ETIOLOGIC CLASSIFICACTION

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 DWS 2010

Type 1 Clinical Features Age at onset Onset Weight Spontaneous ketosis Chronic complication Epidemiology Prevalence Sex Insulin (C-peptide) 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

Type 2

Usually < 30 Acute Non obese Common (++) 0,5% Male prepdominancece / (-)
40% (+) (DR3/DR4) Severely reduced Present Frequent

Usually > 40 Insidious Obese Rare (++) 2% Female predominance /N/

70 90% (-) Moderately reduced ? Frequent

60 80% at onset 35 50% at onset

5 20% < 5%

DWS 2010

Symptoms (+) Casual plasma glucose > 200 mg% (11.1 mmol/L)
1.

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
DWS 2010 (The

Expoert Committee,1997)

Normal

IFG or IGT

Diabetes
FPG 126 mg/dl 2-hPG 200 mg/dl Symptoms of diabetes and causal plasma glucose concentration 200 mg/dl

FPG IFG : < 100 mg/dl FPG 100; < 126 mg/dl FPG 100; < 126 mg/dl 2-hPG < 140 mg/dl 2-hPG < 140 mg/dl IGT : FPG < 106 mg/dl 2-hPG 140; < 200 mg/dl

Aggressive Treatment Driven by Target (AIC < 7%) Early Combinations

Oral agent oral agent Oral agent insulin

Aggressive Insulin Treatment

RESUME MECHANISM OF ACTION OF OAD

Blocks Promotes

Liver

Adipose TZD FFA release

Muscle

Biguanide

DPP IV INHIBITOR

Circulation

Glucose
FFA
Glucose absorption AGI

TZD

Biguanide FFA absorption Intestinal lipase inhibitor

Fat
Intestines

Pancreas

Insulin secretagogues

Carbohydrates

FASTING BLOOD GLUCOSE

POST PRANDIAL BLOOD GLUCOSE

Metformin TZD Long acting secretogoue Basal insulin

AGI Short acting secretogogue Rapid / short acting 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 hyperglycemia DWS 2010

Fasting Hyperglycemia

Prandial Hyperglycemia

Insulin basal Long-acting SU Metformin Glitazone

Incretin based
DWS 2010

Insulin prandial Short-acting SU Glinide Glitazones Acarbose

Muscle
Thiazolidinediones

Biguanides

DPP-4 inhibitors

Adipose tissue

Liver

DPP-4 GLP-1

Pancreas
Insulin
Glucose

Stomach

Gut
GLP-1 analogues
Sulphonylureas and Glinides a-glucosidase inhibitors
.

DWS 2010

FBG at target HbA1c above target FBG above target HbA1c above target

Basal bolus
Additional prandial doses as needed

HbA1c above target

Add prandial insulin at main meal

Basal plus

Add basal insulin and titrate

Basal

Oral agents Lifestyle changes

Progressive deterioration of -cell function

Adapted from Raccah D et al. Diabetes Metab Res Rev 2007;23(4):257-64.

T2DM is a progressive disease characterized by increased insulin resistance and decreasing pancreatic -cell function.1

At diagnosis, patients may have already lost approximately 50% of -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.

Lifestyle intervention and metformin If HbA1c 7%*

Add basal insulin (most effective)

Add sulfonylurea (least expensive) If HbA1c 7%

Add TZD** (no hypoglycemia)

Intensify insulin***

Add TZD

Add basal insulin**

Add 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, Nathan DM et al. Diabetes Care 2006;29(8):1963-72. but probably not pioglitazone, may be associated with risk of MI Nathan DM et al. Diabetologia 2008;51(1):8-11.

Normal
HbA1c* (%) FBG, mg/dL (mmol/L) PPBG, mg/dL (mmol/L)
<6.01 <100 (<5.6)2 <140 (<7.8)**1

IDF3
<6.5 <110 (<6.1) <145 (<8.0)**

ADA/EASD4
<7.0 70-130 (3.9-7.2) <180 (<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 1c 1,5 significant hypoglycemia 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.

Stroke Diabetic Retinopathy

Leading cause of blindness in working age adults1
2 to 4 fold increase in cardiovascular mortality and stroke3

Cardiovascular Disease
8/10 diabetic patients die from CV events4

Diabetic Nephropathy
Leading cause of end-stage renal disease2

Diabetic Neuropathy
Leading cause of non-traumatic lower extremity amputations5

1 Fong

DS, et al. Diabetes Care 2003; 26 (Suppl. 1):S99S102. 2Molitch ME, et al. Diabetes Care 2003; 26 (Suppl. 1):S94S98. 3 Kannel WB, et al. Am Heart J 1990; 120:672676. 4Gray RP & Yudkin JS. In Textbook of Diabetes 1997. 5Mayfield JA, et al. Diabetes Care 2003; 26 (Suppl. 1):S78S79.

Diabetic Neuropathy (DN) are among the most frequent complications of diabetes mellitus, leading to great morbidity and mortality. Neuropathy is generally considered to be related to duration and severity of hyperglycaemia. However it may also occur acutely even with hypoglycaemia Epidemiologic data suggest that approximately 30% to 50% of people with type 2 diabetes have a distal peripheral neuropathy. The major morbidity is foot ulceration, which can lead to gangrene and ultimately to limb loss. Diabetic neuropathy is a small-fiber disease

Table 4: Symptoms and signs of autonomic neuropathy. 1. Cardiovascular Postural hypotension Resting tachycardia Painless myocardial infarction Sudden death (with or without association with general anaesthesia) Prolonged QT interval 2. Gastrointestinal Oesophageal motor incoordination Gastric dysrhythmia, hypomotility (gastroparesis diabeticorum) Pylorospasm. Uncoordinated intestinal motility (diabetic diarrhoea, spasm) Intestinal hypomotility (constipation) Gallbladder hypocontraction (diabetic cholecystopathy) Anorectal dysfunction (faecal incontinence)

Table 4: Symptoms and signs of autonomic neuropathy (continued)

3. Genitourinary Diabetic cystopathy (impaired bladder sensation, atonic bladder, post micturition dribbling, detrusor hyporeflexia or hyperreflexia) Male impotence Ejaculatory disorders Reduced vaginal lubrication, dyspareunia 4. Respiratory Impaired breathing control (?) Sleep apnoea ? 5.Thermoregulatory Sudomotor Vasomotor 6. Pupillary Miosis Disturbances of dilatation Argyll Robertson pupil

Pain is the most common symptom which could be superficial, deep or aching. The management of pain is often difficult and disappointing Treatment of Neuropathic Pain Adjuvant Analgesics :

Antidepressants Anticonvulsants Analgesic antiarrhythmics Sympatholytic agents Topical agents NMDA receptor antagonists Opioids Other