• Clinical science

Diabetes mellitus

Abstract

Diabetes mellitus (DM) describes a group of metabolic diseases that are characterized by chronic hyperglycemia (elevated blood glucose levels). The two most common forms are type 1 and type 2 diabetes mellitus. Type 1 is the result of an autoimmune response that triggers the destruction of insulin-producing β cells in the pancreas and results in an absolute insulin deficiency. Type 2, which is much more common, has a strong genetic component as well as a significant association with obesity and sedentary lifestyles. Type 2 diabetes is characterized by insulin resistance (insufficient response of peripheral cells to insulin) and pancreatic β cell dysfunction (impaired insulin secretion), resulting in relative insulin deficiency. This form of diabetes usually remains clinically inapparent for many years. However, abnormal metabolism (prediabetic state or impaired glucose intolerance), which is associated with chronic hyperglycemia, causes microvascular and macrovascular changes that eventually result in cardiovascular, renal, retinal, and neurological complications. In addition, type 2 diabetic patients often present with other conditions (e.g. hypertension, dyslipidemia, obesity) that increase the risk of cardiovascular disease (e.g., myocardial infarction). Renal insufficiency is primarily responsible for the reduced life expectancy of patients with DM.

Because of the chronic, progressive nature of type 1 and type 2 diabetes mellitus, a comprehensive treatment approach is necessary. The primary treatment goals for type 2 diabetes are the normalization of glucose metabolism and the management of risk factors (e.g., arterial hypertension). In theory, weight normalization, physical activity, and a balanced diet should be sufficient to prevent the manifestation of diabetes in prediabetic patients or delay the progression of disease in diabetic patients. Unfortunately, these general measures alone are rarely successful, and treatment with oral antidiabetic drugs and/or insulin injections is often required for optimal glycemic control. In type 1 diabetes, insulin replacement therapy is essential and patients must learn to coordinate insulin injections and dietary carbohydrates. Both type 1 and type 2 diabetic patients require regular self-management training to improve glycemic control, reduce the risk of life-threatening hypoglycemia or hyperglycemia, and prevent diabetic complications.

Epidemiology

  • Type 1:
    • ∼ 5% of all diabetics
    • Childhood onset: typically < 20 years; but can occur at any age; peaks at age 4–6 years and 10–14 years
    • Highest prevalence in non-hispanic whites (Scandinavian heritage)
  • Type 2:
    • The estimated prevalence in the US is 9.1%.
    • Adult onset: typically > 40 years ; mean age of onset is decreasing
    • Highest prevalence in hispanics, native Americans, Asian Americans, African Americans, and Pacific Islanders (e.g., Tokelau, Marshall Islands, Micronesia)

References:[1][2][3][4][5]

Epidemiological data refers to the US, unless otherwise specified.

Etiology

References:[6][7][8][9]

Classification

Classification according to the WHO and American Diabetes Association (ADA)

  1. Type 1: formerly known as insulin-dependent (IDDM) or juvenile-onset diabetes mellitus
    • Autoimmune (type 1A)
    • Idiopathic (type 1B)
  2. Type 2: formerly known as non-insulin-dependent (NIDDM) or adult-onset diabetes mellitus
  3. Other types of diabetes mellitus
  4. Gestational diabetes

References:[10]

Pathophysiology

Normal insulin physiology

  • Secretion: Insulin is synthesized in the β cells of the islets of Langerhans; . The cleavage of proinsulin (precursor molecule of insulin) produces the C-peptide (connecting peptide) and insulin, which consists of two peptide chains (A and B chains).
  • Action: Insulin has a variety of metabolic effects on the body, primarily contributing to the generation of energy reserves and glycemic control.
    • Carbohydrate metabolism: Insulin is the only hormone in the body that lowers the blood glucose level.
    • Protein metabolism: stimulates protein synthesis Stimulates amino acid uptake into cells; inhibits proteolysis
    • Lipid metabolism: maintains a fat depot and has an antiketogenic effect
    • Electrolyte regulation: stimulates intracellular potassium accumulation

Type 1 diabetes

  1. Genetic susceptibility
  2. Environmental trigger
  3. Autoimmune response with production of autoantibodies that target insulin-producing cells → progressive destruction of insulin-producing β cells in the pancreatic islets by autoreactive T cells → destruction of 80–90% of β cells
  4. Absolute insulin deficiency → elevated blood glucose levels

Type 2 diabetes

Two major mechanisms:

  1. Peripheral insulin resistance
    • Numerous genetic and environmental factors
      • Central obesity → increased plasma levels of free fatty acids → impaired insulin-dependent glucose uptake into hepatocytes, myocytes, and adipocytes
      • Increased serine kinase activity in liver, fat and skeletal muscle cells → phosphorylation of insulin receptor substrate (IRS)-1 → decreased affinity of IRS-1 for PI3K → decreased expression of GLUT4 channels → decreased cellular glucose uptake
  2. Pancreatic β cell dysfunction
    • Accumulation of pro-amylin (islet amyloid polypeptide) in the pancreas; decreased endogenous insulin production

References:[1][6][7][11]

Clinical features

Type 1 diabetes Type 2 diabetes
Onset
  • Sudden; diabetic ketoacidosis (diabetic coma) is often the first manifestation
  • Alternatively, children may present with acute illness and classic symptoms (see “Characteristic features” below)
  • Gradual; the majority of patients are asymptomatic
  • Symptoms of complications may be the first clinical sign of disease.
Characteristic features
  • Classic
    • Polyuria
      • Secondary enuresis and nocturia in children
    • Polydipsia
    • Polyphagia
  • Nonspecific
  • Weight loss; a thin appearance is typical for type 1 diabetic patients
  • Benign acanthosis nigricans

Diabetes mellitus should be suspected in patients with recurrent cellulitis, candidiasis, dermatophyte infections, gangrene, pneumonia (particularly TB reactivation), influenza, genitourinary infections (UTIs), osteomyelitis, and/or vascular dementia.

References:[12][7][13][14]

Diagnostics

Indication for testing Diagnostic criteria
Symptomatic patients
  • Symptoms or signs of diabetes
Asymptomatic patients
  • < 45 years of age who are obese and have one other risk factor for diabetes (see “Etiology” above)
  • > 45 years of age
  • A pathological result in the FPG, OGTT, or HbA1C test must be confirmed in a repeat test on a subsequent day to establish the diagnosis.
Results (venous blood plasma) Diabetes mellitus Prediabetes Healthy
Fasting plasma glucose (FPG) in mg/dL (mmol/L) ≥ 126 (≥ 7.0) 100–125 (5.6–6.9) = impaired fasting glucose < 100 (< 5.6)
2-hour glucose value after oral glucose tolerance test (OGTT) in mg/dL (mmol/L) ≥ 200 (≥ 11.1) 140–199 (7.8–11.0) = impaired glucose tolerance < 140 (< 7.8)
Hemoglobin A1C (HbA1c or A1C) in % ≥ 6.5 5.7–6.4 < 5.7

References:[15][16][17]

Differential diagnoses

DM type 1 vs. type 2

Type 1 Type 2
Relative frequency 10–20% 80–90%
Genetics Positive HLA association Negative HLA association; strong genetic predisposition
Pathogenesis Absolute insulin deficiency Insulin resistance
Association with obesity No Yes
Onset Acute decompensation, typically at age < 20 years Gradual; usually at age > 40 years
C-peptide (Insulin) Decreased or absent Initially elevated
Metabolism Unstable Stable
Risk of ketoacidosis High Low
Treatment Insulin therapy Lifestyle changes → oral antidiabetic drugsinsulin therapy

Glucagonoma

Somatostatinoma

References:[2][18][16][19][20][21][22]

The differential diagnoses listed here are not exhaustive.

Treatment

Aspects of treatment Approach

Individual treatment targets

  • Blood glucose control and regular glycemic monitoring: A1C values
  • Weight loss : Type 2 diabetic patients with a BMI of 27–35 benefit from a weight reduction of 5%; in patients with a BMI > 35 kg/m2, weight reduction of > 10% is recommended.
  • Blood pressure control
  • Improved blood lipid profile with statin therapy
  • Low dose aspirin for men > 50 years and women > 60 years with cardiovascular risk factors
Lifestyle modification
Type of food kcal/g kJ /g
Carbohydrate ≈ 4 ≈ 17
Protein ≈ 4 ≈ 17
Fat ≈ 9 ≈ 37
Ethanol ≈ 7.2 ≈ 29
Self-management education
  • DSME/S programs
Medical treatment
  • Oral antidiabetic drugs (see below)
  • Insulin therapy (see below)
  • Patients with prediabetes usually do not require medical treatment but do benefit from a healthy diet, weight loss, and exercise.
Monitoring complications
  • Regular monitoring of weight, abdominal circumference, blood pressure, blood lipids, renal retention parameters (creatinine, electrolytes), injection site in patients receiving insulin therapy
  • Yearly eye exam (type 1: after 5 years with diabetes mellitus or after the age of 11 years); more frequently in patients with abnormal findings or diagnosed retinopathy
  • Annual urine testing for microalbuminuria
  • Foot exam for neuropathy and ulcers; advise patients to wear appropriate footwear and avoid injury
  • Routine screening for psychosocial problems, including signs of depression and cognitive impairment
  • Pneumococcal vaccines

References:[23][24][17][25]

Antihyperglycemic therapy algorithm for type 2 diabetes

  • 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
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]

Insulin therapy

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:
  • 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
  • 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.

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

Complications

Acute
Long-term

Strict glycemic control is crucial in preventing microvascular disease.

Other complications

  • Necrobiosis lipoidica
    • Definition: inflammatory granulomatous disorder of the skin; characterized by collagen degeneration and lipid accumulation in the surface of the skin.
    • Epidemiology
      • > 60% association with DM
      • >>
    • Symptoms
      • Rash: circumscribed, erythematous plaques with atrophic centers and irregular margins
      • Common sites: pretibial region
      • Usually asymptomatic
      • Ulcerations with subsequent scarring may occur
    • Histopathology: necrobiotic palisading granuloma
    • Treatment: Corticosteroids may be effective (e.g., intralesional corticosteroid injections).

  • Mucormycosis (zygomycosis)
    • Definition: rare fungal infection, primarily affecting immunocompromised patients and patients with diabetes mellitus
    • Etiology: fungi of the order Mucorales, most commonly Rhizopus oryzae; ubiquitous fungi found in vegetation and soil
    • Pathophysiology: Inhalation of the spores into the nose and maxillary sinus (diabetic ketoacidosis stimulates fungal growth) causes sinusitis, tissue necrosis, and contiguous spread to the orbit, brain, and palate. Inhalation of the spores into the pulmonary system may lead to contiguous spread to the mediastinum and heart.
    • Risk factors
    • Symptoms and clinical findings
    • Diagnostics
      • Biopsy: broad, nonseptate hyphae, with right-angle branching on microscopy
      • Imaging: assess the extent of tissue damage and organ involvement
    • Treatment
      • Antifungal treatment: amphotericin B, step-down therapy with oral azole
      • Surgical debridement
      • Elimination of risk factors, aggressive blood glucose control
    • Complications: : palatal eschars , cerebritis, mediastinitis, cardiac involvement

References:[1][7][37][38][39][40][41][42][43]

We list the most important complications. The selection is not exhaustive.

Diabetic nephropathy

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]

Diabetic retinopathy

References:[50][51][52][53][54][55]

Diabetic neuropathy

Distal symmetric polyneuropathy (∼ 80%)

Autonomic neuropathy

Urogenital system
Cardiovascular system
Gastrointestinal system
Other manifestations

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

Diabetic foot

Neuropathic diabetic foot Ischemic diabetic foot
Clinical features
  • Warm, dry skin, foot pulses are palpable
  • Cool, pale foot with no palpable pulses
Additional info
  • 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]