Diabetic Glomerulosclerosis & Hyperglycemia

• Learning outcomes include listing microvascular and macrovascular complications of diabetes, explaining pathophysiology, outlining risk factors, signs and symptoms, principles of investigation and management, and analyzing the impact on quality of life, healthcare costs, and mortality rates.
• Diabetes is the number one cause of renal failure, new cases of blindness, and nontraumatic amputations.
• Health impacts of diabetes are renal failure, blindness, amputation, and nerve damage in 60-70% of patients.
• Other health impacts are a 5th leading cause of death and life expectancy decreased by 5-10 years.
• Cardiovascular disease can increase 2-4X

Hyperglycemia and Microvascular Disease

• Hyperglycemia correlates strongly with microvascular disease.
• As HbA1c increases, the relative risk of retinopathy, albuminuria (>300 mg/dL), clinical neuropathy, and microalbuminuria (>40 mg/dL) also increases.

Complications

• Coma can result from hypoglycaemia, ketoacidosis, hyperosmolar non-ketotic conditions; diabetics also get other causes of coma.
• Atheroma can cause cardiovascular disease, stroke, and peripheral vascular disease.
• Microangiopathy can cause cardiac failure, retinopathy, diabetic kidney disease, and neuropathy.
• Other complications include renal failure, sepsis and infections, eye issues(retinopathy, cataracts, macular edema and glaucoma), and pregnancy issues by gestational diabetes

Diabetes Tissue Damage

• In diabetes, the protein basement membrane becomes abnormally thickened, reduces blood flow causing ischaemia, and becomes fragile causing haemorrhage.
• Proteins damaged are blood vessel walls and capillary basement membranes
• Vessels in the kidney can cause diabetic glomerulosclerosis and renal papillary necrosis
• Vessels in the eyes cause diabetic retinopathy
• Vessels in the skin result in ulcers, especially in the feet
• Vessels supplying the nerves leads to neuropathy

Diabetic Nephropathy

• Best observed in the kidneys with a PAS stain.
• Characterized by thickening of capillary basement membranes and increased protein deposition in the mesangium within kidney glomerulus.

Mechanisms of Hyperglycemia-Induced Tissue Damage

• Damage can be induced by genetic factors, repeated acute changes in cellular metabolism, cumulative long-term changes in stable macromolecules, and independent accelerating factors (hypertension, hyperlipidemia, etc.).

Molecular Pathways in Diabetic Tissue Damage

• Polyol pathway: Aldose Reductase: Glucose -> Sorbitol and Decreased NADPH -> Decreased Glutathione.
• Advanced glycosylation end-products (AGE): Modification of intracellular and extracellular proteins; Increased inflammatory cytokines and growth factors
• Protein Kinase C activation: altered gene expression; Decreased endothelial nitric oxide synthase (eNOS).
• Protein Kinase C activation: Increased Endothelin-1, TGF-β, PAI-1, VEGF, NFKB; Net: Vasoconstriction, coagulation, angiogenesis, inflammation
• Hexosamine pathway: Diversion from the glycolysis pathway (G-G6P—F6P…); Increased N-acetyl glucosamine = Altered gene expression: TGF-β, PAI-1

Microvascular Conditions

• Retinopathy damage to the eyes
• Nephropathy damage to the kidneys
• Neuropathy damage to the nerves

Diabetic Retinopathy (DR)

• Leading cause of blindness in adults between 20-74.
• Decreased visual acuity is a symptom.
• Many patients don't have symptoms until very late stages, making effective treatment difficult.
• Prevalence increases with the increase of disease duration.
• Onset of Type 1 diabetes occurs 3-5 years after diagnosis; Nearly all patients are affected at 15-20 years
• 20% of Type 2 Diabetes presents at the time of DM Diagnosis with an Onset average of 4-7 years before diagnosis with a 50-80% incidence at 20 years

DR Risk Factors

• Include duration of diabetes, level of glycemic control, hypertension, presence of other microvascular complications, dyslipidemia, and pregnancy (transiently increases risk & progression).

DR Pathophysiology

• Hyperglycemia, causing dysregulated retinal blood flow, oxidative stress and inflammation, increased vascular permeability (edema), microthrombosis (ischemia), and growth factor.
• Genetic factors include increased incidence in first-degree relatives and association with nephropathy (in T1DM).
• Other factors include hypertension and dyslipidemia (+/-).

Retinopathy Classification

• Two major categories: Non-proliferative retinopathy (NPDR) and Proliferative retinopathy (PDR).
• Non-proliferative retinopathy can be mild, moderate, or severe with varying degrees of severity.
• Proliferative retinopathy that can be early/High-Risk/Severe
• Macular edema can occur at any stage and is considered "clinically significant" (CSME) based on the size of affected area, proximity to macula
• Characteristics are Microaneurysms, Dot Hemorrhages, and Hard exudates from lipid leakage within macrophages
• Moderate/Severe characteristics also include soft exudates (cotton wool spots), venous beading, and intraretinal microvascular abnormalities (IRMA).

Eye Findings in Retinopathy

• Occluded vessels/dilated and tortuous capillaries are findings when examining the eyes.
• Mild NPDR characteristics: Microaneurysms and dot hemorrhages in the normal fundus.
• Severe NPDR has a 50-75% progression to PDR
• PDR is neovascularization of the Optic Disc (NVD) and Elsewhere on your Retina (NVE)

Retinopathy Prevention

• Cornerstone therapy: Glycemic control (DCCT, UKPDS Trials) and Antihypertensive therapy
• Weaker evidence therapy: Lipid-lowering therapy, Antiplatelet agents, and Carbonic anhydrase inhibitors

Retinopathy Treatment

• NPDR w/ CSME can be treated with focal laser photocoagulation
• High-risk and severe PDR can be treated with Panretinal photocoagulation (PRP) with 600-1600 laser burns per grid.
• Medical therapy can be administered via Intravitreal glucocorticoids and VEGF inhibitors
• Vitrectomy is indicated when there is non-clearing vitreous hemorrhage, traction retinal detachment involving the fovea, and Severe PDR not responding to PRP

Nephropathy

• It is a leading cause of kidney disease, with onset 5-20 years after diabetes.
• The incidence is approximately 2.5% annually with a 25-35% lifetime risk.
• It effects Less than 1% per year after 20-25 years for T1DM patients and is Present at onset for 3% of T2DM patients
• Most common cause of kidney failure, accounting for 40% of patients on dialysis, with incidence 4-20% after 20 years.

Risk Factors for Nephropathy

• This includes poor glycemic control, hypertension, age, genetic factors, race, obesity, tobacco use, and other microvascular diseases such as retinopathy.

Pathologic Changes of Kidney Disease

• This includes glomerular disease with Mesangial expansion, glomerular basement membrane thickening, and glomerular sclerosis
• Albuminuria which contains Microalbuminuria (high albuminuria) at 30-300 mg/g creatinine and Proteinuria (macro- or very-high albuminuria) at over 300 mg/g creatinine
• The basement membrane thickens with Mesangial Expansion and Glomerular sclerosis

Diabetic Nephropathy Manifestations

• H&E shows glomerulus with diffuse and nodular glomerulosclerosis.
• Kimmelstiel-Wilson nodules are also characteristic of nodular glomerulosclerosis.

Natural History of Glomerular Condition

• Glomerular hyperfiltration causes an Increased kidney size on ultrasound
• Microalbuminuria can be present
• Regression to normoalbuminuria is between 15-65% and is associated with risk-factor management.
• Progression to macroalbuminuria and Decreased GFR and may precede or follows the development of Albuminuria
• Can progress to the end-stage kidney failure (ESKD) and Dialysis
• Prevention and Management: Glycemic control, Blood pressure control, and Treatment of dyslipidemia
• Measurement of spot urine microalbumin to creatinine ratio (i.e.- Screening for DM nephropathy) Annually after 5 years in T1DM and at Begin at diagnosis in T2DM

Prevention of Nephropathy

• Measurement of spot urine microalbumin to creatinine ratio is important
• This should be done annually after 5 years in T1DM and at the beginning of diagnosis in T2DM

Treatment of Nephropathy

• ACE Inhibitors or Angiotensin II Receptor Blockers improve or normalize albuminuria but does not prevent the onset of microalbuminuria.
• ACE-I: Perindopril, Enalapril, Lisinopril/ARB: Losartan, Valsartan, Irbesartan.
• Other treatments include dietary restrictions such as sodium and weight loss.
• Efferent arteriole is dilated to reduce glomerular pressure causeing decrease of urinary protein

Diabetic Neuropathy

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

Risk Factors for Diabetic Neuropathy

• Including age, duration of diabetes, poor glucose control, blood vessel damage, mechanical injury to nerves, genetic susceptibility, hypertension, dyslipidemia, tobacco use and excessive alcohol use.

Types of DM Neuropathy

• Including motor neuropathy, sensory neuropathy, mixed sensorimotor neuropathy, compression neuropathies, cranial nerve palsies, mononeuritis multiplex and autonomic neuropathy.

Peripheral Neuropathy

• It is the most common type of diabetic neuropathy
• distal, symmetric polyneuropathy includes axonal neuropathy with Stocking-glove distribution(Sensory > Motor) with Decrease sensation and Paresthesia
• Symptoms include tingling, burning, electric shock, hyperesthesia that presents worse at night
• Treatment is Anticonvulsants (Pregabalin, Valproic Acid, Gabapentin), Tricyclic Antidepressants (Amitriptyline, Desipramine), and Serotonin Norepinephrine Reuptake Inhibitors (Duloxetine, Venlafaxine)
• Additional treatments: topical agents (caspaicin cream), opioids (Dextromethorphan, Mo norphine, Oxycodone), antioxidants (Alpha-Lipoic Acid), and TENS
• Preventative measures are the same: to maintain Glucose control, blood pressure control, treatment of dyslipidemia and cessation of smoking and alcohol abuse

Prevention of Neuropathy

• Include Glucose control, blood pressure control, treatment of dyslipidemia, smoking cessation and decreased alcohol intake
• Feet should also be inspected

Microvascular Summarization

• This list shows microvascular prevention techniques against Retinopathy, Nephropathy, and Neuropathy
• NPDR without CSME is to manage risk factors while PDR and CSME requires photocoagulation
• Nephropathy cases require control via microalbuminuria and renin-angiotensin inhibition
• Neuropathy requires Polynucleopathy Treatment

Macrovascular Complications

• This list shows microvascular prevention techniques includes Coronary artery disease, Cerebrovascular disease, and peripheral vascular disease
• Cardiovascular disease is the Number one cause of death for 2/3 of all deaths in people with DM and Risk of CVD increases 2-fold in men and 3-4-fold in women

Diabetes Effect on Cardiovascular Mortality

• Nondiabetics without prior MI have the best odds of survival
• Diabetics that have a prior MI have the worst Survival rate

Macrovascular Complications

• Heart: 3-5X risk of MI with more deaths and complications following tx.
• MI may be a presenting feature of type 2 diabetes and presents Often silent ischaemia
• Stroke: 2-3X risk (thrombo-embolic/ischaemic stroke)
• Peripheral vascular disease (atheroma in lower limb arterial supply) in Multiple/diffuse lesions or a 40X risk of amputation
• This condition is Gangrene - isolated toe or heel typical (pressure points)

Risk Factor for Cardiovascular Disease

• Include age, duration of diabetes, poor glucose control, hypertension, dyslipidemia, albuminuria, kidney disease, Gender, Obesity, Smoking and a sedentary lifestyle
• Macrovascular conditions can be prevented in patients who maintain stable Glucose and Blood pressure control along with regulated lipids, Reduction of microalbuminuria, loss of Weight, Smoking and prescribed Aspirin
• For those with ASCVD, treatment with GLP-1 agonists & SGLT-2 inhibitor (more on this is discussed in pharmacology lecture)
• In 2017 diagnosed diabetes totalled to $327 billion in costs
• This total cost is the total cost amount of hospital visits from 30 different hospitals via Prescribed medications at 30% and diabetes supplies accounting for 15% total cost

Macrovascular Summarization

• Includes early intervention via glucose control and risk factor management.
• Management includes monitoring blood pressure, dyslipidemia, microalbuminuria, weight-loss, smoking cessation, and aspirin use.

Explore the pathological changes in diabetic glomerulosclerosis due to hyperglycemia-induced tissue damage. This quiz covers the mechanisms of hyperglycemia in diabetic nephropathy with factors affecting blood vessels and tissues. Understand the risks and management of conditions like silent ischemia in diabetes.