Causes and Complications of Diabetes Flashcards
What is Diabetes?
- Metabolic disease - raised plasma glucose levels
- Caused by failure of insulin- regulation of metabolism
- Hyperglycemia causes microvascular and macrovascular complications
How does hyperglycemia cause diabetic complications?
- Microvascular complications caused by hyperglycemia
- Damage to endothelial lining of small blood vessels
- Macrovascular complications increased free fatty acids
- Plaque deposition in arterial walls
- Increased FAOx -> oxidative stress?
Macrovascular complications
- Diabetes an independent risk factor for
- coronary artery disease,
- cerebrovascular disease,
- peripheral vascular disease. eg deep vein thrombosis
- Often comorbid for other risk factors, including:
- obesity,
- hypertension,
- hyperlipidemia,
- altered platelet function.
- Type 2 diabetes - macrovascular disease often present at diagnosis.
- Type 1 diabetes - age and duration of diabetes correlate with degree of macrovascular disease
Implications for treatment
- Most treatments target hyperglycemia
- Clear benefits of tight glycemic control for microvascular complications
- DM clear risk-factor for macrovascular disease
- Macrovascular benefits of glycemic control less clear
- Important to treat co-morbities
Insulin Dependent Diabetes Mellitus
- Type 1 Diabetes Juvenile-onset diabetes
- defect: Autoimmune destruction of β-cells
- age of onset: 1-25 Years
- physique: lean
- prevalence - 0.5%
- treatment: insulin
Non-Insulin Dependent Diabetes Mellitus
- Type 2 Diabetes Late-onset diabetes
- defect: insulin resistance Defective insulin secretion,
- age of onset: >40 Years (but getting younger)
- physique: obese
- prevalence - >2%
- treatment: Diet, drugs, insulin
Type I diabetes is an autoimmune disease
- Antibody-mediated immune destruction of beta cells
- Insulin-secreting cells in islets of Langerhans
- Progressive loss (months to years)
- Usually during adolescence
- Marked hyperglycaemia seen when 80-90% of beta cells lost
Geographic and seasonal variations suggest environmental factors
- Candidates include:
- Viruses (incl. mumps, Coxsackie B4, retroviruses, rubella)
- Specific drugs or chemicals (dietary nitrosamines (found in smoked and cured meats) and coffee)
- Dietary constituents (cow’s milk in infancy)
- Reduced exposure to microorganisms in early childhood (hygiene hypothesis)
Major complications of Type I diabetes
- Chronic effects of hyperglycemia
- Hypoglycemia
- Due to overadministration of insulin
- Diabetic ketoacidosis
- generation of ketone bodies exceeds metabolism
- Latter both potentially fatal
Diabetic Ketoacidosis
- fatty acids are converted to ketone bodies in the liver
• Uncontrolled lipolysis & β-oxidation -> over- production of ketone bodies
• Ketone bodies are strong acids -> overwhelms the buffering capacity of the body -> acidosis -> coma & death
What Causes Type II diabetes?
- Inability of insulin to exert effects on liver & adipose
- Insulin resistance
- Secondary “islet exhaustion”
- Hyperglycemia & high FFA
What causes insulin resistance?
- Strong genetic component
- Identical twins >90% concordant
- Indigenous populations
- Environment Important
- Increased incidence over last century
- Genotype clearly hasn’t changed!!
- What’s changed?
- Lifestyle, exercise, habits,
- Most commonly associated with obesity (>80% of cases)
- DIET!
What causes insulin resistance?
• Ectopic lipid accumulation
• Liver and muscle triglyceride “ insulin sensitivity
• Accumulation of lipid mediators (diacylglycerol & ceramide) may alter protein phosphorylation
• Cellularstress-responses
• Mitochondrial and protein-production machinery
breaks down
• Alters insulin signaling pathways
• Likely downstream of ectopic lipid accumulation
• Inflammation
• Macrophages in adipose tissue accumulate lipid
• ->secretion of inflammatory cytokines (TNFα)
• Alters insulin signalling pathways in muscle & liver
• Ectopic lipid accumulation underlies Insulin resistance
• Driven by over consumption of nutrients
• Fat-storage capacity of adipose tissue overwhelmed
Complications Due To Diabetes
- Microvascular damage leads to:
- Retina (diabetic retinopathy): leading, ultimately, to blindness
- Kidney (niabetic nephropathy): leading to end stage renal failure
- Nerves (diabetic neuropathy): leading to debilitating neuropathy
Peripheral neuropathies Caused by
- Endothelial damage !wall thickening -> ischemia & neural death
- Segmental demyelinization & slowing of nerve conduction.
- The clinical manifestations vary with the location of the lesion.
Diabetic Peripheral Neuropathies
Somatic: (sensory and motor nerves
• Paresthesias, including numbness and tingling
• Impaired pain, temperature, light touch, two- point discrimination, and vibratory sensation
Autonomic:
• Vasomotor function - Postural hypotension
• Gastrointestinal function - Gastric atony, postprandial and nocturnal Diarrhoea,
• Genitourinary function - Paralytic bladder/ Incomplete voiding; Impotence
• Cranial nerve - Impaired pupillary responses
Diabetic foot ulcers
• Foot problems are common
• ulceration and infection, even amputation.
• Impaired pain sensation
• often unaware of poorly fitting shoes, improper weight
bearing or infections.
• Motor neuropathy may result in foot deformities
• -> focal areas of high pressure.
• Common sites of trauma
• back of the heel, plantar metatarsal area, or the great toe
Diabetic nephropathy
- Diabetic nephropathy is the leading cause of end-stage renal disease,
- 40% of new cases.
- Among the suggested risk factors for diabetic nephropathy are:
- Genetic and familial predisposition
- Elevated blood pressure
- Poor glycemic control
- Smoking
- Hyperlipidemia
- Microalbuminuria
- Diabetic nephropathy is an independent risk factor for cardiovascular events
- Hence albumin urea closely monitored in type II diabetic patients
Diabetic nephropathy - Pathogenesis
- Hyperglycemia -> Transforming growth factor-beta (TGF-beta) in the glomeruli.
- cellular hypertrophy and enhanced collagen synthesis
- Patients with overt diabetic nephropathy (dipstick- positive proteinuria and decreasing GFR) generally develop hypertension.
- adverse factor in all progressive renal diseases
- Familial/genetic factors.
- African Americans, persons of Hispanic origin,and American Indians disposed to diabetic renal complications.
Retinopathies
• Diabetes -> increased risk of glaucoma and retinopathy
cataracts,
• retinopathy is the most common eye disease.
• Risk factors include
• poor glycemic control,
• elevated blood pressure,
• hyperlipidemia.
• Important that people with diabetes have regular eye examinations.
• Macular edema
• damaged blood vessels leak fluid under the macula, the part of the retina that lets us see detail.
• The fluid makes the macula swell, which blurs vision.
Diabetic Retinopathy - Pathogenesis
- Microvascular retinal changes.
- Endothelial change ! of the vascular walls
- Microaneurysms
- Ischemia
- Microaneurysms ! burst
- Scarring, damage to cellular environment
- Macular oedema - fluid under the macula makes it swell -> blurred vision
- Ischemia !fragile,new,bloodvessels.
- More prone to aneurysms & bursting
- grow into the angle of the anterior chamber and cause neovascular glaucoma.
Summary
- Diabetic metabolism alters structure and function of vasculature
- Microvascular changes cause damage to many peripheral tissues increasing morbidity and mortality of diabetic patients
- Macrovascular damage causes increased risk of cardiovascular disease and mortality
- Majority of treatments address hyperglycaemia
