Transcript What’s new and exciting with type 1 diabetes?

Classification and
Pathophysiology of Diabetes
Peter Colman
Department of Diabetes and
Endocrinology,
Royal Melbourne Hospital
Royal Melbourne Hospital
Matthew
Age 27 works as a plumber; family lives in
NSW; lives in a shared house with mates;
eats a lot of takeaways currently. Plays
basketball regularly and also likes hiking
No past history; always good health
Royal Melbourne Hospital
Matthew
For last 3 weeks
• Polyuria and thirst; has had to get up 3
times overnight
• Hungry and eating a lot but has lost 8 kg
over last few weeks
Vision has been blurred
Having trouble playing basketball – poor
energy levels
Royal Melbourne Hospital
Matthew
Yesterday when he woke he felt very dry and
nauseated so went to see his GP.
GP suspected diabetes
Glucose Hi (blood glucose meter); ketones
2.6mmol/L
Sent to emergency department
Royal Melbourne Hospital
Matthew
On arrival
• Anxious
• P 90 reg; BP 110/70; mouth dry
• General examination normal
• Weight 58kg; height 1.8m; BMI 18
Electrolytes normal
Glucose 25mmol/L
Royal Melbourne Hospital
Matthew
Blood sent to the laboratory for antibodies
to islet cells:
GAD antibodies
IA2 antibodies
insulin antibodies
Royal Melbourne Hospital
What type of diabetes does
Matthew have?
Royal Melbourne Hospital
Classification - types of
diabetes
Aetiological classification of
diabetes
Type 1 (ß-cell destruction, usually leading
to absolute insulin deficiency)
Type 2 (may range from predominantly
insulin resistance with relative insulin
deficiency to a predominantly secretory
defect with or without insulin resistance)
Other specific types
Gestational diabetes
Aetiological classification of
diabetes
Other specific types
–
–
–
–
–
–
–
–
Genetic defects of ß-cell function
Genetic defects in insulin action
Diseases of the exocrine pancreas
Endocrinopathies
Drug or chemical induced
Infections
Uncommon forms of immune-mediated diabetes
Other genetic syndromes sometimes associated with
diabetes
Type 1 diabetes
Pathogenesis
– chronic autoimmune destruction of ß-cells of the
pancreas in genetically predisposed individuals
Age of onset
– young - usually age < 30 years
Symptoms at presentation - usually acute
– weight loss
– thirst, polyuria, polydipsia
– occasionally ketoacidosis
Treatment
– insulin dependent from the time of diagnosis
Natural History of type 1 diabetes
GENETICALLY AT-RISK
ENVIRONMENTAL TRIGGER/S
ISLET ANTIBODY POSITIVE
BETA CELLS
100%
FIRST PHASE
INSULIN RESPONSE IMPAIRED
GENETIC
PREDISPOSITION
INSULITIS
BETA-CELL DAMAGE
PREDIABETES
DIABETES
0%
TIME
Init II
A randomized double-blind, placebocontrolled trial of intranasal insulin
(440 units) in children and young
adults at risk of type 1 diabetes
Please ask your
patients to tell
their relatives
about the study
and give it your
full support
Matthew
Treatment
• Initial treatment with insulin infusion and
intravenous fluids overnight
• Next day
–
–
–
–
–
–
Education
Taught home blood glucose monitoring
Taught how to inject insulin
Taught about hypoglycemia
Given initial dietary information
Home the next day
Royal Melbourne Hospital
Blood glucose monitoring is essential
Insulin Pen
Approximate normal insulin production with
basal insulin and mealtime short acting insulin
Basal insulin
B
L
D
HS
Time of administration
Insulin Pumps
Intensive Therapy
Lena
65 yo.
Greek speaking; limited English; married and lives
with her husband. She has 3 adult children and 9
grandchildren.
Admitted with chest pain
Diabetes 12 years
Royal Melbourne Hospital
Lena
Diabetes history
• Diagnosed age 53 on a routine blood test
done by her GP.
• Strong FH of diabetes in her mother and
one of her sisters
• At the time of diagnosis had no particular
symptoms
• For 2 years she didnt need any tablets but
is now on multiple tablets
Royal Melbourne Hospital
Lena
Diabetes history
• Doesn’t do home glucose monitoring – goes
to the doctor for these tests
• Doesn’t know what HbA1c is
• Thinks she had a check of the eyes in the
past
• Feet feel a bit numb sometimes
Royal Melbourne Hospital
Lena
Medications
• Diamicron MR ii bd
• Metformin 1g tds
• Lipitor 40mg
• Avapro 300mg daily
• Norvasc 10mg daily
• Natrilix 5mg daily
• Losec 10mg
Royal Melbourne Hospital
Lena
Examination
• Height 5’4” (1.62m); weight 79kg; BMI 30
• BP 155/95
• Feet – reduced sensation to monofilament;
pulses difficult to palpate
Royal Melbourne Hospital
Aetiological classification of
diabetes
Type 1 (ß-cell destruction, usually leading
to absolute insulin deficiency)
Type 2 (may range from predominantly
insulin resistance with relative insulin
deficiency to a predominantly secretory
defect with or without insulin resistance)
Other specific types
Gestational diabetes
Type 2 diabetes
Pathogenesis
– resistance to insulin action; defect of insulin
secretion
Age of onset
– older - usually age > 40 years
Symptoms at presentation - often chronic, mild
– often associated with overweight
– thirst, polyuria, polydipsia, infections, tiredness
– occasionally hyperosmolar coma
Treatment
– often controlled by diet alone or diet and tablets.
30% of patients eventually need insulin
Metabolic Defects in
Type 2 Diabetes
Insulin secretion
Pancreas
Hyperglycemia
HGP
Glucose
uptake
Liver
Muscle
Natural History of Type 2 Diabetes
Secondary
Failure
The metabolic
syndrome
- overweight
- insulin resistance
- hypertension
- hyperlipidemia
Type 2 diabetes
Insulin Resistance – Vascular
Abnormalities Start Early
T2 DM: TREATMENT
• Healthy Eating
• Exercise
• Self blood glucose tests
Type 2 diabetes management
• Lipids
• Blood pressure
• Aspirin
• Control blood glucose
T2 DM: TREATMENT
• Healthy Eating
• Exercise
• Self Blood Glucose Monitoring
• Oral anti-diabetic agents
Standard Approach to the Management
of T2DM: Treatment Intensification
Insulin
Oral + Insulin
Oral Combination
Oral Monotherapy
Diet and Exercise
+
+
+
Pharmacologic Targets of Current Drugs Used in
the Treatment of T2DM
GLP-1 analogues
Improve pancreatic islet glucose sensing,
slow gastric emptying, improve satiety
DPP-4 inhibitors
Prolong GLP-1 action leading to
improved pancreatic islet glucose
sensing, increase glucose uptake
Thiazolidinediones
Decrease lipolysis in adipose
,
tissue increase glucose
Sulfonylureas
Increase insulin
secretion from
pancreatic -cells
uptake in skeletal muscle
and decrease glucose
production in liver
-glucosidase inhibitors
Delay intestinal
carbohydrate absorption
What are the side effects
of sulphonylureas?
• The most clinically significant side
effect is hypoglycemia
• Others
– gastrointestinal upset
– rash
– weight gain ****
What are the side effects
of Metformin?
• Gastrointestinal - anorexia, nausea,
abdominal discomfort and diarrhoea
– occurs in 5-20% of patients but usually
transient and can be minimised if
therapy is introduced with a low dose
taken after meals
• No hypoglycemia if used alone
• Lactic acidosis
Blood glucose and
development of diabetes
complications
Control vs Complications
Risk of complications
developing or progressing
12
10
8
6
4
2
6.0
Diabetes Control and Complication Trial (DCCT)
7.0
8.0
9.0
10.0
HbA1c %
GLOBAL PROJECTIONS FOR THE DIABETES
EPIDEMIC: 1995-2010 (millions)
22.0
32.9
50%
13.0
17.5
35%
7.3
14.1
93%
12.4
22.5
81%
62.8
132.3
111%
0.9
1.3
44%
World
1995 = 118 million
2010 = 221 million
Increase 87%
Diagnosis
Diagnostic Criteria
Diagnostic level of fasting plasma glucose
is > 7.0 mmol/L.
With typical symptoms of diabetes,
– a single fasting plasma glucose level of > 7.0
mmol/L, or
– a 2 hour post prandial or random glucose of >
11.1 mmol/L are sufficient for diagnosis.
Diagnostic Criteria
If no or equivocal symptoms of diabetes
– at least one additional glucose measurement
(preferably fasting) on a different day with a
value in the diabetic range is necessary to
confirm diagnosis
Severe hyperglycaemia detected under
conditions of acute infective, traumatic,
circulatory or other stress may be
transitory and should not be regarded as
diagnostic
– further testing when the condition has
stabilised
Diagnostic criteria
Glucose concentration, mmol/L
Whole blood
Plasma*
Venous
Capillary
Venous
Diabetes Mellitus:
Fasting or
2-h post glucose load
Impaired Glucose Tolerance
(IGT)
Fasting concentration
2-h post glucose load
Impaired Fasting Glycaemia
(IFG)
Fasting
2-h post glucose load
>6.1
>10.0
>6.1
>11.1
>7.0
>11.1
>6.1 and
>6.7
>6.1 and
>7.8
>7.0 and
>7.8
>5.6 and
>6.7
>5.6 and
<7.8
>6.1
<7.8
Prevalence (%) of abnormal glucose
tolerance among Australian residents
%
15
12.0
Males
Females
Total
10.6
10
9.2
8.1
8.0
7.0
5.7
5
3.3
0
IGT
IFG
Glucose tolerance status
Diabetes
7.5
Disorders of glycaemia:
aetiological types and clinical stages
Why control glucose, lipids and blood
pressure?…..to avoid devastating
diabetic complications
• Cardiovascular
problems • Diabetic
neuropathy
• Diabetic
retinopathy
• Renal
disease
What about prevention of
type 2 diabetes?
Pre-diabetes management:
Lifestyle intervention
Finnish Diabetes Prevention
Study
(DPS)
Management – wt
reduction/exercise
Finnish Diabetes Prevention Study
-n=522, mean 55 years, BMI 33.2 kg/m2
-IGT
- weight-reduction & exercise v control
- individualized counseling aimed at
reducing weight, total intake of fat, and
intake of saturated fat and increasing
intake of fiber and physical activity
Finnish Diabetes Prevention Study
(DPS)
58% RRR
Control
Weight
reduction &
exercise
Wt
0.8kg
3.5kg
Diabetes
23%
11%
Lancet 368:1673-1697, 2006