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 www.drharper.ca

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

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

Pathophysiology of T1DM antibodies attack islets!

Pathophysiology of T2DM _ Hepatic glucose output INSULIN + Blood glucose Peripheral Tissue Uptake diet

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

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)

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 - 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)

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.

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 1155 patients MI 1347 patients Cohort study DM 3477 patients MI 7414 patients

Insulin Glargine (Lantus)

Insulin Glargine (Lantus)

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

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

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 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 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 = 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 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.

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 “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?