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Chronic Complications of Diabetes Mellitus

Chronic complications can be divided into vascular and non-vascular complications.

The vascular complications of DM are further subdivided into micro vascular (retinopathy, neuropathy, and nephropathy) and macro vascular complications [coronary artery disease (CAD), peripheral arterial disease (PAD), cerebrovascular disease]. Nonvascular complications include problems such as gastroparesis, infections, and skin changes. Long-standing diabetes may be associated with hearing loss.

The risk of chronic complications increases as a function of the duration of hyperglycemia; they usually become apparent in the second decade of hyperglycemia. Since type 2 DM often has a long asymptomatic period of hyperglycemia, many individuals with type 2 DM have complications at the time of diagnosis.

Mechanisms of Complications

Following prominent theories, which are not mutually exclusive, have been proposed to explain how hyperglycemia might lead to the chronic complications of DM.

1) Advanced Glycosylation End Products

Increased intracellular glucose leads to the formation of advanced glycosylation end products (AGEs) via the nonenzymatic glycosylation of intra and extra cellular proteins. Nonenzymatic glycosylation results from the interaction of glucose with amino groups on proteins. AGEs have been shown to cross-link proteins (e.g., collagen, extracellular matrix proteins), accelerate atherosclerosis, promote glomerular dysfunction, reduce nitric oxide synthesis, induce endothelial dysfunction, and alter extracellular matrix composition and structure (Figure-1).The serum level of AGEs correlates with the level of glycemia, and these products accumulate as glomerular filtration rate declines.

Figure-1-Pathogenic effects of advanced glycation end products (AGEs). By binding and crosslinking extracellular matrix, e.g. collagen, AGEs induce vascular stiffness and increased vascular permeability. The interaction with AGE receptors (e.g. RAGE) induces endothelial dysfunction by reducing nitric oxide (NO) release ,  promoting inflammatory reactions, and oxidative stress. Binding to lipoproteins increases the uptake of e.g. low density lipoproteins (LDL) by macrophages, which may lead to the formation of foam cells.

2) Sorbitol pathway

Hyperglycemia increases glucose metabolism via the Sorbitol pathway. Intracellular glucose is predominantly metabolized by phosphorylation and subsequent glycolysis, but when increased, some glucose is converted to sorbitol by the enzyme aldose reductase. Increased sorbitol concentration alters redox potential, increases cellular osmolality, generates reactive oxygen species, and likely leads to other types of cellular dysfunction.


Figure-2- showing  mechanism of sorbitol formation from Glucose. (SDH- Sorbitol dehydrogenase catalyzes conversion of sorbitol to fructose, but this enzyme  is absent in most of the tissues.)

3) Activation of protein kinase C (PKC)

A third hypothesis proposes that hyperglycemia increases the formation of diacylglycerol leading to activation of protein kinase C (PKC). Among other actions, PKC alters the transcription of genes for fibronectin, type IV collagen, contractile proteins, and extracellular matrix proteins in endothelial cells and neurons. Inhibitors of PKC are being studied in clinical trials.

4) Hexosamine pathway

A fourth theory proposes that hyperglycemia increases the flux through the hexosamine pathway, which generates fructose-6-phosphate, a substrate for O-linked glycosylation and proteoglycan production. The hexosamine pathway may alter function by glycosylation of proteins such as endothelial nitric oxide synthase or by changes in gene expression of transforming growth factor β (TGF- β) or plasminogen activator inhibitor-1 (PAI-1).

Growth factors appear to play an important role in DM-related complications, and their production is increased by most of these proposed pathways.

5) Oxidative stress

Hyperglycemia leads to increased production of reactive oxygen species or Superoxide in the mitochondria; these compounds may activate all four of the pathways described above. (Figure-3). Although hyperglycemia serves as the initial trigger for complications of diabetes, it is still unknown whether the same pathophysiological processes are operative in all complications or whether some pathways predominate in certain organs.

Figure-3- showing implications of hyperglycemia

Vascular complications

1) Micro vascular complications

A) Ocular Complications

DM is the leading cause of blindness between the ages of 20 and 74 in the United States. Blindness is primarily the result of progressive diabetic retinopathy and clinically significant macular edema.

a) Diabetic retinopathy

Diabetic retinopathy is classified into two stages: nonproliferative and proliferative. Nonproliferative diabetic retinopathy usually appears late in the first decade or early in the second decade of the disease and is marked by retinal vascular micro aneurysms, blot hemorrhages, and cotton wool spots .Mild nonproliferative retinopathy progresses to more extensive disease, characterized by changes in venous vessel caliber, intraretinal microvascular abnormalities, and more numerous micro aneurysms and hemorrhages (Figure-4)

Figure-4 – showing Diabetic retinopathy

The appearance of neovascularization in response to retinal hypoxia is the hallmark of proliferative diabetic retinopathy These newly formed vessels appear near the optic nerve and/or macula and rupture easily, leading to vitreous hemorrhage, fibrosis, and ultimately retinal detachment. Clinically significant macular edema can occur when only nonproliferative retinopathy is present.

Duration of DM and degree of glycemic control are the best predictors of the development of retinopathy; hypertension is also a risk factor. Nonproliferative retinopathy is found in almost all individuals who have had DM for >20 years (25% incidence with 5 years, and 80% incidence with 15 years of type 1 DM). Although there is genetic susceptibility for retinopathy, it confers less influence than either the duration of DM or the degree of glycemic control.


The most effective therapy for diabetic retinopathy is prevention. Intensive glycemic and blood pressure control will delay the development or slow the progression of retinopathy in individuals with either type 1 or type 2 DM.  Laser photocoagulation is very successful in preserving vision. Proliferative retinopathy is usually treated with panretinal laser photocoagulation, whereas macular edema is treated with focal laser photocoagulation.

b) Diabetic cataract

Premature cataracts occur in diabetic patients (Figure-5) and seem to correlate with both the duration of diabetes and the severity of chronic hyperglycemia. Nonenzymatic glycosylation of lens protein contributes to the premature occurrence of cataracts.

Figure-5 – showing Diabetic cataract

c) Glaucoma

Glaucoma occurs in approximately 6% of persons with diabetes. It is responsive to the usual therapy for open-angle disease. Neovascularization of the iris in diabetics can predispose to closed-angle glaucoma, but this is relatively uncommon except after cataract extraction, when growth of new vessels has been known to progress rapidly, involving the angle of the iris and obstructing outflow.

B) Renal Complications

Diabetic nephropathy- Diabetic nephropathy (nephropatia diabetica), also known as Kimmelstiel-Wilson syndrome, and intercapillary glomerulonephritis, is a progressive kidney disease, caused by angiopathy of capillaries in the kidney glomeruli, and it is characterized by Nephrotic syndrome and diffuse glomerulosclerosis. It is due to long standing diabetes mellitus, and is a prime cause for dialysis in many Western countries.


Like other microvascular complications, the pathogenesis of diabetic nephropathy is related to chronic hyperglycemia.The mechanisms by which chronic hyperglycemia leads to End Stage Renal Disease ( ESRD), though incompletely defined, involve the effects of soluble factors (growth factors, angiotensin II, Endothelin, AGEs), hemodynamic alterations in the renal microcirculation (glomerular hyper filtration or hyper perfusion, increased glomerular capillary pressure), and structural changes in the glomerulus (increased extracellular matrix, basement membrane thickening, mesangial expansion, fibrosis). Some of these effects may be mediated through angiotensin II receptors.

The earliest detectable change in the course of diabetic nephropathy is a thickening in the glomerulus. At this stage, the kidney may start allowing more albumin than normal in the urine (albuminuria), and this can be detected by sensitive medical tests for albumin. This stage is called “microalbuminuria”. After 5–10 years of type 1 DM, ~40% of individuals begin to show microalbuminuria. Microalbuminuria is defined as 30–300 mg/d of albumin in a 24-h collection of urine. As diabetic nephropathy progresses, increasing numbers of glomeruli are destroyed by nodular glomerulosclerosis. Although the appearance of microalbuminuria in type 1 DM, is an important risk factor for progression to overt proteinuria (in>300 mg/d), only ~50% of individuals will progress to macroalbuminuria over the next 10 years. In some individuals with type 1 diabetes and microalbuminuria of short duration, the microalbuminuria regresses. Once macroalbuminuria is present, there is a steady decline in GFR (Glomerular Filtration Rate), and ~50% of individuals reach ESRD (End Stage Renal Disease) in 7–10 years. Once macroalbuminuria develops, blood pressure rises slightly and the pathologic changes are likely to be irreversible. At this stage, a kidney biopsy clearly shows diabetic nephropathy.

Clinical Manifestations

Kidney failure provoked by glomerulosclerosis leads to fluid filtration deficits and other disorders of kidney function. There is an increase in blood pressure and fluid retention in the body causing edema. Other complications may be arteriosclerosis of the renal artery and proteinuria.

Throughout its early course, diabetic nephropathy has no symptoms. They develop in late stages and may be a result of excretion of high amounts of protein in the urine or due to renal failure:

  • edema: swelling, usually around the eyes in the mornings; later, general body swelling may result, such as swelling of the legs
  • foamy appearance or excessive frothing of the urine (caused by the proteinuria)
  • unintentional weight gain (from fluid accumulation)
  • anorexia
  • nausea and vomiting
  • malaise
  • fatigue
  • headache
  • frequent hiccups
  • generalized itching

Laboratory Diagnosis

The first laboratory abnormality is a positive microalbuminuria test. Most often, the diagnosis is suspected when a routine urinalysis of a person with diabetes shows too much protein in the urine (proteinuria). The urinalysis may also show glucose in the urine, especially if blood glucose is poorly controlled. Serum creatinine and BUN may increase as kidney damage progresses. Dyslipidemia is a common associated finding. A Renal biopsy confirms the diagnosis.

The nephropathy that develops in type 2 DM differs from that of type 1 DM in the following respects:

(1) microalbuminuria or macroalbuminuria may be present when type 2 DM is diagnosed, reflecting its long asymptomatic period;

(2) hypertension more commonly accompanies microalbuminuria or macroalbuminuria in type 2 DM; and

(3) microalbuminuria may be less predictive of diabetic nephropathy and progression to macroalbuminuria in type 2 DM. 


The optimal therapy for diabetic nephropathy is prevention by control of glycemia. As a part of comprehensive diabetes care, microalbuminuria detection, and measurement of the serum creatinine to estimate GFR, should be done at an early stage, when effective therapies can be instituted.

Interventions effective in slowing progression from microalbuminuria to macroalbuminuria include: (1) normalization of glycemia, (2) strict blood pressure control, and (3) administration of ACE inhibitors (Angiotensin-converting enzyme inhibitors), or ARBs( Angiotensin II receptor blockers),Dyslipidemia should also be treated. Modest restriction of protein and fat intake is recommended. Once macroalbuminuria ensues, the likelihood of ESRD is very high. Survival after the onset of ESRD is shorter in the diabetic population compared to nondiabetics with similar clinical features. Dialysis may be necessary once end-stage renal disease develops. At this stage, a kidney transplantation must be considered. Another option for type 1 diabetes patients is a combined kidney-pancreas transplant.

C) Diabetic Neuropathy

Diabetic neuropathy occurs in ~50% of individuals with long-standing type 1 and type 2 DM. It may manifest as polyneuropathy, mononeuropathy, and/or autonomic neuropathy. Both myelinated and unmyelinated nerve fibers are lost.

a) Polyneuropathy/Mononeuropathy

The most common form of diabetic neuropathy is distal symmetric polyneuropathy. It most frequently presents with distal sensory loss, but up to 50% of patients do not have symptoms of neuropathy. Loss of function appears in a stocking-glove pattern. Hyperesthesia, paresthesias, and dysesthesia also may occur. Symptoms may include a sensation of numbness, tingling, sharpness, or burning that begins in the feet and spreads proximally. Neuropathic pain develops in some of these individuals, occasionally preceded by improvement in their glycemic control. Pain typically involves the lower extremities, is usually present at rest, and worsens at night. Both an acute (lasting <12 months) and a chronic form of painful diabetic neuropathy have been described. As diabetic neuropathy progresses, the pain subsides and eventually disappears, but a sensory deficit in the lower extremities persists. Physical examination reveals sensory loss, loss of ankle reflexes, and abnormal position sense.

Mononeuropathy (dysfunction of isolated cranial or peripheral nerves) is less common than polyneuropathy in DM and presents with pain and motor weakness in the distribution of a single nerve. A vascular etiology has been suggested, but the pathogenesis is unknown.

b) Autonomic Neuropathy

Individuals with long-standing type 1 or 2 DM may develop signs of autonomic dysfunction involving the cholinergic, noradrenergic, and peptidergic (peptides such as pancreatic polypeptide, substance P, etc.) systems. DM-related autonomic neuropathy can involve multiple systems, including the cardiovascular, gastrointestinal, genitourinary, and metabolic systems. Autonomic neuropathy may reduce counterregulatory hormone release, leading to an inability to sense hypoglycemia appropriately thereby subjecting the patient to the risk of severe hypoglycemia and complicating efforts to improve glycemic control. Anhidrosis of the feet can promote dry skin with cracking, which increases the risk of foot ulcers.

Diabetic nerve damage can affect the nerves that are important for penile erection, causing erectile dysfunction .Erectile dysfunction can also be caused by poor blood flow to the penis from diabetic blood vessel disease.

Diabetic neuropathy can also affect nerves to the stomach and intestines, causing nausea, weight loss, diarrhea, and other symptoms of gastroparesis (delayed emptying of food contents from the stomach into the intestines, due to ineffective contraction of the stomach muscles).

Diabetic Neuropathy: Treatment

Despite advances in the understanding of the metabolic causes of neuropathy, treatments aimed at interrupting these pathological processes have been limited. Thus, with the exception of tight glucose control, treatments are for reducing pain and other symptoms.

Options for pain control include tricyclic antidepressants (TCAs), serotonin reuptake inhibitors (SSRIs) and antiepileptic drugs (AEDs).


The mechanisms of diabetic neuropathy are poorly understood. At present, treatment alleviates pain and can control some associated symptoms, but the process is generally progressive.

As a complication, there is an increased risk of injury to the feet because of loss of sensation. Small infections can progress to ulceration and this may require amputation.

c) Diabetic gangrene

The incidence of gangrene of the feet in diabetics(Figure-6) is 30 times more than that in age-matched controls. The factors responsible for its development, in addition to peripheral vascular disease, are small vessel disease, peripheral neuropathy with loss of both pain sensation and neurogenic inflammatory responses, and secondary infection.

Figure-6-showing Diabetic foot

The peripheral sensory neuropathy interferes with normal protective mechanisms and allows the patient to sustain major or repeated minor trauma to the foot, often without knowledge of the injury. Motor and sensory neuropathy lead to abnormal foot muscle mechanics and to structural changes in the foot (hammer toe, claw toe deformity, prominent metatarsal heads, Charcot joint). Autonomic neuropathy results in anhidrosis and altered superficial blood flow in the foot, which promote drying of the skin and fissure formation. PAD and poor wound healing impede the resolution of minor breaks in the skin, allowing them to enlarge and to become infected.

Approximately 15% of individuals with DM develop a foot ulcer (great toe or MTP areas are most common), and a significant subset will ultimately undergo amputation (14–24% risk with that ulcer or subsequent ulceration). Risk factors for foot ulcers or amputation include: male sex, diabetes >10 years’ duration, peripheral neuropathy, abnormal structure of foot (bony abnormalities, callus, and thickened nails), peripheral arterial disease, and smoking, history of previous ulcer or amputation, and poor glycemic control.


The optimal therapy for foot ulcers and amputations is prevention through identification of high-risk patients, education of the patient, and institution of measures to prevent ulceration. Despite preventive measures, foot ulceration and infection are common and represent a serious problem. Due to the multifactorial pathogenesis of lower extremity ulcers, management of these lesions is multidisciplinary.

Agents that reduce peripheral blood flow such as tobacco and propranolol should be avoided. Control of other risk factors such as hypertension is essential. Cholesterol-lowering agents are useful as adjunctive therapy when early ischemic signs are detected and when dyslipidemia is present. Patients should be advised to seek immediate medical care if a diabetic foot ulcer develops. Improvement in peripheral blood flow with endarterectomy and bypass operations is possible in certain patients.

2) Large vessel diseases (Macro vascular complications)

Atherosclerosis and its effects produce the large vessel diseases.

a) Involvement of the coronary vessels can produce myocardial infarction,

b) Involvement of cerebral vessels can produce ‘stroke’.

c) Peripheral vascular disease-Atherosclerosis is markedly accelerated in the larger arteries. It is often diffuse, with localized enhancement in certain areas of turbulent blood flow, such as at the bifurcation of the aorta or other large vessels. Clinical manifestations of peripheral vascular disease include ischemia of the lower extremities, impotence, and intestinal angina.

Non vascular complications

Skin and Mucous Membrane Complications

Chronic pyogenic infections of the skin may occur, especially in poorly controlled diabetic patients. Eruptive xanthomas can result from hypertriglyceridemia, associated with poor glycemic control. An unusual lesion termed necrobiosis lipoidica diabeticorum is usually located over the anterior surfaces of the legs or the dorsal surfaces of the ankles. They are oval or irregularly shaped plaques with demarcated borders and a glistening yellow surface and occur in women two to four times more frequently than in men.

Fungal infections are also very common in diabetics. Candidal infection can produce erythema and edema of intertriginous areas below the breasts, in the axillas, and between the fingers. It causes vulvovaginitis in most chronically uncontrolled diabetic women with persistent glucosuria and is a frequent cause of pruritus.While antifungal creams containing miconazole or clotrimazole offer immediate relief of vulvovaginitis, recurrence is frequent unless glucosuria is reduced.

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