Complications of diabetes mellitus

Diabetes complication
Classification and external resources
Specialty endocrinology
ICD-10 E10-E14
ICD-9-CM 250.1-250.9
MeSH D048909

The complications of diabetes mellitus are far less common and less severe in people who have well-controlled blood sugar levels.[1][2][3]

Wider health problems accelerate the deleterious effects of diabetes. These include smoking, elevated cholesterol levels, obesity, high blood pressure, and lack of regular exercise.

Acute

Diabetic ketoacidosis

Main article: 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

Hyperosmolar nonketotic state (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.

Hypoglycemia

Main article: hypoglycemia

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) 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

Main article: Diabetic coma

Diabetic coma is a medical emergency 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.

In most medical contexts, the term diabetic coma refers to the diagnostical dilemma posed when a physician is confronted with an unconscious patient about whom nothing is known except that he has diabetes. An example might be a physician working in an emergency department who receives an unconscious patient wearing a medical identification tag saying DIABETIC. Paramedics may be called to rescue an unconscious person by friends who identify him as diabetic. Brief descriptions of the three major conditions are followed by a discussion of the diagnostic process used to distinguish among them, as well as a few other conditions which must be considered.

An estimated 2 to 15 percent of diabetics will suffer from at least one episode of diabetic coma in their lifetimes as a result of severe hypoglycemia.

Respiratory infections

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. The vascular effects of diabetes also tend to alter lung function, all of which leads to an increase in susceptibility to respiratory infections such as pneumonia and influenza among individuals with diabetes. Several studies also show diabetes associated with a worse disease course and slower recovery from respiratory infections.[4]

Periodontal disease

Diabetes is associated with periodontal disease (gum disease)[5] and may make diabetes more difficult to treat.[6] Gum disease is frequently related to bacterial infection by organisms such as Porphyromonas gingivalis and Actinobacillus actinomycetemcomitans.[7] A number of trials have found improved blood sugar levels in type 2 diabetics who have undergone peridontal treatment.[6]

Chronic

Image of fundus showing scatter laser surgery for diabetic retinopathy

Mechanisms of chronic complications

Chronic elevation of blood glucose level leads to damage of blood vessels (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. In diabetes, the resulting problems are grouped under "microvascular disease" (due to damage to small blood vessels) and "macrovascular disease" (due to damage to the arteries).

However, some research challenges the theory of hyperglycemia as the cause of diabetic complications. The fact that 40% of diabetics who carefully control their blood sugar nevertheless develop neuropathy,[8] requires explanation. It has been discovered that the serum of diabetics with neuropathy is toxic to nerves even if its blood sugar content is normal.[9] Recent research suggests that in type 1 diabetics, the continuing autoimmune disease which initially destroyed the beta cells of the pancreas may also cause retinopathy,[10] neuropathy,[11] and nephropathy.[12] One researcher has even suggested that retinopathy may be better treated by drugs to suppress the abnormal immune system of diabetics than by blood sugar control.[13] The familial clustering of the degree and type of diabetic complications[14] indicates that genetics may also play a role in causing complications such as diabetic retinopathy[15] and nephropathy.[16] Non-diabetic offspring of type 2 diabetics have been found to have increased arterial stiffness and neuropathy despite normal blood glucose levels,[17] and elevated enzyme levels associated with diabetic renal disease have been found in non-diabetic first-degree relatives of diabetics.[18][19] However, one study continued for 41 months found that the initial worsening of complications from improved glucose control was not followed by the expected improvement in the complications.[20] In a systematic review with meta-analysis including 6 randomized controlled trials involving 27,654 patients, tight blood glucose control reduces the risk for some macrovascular and microvascular events, without effect on all-cause mortality and cardiovascular mortality.[21] In terms of pathophysiology, studies show that the two main types of DM (DM1 and DM2) cause a change in balancing of metabolites such as carbohydrates, lipids and blood coagulation factors,[22] and subsequently bring about complications like microvascular and cardiovascular complications,[23]

Examples of chronic complications

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

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

Diabetic foot, often due to a combination of sensory neuropathy (numbness or insensitivity) and vascular damage, increases rates of skin ulcers (diabetic foot ulcers) and infection and, in serious cases, necrosis and gangrene. It is why diabetics are prone to leg and foot infections and why it takes longer for them to heal from leg and foot wounds. It is the most common cause of non-traumatic adult amputation, usually of toes and or feet, in the developed world.[28]

Carotid artery stenosis does not occur more often in diabetes, and there appears to be a lower prevalence of abdominal aortic aneurysm. However, diabetes does cause higher morbidity, mortality and operative risks with these conditions.[29]

In the developed world, diabetes is the most significant cause of adult blindness in the non-elderly and the leading cause of non-traumatic amputation in adults, and diabetic nephropathy is the main illness requiring renal dialysis in the United States.[30]

A review of type 1 diabetes came to the result that, despite modern treatment, women with diabetes are at increased risk of female infertility, such as reflected by delayed puberty and menarche, menstrual irregularities (especially oligomenorrhoea), mild hyperandrogenism, polycystic ovarian syndrome, fewer live born children and possibly earlier menopause.[31] Animal models indicate that abnormalities on the molecular level caused by diabetes include defective leptin, insulin and kisspeptin signalling.[31]

Restrictive lung defect is known to be associated with diabetes. Lung restriction in diabetes could result from chronic low-grade tissue inflammation, microangiopathy, and/or accumulation of advanced glycation end products.[32] In fact the presence restrictive lung defect in association with diabetes has been shown even in presence of obstructive lung diseases like asthma and copd in diabetic patients.[33]

Lipohypertrophy may be caused by insulin therapy. Repeated insulin injections at the same site, or near to, causes an accumulation of extra subcutaneous fat and may present as a large lump under the skin. It may be unsightly, mildly painful, and may change the timing or completeness of insulin action.

Researchers have found an association of depression and diabetes in a 2010 study. A longitudinal study of 4,263 individuals diagnosed with type 2 diabetes were followed from 2005-2007 and were found to have a statistically significant association with depression and a high risk of micro and macro-vascular events. [34]

Statistics

In the United States, there were approximately 675,000 diabetes-related emergency department (ED) visits in 2010 that involved neurological complications, 409,000 ED visits with kidney complications, and 186,000 ED visits with eye complications.[35]

Management

Modulating and ameliorating diabetic complications may in turn 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.[36] Many observational and clinical studies had been conducted to investigate the role of several vitamins on diabetic complications,[37][38][39] the results of these studies elevated a suggested beneficial role of vitamins on diabetic complications. In the First National Health and Nutrition Examination Survey (NHANES I) Epidemiologic Follow-up Study, vitamin supplementations were observed to be associated with 24% reduction on the risk of diabetes was observed during 20 years of follow-up.[40] Many observational studies and clinical trials have linked several vitamins with the pathological process of diabetes; these vitamin include folate,[41] thiamine,[42] β-carotene, and vitamin E,[38] C,[43] B12,[44] and D.[39] However, numerous researches had been shown inconsistent results about the roles of vitamins on diabetic risk and complications. Most of these researches performed to investigate effect of individual vitamin without looking to status of other vitamins. Even though, it is expected that vitamin(s) supplementation might be more effective and might induce a beneficial role on diabetic process when deficiency exists.[45] Despite the current contradictory in the association between the discussed vitamins and diabetic complications, and regardless of the lack of strong and inclusive evidence about their mechanism(s) of action, the discussed effects of these vitamins seem promising for preventing and reducing the severity of diabetic complications. Since optimal blood level of all vitamins is important for normal metabolic process, it is essential to encourage diabetic patients and high risk population to try to achieve and maintain this level. And until more inclusive evidence is established about vitamins supplementations, the awareness of diabetic patients should be elevated toward the importance of consuming adequate amounts of all vitamins.
Thiamine: Thiamine acts as an essential cofactor in glucose metabolism,[46] therefore, it may modulate diabetic complications by controlling glycemic status in diabetic patients.[46][47] Additionally, deficiency of thiamine was observed to be associated with dysfunction of β-cells and impaired glucose tolerance.[47] Different studies indicated possible role of thiamin supplementation on the prevention or reversal of early stage diabetic nephropathy,[48][49] as well as significant improvement on lipid profile.[47]
vitamin B12: Low serum B12 level is common finding in diabetic patients especially those taking Metformin or advanced age patients.[50] Vitamin B12 deficiency has been linked to two diabetic complications; atherosclerosis and diabetic neuropathy.[37][51]
Folic acid: Low plasma concentrations of folic acid were found to be associated with high plasma homocysteine concentrations.[52] In clinical trials, homocysteine concentrations were effectively reduced within 4 to 6 weeks of oral supplementation of folic acid.[41][53] Moreover, since the activity of endothelial NO synthase enzyme might be potentially elevated by folate,[54] folate supplementation might be capable of restoring the availability of NO in endothelium,[55] 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.[56]
Antioxidants: Three vitamins, ascorbic acid; α-tocopherol; and β-carotene, are well recognized for their antioxidant activities in human.[38] Free radical-scavenging ability of antioxidants may reduce the oxidative stress and thus may protect against oxidative damage.[57] Based on observational studies among healthy individuals, antioxidant concentrations were found to be inversely correlated with several biomarkers of insulin resistance or glucose intolerance.[38][58] Antioxidants may induce beneficial effects on diabetic complications by reducing blood pressure, attenuating oxidative stress and inflammatory biomarkers, improving lipid metabolism and insulin-mediated glucose disposal, as well as by enhancing endothelial function.[38][59][60] In addition to its antioxidant capacity, vitamin C has been proposed to induce beneficial effects on diabetes by two other mechanisms. Firstly; vitamin C may replace the glucose in many chemical reactions due to their similarity in structure, thus, it may prevent the non-enzymatic glycosylation of proteins,[44] and therefore it might reduce glycated hemoglobin (HbA1c) levels.[58] Secondly, vitamin C has also been suggested to play an important role in lipid regulation as a controller of catabolism of cholesterol to bile acid.[44]
Vitamin D: The insufficiency of vitamin D is a common finding in diabetic patients.[39] Observational studies showed that serum vitamin D is inversely associated with biomarkers of diabetes; impaired insulin secretion, insulin resistance, and glucose intolerance.[61][62] It has been suggested that vitamin D may induce a beneficial effects on diabetic complications by several mechanisms. Firstly; it could modulate differentiation and growth of pancreatic β-cells and it may also protect these cells from apoptosis, thus improving β-cells functions and survival.[63] Vitamin D has also been suggested to act on immune system and modulate inflammatory responses by influencing proliferation and differentiation of different immune cells.[64] 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.[39][61] Finally, vitamin D may reduce the risk of vascular complications by modulating lipid profile.[65]

References

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  38. 1 2 3 4 5 Song, Y., Cook, N., Albert, C., Denburgh, M. V., & Manson, J. E. (2009). Effects of vitamins C and E and beta-carotene on the risk of type 2 diabetes in women at high risk of cardiovascular disease: A randomized controlled trial. The American Journal of Clinical Nutrition, 90(2), 429-437
  39. 1 2 3 4 Sugden, J. A., Davies, J. I., Witham, M. D., Morris, A. D., & Struthers, A. D. (2008). Vitamin D improves endothelial function in patients with type 2 diabetes mellitus and low vitamin D levels. Diabetic Medicine, 25(3), 320-325
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  41. 1 2 Mangoni, A. A., Sherwood, R. A., Swift, C. G., & Jackson, S. H. D. (2002). Folic acid enhances endothelial function and reduces blood pressure in smokers: A randomized controlled trial. Journal of Internal Medicine, 252(6), 497-503
  42. ↑ Karachalias, N., Babaei-Jadidi, R., Rabbani, N., & Thornalley, P. J. (2010). Increased protein damage in renal glomeruli, retina, nerve, plasma and urine and its prevention by thiamine and benfotiamine therapy in a rat model of diabetes. Diabetologia, 53(7), 1506-1516
  43. ↑ Ceriello, A., Novials, A., Ortega, E., Canivell, S., Pujadas, G., La Sala, L., et al. (2013). Vitamin C further improves the protective effect of GLP-1 on the ischemia-reperfusion-like effect induced by hyperglycemia post-hypoglycemia in type 1 diabetes. Cardiovascular Diabetology, 12, 97
  44. 1 2 3 Afkhami-Ardekani, M., & Shojaoddiny-Ardekani, A. (2007). Effect of vitamin C on blood glucose, serum lipids & serum insulin in type 2 diabetes patients. Indian Journal of Medical Research, 126(5), 471-474
  45. ↑ Bonnefont-Rousselot, D. (2004). The role of antioxidant micronutrients in the prevention of diabetic complications. Treatments in Endocrinology, 3(1), 41-52
  46. 1 2 Arora, S., Lidor, A., Abularrage, C. J., Weiswasser, J. M., Nylen, E., Kellicut, D., et al. (2006). Thiamine (vitamin B-1) improves endothelium-dependent vasodilatation in the presence of hyperglycemia. Annals of Vascular Surgery, 20(5), 653-658
  47. 1 2 3 Thornalley, P. J. (2005). The potential role of thiamine (vitamin B1) in diabetic complications. Current Diabetes Reviews, 1(3), 287-98
  48. ↑ Rabbani, N., & Thornalley, P. J. (2011). Emerging role of thiamine therapy for prevention and treatment of early-stage diabetic nephropathy. Diabetes Obesity & Metabolism, 13(7), 577-583
  49. ↑ Karachalias, N., Babaei-Jadidi, R., Rabbani, N., & Thornalley, P. J. (2010). Increased protein damage in renal glomeruli, retina, nerve, plasma and urine and its prevention by thiamine and benfotiamine therapy in a rat model of diabetes. Diabetologia, 53(7), 1506-1516.
  50. ↑ Pflipsen, M., Oh, R., Saguil, A., Seehusen, D., Seaquist, D., & Topolski, R. (2009). The prevalence of vitamin B12deficiency in patients with type 2 diabetes: A cross-sectional study. The Journal of the American Board of Family Medicine, 22(5), 528-534
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  52. ↑ Mangoni, A. A., Sherwood, R. A., Asonganyi, B., Swift, C. G., Thomas, S., & Jackson, S. H. D. (2005). Short-term oral folic acid supplementation enhances endothelial function in patients with type 2 diabetes. American Journal of Hypertension, 18(2), 220-226
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  54. ↑ Title, L. M., Ur, E., Giddens, K., McQueen, M. J., & Nassar, B. A. (2006). Folic acid improves endothelial dysfunction in type 2 diabetes - an effect independent of homocysteine-lowering. Vascular Medicine, 11(2), 101-109
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  57. ↑ Rahimi, R., Nikfar, S., Larijani, B., & Abdollahi, M. (2005). A review on the role of antioxidants in the management of diabetes and its complications. Biomedicine & Pharmacotherapy, 59(7), 365-373
  58. 1 2 Sargeant, L. A., Wareham, N. J., Bingham, S., Day, N. E., Luben, R. N., Oakes, S., et al. (2000). Vitamin C and hyperglycemia in the european prospective investigation into cancer - norfolk (EPIC-norfolk) study - A population-based study. Diabetes Care, 23(6), 726-732
  59. ↑ Mullan, B. A., Young, I. S., Fee, H., & McCance, D. R. (2002). Ascorbic acid reduces blood pressure and arterial stiffness in type 2 diabetes. Hypertension, 40(6), 804-809
  60. ↑ Regensteiner, J. G., Popylisen, S., Bauer, T. A., Lindenfeld, J., Gill, E., Smith, S., et al. (2003). Oral L-arginine and vitamins E and C improve endothelial function in women with type 2 diabetes. Vascular Medicine, 8(3), 169-175
  61. 1 2 Takiishi, T., Gysemans, C., Bouillon, R., & Mathieu, C. (2010). Vitamin D and diabetes. Endocrinology and Metabolism Clinics of North America, 39(2), 419-446
  62. ↑ Talaei, A., Mohamadi, M., & Adgi, Z. (2013). The effect of vitamin D on insulin resistance in patients with type 2 diabetes Diabetology & Metabolic Syndrome, 5(8)
  63. ↑ Takiishi, T., Gysemans, C., Bouillon, R., & Mathieu, C. (2010). Vitamin D and diabetes. Endocrinology and Metabolism Clinics of North America, 39(2), 419-446.
  64. ↑ Muthian, G., Raikwar, H. P., Rajasingh, J., & Bright, J. J. (2006). 1,25 dihydroxyvitamin-D3 modulates JAK-STAT pathway in IL-12/IFN gamma axis leading to Th1 response in experimental allergic encephalomyelitis. Journal of Neuroscience Research, 83(7), 1299-1309
  65. ↑ Gannage-Yared, M. H., Azoury, M., Mansour, I., Baddoura, R., Halaby, G., & Naaman, R. (2003). Effects of a short-term calcium and vitamin D treatment on serum cytokines, bone markers, insulin and lipid concentrations in healthy post-menopausal women. Journal of Endocrinological Investigation, 26(8), 748-753
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