diabetic neuropathy and retinopathy

DIABETES MELLITUS DIABETES MELLITUS CHRONIC CHRONIC

COMPLICATIONSCOMPLICATIONS

affect many organ systems affect many organ systems and are responsible for the and are responsible for the majority of morbidity and majority of morbidity and

mortality associated with the mortality associated with the disease.disease.

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CHRONIC CHRONIC COMPLICATIONSCOMPLICATIONS

Chronic complications can be Chronic complications can be divided into vascular and divided into vascular and nonvascular complicationsnonvascular complications


vascular complications of vascular complications of DMDM

subdividedsubdivided microvascular (microvascular (retinopathy, retinopathy,

neuropathyneuropathy, nephropathy) , nephropathy) macrovascular complications macrovascular complications

(coronary artery disease, (coronary artery disease, peripheral vascular disease, peripheral vascular disease, cerebrovascular disease)cerebrovascular disease)


Nonvascular complicationsNonvascular complications

include problems such asinclude problems such as:: GastroparesisGastroparesis sexual dysfunctionsexual dysfunction skin changesskin changes


chronic complicationschronic complications

The risk increases The risk increases with thewith the duration of hyperglycemiaduration of hyperglycemia

apparent in the second decade of apparent in the second decade of hyperglycemia. hyperglycemia.

TyType 2 DM may have a long pe 2 DM may have a long asymptomatic period of asymptomatic period of hyperglycemia, many individuals hyperglycemia, many individuals with type 2 DM have complications with type 2 DM have complications at the time of diagnosis. at the time of diagnosis.



Randomized, prospective clinical trials Randomized, prospective clinical trials involving large numbers of individuals involving large numbers of individuals with type 1 or type 2 DM have with type 1 or type 2 DM have conclusively demonstrated that a conclusively demonstrated that a reduction in chronic hyperglycemia reduction in chronic hyperglycemia prevents or reduces retinopathy, prevents or reduces retinopathy, neuropathy, and nephropathy. Other neuropathy, and nephropathy. Other incompletely defined factors also incompletely defined factors also modulate the development of modulate the development of complications. complications.



BeBecause of these observations, it is cause of these observations, it is suspected that a genetic suspected that a genetic susceptibility for developing susceptibility for developing particular complications exists. particular complications exists.

the genetic loci responsible for the genetic loci responsible for these susceptibilities have not yet these susceptibilities have not yet been identified. been identified.


MECHANISMS OF MECHANISMS OF COMPLICATIONSCOMPLICATIONS

Three major theories Three major theories

increased intracellular glucose leads to increased intracellular glucose leads to the formation of advanced glycosylation the formation of advanced glycosylation end products (AGEs) via the end products (AGEs) via the nonenzymatic glycosylaton of cellular nonenzymatic glycosylaton of cellular proteins. Nonenzymatic glycosylation proteins. Nonenzymatic glycosylation results from the interaction of glucose results from the interaction of glucose with amino groups on proteinswith amino groups on proteins


Intracellular glucose is Intracellular glucose is predominantly metabolized by predominantly metabolized by phosphorylation and subsequent phosphorylation and subsequent glycolysis, but when intracellular glycolysis, but when intracellular glucose is increased, some glucose glucose is increased, some glucose is converted to sorbitol by the is converted to sorbitol by the enzyme aldose reductase. enzyme aldose reductase.


Increased sorbitol concentrations Increased sorbitol concentrations affect several aspects of cellular affect several aspects of cellular physiology (decreased myoinositol, physiology (decreased myoinositol, altered redox potential) and may altered redox potential) and may lead to cellular dysfunction.lead to cellular dysfunction.


However, testing of this theory in However, testing of this theory in humans, using aldose reductase humans, using aldose reductase inhibitors, has not demonstrated inhibitors, has not demonstrated beneficial effects on clinical beneficial effects on clinical endpoints of retinopathy, endpoints of retinopathy, neuropathy, or nephropathy.neuropathy, or nephropathy.


third hypothesisthird hypothesis

hyperglycemia increases the formation of hyperglycemia increases the formation of diacylglycerol leading to activation of diacylglycerol leading to activation of certain isoforms of protein kinase C (PKC)certain isoforms of protein kinase C (PKC)..

affect a variety of cellular events that affect a variety of cellular events that lead to DM-related complications. lead to DM-related complications.

EExample, PKC activation by glucose alters xample, PKC activation by glucose alters the transcription of genes for fibronectin, the transcription of genes for fibronectin, type IV collagen, contractile proteins, and type IV collagen, contractile proteins, and extracellular matrix proteins in endothelial extracellular matrix proteins in endothelial cells and neurons in vitro.cells and neurons in vitro.


Growth factors appear to play an Growth factors appear to play an important role in DM-related important role in DM-related complications. complications.

Other growth factors, such as platelet-Other growth factors, such as platelet-derived growth factor, epidermal growth derived growth factor, epidermal growth factor, insulin-like growth factor I, factor, insulin-like growth factor I, growth hormone, basic fibroblast growth growth hormone, basic fibroblast growth factor, and even insulin, have been factor, and even insulin, have been suggested to play a role in DM-related suggested to play a role in DM-related complications. complications.


Finally, oxidative stress and free Finally, oxidative stress and free radical generation, as a radical generation, as a consequence of the consequence of the hyperglycemia, may also promote hyperglycemia, may also promote the development of complications.the development of complications.


GLYCEMIC CONTROL AND GLYCEMIC CONTROL AND COMPLICATIONSCOMPLICATIONS

The Diabetes Control and Complications The Diabetes Control and Complications Trial (DCCT) provided definitive proof that Trial (DCCT) provided definitive proof that reduction in chronic hyperglycemia can reduction in chronic hyperglycemia can prevent many of the early complications prevent many of the early complications of type 1 DM. of type 1 DM.

This large multicenter clinical trial This large multicenter clinical trial randomized over 1400 individuals with randomized over 1400 individuals with type 1 DM to either intensive or type 1 DM to either intensive or conventional diabetes management, and conventional diabetes management, and then evaluated the development of then evaluated the development of retinopathy, nephropathy, and retinopathy, nephropathy, and neuropathyneuropathy


glycemic controlglycemic control

nonproliferative and proliferative nonproliferative and proliferative retinopathy (47% reduction), retinopathy (47% reduction),

microalbuminuria (39% reduction), microalbuminuria (39% reduction), clinical nephropathy (54%clinical nephropathy (54%

reduction)reduction) neuropathy (60% reduction). neuropathy (60% reduction).


intensive diabetes intensive diabetes managementmanagement

group would experience 15.3 more group would experience 15.3 more years of life without significant years of life without significant microvascular or neurologic microvascular or neurologic complications of DM as compared complications of DM as compared to individuals who received to individuals who received standard therapy.standard therapy.


NEUROPATHY AND DIABETES NEUROPATHY AND DIABETES MELLITUSMELLITUS

occurs in approximately 50% of occurs in approximately 50% of individuals with long-standing type individuals with long-standing type 1 and type 2 DM.1 and type 2 DM.

It may manifest as It may manifest as polyneuropathy, mononeuropathy, polyneuropathy, mononeuropathy, and/or autonomic neuropathy.and/or autonomic neuropathy.



The most common form of diabetic The most common form of diabetic neuropathy is distal symmetric neuropathy is distal symmetric polyneuropathypolyneuropathy

It most frequently presents with It most frequently presents with distal sensory loss. Hyperesthesia, distal sensory loss. Hyperesthesia, paresthesia, and pain paresthesia, and pain


Physical examination reveals Physical examination reveals sensory loss, loss of ankle reflexes, sensory loss, loss of ankle reflexes, and abnormal position sense. and abnormal position sense. Paresthesia is characteristically Paresthesia is characteristically perceived as a sensation of perceived as a sensation of numbness, tingling, sharpness, or numbness, tingling, sharpness, or burning that begins in the feet and burning that begins in the feet and spreads proximally. spreads proximally.


Pain typically involves the lower Pain typically involves the lower extremities, is usually present at extremities, is usually present at rest, and worsens at night. rest, and worsens at night.

As diabetic neuropathy progresses, As diabetic neuropathy progresses, the pain subsides and eventually the pain subsides and eventually disappears, and a sensory deficit in disappears, and a sensory deficit in the lower extremities persists.the lower extremities persists.


Diabetic polyradiculopathyDiabetic polyradiculopathy is a is a syndrome characterized by severe syndrome characterized by severe disabling pain in the distribution of one disabling pain in the distribution of one or more nerve roots. It may be or more nerve roots. It may be accompanied by motor weakness. accompanied by motor weakness.

Fortunately, diabetic Fortunately, diabetic polyradiculopathies are usually self-polyradiculopathies are usually self-limited and resolve over 6 to 12 limited and resolve over 6 to 12 months.months.


MononeuropathyMononeuropathy (dysfunction of (dysfunction of isolated cranial or peripheral isolated cranial or peripheral nerves) is less common than nerves) is less common than polyneuropathy in DM and polyneuropathy in DM and presents with pain and motor presents with pain and motor weakness in the distribution of a weakness in the distribution of a single nerve.single nerve.


Autonomic NeuropathyAutonomic Neuropathy

Can Can involvinvolvee the cholinergic, the cholinergic, noradrenergic, and peptidergic noradrenergic, and peptidergic (peptides such as pancreatic (peptides such as pancreatic polypeptide, substance P, etc.) systems. polypeptide, substance P, etc.) systems.

multiple systems, including: the multiple systems, including: the cardiovascular, gastrointestinal, cardiovascular, gastrointestinal, genitourinary, sudomotor, and genitourinary, sudomotor, and metabolic systems. metabolic systems.


IsIs less than satisfactory. less than satisfactory. glycemic control and will improve glycemic control and will improve

nerve conduction velocity, nerve conduction velocity, Avoidance of neurotoxins (alcohol), Avoidance of neurotoxins (alcohol),

supplementation with vitamins for supplementation with vitamins for possible deficiencies (Bpossible deficiencies (B1212, B, B66, , folate; folate;

symptomatic treatment are the symptomatic treatment are the mainstays of therapymainstays of therapy


GASTROINTESTINAL/GASTROINTESTINAL/GENITOURINARY DYSFUNCTIONGENITOURINARY DYSFUNCTION

GastroparesisGastroparesis genitourinary dysfunction including genitourinary dysfunction including

cystopathy, erectile dysfunction, and cystopathy, erectile dysfunction, and female sexual dysfunction (reduced female sexual dysfunction (reduced sexual desire, dyspareunia, reduced sexual desire, dyspareunia, reduced vaginal lubrication). Symptoms of vaginal lubrication). Symptoms of diabetic cystopathy begin with an diabetic cystopathy begin with an inability to sense a full bladder and a inability to sense a full bladder and a failure to void completelyfailure to void completely


DIABETES MELLITUS DIABETES MELLITUS CHRONIC CHRONIC

COMPLICATIONSCOMPLICATIONS

affect many organ systems affect many organ systems and are responsible for the and are responsible for the majority of morbidity and majority of morbidity and

mortality associated with the mortality associated with the disease.disease.


CHRONIC CHRONIC COMPLICATIONSCOMPLICATIONS

Chronic complications can be Chronic complications can be divided into vascular and divided into vascular and nonvascular complicationsnonvascular complications


vascular complications of vascular complications of DMDM

subdividedsubdivided microvascular (microvascular (retinopathy, retinopathy,

neuropathyneuropathy, nephropathy) , nephropathy) macrovascular complications macrovascular complications

(coronary artery disease, (coronary artery disease, peripheral vascular disease, peripheral vascular disease, cerebrovascular disease)cerebrovascular disease)


Nonvascular complicationsNonvascular complications

include problems such asinclude problems such as:: GastroparesisGastroparesis sexual dysfunctionsexual dysfunction skin changesskin changes



The risk increases The risk increases with thewith the duration of hyperglycemiaduration of hyperglycemia

apparent in the second decade of apparent in the second decade of hyperglycemia. hyperglycemia.

TyType 2 DM may have a long pe 2 DM may have a long asymptomatic period of asymptomatic period of hyperglycemia, many individuals hyperglycemia, many individuals with type 2 DM have complications with type 2 DM have complications at the time of diagnosis. at the time of diagnosis.
