Day: September 5, 2025

Dr. Ahmad Shahzad
Founder | Lyallpur Diabetes Foundation
Consultant Diabetologist | Educator | Advocate for Preventive Care

As we know, diabetes can have an impact on blood sugar and general metabolic wellbeing, but that is just the tip of the iceberg. Bone health is a field that is not given much attention. As per the research, individuals with diabetes have a greater risk of fractures, low bone density, and low bone strength. It is important to understand the impact of diabetes on the skeletal system to prevent this condition, detect it early and improve the long-term health outcomes.

Understanding the Link Between Diabetes and Bone Health

Diabetes causes serious complications in bone health, bone density, and bone quality, predisposing individuals to fracture. Type 1 diabetes (T1DM) and type 2 diabetes (T2DM) both cause bone problems, albeit in slightly different ways.

Impact on Bone Density and Structure

·       T1DM is typically linked to reduced bone mineral density (BMD), which disables bone formation. This is attributed to hyperglycemia leading to accumulation of advanced glycation end products (AGEs) which destroy bone cells, disrupt the activity of osteoblasts (bone-building cells) and augment bone resorption by osteoclasts. T1DM also depletes growth factors like insulin-like growth factor-1 (IGF-1), which also inhibits bone growth and bone remodeling.

·       T2DM, ironically, is commonly characterized by normal or even better BMD but worse bone quality. The prolonged hyperglycemia and related metabolic alterations worsen the organic structure and biomechanical characteristics of the bone, making bones weaker despite increased density. The bone-forming cells are also adversely affected by increased bone marrow fat and inflammation in T2DM.

Increased Fracture Risk and Healing Complications

·       T1DM and T2DM patients are more likely than non-diabetics to suffer a fracture. This is not necessarily attributed to structural integrity of the bone but also due to complications of diabetes like neuropathy and muscle weakness, eye issues and frequent falls which increase the risk of fracture.

·       The recovery of fractured bones in diabetics may be delayed due to impaired bone cell activity, reduced progenitor cells and poor vascularization of fracture locations. Long-term hyperglycemia may have permanent adverse effects on bone cell activity, which impairs proper repair.

Clinical and Treatment Considerations

• Prevent or reduce diabetic bone disease through good glycemic control. Certain antidiabetic drugs (e.g., metformin) are potentially better since they have fewer adverse effects on bone health, whereas other drugs (such as thiazolidinediones) can increase bone loss.
• Therapies focused on the enhancement of bone density and quality, including anti-resorptive medications (e.g., alendronate), bone-forming (e.g., intermittent PTH in T1DM), and vitamin K2 and vitamin D3 supplementation in T2DM, have potential in the treatment of bone complications in diabetes.
• As well as acting to regulate blood sugar, insulin therapy has direct positive effects on bone formation by stimulating osteoblastic activity.

Mechanisms: How Diabetes Affects Bones

Diabetes affect bone health through several interconnected mechanisms centered around hyperglycemia, insulin deficiency or resistance, and inflammation, which alter bone cell function, bone matrix quality, and bone remodeling processes.

Key Mechanisms

• Hyperglycemia and Advanced Glycation End Products (AGEs): Chronic high blood sugar causes the development of AGEs that build up in bone collagen. This deposition makes the collagen matrix weaker and less durable, which reduces the mechanical strength and quality of bone. AGEs also induce bone progenitor cell apoptosis (death), osteoblast differentiation and function, and osteoclastic activity, resulting in elevated bone resorption.
• Impaired Osteoblast Function and Reduced Bone Formation: In type 1 diabetes (T1DM), there is a lack of insulin and growth factors such as insulin-like growth factor 1 (IGF-1) that inhibits the differentiation of mesenchymal stem cells (MSC) to osteoblasts. New bones are formed by osteoblasts, and thus their dysfunction reduces bone formation and bone mineral density (BMD). Repeated hyperglycemia suppresses important genes and proteins in osteoblast maturation and activity as well.
• Disturbed Bone Remodeling Dynamics: Diabetes causes disequilibrium in bone remodeling. The AGEs and the inflammatory cytokines enhance the activity of osteoclasts (bone resorption cells) and reduce the activity of osteoblasts, impairing normal bone turnover. This leads to poorer bone structure and fragility even with normal or even higher BMD particularly in diabetes type 2 (T2DM).
• Inflammation and Oxidative Stress: High blood sugar increases oxidative stress and proinflammatory pathways (e.g., NF-kB) and releases cytokines, such as TNF-a and IL-6. Such cytokines also suppress osteogenic differentiation of bone marrow stem cells and bone repair. Ironic inflammation also leads to bone quality and healing capacity.
• Bone Marrow Adiposity and Cellular Changes: In T2DM, bone marrow fat accretion leads to release of free fatty acids and pro-inflammatory cytokines, which worsen insulin resistance and suppress osteoblast activity. Bone marrow population of MSC also reduces which hinders the formation of new bone cells and restoration of broken bones.
• Vascular and Healing Losses Diabetes-induced loss of MSC viability and function also impairs vascularization of fracture sites, resulting in delayed bone healing, increased incidence of non-union fracture, and postoperative complications in diabetic patients.

Simply put, diabetes impairs bone health by exerting hyperglycemia-induced biochemical effects, inflammation, and altered stem cell processes that increase the risk of fracture and decrease bone repair potential.

Increased Risk of Fractures in People with Diabetes

Individuals with diabetes, especially type 2 diabetes (T2DM), are at a higher risk of developing bone fractures because of multifactorial etiological factors other than bone mineral density (BMD). This increased risk of fracture is due to several factors:

Risk Factors

• Bone Quality Impairment: Although many T2DM patients have normal or increased BMD, their bone quality is impaired by the deposition of advanced glycation end products (AGEs), low bone turnover, and alteration of bone microstructure, which impair bone tissue mechanical strength and strength.
• Duration and Severity of Diabetes: Long diabetes time (particularly 15 years and above) and inadequate glycemic control raise the risk of fractures. Fracture risk is also linked to insulin therapy which often is a sign of severe or advanced disease.
• Age and Body Mass Index (BMI): Elderly diabetic patients are at risk of getting a fracture. There is a significant increase in the risk of fractures in diabetic patients with a low BMI (<25 kg/m2), and a moderate effect of higher BMI.
• Diabetes Complications and Hypoglycemia: Diabetes-related conditions, including peripheral neuropathy, muscle weakness, impaired vision, and hypoglycemia (particularly because of drug use) are known to put patients at risk of falls and fractures.
• Medications: Thiazolidinediones, SGLT2 inhibitors, and insulin are some diabetes therapies that have been associated with an increased risk of fractures either via their impact on bone metabolism or by raising the risk of falls.
• T2DM patients experience higher fractures at the hip, vertebrae, and feet, but not always wrists, shoulders, or ankles.

Additional Factors Contributing to Poor Bone Health in Diabetes

Additional factors contributing to poor bone health in people with diabetes go beyond changes in bone mineral density (BMD) and include both skeletal and extra-skeletal influences:

• Advanced Glycation End Products (AGEs) Accumulation Hyperglycemia increases AGEs formation, changes bone collagen, making bones more rigid, fracture-prone, and brittle. This affects bone quality without BMD.
• Raised Fall Risk: Diabetes complications like peripheral neuropathy, impaired balance, muscle weakness, vision issues, and hypoglycemic episodes predispose one to fall, significantly contributing to the risk of fractures.
• Negative Effect of Some Medicines: Some antidiabetic medications (e.g. thiazolidinedions) have been shown to increase the risk of fractures by either impairing the formation of bone or enhancing its resorption. There are certain reservations about SGLT2 inhibitors that are mixed. Insulin therapy is anabolic to bone on its own, and usually a sign of advanced diabetes that correlates with bone fragility.
• Physical Inactivity: Diabetes complications reduce mobility, which slows down mechanical loading of bones and increases bone loss and skeletal weakness.
• Inflammation and Oxidative Stress: Chronic inflammation caused by diabetes and oxidative stress destroys bone cells, alters the work of osteoblasts and stimulates bone resorption.
• Finally, The Bone Marrow Composition Changes Type 2 diabetes alters the balance of bone marrow fat content which disrupts normal bone remodeling by preventing osteoblast differentiation and enhancing adipogenesis in bone marrow.
• Vitamin D Deficiency and Calcium Imbalance: Diabetes may be associated with a lack of vitamin D and poor calcium metabolism to weaken bone mineralization and strength.
• Comorbid Conditions: Diabetes may be comorbid with many conditions, including kidney disease, autoimmune diseases (e.g., celiac disease, Graves’ disease), hormone imbalance, and eating disorders, all of which may lead to poor bone health.
• Genetic Factors: Genetic polymorphisms in collagen synthesis genes and vitamin D receptor genes can also be involved in bone fragility in diabetes.

You may also like to read: Connection between Diabetes and Cognitive Decline

Strategies for Protecting Bone Health in Diabetes

Treatment of bone in diabetic individuals is a multifaceted process that involves proper glycemic control, lifestyle changes, nutritional interventions, drug-specific selection and, in some cases, bone-specific therapy.

Key Strategies

• Optimal Glycemic Control: Good blood sugar control minimizes the development of damaging advanced glycation end products (AGEs) in bone tissue and the risk of diabetic complications such as neuropathy and hypoglycemia that elevates the risk of falls and fractures. It is important to prevent hypoglycemic episodes by avoiding frequent ones.
• Lifestyle and Physical Activity: Resistance and weight bearing exercises (walking, strength training) promote bone density and bone strength. Exercise also enhances muscle tone and stability, which prevent falls. Quitting smoking and alcohol reduction are essential because these two habits undermine bones and predispose them to fractures.
• Nutritional Support: Optimal consumption of calcium and vitamin D is the key to good bone health. When the dietary intake is inadequate or vitamin D is low, supplements may be required especially in type 1 diabetes and the elderly with type 2 diabetes. Proteins are useful to maintain bones and muscles.
• Drug prescribing and Reimbursement: Select bone-neutral or bone-positive diabetes agents, including metformin, GLP-1 receptor agonists, and DPP-4 inhibitors. Thiazolidinediones (TZDs) should be avoided and SGLT2 inhibitors should be monitored because they may increase the risk of fractures. Insulin is to be administered with caution to prevent hypoglycemia.
• Bone-Targeted Therapies: In patients with osteoporosis or with a high risk of fracture, antiresorptive medications such as bisphosphonates (e.g., alendronate) and anabolic therapies such as teriparatide (PTH 134) have demonstrated effectiveness in enhancing bone density and fracture risk. Vitamin K2/D3 combination therapy has been demonstrated to induce bone formation in diabetic bones.
• Bone Health Check: It is essential to monitor bone mineral density (BMD) and bone turnover, as well as assess fracture risk, to ensure prompt treatment. Improved risk prediction of fractures in diabetes might be achieved by newer imaging methods and customized risk models.
• Make improvements to Fall Risk and Comorbidities: Fall management: treat diabetic neuropathy, visual issues, and muscle weaknesses to decrease falls. Vitamin D deficiency and other comorbidities of bone health are significant aspects of care that require screening and treatment.

Final Thoughts

Finally, diabetes does not only influence the level of blood sugar but also has an important effect on the strength of bones and general skeletal health. Diabetes demonstrates the need to make proactive care a priority by raising the risk of low bone density, fractures, and slow healing. It can be avoided by keeping blood sugar levels, consuming a balanced diet with bone strengthening nutrients, exercise, and regular examinations. People with diabetes can minimize the complications and help secure a healthier and stronger future with the right preventive measures.

Dr. Ahmad Shahzad
Founder | Lyallpur Diabetes Foundation
Consultant Diabetologist | Educator | Advocate for Preventive Care

The effect of diabetes on blood sugar control is well known; however, its effects extend far beyond just physical health. Studies indicate a Connection between Diabetes and Cognitive Decline, attributing the disease to memory loss, diminished attention and even increased dementia susceptibility. This relationship is paramount as it reveals the necessity of controlling diabetes to not only preserve the body but also the health of the brain in the long term.

Understanding Cognitive Decline

Cognitive decline is a progressive loss of mental abilities like memory, reasoning and attention. It is commonly an aging process but may be hastened or aggravated by multiple factors such as illnesses and habits.

Symptoms

Symptoms can vary but often include:

• Memory loss or trouble recalling recent events.
• Difficulty finding words or expressing oneself.
• Getting lost in familiar places.
• Trouble with concentration and complex tasks.
• Mood changes such as increased anxiety or irritability.

How Diabetes Affects the Brain

Brain- Diabetes has several serious effects on the brain, including cognitive impairment, memory loss and dementia. Brain dysfunction is caused by both type 1 and type 2 diabetes, but type 2 diabetes is more closely associated with faster brain aging and dementia, such as Alzheimer disease and vascular dementia.

Mechanisms of Brain Impact

• Diabetes leads to injury of small and large blood vessels in the brain that limits blood flow and oxygen supply to the brain thus affecting the functioning of brain cells leading to stroke and vascular dementia.
• And high blood sugar (hyperglycemia) and insulin resistance impair brain metabolism. Brain insulin resistance may also change how energy is used and lead to accumulation of harmful proteins (amyloid and tau) that cause Alzheimer disease.
• There is observed brain atrophy (shrinkage), especially in memory and executive functions such as hippocampus, medial temporal, and frontal lobes in individuals with diabetes.
• Neuroinflammation and disturbances in the metabolism of neurotransmitters in the brain due to diabetes are other factors that contribute to the neuronal damage and cognitive decline.

Cognitive Effects and Risk

• Diabetics (type 2) show increased rates of cognitive impairment compared to healthy people; memory, speed of processing, and some executive functions like planning and attention.
• There are slight variations in brain functions in children with type 1 diabetes that can influence learning and behavior.
• • The more a person has diabetics and the poorer the blood glucose management, the greater the risk of cognitive impairment and dementia.

Scientific Evidence Linking Diabetes and Cognitive Decline

There is strong scientific evidence of the association between diabetes and cognitive impairment, such as, higher risk of dementia and Alzheimer disease. Numerous studies of high quality, systematic reviews and meta-analyses have found this relation based on observational research, neuroimaging and biochemical studies.

Key Evidence and Findings

• Diabetes worsens cognitive impairment through chronic hyperglycemia, insulin resistance, inflammation, vascular damage, and oxidative stress, which cause brain cell damage and neurodegenerative protein buildup (tau and amyloid-beta).
• Meta-analyses indicate that individuals with diabetes face an increased risk of getting dementia (59-73 percent higher than non-diabetics) and an almost doubled risk of getting Alzheimer disease.
• The risk of cognitive loss is increased by diabetes and the occurrence of complications like hypoglycemia.
• A. Neuroimaging showed accelerated brain atrophy and accelerated cognitive decline in individuals with type 2 diabetes compared to age controls.
• Mechanistic studies (1) connect neurodegeneration and impaired neurotransmitter balance to diabetes-related brain insulin resistance, mitochondrial dysfunction, and chronic inflammation.
• Glucose-lowering treatments such as metformin and SGLT-2 inhibitors demonstrate the possibility to decrease dementia risk in diabetic groups, which indicates modifiable aspects in diabetes treatment to reduce cognitive impairment.

Risk Factors and Contributing Elements

Diabetes-related cognitive decline is influenced by multiple risk factors and contributing elements spanning vascular, metabolic, inflammatory, and lifestyle domains.

Major Risk Factors

• Vascular Disease: Macrovascular (stroke, heart disease) and microvascular (retinopathy, nephropathy) diabetes complicates are significant in terms of cognitive impairment. These risks are worsened by hypertension and dyslipidemia.
• Hyperglycemia: Persistent elevated blood sugar and glucose levels cause neuronal oxidative stress, mitochondrial dysfunction, and the generation of toxic AGEs, enabling damaging brain inflammation.
• Hyperinsulinemia and Insulin Resistance: Early insulin resistance and elevated insulin levels are associated with worse cognition and risk of Alzheimer, in part because of impaired brain insulin signaling.
• Neuroinflammation: The diabetic brain is persistently inflamed with increased levels of inflammatory cytokines and microglial activation leading to neuronal damage resulting in the exacerbation of cognitive impairment.
• Period and Level of Diabetes: Longer diabetes and high HbA1c decrease the cognitive impairment potential and severity.
• Other Factors: It is also increased by age (greater than 60 years), female sex, low education level, stroke or depressive history, obesity, smoking and lack of exercise.

Additional Considerations

• The abnormalities in the brain metabolic markers and neurotransmitters of memory and cognitive processing are usually identified in diabetic patients.
• Mild cognitive impairment (MCI) is prevalent in older adults with type 2 diabetes, which usually evolves into dementia unless treated.
• Certain antidiabetic medications such as metformin can protect cognition, but the evidence is inconclusive and needs to be examined further.

You may also like to read: Role of Oxidative Stress in Diabetic Complications

Prevention and Management Strategies

Cognitive decline in diabetes is prevented and managed by maximizing metabolic control, vascular risk factors, and healthy lifestyle behaviors.

Glycemic Control

·       Antidiuretic drugs like metformin and SGLT-2 blockers have demonstrated some neuroprotective effects by risk-reducing dementia and enhancing cognitive performance.

·       Good glucose control is paramount but excessive tight control resulting in a higher risk of hypoglycemia can exacerbate cognition. HbA1c targets are to be individualized depending on cognitive status and age to prevent hypoglycemia.

Cardiovascular and Vascular Risk Management

·       Regular aerobic physical activity is associated with enhanced cardiovascular health, cerebral blood flow, neurotrophic, and inflammation, which in totality safeguard cognition.

·       Management of hypertension, dyslipidemia and other cardiovascular risk factors minimize cerebrovascular loss which causes impairment in cognition.

Lifestyle Interventions

·       Vascular and metabolic health can be supported by a healthy diet, including the Mediterranean diet.

·       Physical activity is one of the most supported methods of preventing age-related cognitive decline and dementia.

·       Cognitive stimulation and socialization are suggested as effective in keeping the brain functioning.

Additional Strategies

• Prevention of hypoglycemia is vital as it is linked to progressive cognitive impairment and a higher risk of severe events among the cognitively impaired diabetics.
• Cognitive health is further supported by monitoring and the management of comorbidities such as depression and obesity.
• Studies of new treatments of brain insulin resistance, inflammation, and amyloid deposition are in progress.

Final Thoughts

Diabetes is also associated with mental degradation, where both biological and lifestyle determinants contribute to the phenomenon. The risks are severe, but the brain can be preserved with proper blood sugar management, healthy lifestyle, and frequent cognitive monitoring. With some proactive measures, people with diabetes can mitigate the risk and help to maintain their physical and psychological health in the long term.

Dr. Ahmad Shahzad
Founder | Lyallpur Diabetes Foundation
Consultant Diabetologist | Educator | Advocate for Preventive Care

Diabetes is a complicated metabolic condition that could cause severe health problems besides high blood sugar. Oxidative stress is one of the major contributors to these complications, as this is a condition of imbalance in the body between free radicals and antioxidants. It is also proven that oxidative stress contributes significantly to the destruction of blood vessels, nerves, kidneys and other organs and thus is directly connected to diabetic complications. Understanding the role of oxidative stress in diabetic complications is essential for developing better strategies to prevent, manage, and treat long-term effects of the disease.

What is Oxidative Stress?

Oxidative stress refers to a situation in which the formation and accumulation of reactive oxygen species (ROS), or free radicals, and the capacity to eliminate the reactive species or the damage caused by them is imbalanced. The result of this imbalance is cell and tissue damage since the surplus free radicals can damage vital structures in cells like proteins, lipids, and DNA. Although ROS are necessary in normal cellular activities such as signaling, immune defense, high levels of ROS because of environmental factors or metabolic imbalance led to oxidative stress, which causes aging and many diseases, including cancer, diabetes, cardiovascular and neurodegeneration diseases.

This imbalance arises when the free radicals exceed the antioxidant capacity of antioxidants, the molecules that could stabilize free radicals by donating electrons. Pollution, UV radiation, smoking and some drugs are some of the factors that can initiate oxidative stress. Enzymatic antioxidants like superoxide dismutase, catalase and glutathione peroxidase are used by the body to defend itself, yet, when these systems become overburdened, cell damage occurs.

Oxidative Stress and Diabetes: The Connection

Diabetes is closely related to oxidative stress in a complex way where oxidative stress is essential in pathogenesis, progression, and complications of diabetes. Prolonged high blood glucose (hyperglycemia) and mitochondrial dysfunction in diabetes, especially in type 2 diabetes, cause excess production of reactive oxygen species (ROS). Such surges in ROS exacerbate oxidative stress, which harms pancreatic beta cells that produce insulin, disabling their activity and leading to cell death, decreasing insulin production. Several other causes also lead to insulin resistance, including oxidative stress, when the cells of the body cannot react to insulin, further disrupting the glucose regulation.

Besides, oxidative stress contributes significantly to diabetic complications involving various organs. It harms the vascular system by fostering inflammation and endothelial dysfunction resulting in microvascular complications such as diabetic retinopathy (eye destruction), nephropathy (kidney destruction) and neuropathy (nerve destruction). It also leads to macrovascular problems, which are a risk factor of developing cardiovascular diseases in diabetics. The permanent oxidative injury may perpetuate a deleterious hyperglycemic memory, continuing tissue dysfunction despite normalization of blood glucose.

Antioxidant therapies, lifestyle activities, including diet and exercise, as well as careful blood sugar control, are strategies to counter oxidative stress in diabetes. Nevertheless, the mechanisms remain unclear, and more studies are required to maximize the therapies that address oxidative stress to prevent and manage diabetic complications.

Mechanisms Behind Oxidative Stress in Diabetes

Oxidative stress mechanisms in diabetes entail a series of interacting events that cause an overproduction of reactive oxygen species (ROS) and dysfunction of antioxidant responses and play a direct role in the pathogenesis and complications of diabetes.

Sources of ROS in Diabetes:

Mitochondria during cellular respiration are the major source of oxidative stress in diabetes. Hyperglycemia (high blood sugar) leads to excess glucose metabolism via glycolysis and Krebs cycle leading to high levels of electron donors (NADH and FADH2) overloading the electron transport chain. This leads to loss of electrons to oxygen to form superoxide radicals (O2- -) and other ROS like hydrogen peroxide (H2O2) and hydroxyl radicals (- OH). Moreover, there is hyperactivity of enzymatic systems such as NADPH oxidase, which increases the production of ROS in endothelial cells, smooth muscle cells, and fibroblasts especially when hyperglycemia occurs.

Impaired Antioxidant Defense:

Diabetes is known to break the equilibrium by reducing the activity of protective antioxidant enzymes such as superoxide dismutase (SOD), catalase and glutathione peroxidase (GSH-Px). Decreased antioxidants result in accumulating ROS with destruction of cells.

Molecular Pathways Amplifying Oxidative Stress:

Protein Glycation and lipid peroxidation: Non-enzymatic glycation of proteins and lipid peroxidation leads to the production of free radicals and advanced glycation end products (AGEs), which further enhance the production of ROS and inflammation.

• Polyol Pathway Activation: Aldose reductase converts excess glucose into sorbitol and depletes NADPH and weakens the ability to regenerate antioxidants.
• Protein Kinase C (PKC) Activation: Hyperglycemia triggers PKC, which promotes NADPH oxidase, elevates inflammatory cytokines and modulates gene expression of cell damage and vascular dysfunction.
• Hexosamine Pathway: Enhanced activity of this pathway alters transcription factors by O-linked glycosylation and impacts diabetic complication related genes.
• Chronic Inflammation: ROS stimulate inflammatory transcription factors (e.g., NF-kB) which leads to driving cytokine production and maintaining a vicious cycle of ROS production.

Impact on Insulin and Beta Cells:

The low antioxidant capacity of ROS leads to insulin secretion and beta cell apoptosis as these molecules cause oxidative damage to pancreatic beta cells. Furthermore, oxidative stress causes insulin resistance by disrupting the insulin signaling that occurs in insulin metabolic dysfunction that is typical of type 2 diabetes.

Contribution to Diabetic Complications

Oxidative stress injures endothelial cells, resulting in vascular dysfunction, microvascular (retinopathy, nephropathy, neuropathy) and macrovascular (cardiovascular disease) complications.

Oxidative Stress in Diabetic Complications

Oxidative stress has been at the center of the development and progress of diabetic complications, micro and macro vascular. Chronic elevated blood sugar in diabetes leads to mitochondrial overproduction of reactive oxygen species (ROS) in endothelial cells and other tissues, resulting in several harmful effects that cause diabetic complications.

Key pathways activated by oxidative stress in diabetes complications include:

1. Polyol Pathway Flux: Surplus glucose is metabolized to sorbitol by aldose reductase, depleting NADPH, decreasing antioxidant regeneration, and predisposing cells to oxidative damage.
2. Advanced Glycation End-Products (AGEs): High glucose enhances the development of AGEs which bind to their receptors (RAGE), leading to the production of ROS, inflammation and tissue damage observed in diabetic nephropathy, retinopathy and neuropathy.
3. Activation of Protein Kinase C (PKC): ACTH hyperglycemia-activated PKC isoforms upregulate ROS, inflammation, vascular permeability, and abnormal blood flow, which add to vascular complications.
4. Hexosamine Pathway: Overflow of glucose flux causes changes in transcription factors that control fibrosis and inflammatory genes, exacerbating tissue injury.
5. Direct Enzyme Inactivation: ROS directly inactivates protective against atherosclerosis, including endothelial nitric oxide synthase (eNOS) and prostacyclin synthase, disrupting vascular activity.

Activation of transcription factors such as NF-KB through oxidative stress results in a vicious cycle of cytokine release and immune cell recruitment that exacerbates vascular and tissue injury.

Most heavily impacted organs are kidneys (diabetic nephropathy), eyes (retinopathy), nerves (neuropathy), and the cardiovascular system, which cause greater risk of kidney failure, blindness, neuropathic pain, and heart disease. Epigenetic changes which persist pro-inflammatory gene activity in the face of controlled blood sugar, or so-called metabolic memory, are also caused by oxidative stress.

Superoxide dismutase, catalase, and glutathione peroxidase are the antioxidant defenses that are also impaired in diabetes, thus worsening oxidative damage.

You may also like to read: Importance of Foot Care in Preventing Diabetic Foot Ulcers

Role in Beta-Cell Dysfunction and Insulin Resistance

There are multiple ways that oxidative stress contributes to beta-cell dysfunction and insulin resistance in diabetes:

Beta-Cell Dysfunction

• Susceptibility: Pancreatic beta cells possess low intrinsic antioxidant capacity and are therefore extremely susceptible to oxidative stresses produced by overproduction of reactive oxygen species (ROS) under hyperglycemic and inflammatory conditions.
• Damage and Death: Overproduction of ROS results in mitochondrial dysfunction and endoplasmic reticulum (ER) stress in beta cells, leading to cell apoptosis and insulin secretion.
• Loss of Identity: Oxidative stress results in loss of important beta-cell maturity transcription factors like MAFA and PDX1 to cause beta-cell dedifferentiation and decreased insulin synthesis.
• Inflammation: ROS activate immune systems through pro-inflammatory cytokines (e.g., IFN-7, IL-1 1, TNF-7) that contribute to additional beta cell death, particularly in diabetes type 1.
• Antioxidant Downregulation: Downregulation of endogenous antioxidants such as superoxide dismutase (SOD2) enhances oxidative beta cell injury.
• Protective Pathways: FOXO1 to the nucleus is a defense to oxidative stress that can be overwhelmed in chronic conditions.

Insulin Resistance

·       Disruption of the Insulin Signaling: ROS trigger serine/threonine kinases including JNK, p38 MAPK, and IKK that phosphorylate insulin receptor substrates (IRS) on serine residues and disrupt their function in relaying insulin signals in cells like muscle and adipose tissue.

·       PI3K Disruption: Oxidative stress interferes with translocation and activation of PI3K, an insulin signaler, facilitating insulin resistance.

·       PI3K Disruption: Oxidative stress interferes with translocation and activation of PI3K, an insulin signaler, facilitating insulin resistance.

·       Inflammatory Pathways: ROS stimulate inflammatory pathways (NF-KB), prolonging the systemic inflammation thereby worsening further insulin insensitivity.

·       Redox Imbalance: The imbalance between the production of ROS and antioxidant defense is one of the causes of disturbed metabolism and desensitization of insulin receptors in peripheral tissues.

Strategies to Reduce Oxidative Stress in Diabetes

Oxidative stress reduction strategies in diabetes involve a combination of lifestyle change, antioxidant therapy, and appropriate management of the disease to regain redox balance and alleviate cellular injury:

Lifestyle Modifications

• Diet: The Mediterranean diet is rich in natural antioxidants in fruits, vegetables, whole grains, olive oil, nuts, and fish, and has been shown to be effective in improving antioxidant enzyme activity and reducing oxidative stress markers. The activation of NRF2 pathway by key phytochemicals upregulates the protective antioxidant genes such as glutathione peroxidase and superoxide dismutase. Low-calorie diets decrease the variability of blood glucose and the production of reactive oxygen species (ROS).
• Exercise: Mediate aerobic exercise (e.g., walking, cycling) enhances mitochondrial activity and increases endogenous antioxidant enzymes, alleviating oxidative injury in diabetic individuals. Resistance training and high-intensity interval training (HIIT) also have potential in improving antioxidant defenses and glycemic control, but individual health status and age can vary in response. Moderate workouts will avoid the overload of ROS that may exacerbate stress.
• Stress Management and Sleep: Mindfulness, yoga, and sufficient sleep, lower systemic inflammation and cortisol which otherwise contribute to increased oxidative stress and insulin resistance.

Antioxidant Therapies

• Supplementation: Alpha-lipoic acid, coenzyme Q10, glutathione and vitamins C and E have also been studied to restore insulin sensitivity and prevent oxidative damage, although the clinical benefit is inconsistent.
• Targeted Therapeutics: New therapeutic strategies target mitochondria-targeted antioxidants and activators of transcription factors such as NRF2 that control antioxidant defenses. It is also being investigated to inhibit NADPH oxidase (NOX) enzymes, which are key sources of ROS.
• Nanotechnology and Microbiome: new directions involve nanocarrier-delivered antioxidants to pancreatic islands or atherosclerotic foci, or the regulation of the gut microbiota to ease overall oxidative stress in the body.

Effective Diabetes Management

• Blood Sugar Control: Tight glycemic control by diet, medication and monitoring mitigate excessive ROS generation in response to hyperglycemia and oxidative stress.
• Medications: some antidiabetic drugs such as metformin and GLP-1 receptor agonists are antioxidants that minimize oxidative stress beyond the effect of glucose.

Final Thoughts

Summing up, oxidative stress plays a key role in most diabetic complications, including nerve and kidney damage and cardiovascular disease. It impairs the long-term outcomes of diabetes by destabilizing the cellular balance and triggering inflammation. Addressing the role of oxidative stress in diabetic complications through lifestyle changes, antioxidant support, and targeted therapies offers a promising path to protect patients’ health and improve quality of life.

Dr. Ahmad Shahzad
Founder | Lyallpur Diabetes Foundation
Consultant Diabetologist | Educator | Advocate for Preventive Care

Having diabetes does not only entail checking blood sugar but also taking care of the feet. Foot ulcers are among the worst complications diabetics can get, as they may become infected and result in amputation without treatment. The positive is that this risk can be significantly decreased with proper foot care. Daily foot checks and healthy habits can help people with diabetes to keep their feet safe and enjoy a higher quality of life.

Understanding Diabetic Foot Ulcers

A diabetic foot ulcer is an exposed wound or sore on a foot whose underlying cause is diabetes. It occurs because of the combination of multiple factors such as peripheral neuropathy (damage to nerves), poor circulation (ischemia), foot defects and recurring pressure or trauma. Neuropathy decreases sensation, i.e. injury or pressure, which leads to the ulcer not being noticed and untreated. Low circulation also worsens recovery and risks infection. They are severe complications of diabetes and may result in infection, hospitalization, and amputation unless timely and adequately treated.

Why Foot Care Matters for Diabetics

Foot care is very important to individuals with diabetes since diabetes can lead to nerve damage (neuropathy) and poor circulation, both of which increase the likelihood of foot injuries not being noticed and not healing. Damage of nerves lowers the sensation of pain, heat, or cold, thus simple cuts, blisters, or sores may turn into severe infections before they are noticed. Healing and the ability to combat infection are further affected by poor blood flow. Consequently, ulcers, infections, and even amputations may result when diabetic foot wounds are not properly tackled.

Good foot care prevents these complications by promoting early detection of injuries through daily inspection, skin hygiene and moisture, foot protection through footwear and socks, and frequent check-ups. Socking and shoing feet prevent unseen trauma injuries even at home. Better foot health is also facilitated by management of blood sugar and general control of diabetes. Various studies indicate that active foot care and early interventions decrease the chances of severe infections and amputations. Foot care will therefore be critical component of diabetes self-management to sustain mobility and quality of life.

Essential Foot Care Practices to Prevent Ulcers

Essential foot care practices to prevent diabetic foot ulcers include the following key measures:

• Daily Foot Inspection: Inspect both feet daily to observe any cuts, blisters, redness, swelling or any evidence of injury or infection. Look at the soles with a mirror. Early diagnosis aids in the treatment of problems before they aggravate.
• Foot Hygiene: Wash feet with lukewarm water daily, dry them completely between toes, and keep skin moist to avoid cracks. Do not keep feet long soaked or rub them with harsh chemicals.
• Dress Shoes: Use well-fitting shoes that are not tight or loose and high-heeled shoes. Wear clean and dry socks in place of tight bands and never walk barefoot to avoid injury.
• Frequent Nail Maintenance: Clip toenails in a straight line and do not dig into corners to prevent ingrowth and infection of nails.
• Pre-ulcerative Signs: Calluses, blisters, fissures, fungal infection, ingrown nails should be treated promptly and with proper care or professional assistance.
• Pressure Offloading: Special footwear, insoles or orthotics are used to alleviate pressure in specific areas that may have foot deformities or those with a history of ulcers.
• Blood Sugar and Health Control: Achieve a good level and control of diabetes and vascular risk factors such as smoking cessation to promote healing and prevent complications.
• Foot Screening and Education: Professional foot examinations and patient education on foot care lower risk of ulceration by supporting good habits and watching at-risk feet.

The combination of these practices decreases the chances of getting foot ulcers, helps avoid minor injuries that evolve, and reduces the complications of infections and amputations.

Warning Signs Not to Ignore

Warning signs not to ignore for diabetic foot ulcers include:

• Redness and Tenderness: Early inflammation with resultant skin redness and swelling with or without pain or discomfort on touch.
• Swelling: Localized swelling of the foot or ankle may be accompanied by warmth and tightness.
• Constant pain or discomfort: Worsening pain with pressure or walking.
• Cracked or Dry Skin: Undue dryness that results in cracked skin is a source of infection.
• Blisters: Can begin in white or fluid-filled blisters which can progress into ulcers when left untreated.
• Open Sores or Wounds: A sore that does not heal or becomes worse, may drain fluid or pus.
• Slow Wound Healing: Wounds or ulcers that do not end in weeks.
• Drainage on Socks or Shoes: Pus, blood, or fluid noticeable on sock or shoes showing an infected ulcer.
• Skin Color: Discoloration (brown, black, blue, red, or purple) of the skin can result in poor circulation, tissue death, or gangrene.
• Foul odor: A malodorous smell can indicate an infection or necrosis of tissue.
• Fever and Chills: Body systems symptoms of spreading infection.

Early detection and prompt medical care is critical to avoid severe infection, complications and even amputation. All these symptoms should be evaluated urgently by a healthcare expert in diabetic foot management.

You may also like to read: Pathophysiology of Diabetic Nephropathy

Lifestyle Habits That Support Foot Health

Foot lifestyle choices in diabetic patients aim to prevent injury to feet, preserve skin integrity, and improve general circulation. Key habits include:

• Foot care and inspection: my plan is to inspect my feet daily (cuts, blisters, redness or swelling), to identify issues early. Feet must be washed everyday using mild soap, lukewarm water and dried thoroughly between toes to avoid fungus. Wetting the skin frequently can help to avoid dryness and cracking, but lotion should not be used between toes to prevent moisture build-up.
• Wear Shoes and socks: It is important to always wear shoes that offer protection and support, even in the house. Socks must be clean, dry, well-fitting and ideally of moisture-wicking materials like wool or synthetic blends. Wear shoes to avoid unnoticeable wounds.
• Nail Care: Cut toenails straight and file the sharp edges to prevent ingrown toenails that may lead to infection.
• Blood Sugar Control: Proper glycemic management prevents nerve damage and improves circulation, lowering foot complication risks.
• Exercise: Exercise enhances blood circulation to the lower extremities and general nerve condition. Exercise of the feet in comfortable shoes prevents new injuries.
• Stop Smoking: Smoking constricts blood vessels, slows healing, and heightens the likelihood of complications.
• Regular Health Check-ups: The healthcare provider should regularly check the feet annually, and foot orthotics should be prescribed when necessary.
• Keep Feet out of Extremes of Temp: Do not put feet in hot or very cold areas, as the loss of sensation can lead to burns or frostbite.

Adhering to this lifestyle habits can significantly reduce foot complications, ulcers, and even amputations in diabetes by preserving foot health and detecting problems early.

Bottom Line

The complication is diabetic foot ulcers which can be prevented by consistent foot care. Simple routines like my daily checks, hygiene, wearing supportive shoes and regular checkups with the doctor can contribute a lot. Through remaining proactive and sensitive to foot care, diabetics can prevent severe issues, retain their mobility and health, and safeguard their well-being. Your current foot care is a future investment in your health.

Dr. Ahmad Shahzad
Founder | Lyallpur Diabetes Foundation
Consultant Diabetologist | Educator | Advocate for Preventive Care

Diabetic nephropathy is one of the most serious complications of diabetes and is a leading cause of chronic kidney disease worldwide. Understanding the pathophysiology of diabetic nephropathy is crucial, as it reveals the complex biological processes that drive kidney damage in people with diabetes. It starts with early dysfunction of the glomeruli because of long-term hyperglycemia and slowly develops into structural dysfunction of the basement membrane, mesangial cells, and podocytes. Such changes gradually culminate into proteinuria, decreased kidney performance, and later onset of end-stage renal disease. Understanding the underlying mechanisms, researchers and clinicians can find more strategies to detect, prevent, and treat it early.

Early Pathophysiological Changes

Diabetic nephropathy is initiated by unique hemodynamic changes, metabolic distress, and molecular damage, all of which play a role in early glomerular injury.

1. Hemodynamic Alterations and Hyperfiltration

Glomerular hyperfiltration, or an abnormally high glomerular filtration rate (GFR), is one of the earliest nephropathy signs of diabetes. This is because the afferent arteriole dilates, and the efferent arteriole constricts cause an increase in intraglomerular pressure and increased filtration rate at the single-nephron level.

Such vascular tone imbalance is caused by several vasoactive factors such as angiotensin II, nitric oxide, prostaglandins, VEGF, and TGF-B and poor autoregulation through tubuloglomerular feedback (TGF).

Recent studies have proposed that in addition to impaired TGF, acute hyperglycemia itself can activate afferent arteriolar dilation via a Piezo1 eNOS signaling pathway, further complicating the mechanisms driving hyperfiltration.

2. Metabolic Stress: Hyperglycemia, AGEs, and Oxidative Stress

Persistent hyperglycemia triggers multiple pathways that contribute to early renal injury:

• Advanced Glycation Endproducts (AGEs): 1. Nonenzymatic glycation of proteins and lipids results in AGEs that may accumulate in the glomerular basement membrane (GBM), mesangium, and vascular endothelium. Connection with receptors of AGEs (RAGE) facilitates oxidative stress, pro-inflammatory, and profibrotic growth factor.
• Mesangial Cell Response: High glucose enhances mesangial cell hypertrophy and matrix expansion, which drives GBM thickening and structural glomerular damage.
• Oxidative Stress and Signaling Pathways: Protein kinase C (PKC) and growth factors (TGF-b and VEGF) are activated by metabolic derangements, which contributes to the further tissue injury.

3. Endothelial and Podocyte Injury

Hyperglycemia not only stresses glomerular blood flow but also damages the cellular components of the filtration barrier:

Glomerular Endothelial Cells (GECs): High glucose provokes endothelial dysfunction associated with glycocalyx loss, mitochondrial oxidative stress, endothelin-1 release, and decreased nitric oxide supply – all of which disrupt vascular integrity and increase inflammatory and fibrotic responses.

·       Podocytes: These epithelial cells are very delicate to metabolic stress. Hyperglycemia induces podocyte apoptosis, foot-process afflation and epithelial-mesenchymal transition (EMT), which cause loss of filtration components of nephrin and podocin.

Molecular and Biochemical Mechanisms

Diabetic nephropathy is a complex of molecular and biochemical mechanisms that enhance the destruction of the kidney. These processes include activation of RAAS, oxidative stress, advanced glycation, growth factor signaling as well as inflammatory pathways.

1. Activation of RAAS & Oxidative Stress

The renin-angiotensin-aldosterone system (RAAS), more particularly the elevated angiotensin II (Ang II), is central to the etiology of kidney disease. Ang II binding to the AT 1 receptor activates downstream cascades through both G-protein-dependent (e.g. PLC->DAG->PKC) and non-G-protein signaling, leading to NAD(P)H oxidase and increased production of reactive oxygen species (ROS).

This oxidative condition encourages expression of pro-inflammatory transcription factors such as NF-KB, increase growth factors such as TGF-b and ECM accumulation which result in renal injury and proteinuria.

2. Advanced Glycation End Products (AGEs) & RAGE

Continued hyperglycemia results in AGEs, which bind to the receptor of AGEs (RAGE) that is abundantly expressed in kidney cells, including mesangial cells and podocytes. This interaction induces ROS and PKC and NF-KB, and activates fibrotic pathways such as TGF-3 and VEGF, promoting inflammation, damage to filtration barrier, and fibrosis.

3. TGF-β Signaling: The Fibrosis Driver

TGF-b1 is a focal mediator of renal fibrosis in diabetic nephropathy. It works through canonical Smad-dependent and non-Smad pathways to stimulate ECM deposition, and to prevent degradation.

• Smad-mediated: TGF-b interacts with its receptor complex and activates Smad2/3 that translocate to the nucleus (with Smad4) to control the expression of fibrotic genes.
• Non-Smad pathways TGF- replies through ERK, p38 MAPK, and PI3K/AKT signaling that strengthen fibrotic responses.

TGF-β promotes fibrosis through:

• Enhanced ECM production (e.g., collagen, fibronectin),
• ECM stabilization via lysyl oxidase and crosslinking enzymes,
• Suppressed ECM degradation, by upregulating PAI-1 and TIMPs while downregulating MMPs.

4. Oxidative Stress & MAPK Pathways

Hyperglycemia-induced ROS also stimulates inflammatory processes, ECM deposition, and cell growth in the kidney via mitogen-activated protein kinases (MAPKs), especially, p38 MAPK and JNK.

TGF-b is also enhanced by ROS via AP-1 activation, establishing the vicious circle of oxidative stress and fibrogenesis.

5. Cytokines, JAK/STAT, and Inflammatory Cascades

NF-KB is activated and leads to increased levels of TGF-B and inflammatory cytokines such as TNF-alpha and IL-6. Also, JAK2/STAT3 signaling axis reacts to hyperglycemic stress by elevating apoptosis and fibrosis of renal cells by promoting proinflammatory and ROS-mediated mechanisms.

6. VEGF, CTGF & Growth Factors

High glucose and Ang II also activate VEGF-A and CTGF among other growth factors that induce further mesangial proliferation, deposition of ECM, and podocyte apoptosis. Although VEGF appears to regulate TGF-b in some cases, in diabetic nephropathy VEGF overexpression enhances glomerulosclerosis and fibrosis.

Summary Table

Progressive Kidney Damage

With progression of diabetic nephropathy, the combined effects of glomerular damage, proteinuria, and tubular damage combined to lead to permanent damage of the kidneys. The period between early symptomatic dysfunction of the kidney, which may be silent, and the open expression of kidney dysfunction is this phase that makes a transition into end-stage kidney disease (ESKD).

1. From Microalbuminuria to Proteinuria and Renal Decline

There is usually a clear clinical course. Microalbuminuria, faint evidence of early nephropathy, frequently occurs in patients after an average of 10 years of diabetes. In type 1 diabetes, nearly 80 percent of patients with persistent microalbuminuria develop overt proteinuria (macroalbuminuria) within 5-7 years.

The glomerular machinery starts to decline faster once the proteinuria appears. Glomerulosclerosis—diffuse or nodular—becomes evident on biopsy, alongside arteriolar hyalinosis and tubulointerstitial fibrosis. The glomerular filtration rate (GFR) starts to decrease at a steady rate- on average 0.5 to 1.0 mL/min per month in untreated patients.

With the accumulation of nephron loss, serum creatinine can be falsely kept in the normal range, until much of the filtration capacity has already been impaired.

2. Glomerulosclerosis and Nephron Loss

Damage of the glomeruli increases the rate of loss of filtering units. Mesangial expansion decreases surface area to be filtered, which directly correlates with GFR declines.

Diffuse and nodular glomerulosclerosis with the classic Kimmelstiel-Wilson lesions continues to impair filtration capacity, introducing a massive loss of nephrons.

3. Tubulointerstitial Fibrosis and Tubular Atrophy

It is not only the glomerulus that is affected by injury. Proteinuria itself—especially large amounts of filtered protein—acts as a pro-inflammatory and profibrotic catalyst in the tubular compartment. Excessive protein in tubular epithelial cells triggers NF-KB activation, release of chemokines and cytokines, and macrophage recruitment, which promotes interstitial inflammation and fibrosis.

In addition, changes induced by hyperglycemia, such as increased SGLT2 activity, local angiotensin II, TGF-b1, and CTGF in tubules, initiate tubular hypertrophy, oxidative stress, apoptosis, and matrix deposition-all drivers of tubulointerstitial fibrosis.

It has been confirmed that in some instances tubular dysfunction may predate or precede through the urinary-based biomarkers, including kidney injury molecule-1 and N-acetyl-B-D-glucosaminidase.

4. Encroachment and Global Sclerosis

Pathology is also expressed structurally: Bowman capsule injury reaches adjacent tubules, causing tubular atrophy and subsequent global sclerosis. With the cessation of glomerular filtration, tubules degenerate, losing epithelial architecture and being replaced by fibrotic interstitium.

5. Final Common Pathway: ESRD

Advanced diabetic nephropathy culminates in chronic kidney disease and eventually ESKD—requiring dialysis or transplantation. This terminal phase is characterized by the interaction between structural damage, ongoing proteinuria, glomerulosclerosis, tubulointerstitial fibrosis, and nephron loss.

You may also like to read: Diabetes Mellitus and Kidney

Clinical Correlation with Pathophysiology

To diagnose, risk stratify, and intervene with diabetic nephropathy, an understanding of the clinical manifestation of the condition in relation to its underlying pathophysiology is imperative.

Clinical Stages and Diagnostic Markers

Stage 1 – Hyperfiltration (“Hyperfunction”)

• Pathophysiology: Glomerular hyperfiltration through the action of afferent dilatation and efferent constriction, RAAS activation, and greater glomerular pressure.
• Clinical Correlate: Swollen kidneys, and increased GFR- usually not noticeable.
• Significance: Marks functional change before gross damage–and can be reversed by glycemic and pressure control.

Stage 2 – Silent Structural Damage

·       Pathophysiology: The histological alterations of GBM thickening and mesangial enlargement start, but without albuminuria.

·       Clinical Correlate: GFR can return to normal or be elevated; routine clinical analysis can still be normal.

Stage 3 – Microalbuminuria (Incipient Nephropathy)

• Pathophysiology: Trace albumin leakage is enabled by podocyte and GBM permeability alterations.
• Clinical Correlate: Urine albumin excretion increases to 30300 mg/day (microalbuminuria), which can only be identified through sensitive tests such as ACR. May be associated with increased blood pressure.
• Impact: Microalbuminuria is a predictor of the development of overt proteinuria and increased cardiovascular risk.

Stage 4 – Overt Nephropathy (Macroalbuminuria)

• Pathophysiology: Glomerulosclerosis and advanced loss of podocytes result in high protein leakage.
• Clinical Correlate: Urinary albumin excretion exceeds 300 mg/day (macroalbuminuria) and the blood pressure persists with deteriorating GFR.
• Progression: In the untreated, GFR decreases gradually (e.g. 1.2 mL/min/month in Type 1 DM) and then speeds up to ESRD.

Stage 5 – End-Stage Renal Disease (ESRD)

• Pathophysiology: Irreversible nephron loss from advanced glomerular and tubular fibrosis.
• Clinical Correlate: GFR is less than 15 mL/min/1.73 m 2 resulting in overt kidney failure that necessitates dialysis or transplantation.

Diagnostic and Prognostic Utilities of GFR & Albuminuria

Current clinical practice (e.g., KDIGO) classifies chronic kidney disease in terms of GFR (G1-G5) and albuminuria (A1-A3). This two-fold coding enhances risk evaluation and guides monitoring rate and treatment.

G1–G2 with A1: Early disease—low risk.

Increase in ACR (A2 and higher) and/or decrease in eGFR: Signs of progression and increases cardiovascular and renal risks.

Remarkably, GFR can decrease without extensive albuminuria in some patients, notably with the RAAS blockade-so both the markers are important.

Final Thoughts

The pathophysiology of diabetic nephropathy involves a cascade of early functional disturbances, structural alterations, and complex molecular mechanisms that ultimately lead to progressive kidney damage. By linking these pathological changes with clinical outcomes, it becomes clear why early detection and intervention are critical. A deeper understanding of these processes not only aids in better disease management but also paves the way for developing targeted therapies to slow or prevent the progression of this serious complication of diabetes.