DSB 202: General and Systemic Pathology (Endocrine disorders)

Obesity, Metabolic Syndrome, Diabetes Mellitus

1GKM/MLS3202/LECT 02/2014

Lecturer: Dr. G. Kattam Maiyoh

Obesity: definition

• Chronic disease characterized by accumulation of fat. Obesity is defined as a condition when ideal body weight is exceeded by 20%

• Medical condition responsible for serious co-morbidity and mortality.

Psychosocial consequence• Economical impact of obesity• Prejudice and Discrimination (pay double fare

in matatus)• Considered lazy, incompetent and more often

absent due to illness• Confronted with more problems at job

application : – Very few executive managers with overweight in the

US

Epidemiology

0

102030

4050

19601970

19801990

20002010

20202030

USAEngland

MauritiusAustralia

BrazilPopulation percentage with BMI > 30kg/m2

Obesity rates:

current and projected

What causes Obesity?

• Genetic predisposition

• Disruption in energy balance

• Environmental and social factors

• An individual may have a genetic predisposition to become obese, but will only become obese given the right environmental influences.

• It has been suggested that up to 50% of the variability in body weight is governed by genetic factors.

• Some 360 genes have now been identified and related to the development of obesity although some of them may have a very small role.

Interplay between Genes and Environment

Reduced physical activity as computer/ communication technology advances penetrate the masses.

Leisure activity

Increased participation in computer games

Increased use of computer as a communication device for recreational purposes (chat rooms, etc.)

Increased use of home-based video - including video access on the internetContinued watching of television - cable, satellite

New Remote Control Can Be Operated by Remote

No more leaning forward to

get remote from coffee table

means greater convenience

for TV viewers.Television watching became

even more convenient

with Sony’s introduction

of a new remote-controlled

remote control.

““EAT TO LIVE”EAT TO LIVE”Intake = ExpenditureIntake = Expenditure

Weight StableWeight Stable

““LIVE TO EAT”LIVE TO EAT”Intake > ExpenditureIntake > Expenditure

ObeseObese

Disruption in energy balance

Ageing and Energy Expenditure

James, Ralph and Ferro-Luzzi, 1989

Kca

ls/d

Intenseexercise OccupationalDiscretionary

Sitting, coffee,smoking

Basal metabolicrate

Dietary induced thermogenesis

70 kg, Aged 25 years 70 kg, Aged 70 years

4000

2000

0

3000

1000

Fat as the Macronutrient Culprit

Adapted from WHO Consultation 1998Adapted from WHO Consultation 1998

ProteinProtein CarbohydraCarbohydratete FatFat

Energy content per gEnergy content per g

Ability to end eatingAbility to end eating

Ability to suppress Ability to suppress hungerhunger

Storage capacityStorage capacityPathway to transfer Pathway to transfer

excessexcess to alternative to alternative compartmentcompartment

Ability to stimulate own Ability to stimulate own oxidationoxidation

44

HighHigh

HighHigh

LowLow

YesYes

ExcellentExcellent

44

ModerateModerate

HighHigh

LowLow

YesYes

ExcellentExcellent

99

LowLow

LowLow

HighHigh

NoNo

PoorPoor

Consequences of obesity

Cardiovascular risk factors

Respiratory diseaseHeart disease

Gallbladder disease

Hormonal abnormalities

Hyperuricaemiaand gout

Stroke

Diabetes

OsteoarthritisCancer

……because of fat infiltrationbecause of fat infiltrationin eyelids...in eyelids...

Blindness in a child...

The Metabolic Syndrome (MS)•Is a multiplex risk factor for cardiovascular disease and type 2 diabetes’• Reflects the clustering of individual risk factors due to abdominal obesity and insulin resistance. •This multiplex comprises the following interrelated metabolic risk conditions:

Atherogenic dyslipidemia, glucose intolerance, elevated blood pressure, proinflammatory state, and prothrombotic state.

•Atherogenic dyslipidemia is itself an aggregate term comprised of elevated fasting and nonfasting triglycerides, elevated VLDL, reduced HDL, and an atherogenic small dense LDL phenotype

• Over-represented among populations with CVD

• Often occurs in individuals with a distinctive body-type including an increased abdominal circumference

The Metabolic Syndrome (MS)

Android obesity

or

• APPLE TYPE Central or abdominal adiposity (ANDROID) increased WHR & associated with higher morbidity risk.

> ♂ ♀

Gynoid obesity

or

• PEAR TYPE : GYNOID or typical female distribution of fat : less health risks

Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults. JAMA 2001;285:2486-2497

Risk Factor Defining Level

Waist circumference (abdominal

obesity)

>40 in (>102 cm) in men

>35 in (>88 cm) in women

Triglyceride level >150 mg/dl

HDL-C level <40 mg/dl in men

<50 mg/dl in women

Blood pressure >130/>85 mmHg

Fasting glucose >100 mg/dl

Definition of the Metabolic Syndrome

Defined by the presence of >3 risk factors

HDL-C=High-density lipoprotein cholesterol

Metabolic Syndrome: CHD Prevalence and assoc. with Diabetes• The metabolic syndrome is associated

with an increased prevalence of coronary heart disease.

• Among individuals with the metabolic syndrome and diabetes, there is an even greater prevalence of coronary heart disease.

CHD

Pre

vale

nce

No MS/No DM

54%

MS/No DM

29%

DM/No MS

2%

DM/MS

15%

8.7%

13.9%

7.5%

19.2%

0%

5%

10%

15%

20%

25%

Metabolic Syndrome: CHD Prevalence*

National Health and Nutrition Examination Survey (NHANES)

% of Population =

Alexander CM et al. Diabetes 2003;52:1210-1214

*Among individual >50 years

CHD=Coronary heart disease, DM=Diabetes mellitus, MS=Metabolic syndrome

0

1

2

3

4CVD*

CHD†

0 1 2 3 4 5

Mor

talit

y ha

zard

ratio

Number of Metabolic Syndrome Criteria

*Adjusted for age, sex, race or ethnicity, education, smoking status, non–HDL-C level, recreational and non-recreational activity, white blood cell count, alcohol use, prevalent heart disease, and stroke †Similar adjustments except for prevalent stroke

Ford ES et al. Atherosclerosis 2004;173:309-314

Metabolic Syndrome: Risk of Death

CHD=Coronary heart disease, CVD=Cardiovascular disease

Risk is Proportional to the Number of ATP III Criteria

Tuomilehto J et al. NEJM 2001;344:1343-1350

0

0.05

0.1

0.15

0.2

0.25

InterventionControl

11%

23%

% with Diabetes Mellitus

Metabolic Syndrome: Risk of Developing DMMetabolic Syndrome: Risk of Developing DM

Finnish Diabetes Prevention Study

†Defined as a glucose >140 mg/dl 2 hours after an oral glucose challenge

522 overweight (mean BMI=31 kg/m2) patients with impaired fasting glucose† randomized to intervention‡ or usual care for 3 years

Lifestyle modification reduces the risk of developing DM

‡Aimed at reducing weight (>5%), total intake of fat (<30% total calories) and saturated fat (<10% total calories); increasing uptake of fiber (>15 g/1000 cal); and physical activity (moderate at least 30 min/day)

Metabolic Syndrome: Risk of Developing DM

Diabetes Prevention Program (DPP)

Knowler WC et al. NEJM 2002;346:393-403

0 1 2 3 4

0

10

20

30

40Placebo (n=1082)Metformin (n=1073, p<0.001 vs. Plac)Lifestyle (n=1079, p<0.001 vs. Met , p<0.001 vs. Plac )

Percent developing diabetes

All participants

All participants

Years from randomization

Cum

ula

tive in

cidence

(%

)

*Includes 7% weight loss and at least 150 minutes of physical activity per week

PlaceboMetforminLifestyle modification

Inci

denc

e of

DM

(%)

0

20

30

10

40

00 1 42 3Years

3,234 patients with elevated fasting and post-load glucose levels randomized to placebo, metformin (850 mg bid), or lifestyle modification* for 3 years

Lifestyle modification reduces the risk of developing DM

Diabetes Mellitus

Type 1 diabetes

Most frequently affects children and adolescents. Symptoms include excessive thirst, excessive urination,

weight loss and lack of energy. Daily insulin injections required for survival.

Type 2 diabetes

Occurs mainly in adults. Usually people have no early symptoms. People may require oral hypoglycaemic drugs and may also

need insulin injections at later stages.

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WORLD MAP

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People at high risk of diabetesFactors associated with increased risk for diabetes include:

Increasing age Metabolic syndrome Impaired glucose tolerance Polycystic ovary syndrome Ethnicity History of gestational diabetes

having a baby over 4 kg Family history of diabetes

Physical inactivity Increased BMI Central obesity Hypertension Adverse lipid profile Elevated LFTs Patients taking some drugs e.g.

prednisone or anti-psychotic drugs (haloperidol, chlorpromazine, and newer atypical anti-psychotics).

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Most important risk

factor !

61% of new cases DM result of

overweight

NEJM 2001, 345:790-797

People at high risk of diabetesRisk Factor

Defining Level

Waist circumference*

Men ≥ 100 cmWomen ≥ 90 cm

Triglycerides ≥ 1.7 mmol/L

HDL cholesterol

Men < 1.0 mmol/LWomen < 1.3 mmol/L

Blood pressure

SBP ≥ 130 or DBP ≥ 85

Fasting glucose

≥ 6.1 mmol/L

Three or more of the following risk factors listed below are required for a diagnosis of metabolic syndrome.

People with the metabolic syndrome are at increased risk of diabetes, cardiovascular disease, sub-fertility and gout despite only moderate elevation in individual risk factors.

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IGT and IFG are intermediate stagesBoth impaired glucose tolerance (IGT) and impaired fasting glucose (IFG) refer to metabolic stages intermediate between normal glucose homeostasis and diabetes, in which there is an increased risk of progressing to diabetes.

33GKM/MLS3202/LECT 02/2014

Prevention – by early testing Age to commence testing

Population group Men WomenAsymptomatic people without other known risk factors

45 years

55 years

People with other known cardiovascular risk factors or at high risk of developing diabetes

35 years

45 years

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How to test

Testing for diabetes

• Fasting morning blood glucose is the best initial test.

• Urine glucose and HbA1C should not be used for diagnosis.

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People with symptomatic hyperglycaemia

•Symptomatic hyperglycaemia may have an acute onset, usually in younger people with type 1 diabetes, or a more insidious onset, usually in older people with type 2 diabetes.

•The usual symptoms of hyperglycaemia are thirst, polyuria and weight loss but hyperglycaemia can also cause fatigue, lack of energy, blurring of vision or recurrent infections, such as candida. For people with symptomatic hyperglycaemia, a single fasting glucose of ≥ 7.0 mmol/L ORa random glucose of ≥ 11.1 mmol/L is diagnostic of diabetes.

36GKM/MLS3202/LECT 02/2014

Action following fasting plasma glucoseCriteria for the diagnosis of diabetes, IGT and IFG.

Normal

Diabetes

Fasting glucose result (mmol/L )

< 5.5 5.5 - 6.0 6.1 - 6.9 ≥ 7.0

Interpretation

Normal result

Borderline result

IFG Diabetic

Action

Retest in 3-5 years orfor those at risk.

OGTT for those at increased risk of diabetes.Re-test annually those with IFG or IGT.

Assess with OGTT.Re-test annually

Two results > 7 on two different days are diagnostic of diabetes. OGTT is not required.

37

OGTT and its Interpretation•A 75 gram of glucose administered orally (oral glucose tolerance test - OGTT) •Is used to follow up people with equivocal results who may have diabetes, IFG or IGT.

Fastingmmol/L

2 hours post load mmol/L

Normal < 5.5 and < 7.8

IFG 6.1 – 6.9 and < 7.8

IGT < 7.0 and 7.8 – 11.0

Diabetes mellitus

≥ 7.0 and/or ≥ 11.1

GDM ≥ 5.5 and/or ≥ 9.0

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• Patient 1 = Normal

• Patient 2 = IGT

• Patient 3 = Diabetic

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Gestational diabetes mellitusGestational diabetes mellitus (GDM) increases the risk of many foetal and maternal complications in pregnancy and the development of type 2 diabetes later in life (Kjos, 1999). Screening is recommended for all women between 24 - 28 weeks gestation.

Screening for GDM using 50 gram load (1 hr OGGT)

If the one hour blood glucose is ≥ 7.8 mmol/L, a two hour OGTT is performed.

OGTT for diagnosis of GDM

A fasting glucose ≥ 5.5 and/or a 2 hour value

≥ 9.0 mmol/L is diagnostic of GDM.

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GDM

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Types of gestational diabetes Type A1 – Reveals altered finding during oral glucose tolerance test (OGTT), but

with normal blood glucose levels with fasting and after two hours with meals.

– With this stage of gestational diabetes, diet modification is enough to manage the increased glucose levels.

• Type A2 – Reveals altered finding during oral glucose tolerance test (OGTT), it also

has elevated glucose levels even during fasting and/ or during after meals.

– Apart from modification of lifestyle and diet, adjunct therapy with insulin and other diabetes medications are indicated and necessary.

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Hyperglycemia causes glycosylation

– glucose attaches to proteins– indicators are

• Haemoglobin A1c (Hgb A1C)–average of blood glucose over the past 2-3

months• fructosamine

–average of blood glucose over the past 2-3 weeks

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HbA1C and Target levels Any sustained reduction of HbA1C is worthwhile because there

appears to be a direct relationship between cardiovascular risk and HbA1C.

The goal is to achieve an HbA1C as low as possible, preferably less than 7.0%, without causing unacceptable hypoglycaemia.

HbA1C > 8 mmol/L is a sign of inadequate control for most people.HbA1C targets need to be indiviadualized, taking into

consideration factors such as the patient’s age .

Stable diabetes Test six monthly

Changes in treatmentTest no more than three monthly

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Self monitoring blood glucose (SMBG)People who take insulin should regularly self monitor blood glucose.

For people with non-insulin treated type 2 diabetes testing is most useful if patients use the results to learn and alter behaviour, or medication.

“...SMBG is most useful if patients use the results to learn, as part of an overall diabetes education package….”

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Laboratory tests to prevent and delay complications of diabetes

People with diabetes usually die from macrovascular complications of their diabetes; namely cardiovascular disease. This is influenced by all of the commonly recognised risk factors for cardiovascular disease as well as glycaemic control. Fasting lipid levels are measured three monthly until stable and then 6 - 12 monthly thereafter. It is important that management should be individualised

ParameterOptimal value

Total cholesterol

< 4 mmol/L

LDL cholesterol

< 2.5 mmol/L

HDL cholesterol

> 1 mmol/L

TC:HDL ratio

< 4.5

Triglycerides

< 1.7 mmol/L

HbA1C < 7 mmol/L

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Short-term Complications

47

Long-term Complications

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• Glycosylation damages blood vessels

• Mostly affects blood vessels & nerves– glycolated proteins in vessel wall makes it stiffer &

less elastic– in large vessels, accelerates atherosclerosis– in small vessels, slows blood flow & diffusion

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• Vascular disease

• impairs blood flow causing ischemia (restriction in blood supply to tissues) & infarction

• high incidence of – Myocardial infarction (MI)– stroke– lower limb gangrene

– microvascular disease• characterized by hyaline arteriolosclerosis (refers to

thickening of the walls of arterioles)• leads to diabetic nephropathy & diabetic retinopathy

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• Kidney disease

– diabetic nephrosclerosis– atherosclerosis of renal arteries

• Among the leading causes of renal failure

– infections of bladder & kidney

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• Eye disease

– Important cause of blindness associated with

• cataracts• glaucoma• diabetic

retinopathy

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• Conclusion –combination of different factors can prevent

Diabetes• BMI 25• Diet : high fibre intake; PUFA, Low SFA; trans fats and GI• Regular physiacl activity• Non Smoker• Moderate alcohol use

–incidence of diabetes approx. 90 % lower in this group

Thank you for listening