Complications of Diabetes:
An Overview of the
Pathophysiology
Megha Poddar
PGY - 4 Endocrinology
10/2013
OBJECTIVES
1. To understand the pathophysiology of acute complications of DM
due to:
• Diabetic Ketoacidosis
• Hyperosmolar state
2. To understand the pathophysiology of chronic complications of DM
due to hyperglycemia (micro vascular and macro
vascular complications)
3. To gain an understanding of the mechanisms that lead
to glucose induced vascular damage.
Diabetes
• Group of metabolic disorders that share a common
feature of HYPERGLYCEMIA
• Type 1 DM: absolute deficiency of insulin cause by beta
cell destruction
• Type 2 DM: combination of peripheral resistance to
insulin action and inadequate secretory response
• Results from defects in Insulin secretion, action or
most commonly both
• Leading cause of end stage renal disease, adult onset
blindness and non traumatic lower extremity
amputation
Pathogenesis of Type 1 DM
• Lack of insulin is caused by an immunologically
mediated destruction of the beta cells
• Genetic susceptibility: multiple loci are associated,
most commonly MHC class II
• The autoimmune insult is chronic by the time the
patients first presents, 80-90% b cell destruction has
already occurred
Development of
Type 1 Diabetes
Pathogenesis of Type 2 DM
• Environmental factors play a large role (lifestyle,
dietary habits etc.)
• Twin-twin concordance shows a stronger genetic
relationship than DM2
• 2 Metabolic defects
• Decreased ability of peripheral tissues to respond to
insulin
• b-cell dysfunction that is manifested as impaired insulin
secretion
Development of
Type 2 Diabetes
Complications of Diabetes
Though the pathogenesis of DM differs, the complications
are the same and are the main cause of mortality and
morbidity
Acute complications due to hyperglycemia
• Diabetic ketoacidosis
• HHS
Chronic complications due to vascular damage
• Microvascular complications:
• Neuropathy, Nephropathy, Retinopathy
• Macrovascular complications:
• Coronary artery disease, peripheral vascular disease, stroke
Diabetic Ketoacidosis
• MEDICAL EMERGENCY!!!
• Due to lack of insulin
• Most often seen in Type 1 DM but also can be present in
Type 2 DM who have predominantly secretory defects
• Common in younger patients (<65), Women>Men
• Mortality 5%
• Most often due to the underlying illness and not the
metabolic complications
Hyperosmolar Hyperglycemic
State
• Less common than DKA
• Seen in Type 2 DM
• Age group is often older (>65 years)
• Mortality 5-20%!
• Often present with altered level of consciousness due
to hyperosmolar state (when sOsm > 300mosm/kg)
HHS
• Hyperglycemia, hyper osmolality and dehydration
without ketosis
• Most frequent precipitants:
• Acute Stressors (5 I’s)
• Renal Failure
• Hyperglycemic inducing medications
Precipitating Factors
• Acute stressors or illness increase the secretion of
glucagon, cortisol and epinephrine precipitating
hyperglycemia
• 5 I’s:
•
•
•
•
•
Infection
Infarction
Insulin (compliance/omission)
Ischemia
Intoxication (alcohol, drug abuse)
Regulatory Hormones
• 2 main hormones responsible to hyperglycemia and
ketoacidosis
• Insulin - deficiency or resistance
• Glucagon - excess
Normal Response
• Glucose is ingested during a meal, stimulates the
release of Insulin from b-cells of the pancreas
• Insulin action is to restore normoglycemia:
•
•
•
•
Decreasing hepatic glucose production
Inhibiting glycogenolysis and gluconeogensis
Increases the skeletal muscle and adipose tissue uptake
Inhibits glucagon secretion and production
Hyperglycemia
• Overall net reduction in effective circulation insulin
with a net increase in counter regulatory hormones
(epinephrine, cortisol, glucagon)
• Hyperglycemia is due to:
• Impaired peripheral utilization in tissue (post prandial)
• Increased gluconeogenesis (fasting state)
• Insulin deficiency is more prominent in DKA over
HHS
• HHS ketoacidosis is not seen
• Glucose levels are much higher in HHS than in DKA
Ketoacidosis
• Insulin deficiency results in loss of uptake of glucose by
peripheral glucose transporters  Hyperglycemia
• Insulin deficiency activates hormone dependent lipase 
Increased lipolysis (unregulated)
• This leads to conversion of triglycerides to free fatty acids
and glycerol
Fatty acids are converted to acetyl CoA which is shuttled into
1) Krebs cycle (insulin dependent)
2) Ketones bodies (without insulin) including BHB and
acetoacetate.
Ketoacidosis
• Inadequate insulin
leads to energy
stores from fat and
muscle to be broken
down into fatty
acids and amino
acids
• These precursors are
transported to the
liver for conversion
to glucose and
ketones
Diagnostic criteria for diabetic ketoacidosis (DKA)
and hyperosmolar hyperglycemic state (HHS)
Pathophysiology of Chronic
Complications
Macrovascular Complications
• Main cause of mortality
• large and medium vessel disease due to accelerated
atherosclerosis
Microvascular Complications
• Significant source disability and decrease in quality of
life
• Capillary dysfunction in target organs
Macrovascular Complications
• Coronary Artery Disease
• 2-4 times increased risk compared to general population
• Greater incidence of “Silent MI”
• Likely due to sensory neuropathy
• May present as CHF
• Peripheral Vascular Disease
• Cerebrovascular disease
Microvascular Complications
• Retinopathy
• Neuropathy
• Nephropathy
Retinopathy
• Diabetes is the most common cause of blindness in the US
• Retinopathy has the highest correlation with severity and
duration of diabetes
• Hyperglycemia is the primary cause of diabetic retinopathy
but the specific pathophysiologic mechanisms are not well
understood.
• thought to be death of microvascular contractile cells
(pericytes) and the loss of intracellular contacts which leads to
microaneurysms and leakage.
• Growth factors have been implicated in the development of the
next phase - proliferative retinopathy.
• Vascular Endothelium Growth Factor (VGEF)
Classification of Diabetic
Retinopathy
• Pre proliferative
•
•
•
•
•
•
increased vascular permeability
venous dilation
Microaneurysms
intraretinal hemorrhage
Fluid leakage
Retinal ischemia.
• Proliferative
• Neovascularization
• Vitreous hemorrhage
• Fibrous proliferation (scarring).
Nephropathy
• Both the DCCT and the UKPDS showed that near
euglycemia can decrease the development of
microalbuminuria and progression of diabetic
nephropathy.
• However, tight glycemic control has no effect in
reducing proteinuria or improving GFR if clinical
nephropathy is present.
• Early recognition of nephropathy is crucial
Neuropathy
• Diabetic neuropathy can present as mononeuropathy or
polyneuropathy and can also be divided in sensory, motor
and autonomic.
• The pathogenesis is not well elucidated, but it is believed
that the mononeuropathies, such as the acute cranial
nerve palsies and diabetic amyotrophy, are due to
ischemic infarction of the peripheral nerves.
•
The peripheral sensori-motor neuropathies and
autonomic neuropathies may be caused by a metabolic
factor or osmotic toxicity secondary to hyperglycemia.
Hyperglycemia Induced
Complications
• Many proposed mechanisms of vascular damage
from hyperglycemia
•
•
•
•
Aldose reductase pathway
Reactive Oxygen Species
Advanced Glycation Endproducts theory
Protein Kinase Theory
Aldose reductase pathway
• Certain cells are unable to regulate glucose uptake in
hyperglycemic states (ex. Endothelial cells)
• In a hyperglycemic state glucose is metabolized
intracellularly by an enzyme aldose reductase into
sorbitol and eventually into fructose
• Intracellular NADPH is used as a cofactor in the
pathway but is also used to regenerate glutathione
• Glutathione is an antioxidant which prevent which
decreases cellular susceptibility to oxidative stress
Aldose Reductase Pathway
Reactive Oxygen Species
• The depletion of NADPH by aldose reductase leads
to inability to regenerate GSH leading to oxidative
stress reactions and cell death
• Increased Sorbitol causes a decrease in nitric oxide –
vasoconstriction in neuronal tissue and eventually
ischemia
Advanced Glycation End
products theory
• AGE’s are formed from nonenzymatic reactions between
high levels of intracellular glucose, defects in the glucose
metabolism pathway due to reactive oxygen species and
build up of precursors
• AGE’s effect extracellular matrix (collagen, laminin) –
causes cross link between polypeptides and abnormal
matrix and interrupts normal cell interactions
• Ex: cross linking type 1 collagen in large vessels may lead to
increase endothelial injury and atherosclerotic plaque build
up
• Ex: Cross linking type IV collagen in basement membrane
decreases endothelial adhesion and increases fluid filtration
AGE effects on Protein
• AGE’s cross link proteins – causing them to be
resistant to degradation
• Increases protein deposition
• Plasma proteins may bind to glycated basement
membrane – may cause increased basement membrane
thickness seen in nephropathy
• proteins bind to AGE receptors and activate nuclear
transcription of NF-Kb, cytokines, inflammatory
markers
Advanced glycation products in
vascular pathology.
Advanced glycation products
in nephropathy
Advanced glycation products are
metabolized to small peptides
Goh S , Cooper M E JCEM 2008;93:1143-1152
©2008 by Endocrine Society
Biological effects of Activating
AGE receptors
• Release cytokines and growth factors from
macrophages (VEGF, IGF-1)
• Increases endothelial permeability
• Increases procoagulant activity
• Enhances proliferation of synthesis of extracellular
matrix by fibroblasts and smooth muscle cells
Protein Kinase Theory
• Activating PKC and DAG pathway by calcium ion is
an important signalling pathway for many
intracellular systems
• Hyperglycemia stimulates the DeNovo synthesis of
DAG and causes unregulated activation of PKC
Effects of PKC activation
• Production of VEGF – proangiogenic, implicated in
neovascularization in retinopathy
• Increased vasoconstrictor endothelin-1 and decreased
vasodilator NOsynthetase
• Production of profibrogenic molecules- leading to
deposition of extracellular matrix
• Procoagulant molecule plasminogen activator inhibitor -1
– leading to fibrinolysis and possible vaso-occlusive
episodes
• Production of pro-inflammatory cytokines
Pathways of micro vascular complications initiated by
hyperglycemia. AGEs, advanced glycation end
products; DAG, diacylglycerol; PKC, protein kinase C.
Hyperglycemia-induced production of superoxide by the
mitochondrial electron transport chain.
Hyperglycemic damage by inhibiting NAPDH.
From Brownlee M: Biochemistry and molecular cell biology of diabetic complications. Nature
414:813–820, 2001.
Effects of glycemic control on
microvascular complications
• The importance of tight glycemic control for protection against
micro vascular disease in diabetes was established in the
DCCT/EDIC study for type 1 diabetes
• Reduction (42% in any cardiovascular event), decrease in LDL
• Coronary calcification and carotid intimal thickness (measures of
atherosclerosis were reduced in the IT group)
• Nephropathy/albuminuria was related to higher rates of cardiovascular event
• The role of glycemic control on micro vascular disease in type 2
diabetes was documented in the United Kingdom Prospective
Diabetes Study (UKPDS), its role in reducing cardiovascular risk has
not been established as clearly for type 2 diabetes.
Pathogenesis Diabetic macrovascular
disease?
• In contrast to diabetic microvascular disease, data from the
UKPDS have shown that hyperglycemia is not the major
determinant of diabetic macrovascular disease.
• Consequence of insulin resistance is increased free fatty acid
(FFA) flux from adipocytes leading to plaque deposition in
arterial endothelial cells.
• In macrovascular, but not in microvascular endothelial cells,
this increased flux results in increased FFA oxidation by the
mitochondria.
? Similar Mechanism
• Oxidation of fatty acids and FFA-derived acetyl CoA
generate the same electron donors (NADH and FADH2)
• Hypothesized that the increased FFA oxidation causes
mitochondrial overproduction of ROS by the same
mechanism described for hyperglycemia.
• In addition to hyperglycemia FFA-induced increase in
ROS activates the same damaging pathways: AGEs, PKC,
Aldose pathway
Insulin resistance causes mitochondrial
overproduction of ROS in macrovascular endothelial
cells by increasing FFA flux and oxidation.
Glycemic control and vascular
complications in DM
• Hyperglycemia is an important risk factor for the development
of micro vascular disease in patients with type 2 diabetes, as it
is in patients with type 1 diabetes
• Many trials have shown microvascular benefit with intensive
glycemic control
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•
•
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DCCT/EDIC
UKPDS
Advance/Accord
VADT
ADVANCE
• 5571 type 2 diabetes patients receiving intensive
therapy to lower A1C (mean A1C 6.5 percent)
• Reduction in the incidence of nephropathy and the need
for renal-replacement therapy or death due to renal
disease compared with patients receiving standard
therapy (A1C 7.3 percent)
• There was no significant effect of glycemic control on the
incidence of retinopathy.
ACCORD trial
• 10,250 patients with long-standing type 2 diabetes were
assigned to intensive or standard glycemic control. (follow-up
of 3.7 years)
• Intensive therapy was stopped due to a higher number of
total and cardiovascular deaths in subjects assigned to
intensive therapy (median A1C 6.4%) compared with the
standard treatment group (median A1C 7.5%).
Veteran's Affairs Diabetes Trial
(VADT)
•
892 veterans with long-standing type 2 diabetes receiving
intensive therapy (A1C 6.9 percent)
• Did not have a reduction in retinopathy or major
nephropathy outcomes, which were predefined secondary
endpoints, compared with 899 veterans receiving standard
therapy (A1C 8.4 percent)
• Perhaps due to patients with longer history of diabetes (>10
yrs versus newly diagnosed in UKPDS)
• Aggressive treatment of hypertension and hyperlipidemia in
all VADT participants may have contributed to the inability to
show a microvascular benefit of intensive glucose control
Micro vascular summary:
• The results of the UKPDS, ADVANCE and ACCORD
trials are consistent with those of the DCCT for patients
with type 1 diabetes, taking into account the relative
differences in A1C achieved between treatment groups
and the differences in study duration (or exposure):
intensive therapy improves the outcome of micro
vascular disease.
• The results of the post-trial monitoring phase of the
UKPDS show that a sustained period of glycemic control
in newly diagnosed patients with type 2 diabetes has
lasting benefit in reducing micro vascular disease.
• Despite these differences, all three trials consistently show
that over the time period studied (3.5 to 6 years), near-normal
glycemic control (A1C 6.4 to 6.9 percent) does not reduce
cardiovascular events in patients with longstanding diabetes.
•
However, in patients with newly diagnosed type 2 diabetes, a
goal A1C of ≤7.0 percent is reasonable and supported by the
findings of the UKPDS follow-up study.
Macrovascular summary:
• Epidemiological studies suggest correlation between
DM and cardiovascular events
• RCTs have not been able to prove this association,
ACCORD showed increased risk in intensive group
• May be due to variety of factors with study design (A1C
targets, intensive regimen, number of hypoglycemic
events)
Reducing risk factors has been shown to decrease
cardiovascular events
•
•
•
•
Aggressive hypertension management
Achieving dyslipidemia targets
Smoking cessation
Secondary Risk Factor reduction
Thank You!
References
1. Uptodate
2. Robbins and Cotran Pathologic Bases of Disease –
Kumar,Abbas,Fausto
3. http://www.nature.com/nrm/journal/v9/n3/fig_t
ab/nrm2327_F1.html
4. http://ocw.tufts.edu/Content/14/lecturenotes/266
734