diabetes: causes and consequences carlos o. mendivil, md

Diabetes:Causes and consequences

Carlos O. Mendivil , MD

What is Diabetes?It is:

A syndrome

Heterogeneous

Characterized by high blood glucose

Not curable as of today

Potentially fatal (directly or indirectly)

What causesDiabetes Mellitus?

Multifactorial

Genetic factorsGenetic factors Environmental factorsEnvironmental factors

There is always a deficit of

INSULIN ACTIONThere is always a deficit of

INSULIN ACTION

Obesity prevalence

Diabetesincidence

Diabetesprevalence

0

9

0

25

Year´63 ´05

Trends in the prevalence and incidence ofdiabetes and obesity in the US

ADA Scientific Sessions, Chicago, 2007

What causesDiabetes Mellitus?

%

Why is there insuficient insulin action?

11

22Relative or absolute deficit of insulin secretionRelative or absolute deficit of insulin secretion

Secretory dysfunction in pancreatic beta cells

Insuficient tissue response to the actions of insulin, DESPITE NORMAL CONCENTRATIONS of insulin

Insuficient tissue response to the actions of insulin, DESPITE NORMAL CONCENTRATIONS of insulin

Insulin resistance

How does diabetes affect the body ?

Insuficient insulin action alters metabolism of:- Lipids- Carbohydrates- Proteins

Insuficient insulin action alters metabolism of:- Lipids- Carbohydrates- Proteins

ComplicationsComplications

Acute Chronic

Life-threatening - Severe- Disabling- Debilitating- Costly- Some of them may cause death

The chronic complications of diabetes

MacrovascularMacrovascular MicrovascularMicrovascular

CoronarydiseaseCoronarydisease

CerebrovasculardiseaseCerebrovasculardisease

PeripheralArterialdisease

PeripheralArterialdisease

NephropathyNephropathy

NeuropathyNeuropathy

RetinopathyRetinopathy

+ Orthopedic alterationsMetabolic alterations

Diabetic foot

Why are the complications of diabetes important?

DM is the #1 cause of renal failure worldwide

The kidney foundation: www.kidney.org

Contributes importantly to the risk of:

Myocardial infarction (heart attacks)

Cerebrovascular disease (strokes)

Worlwide #1 cause of:

Acquired blindness

Amputation not due to trauma


www.ambrosio-eye-care-boston.com

Diabetic retinopathy

Diabetic nephropathy

http://www.videolife.tk/video/ikGl7DPXUK0/Diabetic-Nephropathy.html

The progression of diabetic nephropathy

http://www.youtube.com/watch?v=ikGl7DPXUK0

Diabetic neuropathy

The “diabetic foot”

Diabetes and erectile dysfunction

NO DMNO prior MI

NO DMPrior MI

DMNO prior MI

DM+ prior MI

%

Haffner et al NEJM 1997

3,5

18,8 20

45


Diabetes and risk of myocardial infarction

Joslin fifty year medal

More than 2,500 granted so far

Because they can be avoided !!

Given to patients who live at least 50 years after the diagnosis of type 1 diabetes


123

Random plasma glucose

Fasting plasma glucose (FPG)

Oral glucose tolerance test (OGTT)

4 Glycated hemoglobin (A1c)

Fasting

A1c

100 mg/dL 126 mg/dL

6% 6.5%

Normal IFG DM

NormalPre-

diabetes DM

Postload

140 mg/dL 200 mg/dL

Normal IGT DM

What’s the difference ?

Diabetes Care 2003; suppl 1:S5

When two different tests classify a patient differently, he must be classified in the

most severe category

When two different tests classify a patient differently, he must be classified in the

most severe category

Which tests DO NOT diagnose diabetes ?

Capillary glucose

Fructosamine

C peptide

Insulinemia

Triglycerides

Classification ofClassification ofDiabetes MellitusDiabetes Mellitus

Classification of Diabetes Mellitus

Type1

Type 2

Gestational

Other types

Type 1 diabetes

Destruction of beta cells

Autoimmune process

Total or near total insulin deficiency

Insulin required for survival

More incident in infancy and puberty

High propensity to ketoacidosis

Predilection for female gender and caucasian ethnicity


Type1

Type 2

Gestational

Other types

Type 2

Relative secretory dysfunction of beta cells

Relative insulin deficit

Peripheral resistance to insulin actions

80% of patients are overweight

More incident in adulthood and older age

Less prone to ketoacidosis

Not as much gender/ethnicity imbalance


Type1

Type 2

Gestational

Other types

Any degree of carbohydrate intoleranceThat is discovered during pregnancy


Type1

Type 2

Gestational

Other types

What’s the origin of type 1 diabetes ?

The natural history of type 1 diabetes

% intact% intactbeta cellsbeta cells

100%

Geneticsusceptibility

Autoimmunity

IGT

IFGT1DM

Compl

Time

Environmental trigger

Loss of first peakof insulin secretion



100%

Time


RISK MARKERS

HLA Class IIHLA DRHLA DQ HLAHLA

Gene cluster in chromosome 6p

Class 1

A B C

Class 2

DP DQ alfa DRDQ beta

Genetic susceptibility to type 1 diabetes

IDDM 1-12markers

x

Proteins of the body

Thymus dendritic cell

HLA class II molecule

Pre-T lymphocyte

T-cell receptor

Recognizes very well

Does not recognize

“Half recognizes”

x

Lymphocyte selection during embryonic life

Hypotheses about HLA and type 1 diabetes

Some class II HLA’s present self-antigens better

Sme HLA class II activate helper lymphocytesbetter

Some HLA’s class II activate regulatory TLymphocytes better

Environmentaltrigger



100%

Time



Geneticsusceptibility% intact% intact

beta cellsbeta cells

100%

Time

Autoimmunity


How is the autoimmune process manifested?

IAAIAA

ICAICA

GADAGADA

IA-2IA-2

Insulin Antibodies

Islet Cell Antibodies

Glutamic Acid Decarboxylase Antibodies

Ab’s against IA-2 phosphatase


Geneticsusceptibility% intact% intact

B cellsB cells

100%

Autoimmunity

IGT

IFGT1 DM

Loss of first insulinSecretory peak

What determines the speed of progression ?


Determining factors in the progression of type 1 diabetes

SexSex

AgeAge

# of antibodies# of antibodies

Ketoacidosis atKetoacidosis atdiagnosisdiagnosis

MaleMale

Earlier age atEarlier age atdiagnosisdiagnosis

MoreMore

Faster progression

Faster progression

Faster progression

Faster progression

Compl



Autoimmunity

IGT

IFGT1 DM

Loss of first insulinSecretory peak


What is the originof type 2 diabetes ?

The Natural History of Insulin Secretory Dysfunction and Insulin Resistance in the Pathogenesis of type 2 Diabetes Mellitus

Journal of Clinical Investigation, Vol 104 #6 Sep 1999

Type 2 diabetes is characterized by 4 basic metabolic Disturbances:

Obesity

Insulin resistance

Insulin secretory dysfunction

Increase in hepatic glucose production (HGP)

Methods

1982 404 individuals from the Gila River community in Arizona

Clinical history, physical exam, routine labs

Measurement of:

Body composition

Fat distribution

Glucose tolerance

Insulin sensitivity

Hepatic glucose production

Yearly follow-ups for over a decade (11 yrs)

Bogardus et al, JCI 2000

Insulin response

Fasting

120 min post30 m post

ProgressorsNonprogressors

NGT IGT DM2NGT NGT NGT

200400600800

1000120014001600

18002000

pmol

/L

Insulin sensitivity in muscle

M (m

g/Kg

EBM

S/m

in)


NGT NGT DM2NTG NTG NTG

0,51

1,52

2,53

3,54

4,55

Beta cell function

Acut

e In

sulin

Res

pons

e (m

icro

UI/

ml)

Progressors

Nonprogressors

NTG IHC DM2NTG NGT NGT

50100150200250300350

400450500

Liver glucose production

EGO

(mg/

Kg E

BMS/

min

)


NTG IHC DM2NTG NGT NGT

0.51

1,52

2,53

3,54

4,55

Genetically “weak” beta cell

Unhealthy lifestyleUnhealthy lifestyle Free fatty acids

TNF-

Insulin resistance

Greater demands for cell

More secretion

Secretory dysfunction Loss of 1st insulinsecretion peak - IGTLoss of 1st insulin

secretion peak - IGT

Increased liver glucose production IFGIFG

DM2

Adiposity

What’s the origin of type 2 diabetes ?

Compl

Sedentary lifeCaloric

imbalance

GeneticSusept.% beta% beta

cell cell functionfunction

100%

Insulin resistance

IFGor

IGTDM2

Loss of 1st insulinSecretion peak

Excessadiposity

Threshold for insulin actions

Insulin effectsInsulin effects 100 UI/mL100 UI/mL

20 UI/mL20 UI/mL

- Muscle glucose uptake- K+ uptake by cells- Stimulation of protein synthesis- Effects on gene expression- Inhibition of lipolysis

Just inhibition of lipolysis

When does diabetes give you symptoms ?

708090100110120130140150160170180190200210220230

mg/dL

Total reabsorption of filtered glucose

Glucose escapesinto urine

SYMPTOMS

Origin of the symptoms of type 2 diabetes

Deficit of insulin action

Hiperglycemia

GlycosuriaPolyuria

Dehydration

Polydipsia

Nutrientloss

Polyphagia Weightloss

Severe

Lipolysis

-oxidation

Ketogenesis

Ketonemia

Acidosis Ketonuria

Some interesting observations on the environmental

determinants of type 2 diabetes

Hu et al. Arch Int Med 2010

Depressed mood and risk of diabetes

Urinary BPA in type 2 diabetics

Lang et al. JAMA 2008

How to prevent it ?

Tuomilehto NEJM 2001

Thank you

diabetes: causes and consequences carlos o. mendivil, md

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