Complications of diabetes

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Diabetes complication
Specialty Endocrinology

Complications of diabetes mellitus include problems that develop rapidly (acute) or over time (chronic) 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. [1] [2] [3] 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. Complications of diabetes are a strong risk factor for severe COVID-19 illness. [4]



Diabetic ketoacidosis

Diabetic ketoacidosis (DKA) 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 (i.e., ketosis); 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 (which have exceeded their renal threshold blood levels to appear in the urine, often before other overt symptoms). Prompt, proper treatment usually results in full recovery, though death can result from inadequate or delayed treatment, or from complications (e.g., brain edema). Ketoacidosis is much more common in type 1 diabetes than type 2.

Hyperglycemia hyperosmolar state

Nonketotic hyperosmolar coma (HNS) is an acute complication sharing many symptoms with DKA, but an entirely different origin and different treatment. A person with very high (usually considered to be above 300 mg/dl (16 mmol/L)) 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 (by mouth or intravenously), 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. [5]


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 (exercise decreases insulin requirements) or not enough food (specifically glucose containing carbohydrates). 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 (or relative) 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 (more or less rapidly) correct hypoglycemia. In insulin-deficient diabetes (exogenous) 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 (HAAF) or Cryer syndrome [6] in diabetes posits that recent incidents of hypoglycemia causes both defective glucose counterregulation and hypoglycemia unawareness. By shifting glycemic thresholds for the sympathoadrenal (including epinephrine) 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 (but not all), 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 (a hormone with effects largely opposite to those of insulin) 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

Diabetic coma is a medical emergency [7] in which a person with diabetes mellitus is comatose (unconscious) 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.


Image of fundus showing scatter laser surgery for diabetic retinopathy Fundus photo showing scatter laser surgery for diabetic retinopathy EDA09.JPG
Image of fundus showing scatter laser surgery for diabetic retinopathy


The damage to small blood vessels leads to a microangiopathy, which can cause one or more of the following:

Macrovascular disease

Macrovascular disease leads to cardiovascular disease, to which accelerated atherosclerosis is a contributor:

Immune compromise

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.

Risk factors


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. [23]

Poor glucose control

In the early days of insulin treatment for type 1 diabetes there was much debate as to whether strict control of hyperglycaemia would delay or prevent the long-term complications of diabetes. The work of Pirart [24] suggested that microvascular complications of diabetes were less likely to occur in individuals with better glycaemic control. The issue was finally settled in 1993 with the publication of the Diabetes Control and Complications Trial. [25] In the DCCT, subjects without prior retinopathy who maintained good glycaemic control for a mean of 6.5 years were 76% less likely to develop diabetic retinopathy than subjects with less strict control. Similar results were seen for microalbuminuria and peripheral neuropathy. The benefits of strict control of blood glucose were confirmed in longer-term follow-up by the DCCT EDIC study group. [26] So far as macrovascular disease in type 1 diabetes is concerned, the same group reported improved outcomes for cardiovascular events in the group who had been managed by strict blood glucose control: in this group the incidence of any cardiovascular disease was reduced by 30% (95% CI 7, 48; P = 0.016) compared to the group with less intensive control and the incidence of major cardiovascular events (nonfatal myocardial infarction, stroke, or cardiovascular death) was reduced by 32% (95% CI −3, 56; P = 0.07). [27]

The situation regarding glycaemic control and complications in type 2 diabetes is less clear cut than for type 1, though there is evidence from the United Kingdom Prospective Diabetes Study Group that strict blood glucose control is beneficial for both microvascular and macrovascular complications. In the original study [28] a relatively modest difference in glycaemic control between the well-controlled and less well-controlled groups resulted in a 25% lower rate of microvascular complications. In follow-up studies from the same group significant relative risk reductions emerged for myocardial infarction (15%, P=0.014) and all-cause mortality (12%, P=0.007). [29]

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, [30] and nephropathy. [31] In 2008 it was even suggested to treat retinopathy with drugs to suppress the abnormal immune response rather than by blood sugar control. [32]

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. [38] [39]


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. [40]

Studies show that DM1 and DM2 cause a change in balancing of metabolites such as carbohydrates, blood coagulation factors,[ citation needed ] and lipids,[ citation needed ] and subsequently bring about complications like microvascular and cardiovascular complications.

The role of metalloproteases and inhibitors in diabetic renal disease is unclear. [41]

Numerous researches have found inconsistent results about the role of vitamins in diabetic risk and complications. [42] [ clarification needed ]

Thiamine acts as an essential cofactor in glucose metabolism, [43] therefore, it may modulate diabetic complications by controlling glycemic status in diabetic patients. [43] [44] Additionally, deficiency of thiamine was observed to be associated with dysfunction of β-cells and impaired glucose tolerance. [44] Different studies indicated possible role of thiamin supplementation on the prevention or reversal of early stage diabetic nephropathy, [45] [46] as well as significant improvement on lipid profile. [44]

Low serum B12 level is a common finding in diabetics especially those taking Metformin or in advanced age. [47] Vitamin B12 deficiency has been linked to two diabetic complications; atherosclerosis and diabetic neuropathy. [48] [49]

Low plasma concentrations of folic acid were found to be associated with high plasma homocysteine concentrations. [50] In clinical trials, homocysteine concentrations were effectively reduced within 4 to 6 weeks of oral supplementation of folic acid. [51] [52] Moreover, since the activity of endothelial NO synthase enzyme might be potentially elevated by folate, [53] folate supplementation might be capable of restoring the availability of NO in endothelium, [54] 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. [55]

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. [56] Based on observational studies among healthy individuals, antioxidant concentrations were found to be inversely correlated with several biomarkers of insulin resistance or glucose intolerance. [57] [58]


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. [59]


Many observational and clinical studies have been conducted to investigate the role of vitamins on diabetic complications, [48]

In the First National Health and Nutrition Examination Survey (NHANES I) Epidemiologic Follow-up Study, vitamin supplementations were associated with 24% reduction on the risk of diabetes[ clarification needed ], observed during 20 years of follow-up. [60]

Many observational studies and clinical trials have linked several vitamins with the pathological process of diabetes; these vitamins include folate, [51] thiamine, [45] β-carotene, and vitamin E, [57] C, [61] B12, [62] and D. [63]

Vitamin D insufficiency is common in diabetics. [63] Observational studies show that serum vitamin D is inversely associated with biomarkers of diabetes; impaired insulin secretion, insulin resistance, and glucose intolerance. [64] [65] 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. [66] Vitamin D has also been suggested to act on immune system and modulate inflammatory responses by influencing proliferation and differentiation of different immune cells. [67] [ clarification needed ], 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. [63] [64] Finally, vitamin D may reduce the risk of vascular complications by modulating lipid profile. [68]

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, [62] and might reduce glycated hemoglobin (HbA1c) levels. [58] Secondly, vitamin C has also been suggested to play a role in lipid regulation as a controlling catabolism of cholesterol to bile acid. [62]

Related Research Articles

The following is a glossary of diabetes which explains terms connected with diabetes.

Diabetic retinopathy Medical condition

Diabetic retinopathy, also known as diabetic eye disease (DED), is a medical condition in which damage occurs to the retina due to diabetes mellitus. It is a leading cause of blindness in developed countries.

Hyperglycemia Too much blood sugar, usually because of diabetes

Hyperglycemia is a condition in which an excessive amount of glucose circulates in the blood plasma. This is generally a blood sugar level higher than 11.1 mmol/l (200 mg/dl), but symptoms may not start to become noticeable until even higher values such as 13.9–16.7 mmol/l (~250–300 mg/dl). A subject with a consistent range between ~5.6 and ~7 mmol/l is considered slightly hyperglycemic, and above 7 mmol/l is generally held to have diabetes. For diabetics, glucose levels that are considered to be too hyperglycemic can vary from person to person, mainly due to the person's renal threshold of glucose and overall glucose tolerance. On average, however, chronic levels above 10–12 mmol/L (180–216 mg/dl) can produce noticeable organ damage over time.

Type 2 diabetes Type of diabetes mellitus with high blood sugar and insulin resistance

Type 2 diabetes (T2D), formerly known as adult-onset diabetes, is a form of diabetes that is characterized by high blood sugar, insulin resistance, and relative lack of insulin. Common symptoms include increased thirst, frequent urination, and unexplained weight loss. Symptoms may also include increased hunger, feeling tired, and sores that do not heal. Often symptoms come on slowly. Long-term complications from high blood sugar include heart disease, strokes, diabetic retinopathy which can result in blindness, kidney failure, and poor blood flow in the limbs which may lead to amputations. The sudden onset of hyperosmolar hyperglycemic state may occur; however, ketoacidosis is uncommon.

Microangiopathy is an angiopathy affecting small blood vessels in the body. It can be contrasted to macroangiopathy, or large vessel disease.

Diabetic neuropathy refers to various types of nerve damage associated with diabetes mellitus. Symptoms depend on the site of nerve damage and can include motor changes such as weakness; sensory symptoms such as numbness, tingling, or pain; or autonomic changes such as urinary symptoms. These changes are thought to result from microvascular injury involving small blood vessels that supply nerves. Relatively common conditions which may be associated with diabetic neuropathy include distal symmetric polyneuropathy; third, fourth, or sixth cranial nerve palsy; mononeuropathy; mononeuropathy multiplex; diabetic amyotrophy; and autonomic neuropathy.

Glycated hemoglobin is a form of hemoglobin (Hb) that is chemically linked to a sugar. Most monosaccharides, including glucose, galactose and fructose, spontaneously bond with hemoglobin, when present in the bloodstream of humans. However, glucose is less likely to do so than galactose and fructose, which may explain why glucose is used as the primary metabolic fuel in humans.

Diabetic nephropathy Chronic loss of kidney function

Diabetic nephropathy, also known as diabetic kidney disease, is the chronic loss of kidney function occurring in those with diabetes mellitus. Diabetic nephropathy is one of the leading causes of chronic kidney disease (CKD) and end-stage renal disease (ESRD) globally. Protein loss in the urine due to damage to the glomeruli may become massive, and cause a low serum albumin with resulting generalized body swelling (edema) and result in the nephrotic syndrome. Likewise, the estimated glomerular filtration rate (eGFR) may progressively fall from a normal of over 90 ml/min/1.73m2 to less than 15, at which point the patient is said to have end-stage renal disease. It usually is slowly progressive over years.

Type 1 diabetes Form of diabetes mellitus

Type 1 diabetes (T1D), previously known as juvenile diabetes, is an autoimmune disease that is a form of diabetes in which very little or no insulin is produced by the islets of Langerhans in the pancreas. Insulin is a hormone required for the cells to use blood sugar for energy and it helps regulate normal glucose levels in the bloodstream. Before treatment this results in high blood sugar levels in the body. The common symptoms are frequent urination, increased thirst, increased hunger, and weight loss. Additional symptoms may include blurry vision, tiredness, and slow wound healing. Symptoms typically develop over a short period of time, often a matter of weeks.

The term diabetes includes several different metabolic disorders that all, if left untreated, result in abnormally high concentration of a sugar called glucose in the blood. Diabetes mellitus type 1 results when the pancreas no longer produces significant amounts of the hormone insulin, usually owing to the autoimmune destruction of the insulin-producing beta cells of the pancreas. Diabetes mellitus type 2, in contrast, is now thought to result from autoimmune attacks on the pancreas and/or insulin resistance. The pancreas of a person with type 2 diabetes may be producing normal or even abnormally large amounts of insulin. Other forms of diabetes mellitus, such as the various forms of maturity onset diabetes of the young, may represent some combination of insufficient insulin production and insulin resistance. Some degree of insulin resistance may also be present in a person with type 1 diabetes.

Diabetes and pregnancy

For pregnant women with diabetes, some particular challenges exist for both mother and child. If the woman has diabetes as a pre-existing or acquired disorder, it can cause early labor, birth defects, and larger than average infants.

The polyol pathway is a two-step process that converts glucose to fructose. In this pathway glucose is reduced to sorbitol, which is subsequently oxidized to fructose. It is also called the sorbitol-aldose reductase pathway.

A diabetic diet is a diet that is used by people with diabetes mellitus or high blood sugar to minimize symptoms and dangerous complications of long term elevations in blood sugar.

Prediabetes Predisease state of hyperglycemia with high risk for diabetes

Prediabetes is a component of the metabolic syndrome and is characterized by elevated blood sugar levels that fall below the threshold to diagnose diabetes mellitus. It usually does not cause symptoms but people with prediabetes often have obesity, dyslipidemia with high triglycerides and/or low HDL cholesterol, and hypertension. It is also associated with increased risk for cardiovascular disease (CVD). Prediabetes is more accurately considered an early stage of diabetes as health complications associated with type 2 diabetes often occur before the diagnosis of diabetes.

Diabetic cardiomyopathy Medical condition

Diabetic cardiomyopathy is a disorder of the heart muscle in people with diabetes. It can lead to inability of the heart to circulate blood through the body effectively, a state known as heart failure, with accumulation of fluid in the lungs or legs. Most heart failure in people with diabetes results from coronary artery disease, and diabetic cardiomyopathy is only said to exist if there is no coronary artery disease to explain the heart muscle disorder.

Minimed Paradigm Insulin pumps

MiniMed Paradigm is a series of insulin pumps manufactured by Medtronic for patients with diabetes mellitus. The pump operates with a single AAA battery and uses a piston-plunger pump to infuse a programmed amount of insulin into the patient through a length of tubing. The Paradigm uses a one-way wireless radio frequency link to receive blood sugar measurements from select glucose meters. The Paradigm RT series adds the ability to receive data from a mated continuous blood-glucose monitor. Although the pump can use these measurements to assist in calculating a dose of insulin, no actual change in insulin delivery occurs without manual user-intervention.

Diabetes usually refers to diabetes mellitus, a group of metabolic diseases in which a person has high blood glucose levels over a prolonged period.

In recent years it has become apparent that the environment and underlying mechanisms affect gene expression and the genome outside of the central dogma of biology. It has been found that many epigenetic mechanisms are involved in the regulation and expression of genes such as DNA methylation and chromatin remodeling. These epigenetic mechanisms are believed to be a contributing factor to pathological diseases such as type 2 diabetes. An understanding of the epigenome of Diabetes patients may help to elucidate otherwise hidden causes of this disease.

Diabetes Group of metabolic disorders

Diabetes mellitus (DM), commonly known as just diabetes, is a group of metabolic disorders characterized by a high blood sugar level over a prolonged period of time. Symptoms often include frequent urination, increased thirst and increased appetite. If left untreated, diabetes can cause many health complications. Acute complications can include diabetic ketoacidosis, hyperosmolar hyperglycemic state, or death. Serious long-term complications include cardiovascular disease, stroke, chronic kidney disease, foot ulcers, damage to the nerves, damage to the eyes and cognitive impairment.

Type 3c (pancreatogenic) diabetes Medical condition

Type 3c diabetes is diabetes that comes secondary to pancreatic diseases, involving the exocrine and digestive functions of the pancreas.


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