Diabetes mellitus
McMaster Mini-Med School
March 17, 2004
Dr. William Harper
Assistant Professor of Medicine, McMaster University.
Endocrinologist, Hamilton General Hospital
www.drharper.ca
Diabetes Mellitus

Type 1, IDDM, Juvenile-onset

Type 2, NIDDM, Adult-onset
The pancreas!
Type 1 v.s. Type 2 Diabetes
Age of onset
Type 1 DM
(< 10%)
< 40
Type 2 DM
(> 90%)
> 40
DKA
Yes
No
Weight
Usually lean
80% overweight
Cause
Autoimmune or No autoimmune
unknown
markers
Pathophysiology of T1DM
antibodies
attack islets!
Pathophysiology of T2DM
Hepatic glucose output
_
Blood glucose
diet
INSULIN
+
Peripheral
Tissue
Uptake
Natural History of Type 2 Diabetes
Insulin
resistance
Glucose
level
b -cell
dysfunction
Normal
Impaired glucose
tolerance
Insulin
production
Time
Type 2 diabetes
Rising DM Prevalence (Diagnosed)
5.4
N (millions)
300
250
200
150
4.9
3.5
3.3
100
50
4.2
4.0
Whole World
5.9
6.2
7.6
1995
2000
2025
0
Developing World
Developed World
(Decimal Numbers = Percent of the population affected)
Why is the prevalence of Type 2
Diabetes mellitus increasing?
The answer is magically ridiculous…
Summary: Public Health Impact

DM Prevalence - 1/14; 1/8 of age 40-75; 1/5 of 75+
- 1/3 unaware that they have DM
- increasing throughout world

IGT

DM Risk in IGT:
 DM Impact (USA)
- age 40-49: 12%
- age 50-59: 14%
- age 60-74: 21%
- from epi studies: 4 – 6%/year
- $130B/yr (much of it  CVD)
Complications
Diabetes: Complications
Macrovascular
Stroke
Microvascular
Diabetic eye disease
(retinopathy and cataracts)
Heart disease and
hypertension
2-4 X increased risk
Renal disease
Peripheral
vascular disease
Erectile Dysfunction
Peripheral Neuropathy
Foot problems
Meltzer et al. CMAJ 1998;20(Suppl 8):S1-S29.
Disease Burden of Diabetes Mellitus
•
•
•
•
•
•
•
Leading cause of blindness (12.5% of cases)
Leading cause of ESRD (42% of cases)
50% of all non-traumatic amputations
2.5x increase risk of stroke
2-4x increase in cardiovascular mortality
DM responsible for 25% of cardiac surgeries
Mortality in DM: 70% due to Cardiovascular
disease
Haffner et al, NEJM, 339(4):229-34, 1998.
Is there any reason to be hopeful?
Is there any reason to be hopeful?
YES!
Evans et al.

BMJ 324: 939-942
 April 2002
 Cross-sectional study



DM
MI
1155 patients
1347 patients
Cohort study


DM
MI
3477 patients
7414 patients
Insulin Glargine (Lantus)
Insulin Glargine (Lantus)
Insulin
Type
Starts
Peaks
Duration
Humalog
NovoRapid
5-10 min
0.5-1hrs
3.5 hrs
Regular
30 min
2-4 hrs
6-8 hrs
NPH
Lente
1-2 hrs
6-10 hrs
16-24 hrs
Ultralente
4-6 hrs
8-24 hrs
24-36 hrs
Glargine
1.5h
None
Up to 24 hrs
Sites of Action of Currently
Available Therapeutic Options
ADIPOSE
TISSUE
LIVER
MUSCLE
PANCREAS
GLUCOSE
PRODUCTION
Metformin
Thiazolidinediones
INTESTINE
PERIPHERAL
GLUCOSE UPTAKE
Thiazolidinediones
Metformin
INSULIN SECRETION
Sulfonylureas: Glyburide, Gliclazide, Glimepiride
Non-SU Secretagogues: Repaglinide, Nateglinide
GLUCOSE
ABSORPTION
Alpha-glucosidase inhibitors
Thiazolidinedione β-cell preservation:
Animal studies
12 weeks
16 weeks
Control Zucker Rats
ROSIG Zucker Rats
STENO-2, NEJM, 348:383-93, 2003.
UKPDS 33, Lancet 352:837-53, 1998.
DCCT, NEJM 329:977-86, 1993.
Heart Protection Study
BP Trials in DM patients




UKPDS
atenolol = captopril at
reducing outcomes
(UKPDS 39)
Benefit to reducing SBP < 120
(UKPDS 36, post-hoc
subgroup analysis)
Currently SBP target < 120
being assessed in BP arm of
the ACCORD Study
BP Trials in DM patients
UKPDS: atenolol = captopril in  events
 HOT: felodipine,  CV events with DBP < 80
 ALLHAT




LIFE (DM substudy)



Chlorthalidone > lisinopril or amlodipine (less CHF)
Chlorthalidone  BS/diagnosis of DM
1195 patients with DM/HTN/LVH
Losartan > atenolol in  CV death/MI/CVA despite equivalent
BP lowering effects
HOPE: not a BP trial per se
Complications
Effect of ACE Inhibition
in Diabetes
HOPE Study
Relative Risk Reduction of Ramipril vs. Placebo in Subjects with Diabetes
22%
33%
37%
24%
17%
20%
Myocardial infarction
Stroke
Cardiovascular death
Overt nephropathy
Revascularization
Heart failure
p = 0.01
p = 0.0074
p = 0.0001
p = 0.027
p = 0.031
p = 0.019
DM Nephropathy
Microalbuminuria: 30-300 mg/d (20-200 ug/min)
Macroalbuminuria: > 300 mg/d (> 200 ug/min)
Smoking
Reducing risk in diabetes

Glycemic control:








New insulins
New oral agents
CBG testing: new sites (forearm), smarter monitors
BP control
ACE inhibitors
Cholesterol control
Aspirin
Smoking cessation
Future…

Non-invasive BS testing
 Continuous BS monitor + insulin pump


Islet cell transplants


“Artificial Pancreas”
Stem-cell research
Energy homeostasis breakthroughs…
Cause for insulin resistance?
Cause for Type 2 DM?
Cause for obesity?
An exercise pill?