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 Is)
Renal Failure
Hyperglycemic inducing medications

Precipitating Factors
Acute stressors or illness increase the secretion of
glucagon, cortisol and epinephrine precipitating
hyperglycemia
5 Is:
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
AGEs 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
AGEs 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
AGEs 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
414:813820, 2001.

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.

Effects of glycemic control on
microvascular complications
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
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_tab/
nrm2327_F1.html
4. http://ocw.tufts.edu/Content/14/lecturenotes/2667
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