Diabetes mellitus

• HbA1C target for adults: < 7% (53 mmol/mol)
• The guidelines for the treatment of DM recommend an individualized treatment strategy.
  • Stringent target: A1C target of < 6.5% (48 mmol/mol) is indicated for young patients with recent onset of diabetes, long life expectancy, and no comorbidities or diabetic complications (however, only if this target can be achieved with lifestyle modifications, monotherapy with metformin, or other treatment regimes without any side effects such as weight gain or the risk of significant hypoglycemic episodes). Stringent treatment concepts require regular training and require a high degree of patient compliance.
  • Lenient target: An A1C goal of < 8% (64 mmol/mol) is indicated for elderly patients with a long history of diabetes, comorbidities, diabetic complications, and/or a short life expectancy.
• If the target A1C is not reached within 3 months with conservative measures (e.g., diet, exercise), the next step in the therapeutic algorithm should be initiated.

Treatment algorithm	Description
General measures	Weight reduction, increased physical activity, medical nutrition therapy, self-management education
Monotherapy	The drug of choice is metformin.
Dual therapy	Metformin + A second oral antidiabetic drug: dipeptidyl peptidase-4 inhibitor, sulfonylureas, thiazolidinedione, meglitinides, SGLT-2 inhibitors, alpha-glucosidase inhibitors, amylin analogs GLP-1 receptor agonists (incretin mimetics) Basal insulin
Triple therapy	Add a third oral antidiabetic drug, nightly basal insulin, or injectable GLP-1 receptor agonist
Combination injectable therapy	Metformin + basal insulin + mealtime insulin or GLP-1 receptor agonist
Only consider the substitution of drugs in cases in which the drug is not tolerated or side effects occur.

Oral antidiabetic drugs should be avoided in patients undergoing surgery or suffering from severe illness. Instead, insulin therapy should be initiated!

• The choice of antidiabetic drugs primarily depends on patient characteristics and risk factors.
  • Patient's age: Multimorbidity increases with age. Contraindications must be carefully considered and potential side effects monitored. If in doubt, conservative treatment principles should be favored.
  • Risk of hypoglycemia: There is an increased risk, particularly in sulfonylurea treatment.
    • Special patient groups: individuals working in the transport sector (e.g., pilots, bus drivers, and taxi drivers), who would put the general public at risk in the event of hypoglycemia
    • Glycemic monitoring: Patients must learn to self-monitor blood glucose levels at regular intervals.
  • Baseline weight and the risk of weight gain: particularly relevant for patients with concurrent metabolic syndrome and (secondary) cardiovascular diseases
  • Comorbidities: Numerous conditions are contraindications for antidiabetic drugs; careful consideration is required.
  • Additional factors
    • Patient preference
    • Patient weight

References:^[7][17]

Principles of insulin therapy

Total daily requirement of insulin	On average, the body requires 40 USP units of insulin daily. 20 units for basic metabolism → basal insulin 20 units for calorie consumption → bolus insulin
Insulin correction factor	1 unit of insulin lowers the blood glucose level by 30–40 mg/dL (1.7–2.2 mmol/L)
Carbohydrate counting	10 g of carbohydrates increases the blood glucose level by 30–40 mg/dL (1.7–2.2 mmol/L).
Insulin-to-carbohydrate ratio	On average, 1 unit of insulin is required for 15 g carbs = 1 carb serving (carb unit); however, this varies greatly from patient to patient. Insulin sensitivity fluctuates over the course of a day → Insulin-to-carbohydrate ratio changes over the course of a day. Morning hours: 2 units insulin, lunchtime: 1 unit, evening hours: 1.5 units
Type 1 diabetes	Insulin replacement therapy: The exogenous insulin requirement depends on the residual insulin production of the pancreas. The initial total daily dose (TDD) of insulin should be 0.6–1.0 U/kg. After beginning insulin treatment, there is often a temporary reduction in exogenous insulin demand.
Type 2 diabetes	Residual endogenous insulin production is augmented with exogenous insulin, depending on the extent of insulin resistance (which in turn depends on the level of obesity). The TDD of insulin should be 0.1–0.2 U/kg.

Indications for insulin therapy

• Newly diagnosed patients with significantly elevated A1C levels (> 8.5%) or symptomatic diabetes: Initiate insulin therapy with or without an antidiabetic drug.
• Patients with insufficient glycemic control (target A1C not reached) over a 3-month treatment period with metformin or another antidiabetic drug:
  • Initiate basal insulin supported oral therapy (BOT).
  • Consider initiating insulin therapy.
• Pregestational and gestational diabetes
• Diabetic patients with end stage renal failure (oral antidiabetic drugs are contraindicated in this case)

Regimens of insulin therapy

Conventional insulin therapy

• Fixed regimen of insulin injections: usually twice daily injection; of insulin (mixture of 30% regular insulin and 70% intermediate insulin) with self-monitoring of blood glucose levels
• Advantages: simple regimen, requiring minimal patient education, not very time-consuming
• Disadvantages: patients must adhere to a rigid diet and exercise plan. Snacks may be required between meals to avoid hypoglycemia.

Intensive insulin therapy

• The goal is to simulate physiological glucose metabolism by keeping fasting blood glucose levels < 100 mg/dL (5.6 mmol/L) and postprandial blood glucose levels < 140 mg/dL (< 7.8 mmol/L)
• Intensified conventional therapy
  • Basal-bolus regimen: basal insulin 1–2 times daily; , + bolus insulin injection 30–45 minutes before meals adjusted to preprandial blood glucose measurements
  • The bolus insulin dose depends on the preprandial blood glucose level, meal size and time of day
  • Indication: type 1 diabetes; insulin-dependent type 2 diabetes with a high degree of compliance
• Insulin pump
  • Continuous subcutaneous insulin infusion (regular or rapid-acting insulin analogs)
  • Basal and bolus insulin may be managed individually
    • Indication: type 1 diabetes, children, pregnancy, dawn phenomenon (see “Problems” below)
• Advantages
  • Optimal glycemic control and reduced risk of complications in patients with good compliance
  • More flexibility in the daily diet and exercise plan
• Disadvantages
  • Complex and time-consuming therapy; requires frequent blood glucose measurements
  • High risk of hypoglycemia
  • Patients require intensive education and must be motivated and committed.

Basal supported oral therapy (BOT)

• Alternative to conventional or intensive insulin therapy
• Indication: combination therapy for type 2 diabetic patients with persistently elevated A1C levels despite oral antidiabetic regimen
• Regimen: long-acting insulin injection (e.g., glargine); before bedtime combined with an oral antidiabetic drug regimen

Types of insulin (see insulin)

Problems: early-morning hyperglycemia

• Dawn phenomenon
  • A common problem (especially in young type 1 diabetic patients)
  • Definition: early-morning hyperglycemia; occurs because of the physiological increase of growth hormone levels; in the early morning hours, which stimulates hepatic gluconeogenesis; . The subsequent increase in insulin demand cannot be met in diabetic insulin-dependent patients, resulting in elevated blood glucose levels in the morning.
  • Treatment: measurement of nocturnal blood glucose levels; before initiating insulin therapy. The long-acting insulin dose may be given later (around 11 p.m.) or increased under careful glycemic control. Treatment with an insulin pump may be considered in children.
• Somogyi effect
  • Rare
  • Definition: early-morning hyperglycemia; because of a counterregulatory secretion of hormones; that is triggered by nocturnal hypoglycemia secondary to an evening insulin injection
  • Treatment: reduction of the evening dose of the long-acting insulin
• For additional side effects, see insulin.

Conditions that require insulin adjustments

• Physical activity: decreases insulin by 1–2 units per 20–30 minutes activity
• Illness, stress, and changes in diet
  • Increase in insulin demand: : many illnesses are associated with elevated blood glucose levels due to an acute stress reaction. The subsequent increase in insulin demand cannot be met by patients with insulin deficiency. A higher insulin dose is required.
  • Decrease in insulin demand: vomiting and diarrhea lead to decreased glucose uptake, increasing the risk of hypoglycemia.
• Surgery: ⅓–½ of the usual daily requirement with frequent monitoring

Insulin purging

• Definition: attempting to lose weight by purposefully not injecting insulin after meals
• Population: young type 1 diabetic patients with eating disorders use insulin purging as an alternative to fasting, vomiting, and other methods of weight loss
• Result: self-induced insulin deficiency reduces insulin-dependent glucose uptake in cells and reduces the anabolic effect of insulin.
  • Poor glycemic control
  • Increased risk of hyperglycemic coma

References:^{[6][26][27][28][29][30][31][32][33][34][35][36]}

• A major cause of end stage renal disease (ESRD)
• Pathophysiology: chronic hyperglycemia → non-enzymatic glycosylation (NEG) of the basement membrane (protein glycation)→ increased permeability and thickening of the basement membrane and stiffening of the efferent arteriole → hyperfiltration (increase in GFR) → increase in intraglomerular pressure → progressive glomerular hypertrophy and increased renal size → worsening of filtration capacity
• Pathology
  • Three major histological changes occur:
    • Mesangial expansion
    • Glomerular basement membrane thickening
    • Glomerulosclerosis (later stages): may be diffuse (most common) or pathognomonic nodular glomerulosclerosis (Kimmelstiel-Wilson nodules)
• Clinical findings
  • Often asymptomatic; ; patients may complain of foamy urine
  • Progressive diabetic kidney disease with signs of renal failure and risk of uremia (e.g., uremic polyneuropathy)
  • Arterial hypertension
• Urine analysis
  • Proteinuria
    • Initially moderately increased albuminuria (microalbuminuria) ,
    • Eventually significantly increased albuminuria (macroalbuminuria): nephrotic syndrome may develop.
• Differential diagnoses: other causes of chronic kidney disease (e.g., hypertensive nephropathy) and nephrotic syndrome
• Prevention and management
  • Stringent glycemic control
  • Antihypertensive treatment: ACE inhibitors OR angiotensin-receptor blockers are the first-line antihypertensive drugs in diabetic patients.
  • Dietary modification: daily salt intake < 5–6 g/day; phosphorus and potassium intake restriction in advanced nephropathy; protein restriction

Microalbuminuria is the earliest clinical sign of diabetic nephropathy. The extent of albuminuria correlates with the risk of cardiovascular disease!

Early antihypertensive treatment delays the progression of diabetic nephropathy!

References:^{[2][44][45][46][47][48][49][17]}

• Epidemiology
  • After 15 years with disease, approx. 90% of type 1 diabetic patients and approx. 25% of type 2 diabetic patients develop diabetic retinopathy.
  • The most common cause of visual impairment and blindness in patients aged 25–74 years in the US
• Symptoms: asymptomatic until very late stages of disease
  • Visual impairment
  • Progression to blindness
• Ophthalmological findings and classification of diabetic retinopathy
  • Nonproliferative retinopathy (mild, moderate, severe): accounts for most cases of diabetic retinopathy
    • Findings: intraretinal microvascular abnormalities; (IRMA), including microaneurysms; ; caliber changes in venous vessels; intraretinal hemorrhage; hard exudates retinal edema, and cotton-wool spots
    • Visual loss, most commonly due to macular edema
  • Proliferative retinopathy
    • Findings: Preretinal neovascularization is the hallmark of PDR , fibrovascular proliferation , vitreous hemorrhage, traction retinal detachment , rubeosis iridis → secondary glaucoma. Additionally, findings of nonproliferative retinopathy are usually present.
    • Visual loss may be due to vitreous hemorrhage, retinal detachment, or neovascular glaucoma.
  • Macular edema
    • Findings: clinically significant retinal thickening and edema involving the macula, hard exudates, macular ischemia
    • May occur in all stages of NPDR and PDR
• Treatment
  • Nonproliferative retinopathy
    • Laser treatment: focal photocoagulation
    • Intravitreal anti-vascular endothelial growth factor (VEGF) injection
  • Proliferative retinopathy and severe nonproliferative retinopathy
    • Laser treatment: panretinal photocoagulation over the course of numerous appointments
      • Risks associated with laser treatment: night vision impairment, visual field loss, further fibrosis of the vitreous body with risk of retinal detachment
    • Vitrectomy in case of traction retinal detachment and vitreal hemorrhage
  • Macular edema
    • VEGF inhibitors
    • Focal photocoagulation

References:^{[50][51][52][53][54][55]}

Distal symmetric polyneuropathy (∼ 80%)

• Pathophysiology: Chronic hyperglycemia causes glycation of axons with subsequent development of progressive sensomotoric neuropathy; typically affects multiple peripheral nerves
• Epidemiology: Diabetic polyneuropathy is the most common form of polyneuropathy in Western countries.
• Clinical features
  • Early: progressive symmetric loss of sensation in the distal lower extremities
    • A "stocking-glove" sensory loss pattern with proximal progression is typical
    • Dysesthesia (burning feet) may occur
    • A similar sensory loss pattern may occur in the upper extremities.
  • Late: pain at rest and at night (painful diabetic neuropathy), but also decreased pain perception, motor weakness, and areflexia
• Special types:
  • Mononeuropathy
    • Cranial mononeuropathy
    • Peripheral mononeuropathy
    • Mononeuropathy multiplex: asymmetric neuropathy, affecting the multiple peripheral and cranial nerves
    • Diabetic truncal neuropathy
  • Diabetic lumbosacral plexopathy
• Screening
  • Tuning fork: decreased vibration sense
  • Monofilament test: decreased pressure sense
  • Pinprick (pain assessment) or temperature assessment: decreased sensation
• Treatment
  • Optimal glycemic control
  • Pain management
    • Anticonvulsants; : pregabalin; (most effective; usually first-choice), gabapentin, and sodium valproate
    • Antidepressants
      • Tricyclic antidepressants: amitriptyline
      • SNRI: duloxetine, venlafaxine
    • Miscellaneous: lidocaine patch, capsaicin spray, isosorbide dinitrate spray
    • Opioids: dextromethorphan, morphine sulfate, tramadol, and oxycodone

Autonomic neuropathy

Urogenital system	Erectile dysfunction (most common) Bladder dysfunction: urinary retention, incomplete bladder emptying, bladder distention, overflow incontinence, poor urinary stream
Cardiovascular system	Silent myocardial infarction Decreased heart variability or fixed rhythm Orthostatic hypotension Persistent sinus tachycardia Ventricular arrhythmia
Gastrointestinal system	Gastroparesis (→ delayed gastric emptying, risk of postprandial hypoglycemia): nausea, abdominal bloating, loss of appetite, early satiety Diarrhea, constipation, incontinence Treatment involves prokinetic agents (e.g. ,metoclopramide, erythromycin, cisapride).
Other manifestations	Sweat gland dysfunction associated with heat intolerance Pupillary dysfunction Risk of hypoglycemia due to absence of hormonal counterregulation (secretion of cortisol, glucagon, and catecholamines)

References:^{[50][56][57][58][59][60][61][62]}

	Neuropathic diabetic foot	Ischemic diabetic foot
Clinical features	Warm, dry skin, foot pulses are palpable	Cool, pale foot with no palpable pulses
Additional info	Diagnostics Neurological examinations: evaluation of peripheral neuropathy Foot ulcer risk assessment (see “Screening” for diabetic polyneuropathy above) Complications Malum perforans: painless neuropathic ulcers (usually located on the plantar pressure points of the foot: over the head of the metatarsal bones or the heel) Complex, multifactorial pathophysiology. Major risk factors include peripheral sensory neuropathy, autonomic neuropathy, microvascular changes , as well as macrovascular disease. Secondary infection of foot ulcers may lead to cellulitis and acute or chronic osteomyelitis. Diabetic neuropathic arthropathy (Charcot foot): deformation of joints and bones Foot deformities and malalignment (loss of lateral and longitudinal arch), osteolysis, risk of fractures, destruction of skeletal foot structures	Prevention Glycemic control Regular foot examinations Self-monitoring and proper foot care
Treatment of foot ulcers	Surgical debridement Regular wound dressing Mechanical offloading: fitting of therapeutic footwear or total contact cast Antibiotic therapy if foot ulcers become infected Interventional or surgical revascularization: in patients with underlying peripheral artery disease Amputation if all else fails or severe life-threatening complications arise

In about ⅓ of patients with diabetic foot, the underlying cause is both ischemic and neuropathic.

References:^[59][63][64]