2013-10-23 Pathophysiology of Diabetes Complications Dr M. Poddar

8/11/2019 2013-10-23 Pathophysiology of Diabetes Complications Dr M. Poddar

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Complications of Diabetes:

An Overview of thePathophysiology

Megha Poddar

PGY - 4 Endocrinology

10/2013


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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 leadto glucose induced vascular damage.


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Diabetes

Group of metabolic disorders that share a commonfeature of HYPERGLYCEMIA

Type 1DM: absolute deficiency of insulin cause bybeta cell destruction

Type 2 DM: combination of peripheral resistance toinsulin action and inadequate secretory response

Results from defects in Insulin secretion, action ormost commonly both

Leading cause of end stage renal disease, adultonset blindness and non traumatic lower extremityamputation


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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 destructionhas already occurred


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Development of

Type 1 Diabetes


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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 toinsulin

b-cell dysfunction that is manifested as impaired

insulin secretion


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Development of

Type 2 Diabetes


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Complications of Diabetes

Though the pathogenesis of DM differs, thecomplications are the same and are the main cause ofmortality 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


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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 (Men

Mortality 5%

Most often due to the underlying illness and not the

metabolic complications


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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 consciousnessdue to hyperosmolar state (when sOsm >

300mosm/kg)


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HHS

Hyperglycemia, hyper osmolality and dehydration

without ketosis

Most frequent precipitants:

Acute Stressors (5 Is)

Renal Failure

Hyperglycemic inducing medications


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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)


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Regulatory Hormones

2 main hormones responsible to hyperglycemia

and ketoacidosis

Insulin - deficiency or resistance Glucagon - excess


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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


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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


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Ketoacidosis

Insulin deficiency results in loss of uptake of glucose byperipheral glucose transportersHyperglycemia

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 BHBand acetoacetate.


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Ketoacidosis

Inadequate insulinleads to energystores from fat andmuscle to be

broken down intofatty acids andamino acids

These precursors

are transported tothe liver forconversion toglucose andketones


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Diagnostic criteria for diabetic ketoacidosis (DKA)

and hyperosmolar hyperglycemic state (HHS)


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Pathophysiology of Chronic

Complications

Macrovascular Complications

Main cause of mortality

large and medium vessel disease due to acceleratedatherosclerosis

Microvascular Complications

Significant source disability and decrease in quality

of life

Capillary dysfunction in target organs


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Retinopathy

Diabetes is the most common cause of blindness in theUS

Retinopathy has the highest correlation with severity and

duration of diabetes Hyperglycemia is the primary cause of diabetic

retinopathy but the specific pathophysiologicmechanisms are not well understood.

thought to be death of microvascular contractile cells

(pericytes) and the loss of intracellular contacts which leadsto microaneurysms and leakage.

Growth factors have been implicated in the development ofthe next phase - proliferative retinopathy.

Vascular Endothelium Growth Factor (VGEF)


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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).


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Nephropathy

Both the DCCT and the UKPDS showed that near

euglycemia can decrease the development of

microalbuminuria and progression of diabeticnephropathy.

However, tight glycemic control has no effect in

reducing proteinuria or improving GFR if clinical

nephropathy is present.

Early recognition of nephropathy is crucial


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Hyperglycemia Induced

Complications

Many proposed mechanisms of vascular damage

from hyperglycemia

Aldose reductase pathway Reactive Oxygen Species

Advanced Glycation Endproducts theory

Protein Kinase Theory


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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


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Aldose Reductase

Pathway


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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

oxidevasoconstriction in neuronal tissue and

eventually ischemia


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Advanced Glycation End

products theory

AGEs are formed fromnonenzymatic reactionsbetween high levels of intracellular glucose, defects inthe glucose metabolism pathway due to reactiveoxygen species and build up of precursors

AGEs effect extracellular matrix (collagen, laminin) causes cross link between polypeptides and abnormalmatrix and interrupts normal cell interactions Ex: cross linking type 1 collagen in large vessels may lead

to increase endothelial injury and atherosclerotic plaquebuild up

Ex: Cross linking type IV collagen in basement membranedecreases endothelial adhesion and increases fluidfiltration


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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

membranemay cause increased basement

membrane thickness seen in nephropathy

proteins bind to AGE receptors and activate nuclear

transcription of NF-Kb, cytokines, inflammatory

markers


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Advanced glycation products in

vascular pathology.


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Advanced glycation

products in nephropathy

Ad anced gl cation prod cts


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Advanced glycation products

are metabolized to small

peptides


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Goh S , Cooper M E JCEM 2008;93:1143-1152

2008 by Endocrine Society


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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


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Effects of PKC activation

Production of VEGFproangiogenic, implicated inneovascularization in retinopathy

Increased vasoconstrictor endothelin-1 and decreasedvasodilator NOsynthetase

Production of profibrogenic molecules- leading todeposition of extracellular matrix

Procoagulant molecule plasminogen activator inhibitor

-1leading to fibrinolysis and possible vaso-occlusiveepisodes

Production of pro-inflammatory cytokines


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Pathways of micro vascular complications initiated by

hyperglycemia. AGEs, advanced glycation end

products; DAG, diacylglycerol; PKC, protein kinase C.


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Hyperglycemia-induced production of superoxide by the

mitochondrial electron transport chain.


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Hyperglycemic damage by inhibiting NAPDH.From Brownlee M: Biochemistry and molecular cell biology of diabetic complications. Nature

414:813820, 2001.


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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


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Pathogenesis Diabetic macrovascular

disease?

In contrast to diabetic microvascular disease, data from the

UKPDS have shown that hyperglycemia is notthe 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.


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? 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

I li i t it h d i l


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Insulin resistance causes mitochondrial

overproduction of ROS in macrovascular endothelial

cells by increasing FFA flux and oxidation.

Gl i l d


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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


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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.


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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 oftotal and cardiovascular deaths in subjects assigned to

intensive therapy (median A1C 6.4%) compared with the

standard treatment group (median A1C 7.5%).

V ' Aff i Di b T i l


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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 secondaryendpoints, 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


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Micro vascular summary:

The results of the UKPDS, ADVANCE and ACCORDtrials are consistent with those of the DCCT forpatients with type 1 diabetes, taking into account the

relative differences in A1C achieved betweentreatment groups and the differences in study duration(or exposure): intensive therapy improves the outcomeof micro vascular disease.

The results of the post-trial monitoring phase of the

UKPDS show that a sustained period of glycemiccontrol in newly diagnosed patients with type 2diabetes has lasting benefit in reducing micro vasculardisease.


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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 andsupported by the findings of the UKPDS follow-up study.


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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)


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Reducing risk factors has been shown to decrease

cardiovascular events

Aggressive hypertension management

Achieving dyslipidemia targets

Smoking cessation

Secondary Risk Factor reduction


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Thank You!


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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/266734
http://www.nature.com/nrm/journal/v9/n3/fig_tab/nrm2327_F1.htmlhttp://www.nature.com/nrm/journal/v9/n3/fig_tab/nrm2327_F1.htmlhttp://www.nature.com/nrm/journal/v9/n3/fig_tab/nrm2327_F1.htmlhttp://ocw.tufts.edu/Content/14/lecturenotes/266734http://ocw.tufts.edu/Content/14/lecturenotes/266734http://ocw.tufts.edu/Content/14/lecturenotes/266734http://ocw.tufts.edu/Content/14/lecturenotes/266734http://www.nature.com/nrm/journal/v9/n3/fig_tab/nrm2327_F1.htmlhttp://www.nature.com/nrm/journal/v9/n3/fig_tab/nrm2327_F1.htmlhttp://www.nature.com/nrm/journal/v9/n3/fig_tab/nrm2327_F1.html

2013-10-23 Pathophysiology of Diabetes Complications Dr M. Poddar

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