1. McMaster Mini-Med School
Diabetes mellitus
McMaster Mini-Med School
March 17, 2004
Dr. William Harper
Assistant Professor of Medicine, McMaster University.
Endocrinologist, Hamilton General Hospital

2. Diabetes Mellitus Type 1, IDDM, Juvenile-onset
Type 2, NIDDM, Adult-onset
The pancreas!

4. Type 1 v.s. Type 2 Diabetes Type 1 DM (< 10%) Type 2 DM (> 90%)
Age of onset
< 40
> 40
DKA
Yes No
Weight
Usually lean
80% overweight
Cause
Autoimmune or unknown
No autoimmune markers

5. Pathophysiology of T1DM
antibodies
attack islets!

6. Pathophysiology of T2DM_
Hepatic glucose output
INSULIN +
Blood glucose
Peripheral
Tissue
Uptake
diet

7. Natural History of Type 2 Diabetes
Insulin
resistance
Glucose
level
Insulin
Natural History of Type 2 Diabetes
Prior to type 2 diabetes insulin levels are similar and constant. In the majority of patients that go on to develop type 2 diabetes, increasing insulin resistance leads to an increases in circulating insulin. So as insulin resistance increases, so does the production of insulin needed to keep blood sugars normal. As time progresses, the insulin resistance reach a peak and stabilize while the insulin producing cells begin to wear out. We call it pooped out pancreas.
First,
Impaired Glucose Tolerance (IGT): This is the point that the Beta cell begins to fail and blood sugars begin to elevate, especially after a large CHO load..
Type 2 Diabetes: Following the onset of Beta-cell dysfunction, insulin levels can no longer overcome insulin resistance, and fasting and postprandial glucose levels increase progressively over time.
production b
-cell
dysfunction
Time
Normal
Impaired glucose
Type 2 diabetes
tolerance

8. Rising DM Prevalence (Diagnosed)
5.4
4.2
4.0
4.9
3.5
3.3
5.9
6.2
7.6
(Decimal Numbers = Percent of the population affected)

9. Why is the prevalence of Type 2 Diabetes mellitus increasing?

10. The answer is magically ridiculous…

11. 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 - age 40-49: 12%
- age 50-59: 14%
- age 60-74: 21%
DM Risk in IGT: - from epi studies: 4 – 6%/year
DM Impact (USA) - $130B/yr (much of it  CVD)

12. Diabetes: Complications
Macrovascular
Microvascular
Stroke
Diabetic eye disease
(retinopathy and cataracts)
Heart disease and hypertension
2-4 X increased risk
Renal disease
Peripheral
vascular disease
Erectile Dysfunction
The risk of CAD and stroke is increased two to four times in patients with diabetes. Cardiovascular disease is a major cause of morbidity and mortality in diabetes. Morbidity and mortality rates are two to four times higher than in age- and sex-matched groups in the population without diabetes.
The eye and the kidney are common sites for microvascular complications of diabetes. Diabetic retinopathy is the leading cause of adult blindness in North America. Cataracts and glaucoma are also significantly more frequent in patients with diabetes, especially those over age 65. Diabetes is the leading cause of end-stage renal failure.
Foot problems, a frequent consequence of neuropathy and peripheral vascular disease, constitute a major complication. Diabetes is the leading cause of non-traumatic lower-extremity amputations in North America.
Peripheral Neuropathy
Foot problems
Meltzer et al. CMAJ 1998;20(Suppl 8):S1-S29.

13. 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

14. Haffner et al, NEJM, 339(4):229-34, 1998.

15. Is there any reason to be hopeful?

16. Is there any reason to be hopeful? YES!

17. Evans et al. BMJ 324: 939-942 April 2002 Cross-sectional study
DM 1155 patients
MI 1347 patients
Cohort study
DM 3477 patients
MI 7414 patients

19. Insulin Glargine (Lantus)

20. Insulin Glargine (Lantus)

21. Insulin Type Starts Peaks Duration Humalog NovoRapid 5-10 min 0.5-1hrs
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

22. Sites of Action of Currently Available Therapeutic Options
MUSCLE
ADIPOSE TISSUE
LIVER
PANCREAS
GLUCOSE PRODUCTION
Metformin
Thiazolidinediones
PERIPHERAL
GLUCOSE UPTAKE
Thiazolidinediones
Metformin
INSULIN SECRETION
Sulfonylureas: Glyburide, Gliclazide, Glimepiride
Non-SU Secretagogues: Repaglinide, Nateglinide
INTESTINE
GLUCOSE ABSORPTION
Alpha-glucosidase inhibitors

23. Thiazolidinedione β-cell preservation: Animal studies
12 weeks
16 weeks
Control Zucker Rats
ROSIG Zucker Rats

24. STENO-2, NEJM, 348:383-93, 2003.
UKPDS 33, Lancet 352:837-53, 1998.
DCCT, NEJM 329:977-86, 1993.

25. Heart Protection Study

26. 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

27. BP Trials in DM patients
UKPDS: atenolol = captopril in  events
HOT: felodipine,  CV events with DBP < 80
ALLHAT
Chlorthalidone > lisinopril or amlodipine (less CHF)
Chlorthalidone  BS/diagnosis of DM
LIFE (DM substudy)
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

29. Effect of ACE Inhibition in Diabetes HOPE Study
Complications
Effect of ACE Inhibition in Diabetes HOPE Study
Relative Risk Reduction of Ramipril vs. Placebo in Subjects with Diabetes
22% Myocardial infarction p = 0.01
33% Stroke p =
37% Cardiovascular death p =
24% Overt nephropathy p = 0.027
17% Revascularization p = 0.031
20% Heart failure p = 0.019
This study investigated whether the ACE inhibitor ramipril could lower the risks of cardiovascular and renal disease in patients with diabetes. Ramipril significantly lowered the risks of myocardial infarction, stroke, cardiovascular death, total mortality, revascularization and overt nephropathy during the study.
The study concluded that ramipril provides a vasculoprotective and renoprotective effect in patients with diabetes.

30. DM Nephropathy Microalbuminuria: 30-300 mg/d (20-200 ug/min)
Macroalbuminuria: > 300 mg/d (> 200 ug/min)

31. Smoking

33. 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

35. Future… Non-invasive BS testing Continuous BS monitor + insulin pump
“Artificial Pancreas”
Islet cell transplants
Stem-cell research
Energy homeostasis breakthroughs…

36. Cause for insulin resistance?
Cause for Type 2 DM?
Cause for obesity?
An exercise pill?