon-like peptide-1; T2DM=type 2 diabetes mellitusAdapted from Cheng AY, Fantus IG. CMAJ. 2005; 172: 213226.Ahrn B, Foley JE. Int J Clin Pract. 2008; 62: 814.

Glinides Increase insulin secretion from pancreatic -cells

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

Target Sites for Different Oral Drug Classes Used in Type 2 Diabetes

Ways to reduce hyperglycemia

Biguanides (eg metformin) TZDs (eg, rosiglitazone)

TZDs (eg rosiglitazone) Biguanides (eg, metformin)

GutDelay intestinal

carbohydrate absorption

SU (eg glimepiride) Meglitinides/D-Phenylalanine derivatives (eg, repaglinide, nateglinide)

Pancreatic -cells Increase insulin secretion

LiverDecrease glucose production

-glucosidase inhibitors (eg, acarbose)

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

Muscle and Adipose TissueIncrease glucose uptake

A N T I - D I A B E T I C A G E N T SAgent Advantages Disadvantages

Sulfonylureas Inexpensive, extensive experience

Weight gain, hypoglycemia

RepaglinideReduce postprandial blood glucose, Lifestyle flexibility usable in renal failure; mild to moderate

Expensive, multiple daily dose, weight gain, long-tern efficacy/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

A N T I - D I A B E T I C A G E N T S

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 analogWeight loss, low risk of hypoglycemia

Expensive, subcutneous form! inconvenience, possible link to pancreatitis

SGLT2-inhibitor

>>> >>>

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

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 < 8% and/or FPG < 180 mg/dL

FPG 180-250 mg/dL

At Diagnosis

Oral hypoglycemic agentMetformin Sulfonylurea

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

Insulin deficiency (BMI 9%

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C O M B I N E D R U G G U I D E

1 S T D R U G M E T F O R M I N S U L F O N Y L U R E A

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 O R G L I N I D E

2. T Z D 3. D D P - 4

I N H I B I T O R 4. B A S A L I N S U L I N

1. M E T F O R M I N 2. T Z D 3. D D P - 4

I N H I B I T O R 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

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

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

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

HbA1C >11% and/or FPG >300 mg/dL +

symptomatic hyperglycemia

Treat to Target

1. Target of treatment is HbA1c 0.7 U/kg.

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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

Lifestyle + Metformin +

Basal insulin

Lifestyle + Metformin +

sulfonylurea

At diagnosis: Lifestyle

+ Metformin

Lifestyle + Metformin +

Intensive insulin

Lifestyle + Metformin +

Pioglitazone No hypoglycemia Edema/CHF Bone loss

Lifestyle + Metformin +

GLP-1 agonist No hypoglycemia Weight loss Nausea/vomiting

Lifestyle + Metformin +

Pioglitazone +

sulfonylurea

Lifestyle + Metformin +

Basal insulin

STEP 1 STEP 2 STEP 3

Consensus statement of ADA and EASD. Diabetes Care 2008;31:1-11