Complications of diabetes


Complications of diabetes mellitus include problems that develop rapidly or over time and may affect many organ systems. The complications of diabetes can dramatically impair quality of life and cause long-lasting disability. Overall, complications are far less common and less severe in people with well-controlled blood sugar levels. Some non-modifiable risk factors such as age at diabetes onset, type of diabetes, gender and genetics may influence risk. Other health problems compound the chronic complications of diabetes such as smoking, obesity, high blood pressure, elevated cholesterol levels, and lack of regular exercise.

Acute

Diabetic ketoacidosis

is an acute and dangerous complication that is always a medical emergency and requires prompt medical attention. Low insulin levels cause the liver to turn fatty acid to ketone for fuel ; ketone bodies are intermediate substrates in that metabolic sequence. This is normal when periodic, but can become a serious problem if sustained. Elevated levels of ketone bodies in the blood decrease the blood's pH, leading to DKA. On presentation at hospital, the patient in DKA is typically dehydrated, and breathing rapidly and deeply. Abdominal pain is common and may be severe. The level of consciousness is typically normal until late in the process, when lethargy may progress to coma. Ketoacidosis can easily become severe enough to cause hypotension, shock, and death. Urine analysis will reveal significant levels of ketone bodies. Prompt, proper treatment usually results in full recovery, though death can result from inadequate or delayed treatment, or from complications. Ketoacidosis is much more common in type 1 diabetes than type 2.

Hyperglycemia hyperosmolar state

is an acute complication sharing many symptoms with DKA, but an entirely different origin and different treatment. A person with very high blood glucose levels, water is osmotically drawn out of cells into the blood and the kidneys eventually begin to dump glucose into the urine. This results in loss of water and an increase in blood osmolarity. If fluid is not replaced, the osmotic effect of high glucose levels, combined with the loss of water, will eventually lead to dehydration. The body's cells become progressively dehydrated as water is taken from them and excreted. Electrolyte imbalances are also common and are always dangerous. As with DKA, urgent medical treatment is necessary, commonly beginning with fluid volume replacement. Lethargy may ultimately progress to a coma, though this is more common in type 2 diabetes than type 1.

Hypoglycemia

, or abnormally low blood glucose, is an acute complication of several diabetes treatments. It is rare otherwise, either in diabetic or non-diabetic patients. The patient may become agitated, sweaty, weak, and have many symptoms of sympathetic activation of the autonomic nervous system resulting in feelings akin to dread and immobilized panic. Consciousness can be altered or even lost in extreme cases, leading to coma, seizures, or even brain damage and death. In patients with diabetes, this may be caused by several factors, such as too much or incorrectly timed insulin, too much or incorrectly timed exercise or not enough food. The variety of interactions makes cause identification difficult in many instances.
It is more accurate to note that iatrogenic hypoglycemia is typically the result of the interplay of absolute insulin excess and compromised glucose counterregulation in type 1 and advanced type 2 diabetes. Decrements in insulin, increments in glucagon, and, absent the latter, increments in epinephrine are the primary glucose counterregulatory factors that normally prevent or correct hypoglycemia. In insulin-deficient diabetes insulin levels do not decrease as glucose levels fall, and the combination of deficient glucagon and epinephrine responses causes defective glucose counterregulation.
Furthermore, reduced sympathoadrenal responses can cause hypoglycemia unawareness. The concept of hypoglycemia-associated autonomic failure or Cryer syndrome in diabetes posits that recent incidents of hypoglycemia causes both defective glucose counterregulation and hypoglycemia unawareness. By shifting glycemic thresholds for the sympathoadrenal and the resulting neurogenic responses to lower plasma glucose concentrations, antecedent hypoglycemia leads to a vicious cycle of recurrent hypoglycemia and further impairment of glucose counterregulation. In many cases, short-term avoidance of hypoglycemia reverses hypoglycemia unawareness in affected patients, although this is easier in theory than in clinical experience.
In most cases, hypoglycemia is treated with sugary drinks or food. In severe cases, an injection of glucagon or an intravenous infusion of dextrose is used for treatment, but usually only if the person is unconscious. In any given incident, glucagon will only work once as it uses stored liver glycogen as a glucose source; in the absence of such stores, glucagon is largely ineffective. In hospitals, intravenous dextrose is often used.

Diabetic coma

is a medical emergency in which a person with diabetes mellitus is comatose because of one of the acute complications of diabetes:
  1. Severe diabetic hypoglycemia
  2. Diabetic ketoacidosis advanced enough to result in unconsciousness from a combination of severe hyperglycemia, dehydration and shock, and exhaustion
  3. Hyperosmolar nonketotic coma in which extreme hyperglycemia and dehydration alone are sufficient to cause unconsciousness.

    Chronic

Microangiopathy

The damage to small blood vessels leads to a microangiopathy, which can cause one or more of the following:
leads to cardiovascular disease, to which accelerated atherosclerosis is a contributor:
The immune response is impaired in individuals with diabetes mellitus. Cellular studies have shown that hyperglycemia both reduces the function of immune cells and increases inflammation.

Age

Type 2 diabetes in youth brings a much higher prevalence of complications like diabetic kidney disease, retinopathy and peripheral neuropathy than type 1 diabetes, though no significant difference in the odds of arterial stiffness and hypertension.

Poor glucose control

A 1988 study over 41 months found that improved glucose control led to initial worsening of complications but was not followed by the expected improvement in complications. In 1993 it was discovered that the serum of diabetics with neuropathy is toxic to nerves, even if its blood sugar content is normal.
Research from 1995 also challenged the theory of hyperglycemia as the cause of diabetic complications. The fact that 40% of diabetics who carefully controlled their blood sugar nevertheless developed neuropathy made clear other factors were involved.
In a 2013 meta-analysis of 6 randomized controlled trials involving 27,654 patients, tight blood glucose control reduced the risk for some macrovascular and microvascular events but without effect on all-cause mortality and cardiovascular mortality.

Autoimmune processes

Research from 2007 suggested that in type 1 diabetics, the continuing autoimmune disease which initially destroyed the beta cells of the pancreas may also cause neuropathy, and nephropathy.
In 2008 it was even suggested to treat retinopathy with drugs to suppress the abnormal immune response rather than by blood sugar control.

Genetic factors

The known familial clustering of the type and degree of diabetic complications indicates, that genetics play a role in causing complications:
Some genes appear to provide protection against diabetic complications, as seen in a subset of long-term diabetes type 1 survivors without complications.

Mechanisms

Chronic elevation of blood glucose level leads to damage of blood vessels called angiopathy. The endothelial cells lining the blood vessels take in more glucose than normal, since they do not depend on insulin. They then form more surface glycoproteins than normal, and cause the basement membrane to grow thicker and weaker. The resulting problems are grouped under "microvascular disease" due to damage to small blood vessels and "macrovascular disease" due to damage to the arteries.
Studies show that DM1 and DM2 cause a change in balancing of metabolites such as carbohydrates, blood coagulation factors, and lipids, and subsequently bring about complications like microvascular and cardiovascular complications.
The role of metalloproteases and inhibitors in diabetic renal disease is unclear.
Numerous researches have found inconsistent results about the role of vitamins in diabetic risk and complications.
Thiamine acts as an essential cofactor in glucose metabolism, therefore, it may modulate diabetic complications by controlling glycemic status in diabetic patients. Additionally, deficiency of thiamine was observed to be associated with dysfunction of β-cells and impaired glucose tolerance. Different studies indicated possible role of thiamin supplementation on the prevention or reversal of early stage diabetic nephropathy, as well as significant improvement on lipid profile.
Low serum B12 level is a common finding in diabetics especially those taking Metformin or in advanced age. Vitamin B12 deficiency has been linked to two diabetic complications; atherosclerosis and diabetic neuropathy.
Low plasma concentrations of folic acid were found to be associated with high plasma homocysteine concentrations. In clinical trials, homocysteine concentrations were effectively reduced within 4 to 6 weeks of oral supplementation of folic acid. Moreover, since the activity of endothelial NO synthase enzyme might be potentially elevated by folate, folate supplementation might be capable of restoring the availability of NO in endothelium, therefore, improving endothelial function and reducing the risk for atherosclerosis. van Etten et al., found that a single dose of folic acid might help in reducing the risk of vascular complications and enhancing endothelial function in adults with type 2 diabetes by improving nitric oxide status.
Three vitamins, ascorbic acid; α-tocopherol; and β-carotene, are well recognized for their antioxidant activities in human. Free radical-scavenging ability of antioxidants may reduce the oxidative stress and thus may protect against oxidative damage. Based on observational studies among healthy individuals, antioxidant concentrations were found to be inversely correlated with several biomarkers of insulin resistance or glucose intolerance.

Management

Blood pressure control

Modulating and ameliorating diabetic complications may improve the overall quality of life for diabetic patients. For example; when elevated blood pressure was tightly controlled, diabetic related deaths were reduced by 32% compared to those with less controlled blood pressure.

Vitamins

Many observational and clinical studies have been conducted to investigate the role of vitamins on diabetic complications,
In the First National Health and Nutrition Examination Survey Epidemiologic Follow-up Study, vitamin supplementations were associated with 24% reduction on the risk of diabetes, observed during 20 years of follow-up.
Many observational studies and clinical trials have linked several vitamins with the pathological process of diabetes; these vitamins include folate, thiamine, β-carotene, and vitamin E, C, B12, and D.
Vitamin D insufficiency is common in diabetics. Observational studies show that serum vitamin D is inversely associated with biomarkers of diabetes; impaired insulin secretion, insulin resistance, and glucose intolerance.
It has been suggested that vitamin D may induce beneficial effects on diabetic complications by modulating differentiation and growth of pancreatic β-cells and protecting these cells from apoptosis, thus improving β-cells functions and survival. Vitamin D has also been suggested to act on immune system and modulate inflammatory responses by influencing proliferation and differentiation of different immune cells., Moreover, deficiency of vitamin D may contribute to diabetic complications by inducing hyperparathyroidism, since elevated parathyroid hormone levels are associated with reduced β-cells function, impaired insulin sensitivity, and glucose intolerance. Finally, vitamin D may reduce the risk of vascular complications by modulating lipid profile.
Vitamin C has been proposed to induce beneficial effects by two other mechanisms. It may replace glucose in many chemical reactions due to its similarity in structure, may prevent the non-enzymatic glycosylation of proteins, and might reduce glycated hemoglobin levels. Secondly, vitamin C has also been suggested to play a role in lipid regulation as a controlling catabolism of cholesterol to bile acid.