Overview

• Type 2 diabetes mellitus (T2DM) is a chronic, progressive metabolic disorder characterised by persistent hyperglycemia.
• It results primarily from a combination of insulin resistance in peripheral tissues and an inadequate compensatory insulin secretory response by pancreatic beta cells.
• Unlike type 1 diabetes, which typically involves autoimmune destruction of beta cells, T2DM is largely influenced by genetic and environmental factors, including lifestyle.

Key Characteristics

• Hyperglycemia: Persistent high blood sugar levels due to impaired glucose uptake in muscles and fat and unchecked glucose production in the liver.
• Insulin Resistance: A diminished cellular response to insulin in target tissues such as skeletal muscle, liver, and adipose tissue.
• Beta-Cell Dysfunction: Progressive loss of insulin-secreting capacity of pancreatic beta cells.

Diagnostic Criteria

• Diagnosis is confirmed based on one of the following laboratory criteria:
  • Fasting Plasma Glucose (FPG): ≥7.0 mmol/L (126 mg/dL) after at least 8 hours of fasting.
  • 2-Hour Plasma Glucose (OGTT): ≥11.1 mmol/L (200 mg/dL) after a 75 g oral glucose tolerance test.
  • Glycated Hemoglobin (HbA1c): ≥6.5% (reflecting average glucose levels over the past 2–3 months).
  • Random Plasma Glucose: ≥11.1 mmol/L (200 mg/dL) in individuals with classic symptoms of hyperglycemia (e.g., polyuria, polydipsia, unexplained weight loss).

Risk Factors

Genetic Predisposition

• T2DM demonstrates a strong hereditary component. Studies show that having one parent with T2DM doubles the risk, while having both parents increases the risk even further.
• Specific gene polymorphisms, such as TCF7L2, are strongly associated with insulin secretion abnormalities and beta-cell dysfunction.
• Differences in genetic susceptibility may explain the variability in T2DM prevalence across ethnic groups.

Obesity and Sedentary Lifestyle

• Central obesity, characterised by excessive visceral fat, is a key driver of insulin resistance due to its role in chronic low-grade inflammation and altered adipokine secretion.
• Physical inactivity exacerbates insulin resistance by reducing glucose uptake in skeletal muscle and contributing to weight gain.
• A higher waist-to-hip ratio and increased BMI are independent predictors of T2DM development.

Ethnic Background

• South Asian, African-Caribbean, and Indigenous populations exhibit a disproportionately higher risk for T2DM, often at a lower BMI threshold compared to Caucasians.
• Genetic predispositions combined with cultural, dietary, and socioeconomic factors contribute to this disparity.

Age

• T2DM prevalence increases with age due to progressive beta-cell dysfunction, increased insulin resistance, and the cumulative effects of lifestyle factors.
• Hormonal changes and sarcopenia in older adults also play a role in glucose intolerance.

Metabolic Syndrome

• Defined by the presence of central obesity, hypertension, hyperglycemia, and dyslipidemia, metabolic syndrome is a significant precursor to T2DM.
• These interrelated abnormalities are driven by insulin resistance and chronic inflammation, accelerating the pathogenesis of T2DM.

Environmental and Lifestyle Influences

Diet

• High intake of energy-dense, nutrient-poor foods, particularly those rich in refined carbohydrates, saturated fats, and added sugars, increases the risk of T2DM.
• Diets lacking in dietary fiber, fruits, and vegetables contribute to poor glycemic control and insulin resistance.

Sleep and Stress

• Chronic sleep deprivation, poor sleep quality, and irregular sleep patterns disrupt hormonal regulation, particularly increasing cortisol and decreasing insulin sensitivity.
• Prolonged psychosocial stress promotes hypercortisolemia, which can impair glucose metabolism and promote central fat deposition.

Socioeconomic Factors

• Lower socioeconomic status correlates with higher T2DM prevalence due to limited access to healthy foods, reduced opportunities for physical activity, and greater exposure to stressors.
• Food deserts and marketing of unhealthy food options in economically disadvantaged communities exacerbate these risks.

Intrauterine Factors

Low Birth Weight and Fetal Programming

• Intrauterine growth restriction (IUGR) and low birth weight are linked to higher rates of insulin resistance and metabolic disorders later in life.
• Epigenetic changes induced by an adverse intrauterine environment, such as maternal malnutrition or gestational diabetes, predispose offspring to beta-cell dysfunction and metabolic dysregulation.

Maternal Health

• Offspring of mothers with gestational diabetes mellitus (GDM) or T2DM during pregnancy have a significantly increased lifetime risk of developing the disease due to both genetic and intrauterine influences.

Core Defects in T2DM Pathophysiology

• T2DM arises from the interplay of insulin resistance and pancreatic beta-cell dysfunction, leading to chronic hyperglycemia.
• Insulin resistance is observed in skeletal muscle, adipose tissue, and the liver, impairing glucose uptake and increasing hepatic glucose production.
• Progressive beta-cell dysfunction exacerbates hyperglycemia as the pancreas fails to compensate for increased insulin demand.

Insulin Resistance

Skeletal Muscle

• Reduced glucose uptake due to impaired insulin signaling, particularly at the level of insulin receptor substrates and GLUT-4 translocation.

Liver

• Enhanced hepatic glucose output, driven by increased gluconeogenesis and glycogenolysis despite hyperinsulinemia.

Adipose Tissue

• Lipolysis leads to elevated free fatty acid levels, which further impair insulin sensitivity and increase hepatic glucose production.

Inflammation and Adipokines

• Obesity-associated low-grade inflammation and altered adipokines (e.g., reduced adiponectin and increased leptin) contribute to insulin resistance.

Beta-Cell Dysfunction

• Beta-cell mass and function decline over time due to genetic predisposition, glucotoxicity, and lipotoxicity.
• Chronic hyperglycemia induces beta-cell exhaustion through oxidative stress, endoplasmic reticulum stress, and amyloid deposition.
• Hyperinsulinemia, as a compensatory response to insulin resistance, accelerates beta-cell failure.

Role of Gut Hormones and Incretins

• Decreased secretion of incretins like glucagon-like peptide-1 (GLP-1) contributes to reduced postprandial insulin secretion.
• Dysregulated glucagon secretion by alpha cells exacerbates hyperglycemia through increased hepatic glucose production.

Genetic and Epigenetic Factors

• Genetic predisposition plays a significant role, with over 400 genetic loci identified as contributing to T2DM risk.
• Epigenetic modifications, influenced by environmental and lifestyle factors, affect gene expression related to glucose metabolism and insulin signaling.

• Lipid accumulation in non-adipose tissues such as liver, pancreas, and muscle disrupts cellular function, exacerbating insulin resistance and beta-cell dysfunction.
• Non-alcoholic fatty liver disease (NAFLD) is strongly associated with T2DM.

Mitochondrial Dysfunction

• Impaired mitochondrial function in muscle and beta-cells reduces energy production, exacerbating insulin resistance and beta-cell failure.

The Role of the Central Nervous System

• Dysregulated central regulation of appetite and energy balance contributes to obesity and insulin resistance.
• Hypothalamic insulin resistance impairs the suppression of hepatic glucose production.

Microbiome and Gut Dysbiosis

• Altered gut microbiota composition and function contribute to systemic inflammation, insulin resistance, and altered glucose metabolism.
• Metabolites such as short-chain fatty acids (SCFAs) and lipopolysaccharides (LPS) play a role in T2DM pathogenesis.

Glucotoxicity and Lipotoxicity

• Chronic hyperglycemia (glucotoxicity) induces oxidative stress and damages beta-cells.
• Elevated free fatty acids (lipotoxicity) interfere with insulin signaling and beta-cell function.

Systemic Inflammation

• T2DM is associated with a chronic low-grade inflammatory state, characterised by elevated levels of pro-inflammatory cytokines like TNF-α, IL-6, and C-reactive protein (CRP).
• These cytokines disrupt insulin signaling pathways and contribute to endothelial dysfunction.

Global Prevalence

• Type 2 diabetes mellitus (T2DM) is one of the most prevalent non-communicable diseases worldwide.
• It accounts for approximately 90–95% of all diabetes cases globally.
• The International Diabetes Federation (IDF) reported that in 2021, over 537 million adults (20–79 years) were living with diabetes, a figure expected to rise to 783 million by 2045.

Geographic Distribution

• T2DM prevalence is highest in low- and middle-income countries, particularly in South Asia, the Middle East, and parts of Sub-Saharan Africa.
• Rapid urbanisation and lifestyle changes, such as decreased physical activity and unhealthy diets, contribute to the rising prevalence in these regions.
• High-income countries are also significantly affected, though prevalence rates have plateaued in some areas due to preventive measures.

Age and Gender Distribution

• T2DM predominantly affects middle-aged and older adults but is increasingly diagnosed in children and adolescents due to the global obesity epidemic.
• Men and women are affected at similar rates, though some studies suggest that men may develop T2DM at lower body mass indices (BMI) compared to women.

Ethnic and Genetic Predisposition

• Certain ethnic groups, such as South Asians, African Americans, Hispanic populations, and Indigenous peoples, exhibit higher T2DM prevalence and earlier onset compared to others.
• Genetic factors, including family history and specific gene polymorphisms, play a significant role in susceptibility.

Obesity and Lifestyle Factors

• Obesity is a major risk factor, with approximately 80–90% of individuals with T2DM being overweight or obese.
• Sedentary lifestyles and diets high in processed foods and sugar contribute significantly to T2DM risk.
• Prevention strategies focusing on lifestyle modifications, such as weight management and increased physical activity, have proven effective in reducing disease burden.

Urban vs. Rural Disparities

• Urban areas show higher T2DM prevalence due to greater access to high-calorie foods, reduced physical activity, and higher stress levels.
• However, rural areas in developing countries are witnessing a rapid increase in cases due to lifest

Comorbidities and Mortality

• T2DM is a leading cause of morbidity and mortality globally.
• It contributes significantly to cardiovascular disease (CVD), chronic kidney disease (CKD), blindness, and lower-limb amputations.
• The condition is also associated with reduced life expectancy, with an estimated loss of 5–10 years depending on age of diagnosis and glycemic control.

Trends and Future Projections

• The global diabetes burden is increasing rapidly, driven by population growth, aging, urbanisation, and lifestyle changes.
• The World Health Organization (WHO) has recognised T2DM as a global health emergency, necessitating widespread preventive and management measures.

Impact on Healthcare Systems

• The economic burden of T2DM is substantial, with high costs attributed to medical care, complications, and lost productivity.
• Health systems in developing countries face significant challenges in managing the dual burden of infectious diseases and T2DM.

Symptoms Suggestive of Diabetes

• Classic Symptoms: Polyuria, polydipsia, polyphagia, and unexplained weight loss. These symptoms often indicate significant hyperglycemia.

Other Symptoms

• Blurred vision.
• Fatigue and lack of energy, which may signal progressive cardiovascular disease or other systemic impacts.
• Numbness or tingling in extremities, often due to peripheral neuropathy.
• Recurrent fungal infections, such as vaginal or penile candidiasis, or skin fold infections.
• Delayed wound healing or recurrent skin infections (e.g., cellulitis or abscesses).

Risk Factor Assessment

Personal Risk Factors

• Age: Higher prevalence in older adults, though increasingly common in children and adolescents.
• Weight: Obesity, particularly central obesity, is strongly associated with T2DM.
• Comorbidities: Hypertension, dyslipidemia, cardiovascular disease, and polycystic ovary syndrome.
• History of gestational diabetes or non-diabetic hyperglycemia.

Family History

• A strong familial component is often present, especially if first-degree relatives are affected.

Ethnicity

• Increased prevalence in individuals of African, African-Caribbean, South Asian, and Hispanic descent.

Disease-Specific History

Established Diabetes

• Duration: Complications are closely related to the length of time the patient has had diabetes.
• Control: Poor glycemic control is linked to higher risks of infection, slower healing, and long-term complications.

Hypoglycemic Episodes

• Frequency, severity, and management strategies.
• Presence of hypoglycemia unawareness, increasing risk for severe episodes.

Complication History

• Retinopathy: Last ophthalmologic assessment and findings.
• Nephropathy: Recent kidney function tests (e.g., serum creatinine, eGFR, urine albumin).
• Neuropathy: Symptoms of peripheral or autonomic dysfunction (e.g., erectile dysfunction, orthostatic hypotension).
• Vascular Disease: History of claudication, vascular procedures, or cardiovascular events.
• Foot Health: History of ulcers, infections, or amputations.

Self-Monitoring

• Frequency and trends in blood glucose levels.
• Most recent hemoglobin A1c (HbA1c) measurement.

Medication Adherence

• Use of glucose-lowering agents and their effects.
• Other therapies for comorbid conditions like statins or antihypertensives.

Historical Clues to Complications

Microvascular Complications

• Symptoms such as vision changes, tingling, or burning in extremities.
• Increased thirst or urination indicating hyperglycemia or kidney dysfunction.

Macrovascular Complications

• History of myocardial infarction, stroke, or transient ischemic attacks.
• Symptoms of peripheral arterial disease, such as claudication.

Infection Susceptibility

• Frequent urinary tract infections, pneumonia, or cellulitis.

Additional Historical Components

Lifestyle and Social History

• Diet and physical activity patterns.
• Tobacco and alcohol use, which significantly impact disease management and complications.
• Psychological factors, including stress or depression, which are common in chronic illness.

Vaccination History

• Influenza, pneumococcal, hepatitis B, and COVID-19 vaccines are critical for preventing infections in individuals with T2DM.

General Physical Examination

 Anthropometric Measurements

• Record height, weight, and calculate Body Mass Index (BMI) to evaluate obesity, which is a significant risk factor for Type 2 Diabetes Mellitus (T2DM).
• Assess waist circumference as a marker of central obesity.

Vital Signs

• Measure blood pressure, as hypertension often coexists with T2DM and contributes to cardiovascular complications.

Skin Examination

 Acanthosis Nigricans

• Check for velvety, hyperpigmented plaques, typically found on the neck or axillae, indicative of insulin resistance.

Infections

• Look for signs of skin infections, such as cellulitis, abscesses, or fungal infections (e.g., candidiasis in skin folds).

Poor Wound Healing

• Assess for chronic, non-healing wounds, particularly on the lower extremities.

Eye Examination

Diabetic Retinopathy

• Look for signs like microaneurysms, hemorrhages, or cotton wool spots.
• Early detection is essential to prevent vision loss.

Cataracts and Glaucoma

• Assess for these conditions, which are more prevalent in diabetic patients.

Neurological Examination

 Peripheral Neuropathy

• Evaluate for sensory deficits (e.g., using a monofilament, vibration, or pinprick tests) in the feet and lower extremities.
• Document symptoms like numbness, tingling, or burning sensations.

Autonomic Neuropathy

• Assess for orthostatic hypotension, gastroparesis symptoms, erectile dysfunction, or urinary retention.

Cardiovascular Examination

 Peripheral Vascular Disease

• Palpate peripheral pulses (dorsalis pedis, posterior tibial) to assess for arterial insufficiency.
• Look for signs of claudication or limb ischemia.

Cardiac Assessment

• Auscultate for murmurs or other abnormalities to evaluate for coronary artery disease or heart failure.

Abdominal Examination

 Hepatomegaly

• Check for liver enlargement, which may suggest non-alcoholic fatty liver disease (NAFLD), commonly associated with T2DM.

Bladder Palpation

• Assess for bladder distention, which may indicate autonomic neuropathy-related urinary dysfunction.

Foot Examination

• Perform a comprehensive foot evaluation, including:
  • Inspection for ulcers, calluses, deformities, or signs of infection.
  • Assessment of skin temperature and capillary refill time.
    Monofilament testing for sensory neuropathy.
  • Evaluation of pedal pulses to assess blood flow.

Oral Examination

 Periodontal Disease

• Examine for gingivitis or periodontitis, as T2DM increases susceptibility to these conditions.

Mental Health Screening

• Assess for signs of depression or anxiety, which are common comorbidities in T2DM.

Diagnostic Criteria

 Fasting Plasma Glucose (FPG)

• A fasting plasma glucose level of ≥126 mg/dL (7.0 mmol/L) on two separate occasions is diagnostic for diabetes.
• This test reflects basal glucose metabolism and is convenient for clinical use but less sensitive for early-stage diabetes detection.

Hemoglobin A1c (HbA1c)

• An HbA1c level ≥6.5% confirms the diagnosis of diabetes.
• HbA1c indicates average blood glucose levels over the past 2–3 months and is less affected by day-to-day glucose fluctuations or acute stressors.
• Limitations include reduced accuracy in individuals with hemoglobinopathies, anaemia, or conditions altering red blood cell turnover.

Oral Glucose Tolerance Test (OGTT)

• A plasma glucose level ≥200 mg/dL (11.1 mmol/L) two hours after consuming 75 g of glucose is diagnostic for diabetes.
• This test is more sensitive for identifying impaired glucose tolerance but is less practical due to the requirement for fasting, timed samples, and patient compliance.

Random Plasma Glucose (RPG)

• A glucose level ≥200 mg/dL (11.1 mmol/L) in the presence of classic symptoms such as polyuria, polydipsia, or unexplained weight loss confirms the diagnosis without requiring repeat testing.

Screening and Monitoring

 Population Screening

• Recommended for asymptomatic individuals over 40 years old or with risk factors such as obesity, hypertension, dyslipidemia, family history of diabetes, or a history of gestational diabetes.
• Common tests include FPG, HbA1c, and OGTT.

Prediabetes Identification

• HbA1c levels between 5.7% and 6.4%, fasting glucose between 100–125 mg/dL, or a 2-hour OGTT result of 140–199 mg/dL indicate prediabetes.
• Early identification is critical for intervention to delay or prevent progression to diabetes.

Additional Laboratory Tests

• Screens for glucosuria and ketonuria in patients with severe hyperglycemia or classic symptoms of diabetes.
• Although less specific, it helps identify patients requiring further investigation.

Renal Function Tests

• Serum creatinine and urine albumin-to-creatinine ratio (ACR) assess renal function and detect early nephropathy, a common complication of diabetes.
• Microalbuminuria is an early marker of kidney damage.

Lipid Profile

• Dyslipidemia in diabetes often presents with elevated LDL, reduced HDL, and increased triglycerides.
• Regular lipid monitoring is essential for cardiovascular risk management.

Specialised Investigations

 C-Peptide Levels

• Helps differentiate type 1 from type 2 diabetes in atypical cases.
• Low C-peptide levels suggest reduced beta-cell function, characteristic of type 1 diabetes.

Autoantibody Testing

• Identifies islet autoantibodies (e.g., GAD, IA-2) in suspected type 1 diabetes or latent autoimmune diabetes of adults (LADA).

Ketone Testing

• Recommended in hyperglycemic crises to diagnose diabetic ketoacidosis (DKA) or hyperosmolar hyperglycemic state (HHS).
• Blood ketone testing is preferred for accuracy over urine testing.

Contextual Investigations

 Electrolytes and Acid-Base Balance

• Assessed during hyperglycemic crises to monitor for imbalances such as hypokalemia or acidosis.

Ankle-Brachial Index (ABI)

• Screening for peripheral arterial disease, particularly in patients with claudication or non-healing ulcers.

Interpretation and Follow-Up

• Repeat confirmatory testing is advised unless diagnostic thresholds are unequivocally exceeded alongside classic symptoms.
• Limitations of specific tests (e.g., HbA1c inaccuracies in hemoglobinopathies or pregnancy) necessitate context-specific adjustments.

Type 1 Diabetes Mellitus (T1DM)

• Key Characteristics: Autoimmune destruction of pancreatic beta cells, leading to absolute insulin deficiency.
• Presentation: Commonly occurs in childhood or adolescence but can develop at any age. Symptoms include polyuria, polydipsia, weight loss, and ketosis.
• Differentiation: Presence of islet cell autoantibodies (e.g., GAD, ICA, IAA) and low or undetectable C-peptide levels are diagnostic.
  
  

Latent Autoimmune Diabetes in Adults (LADA)

• Overview: A slowly progressing form of T1DM, often misclassified as T2DM.
• Clinical Features: Onset typically after age 30, with initial response to oral agents but eventual need for insulin therapy.
• Diagnostic Criteria: Positive for one or more autoantibodies seen in T1DM and a progressive decline in C-peptide levels.
  
  

Non-Diabetic Hyperglycemia (Pre-Diabetes)

• Definition: Raised blood glucose levels (HbA1c 42-47 mmol/mol [6.0%-6.4%] or fasting glucose 5.5-6.9 mmol/L [99-124 mg/dL]) below the diabetic threshold.
• Clinical Presentation: Often asymptomatic, identified during routine screening.
• Risk: Associated with a significantly increased likelihood of developing T2DM.
  
  

Monogenic Diabetes (e.g., MODY)

• Description: A rare genetic form of diabetes resulting from single-gene mutations affecting insulin production or secretion.
• Clinical Clues: Early-onset diabetes (<25 years), autosomal dominant inheritance, and lack of autoantibodies. Often misdiagnosed as T1DM or T2DM.
• Confirmation: Genetic testing targeting specific mutations (e.g., HNF1A, glucokinase).
  
  

Ketosis-Prone Diabetes

• Definition: Diabetes characterised by episodic ketoacidosis, with features overlapping T1DM and T2DM.
• Presentation: Unprovoked ketosis, often with obesity or metabolic syndrome traits.
• Differentiation: Lack of autoantibodies and varying insulin requirements during remission phases.
  
  

Secondary Diabetes

• Aetiologies:
  • Endocrinopathies: Conditions like Cushing’s syndrome, acromegaly, and pheochromocytoma can impair glucose metabolism.
  • Pancreatic Diseases: Chronic pancreatitis, pancreatic cancer, and cystic fibrosis damage insulin-producing cells.
  • Drug-Induced: Caused by medications like corticosteroids, atypical antipsychotics, or immunosuppressants.
• Diagnostic Approach: Focused testing for underlying causes (e.g., hormone assays, imaging studies).
  
  

Gestational Diabetes Mellitus (GDM)

• Definition: Diabetes diagnosed during pregnancy, usually detected through routine screening.
• Risk Factors: Include obesity, a history of macrosomic infants, and ethnic backgrounds associated with a higher prevalence of diabetes.
• Challenges: Distinguishing between undiagnosed pre-existing T2DM and true GDM.
  
  

Other Considerations

• Infections: Viral infections (e.g., CMV, rubella) can transiently disrupt glucose metabolism.
• Hemochromatosis: Iron overload leads to pancreatic damage and insulin deficiency.
• Metabolic Syndrome: Overlapping features with diabetes, such as obesity and dyslipidemia, can complicate diagnosis.
  
  

Individualised Care

• Personalised Approach: Care should be tailored to each patient’s specific needs, preferences, and comorbidities, especially in the presence of multimorbidity. Consider:
  • Disabilities, such as visual or physical impairments.
  • Risks associated with polypharmacy.
  • Potential benefits of long-term interventions like glycaemic control and cardiovascular risk reduction.
  • Assessment of frailty in older adults using validated tools such as the electronic Frailty Index or Rockwood frailty score.
• Glycaemic Targets: Collaboratively agree on targets for HbA1c, balancing the benefits of tight glycaemic control against the risk of adverse effects like hypoglycaemia. Relaxed targets may be appropriate for frail or elderly patients or those with a reduced life expectancy.
• Regular Reassessment: Continuously evaluate the patient’s needs and circumstances, with periodic reviews to discontinue ineffective or poorly tolerated medications.
  
  

Structured Education

• Education Programmes:
  • Offer structured education at diagnosis, with annual reviews.
  • Programmes should be evidence-based, culturally sensitive, and tailored to meet individual needs.
  • Include a focus on fostering self-management skills, such as monitoring blood glucose, understanding medication, and adjusting diet and exercise.
• Delivery:
  • Use group education as the preferred format, with alternative options for those unable or unwilling to attend.
  • Ensure educators are trained, competent, and supported with resources to maintain programme quality.
    
    

Dietary and Lifestyle Modifications

• Dietary Advice:
  • Emphasise high-fibre, low-glycaemic index foods, including fruits, vegetables, whole grains, and legumes.
  • Limit consumption of saturated fats, trans fats, and processed meats.
  • Encourage the substitution of sucrose-containing foods with healthier carbohydrates while avoiding excess caloric intake.
  • Discourage consumption of foods marketed specifically for diabetes.
• Weight Management:
  • For overweight patients, aim for a 5–10% reduction in body weight. Greater weight loss (10–15%) can lead to significant metabolic benefits.
  • Use structured weight-loss programmes, including very-low-calorie diets, under professional supervision where appropriate.
• Physical Activity:
  • Recommend at least 150 minutes per week of moderate-intensity aerobic exercise, supplemented by resistance training twice weekly.
  • For those unable to meet these recommendations, encourage any increase in physical activity to reduce sedentary behavior.
    
    

Glycaemic Management

• HbA1c Monitoring and Goals:
  • Measure HbA1c every 3–6 months initially, then every 6 months once stable.
  • Aim for <48 mmol/mol (6.5%) for those on lifestyle or non-hypoglycaemia-inducing therapies, or <53 mmol/mol (7.0%) for those on insulin or sulfonylureas.
  • Adjust targets for frail individuals or those with a high risk of hypoglycaemia.
• Self-Monitoring of Blood Glucose (SMBG):
  • Recommended for those on insulin or with risk factors for hypoglycaemia.
  • Consider intermittent SMBG for short-term needs, such as during corticosteroid therapy or illness.
• Continuous Glucose Monitoring (CGM):
  • Offer CGM to patients on multiple daily insulin injections, especially those with recurrent hypoglycaemia or impaired awareness of hypoglycaemia.
    
    

Pharmacological Treatment

Initial Therapy

• First-line agent:
  • Metformin: Recommended for all adults unless contraindicated. It is initiated at a low dose and titrated gradually to minimise gastrointestinal side effects. Modified-release formulations can be used if standard-release metformin is not well tolerated.
• Alternatives to metformin (when contraindicated or not tolerated):
  • SGLT2 inhibitors: Preferred for patients with cardiovascular disease (CVD), chronic kidney disease (CKD), or high cardiovascular risk due to proven cardiovascular and renal benefits.
  • DPP-4 inhibitors: Offer a lower risk of hypoglycemia and are weight-neutral, suitable for older adults or those with modest glycemic elevations.
  • Pioglitazone: Appropriate for patients without heart failure or risk of fractures, as it may cause fluid retention and weight gain.
  • Sulfonylureas: Effective but associated with a higher risk of hypoglycemia and weight gain. Best suited for short-term use or when cost considerations are significant.
    
    

Dual Therapy

• Indication: When monotherapy with metformin fails to achieve glycemic targets (HbA1c above 7% or patient-specific target), add a second agent.
• Choice of second agent:
  • SGLT2 inhibitors: Preferred in patients with CVD, CKD, or multiple cardiovascular risk factors.
  • DPP-4 inhibitors, pioglitazone, or sulfonylureas: Consider based on individual patient factors such as tolerance, contraindications, and risk of hypoglycemia.
• Sequential titration: Each agent should be introduced in a stepwise manner with close monitoring of response and side effects.
  
  

Triple Therapy

• Indication: For patients whose glycemic targets are not achieved with dual therapy.
• Combination options:
  • Metformin + SGLT2 inhibitor + DPP-4 inhibitor
  • Metformin + SGLT2 inhibitor + GLP-1 receptor agonist (ideal for weight management and cardiovascular protection).
  • Metformin + SGLT2 inhibitor + pioglitazone (preferred if weight gain and fluid retention are not a concern).
• Personalisation: The choice of the third agent depends on patient-specific factors such as body weight, risk of hypoglycemia, comorbidities, and adherence considerations.
  
  

Insulin Therapy

• Indication: For patients whose HbA1c levels remain above target despite maximal oral therapy or who present with significant hyperglycemia or weight loss (suggesting insulin deficiency).
• Basal insulin:
  • Neutral Protamine Hagedorn (NPH): Cost-effective option, given once or twice daily based on glycemic patterns.
  • Long-acting insulin analogs (e.g., insulin glargine, insulin detemir): Preferred for patients at higher risk of hypoglycemia due to their more predictable pharmacokinetics.
  • Titration should be guided by self-monitored blood glucose (SMBG) results, with adjustments every 3–7 days to achieve fasting glucose targets.
• Basal-bolus regimens:
  • Add rapid-acting insulin before meals for patients with significant postprandial glucose excursions or persistently elevated HbA1c levels despite basal insulin.
  • Adjust pre-meal doses based on carbohydrate intake, activity levels, and preprandial glucose readings.
• Other considerations:
  • GLP-1 receptor agonists may be considered as an alternative to initiating basal insulin for patients requiring more aggressive glycemic control but desiring to avoid weight gain or hypoglycemia.
    
    

Cardiovascular and Renal Risk Management

• Blood Pressure Management:
  • Target <135/85 mmHg (<130/80 mmHg for those with CKD and significant proteinuria).
  • Use ACE inhibitors or ARBs as first-line agents, particularly for patients with albuminuria.
• Lipid Management:
  • Offer high-intensity statins (e.g., atorvastatin) for primary prevention in patients with a QRISK3 score ≥10% and for secondary prevention in those with established CVD.
  • Target LDL <1.8 mmol/L (<1.4 mmol/L for very high-risk individuals).
• SGLT2 Inhibitors and CKD:
  • Recommended for CKD patients with albuminuria to reduce progression to end-stage renal disease and cardiovascular events.
    
    

Emerging Technologies and Lifestyle Support

• CGM and IsCGM:
  • Provide access to CGM for patients with significant glycaemic variability or those requiring frequent monitoring.
  • Ensure patients receive education on CGM use and periodic assessment of its utility.
• Psychological Support:
  • Address diabetes distress and psychosocial barriers to adherence through structured counselling and support groups.
• Smoking Cessation:
  • Offer evidence-based cessation programmes, including pharmacological therapies (e.g., nicotine replacement, varenicline).
    
    

Overview

• Improving Life Expectancy: Advances in treatment have significantly improved life expectancy for individuals with type 2 diabetes in many high-income countries. Despite these gains, the disease's burden remains substantial due to its chronic nature and associated complications.
• Excess Mortality:
  • Individuals diagnosed with type 2 diabetes at age 40 lose an average of 5.8 years (men) and 6.8 years (women) of life compared to those without diabetes.
  • The overall mortality risk is approximately 15% higher, ranging widely. Younger adults with poor glucose control and renal impairment face a markedly elevated risk, whereas older adults with good management and no renal impairment may have comparable or better outcomes than their peers without diabetes.
    
    

Cardiovascular Risks

• Major Cardiovascular Events: Type 2 diabetes is a critical risk factor for atherosclerotic cardiovascular disease (ASCVD). The likelihood of cardiovascular events and mortality depends on:
  • Age of onset: Earlier onset correlates with higher lifetime risk.
  • Duration of diabetes: A longer duration worsens outcomes.
  • Control of Risk Factors: Optimizing glycemic control (HbA1c), blood pressure, lipid levels, smoking cessation, and renal function significantly reduces cardiovascular risks.
• Mortality and HbA1c: Maintaining an HbA1c of 6%-6.9% (42–52 mmol/mol) correlates with the lowest mortality. Poor glucose control, compounded by hypertension and dyslipidemia, exacerbates cardiovascular risks.
  
  

Microvascular Complications

1. Diabetic Retinopathy:
   • A leading cause of blindness among working-age adults in many countries.
   • Prevalence at diagnosis: Approximately 12%-19% of individuals with diabetes already have some form of retinopathy, with 4% developing proliferative retinopathy after 20 years of diabetes.
2. Chronic Kidney Disease (CKD):
   • CKD affects about 40% of patients with type 2 diabetes over time.
   • Diabetes remains a leading cause of end-stage renal disease (ESRD), although improved detection and management have contributed to a declining incidence of ESRD attributed to diabetes.
     
     

Diabetes Remission

• Definition and Criteria: Sustained remission is defined as an HbA1c <6.5% (<48 mmol/mol) maintained for at least three months without glucose-lowering therapy.
• Implications: Achieving remission is possible but rare. Its long-term impact on clinical outcomes remains unclear, necessitating further research. Efforts to standardise definitions and criteria aim to advance understanding and clinical applications in this field.

Management Impact

• Comprehensive Care:
  • Effective management requires a collaborative approach involving motivated patients actively engaged in self-care and adaptable clinical teams.
  • Treatment includes lifestyle interventions, regular medication adjustments, and continuous monitoring.
• Reduced Morbidity and Mortality:
  • Advances in pharmacological therapies (e.g., SGLT2 inhibitors, GLP-1 receptor agonists) and preventive measures targeting cardiovascular and microvascular complications have led to measurable reductions in diabetes-related morbidity and mortality.
  • Secondary prevention strategies, including aspirin for those at high risk and rigorous management of dyslipidemia and hypertension with ACE inhibitors or ARBs, are critical to improving long-term outcomes.
    
    

Future Perspectives

• Sustained glucose control, personalised medicine, and continued advancements in pharmacotherapy offer promise for improving the prognosis of individuals with type 2 diabetes.
• Research focusing on remission, long-term complications, and effective risk factor management is vital to alleviating the disease's burden further.
  
  

Microvascular Complications

1. Diabetic Nephropathy:
   • Occurs in approximately 40% of patients with T2DM over time.
   • Leading cause of end-stage renal disease (ESRD) globally.
   • Diagnostic markers include reduced estimated glomerular filtration rate (eGFR) and presence of albuminuria.
   • Risk factors include poor glucose and blood pressure control.
   • Management involves:
     • Use of ACE inhibitors or angiotensin receptor blockers (ARBs).
     • SGLT2 inhibitors or GLP-1 receptor agonists for renal protection.
     • Referral to a nephrologist for advanced disease.
2. Diabetic Retinopathy:
   • Leading cause of blindness among working-age adults.
   • Prevalence varies from 1.5% to 31% in newly diagnosed patients, with a higher prevalence in low- and middle-income countries.
   • Screening for retinopathy, macular degeneration, glaucoma, and cataracts is critical.
   • Tight blood glucose and blood pressure control reduce progression risk.
3. Diabetic Neuropathy:
   • Peripheral neuropathy: characterised by sensory deficits or pain in the extremities.
   • Autonomic neuropathy: Manifests as gastroparesis, erectile dysfunction, or orthostatic hypotension.
   • Effective glycemic control modestly slows progression but rarely reverses damage.
     
     

Macrovascular Complications

1. Cardiovascular Disease (CVD):
   • Leading cause of death in T2DM patients.
   • Includes coronary artery disease (CAD), stroke, and peripheral artery disease (PAD).
   • Risk reduction strategies:
     • Glycemic control (avoiding overly aggressive targets that increase mortality risk).
     • Lipid management with statins or PCSK9 inhibitors.
     • Blood pressure management with ACE inhibitors or ARBs.
     • SGLT2 inhibitors and GLP-1 receptor agonists for cardioprotection.
2. Congestive Heart Failure (CHF):
   • Increased risk in T2DM, with CHF often presenting as the initial cardiovascular manifestation.
   • Management includes beta-blockers, aldosterone antagonists, and SGLT2 inhibitors.
   • Comprehensive evaluation for secondary causes, such as ischemia or thyroid dysfunction, is essential.
3. Stroke:
   • Diabetes doubles the risk of ischemic and hemorrhagic stroke.
   • Prevention focuses on managing blood pressure, lipids, and glucose.
     
     

Acute Complications

1. Diabetic Ketoacidosis (DKA):
   • Though more common in type 1 diabetes, DKA can occur in T2DM, particularly in cases of ketosis-prone diabetes.
   • Triggers include infection, poor medication adherence, and severe metabolic stress.
   • Treatment involves fluid resuscitation, insulin therapy, and correction of electrolyte imbalances.
2. Hyperosmolar Hyperglycemic State (HHS):
   • characterised by extreme hyperglycemia, dehydration, and high osmolality, without significant ketoacidosis.
   • Most common in older adults with T2DM.
   • Management mirrors that of DKA but requires a slower correction of hyperglycemia to prevent cerebral oedema.
3. Hypoglycemia:
   • Commonly results from insulin or sulfonylurea therapy.
   • Symptoms range from mild (sweating, anxiety) to severe (seizures, coma).
   • Prevention includes patient education and careful titration of glucose-lowering medications.
     
     

Other Complications

1. Lower Extremity Complications:
   • Includes peripheral vascular disease, neuropathy, and diabetic foot ulcers.
   • Aggressive management of infections and ischemia reduces the risk of amputation.
2. Infections:
   • Diabetes impairs immune function, increasing susceptibility to infections such as pneumonia, urinary tract infections, and cellulitis.
   • Vaccination against influenza, pneumococcus, and COVID-19 is recommended.
3. Cognitive Decline and Dementia:
   • T2DM increases the risk of vascular and non-vascular dementia.
   • Poor glycemic control and microvascular complications exacerbate risk.
4. Periodontal Disease:
   • Associated with poor glycemic control and chronic inflammation.
   • Dental care and periodontal treatment improve both oral health and glycemic control.
     
     

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