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

Diabetes MellitusDiabetes Mellitus

Type 1, IDDM, Juvenile-onset

Type 2, NIDDM, Adult-onset

The pancreas!

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

Pathophysiology of T1DMPathophysiology of T1DM

antibodiesattack islets!

Pathophysiology of T2DMPathophysiology of T2DM

Blood glucose

diet

Hepatic glucose output INSULIN

PeripheralTissueUptake

+

_

Natural History of Type 2 DiabetesNatural History of Type 2 Diabetes

Normal Impaired glucosetolerance

Type 2 diabetes

Time

Insulinresistance

Insulinproduction

Glucoselevel

-celldysfunction

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)

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

The answer is magically ridiculous…The answer is magically ridiculous…

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)

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

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

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

Is there any reason to be hopeful?Is there any reason to be hopeful?

Is there any reason to be hopeful?Is there any reason to be hopeful?

YES!YES!

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

Insulin Glargine (Lantus)Insulin Glargine (Lantus)

Insulin Glargine (Lantus)Insulin Glargine (Lantus)

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

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

Control Zucker Rats ROSIG Zucker Rats

12 weeks

16 weeks

Thiazolidinedione Thiazolidinedione ββ-cell preservation: -cell preservation: Animal studiesAnimal studies

UKPDS 33, Lancet 352:837-53, 1998.

STENO-2, NEJM, 348:383-93, 2003.

DCCT, NEJM 329:977-86, 1993.

Heart Protection StudyHeart Protection Study

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

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

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

DM NephropathyDM Nephropathy

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

SmokingSmoking

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

Future…Future…

Non-invasive BS testingContinuous BS monitor + insulin pump

“Artificial Pancreas”

Islet cell transplants Stem-cell research

Energy homeostasis breakthroughs…

Cause for insulin resistance?Cause for Type 2 DM?Cause for obesity?

An exercise pill?