Type 1 and type 2 Diabetes Mellitus

Exocrine and Endocrine Pancreas

Diabetes mellitus is a chronic disease caused by relative or absolute insulin deficiency. Its main feature is chronic hyperglycemia and its consequences.

The causes are divided into primary and secondary:

• Primary forms include type 1 diabetes, type 2 diabetes, and gestational diabetes.
• Secondary causes include destruction of the islets of Langerhans, for example due to inflammation of the exocrine pancreas, and drugs.

Insulin is a hormone produced by β-cells of the islets of Langerhans. It is synthesized as preproinsulin, which is converted to proinsulin containing C-peptide, and then cleaved into active insulin and C-peptide.

Its release is stimulated by hyperglycemia. Increased glucose metabolism in β-cells raises ATP levels, which close K⁺ channels, causing depolarization. This opens Ca²⁺ channels, leading to calcium influx and exocytosis of insulin-containing vesicles.

Insulin acts via its receptor. In adipose tissue, muscle, and myocardium, it activates GLUT-4 transporters, increasing glucose uptake. In the liver, it promotes glycogen synthesis and lipogenesis.

Causes of diabetes mellitus

Type 1 DM

Type 1 diabetes mellitus is caused by an absolute deficiency of insulin due to destruction of β-cells. The mechanism is autoimmune, where β-cells are destroyed by autoreactive T-lymphocytes.

It typically arises from a combination of factors. There is a genetic predisposition, especially polymorphisms in HLA class II (MHC II). This predisposition is then triggered by an external impulse, most commonly a viral infection such as measles, varicella (chickenpox), rubella, or Epstein–Barr virus.

The result is progressive loss of β-cells, leading to a complete lack of insulin production. This form is typically referred to as juvenile (childhood) diabetes and is considered congenital in predisposition.

Type 2 DM

Type 2 diabetes mellitus is caused primarily by peripheral insulin resistance, meaning tissues do not respond adequately to insulin. This form is known as adult-onset diabetes and is typically acquired.

There are multiple contributing mechanisms. One is genetic defects, such as mutations affecting the insulin receptor or post-receptor signaling pathways. Another major factor is lifestyle, especially chronic excessive food intake, obesity, and a sedentary lifestyle, which lead to persistent hyperglycemia.

A key pathological feature is the involvement of amylin, a hormone co-secreted with insulin by β-cells that normally promotes satiety. Amylin has a tendency to form amyloid deposits. Chronic stimulation of β-cells leads to increased secretion of both insulin and amylin, resulting in amyloid deposition in the islets of Langerhans. These deposits damage β-cell function and reduce insulin secretion over time.

Initially, the body compensates for insulin resistance by increasing insulin secretion, leading to hyperinsulinism. This causes down-regulation of insulin receptors, which further worsens insulin resistance. Over time, chronic overproduction leads to β-cell exhaustion, resulting in decreased insulin secretion.

Gestational diabetes mellitus

Gestational diabetes mellitus is a disorder of glucose metabolism that develops during pregnancy due to a relative insulin deficiency caused by increased insulin resistance.

The mechanism is primarily hormonal. Placental hormones such as human placental lactogen, estrogen, progesterone, and cortisol exert anti-insulin effects, leading to decreased insulin sensitivity, especially in the second and third trimester.

It typically arises when β-cells are unable to sufficiently compensate by increasing insulin secretion. This results in maternal hyperglycemia.

Maternal hyperglycemia leads to fetal hyperglycemia, which stimulates increased insulin production in the fetus. This can result in macrosomia, increased fat deposition, and complications during delivery. After birth, persistent fetal hyperinsulinemia may cause neonatal hypoglycemia.

This condition is usually asymptomatic and detected through screening during pregnancy. It is considered a transient disorder, but it significantly increases the risk of developing type 2 diabetes later in life.

Complications of diabetes mellitus

Acute complications

1) Hypoglycemic coma

Caused by excessively low blood glucose, most often due to an inappropriate insulin dose. It can also be triggered by physical exertion or alcohol.

Clinically, it resembles intoxication. Patients develop confusion, impaired speech and vision, CNS depression, which can progress to coma. At the same time, hypoglycemia activates the sympathetic nervous system, leading to tachycardia, pallor, sweating, and tremor.

2) Hyperglycemic coma

a) Hyperosmolar (without ketoacidosis)

Caused by severe hyperglycemia.

Diabetic ketoacidosis

High glucose levels (≈ 30–45 mmol/L) lead to glycosuria, polyuria, fluid loss, hypovolemia, and hypotension.

Treatment consists of rehydration, insulin, and glucose (to prevent hypoglycemia). Insulin must be administered gradually and diluted, because a rapid decrease in osmolarity would make plasma relatively hypoosmolar compared to the brain, leading to cerebral edema. Therefore, glycemia is reduced slowly (≈ 5 mmol/L/hour).

b) Ketoacidotic (diabetic ketoacidosis)

Decreased insulin leads to inability of glucose to enter cells, resulting in cellular starvation and increased glucagon, which stimulates lipolysis. Free fatty acids are transported to the liver, where β-oxidation produces acetyl-CoA.

Fatty acids are degraded faster than acetyl-CoA can be processed in the Krebs cycle, leading to accumulation of acetyl-CoA and its conversion into ketone bodies (acetone, acetoacetate, β-hydroxybutyrate).

Ketone bodies serve as an alternative energy source, but are acidic, causing metabolic acidosis.

Causes include decreased insulin, stress, infection, and trauma.

Clinical manifestations include hyperventilation (as compensation), central nervous system symptoms such as restlessness, tremor, and mental status changes progressing to coma, nausea, vomiting, polyuria, polydipsia, and tachycardia.

Compensation occurs via the respiratory system through Kussmaul breathing and via the kidneys through increased acid excretion and increased ammonium (NH₄⁺) secretion.

Hydrogen ions (H⁺) consume bicarbonate (HCO₃⁻), leading to decreased HCO₃⁻ levels and a negative base excess.

Treatment primarily consists of rehydration. Bicarbonate is not routinely administered because, during treatment, metabolism of acetoacetate and β-hydroxybutyrate consumes H⁺ and regenerates HCO₃⁻, which can result in metabolic alkalosis if additional bicarbonate is given.

Note: Lactic acidosis

May occur during treatment with oral antidiabetics (biguanides).

Marked increase in lactate (even >10 mmol/L) leads to severe metabolic acidosis (pH down to ~6.8).

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Chronic complications

Non-enzymatic glycation (AGEs)

Chronic hyperglycemia leads to irreversible glycation of proteins and formation of AGE (advanced glycation end-products).

A typical example is glycated hemoglobin (HbA1c), which reflects average glycemia over the last 80–120 days.

Glycated proteins form cross-links (especially in collagen), bind other proteins, and accumulate in the basement membrane (BM). This leads to thickening of the BM and decreased permeability, resulting in diabetic microangiopathy.

Diabetic microangiopathy

Structural changes in small vessels due to glycation lead to impaired perfusion and tissue ischemia.

Diabetic neuropathy

Damage affects axons and Schwann cells (demyelination).

Mechanisms:

• ischemia due to microangiopathy
• glycation of axonal proteins causing dysfunction
• intracellular hyperglycemia in Schwann cells leading to increased osmolarity and cellular edema
• activation of the polyol (sorbitol) pathway with ROS formation

Forms:

• sensory-motor neuropathy: paresthesia, impaired pain perception, risk of diabetic foot
• autonomic neuropathy: GIT motility disorders (constipation, diarrhea)
• radiculopathy: pain from spinal nerve roots

Diabetic foot

Diabetic foot

Combination of neuropathy with loss of pain perception and macroangiopathy with decreased perfusion leads to pressure sores, ulcers (decubitus), and unrecognized injury.

Diabetic retinopathy

• retinal ischemia
• increased capillary permeability with exudates
• microhemorrhages

Ischemia leads to increased VEGF and pathological angiogenesis, followed by fragile vessels and fibrosis, resulting in retinal detachment. Bleeding into the vitreous causes vision impairment.

Diabetic nephropathy

Diabetic nephropathy

Thickening of the basement membrane leads to glomerulosclerosis, followed by loss of glomeruli and renal failure. Proteinuria is a poor prognostic sign.

Diabetic macroangiopathy

Glycated proteins bind LDL, increasing cholesterol deposition and accelerating atherosclerosis, which is worsened by hypertension.

Polyol (sorbitol) pathway

Glucose is converted to sorbitol and then to fructose, increasing intracellular osmolarity.

Effects:

• cellular edema (osmotic damage)
• consumption of reducing equivalents with decreased glutathione regeneration
• increased ROS and oxidative stress

Other consequences

• Hypertension
• Hepatic steatosis (can progress to cirrhosis in obesity)
• Impaired immunity: glycation of membrane proteins (receptors) leading to decreased migration and phagocytosis
• Thrombosis: hyperglycemia increases fibrinogen and other coagulation factors

References

1. ČEŠKA, Richard, et al. Interna. 3. vydání. Praha : Triton, 2020. 970 s. ISBN 978-80-7553-780-5.
2. ZÁMEČNÍK, Josef. Patologie 1–3. 2. přepracované vydání. Praha : LD, s.r.o. – Tiskárna Prager, 2024. 950 s.
3. SILBERNAGL, Stefan a Florian LANG. Atlas patofyziologie. 2. české vydání. Praha : Grada, 2012.