Transcript Features of type 1 diabetes

•Diabetes Mellitus
•Discovery
•In the middle of the 19th century, evidence
from autopsies started to suggest a link
between the pancreas and Diabetes Mellitus.
•The Face of DM
•in 1920 was not
•encouraging
•Diabetics were sometimes seen to have
pancreas damage, and patients with
damaged pancreases almost always had
diabetes.
•
•In 1869 Paul Langerhans (1847-1888)
discovered the existence of two systems of
cells in the pancreas:
• the acinar cells, secreting the
pancreatic juice into the digestive
system
•islets--the islets of Langerhans--floating
among the acini with an unknown
function.
•Discovery
In 1889, Oskar Minkowski (18581931) and Josef Von Mering (18491908) depancreatized a dog, causing
a state of polyuria indistinguishable
from diabetes
This was the first direct evidence of
the link between diabetes and the
pancreas
The effect of ligating the pancreatic
ducts in most cases caused minor
digestive problems, but never
diabetes
•Oskar Minkowski
•Discovery
Sir Frederick Grant Banting (18911941) and biochemist John James
Richard Macleod (1876-1935) successful use of a pancreatic extract
for normalizing blood sugar (glucose)
levels (hyperglycemia) in diabetic dogs
Fredrick Sanger sequenced
bovine insulin in 1955 (Nobel prize
in 1980)
•Discovery
•1916 Nicolas Paulescu (1869-1931)
succeeded in developing an aqueous
pancreatic extract that normalized a diabetic
dog.
•1923 Banting and Best Awarded Nobel
Prize for Discovery and Use of Insulin in the
treatment of DM
•Diabetes mellitus
Definition
•
–A metabolic disorder of multiple aetiology
characterized by chronic hyperglycaemia with
disturbances of carbohydrate, fat and protein
metabolism resulting from defects in insulin
secretion, insulin action or both
•Hyperglycemia in diabetes results
from
Insulin
resistance
Decrease in
insulin
secretion
•Insulin resistance and insulin
•hypersecretion precede type 2 diabetes
• Insulin
•sensitivity
• 30%
•
• 50%
•
• 70%
•
• 100%
Insulin
secretion
Macrovascular
disease
50%
50%
70–100%
40%
150%
100%
10%
•Type 2
diabetes
•IGT
•Impaired
glucose
metabolism
•Normal glucose
metabolism
•Adapted from: Beck-Nielsen H, Groop LC. J Clin Invest 1994;94:1714–1721
•Symptoms
•Polyuria
•Polydypsia
•Weight loss
•Lethargy
•Tiredness
•Blurred Vision
•Boils/abscesses
•Pruritus Vulvae
•Polyphagia
•Retinopathy
•Nephropathy
•Neuropathy
•Foot ulcers/gangrene
•Angina/MI/CVA
•Diabetes mellitus
Type 1 diabetes
Type 2 diabetes
Gestational diabetes
Other specific types
•Predeabetes
Impaired fasting glucose(IFG)
Impaired glucose tolerance (IGT)
•Pathogenesis of Type 1 Diabetes Mellitus
•Autoimmune disease - destruction of β-cell
•Genetic susceptibility and environmental influences play
important roles in the pathogenesis
• Most commonly develops in childhood, becomes manifest
at puberty, and is progressive with age
•
•Most individuals with type 1 diabetes depend on
exogenous insulin supplementation for survival
•Characteristics
DM 1
DM 2
•Genetic locus
•Ch. 6
•Unknown
•Genetics
•50% concordance
in twins; HLA-D
linked
•90-100%
concordance; no
HLA association
•Pathogenesis
•Autoimmunity (islet •Insulin resistance
cell antibodies)
•Relative insulin
•Immunopathologic deficiency
mechanisms
•Severe insulin
deficiency
•Islet cells
•Marked atrophy
•Focal atrophy and
and fibrosis
amyloid
•Beta cell depletion •Mild beta cell
depletion
•Risk factors for Type 2 Diabetes
•Factors associated with type 2 diabetes include:
–older age, family history, certain ethnic backgrounds,
overweight/obesity (especially central adiposity),
metabolic syndrome (hypertension, dyslipidemia),
physical inactivity, history of GDM, overt CAD,
polycystic ovary syndrome, history of impaired fasting
glucose, and impaired glucose tolerance
•Growing evidence justifies promotion of weight
reduction/control, diet & exercise
•Type 1 vs diabetes type 2
•Features of type 1 diabetes
•Onset in
childhood/adolescence
•Lean body habitus
•Acute onset of osmotic
symptoms
•Ketosis-prone
•High levels of islet
autoantibodies
•High prevalence of genetic
susceptibility
•Features of type 2 diabetes
•Usually presents in over-30s (but
also seen increasingly in younger
people)
•Associated with overweight/obesity
•Onset is gradual and diagnosis
often missed (up to 50% of cases)
•Not associated with ketoacidosis,
though ketosis can occur
•Immune markers in only 10%
•Family history is often positive with
almost 100% concordance in
identical twins
•Gestational diabetes mellitus
•Develops only during pregnancy
•More common in:
– African Americans
–American Indians
–Hispanic Americans
–women with a family history of
diabetes
•Women with a history of gestational diabetes have a
20-50% chance of getting type 2 DM within 5-10 years
•
•ADA: Standards of Medical Care in Diabetes - 2012
•Criteria for the diagnosis of diabetes
•
•A1C ≥ 6.5%. The test should be performed in a laboratory using
a method that is NGSP certified and standardized to the DCCT
assay.*
•
OR
•FPG ≥ 126 mg/dl (7.0 mmol/l). Fasting is defined as no caloric
intake for at least 8 h.*
•
OR
•2-h plasma glucose ≥ 200mg/dl (11.1mmol/l) during an OGTT.
•
OR
•In a patient with classic symptoms of hyperglycemia or
hyperglycemic crisis, a random plasma glucose ≥ 200 mg/dl (11.1
mmol/l).
•*In the absence of unequivocal hyperglycemia, criteria 1–3 should be confirmed by
repeat testing.
•Glicated hemoglobin
Caused by non-enzymatic glycosylation
–Glycosylated hemoglobin
• HbA1c - LGI ref range 4.6-6.5 %
• indicates previous 2-3 months glycaemic exposure
• n.b. affected by altered red cell survival
–Fructosamine
•mirrors glycosylation of all serum proteins
•indicates previous 2-3 weeks glycaemic exposure
•used pregnancy/children in some sites
–Glycosylated albumin
•indicates previous several days glycaemic exposure
•not commonly used
•Prediabetes
•Defined as a fasting plasma blood glucose 6.1 - <7.0 mmoi/l (110 - < 126
mg/dl), while GTT is normal
•Increased risk for DM
•Education regarding risks and need for lifestyle modifications
•Diabetes Mellitus
•Complications of chronic hyperglycemia
–Macrovascular complications
•Cardiovascular disease (MI, angina)
•Cerebrovascular disease (stroke)
• Peripheral vascular disease – (Diabetic foot)
–Microvascular
• Retinopathy - Blindness (retinal proliferation,
macular degeneration)
• Nephropathy - ESRD
• Neuropathy (diffuse, generalized, or focal)
•
•Macrovascular/ Microvascular
Complications• of Diabetes
•Stroke
•Diabetic
•retinopathy
•2- to 4-fold
increase
•in cardiovascular
mortality and
stroke3
•Leading cause
•of blindness
•in working-age
•adults1
•Diabetic
•nephropath
y•Leading cause of
•end-stage renal
•disease2
•Cardiovascular
•disease
•8/10 diabetic
patients
•die from
cardiovascular
events4
•Peripheral
arterial
disease
•Contributes to amputation
•Diabetic
•neuropath
•Leading
cause of
y
non-traumatic lower
extremity
amputations5
•Diabetic Ketoacidosis
•
•Severe, uncontrolled diabetes, resulting from
insufficient insulin for glucose utilization
•Causes severe disturbances in fat and protein
metabolism
•Ketone bodies (acids) in the blood
•Symptoms:
–Polyuria, polydipsia, dehydration, fatigue, vomiting,
fruity odor to breath, labored breathing (Kussmaul
respiration)
•If not treated with insulin and fluids immediately, can
result in coma and death
•22
•Hypoglycemia
•Low blood glucose level (<2.8 mmol/L)
–Caused
•excessive insulin or oral anti-hyperglycemic agents
•too little food, delayed or skipped meals/snacks
•Exercise
•alcohol intake without food
•Symptoms:
–headache, blurred vision, mood changes, seizures,
coma
•Corrected by ingesting glucose 40%, per os or glucagon
injection
•23
•Goals of management
•Manage symptoms
•Prevent acute and late complications
•Improve quality of life
•Avoid premature diabetes-associated death
•An individualised approach
•Glycaemic
control
•Lifestyle
(e.g. diet & exercise,
cessation of smoking)
•
Microalbuminuria
& kidneys
•BP
•Lipids
•Management
BP
BPn
•Lipids
•Eye care
•Foot care
•Oral Glucose-Lowering Medications
•Sulfonylureas
–stimulate pancreas to release insulin
•Meglitinides
–new class which increases pancreatic secretion of insulin,
quick acting and can be taken before meals
•Biguanides
–decrease liver glucose production, delay glucose absorption
and enhance glucose uptake
•Alpha-glucosidase inhibitors
–slows down absorption of starch and sucrose in small intestine
•Thiazolidinediones
–Lowers insulin resistance and enhances insulin action in cells
•27
•Sites of Action of Therapeutic Options for
•Type 2 Diabetes
•Treatment strategy
•Lowering A1C to below or around 7% has been shown to
reduce microvascular complications of DM, and if implemented
soon after the diagnosis of diabetes is associated with longterm reduction in macrovascular disease. Therefore, a
reasonable A1C goal for many nonpregnant adults is 7%. (B)
•More stringent A1C goals (such as,6.5%) are for selected
individual patients, if this can be achieved without significant
hypoglycemia or other adverse effects of treatment. Appropriate
patients might include those with short duration of DM, long life
expectancy, and no significant CVD. (C)