Diabetes Overview. Sarah Capes MD, FRCPC Assistant Professor, McMaster University Spring 2003

Transcription

1 Diabetes Overview Sarah Capes MD, FRCPC Assistant Professor, McMaster University Spring 2003 Outline What is diabetes and why is it important? How is diabetes treated and how can serious health consequences be prevented? Can diabetes be prevented? What is diabetes? Diabetes is a disease defined by fasting glucose levels of 7 or higher This level is important because it means that, if ignored, there is a high future risk of microvascular disease (heart, eye, kidney, nerve) CVD occurs at lower glucose cut-offs Diagnosis of Diabetes Plasma glucose after an 8-hour fast of 7.0 or higher on 2 separate occasions OR Random glucose 11.1 or higher plus symptoms OR 2-hour glucose 11.1 or higher on 75-g OGTT Note Normal av g fasting glucose: 5.1 mmol/l Normal av g 2 hr glucose: 5.4 mmo/l How Common is Diabetes? 8% (1 in 12 ) of adults age 20 and over 13% (1 in 8) age % (1 in 5) age 75 and over Note: If fasting glucose was done on everyone, 1 new case of diabetes would be diagnosed for every 2 people who already have diabetes Who is at risk for Diabetes? Age > 45 Ancestry 1 st Nations > S. Asians > Black Canadians >White Canadians Westernized Society Overweight + abdominal distribution Family History Previous Gestational Diabetes (or baby over 4.5 kg) Hypertension or heart disease Polycystic ovary syndrome

2 What Causes Diabetes? Diabetes develops when the beta cells of the pancreas can t make enough insulin to maintain normal glucose level. The beta cells may be destroyed, or damaged. For most diabetes, reasons for this beta cell problem are poorly understood. Type 1: Autoimmune Antibodies against beta cells (eg islet cell antibodies, insulin autoantibodies, GAD antibodies etc present at diagnosis)? Environmental trigger (viruses, cow s milk) Genetic (HLA-DR3 & DR4, HLA-DQ) Type 2: Overworked pancreas Strong genetic component Physiologic Effects of Insulin Deficiency Hyperglycemia Blood glucose rises above normal level of about 5 Glucosuria, polyuria, polydipsia Weight loss Breakdown of muscle and stored fats Ketone production Liver oxidizes fatty acids to ketones Types of Diabetes Type 1 Diabetes Mellitus Due to Beta-cell destruction Prone to ketoacidosis Most are due to autoimmune processes; rest are idiopathic Type 2 Diabetes Mellitus Results from insulin resistance + insulin secretory defect Gestational Diabetes Mellitus (GDM) Diabetes recognized for the first time in pregnancy Other Types-eg secondary to CF, steroids, etc Clinical Features of Diabetes If not treated appropriately, DM can lead to. blindness (most common cause worldwide) renal failure (most common cause of new cases of ESRD in N America) amputation (most common cause) MI and strokes ½ of people with diabetes have CVD foot ulcers, foot pain, gastroparesis, erectile dysfunction, other complaints

3 Diabetic Retinopathy Background retinopathy: o blot hemorrhages o hard exudates (leakage into deep retinal layers) o soft exudates (microinfarcts in superficial retinal layer) Proliferative retinapathy: o fragile new vessels form that may rupture & bleed Diabetic Nephropathy Pathology: diffuse & nodular glomerulosclerosis; mesangial expansion; hyaline thickening of afferent and efferent arterioles Microalbuminuria is the earliest recognizable stage of diabetic nephropathy Microalbuminuria progresses to clinical proteinuria at a rate of 4% per year Diabetic Neuropathies Transient Acute painful neuropathies (eg femoral neuropathy) Mononeuropathies (eg 3 rd or 6 th cranial nerve palsy) Radiculopathies Progressive Sensorimotor polyneuropathies, with or without autonomic symptoms and signs Diabetic amyotrophy Pathophysiology of microvascular complications Chronic hyperglycemia is primary cause Exact mechanism not understood Hypotheses: Accumulation of advanced glycosylation end products Accumulation of sorbitol Impaired vascular autoregulation Genetic factors important Population Impact of Diabetes In Canada, diabetes costs taxpayers $7-10 billion/yr. In Ontario, there are up to people with diabetes The high cost and rate means that diabetes is a major public health problem

4 Glucose Lowering Drugs (Type 2) Sulfonylureas glyburide (Diabeta), gliclazide (Diamicron) Meglitinides repaglinide (Gluconorm) Thiazolidinediones rosiglitazone (Avandia); pioglitazone (Actos) Acarbose (Prandase) Metformin (Glucophage) Combinations with each other and insulin Natural history of type 2 DM Early type 2 DM is characterized by insulin resistance, which is partially compensated for by overproduction of insulin by the pancreas As time goes on, ability of pancreas to produce insulin declines Eventually, overnight insulin production ceases and fasting hyperglycemia results Insulin in type 2 DM Insulin can be combined with most of the oral hypoglycemic agents to control fasting hyperglycemia Insulin at bedtime with oral agents during day is as effective as multiple daily insulin (MDI) in type 2 DM, and is associated with less weight gain Starting insulin in type 2 DM Add bedtime dose of insulin to 1 oral hypoglycemic agent Start with 5 10 U of NPH qhs Increase by 2-3 U every 3 4 days until fasting glucose is 6 7 mmol/l When endogenous insulin secretion declines further (resulting in hyperglycemia during the day) change to MDI Types of Insulin Rapid-acting: Lispro (Humalog), Aspart (NovoRapid) Short-acting: Humulin Regular, Novolin Toronto Intermediate-acting: N, Lente (Humulin and Novolin) Long-acting: Ultralente Pen devices (simple/complex) Wearable insulin pumps Implantable insulin pumps (research) Inhaled insulin (research) Conventional Insulin Therapy: Mixture of short- and long-acting insulin given twice per day (before breakfast and supper) Patient may mix insulin types, or may use pre-mixed insulin (30/70, 50/50 insulin etc)

5 Basal-bolus Insulin Therapy: Rapid or short-acting insulin before each meal ( bolus ), with one or two daily injections of intermediate or long-acting insulin ( basal ) Mimics physiologic insulin secretion Allows more flexibility with meal times and activity Carbohydrate counting Allows bolus dose of insulin to be matched to carbohydrate intake Can be implemented as: a stable meal plan, OR a way for pt to adjust dose of insulin based on planned carb intake (usually about 1 U per g) Insulin Pumps (CSII) Continuous subcutaneous delivery of insulin (usually U/hr) usually 2 or 3 basal rates in a 24-hr period Boluses of insulin given before meals Minimizes depots of insulin (which can have variable absorption) Most physiologic method of insulin delivery Insulin Pumps (CSII) Advantages: Improved glycemic control (especially if basal-bolus insulin program failed to solve problems such as nocturnal hypoglycemia, dawn phenomenon) Increased lifestyle flexibility (eg. Shift workers, competitive athletes) Disadvantages: Infection at infusion site Interruption of insulin supply can lead rapidly to diabetic ketoacidosis Increased cost Altered body image Glucose Monitoring recommended for all people with diabetes newer monitors are fast, easy, & have memory monitors can often be downloaded to a computer some new meters can be used at alternate test sites (eg forearm) wearable monitors bloodless systems (in development) light beam based Goals for Glycemic Control in DM (1998 Canadian Clinical Practice Guidelines) HbA1c < 0.07 (normal < 0.06) Fasting and pre-prandial: hours after meal: 5-11

6 Preventing Vision Loss in DM Risk factors for vision loss: Poor glycemic control Hypertension (SBP > 130) risk continuous Dyslipidemia Strategies to prevent vision loss Regular eye exams Scatter laser treatment slows progression of retinopathy and reduces vision loss by 50-60% in people with high-risk eyes Control hypertension in UKPDS (United Kingdom Prospective Diabetes Study): reduced deterioration in visual acuity by 47% Tight glycemic control slowed progression of retinopathy in UKPDS (Lancet 352:837, 1998) Renal Disease in DM Clinical proteinuria is a strong risk factor for end-stage renal failure in DM Microalbuminuria is the earliest recognizable stage of diabetic nephropathy Microalbuminuria progresses to clinical proteinuria at a rate of 4% per year Yearly screening for microalbuminuria with a urine sample for albumin:creatinine ratio is recommended (note: microalbuminuria is not detectable on urine dipstick) Risk factors for microalbuminuria & renal insufficiency Poor glycemic control 10-year risk of renal insufficiency almost doubles for every 1% increase in HbA1c Hypertension High cholesterol Longer duration of DM Male sex Strategies to prevent renal insufficiency Blood pressure control (target < 130/80) Reduces decline in GFR and albuminuria ACE inhibitors Reduce progression of microalbuminuria Reduce rate of end-stage renal failure Mild protein restriction (recommended for patients with overt proteinuria) Tight glycemic control

7 Preventing Cardiovascular Disease in DM BP control (target < 130/80) Lipid control (HMG CoA reductase inhibitors statins ) 1 prevention: 37% reduction in CVD (AFCAPS/TEXCAPS study) 2 prevention: 55% reduction in CVD (4S study) ACE inhibitors HOPE study (N Engl J Med 342: 145, 2000): in patients >= 55 at high risk for CVD because of previous CVD or DM + at least 1 other risk factor, the ACE inhibitor ramipril lowered the primary outcome (CV death/mi/stroke) by 25% Glycemic control (under study) Can diabetes be prevented? Preventing Diabetes: Current Research Type 1 diabetes Immunosuppressants Breast-feeding vs. cows milk Type 2 diabetes Proven therapies for patients with impaired glucose tolerance: Diet and exercise (Diabetes Prevention Program) Acarbose (STOP study) Metformin (Diabetes Prevention Program) Under study: ramipril & rosiglitazone (DREAM Study) The Diabetes Prevention Program (NEJM 346:393, 2002) people aged with impaired glucose tolerance and BMI >= 24 kg/m 2 Randomly assigned to standard lifestyle advice vs intensive lifestyle modification: Exercising for at least 150 minutes per week Eating a balanced, low-fat diet Losing some weight (about lbs) Reduced risk of new diabetes by 58% Metformin also reduced new diabetes by 31% Diabetes Cure? Research underway: Islet cell transplantation Islet cell cloning Islet cell growth research is focused on type 1 DM

8 Islet cell transplantation Experimental therapy for type 1 diabetes Indicated for patients with type 1 DM, with uncontrolled DM or recurrent severe hypoglycemia, despite optimal medical therapy Ongoing research at University of Alberta & other sites Initial study published in July 2000: 7 people with type 1 diabetes who had uncontrolled diabetes or recurrent severe hypoglycemia Received transplant of islet cells from donors All 7 insulin-free at 14 months