Endokrin

ETIOLOGIC CLASSIFICACTION

I. Type 1 (ß-cell destruction leading to absolut deficiency)

A. Immune mediated
B. Idiopathic

II. Type 2
• Predominantly insulin resistance + relative insulin
deficiency
• Predominantly secretory defect + insulin resistance

III. Other specific types

IV. Gestasional diabetes mellitus

Type 1 + Type 2 = 70 – 95% of diabetes

ADA. The Expert Committee,1997

DWS 2010
 Type 1 Type 2
Clinical Features
• Age at onset Usually < 30 Usually > 40
• Onset Acute Insidious
• Weight Non obese Obese
• Spontaneous ketosis Common Rare
• Chronic complication (++) (++)
Epidemiology
• Prevalence 0,5% 2%
• Sex Male prepdominancece Female predominance
Insulin (C-petide) level ↓↓ / (-) ↓/N/
Genetics
• Concordance in twins 40% 70 – 90%
• HLA asoociation (+) (DR3/DR4) (-)
Pathology
• Islet cell mass Severely reduced Moderately reduced
• Insulitis at onset Present ?
Immunology
• Associated with other Frequent Frequent
endocrinopathy
• Anti-islet ell immunity 60 – 80% at onset 5 – 20%
Humoral 35 – 50% at onset < 5%
Cell mediatedl

DWS 2010
 Criteria Diagnosis of Diabetes Mellitus
.
1. Symptoms (+)
Casual plasma glucose > 200 mg%
(11.1 mmol/L)

or
2. FPG  126 mg% (7.0 mmol/L)

2. During OGTT
2h post 75 g glucose load  200 mg/dl
DWS 2010
Fasting at least 8 h (The Expoert Committee,1997)
 Diagnosis Criteria of Hyperglycemia

Normal IFG or IGT Diabetes

FPG IFG : FPG ≥ 126 mg/dl

< 100 mg/dl FPG ≥ 100; < 126 mg/dl 2-hPG ≥ 200 mg/dl
FPG ≥ 100; < 126 mg/dl Symptoms of
2-hPG < 140 mg/dl diabetes and causal
2-hPG IGT : plasma glucose
< 140 mg/dl FPG < 106 mg/dl concentration
2-hPG ≥ 140; < 200 mg/dl ≥ 200 mg/dl
 (Type 2) Diabetes is NOT a mild disease
Stroke
Diabetic 2 to 4 fold increase in
cardiovascular mortality
Retinopathy and stroke3
Leading cause
of blindness
in working age Cardiovascular
adults1
Disease
8/10 diabetic patients
die from CV events4

Diabetic
Nephropathy Diabetic
Leading cause of
Neuropathy
end-stage renal disease2 Leading cause of non-
traumatic lower
extremity amputations5

1 Fong DS, et al. Diabetes Care 2003; 26 (Suppl. 1):S99–S102. 2Molitch ME, et al. Diabetes Care 2003; 26 (Suppl. 1):S94–S98.
3 Kannel WB, et al. Am Heart J 1990; 120:672–676. 4Gray RP & Yudkin JS. In Textbook of Diabetes 1997.
5Mayfield JA, et al. Diabetes Care 2003; 26 (Suppl. 1):S78–S79.
 Pathogenic Mechanisms of Type 2
Diabetes

-Cell dysfunction Insulin resistance

-Cell disfunction

DWS 2011
 Insulin Resistance
Normal -cells Abnormal -cells

Compensatory Inadequate Insulin

Hyperinsulinemia Response

Isulin Resistance Type 2 Diabetes

Syndrome

Hypertension Retinopathy
Dyslipidemia Obesity CVD Neuropathy
Nephropaty
DWS 2011
 The Physiological Requirement for Insulin

Prandial
Glucose

Basal

Insulin

• Basal insulin : the amount of insulin necessary to prevent fasting

gluconeogenesis (fasting hyperglycemia) and ketogenesis
Pancreatic output : basal  prandial
• Prandial insulin : the amaount of insulin necessary to cover meals
DWS 2011
without development of posprandial hyperglycemia
 Insulin Deficiency

Basal Insulin Deficiency Prandial Insulin

Deficiency

Basal Hyperglycaemia Prandial

Hyperglycaemia

DWS 2011
 The Paradigm of (Type 2) Diabetes
Treatment
• Aggressive Treatment – Driven by Target (AIC
< 7%)

• Early Combinations
– Oral agent – oral agent
– Oral agent – insulin

• Aggressive Insulin Treatment

RESUME MECHANISM OF ACTION Blocks
OF OAD Promotes

Liver Muscle
Adipose

Biguanide TZD
FFA release

DPP IV INHIBITOR Circulation

Biguanide
⇓Glucose TZD
⇓FFA FFA absorption

Glucose Intestinal lipase inhibitor

absorption

AGI Fat
Pancreas Insulin secretagogues
Carbohydrates Intestines
 Treatment Approach

Fasting Blood Glucose Post Prandial Blood Glucose

• Metformin • AGI
• TZD • Short acting secretogogue
• Long acting secretogoue • Rapid / short acting insulin
• Basal insulin
 The Physiological Requirement for Insulin

Pancreatic output :
basal  prandial

• Basal insulin : the amount of insulin necessary to prevent fasting

gluconeogenesis (fasting hyperglycemia) and ketogenesis

• Prandial insulin : the amaount of insulin necessary to cover meals

without development of posprandial
DWS 2010 hyperglycemia
 Treatment Based on the Pathophysiology
of Hyperglycemia

Fasting Hyperglycemia Prandial Hyperglycemia

Insulin basal Insulin prandial

Long-acting SU Short-acting SU
Metformin Incretin – Glinide
Glitazone based Glitazones
Acarbose
DWS 2010
 Primary Sites of Action of
Anti-diabetic Agents
Biguanides
Muscle
Thiazolidinediones

Adipose
tissue Liver
DPP-4
inhibitors

Pancreas
DPP-4 Stomach
Insulin
Glucose
GLP-1
Gut
Sulphonylureas and -glucosidase inhibitors
GLP-1 Glinides
analogues .

DWS 2010
 Stepwise Intensification of Treatment
for Continuity of Control

FBG at target
HbA1c above target
Basal bolus
FBG above target Additional prandial doses
as needed
HbA1c above target
Basal plus
HbA1c above target Add prandial insulin at main meal

Basal
Add basal insulin and titrate

Oral agents

Lifestyle changes

Progressive deterioration of -cell function

Adapted from Raccah D et al. Diabetes Metab Res Rev 2007;23(4):257-64.
 Type 2 Diabetes Mellitus (T2DM)
Requires Progressive Therapy

• T2DM is a progressive disease characterized

by increased insulin resistance and decreasing
pancreatic β-cell function.1
• At diagnosis, patients may have already lost
approximately 50% of β-cell function.2
• An ideal treatment strategy for T2DM should provide:
– Continuity of care as the disease progresses;
– Flexibility to adapt to individual needs.

1. Bergenstal RM. In: Textbook of Diabetes Mellitus, 3rd edition: John Wiley & Sons; 2004: pp. 995-1015.
2. Holman RR. Diabetes Res Clin Pract 1998;40(Suppl 1):S21-5.
 The ADA/EASD Management Algorithm
Lifestyle intervention and metformin

If HbA1c ≥7%*

Add basal insulin Add sulfonylurea Add TZD**

(most effective) (least expensive) (no hypoglycemia)

If HbA1c ≥7%

Intensify Add basal Add

Add TZD
insulin*** insulin** sulfonylurea

If HbA1c ≥7%

Add basal or intensify

insulin
Intensive insulin + metformin +/− TZD**
* Check HbA1c every 3 months until HbA1c <7%, and then at least every 6 months
** Associated with ↑ risk of fluid retention, CHF and fractures; rosiglitazone,
but probably not pioglitazone, may be associated with ↑ risk of MI
*** Preferred based on effectiveness and expense
 HbA1c, FBG, and PPBG Targets
Normal IDF3 ADA/EASD4

HbA1c* (%) <6.01 <6.5 <7.0†

FBG, mg/dL <100 <110 70-130

(mmol/L) (<5.6)2 (<6.1) (3.9-7.2)

PPBG, mg/dL <140 <145 <180

(mmol/L) (<7.8)**1 (<8.0)** (<10.0)**

* DCCT referenced assays: normal range 4-6%; ** 1-2 hours postprandial;

† ADA and ADA/EASD guidelines recommend HbA levels as close to normal (<6%) as possible without significant
1c
hypoglycemia 1,5

ADA = American Diabetes Association; EASD = European Association for the Study of Diabetes;
IDF = International Diabetes Federation
1. ADA. Diabetes Care 2006;29(Suppl 1):S4-S42.
2. ADA. Diabetes Care 2006;29(Suppl 1):S43-8.
3. IDF. Global Guideline for Type 2 Diabetes. Brussels: International Diabetes Federation, 2005.
http://www.idf.org/webdata/docs/IDF%20GGT2D.pdf.
4. Nathan DM et al. Diabetologia 2006;49:1711-21.