- Clinical science
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.
- ∼ 5% of all patients with diabetes
- 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
- Type 2:
Epidemiological data refers to the US, unless otherwise specified.
- Type 1
- Type 2
Classification according to the WHO and American Diabetes Association (ADA)
Type 1: formerly known as insulin-dependent (IDDM) or juvenile-onset diabetes mellitus
- Autoimmune (type 1A)
- Idiopathic (type 1B)
- Type 2: formerly known as non-insulin-dependent (NIDDM) or adult-onset diabetes mellitus
Other types of diabetes mellitus
Genetic defects in the β cell function: MODY (maturity onset diabetes of the young)
- Different forms of autosomal dominant inherited diabetes mellitus that manifest before the age of 25 years and are not associated with obesity or autoantibodies
- 6 subtypes, the most common being MODY II and MODY III
- Caused by genetic defects in the glucokinase gene and hepatocyte nuclear factor-1-α, respectively
- In contrast to all other subtypes, MODY II is not associated with an increased risk of microvascular disease and can be managed with diet alone, despite stable hyperglycemia and chronically elevated HbA1C levels
- All other subtypes require medical treatment, either with insulin or sulfonylureas
- Genetic defects in insulin function
- Diseases of the exocrine pancreas (pancreoprivic diabetes mellitus)
- Endocrinopathies: Cushing disease, acromegaly
- Drug-induced diabetes: e.g., corticosteroids
- Infections: e.g.,
- Rare immunological diseases:
- Genetic defects in the β cell function: MODY (maturity onset diabetes of the young)
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
- Genetic susceptibility
- Environmental trigger (often associated with previous viral infection)
- → Autoimmune response with production of autoantibodies, e.g., Anti-glutamic acid decarboxylase antibody (Anti-GAD), 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
- → Absolute insulin deficiency → elevated blood glucose levels
Two major mechanisms:
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 → decreased expression of channels → decreased cellular glucose uptake
- Numerous genetic and environmental factors
- Pancreatic β cell dysfunction
- Initially, insulin resistance is compensated by increased insulin and amylin secretion.
- Over the course of the disease, insulin resistance progresses, while insulin secretion capacity declines.
- After a period of with isolated postprandial hyperglycemia, diabetes manifests with fasting hyperglycemia.
|Type 1 diabetes||Type 2 diabetes|
- Hyperglycemia: elevated blood glucose levels
|Indication for testing||Diagnostic criteria|
|Symptomatic patients|| || |
|Asymptomatic patients|| |
|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|
- Additional tests
Specific autoantibodies for diabetes mellitus type 1
- Anti-GAD antibodies
- Anti-tyrosine phosphatase-related islet antigen (IA-2)
- Islet cell surface antibody (ICSA; against ganglioside)
- Urine analysis
- Specific autoantibodies for diabetes mellitus type 1
DM type 1 vs. type 2
|Type 1||Type 2|
|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|
|Risk of ketoacidosis||High||Low|
|Treatment||Insulin therapy||Lifestyle changes → oral antidiabetic drugs → insulin therapy|
- Definition: : a rare neuroendocrine tumor of the pancreas that secretes glucagon. In > 50% of cases, metastasis is present at diagnosis.
Clinical findings: nonspecific symptoms, weight loss (80%), (70%), impaired glucose tolerance or diabetes mellitus (75–95%), chronic diarrhea (30%), , and depression
Necrolytic migratory erythema
- A cutaneous paraneoplastic syndrome; that is mainly associated with pancreatic tumors secreting glucagon, but also hepatitis B, C, and bronchial carcinoma
- Occurrence of multiple areas of centrifugally spreading erythema, located predominantly on the face, perineum, and lower extremities
- Develop into painful and pruritic crusty patches with central areas of bronze-colored induration
- Tend to resolve and reappear in a different location
- Skin biopsy shows epidermal necrosis
- Necrolytic migratory erythema
- Diagnostics: requires a high index of suspicion to make the diagnosis
- Definition: : a rare neuroendocrine tumor of δ-cell (D-cell) origin that is usually located in the pancreas or gastrointestinal tract and secretes somatostatin.
- Clinical findings
The differential diagnoses listed here are not exhaustive.
|Aspects of treatment||Approach|
Individual treatment targets
|Lifestyle modification|| |
|Self-management education|| |
|Medical treatment|| |
|Monitoring complications|| |
- HbA1C target for adults: < 7% (53 mmol/mol)
- The guidelines for the treatment of DM recommend an individualized treatment strategy.
- 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.
|General measures|| |
Weight reduction, exercise , medical nutrition therapy, self-management education
The drug of choice is .
|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.|
Principles of insulin therapy
|Total daily requirement of insulin|
|Insulin correction factor|| |
|Carbohydrate counting|| |
|Insulin-to-carbohydrate ratio|| |
|Type 1 diabetes|
|Type 2 diabetes|
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
- Patients with (oral antidiabetic drugs are contraindicated in this case)
Regimens of 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.
- 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
- Optimal glycemic control and reduced risk of complications in patients with good compliance
- More flexibility in the daily diet and exercise plan
- Complex and time-consuming therapy; requires frequent blood glucose measurements
- High risk of hypoglycemia
- Patients require intensive education and must be motivated and committed.
- 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 )
Problems: early-morning hyperglycemia
- 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 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
- For additional side effects, see .
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
- Definition: attempting to lose weight by purposefully not injecting insulin after meals
- Population: young patients with type 1 diabetes 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
Strict glycemic control is crucial in preventing microvascular disease.
- Definition: inflammatory granulomatous disorder of the skin; characterized by collagen degeneration and lipid accumulation in the surface of the skin.
- > 60% association with DM
- ♀ >> ♂
- Histopathology: necrobiotic palisading granuloma
- Treatment: Corticosteroids may be effective (e.g., intralesional corticosteroid injections).
- 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
- Rhino-orbital-cerebral mucormycosis: the most common form; presents with sinusitis, fever, headache
- Pulmonary mucormycosis: aggressive infection of the bronchioli and alveoli, presenting with fever and hemoptysis
- Disseminated mucormycosis: (rare) invasion of the vasculature with subsequent dissemination; may affect any organ
- Biopsy: broad, nonseptate hyphae, with right-angle branching on microscopy
- Imaging: assess the extent of tissue damage and organ involvement
- Complications: palatal eschars , cerebritis, mediastinitis, cardiac involvement
We list the most important complications. The selection is not exhaustive.
- A major cause of end stage renal disease (ESRD)
- Pathophysiology: chronic hyperglycemia → non-enzymatic glycosylation (NEG) of the basement membrane () → 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
- Clinical findings
- Initially moderately increased albuminuria () ,
- Eventually significantly increased albuminuria (): may develop.
- Differential diagnoses: other causes of chronic kidney disease (e.g., ) and
Prevention and management
- Stringent glycemic control
- Antihypertensive treatment: OR 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
Early antihypertensive treatment delays the progression of diabetic nephropathy!
- 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: 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
- 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
- Vitrectomy in case of traction retinal detachment and vitreal hemorrhage
- VEGF inhibitors
- Focal photocoagulation
- Nonproliferative retinopathy
Distal symmetric polyneuropathy
- Pathophysiology: Chronic hyperglycemia causes glycation of axon proteins 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.
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
- Early: progressive symmetric loss of sensation in the distal lower extremities
- Special types:
- Tuning fork: decreased vibration sense
- Monofilament test: decreased pressure sense
- Pinprick (pain assessment) or temperature assessment: decreased sensation
- Optimal glycemic control
- Anticonvulsants: pregabalin; (most effective; usually first-choice), gabapentin, and sodium valproate
- Miscellaneous: lidocaine patch, capsaicin spray, isosorbide dinitrate spray
- Opioids: dextromethorphan, morphine sulfate, tramadol, and oxycodone