�� 20.8 million Americans have diabetes20.8 million Americans have diabetes
�� 1.5 million new cases in 2005 more than 1.5 million new cases in 2005 more than
3500 each day3500 each day
�� Complications of diabetes are a major Complications of diabetes are a major
Diabetes Today: An EpidemicDiabetes Today: An Epidemic
�� Complications of diabetes are a major Complications of diabetes are a major
cause of mortality and morbidity (2002 cause of mortality and morbidity (2002
statistics)statistics)
90% of patients with diabetes are treated by 90% of patients with diabetes are treated by
primary care physiciansprimary care physicians
ADA National Diabetes Fact Sheet. Available at: http://www.cdc.gov/diabetes/pubs/pdf/ndfs_2005.pdf. Accessed April 11, 2005; ADA Diabetes Statistics. Available at http://www.diabetes.org/utils/printthispage.jsp?PageID=STATISTICS_233181. December 29, 2005.
Countries with the highest numbers of
estimated cases of diabetes for 2030
Egypt
Philippines
Japan
Bangladesh
Brazil
Adapted from Wild SH et al. Diabetes Care 2004; 27: 2569–70.
People with diabetes (millions)
0 20 40 60 80 100
Brazil
Pakistan
Indonesia
USA
China
India
Definition of diabetes
Diabetes mellitus is characterized by
chronic hyperglycemia with
disturbances of carbohydrate, fat, and
protein metabolism resulting from protein metabolism resulting from
defects in insulin secretion, insulin
action, or both.
Definition of diabetesDefinition of diabetes
Chronic hyperglycaemia associated Chronic hyperglycaemia associated
with longwith long--term damage to:term damage to:
•• EyesEyes•• EyesEyes
•• KidneysKidneys
•• NervesNerves
•• Heart and blood vesselsHeart and blood vessels
CLASSIFICATION OF DIABETES
MELLITUS
1. Type 1 diabetes (cell destruction, usually leading to absolute insulin deficiency)
2. Type 2 diabetes (ranging from predominantly insulin resistance with relative insulin insulin resistance with relative insulin deficiency to predominantly an insulin secretory defect with insulin resistance)
3. Other specific types of diabetes
4. Gestational diabetes mellitus (GDM)
Insulin
Gluconeogenesis
Glycogenolysis
Glycogen synthesis
Insulin and glucose disposalInsulin and glucose disposal
Glucose uptakeGlycogen synthesis
Blood glucose
Free fatty acid release
Type 1 diabetes
�� Insulin deficiency secondary to Insulin deficiency secondary to ββ--cell cell destruction usually by autoimmune processdestruction usually by autoimmune process
�� Insulin and CInsulin and C--peptide levels lowpeptide levels low
�� May have islet cell autoantibodies, May have islet cell autoantibodies, �� May have islet cell autoantibodies, May have islet cell autoantibodies, Autoantibodies to insulin, or antibodies to Autoantibodies to insulin, or antibodies to glutamic acid decarboxylase or tyrosine glutamic acid decarboxylase or tyrosine phosphatases. phosphatases.
�� 20% risk of other autoimmune diseases20% risk of other autoimmune diseases
�� Typically will present with DKA due to absolute Typically will present with DKA due to absolute lack of insulinlack of insulin
Glucose uptake
Glycogenolysis
Gluconeogenesis (amino acids)
Ketone production (fatty acids)
Blood glucose
Insulin deficiency in Insulin deficiency in
type 1 diabetestype 1 diabetes
Glucose uptakeProtein degradation → amino acids
Blood glucose
Triglyceride degradation → fatty acids
Pathogenesis of type 1 diabetes
• Genetic susceptibility
• Immune factors– other autoimmune disease– antigen-specific antibodies– antigen-specific antibodies
• Environmental trigger– viruses– bovine serum albumin– nitrosamines: cured meats– chemicals: vacor (rat poison),
streptozotin
Beta-cell
Pathogenesis of type 1 Pathogenesis of type 1
diabetesdiabetesTrigger
GeneticImmunological abnormalities
Beta-cell mass
Time (months - years)
Pre-diabetes ‘Honeymoon’
Chronic phase
Clinical diabetes
Idiopathic type 1 diabetesIdiopathic type 1 diabetes
NonNon--autoimmune type 1 diabetesautoimmune type 1 diabetes
�� No autoimmune markersNo autoimmune markers
�� Permanent insulinopeniaPermanent insulinopenia
�� KetoacidosisKetoacidosis
�� People of African and Asian originPeople of African and Asian origin
Type 2 diabetes
• 90%-95% of people with diabetes
• Insulin insensitivity and • Insulin insensitivity and relative insulin deficiency
• Obesity or overweight
• Complications often present at diagnosis
Pathogenesis of type 2 diabetes
• Multiple genes involved
• Hyperinsulinaemia
• Poor fetal nutrition → ↓ beta-cell • Poor fetal nutrition → ↓ beta-cell formation
• Low birth weight/weight change
• “Thrifty gene”
• 7% beta-cell loss
Epidemiology of type 2 Epidemiology of type 2
diabetesdiabetes
• Dramatic increase
• Aging population
• Disturbing trends parallel obesity • Disturbing trends parallel obesity epidemic
• Especially in adolescents and minority groups
• Increasing in young people
Risk factors for type 2 diabetes
• Age > 40 years
• First-degree relative with diabetes
• Member of high risk population
• History of impaired glucose tolerance, impaired fasting glucose
• Vascular disease
• History of gestational diabetes
• History of delivery of macrosomic baby
CDA 2003
Type 2 Diabetes: Two Principal DefectsType 2 Diabetes: Two Principal Defects
Insulin resistanceββββ-cell dysfunction/
failure
GenesGenes
Reaven GM. Physiol Rev. 1995;75:473-486
Reaven GM. Diabetes/Metabol Rev. 1993;9(Suppl 1):5S-12S;
Polonsky KS. Exp Clin Endocrinol Diabetes. 1999;107 Suppl 4:S124-S127.
±Environment ± Environment
IGT IGT
Type 2 diabetesGlucose
Toxicity
Glucose
Toxicity
Insulin insensitivity in ttype 2 diabetes
Glycogenogenosis
Glycolysis
Gluconeogenesis LipogenesisGlycolysis
Liver Fat tissues Muscles
Gluconeogenesis Lipogenesis
LipolysisGlycogenogenesis
Glycolysis
FFA
Hyperglycaemia
Glucose Storage ↓↓↓↓Glucose production ↑↑↑↑
Possible Mechanisms for Possible Mechanisms for
Decline of Decline of ββββββββ--Cell FunctionCell Function
“Glucose Toxicity”(Hyperglycemia)
•Genetic factors Insulin resistance•Genetic factors•Amyloid deposits•Proinsulin cleavage•Hexosamines•TNF-α•AGEs
β-cell
Insulin resistance
“Lipotoxicity”(Elevated FFA, TG)
Adapted from Reaven GM. Physiol Rev 1995;75:473–486.
Pancreatic ββββ-cell Insulin resistance
Liver
Islet β-cell degranulation
Increased
lipolysis
Elevated plasma FFA
+ - Elevated
Insulin resistance and β-cell dysfunction
produce hyperglycaemia in type 2 diabetes
HYPERGLYCAEMIA
Islet β-cell degranulation
Reduced insulin content
Adipose tissue
Decreased glucose transport
& activity (expression) of GLUT-4
-
Low plasma
insulin
Increased glucose output
ElevatedTNFαααα
Modified from: Turner N, Clapham JC. Prog Drug Res 1998;51:34–94
Development of type 2 diabetesDevelopment of type 2 diabetes
Fasting glucose
Glucose tolerance
Hyperglycemia
Abnormalglucose tolerance
I II III IV V
Normal IGT Type 2 diabetes
Insulin sensitivity
Insulinsecretion
Decreased insulinsensitivity
Hyperinsulinemia,then β-cell failure
Genetics
Environment
• nutrition
• obesity
• exercise
Natural History of Type 2 Natural History of Type 2
DiabetesDiabetes
Onset of
diabetes
Disability
Impaired
Complications
RetinopathyRetinopathyNephropathyNephropathyNeuropathyNeuropathy
BlindnessBlindnessRenal failureRenal failure
Insulin resistanceHyperinsulinemiaHypertensionDecreased HDL-CIncreased TG Atherosclerosis
Coronary diseaseLE amputation
Death
Impaired
glucose
tolerance
Ongoing
hyperglycemia
Impaired entry of glucose into the cellsAccumulation of glucose in the blood
Plasma osmolarity ⇑Inability of the cellsutilize glucose
Pathophysiology Pathophysiology
Cellular starvation
Stimulating hunger
Urinary loss of glucose⇑⇑⇑⇑
Loss of water and Na
Dehydration of cells
Compensatory mechanismSuch as thirst
Lipolysis andproteolysis
Body weight
Common SymptomsCommon Symptoms
Classic symptomsClassic symptoms
�� increased hungerincreased hunger
�� increased thirstincreased thirst
�� frequent urinationfrequent urination
Others symptomsOthers symptoms
�� fatigue fatigue
�� tingling or numbness in tingling or numbness in hands and feethands and feet
�� recurring infectionsrecurring infections�� frequent urinationfrequent urination
�� weight lossweight loss
�� recurring infectionsrecurring infections
•• gums, skin, lung, urinary gums, skin, lung, urinary bladderbladder
�� slow healingslow healing
�� blurred visionblurred vision
�� pruritus vulvaepruritus vulvae
�� erectile dysfunctionerectile dysfunction
ADA definition of hyperglycaemic statesADA definition of hyperglycaemic states
Criteria for the diagnosis of diabetes
Symptoms of diabetes plus casual plasma glucose ≥≥≥≥ 200 mg/dl (11.1 mmol/l)
FPG
< 100 mg/dl (5.6 mmol/l) normal fasting glucose
100–125 mg/dl (5.6–6.9 mmol/l) impaired fasting glucose
or
ADA = American Diabetes Association
OGTT 2-h post-load glucose
< 140 mg/dl (7.8 mmol/l) normal glucose tolerance
140–199 mg/dl (7.8–11.1 mmol/l) impaired glucose tolerance
≥≥≥≥ 200 mg/dl (11.1 mmol/l) diabetes
Adapted from American Diabetes Association. Diabetes Care 2004; 27:S5–S10.
≥≥≥≥ 126 mg/dl (7.0 mmol/l) diabetes
or
Classic symptoms (+)
Fasting BG > 126 mg/dl Fasting BG < 126 mg/dl
(casual BG > 200) (casual BG <200)
Repeat BG
.
Fasting BG < 126 or Fasting BG >126 or
DIABETES MELLITUS OGTT
Diagnosis of type 2 Diabetes
Mellitus
Fasting BG < 126 or
Casual BG < 200Fasting BG >126 or
Casual BG > 200
Impaired glucose toleranceImpaired glucose tolerance
Impaired fasting glucoseImpaired fasting glucose
�� Intermediate statesIntermediate states
�� Increased risk of developing Increased risk of developing �� Increased risk of developing Increased risk of developing
diabetes diabetes
�� Prevention strategies to prevent or Prevention strategies to prevent or
delay progressiondelay progression
�� Increased risk of cardiovascular Increased risk of cardiovascular
diseasedisease
Uncertain diagnosis:Uncertain diagnosis:
Oral glucose tolerance testOral glucose tolerance test
�� 75 g glucose load after 8 hours 75 g glucose load after 8 hours
fastingfastingfastingfasting
�� Readings taken in fasting state Readings taken in fasting state
and at 1 and 2 hoursand at 1 and 2 hours
�� Urinary ketonesUrinary ketones
AntibodiesAntibodies
Tests for differential Tests for differential
diagnosisdiagnosis
�� AntibodiesAntibodies
�� CC--peptidepeptide
Other specific types of diabetes
A. Genetic defects of B-cell function� Chromosome 12, HNF-1 (MODY3); Chromosome 7,
glucokinase (MODY2); Chromosome 20, HNF-4 (MODY1); Chromosome 13, insulin promoter factor-1 (IPF-1; MODY4); Chromosome 17, HNF-1 (MODY5); Chromosome 2, NeuroD1 (MODY6); Mitochondrial DNA
B. Genetic defects in insulin actionB. Genetic defects in insulin action� Type A insulin resistance; Leprechaunism; Rabson-
Mendenhall syndrome; Lipoatrophic diabetes.
C. Diseases of the exocrine pancreas� Pancreatitis; Trauma/pancreatectomy; Neoplasia; Cystic
fibrosis; Hemochromatosis; Fibrocalculous pancreatopathy.
D. Endocrinopathies� Acromegaly; Cushing’s syndrome; Glucagonoma;
Pheochromocytoma; Hyperthyroidism; Somatostatinoma; Aldosteronoma.
Other specific types of diabetes
E. Drug- or chemical-induced� Vacor; Pentamidine; Nicotinic acid; Glucocorticoids; Thyroid
hormone; Diazoxide; adrenergic agonists; Thiazides; Dilantin; Interferon.
F. InfectionsCongenital rubella; Cytomegalovirus.� Congenital rubella; Cytomegalovirus.
G. Uncommon forms of immune-mediated diabetes� “Stiff-man” syndrome; Anti–insulin receptor antibodies.
H. Other genetic syndromes sometimes associated with diabetes� Down’s syndrome; Klinefelter’s syndrome; Turner’s
syndrome; Wolfram’s syndrome; Friedreich’s ataxia; Huntington’s chorea; Laurence-Moon-Biedl syndrome; Myotonic dystrophy; Porphyria; Prader-Willi syndrome
Gestational diabetes mellitus (GDM)Gestational diabetes mellitus (GDM)
� Gestational diabetes mellitus (GDM) is carbohydrate
intolerance associated with hyperglycemia of variable
severity with the onset or first recognition during pregnancy
� Return to normal glucose regulation after delivery is
commoncommon
� Increased perinatal morbidity and mortality if untreated• Risk assessment for GDM should be undertaken at
the first prenatal visit.
• Women with clinical characteristics consistent with
a high risk for GDM (those with marked obesity,
personal history of GDM, glycosuria, or a strong
family history of diabetes) should undergo glucose
testing as soon as possible
PathophysiologyPathophysiology
�� The pregnant woman undergoes a complex series of The pregnant woman undergoes a complex series of maternal hormonal actions (ie, a rise in blood glucose; maternal hormonal actions (ie, a rise in blood glucose; the secondary secretion of pancreatic insulin, glucagon, the secondary secretion of pancreatic insulin, glucagon, somatomedins, and adrenal catecholamines). somatomedins, and adrenal catecholamines).
�� These hormones confer increasing tissue insulin These hormones confer increasing tissue insulin resistance as their levels rise, the demand for increased resistance as their levels rise, the demand for increased resistance as their levels rise, the demand for increased resistance as their levels rise, the demand for increased insulin secretion with feeding escalates progressively insulin secretion with feeding escalates progressively during pregnancy. during pregnancy.
�� If the maternal pancreatic insulin response is If the maternal pancreatic insulin response is inadequate, maternal and, then, fetal hyperglycemia inadequate, maternal and, then, fetal hyperglycemia results. results.
�� This typically manifests as recurrent postprandial This typically manifests as recurrent postprandial hyperglycemic episodes. hyperglycemic episodes.
Gestational diabetes mellitus (GDM)Gestational diabetes mellitus (GDM)
� Diagnostic criteria for the 100-g OGTT are as follows:
� ≥95 mg/dl fasting, ≥ 180mg/dl at 1 h, ≥ 155 mg/dl
at 2 h, and ≥ 140 mg/dl at 3 h. at 2 h, and ≥ 140 mg/dl at 3 h.
� Two or more of the plasma glucose values must be
met or exceeded for a positive diagnosis.
� The test should be done in the morning after an overnight fast of 8–14 h.
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