Type 1 Diabetes Mellitus (T1DM)

Autoimmune Destruction and Genetic Predisposition

HLA Associations

• The most significant genetic risk factors for T1DM are located in the HLA class II region on chromosome 6p21.
• The highest susceptibility is conferred by DRB10301-DQA10501-DQB10201 and DRB10401-DQA10301-DQB10302.
• DRB11501-DQA10102-DQB1*0602 is protective.

Familial Risk

• Monozygotic twins show a concordance rate exceeding 50% by age 40.
• Dizygotic twins have a lower rate of approximately 5–6%.
• Risk in offspring is 2–3% if the mother has T1DM, 5–6% if the father is affected, and up to 30% if both parents have the condition.

Population Distribution

• T1DM prevalence is highest in European populations, particularly in northern Europe.
• The lowest incidence is reported in East Asian populations.

Genetic Loci Beyond HLA

INS Gene (Chromosome 11p15.5)

• A polymorphic variable number of tandem repeats (VNTR) in the insulin gene influences thymic insulin expression and immune tolerance.

PTPN22 (Protein Tyrosine Phosphatase Non-receptor Type 22)

• Plays a role in T-cell receptor signalling, contributing to autoimmune predisposition.

IL2RA/CD25 (Interleukin-2 Receptor Alpha)

• Regulates immune function by affecting T-cell responses.

Other implicated genes include

• CTLA4, UBASH3A, ERBB3, CLEC16A, IL18RAP, and CCR5 — all involved in immune system regulation.

Environmental Triggers

Viral Infections

• Enteroviruses, including Coxsackievirus B, rubella, mumps, and cytomegalovirus, have been associated with the development of T1DM.

Infant Diet

• Early exposure to cow’s milk proteins and gluten has been investigated for potential contributions to T1DM autoimmunity, although findings remain inconclusive.

Vitamin D Deficiency

• Some research suggests that adequate vitamin D intake may lower T1DM risk.

Nitrate Exposure

• High levels of nitrate in drinking water have been linked to increased T1DM incidence.

Childhood Infections

• Frequent upper respiratory infections during the first year of life are associated with the development of diabetes-related autoantibodies.

COVID-19 and Type 1 Diabetes

Direct Pancreatic Beta-Cell Infection

• Viral antigen has been detected in pancreatic tissue, with studies showing decreased insulin secretion in infected cells.

Increased Post-Infection Diabetes Risk

• A study reported a 40% higher risk of diabetes within a year following COVID-19, particularly in those who required hospitalisation.

Potential Mechanisms

• SARS-CoV-2 may contribute to T1DM through direct beta-cell apoptosis, stress hyperglycaemia, and immune dysregulation.

Autoimmune Destruction of Beta Cells

Loss of Beta-Cell Mass and Insulin Secretion

• Progressive beta-cell destruction reduces insulin secretion, leading to loss of blood glucose regulation.
• Clinical diabetes typically manifests when 80–90% of beta cells are destroyed.

Role of Autoantibodies

• Autoantibodies targeting beta-cell antigens—including glutamic acid decarboxylase (GAD65), insulin (IAA), islet antigen-2 (IA-2), and zinc transporter-8 (ZnT8)—are present in up to 90% of newly diagnosed patients.
• These can be detected before the onset of clinical symptoms.

Genetic Predisposition

• The HLA-DR and HLA-DQ haplotypes are strongly associated with disease susceptibility.
• HLA-DR3/4 heterozygosity confers the highest risk, whereas HLA-DR2 appears to provide protection.

Stages of Disease Progression

Stage 1 (Preclinical Phase)

• The presence of two or more islet autoantibodies with normal blood glucose levels.

Stage 2 (Dysglycemia Phase)

• Progressive beta-cell destruction leads to impaired fasting glucose (100–125 mg/dL) and HbA1c levels between 5.7–6.4%.

Stage 3 (Clinical Diabetes)

• Overt hyperglycemia occurs, with random blood glucose ≥200 mg/dL and fasting glucose ≥126 mg/dL.
• Symptoms such as polyuria, polydipsia, weight loss, and fatigue become evident.

Metabolic Consequences of Insulin Deficiency

Disrupted Glucose Utilisation

• Insulin deficiency prevents glucose uptake in peripheral tissues, causing hyperglycaemia.

Counter-Regulatory Hormone Activation

• Elevated levels of glucagon, epinephrine, cortisol, and growth hormone increase glucose production via hepatic gluconeogenesis, glycogenolysis, and ketogenesis.

Diabetic Ketoacidosis (DKA)

• Unchecked lipolysis leads to ketone body accumulation, resulting in metabolic acidosis, dehydration, and electrolyte imbalances.

Systemic Complications

Microvascular Disease

• Chronic hyperglycaemia contributes to diabetic retinopathy, nephropathy, and neuropathy.
• These are driven by oxidative stress, endothelial dysfunction, and advanced glycation end products (AGEs).

Macrovascular Disease

• Insulin deficiency leads to atherosclerosis, coronary artery disease, and cerebrovascular disease.
• Low vitamin D levels have been associated with increased coronary artery calcification in T1DM.

Pancreatic Volume Reduction

• Imaging studies indicate reduced pancreatic volume in T1DM, suggesting concurrent exocrine pancreatic dysfunction.

"Double Diabetes" and Insulin Resistance

• In regions with high obesity prevalence, some individuals with T1DM exhibit insulin resistance, mimicking type 2 diabetes.
• This condition, termed “double diabetes,” is linked to:
  • Lower glucose disposal rates (eGDR)
  • Increased risk of cardiovascular disease
  • Ethnic disparities in disease presentation

Prevalence and Incidence

• Type 1 diabetes mellitus (T1DM) is a common chronic disease in children but can develop at any age.
• It accounts for 5–10% of all diabetes cases worldwide.
• A systematic review estimated that 9.5% of individuals with diabetes have T1DM, with a global incidence of 15 per 100,000 people per year.

Geographic Variation

• The incidence of T1DM varies widely across regions.
• The highest rates are found in Finland and other Northern European countries, where the incidence is 400 times greater than in China and Venezuela, which report the lowest rates.

Annual Increase

• The global incidence of T1DM has been rising by approximately 3% annually.
• A more rapid increase is observed in non-White racial and ethnic groups.

Epidemiology in the United States

• T1DM is the most common metabolic disease of childhood.
• An estimated 304,000 children and adolescents under 20 years old and 1.7 million adults in the U.S. have T1DM.
• Between 2002 and 2018, the incidence of T1DM among youth under 19 years increased by 2.02% per year, with the highest increases observed in:
  • Asian/Pacific Islander youth: 4.84% per year
  • Hispanic youth: 4.14% per year
  • Black youth: 2.93% per year

Epidemiology Worldwide

• In 2021, an estimated 8.4 million people worldwide were living with T1DM.
• Projections indicate that by 2040, this number will rise to 13.5–17.4 million.
• The largest relative increase is expected in low- and lower-middle-income countries.

Age-Related Demographics

• Previously referred to as juvenile-onset diabetes, T1DM is typically diagnosed in childhood or adolescence.
• The peak incidence occurs between ages 10–14 years, although onset can occur at any age.
• 50% of new T1DM cases occur in individuals older than 20 years.
• In adults, T1DM often has a slower onset and is sometimes misdiagnosed as type 2 diabetes (T2DM), a condition known as latent autoimmune diabetes in adults (LADA).

Sex and Ethnic Disparities

• T1DM is slightly more common in males than females, particularly after puberty, with a male-to-female ratio greater than 1.5:1 in populations of European descent.
• The disease is most prevalent among non-Hispanic Whites, followed by African Americans and Hispanic Americans, and is less common in Asian populations.

Familial and Genetic Risk

• First-degree relatives of individuals with T1DM have an increased risk of developing the disease.
• The likelihood of developing islet autoantibodies decreases with age, supporting annual screening in relatives under 10 years old and one additional screening during adolescence.

Date of Diagnosis

• Establishing the duration of diabetes helps assess the risk of complications.

Diabetes Management History

• Prior treatment regimens, including insulin types, dosages, and methods of administration (injection vs. pump).
• Adherence to blood glucose monitoring, including frequency and trends in glucose levels.
• Awareness and application of sick day rules for managing hyperglycemia during illness.

Acute Complications

• History of diabetic ketoacidosis (DKA), including frequency and severity.
• Past episodes of severe hypoglycemia, loss of consciousness, or seizures.

Chronic Complications

• Microvascular complications (retinopathy, nephropathy, neuropathy).
• Macrovascular complications (coronary artery disease, stroke, peripheral arterial disease).
• Foot health (history of ulcers, infections, amputations).
• Dental and skin conditions related to diabetes.

Medication Review

• Insulin regimen (types, dosages, frequency).
• Use of additional agents such as pramlintide (an amylin analogue).
• Over-the-counter supplements or medications that may affect blood glucose.

Pregnancy and Contraception History

• In female patients of reproductive age, assess pregnancy status and any history of gestational diabetes.

Presenting Symptoms at Diagnosis

 Polyuria

• Excessive urination due to osmotic diuresis.

Polydipsia

• Increased thirst in response to dehydration.

 Polyphagia

• Increased hunger due to the inability of glucose to enter cells.

 Fatigue and Weakness

• A consequence of muscle catabolism and hypovolemia.

 Blurred Vision

• Hyperglycemia-induced changes in lens osmolarity.

 Weight Loss

• Despite normal or increased appetite, weight loss occurs due to lipolysis and protein catabolism.

 Gastrointestinal Symptoms

• Nausea, vomiting, and abdominal pain, particularly if DKA is present.
• Chronic symptoms may be due to autonomic neuropathy affecting gastric motility.

 Neuropathy Symptoms

• Numbness and tingling in a glove-and-stocking distribution may occur in longstanding cases.

Assessing Glycemic Control

• Frequency of blood glucose monitoring (capillary or continuous glucose monitoring).
• Patterns of hyperglycemia and hypoglycemia.
• HbA1c Levels: Date and value of the most recent measurement to assess long-term control.
• Hypoglycemia Awareness: Evaluate episodes of hypoglycemia unawareness, which increases the risk of severe hypoglycemia.
• Hyperglycemia Symptoms: Recent history of polyuria, polydipsia, nocturia, or unexplained weight loss.

Screening for Associated Autoimmune Conditions

• Thyroid Disorders: History of Graves' disease or Hashimoto's thyroiditis.
• Coeliac Disease: Gastrointestinal symptoms or known gluten intolerance.
• Adrenal Insufficiency: Features suggestive of Addison’s disease, such as fatigue and unexplained weight loss.

Psychosocial and Behavioral Health Assessment

• Diabetes Distress: Emotional burden of managing a chronic illness.
• Depression and Anxiety: Use of screening tools like PHQ-9 for depression and GAD-7 for anxiety.
• Eating Disorders: Higher prevalence in adolescents and young adults with T1DM, often presenting as insulin omission for weight control.
• Cognitive Impairment: Screening for early cognitive decline, particularly in older adults.

Microvascular and Macrovascular Risk Assessment

• Eye Health: Last dilated eye exam and presence of retinopathy.
• Kidney Function: History of proteinuria or elevated creatinine.
• Cardiovascular Risk: Presence of hypertension, dyslipidemia, or prior cardiovascular events.
• Peripheral Vascular Disease: Claudication symptoms, history of vascular interventions.

Foot Health and Infection Risk

• Foot Ulcers and Amputations: History of poor wound healing or previous infections.
• Frequent Infections: Including urinary tract infections, skin infections, and fungal infections.

Vital Signs

 Blood Pressure and Heart Rate

• Patients with autonomic neuropathy may exhibit orthostatic hypotension (a drop in blood pressure upon standing).
• Persistent tachycardia can indicate autonomic dysfunction.

Respiratory Rate and Pattern

• Kussmaul respiration (deep, labored breathing) suggests DKA and requires urgent evaluation.
• Hypoventilation or irregular breathing patterns may indicate advanced autonomic neuropathy.

Head and Neck Examination

 Funduscopic Examination

• Evaluation for diabetic retinopathy is critical, including microaneurysms, haemorrhages, and exudates.
• Pupillary dilation improves assessment accuracy, and if abnormalities are detected, referral to ophthalmology is required.

Oral Health

• Periodontal disease and oral infections are more common in diabetes.
• Poor glycemic control is associated with gingivitis, periodontitis, and delayed wound healing.

Cardiovascular Examination

 Peripheral Pulses

• Dorsalis pedis and posterior tibial pulses should be palpated to assess peripheral arterial disease (PAD).
• Absent or diminished pulses suggest vascular insufficiency.

Auscultation

• Presence of bruits over the carotid, abdominal, or femoral arteries indicates atherosclerosis.

Blood Pressure Monitoring

• Hypertension is a common comorbidity and accelerates diabetic nephropathy and cardiovascular disease.

Pulmonary Examination

 Breath Odour

• A fruity or acetone-like odour suggests ketosis or ongoing DKA.

Signs of Respiratory Infection

• Recurrent lung infections may be associated with poor glycemic control or immunosuppression.

Abdominal Examination

 Gastrointestinal Symptoms

• Hepatic enlargement due to fatty liver disease or diabetic hepatopathy.
• Chronic abdominal pain may suggest diabetic gastroparesis.

Signs of DKA

• Abdominal tenderness is common but should be differentiated from acute pancreatitis, which can mimic DKA.

Neurologic Examination

 Peripheral Neuropathy

• Glove-and-stocking distribution numbness or tingling is a hallmark of diabetic peripheral neuropathy.
• 10g monofilament testing or vibration sensation with a tuning fork should be used to assess protective sensation.
• Reduced ankle reflexes may indicate nerve dysfunction.

Autonomic Neuropathy

• Gastroparesis symptoms: early satiety, bloating, or nausea.
• Bladder dysfunction: urinary hesitancy or retention.
• Sexual dysfunction: erectile dysfunction in men or decreased libido in women.

Cognitive Function

• Early cognitive decline is increasingly recognised in long-standing diabetes.

Skin Examination

 Lipodystrophy

• Atrophy or hypertrophy at insulin injection sites due to repeated injections in the same area.

Acanthosis Nigricans

• Although more common in type 2 diabetes, its presence suggests coexisting insulin resistance.

Skin Infections

• Fungal infections (Candida spp.) can occur in moist areas, such as intertriginous zones.
• Furuncles, carbuncles, and bacterial infections are common with chronic hyperglycemia.

Extremity and Foot Examination

 Diabetic Foot Ulcers and Infection

• Assess for calluses, ulcers, or signs of infection.
• Charcot foot deformity may be present in long-standing cases.

Temperature and Perfusion

• Cold extremities may indicate peripheral vascular disease.
• Delayed capillary refill suggests impaired circulation.

Primary Diagnostic Tests

Random Plasma Glucose (RPG)

• A level ≥11.1 mmol/L (≥200 mg/dL) in the presence of symptoms such as polyuria, polydipsia, and unexplained weight loss confirms diabetes.
• A repeat test is recommended in most cases to ensure diagnostic accuracy.

Fasting Plasma Glucose (FPG)

• Defined as no caloric intake for at least 8 hours.
• ≥7.0 mmol/L (≥126 mg/dL) confirms diabetes when repeated.

Oral Glucose Tolerance Test (OGTT)

• Plasma glucose ≥11.1 mmol/L (≥200 mg/dL) measured 2 hours after a 75g glucose load confirms diabetes.

Hemoglobin A1c (HbA1c)

• Reflects chronic hyperglycemia over the preceding 3 months.
• ≥6.5% (≥48 mmol/mol) is diagnostic of diabetes.
• Not always reliable in cases of rapid-onset diabetes, such as in young children.

Clinical Diagnosis in Adults

• In adults, T1DM is often diagnosed clinically, especially in those presenting with:
  • Ketosis
  • Rapid weight loss
  • Age <50 years
  • BMI <25 kg/m²
  • Personal or family history of autoimmune disease

Additional Investigations for Diagnostic Confirmation

Plasma or Urine Ketones

• The presence of moderate to high ketones in hyperglycemia suggests T1DM.

C-Peptide Testing

• C-peptide is a byproduct of insulin production and reflects endogenous insulin secretion.
• Indicated when:
  • Differentiating T1DM from T2DM, especially in older adults or those with higher BMI.
  • Suspecting monogenic diabetes.
• Low or undetectable C-peptide levels suggest beta-cell failure, confirming T1DM.

Autoimmune Marker Testing

• Detects antibodies targeting pancreatic beta cells.
• Includes:
  • Glutamic Acid Decarboxylase (GAD65) antibodies
  • Islet Cell Antibodies (ICA)
  • Islet Antigen-2 (IA-2) antibodies
  • Zinc Transporter ZnT8 antibodies
• Most useful at diagnosis, as false-negative rates increase over time.
• Particularly relevant if classification is uncertain, or if insulin pump therapy eligibility depends on confirmation of T1DM.

Monitoring and Secondary Investigations

Plasma Glucose Testing

• Routine self-monitoring via capillary glucose measurements is crucial.
• Continuous glucose monitoring (CGM) can provide real-time glucose trends, helping adjust insulin therapy.

HbA1c Monitoring

• Used for long-term glucose control assessment.
• Recommended every 3 months in patients with unstable glycemia or recent therapy changes.
• Can be unreliable in conditions affecting red blood cell turnover (e.g., hemolytic anaemia).

Fructosamine Levels

• Reflect glucose control over 1–3 weeks.
• Useful in short-term monitoring or when HbA1c is unreliable (e.g., neonatal diabetes).

Ketone Testing

• Urine ketones can indicate DKA risk but are less accurate than blood ketones.
• Plasma beta-hydroxybutyrate is a more reliable marker of ketone accumulation in DKA.

Renal Function Tests

• Urinary albumin-to-creatinine ratio (UACR) to detect early diabetic nephropathy.
• Serum creatinine and estimated glomerular filtration rate (eGFR) to assess renal function.

Lipid Profile

• Evaluates cardiovascular risk.
• T1DM is associated with a higher risk of atherosclerosis, necessitating periodic lipid assessments.

Thyroid Function Tests

• T1DM is frequently associated with autoimmune thyroid disease.
• TSH and free T4 should be checked periodically.

Screening for Other Autoimmune Conditions

• Coeliac disease screening (tissue transglutaminase IgA).
• Adrenal insufficiency screening in select cases (cortisol, ACTH).

Tests to Differentiate Type 1 from Type 2 Diabetes

C-peptide Test

• A fasting C-peptide <0.6 ng/mL suggests T1DM.
• Higher levels (>1 ng/mL) in a patient with diabetes >1–2 years suggest T2DM.

Islet Autoantibody Panel

• Presence of two or more autoantibodies supports an autoimmune etiology.
• Autoantibody-negative diabetes in young adults may indicate monogenic diabetes (MODY).

Genetic Testing

• Considered in suspected monogenic diabetes (e.g., neonatal diabetes, MODY).

Type 2 Diabetes Mellitus

• Clinical Features:
  • Typically older onset, slow progression of hyperglycemia.
  • Obesity and insulin resistance markers (e.g., acanthosis nigricans).
  • Often asymptomatic at diagnosis.
• Investigations:
  • C-peptide present (reflecting residual beta-cell function).
  • Autoantibodies absent.
  • Positive family history of type 2 diabetes.

Latent Autoimmune Diabetes in Adults (LADA)

• Clinical Features:
  • Onset after age 30, initially non-insulin requiring but progressing to insulin dependence within 6 months to 5 years.
  • Often misclassified as type 2 diabetes.
• Investigations:
  • Low or normal C-peptide initially, progressively declines.
  • Presence of at least one diabetes-related autoantibody (GAD65, IA-2, ZnT8, or islet cell antibodies).
  • Absence of significant insulin resistance.

Monogenic Diabetes (Maturity-Onset Diabetes of the Young, MODY)

• Clinical Features:
  • Autosomal dominant inheritance (family history spanning multiple generations).
  • Non-obese, young onset (adolescence or early adulthood).
  • Typically non-ketotic and non-insulin-dependent.
• Investigations:
  • C-peptide present (indicating endogenous insulin production).
  • Absence of autoantibodies.
  • Genetic testing identifies mutations in glucokinase or transcription factor genes.

Neonatal Diabetes Mellitus

• Clinical Features:
  • Diabetes diagnosed before 6 months of age.
  • Often due to monogenic mutations affecting pancreatic beta-cell function.
  • Some cases are transient while others require lifelong treatment.
• Investigations:
  • Genetic testing reveals mutations in KCNJ11, ABCC8, or INS genes.
  • Autoantibodies absent.
  • C-peptide present.

Post-Transplant Diabetes Mellitus

• Clinical Features:
  • Hyperglycemia occurring after solid organ transplantation.
  • Often associated with immunosuppressive therapy (e.g., corticosteroids, calcineurin inhibitors).
• Investigations:
  • C-peptide present.
  • Absence of autoantibodies.
  • History of recent organ transplant.

Steroid-Induced Diabetes Mellitus

• Clinical Features:
  • Onset of hyperglycemia after prolonged glucocorticoid use.
  • Often resolves after steroid discontinuation.
• Investigations:
  • C-peptide present.
  • Absence of autoantibodies.
  • Hyperglycemia predominantly postprandial.

Cystic Fibrosis-Related Diabetes (CFRD)

• Clinical Features:
  • Occurs in patients with cystic fibrosis due to pancreatic dysfunction.
  • May have features of both type 1 and type 2 diabetes.
• Investigations:
  • Low or absent C-peptide (pancreatic insufficiency).
  • Absence of autoantibodies.
  • Elevated sweat chloride test confirming cystic fibrosis.

Chronic Pancreatitis-Associated Diabetes

• Clinical Features:
  • Occurs in patients with chronic pancreatitis due to pancreatic damage.
  • Insulin deficiency but less prone to ketosis than T1DM.
• Investigations:
  • Low C-peptide.
  • Absence of autoantibodies.
  • Imaging evidence of pancreatic calcifications or atrophy.

Psychogenic Polydipsia

• Clinical Features:
  • Excessive water intake, often seen in psychiatric disorders (e.g., schizophrenia).
  • Symptoms mimic polyuria and polydipsia of diabetes.
• Investigations:
  • Normal glucose tolerance.
  • Low urine osmolality (<250 mOsm/kg).
  • Water deprivation test positive.

Individualised Care and Support

• Management should be tailored to each patient’s needs, considering lifestyle, comorbidities, risk factors, and personal preferences.
• Care should be provided by a multidisciplinary team, including endocrinologists, diabetes educators, dietitians, nurses, and mental health professionals.
• Patients should have access to diabetes care through multiple methods, including remote consultations, and should receive information about emergency out-of-hours services.
• A structured, individualised care plan should be developed at diagnosis and reviewed annually.

Components of an Individualised Care Plan

• Comprehensive diabetes education
• Insulin therapy adjustments
• Self-monitoring of blood glucose
• Prevention and management of hypoglycemia
• Cardiovascular risk factor assessment
• Screening for and management of diabetes-related complications
• Psychosocial and mental health support

Diabetes Education and Self-Management

• Structured education programs such as Dose Adjustment for Normal Eating (DAFNE) should be offered within 6–12 months of diagnosis and remain available as needed.
• Alternative educational approaches should be provided for those who cannot attend group sessions.
• Core education should cover:
  • Insulin use and dosage adjustment
  • Impact of diet and physical activity on glucose levels
  • Recognition and management of hypoglycemia
  • Sick-day management strategies

Dietary Management

Carbohydrate Counting

• Essential for optimising postprandial glucose control in individuals on multiple daily injections (MDI) or insulin pumps.
• Training should be included in structured education programs.

General Nutritional Guidelines

• Encouraged Foods:
  • Whole grains, vegetables, nuts, seeds, and lean proteins
  • Low-fat dairy and heart-healthy fats, such as those in fish and nuts
  • Mediterranean or vegetarian diets, which have shown cardiovascular benefits
• Foods to Limit:
  • Processed and refined carbohydrates
  • Saturated and trans fats
  • Sugar-sweetened beverages and high-calorie snacks
  • Excess sodium, especially in hypertensive individuals

Alcohol and Special Considerations

• Patients should understand the glycemic effects of different alcoholic beverages.
• Diabetes-specific food products are generally unnecessary and offer no additional benefits over a standard healthy diet.

Physical Activity

Pre-Exercise Glucose Management

• Monitor glucose before, during, and after exercise.
• Adjust insulin and carbohydrate intake to prevent hypoglycemia.
• If glucose levels exceed 14 mmol/L, test for ketones before exercising to avoid ketoacidosis.

Exercise Recommendations

• At least 150 minutes per week of moderate-intensity aerobic activity or 75 minutes per week of vigorous activity.
• Include resistance training at least twice weekly to improve muscle insulin sensitivity.
• Reduce prolonged sitting time by incorporating regular movement into daily activities.

Blood Glucose Monitoring

HbA1c Targets

• Target: <48 mmol/mol (6.5%), balancing glycemic control with hypoglycemia risk.
• Individualised targets should be set based on patient factors, including frailty, comorbidities, and risk of severe hypoglycemia.

Self-Monitoring of Blood Glucose (SMBG)

• Minimum of four tests per day (before meals and bedtime).
• Up to 10 tests per day in cases of:
  • Frequent hypoglycemia
  • Driving or operating heavy machinery
  • Illness
  • Pre- and post-exercise monitoring

Continuous Glucose Monitoring (CGM)

• Recommended for all adults with type 1 diabetes where available.
• Provides real-time glucose data, reducing hypoglycemia risk and increasing time in range.
• Hybrid closed-loop systems integrating CGM with insulin pumps are becoming a standard of care for selected patients.

Insulin Therapy

Basal-Bolus Regimen (Multiple Daily Injections)

• Basal Insulin (Long-Acting): Detemir, Glargine, or Degludec.
• Bolus Insulin (Rapid-Acting): Lispro, Aspart, or Glulisine, taken before meals.
• Dosage adjustments should be based on SMBG or CGM results and individualised lifestyle needs.

Insulin Pump Therapy (CSII)

• Considered for patients with:
  • Frequent hypoglycemia or erratic glucose control
  • A need for greater flexibility in insulin delivery
  • Gastroparesis to match insulin delivery with delayed gastric emptying

Adjunctive Therapy

• Metformin may be considered in overweight individuals with type 1 diabetes to reduce insulin requirements and improve metabolic outcomes.

Hypoglycemia Prevention and Management

Treatment

• Mild Hypoglycemia: 15–20g of fast-acting carbohydrates (e.g., glucose tablets or fruit juice).
• Severe Hypoglycemia: Intramuscular glucagon injection.

Prevention Strategies

• Adjust insulin dosing based on daily activity levels.
• Use real-time CGM with low-glucose alarms to detect and prevent severe hypoglycemia.

Complications

Cardiovascular Risk Reduction

Blood Pressure Goals

• <130/80 mmHg in individuals with diabetic kidney disease.
• <140/90 mmHg in those without kidney disease.

Lipid Management

• Statins should be considered for those at increased cardiovascular risk.

Aspirin Use

• Not recommended for primary prevention.
• Used for secondary prevention in those with established cardiovascular disease.

Diabetic Kidney Disease

• Annual screening with urine albumin-to-creatinine ratio (ACR) and eGFR.
• ACE inhibitors or ARBs should be initiated in patients with proteinuria.

Diabetic Retinopathy

• Annual diabetic eye screening is essential.
• Immediate ophthalmology referral for sudden vision changes, retinal haemorrhage, or macular oedema.

Neuropathy and Foot Care

• Regular foot examinations should be performed.
• Patients with neuropathy should receive:
  • Footwear advice
  • Education on ulcer prevention

Overall Outlook and Long-Term Complications

• Type 1 diabetes mellitus (T1DM) is associated with increased morbidity and premature mortality due to both acute and long-term complications.
• More than 60% of individuals with T1DM do not develop severe complications, but others experience retinopathy, nephropathy, neuropathy, and increased cardiovascular disease (CVD) risk.
• Patients diagnosed at a younger age (<15 years) have a higher risk of developing end-stage renal disease (ESRD) and proliferative retinopathy, particularly males.
• The risk of ischemic heart disease, cerebrovascular events, and peripheral vascular disease leading to nontraumatic lower-extremity amputations is significantly higher in individuals with T1DM.

Microvascular and Neuropathic Complications

• Diabetic Retinopathy: Leading cause of blindness in adults aged 20–74 years.
• Diabetic Nephropathy: ESRD incidence in T1DM is 2.2% at 20 years and 7.8% at 30 years post-diagnosis.
• Neuropathy:
  • Small-fibre neuropathy is highly prevalent.
  • Large-fibre neuropathy is frequently observed in long-standing T1DM.
• Cognitive Decline: Higher HbA1c levels are associated with an increased risk of long-term cognitive deterioration.

Cardiovascular Risk and Mortality

• Coronary vasodilator dysfunction is an independent predictor of cardiac mortality in both diabetic and non-diabetic individuals.
• The risk of coronary artery disease (CAD) in T1DM patients with impaired coronary flow reserve is similar to non-diabetics who have had prior CAD.
• Cardiac mortality in patients with preserved coronary flow reserve is comparable to those without diabetes.
• Weight gain with intensified insulin therapy is associated with hypertension, insulin resistance, dyslipidemia, and accelerated atherosclerosis.

Long-Term Complications

• Microvascular Complications: Includes diabetic retinopathy, nephropathy, and neuropathy, leading to vision loss, kidney failure, and nerve dysfunction.
• Macrovascular Disease: Increased risk of ischemic heart disease, cerebrovascular disease, and peripheral vascular disease, which can result in amputation.
• Neuropathy: Small-fiber neuropathy is prevalent, with studies showing up to 60% of patients developing symptoms such as sensory loss and pain.
• End-Stage Renal Disease (ESRD): Incidence at 20 years post-diagnosis is around 2.2%, rising to 7.8% after 30 years.

Impact of Glycemic Control

• Tight glycemic control significantly reduces the risk of microvascular and neuropathic complications.
• Intensive insulin therapy in early disease stages lowers the risk of long-term kidney function decline.
• HbA1c levels between 6.0% and 6.9% (42–52 mmol/mol) are linked to the lowest all-cause mortality.
• Excessive weight gain during intensified insulin therapy increases the risk of hypertension, dyslipidemia, and cardiovascular events.

Gender and Age-Related Mortality

• Early-onset T1DM (0–14 years) mortality rates have improved.
• Late-onset T1DM (15–29 years) shows less progress in mortality reduction.
• Women with T1DM tend to have worse long-term outcomes than men.
• Alcohol and drug use contribute to one-third of deaths in young adults with T1DM.

Impact of COVID-19 on Prognosis

• Diabetes and hyperglycemia independently increase mortality risk in COVID-19.
• In-hospital death rate:
  • 29% for those with diabetes or hyperglycemia.
  • 42% for individuals who developed hyperglycemia during hospitalisation despite no prior diabetes.
• Younger T1DM patients (<40 years) have a very low COVID-19 mortality risk.
• Higher HbA1c levels (≥9%) increase the risk of severe COVID-19 outcomes, including intubation, sepsis, and mortality.
• Lower BMI and higher BMI both elevate mortality risk in COVID-19 patients, following a U-shaped pattern.
• Patients with diabetic complications, particularly nephropathy and retinopathy, face worse COVID-19 outcomes.

Improving Prognosis Through Management

• Multifactorial control of diabetes and associated risk factors significantly influences long-term health.
• Tight glucose control reduces microvascular complications but must be balanced against the risk of severe hypoglycemia.
• Cardiovascular risk management through blood pressure and lipid control plays a critical role in extending life expectancy.
• Lifestyle modifications, including weight management, physical activity, and dietary interventions, reduce complications and improve outcomes.
• Diabetes education and self-care programs improve adherence to management and reduce the burden of complications.

Potential for Diabetes Remission

• Early, aggressive intervention with lifestyle and pharmacologic management can lead to long-term remission of diabetes markers.
• The concept of diabetes remission is gaining attention, defined as HbA1c <6.5% (<48 mmol/mol) for at least three months without pharmacotherapy.

Acute Complications

 Hypoglycemia

• The most common acute complication, resulting from insulin overuse, inadequate food intake, or excessive physical activity.
• Severe hypoglycemia can lead to cognitive impairment, seizures, and coma.

Diabetic Ketoacidosis (DKA)

• A life-threatening condition caused by severe insulin deficiency.
• Leads to hyperglycemia, ketonemia, and metabolic acidosis.
• DKA is a frequent cause of hospitalisation in individuals with type 1 diabetes.

Hyperosmolar Hyperglycemic State (HHS)

• Though more common in type 2 diabetes, HHS can occur in type 1 diabetes, especially in older adults.
• It is characterised by profound dehydration and severe hyperglycemia, often without significant ketosis.

Microvascular Complications

 Diabetic Retinopathy

• A leading cause of blindness in adults, with the risk increasing with poor glycemic control and hypertension.
• Regular retinal screening is essential for early detection and management.

Diabetic Nephropathy

• Chronic kidney disease (CKD) occurs in up to 40% of individuals with diabetes.
• Type 1 diabetes is a major cause of end-stage renal disease (ESRD).
• Screening for albuminuria and eGFR monitoring are essential in early detection.

Diabetic Neuropathy

• Affects both small and large nerve fibres, leading to sensory loss, autonomic dysfunction, and increased risk of foot ulcers.
• Small-fiber neuropathy is highly prevalent in long-standing type 1 diabetes.

Macrovascular Complications

 Cardiovascular Disease (CVD)

• Individuals with type 1 diabetes have a significantly increased risk of ischemic heart disease, stroke, and peripheral artery disease.
• The risk is influenced by glycemic control, hypertension, dyslipidemia, and smoking.

Heart Failure

• A major complication, with incidence rates as high as 22% in long-standing diabetes.
• Intensive glucose control alone does not prevent heart failure.
• Emphasises the need for comprehensive cardiovascular risk management.

Stroke

• Individuals with type 1 diabetes have a higher lifetime risk of stroke, particularly women.
• Blood pressure and lipid control are crucial preventive measures.

Neurological and Cognitive Complications

 Cognitive Decline and Dementia

• Poor glycemic control is associated with an increased risk of dementia, particularly vascular dementia.
• Elevated HbA1c levels are linked to faster cognitive decline in older adults with diabetes.

Diabetes-Associated Depression

• Type 1 diabetes is associated with a higher prevalence of depression and anxiety.
• These conditions can negatively impact glycemic control and overall diabetes management.

Endocrine and Metabolic Complications

 Weight Changes

• Rapid weight gain after insulin initiation is common.
• Can lead to insulin resistance, hypertension, and dyslipidemia.

Obstructive Sleep Apnea (OSA)

• Frequently coexists with type 1 diabetes, particularly in individuals with overweight or obesity.
• May exacerbate insulin resistance and contribute to poor glycemic control.

Diabetes and Infections

 Increased Susceptibility to Infections

• Hyperglycemia impairs immune function.
• Increases the risk of bacterial and fungal infections, including urinary tract infections, pneumonia, and soft tissue infections.

COVID-19 and Diabetes

• Individuals with type 1 diabetes face a higher risk of severe COVID-19 outcomes.
• Risk is especially elevated in those with poor glycemic control, kidney disease, and cardiovascular complications.

Complications Related to Diabetes Treatment

 Treatment-Related Hypoglycemia

• Frequent in those on intensive insulin regimens.
• Increases the risk of severe neurological impairment.

Lipodystrophy

• Repeated insulin injections at the same site can cause lipohypertrophy.
• Affects insulin absorption and glycemic control.

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