diabetes mellitus mcmaster mini-med school march 17, 2004 dr. william harper assistant professor of...
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Diabetes mellitusDiabetes mellitus
McMaster Mini-Med School
March 17, 2004
Dr. William HarperAssistant Professor of Medicine, McMaster University.
Endocrinologist, Hamilton General Hospital
www.drharper.ca
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Diabetes MellitusDiabetes Mellitus
Type 1, IDDM, Juvenile-onset
Type 2, NIDDM, Adult-onset
The pancreas!
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Type 1 v.s. Type 2 DiabetesType 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
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Pathophysiology of T1DMPathophysiology of T1DM
antibodiesattack islets!
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Pathophysiology of T2DMPathophysiology of T2DM
Blood glucose
diet
Hepatic glucose output INSULIN
PeripheralTissueUptake
+
_
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Natural History of Type 2 DiabetesNatural History of Type 2 Diabetes
Normal Impaired glucosetolerance
Type 2 diabetes
Time
Insulinresistance
Insulinproduction
Glucoselevel
-celldysfunction
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Rising DM Prevalence (Rising DM Prevalence (DiagnosedDiagnosed))
0
50
100
150
200
250
300
N (
mill
ion
s)
1995 2000 2025
Developed WorldDeveloping World
Whole World
5.9 6.2 7.6
3.3 3.54.9
4.04.2
5.4
(Decimal Numbers = Percent of the population affected)
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Why is the prevalence of Type 2 Why is the prevalence of Type 2 Diabetes mellitus increasing?Diabetes mellitus increasing?
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The answer is magically ridiculous…The answer is magically ridiculous…
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Summary: Public Health ImpactSummary: 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)
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Macrovascular Microvascular
Stroke
Heart disease and hypertension
2-4 X increased risk
Foot problems
Diabetic eye disease(retinopathy and cataracts)
Renal disease
Peripheral Neuropathy
Peripheral vascular disease
Diabetes: ComplicationsDiabetes: Complications
Meltzer et al. CMAJ 1998;20(Suppl 8):S1-S29.
Complications
Erectile Dysfunction
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Disease Burden of Diabetes MellitusDisease 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
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Haffner et al, NEJM, 339(4):229-34, 1998.Haffner et al, NEJM, 339(4):229-34, 1998.
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Is there any reason to be hopeful?Is there any reason to be hopeful?
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Is there any reason to be hopeful?Is there any reason to be hopeful?
YES!YES!
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Evans et al.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
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Insulin Glargine (Lantus)Insulin Glargine (Lantus)
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Insulin Glargine (Lantus)Insulin Glargine (Lantus)
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InsulinInsulin
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
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GLUCOSE ABSORPTION
GLUCOSE PRODUCTION
Metformin Thiazolidinediones
MUSCLE
PERIPHERAL GLUCOSE UPTAKE Thiazolidinediones Metformin
PANCREAS
INSULIN SECRETION Sulfonylureas: Glyburide, Gliclazide, Glimepiride Non-SU Secretagogues: Repaglinide, Nateglinide
ADIPOSE TISSUELIVER
Alpha-glucosidase inhibitors
INTESTINE
Sites of Action of Currently Sites of Action of Currently Available Therapeutic OptionsAvailable Therapeutic Options
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Control Zucker Rats ROSIG Zucker Rats
12 weeks
16 weeks
Thiazolidinedione Thiazolidinedione ββ-cell preservation: -cell preservation: Animal studiesAnimal studies
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UKPDS 33, Lancet 352:837-53, 1998.
STENO-2, NEJM, 348:383-93, 2003.
DCCT, NEJM 329:977-86, 1993.
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Heart Protection StudyHeart Protection Study
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BP Trials in DM patientsBP 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
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BP Trials in DM patientsBP 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
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Effect of ACE InhibitionEffect of ACE Inhibitionin Diabetesin Diabetes
HOPE StudyHOPE Study
Relative Risk Reduction of Ramipril vs. Placebo in Subjects with Diabetes
22% Myocardial infarction p = 0.01
33% Stroke p = 0.0074
37% Cardiovascular death p = 0.0001
24% Overt nephropathy p = 0.027
17% Revascularization p = 0.031
20% Heart failure p = 0.019
Complications
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DM NephropathyDM Nephropathy
Microalbuminuria: 30-300 mg/d (20-200 ug/min)Macroalbuminuria: > 300 mg/d (> 200 ug/min)
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SmokingSmoking
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Reducing risk in diabetesReducing 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
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Future…Future…
Non-invasive BS testingContinuous BS monitor + insulin pump
“Artificial Pancreas”
Islet cell transplants Stem-cell research
Energy homeostasis breakthroughs…
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Cause for insulin resistance?Cause for Type 2 DM?Cause for obesity?
An exercise pill?