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Complications
- The complications of diabetes can be broken down
into acute and chronic complications
o Acute complication include hypoglycemia
and hyperglycemic states of diabetic
ketoacidosis and hyperosmolar
hyperglycemic nonketotic syndrome
o The chronic complications can be further
broken down into the microvascular
complications of retinopathy, neuropathy
and nephropathy AND macrovascular
complications of cerebrovascular disease,
peripheral vascular disease and coronary
artery disease
- Triggers or underlying etiology of acute complications often includes concurrent illness and factors
related to the management of plasma glucose levels including noncompliance with diet or pharm
therapy or side effects of pharmacological therapy
- Chronic hyperglycemia and the resultant metabolic events have been associated with the
underlying etiology of chronic complications of diabetes
- Hyperglycemia affects cells that do not effectively reduce the transport of glucose into the cells in a
hyperglycemic state resulting in intracellular hyperglycemia
o Examples of cells that are vulnerable to chronic hyperglycemia include: capillary endothelial
cells in the retina, mesangial cells in the renal glomerulus and neurons and Shwann cells in
the peripheral nerves
- There are several theories that are well documented and describe the metabolic mechanisms that
are associated with tissue-damaging effects of chronic hyperglycemia and the resultant diabetic
complications
Questions
1. What is the normal plasma glucose level?
o Plasma glucose varies based on last meal
o The homeostatic mechanisms of the body generally maintain glucose at a level <6.0 mmol/L
2. What source of energy does the brain rely on solely?
o Glucose
Hypoglycemia
- Hypoglycemia is defined by:
o Development of neurogenic/autonomic or neuroglycopenic symptoms
o Below than normal blood glucose (BG) levels (<4 mmol/L for diabetic patients treated with
insulin or an insulin secretagogue)
- Severity
o Mild: autonomic symptoms, able to self-treat
o Moderate: autonomic and neuroglycopenic symptoms, able to self-treat
o Severe: unable to self-treat, requires assistance, unconsciousness may occur. BG usually
<2.8 mmol/L
Treatment
Treatment in conscious person
- Mild to moderate
o 15g carb 2.1 mmol/L increase within 20 mins
- Severe conscious
o 20g carb 3.6 mmol/L increase at 45 mins
*Re-test in 15 mins and retreat with another 15 or 20g of carb if BG < 4.0 mmol/L
Treatment in unconscious person with severe hypoglycemia >equal to 5 yrs of age
- 1 mg glucagon SC or IM
- IV glucose 10-25 g (20-55 cc D50W) over 1-3 mins
- Examples of 15g includes 15g of glucose in the form of glucose tabs, 3 tsps. or 3 packets of table
sugar dissolved in water, 175 ml of juice or regular soft drink, 6 Life Savers, 1 tbsps. of honey
o Monosaccharides like glucose are preferred as they are absorbed directly into the
bloodstream
- Some clinical PEARLS to remember from first diabetes module are that if a patient is taking a alpha-
glucosidase inhibitor, dextrose not sucrose should be used to treat hypoglycemia
- Secondly, glucagon will be ineffective in patients whose glycogen stores are depleted
o Glucagon will not be as effective in individuals who have consumed more than 2 standard
alcoholic drinks within the previous few h or those who have advance liver disease
Hyperglycemic Emergencies
- Diabetic Ketoacidosis (DKA)
- Hyperglycemic Hyperosmolar Nonketotic Syndrome (HHNKS)*
- Relative or absolute insulin deficiency
- Trigger increased counterregulatory hormones
- Osmotic diuresis and hypovolemia
- A-B imbalance
- Electrolyte imbalances
- Adverse neurological sequelae
- Hyperglycemic emergencies are life threatening associated with significant morbidity and even
mortality
- The 2 hyperglycemic conditions associated with diabetes are:
1. Diabetic Ketoacidosis (DKA)
2. Hyperglycemic Hyperosmolar Nonketotic Syndrome (HHNKS)
- The features of each of these conditions can overlap however there are some distinct differences
o Both conditions arise from either a relative or absolute insulin deficiency
o And some form of trigger that causes an increase in counterregulatory hormones and
resultant hyperglycemia
o Osmotic diuresis and extracellular fluid volume depletion or hypovolemia is more impressive
with HHNKS
o A-B imbalance specifically metabolic acidosis due to ketoacidosis is less likely to occur in
HHNKS but always present in DKA
o Electrolyte imbalances occurs due to metabolic acidosis and osmotic diuresis. The most
serious electrolyte imbalance is hypo and hyperkalemia due to the associated risk for
cardiac arrhythmias
o And adverse neurological sequelae including cerebral edema, coma and death are reported
in both conditions
DKA/HHNKS Pathophysiology
- First there is an insulin deficiency and some
precipitating factor that increases
counterregulatory hormones including
glucagon
- Glucagon directly stimulates glycogenolysis
in the liver
o Counterregulatory hormones
including glucagon cause decreased
glucose uptake in the peripheral
tissues
- Protein breaks down to provides AAs to the
liver for gluconeogenesis
- Adipose tissue also breaks down to form
glycerol for gluconeogenesis if there is a
relative insulin deficiency and FFAs to form
ketones in the liver in the case of absolute
insulin deficiency
o Specific ketones formed are called beta-hydrobutyric and acetoacetic acids which result in
metabolic acidosis
- The result of glycogenolysis and gluconeogenesis is hyperglycemia
- Hyperglycemia causes osmotic diuresis and large losses of electrolytes in the urine
o The totally body deficit of water in adults is usually about 5-7L in DKA and 7-12L in HHNKS
which represents a loss between 10-15% of body weight
o If left untreated circulatory failure ensues
- Hyperosmolality and metabolic acidosis can both cause CNS depression and if left untreated coma
- As you can visually appreciate whether the hyperglycemia condition is classified as DKA or HHNKS
depends upon whether or not there is a relative or absolute insulin deficiency
Management of DKA/HHNKS
- Fluid rehydration
- Correction of hyperglycemia
- Resolution of ketoacidosis
- NaHCO3 for severe metabolic acidosis
- Monitor and correct electrolytes (**K+)
- Diagnosis and treatment of coexisting illness
- Monitor for and prevent complications specifically adverse neurological sequelae like cerebral edema
- Key principals of the management of DKA and HHNKS involve the following:
o Fluid rehydration to restore normal ECFV and tissue perfusion
o Correction of hyperglycemia by addressing absolute or relative insulin deficiency
o Resolution of ketoacidosis usually occurs with insulin therapy and fluid rehydration
o NaHCO3 for severe metabolic acidosis may be used in the adult population. It is usually not
used in pediatric
o Monitor and correct electrolytes (**K+)
o Diagnosis and treatment of coexisting illness which may have been precipitating factors
o Monitor for and prevent complications specifically adverse neurological sequelae like
cerebral edema
- This is a very simplified summary of the management of DKA and HHNKS
o There are specific clinical algorithms used to manage DKA in both adults and children
- Not necessary to memorize algorithm should be able to make sense and provide rationale for each
step
- K is added to maintenance fluid even if K levels are not abnormally low bc when metabolic acidosis
begins to correct K shifts back into the cell
o Since there is already an overall depletion of K due K having moved out of the cell during
metabolic acidosis and loss of K via osmotic diuresis it is imperative to anticipate this to
avoid life-threatening arrhythmias
- Lastly, a sudden change in extracellular fluid osmolality can occur if hyperglycemia is corrected to
quickly which can result in cerebral edema
- Cerebral edema is more common in DKA and in children. It can be deadly or have devastating
neurological consequences
Chronic/Long-Term Complications
- Chronic and more long-term complications of diabetes can cause disease in several body systems
as illustrated in this figure
- The CDA states that 10% of all acute care hospital admissions are related to diabetes or its
complications
o Some staggering stats about diabetic complication
o It is fortunate that good diabetes care and
management which include health teaching can
prevent or delay the onset of complications
- 2 landmark studies, on called the Diabetes Control and
Complications Trail which looked at type 1 diabetes and the
UK Prospective Diabetes and Study which looked at type 2
diabetes found that intensive diabetic treatment can
reduce the incidence of complications
o 80% of people with diabetes will die of a heart
attack or stroke
o 50% diabetes have chronic kidney disease and
chronic kidney disease with diabetes is the leading
cause of kidney failure in Canada
o Blindness caused by diabetes is the most common
cause of blindness in people aged 65 yr and
younger
o Neuropathy can cause minor injuries to go
unnoticed which if untreated can lead to infection
and gangrene
7/10 non traumatic limb amputations are due
to diabetes
Infections as a chronic complication will not
be discussed in detail in this presentation
o Please refer to Porth patho textbook for further info
- Highlight only some of the most common complications
although others are not really all that uncommon
o For example, erectile dysfunction was the first
clinical sign of diabetes in up 12% of males with
diabetes
- Pharmacologic agents that target these pathophysiological pathways are being evaluated
Polyol Pathway
- Tissues not requiring insulin for glucose transport
- Aldose reductase converts glucose to sorbitol
- NADPH consumed, glutathione decreased increased susceptibility to intracellular oxidative stress
- Sorbitol converted to fructose
- Sorbitol + Fructose Inc. intracellular osmotic pressure cell injury
- The polyol pathway is an alternative metabolic pathway for tissues not requiring insulin for glucose
transport
- These include the kidney, RBCs, blood vessels, eye lens, and nerves
- Aldose reductase normally converts toxic aldehydes to inactive alcohols however in the presence of
hyperglycemia glucose is shunted to this pathway and aldose reductase converts glucose to sorbitol
- In the process a cofactor called NADPH (Nicotinamide adenine dinucleotide phosphate) is consumed
o NADPH is normally an essential cofactor for regenerating glutathione which is a critical
intracellular antioxidant
o This increases the susceptibility of the cell to intracellular oxidative stress
- Sorbitol is then slowly converted to fructose by sorbitol dehydrogenase
- The accumulation of sorbitol and fructose causes increases in intracellular osmotic pressure which
attracts water and leads to cell injury
- This is key part of the pathophysiology process of visual changes in cataracts diabetic patient
- Also,, in nerves sorbitol interferes with ion pumps, damages Schwann cells and disrupts nerve
conduction
- Swollen RBCs can become stiff and perfusion can be compromised
AGE Formation
- Glycoproteins or AGEs: basement membrane components in the microcirculation
- Recurrent/persistent hyperglycemia causes AGEs to be formed through the non-reversible binding
of glucose to proteins, lipids & nucleic acids
- Hyperglycemia increases AGEs in RBCs, blood vessel walls & interstitial tissues
- AGEs + their receptor (RAGE) have properties that can cause tissue injury or pathologic conditions
a/w diabetes
- Glycoproteins AKA advanced glycation and products or AGEs are basement membrane components
in the microcirculation
- Recurrent or persistent hyperglycemia increases the formation of AGEs to be formed through the
non-reversible binding of glucose to proteins, lipids & nucleic acids
- Specifically hyperglycemia increases AGEs in collagen and other proteins in RBCs, blood vessel
walls & interstitial tissues
- AGEs + their receptor (RAGE) have properties that can cause tissue injury or pathologic conditions
a/w diabetes
- Some of these effects include modification of intracellular proteins specifically those involved in
gene transcription; cross-linking and trapping of proteins; thickening of the basement membrane;
increased permeability in blood vessels and nerves; stimulation of cellular proliferation; inducing
lipid oxidation, oxidative stress and inflammation; inactivation of NO and loss of vasodilation and
diminished endothelial function; and promotion of platelet adhesion and reduced fibrinolysis
- Tissue oxygenation theories suggest that many of the chronic complications arise from a decrease
in O2 delivery in small vessels
- One described pathway is a defect in RBCs which impairs the release of O2 from hemoglobin
- Chronic hyperglycemia increases production of ROS and subsequent damaging effects of oxidative
stress
- Advanced glycation end products (AGEs), nitric oxide dysfunction and nicotinamide adenine
dinucleotide phosphate or NADPH discussed in the context of the polyol pathway are some of the
contributors to increased ROS in the setting of chronic hyperglycemia
- ROS damage large and small vessels contributing to atherogenesis, cardiovascular disease,
nephropathy and neuropathy
Protein Kinase C
- Intracellular hyperglycemia increases the synthesis of diacylglycerol (DAG) which activates protein
kinase C
- Consequences:
o Blood flow abnormalities
o Increased vascular permeability & angiogenesis
o Capillary & vascular occlusion
o Pro-inflammatory gene expression
o Increased ROS & disordered mitochondrial fxn in response to chronic hyperglycemia
- Intracellular hyperglycemia increases the synthesis of diacylglycerol (DAG) which activates protein
kinase C
- These are critical intracellular signalling molecules that regulate many vascular functions including
permeability, vasodilator release, endothelial activation and growth factor signaling
- The consequences of elevated DAG and PKC are:
o Blood flow abnormalities due to decreased endothelial NO synthase which is a vasodilator
and increased endothelin-1 which is a vasoconstrictor
o Increased vascular permeability & angiogenesis due to increased vascular endothelial
growth factor
o Capillary & vascular occlusion due to increased collagen and fibronectin and decreased
fibrinolysis respectively
o Pro-inflammatory gene expression
o Increased ROS & disordered mitochondrial fxn in response to chronic hyperglycemia
- Clinically, vascular damage and associated disease of the retina, kidney and nerves can be caused
by activation of PKC in these blood vessels
Hexosamine Pathway
- Newer piece of the diabetes pathogenesis puzzle
- Chronic hyperglycemia shunting of excess intracellular glucose into the hexosamine pathway
O-linked glycosylation of proteins alteration in signal transduction pathways & oxidative stress
- O-linked attachment of N-acetylglucosamine on serine and threonine residues of transcription
factors pathologic changes in gene expression a/w insulin resistance & CV complications
- The increased hexosamine pathway activity is a newer piece of the diabetes pathogenesis puzzle
- Chronic hyperglycemia causes shunting of excess intracellular glucose into the hexosamine
pathway and O-linked glycosylation of proteins causes alteration in signal transduction pathways &
oxidative stress
- Specifically, O-linked attachment of N-acetylglucosamine on serine and threonine residues of
transcription factors often results in pathologic changes in gene expression that are a/w insulin
resistance & CV complications
Microvascular disease
- Diabetes Leading cause of blindness, end-stage renal disease and various neuropathies
- Characterized by thickening of the basement membrane, endothelial cell hyperplasia, thrombosis,
pericyte degeneration
- Hyperglycemia is pre-requisite
- Frequency of these complications r/t duration of diabetes & blood glucose levels
- Involves retina, nerves, kidneys and GI system
- Microvascular diabetic complications are the leading cause of blindness, end-stage renal disease
and various neuropathies
- It is characterized by thickening of the basement membrane, endothelial cell hyperplasia,
thrombosis and pericyte denegation
- These microvascular changes occur in a hyperglycemic state
o Specifically, accumulation of AGEs and resultant tissue injury and pathologic conditions
contributes to microvascular complications in diabetes
- Frequency of these complications seems to be proportionally r/t duration of diabetes & blood
glucose levels
- The Diabetes Control and Complications trial demonstrated that diabetics with tightly controlled
glucose were half as likely to have renal and eye complications as those diabetics receiving
standard therapy
- Microvascular complications in diabetes involves mainly the retina, nerves, kidneys and GI system
- In the Western world, diabetic neuropathy is the most common cause of neuropathy
o Within 10 yrs of the onset of diabetes, detectable sensorimotor polyneuropathy will develop
in 40-50% of people with both type 1 and 2 diabetes
- There are 2 main pathologic changes seen in diabetic neuropathies
- First, vessel ischemia due to thickening of the walls of the nutrient vessels that supply the nerve
o Secondly, the segmental demyelinization process affecting the Schwann cell
o Slowed nerve conduction accompanies this demyelinization process
- The underlying pathophysiology is multi-factorial and includes microangiopathy, oxidative stress,
growth factor deficiency, abnormal signaling from AGE-RAGE interaction, increased polyol pathway
and inflammation
- Neuropathies can be subclinical and peripheral nerve dysfunctions can only be detected with
electromyography (EMG) testing before progressing to the clinical stage in which symptoms or
clinically detectable neurologic deficits are present
- Somatic neuropathy may involve the spinal cord, posterior root ganglia or the peripheral nerves
- Degeneration of the nerves begins in the periphery and sensory nerve involvement usually
precedes motor nerve involvement
o Distal symmetric polyneuropathy is the most common form of neuropathy and involves the
smaller unmyelinated peripheral C fibers and the larger myelinated A-delta fibers
Sensory dysfunction usually occurs first and is distal, bilateral and symmetric
o Loss of small nerve function rests in neuropathic pain, loss of sensation
o Loss of large nerve function results in sensory loss of proprioception and vibration, ataxia,
loss of coordination
- Autonomic neuropathy involves sympathetic and parasympathetic nervous system dysfunction
o In the bladder there may be loss of bladder sensation, urine retention and recurrent
infections
o In the GI system there may be dysfunction of GI enteric nerves which may lead to nausea,
bloating, gastroparesis, diarrhea, constipation
o In men, sensory and autonomic dysfunction may lead to erectile dysfunction
34-35% of Canadian men with diabetes have erectile dysfunction
o Autonomic neuropathy can lead to dysfunction of sweating and body temp regulation
o CV autonomic neuropathy specifically in D1M is associated with heart rate variability,
changes in baroreceptor reflexes, postural hypotension, arrhythmias, exercise intolerance
and painless MI
- Rapid screening for neuropathy is described in the CDA guidelines
o Comprehensive neurological exam is warranted in patients with signs or symptoms of
neuropathy
o Asking a patient about falls and foot injuries can provide valuable info when assessing for
diabetic neuropathy
o EMG testing can provide info on subclinical neuropathy
- Management and prevention of neuropathy involves good glycemic control
- Neuropathic may be managed with tricyclic antidepressant, antidepressants, anticonvulsants like
Gabapentin and opioid analgesia
- Autonomic neuropathies are managed by first ruling out any specific CV, GI or GU pathology
through assessment by a specialist and then treated primarily by expert opinion of the specialists
- Of note, specific to nursing there is a section in the CDA guidelines on foot care which may be
relevant to clinical and is a key intervention for individuals with diabetic neuropathy
- Diabetic nephropathy generally occurs due to lesions of the glomeruli in the kidney
- Glomerular changes include:
o Capillary membrane thickening
o Diffuse glomerular sclerosis
o Nodular glomerulosclerosis is also called Kimmelstiel-Wilson syndrome and is specific to
people with diabetes
- Chronic kidney disease is usually a clinical diagnosis that relies on signs/symptoms and lab findings
that assess kidney function
o If there is any doubt about the diagnosis a kidney biopsy may be performed
- It seems that genetics plays a role in which individuals with diabetes develop kidney disease
- Risk factors for development for this diabetic complication include genetic and familial
predisposition, hypertension, poor glycemic control, smoking, hyperlipidemia and microalbuminuria
- Microalbuminuria or albumin in the urine is one of the 1st clinical manifestations of kidney
dysfunction
o Once microalbuminuria is detected urine should be sent for albumin/creatinine ration (A/Cr)
- Some of the chronic kidney disease signs & symptoms include fluid and electrolyte imbalances,
hypoproteinemia, edema due to decreased plasma oncotic pressure, fluid overload and
hypertension
- Prevention and management include good glycemic control, maintaining normal BP, prevention or
reduction in proteinuria using pharmacologic agents like ACE inhibitor or angiotensin receptor
blockers or through restricting protein in diet, treatment of hyperlipidemia and smoking cessation
Macrovascular Disease
- CAD
o Most common cause of death in people with T2DM , common in T1DM as well
o Risk higher in diabetes than general public even when HTN & hyperlipidemia taken into
account
- PVD
o Atherosclerotic process + neuropathy gangrene & amputation
o Peripheral vascular disease in compounded by microvascular disease of neuropathy
o Often the atherosclerotic process in the peripheral vessels along with neuropathy can lead to
gangrene & amputation
Remember 70% of non-traumatic limb amps are due to diabetes
- Cerebrovascular disease
o Cerebrovascular disease or stroke is twice as common in people with diabetes
o Ischemic stroke is more common than hemorrhagic stroke
Patient Teaching
- How to avoid diabetes complications?
- Maintain normoglycemia (Hgb A1C <7%) through a healthy lifestyle/diet and meds when needed
- Decrease other risk factors for diabetic complications (i.e. obesity, hyperlipidemia, HTN)
- Identify and treat complications
Conclusion
- Achieving glycemic control is paramount to preventing/delaying onset of diabetic complications
- Pathophysiology is multi-factorial, hyperglycemia underlies/triggers all complications
- Complications are a/w significant morbidity & mortality in both Type 1 and 2 diabetes