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.

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

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 followup 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/fi
g_tab/nrm2327_F1.html
4. http://ocw.tufts.edu/Content/14/lecturenot
es/266734