25 Diabetic Complications Overview

Complications of Diabetes

• Diabetes is the 5th leading cause of death.
• Life expectancy decreases by 5-10 years.
• Cardiovascular disease risk increases 2-4 times.
• Nerve damage affects 60-70% of patients.
• Diabetes is the number 1 cause of new cases of renal failure, blindness, and non-traumatic amputations.

Learning Outcomes

• List microvascular and macrovascular complications of diabetes.
• Explain the pathophysiology of each complication.
• Outline the risk factors for the development of complications.
• Outline common signs and symptoms of each complication.
• Outline overarching principles of investigation and management of diabetes complications.
• Analyze the impact of diabetic complications on quality of life, healthcare costs, and mortality.

Health impact

• Hyperglycemia is strongly correlated with microvascular disease.
• Progression to retinopathy, albuminuria, clinical neuropathy, and microalbuminuria is related to increasing HbA1c levels.

Summary of Pathological Complications

• Coma can occur from hypoglycemia, ketoacidosis, and hyperosmolar non-ketotic conditions.
• Cardiovascular complications include atherosclerosis, stroke, and peripheral vascular disease (limb amputation).
• Microvascular complications include cardiac failure, retinopathy, diabetic kidney disease, and neuropathy.
• Renal failure can be associated with diabetic kidney disease, pyelonephritis, and renal papillary necrosis.
• Infections, including tuberculosis, bronchopneumonia, COVID-19, skin infections (diabetic foot), and fungal infections, can be complications.
• Eye complications include retinopathy, cataracts, macular edema, and glaucoma.
• Pregnancy complications can include gestational diabetes, increased risk of developmental abnormalities, and increased obstetric complications for the mother.

How Diabetes Damages Tissues

• In diabetes, the protein basement membrane thickens, reducing blood flow and causing ischemia. The membrane also becomes fragile, increasing risk of hemorrhage.

Proteins Damaged in Blood Vessels

• Capillary basement membranes thicken throughout the body.
• These vessels function poorly, reducing blood flow to adjacent tissues and increasing fragility, leading to bleeding.
• Kidney vessels can develop diabetic glomerulosclerosis and renal papillary necrosis.
• Vessels supplying nerves can develop neuropathy.
• Vessels in the eyes can develop diabetic retinopathy.
• Vessels in the skin, especially the feet, can develop ulcers.

Diabetic Nephropathy

• The abnormal capillaries in the kidneys are best seen with a PAS stain.
• Kidney glomerulus thickening and protein deposition in the mesangium are characteristics of this condition.

Proposed Mechanisms of Hyperglycemia-Induced Tissue Damage

• Genetic factors can contribute to tissue damage.
• Repeated acute changes in cellular metabolism also play a role.
• Cumulative long-term changes in stable macromolecules are another factor.
• Independent factors like hypertension and hyperlipidemia can accelerate tissue damage.

Molecular Pathways Implicated in Diabetic Tissue Damage

• Polyol pathway: Glucose is converted to sorbitol, decreasing NADPH and glutathione, contributing to oxidative stress and modifications of intracellular and extracellular proteins.
• Advanced glycosylation end products (AGE): modification of proteins.
• Increased inflammatory cytokines and growth factors.
• Protein Kinase C activation: alters gene expression.
• Reduced endothelial nitric oxide synthase (eNOS). Increased expression of endothelin-1, TGF-β, PAI-1, VEGF, and NFKB lead to vasoconstriction, coagulation, angiogenesis, and inflammation.
• Hexosamine pathway: Diverts from glycolysis pathway and increases N-acetyl glucosamine leading to altered gene expression of TGF-β and PAI-1.

Microvascular Complications of DM

• Retinopathy
• Nephropathy
• Neuropathy

Diabetic Retinopathy

• Diabetic retinopathy (DR) is a common cause of blindness in adults (20-74).
• Many patients experience no symptoms until the late stages, making treatment difficult.
• Symptoms include reduced visual acuity, worsening with disease progression.
• Type 1 diabetes: onset 3-5 years after diagnosis; 15-20 years after diagnosis nearly all patients are affected.
• Type 2 diabetes: prevalence ~20% at time of diagnosis; onset averages 4-7 years before diagnosis; ~50-80% incidence by 20 years.

Risk Factors for Diabetic Retinopathy

• Duration of diabetes
• Level of glycemic control
• Hypertension
• Other microvascular complications (e.g., nephropathy, neuropathy)
• Dyslipidemia
• Pregnancy

Pathophysiology of Diabetic Retinopathy

• Hyperglycemia disrupts retinal blood flow.
• Oxidative stress and inflammation occur.
• Increased vascular permeability leads to edema
• Microthrombosis causes ischemia.
• Growth factors (IGF-1, PDGF, VEGF) promote proliferation.
• Genetic factors, first-degree relatives
• Hypertension
• Dyslipidemia

Classification of Retinopathy

• Two major categories
  • Non-proliferative retinopathy (NPDR): Mild, moderate or severe
  • Proliferative retinopathy (PDR): Early/High-risk/severe
• Macular edema can occur at any stage: Clinically significant macular edema (CSME).

Eye Findings in Retinopathy

• Mild: Microaneurysms, dot hemorrhages, hard exudates
• Moderate/Severe: Above plus soft exudates (cotton wool spots), venous beading, intraretinal microvascular abnormalities (IRMA) with occluded, dilated and tortuous capillaries.

Diabetic Nephropathy

• Leading cause of kidney disease.

Risk Factors for Nephropathy

• Poor glycemic control
• Hypertension
• Age
• Genetic factors
• Race (e.g., Black or African American, Pima Indian, Mexican-American)
• Obesity
• Tobacco use
• Other microvascular disease (e.g., retinopathy)

Pathologic Changes in Nephropathy

• Glomerular disease (mesangial expansion, basement membrane thickening, glomerular sclerosis)
• Microalbuminuria (30-300 mg/g creatinine)
• Proteinuria (>300 mg/g creatinine)

Natural History of Diabetic Nephropathy

• Glomerular hyperfiltration (increased kidney size on ultrasound).
• Microalbuminuria.
• Regression to normoalbuminuria.
• Progression to macroalbuminuria (associated with risk-factor management).
• Decreased GFR.
• Progression to end-stage kidney failure (ESKD).

Prevention of Nephropathy

• Glycemic control
• Blood pressure control
• Treatment of dyslipidemia
• Measuring spot urine microalbumin/creatinine ration annually after 5 years in T1DM or at diagnosis in T2DM.

Treatment of Nephropathy

• ACE inhibitors or angiotensin II receptor blockers (ARBs).
• Dietary sodium restriction.
• Weight loss.

Diabetic Neuropathy

• Most common microvascular complication.
• Diabetic polyneuropathy is the most common form of neuropathy in developed countries.
• 50-70% lifetime incidence of at least one form of neuropathy.

Risk Factors for Diabetic Neuropathy

• Age
• Duration of diabetes
• Poor glucose control
• Blood vessel damage
• Mechanical injury to nerves
• Genetic susceptibility
• Hypertension
• Dyslipidemia (hypertriglyceridemia)
• Tobacco use
• Excessive alcohol use.

Types of DM Neuropathy

• Motor neuropathy
• Sensory neuropathy
• Mixed sensorimotor neuropathy
• Compression neuropathies
• Cranial nerve palsies
• Mononeuritis multiplex
• Autonomic neuropathy

Peripheral Neuropathy

• Most common type of diabetic neuropathy, distal, symmetric.
• Axonal neuropathy ("Stocking-glove" distribution)
• Sensory symptoms > motor symptoms
• Decreased sensation, paresthesia (tingling, burning, electrical shock), hyperesthesia, worse at night.

Treatment of Painful Neuropathy

• Anticonvulsants (pregabalin, valproic acid, gabapentin).
• Tricyclic antidepressants (TCAs).
• Serotonin norepinephrine reuptake inhibitors (SNRIs).
• Topical agents (capsaicin cream).
• Opioids (dextromethorphan, morphine, oxycodone).
• Antioxidants (alpha-lipoic acid).
• TENS (transcutaneous electrical nerve stimulation).

Prevention of Neuropathy

• Glucose control
• Blood pressure control
• Treatment of dyslipidemia
• Smoking cessation
• Reduced alcohol intake

Diabetic Foot Pathology

• Charcot arthropathy, a complication of neuropathy.

Prevention of Foot Ulcers

• Avoid walking barefoot.
• Proper fitting shoes.
• Trimmed toenails.
• Daily foot inspection (use a mirror, or have someone else check).
• Daily foot washing.
• Use moisturizing cream or lotion.
• Follow up with a podiatrist.

Summary: Microvascular Complications

• Retinopathy (NPDR without CSME: risk factor management; PDR or CSME: photocoagulation).
• Nephropathy (microalbuminuria, renin-angiotensin inhibition).
• Neuropathy (polyneuropathy).

Macrovascular Complications of Diabetes Mellitus

• Coronary artery disease
• Cerebrovascular disease
• Peripheral vascular disease

Cardiovascular Disease (CVD) & Diabetes

• Leading cause of death in people with diabetes.
• Risk is increased approximately 2-fold in men, and 3-4-fold in women. For diabetes, accounts for 2/3 of all deaths

Risk Factors for Cardiovascular Disease in Diabetes

• Age
• Duration of diabetes
• Poor glucose control
• Hypertension
• Dyslipidemia
• Albuminuria and kidney disease
• Gender (W > M)
• Obesity
• Smoking
• Sedentary lifestyle

Prevention of Macrovascular Disease

• Glucose control
• Blood pressure control
• Lipid control
• Reduction of microalbuminuria
• Weight loss and exercise
• Smoking cessation
• Aspirin (secondary prevention or high-risk)
• Treatment with GLP-1 agonists and SGLT-2 inhibitors (for individuals with established ASCVD).

Costs and Effects on QOL

• Total costs of diagnosed diabetes in 2017 were $327 billion.
• 30% of costs for hospital inpatient care.
• Prescription medications for diabetes complications account for 30% of costs.
• Anti-diabetic agents and diabetes supplies account for 15% of costs.
• Physician office visits account for 13% of costs.

Summary: Macrovascular Complications

• Glucose control (early intervention).
• Risk factor management (blood pressure, dyslipidemia, microalbuminuria).
• Weight loss and exercise.
• Smoking cessation.
• Aspirin (secondary prevention or high-risk cases).