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Division of Diabetes and Endocrinology, Department of Medicine, Dr Saiful Anwar Hospital, Medical Faculty, Brawijaya University
TOPICS
Epidemiology, Classification and Diagnosis Pathogenic Mechanisms of Type 2 Diabetes and Pathophysiology of Hyperglycemia Mangement of Type 2 Diabetes - Therapeutic Guidelines - Therapeutic Life-style Changes - Oral and Parenteral Hypoglycemic Agents - Insulin and Insulin Analogues Summary and Conclusions
TOPICS
Epidemiology, Classification and Diagnosis Pathogenic Mechanisms of Type 2 Diabetes and Pathophysiology of Hyperglycemia Mangement of Type 2 Diabetes - Therapeutic Guidelines - Therapeutic Life-style Changes - Oral and Parenteral Hypoglycemic Agents - Insulin and Insulin Analogues Summary and Conclusions
ETIOLOGIC CLASSIFIACTION
I. Type 1 (-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
Type 1
Clinical Features Age at onset Onset Weight Spontaneous ketosis Chronic complication Epidemiology Prevalence Sex Insulin (C-petide) level Genetics Concordance in twins HLA asoociation Pathology Islet cell mass Insulitis at onset Immunology Associated with other endocrinopathy Anti-islet ell immunity Humoral Cell mediatedl
Usually < 30 Acute Non obese Common (++) 0,5% Male prepdominancece / (-) 40% (+) (DR3/DR4) Severely reduced Present Frequent 60 80% at onset 35 50% at onset
Type 2
Usually > 40 Insidious Obese Rare (++) 2% Female predominance /N/ 70 90% (-) Moderately reduced ? Frequent 5 20% < 5%
F A M I L Y S T U D Y
F E N O T Y P E VS G E N O T Y P E
Hyperglycemia
IGT or
IFG
No
Diabetes Mellitus
Insulin requiring
For control For survival
Insulin requirement
+++
+++++
The destruction of -cells and the appearance of type 1 diabetes according to the age of onset and the putative pathogenetic mechanism (Paolo Pozzilli and Umberto Di Mario : Diabetes Care 2001 24: 1460-1467)
Diagnostic Criteria
GDM: Gestational DM
mmol/l
5.3 10.0 8.6 7.8
95 180 155
Two or more of the venous plasma concentrations must be met or exceeded for a positive diagnosis
B
Retinopathy (%)
50 40 30 20 10
0 FPG (mg/dl) 70- 89- 93- 97- 100- 106- 109- 115- 136- 2262hPG (mg/dl) 38- 94- 106- 116- 128- 138- 154- 185- 244- 346HbA1c (%) 3.4- 4.8- 5.0- 5.2- 5.3- 5.5- 5.7- 6.0- 6.7- 7.5-
0 FPG (mg/dl) 57- 79- 84- 89- 93- 99- 108- 130- 176- 2582hPG (mg/dl) 39- 8- 90- 99- 110- 125- 155- 218- 304- 385HbA1c (%) 2.2 4.7 4.9 5.1 5.4 5.6 6.0 6.3 8.5 10.3
C
Retinopathy (%) 15 10 5
87- 90- 93- 94- 96- 101- 104- 109- 12075- 86- 94- 102- 112- 120- 133- 154- 1954.9 5.1 5.2 5.4 5.5 5.4 5.7 5.9 6.2
Cumulative hazard curves for ADA fasting glucose criteria and the World Health Organization 2-h glucose criteria (adjusted by age, sex, and study center)
0-2
Feeting glucose classification
Known diabetes
Diabetes by ADA criteria Impaired fasting glucose Normal
C u m m u l a t I
0-2
2 h glucose classification
Known diabetes
Diabetes by ADA criteria Impaired fasting glucose Normal
0-1
v E
0-1
H a
z a
0 0 2 4 6 8 10 12
r d s
0 0 2 4 6 8 10 12
Follow-up Years
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
Fasting at least 8 h
Increased Risk of Micro- and Macroangiopathy Correlates With Progression From Impaired Glucose Homeostasis to Type 2 DM
Microangiopathy Risk
Macroangiopathy Risk
Diabetes
200 mg/dl 199 mg/dl Impaired Glucose Tolerance (IGT) 140 mg/dl 139 mg/dl Normal 2-h Post-gucose Challenge
Garber AJ et al, 2008
Prevention of Disease
Prediabetes
Healthy At risk
Diabetes
Disease present
Complication (+)
Primordial
Primary
Secondary Tertiary
Prevention
TOPICS
Epidemiology, Classification and Diagnosis Pathogenic Mechanisms of Type 2 Diabetes and Pathophysiology of Hyperglycemia Mangement of Type 2 Diabetes - Therapeutic Guidelines - Therapeutic Life-style Changes - Oral and Parenteral Hypoglycemic Agents - Insulin and Insulin Analogues Summary and Conclusions
Insulin resistance
? vs ?
-cell dysfunction
Genetic
Environmental
Insulin Resistance
Normal -cells
Compensatory Hyperinsulinemia
Type 2 Diabetes
CVD
Islet Dysfunction
Insufficient Insulin secretion (-cell dysfunction) Progressive decline of cell function
TZDs Metformin
Sulfonylureas
TZDs
Incretin-based
Glinides
Insulin
Adapted from DeFronzo RA. Br J Diabetes Vasc Dis 2003;3(suppl 1):S24S40
Pathophysiology of Hyperglycemia
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 hyperglycemia
Mean ( SEM) rates of Insulin Secretion in Type 2 Diabetic Patients compared with Control Subjects
Incretin based
TOPICS
Epidemiology, Classification and Diagnosis Pathogenic Mechanisms of Type 2 Diabetes and Pathophysiology of Hyperglycemia Mangement of Type 2 Diabetes - Therapeutic Guidelines - Therapeutic Life-style Changes - Oral and Parenteral Hypoglycemic Agents - Insulin and Insulin Analogues Summary and Conclusions
3
2 1
Expectation of Life
Dreyer,1997
Therapeutic Guidelines
Individualised Suited to local data and realities For the benefit of Indonesia patient
Tier 1:
well-validated therapies At diagnosis: Lifestyle + Metformin Lifestyle + Metformin + Basal insulin Lifestyle + Metformin + Intensive insulin Basal plus/Basal bolus
STEP 1
STEP 3
Tier 2:
Less well validated therapies Lifestyle + Metformin + Pioglitazone
No hypoglycaemia Oedema/CHF Bone loss
TOPICS
Epidemiology, Classification and Diagnosis Pathogenic Mechanisms of Type 2 Diabetes and Pathophysiology of Hyperglycemia Mangement of Type 2 Diabetes - Therapeutic Guidelines - Therapeutic Life-style Changes - Oral and Parenteral Hypoglycemic Agents - Insulin and Insulin Analogues Summary and Conclusions
Moderate-intense Exercise
At least 30- 60 minutes 4x/week or 150 minutes/week Aerobic Ressistance training 3x/week (if no contraindication)
TOPICS
Epidemiology, Classification and Diagnosis Pathogenic Mechanisms of Type 2 Diabetes and Pathophysiology of Hyperglycemia Mangement of Type 2 Diabetes - Therapeutic Guidelines - Therapeutic Life-style Changes - Oral and Parenteral Hypoglycemic Agents - Insulin and Insulin Analogues Summary and Conclusions
Tier 1:
well-validated therapies At diagnosis: Lifestyle + Metformin Lifestyle + Metformin + Basal insulin Lifestyle + Metformin + Intensive insulin Basal plus/Basal bolus
STEP 1
STEP 3
Tier 2:
Less well validated therapies Lifestyle + Metformin + Pioglitazone
No hypoglycaemia Oedema/CHF Bone loss
Dailey GE. Diabetes Care 2005; 28:220-221 Nathan DM et al. Diabetes Care 2006; 29:1963-1972
DPP-4 inhibitors
Adipose tissue
Liver
DPP-4 GLP-1
Pancreas
Insulin
Glucose
Stomach
Gut
GLP-1 analogues
Sulphonylureas and Glinides -glucosidase inhibitors
Adapted from Kobayashi M. Diabetes Obes Metab 1999; 1(Suppl. 1):S32S40. Nattrass M & Bailey CJ. Baillieres Best Pract Res Clin Endocrinol Metab 1999; 13:309329. Pratley RE & Salsali A. Curr Med Res Opin 2007; 23:919931. Todd JF & Bloom SR. Diabet Med 2007; 24:223232.
Unknown
STEP 2
STEP 3
TOPICS
Epidemiology, Classification and Diagnosis Pathogenic Mechanisms of Type 2 Diabetes and Pathophysiology of Hyperglycemia Mangement of Type 2 Diabetes - Therapeutic Guidelines - Therapeutic Life-style Changes - Oral and Parenteral Hypoglycemic Agents - Insulin and Insulin Analogues Summary and Conclusions
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 hyperglycemia
Soluble (regular)
Rapid-acting analogues (lispro,aspart,glulisine)
30 60 (m)
5 15 (m)
2 3 (m)
3 (m)
5 8
3 5
Basal insulin Intermediate-acting insulin (e.g. NPH) Long-acting analog Glargine Detemir* Mixture (prandial + basal) Novomix (70/30) 30 90 (h) 4 6 (h) 8 16
2 4 (h)
Peakless
20 24
0.5 1 (h)
Dual
10 - 16
Incretin based
STEP 2
STEP 3
Type 2 diabetes
50
0 0600 1200 1800 Time of day
Normal
2400
0600
Riddle MC. Diabetes Care. 1990. 13:676-686; Riddle MC. Practical Cardiology
OPTION 2
Stop oral agents
Oral Agents
S
MEALS
HS
INSULIN EFFECT
Morning Afternoon
Evening
Night
S MEALS
HS
Evening
HS MEALS
Changes from baseline to 3years in clycated hemoglobin, fasting plasma glucose, and body weight and the rate of hypoglycemia
TOPICS
Epidemiology, Classification and Diagnosis Pathogenic Mechanisms of Type 2 Diabetes and Pathophysiology of Hyperglycemia Mangement of Type 2 Diabetes - Therapeutic Guidelines - Therapeutic Life-style Changes - Oral and Parenteral Hypoglycemic Agents - Insulin and Insulin Analogues Summary and Conclusions
Microvascular complications of diabetes are much more closely associated with hyperglycemia than with macrovascular complications
Should the glycaemic target be lowered < 7% ? The effect of lowering of blood glucose to near normal levels on cardiovascular risk ?
Results of Past (UKPDS) and Recent (ADVANCE, ACCORD, VADT) Clinical Trials
Annals of Internal Medicine
Montori VM and Ferna ndez-Balsells M. Ann Intern Med Ann Intern Med. 2009;150:803-808
Old friends (insulin, sulfonylureas and metformin), used appropriately, are and will be still our best friends.
When the facts change, I change my mind. What do you do, sir?
John Maynard Keynes