Patients who have been suffering for years from high blood sugar concentration can expect serious consequences for their entire bodies. Accurate knowledge of the complications that may arise in the course of the disease is important, not only for the exam. Physicians may significantly contribute to the problem, so that amputations, blindness, kidney damage and cardiovascular disease can be avoided.
diabetic foot

Image: “Geschwür am diabetischen Fuß” by Papa1234. License: Public Domain. Diabetic Foot

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Particularly, damage to the small and large blood vessels is the main reason of high mortality in the case of diabetes mellitus (DM). Therefore, early diagnosis and early treatment measures to ensure normoglycemia are crucial to the length and quality of patients’ lives, who are suffering from diabetes mellitus.

Risk of Long-Term Complications

Complications Relative risk
Myocardial infarction Men: 3.7
Women: 5.9
Cardiovascular death Diagnosis before the age of 30: 9.1
Diagnose after the age of 30: 2.3
Apoplexy 2–4
Blindness 5.2
Renal failure in men 12.7
Lower-extremity amputations 22.2 to 45
Foot ulcers Frequently


Hyperglycemia leads to an increased risk of developing atherosclerosis. Even non-diabetics suffer from arteriosclerosis, but diabetes increases the risk in multiple times. This leads to the deposition of calcium, thrombi, fat and connective tissue on the vessel walls. This is caused by the dysfunction of the vascular endothelium which is favored by hyperglycemia.

Firstly, the dysfunction is caused by glycated LDL: the molecules penetrate the tunica intima and activate oxidative and inflammatory processes there. It results in the typical plaques, forming in the endothelium. Secondly, lipolysis is not inhibited by a lack of insulin. The resulting circulatory disorders represent themselves in a variety of conditions, such as:

  • PAOD (peripheral arterial occlusive disease), intermittent claudication
  • CHD (coronary heart disease), myocardial infarction
  • Carotid stenosis (cerebrovascular sclerosis)
  • Ischemic insult
  • Mönckeberg’s arteriosclerosis (medial calcific sclerosis)

What is particularly dangerous for the diabetics is a heart attack, as it often runs painlessly, being not noticed by patients, due to the also occurring diabetic neuropathy. 60 % of diabetics die from cardiovascular disease.

Regular cardiovascular controls, in addition to the blood glucose monitoring, are essential preventive measures in diabetic patients. Such factors as obesity, lack of exercise, smoking, and alcohol contribute to the development of macroangiopathy and should be largely eliminated. Hypertension and elevated blood lipids are other risk factors for the blood vessels to be damaged, and they need to be treated. What is also useful for patients is the administration of anticoagulants that prevent the formation of thrombi.


In the case of diabetes mellitus, not only the large arteries are damaged, but also the small ones. As a result of hyperglycemia, the basement membranes of capillary vessels and renal glomeruli are stenosed and occluded, which leads to hypoxia and reduction of glomerular filtration rate (GFR).

The reason is that proteins are non-enzymatically glycosylated due to hyperglycemia. This produces AGEs (advanced glycosylated end products), which are accumulated in structural proteins and connective tissue contents. In particular, microangiopathy is symptomatically linked to eye and kidney, but it can also affect all the areas of the body.

Diabetic Retinopathy

Diabetic Retinopathy

Image: “Diabetic Retinopathy”. License: Public Domain

Diabetic retinopathy is divided into non-proliferative retinopathy and proliferative retinopathy. Non-proliferative retinopathy is also divided into three levels of severity: mild, moderate, and severe. Due to hypoxia, which is the consequence of hyperglycemia, growth factors are increasingly formed, and new blood vessels appear. In this case, VEGF (vascular endothelial growth factor) plays a decisive role, which is detectable in blood and can be inhibited by drugs.

The new blood vessels can grow even in the vitreous humor. However, it is quite dangerous as they are very unstable; there appear microaneurysms which often rupture, causing bleeding in the eye. If the newly formed blood vessels do not lead to any vision problems, or there appear slight ones, then we deal with non-proliferative retinopathy. If increased bleeding into the vitreous humor and a lot of new blood vessels do cause problems, it is called proliferative retinopathy. The consequences range from blurred vision to retinal detachment, glaucoma, and blindness.

Cell edemas in the retina represent another symptom of diabetic retinopathy. They occur due to high concentrations of sorbitol in the cell. Sorbitol growth occurs due to the metabolism of glucose from the blood into the cell. This is a normal process in tissues that can absorb glucose without insulin. However, in the case of hyperglycemia, there also occurs a shift in metabolism. Another consequence is the inactivation of the Na+/K+-ATPase (sodium-potassium adenosine triphosphatase, also known as the Na+/K+ pump or sodium-potassium pump) and the emergence of polyol and myo-inositol, causing myelin sheath affection.

Note: Diabetes is the main cause of blindness in the working age.

Treatment of diabetic retinopathy

Diabetic retinopathy is primarily treated by laser. Laser therapy should be conducted as soon as neovascularization or vitreous hemorrhages have occurred. The corticosteroid medication Dexamethasone may also positively affect a diabetic macular edema. However, it must be repeatedly injected into the vitreous humor.

Angiogenesis inhibitors such as Pegaptanib and Bevacizumab directly block vessel growth-promoting substances in the eye, which can thus lead to the swelling of the central retina. They are often repeatedly injected in the eye at intervals of a few weeks.

Diabetic Nephropathy

Diabetic nephropathy is divided into five progressive stages which asymptomatically run at the beginning, being partially reversible. However, they eventually lead to irreversible damage. Depending on the stage, we may observe different symptoms; therefore, corresponding therapeutic measures are necessary to be taken. In the first place, however, normoglycemia and normotonia are treatment goals in all the stages.

Stage 1 runs symptom-free. The increased concentration of glucose in the blood is compensated by increased function of kidneys. It leads to kidneys enlargement and increased filtration capacity. This stage is still reversible. Stage 2 also runs symptom-free. It usually begins after several years of diabetes. The basement membrane of the glomeruli is considerably thickened, and consequently, the filtration performance is already restricted. This stage is also reversible, in part.

The clearest indications of stage 3 are microalbuminuria and hypertension. The glomeruli are now permeable to proteins that are detectable in the urine. These symptoms usually occur only after 5 to 15 years of being sick in diabetes. They are a sign of the beginning of renal failure. In order to lower blood pressure, ACE inhibitors that additionally protect kidneys are recommended. In the case of insufficient effect, they can be combined with other antihypertensive agents.

Histopathological image of diabetic glomerulosclerosis with nephrotic syndrome

Image: “Histopathological image of diabetic glomerulosclerosis with nephrotic syndrome.” by KGH. License: CC BY-SA 3.0

In stage 4, after 10 to 25 years of diabetes duration, there appears macroalbuminuria (300 mg/day) with hypoperfusion, hypertension, and reduced filtration performance. In addition to ACE inhibitors, diuretics, calcium channel blockers and beta-blockers must be also used in this stage. A low protein diet is recommended to follow.

The renal failure appearing in stage 5 is no longer reversible: the filtration performance is dramatically reduced, and pathological creatinine values are detectable in blood. At this stage, hypertension usually occurs. Since the renal failure is irreversible, only dialysis and renal transplantation remain as therapeutic measures.

Diabetic Neuropathy

Due to persistent hyperglycemia, micro- and macro-angiopathy lead to nerve damage as well. Nerves are no longer supplied with sufficient oxygen because of circulatory disorder. Both the peripheral and the autonomic nerves are concerned. It restricts the diabetics in the quality of life. The glycation of proteins and fats, as a result of hyperglycemia, also strikes nerves.

Three classes of chronic wound on a diabetic patient’s foot

Image: “Three classes of chronic wound on a diabetic patient’s foot.” by Openi. License: CC BY 3.0

The first symptoms of diabetic neuropathy become noticeable along with tingling, pain, and numbness in the extremities. They should be taken seriously as a warning sign. If diabetic neuropathy is not treated in time, it may cause death of peripheral nerve fibers in the worst case. Thereafter, not only numbness is observed, but also reduced pain perception, as well as a complete loss of pain sensation in the extremities. Injuries will not be noticed by the patient and can spread in an unhindered way. Especially, a diabetic foot is a dangerous complication that can lead to the amputation of the limb.

In the case of very painful neuropathies, tricyclic antidepressants, such as amitriptyline, may be of benefit. Furthermore, Gabapentin and Pregabalin are effective drugs against neuropathic pain.

Diabetics should be necessarily insured medical foot care for the prevention of a diabetic foot syndrome. In addition, attention should be paid to suitable footwear. Every day they should be checked for feet injuries. If the autonomic nerves are damaged, it may cause multiple effects on the body. So, the diabetics may suffer from the following afflictions:

  • Erectile dysfunction
  • Diabetic cystopathy with frequent infections
  • Circulatory disorders of the skin
  • Dizziness, syncope (fainting)
  • Diarrhea, constipation
  • Heartburn, difficulty swallowing (dysphagia), gastroparesis
  • Related cancers

Other Complications

neuropathic arthropathy

Image: “Charcot-Fuß bei Diabetes im Röntgenbild a.p. und schräg. Die Destruktionen mit (Sub-)Luxationen sind um die Lisfranc-Linie am ausgeprägtesten. Am lateralen Fußrand erkennt man auch Lufteinschlüsse als Hinweis auf eine zur Haut fistelnde tiefe Infektion.” by Hellerhoff. License: CC BY-SA 3.0 A neuropathic arthropathy in x-ray

Apart from typical long-term consequences, there are complications that are less well-known. So, hyperglycemia influences joints and connective tissues: patients complain of a stiff shoulder (frozen shoulder) or finger/hand changes (cheiropathy). Diabetic neuropathic osteoarthropathy (DNOAP), also called neuropathic arthropathy, is a disease which leads to a non-infectious, inflammatory destruction of bones and joints. It represents a special form of diabetic foot ulcers.

In diabetes mellitus type 1, the autoimmune reaction may also lead to diabetic mastopathy or Hashimoto’s thyroiditis.

Popular Examination Questions

The correct answers can be found below the references

1. Which disease cannot be included in the list of macroangiopathic complications of diabetes mellitus?

  1. PAOD (peripheral arterial occlusive disease)
  2. CHD (coronary heart disease)
  3. Mönckeberg’s arteriosclerosis (medial calcific sclerosis)
  4. Diabetic nephropathy
  5. Carotid stenosis

2. Which medication is suitable for the treatment of diabetic retinopathy?

  1. Anakinra
  2. Adalimumab
  3. Rituximab
  4. Bevacizumab
  5. Imatinib

3. Stage 3 of diabetic nephropathy is characterized by…

  1. …microalbuminuria and hypertension.
  2. …macroalbuminuria.
  3. …symptomlessness.
  4. …necessity of dialysis.
  5. …ketonuria and basement membrane damage.
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