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Definition
Obesity : An abnormal growth of adipose tissue due to an enlargement of fat cell size
(hypertrophic obesity) or increase in fat cell number (hyperplastic obesity) or a combination of both.
A Body mass index of 30 or more in males and 28.6 or more in female is obesity.
Overweight : A weight in excess of the average fora given sex, height and age.
Overweight is usually due to obesity but can arise from other causes as an abnormal muscle development or fluid retention. 10% increase of weight above normal is considered overweight and over 20% excess of weight above normal in considered to be obese.
Measurement of obesity
(a) Body weight - In epidemiological studies it is conventional to accept + 2 Standard
deviations from median weight for Height as a cut off point for obesity.
Other indicators :
(1) Body mass index (Quetetlet's index)
= Weight (inKR)
Height mts.
(2) Ponderal index
= Height (in cm) .
cube root of body weight (in Kg)
(3) Broca index
= Height (in cm) - 100
(4) Lorentz
Height (in cm)-100- Height (in cm) -150
2(female) or 4 (males)
(5) Corpulence index
= Actual weight
Desirable weight
Should not exceed 1.2
(b) Skin fold thickness - Measured with harpender skin calipers. 4 sites - mid triceps, biceps, subscapular and suprailiac regions. The sum should be less than 40 in bosy and 50 in girls.
Hazards of Obesity.
(1) The increased body fat, increased central fat deposits and increased weight gain are all associated with increased risk of death. Four large and many smaller epidemiologic studies have supported these findings. The studies include.
(a) Build and BP study of 1979.
(b) American Cancer Society Study.
(c) Norwegian population study.
(d) Nurses health trial.
(a) Obesity and heart disease : Data from nurses health trial, the risk of CAD in US
females increase 3.3 fold with Body Mass Index 29Kg/m2 when compared with females with Body Mass Index Kg/m2. Of more importance is the inverse relationship between HDL cholesterol and Body Mass Index. Low HDL increases risk of CAD. Obesity increases the cardiac work which were lead to cardiomyopathy and heart failure.
(b) Obesity and Respiratory System : The major effects are increased residual volume
associated with increased abdominal pressure on diaphragm. Sleep apnea is associated with obesity. THe hypothesis is that the increase neck circumference and fat deposits in pharyngeal area may lead to sleep apnea.
(c) Obesity and DM - Obesity is strongly associated with diabetes.
(d) Gall bladder disease - Obesity leads to Cholelithiasis. For example :
If there is lOKg increase in body fat, the cholesterol increases to the tune of as much
cholesterol in yolk of one egg. This goes in bile and leads to stone formation.
(e) Certain cancers are significantly increases in obesity
In Males Neopalasms of colon, rectum and prostate.
In Females Neoplasms of reproductive tract and gall bladder.
This may be due to increased production of estrogen by adipose tissue.
(f) Changes in Bones, joints, muscles, connective tissue and skin. Obesity leads to :-
Osteo arthritis
Acanthosis nigricans
Hirsutisrn may reflect altered reproduction status.
(g) Endocrinal - The most important are reproductive. Irregular menses and frequent
anovulatery cycles are seen.
(h) Psychosocial function - Obesity is a stigmatized condition. They are exposed to the
consequences or public disapprovar of their ratiress.
Leptin in pathogenesis of obesity and NIDDM
Leptin is a product of the ob'gene and is secreted by fat cells. It has its role in appetite
regulation, energy expenditure and possibly modulation of insulin sensitivity in animal models of obesity. The site of action seems to be hypothalamus. Leptin is closely related to body mass index and waist circumference and also to fasting and two hour insulin levels. Studies also suggest its role in NIDDM and insulin resistance. The hypothalamic mediated resistance to leptin causes a rise in leptin and initiates hyperinsulinemia and insulin resistance in obesity.
Increased insulin levels leads to increased body fat, dyslipidemia (due to lipogenesis and
selective insulin resistance in muscles). The increase adipose tissue produces more leptin but due to down regulation of leptin receptors in hypothalamus unregulated and continuous feedings occurs and vicious cycle of hyperinsulinemia, more fat and more leptin resistance is perpetuated. Other possible mechanism is that increased fat predominantly central accumulated due to insulin resistance may be responsible for increased leptin production. This leads to down regulations of leptin receptor and loss of appetite central and hence perpetuation of vicious cycle.
Fat People Have More Fat Cells Than Skinny People :
The obese subjects have on the average a 40% increase in cell size and an increase of
190% n cell number. Studies document that the number of adipocytes remain constant in an adult.
Thus caloric deprivation results in a decrease in cell size to normal, but the adipose
hypercellulari persists. In man, it is estimated that adipose cells are still increasing in number upto early adolescence. Thus since the cell numbers increase in infancy and adolescence. The obese patient has an excess number of adipocytes which are enlarged as well, it is the effect of early feeding experience and the interplay of such experience with genetic and early psychological events really where the answers to endemic obesity are to be found.
It was Jules Harsh who devised the method of determining both the number and size of
human adipocytes. Could restriction and reformulation of early feeding aid in the prevention of obesity in adult life? answers to such questions are still being sought.
Hormonal Changes in Obesity
Tissue
Adrenal |
Abnormalities associated with obesity Increase cortisol turn over Increase cortisol in central obesity
Increase cortisol response to stress in female with central obesity. |
| Thyroid |
Normal levels.
Possible association between T3 and
resting energy expenditure.
|
| Gonadal Men |
Decrease Sex Hormone Binding Globulin.
Increase aromatization of adrenal androgens
into estrogens
Decrease in free testasterone. |
| Women |
Pattern of hypogonadetrophic hypogonadism with severe disease.
Increase aromatization of adrenal androgens
into estrogens. |
| Prolactin |
Increase in free testasterone. |
| Growth Hormone-Insuline like growth factor |
Normal basal levels Decrease stimulated levels. |
| Endrocrine Pancreas Insulin |
Decrease Growth Hormone secretion Decrease in IGF Decrease in IGF
Increase fasting levels |
| Adipose tissue |
Peripheral tissues insulin resistance
Altered p cell pulsatility
Increase in Tumour Necrosis Factor |
DM & Obesity
A central body fat distribution with a high waist hip ratio and an android and apple shaped
habitues is associated with increase insulin resistance, NIDDM, hyperlipidemia and premature mortality.
A peripheral gynacoid or pear shaped distribution with low waist hip ratio is found in
individuals who exercise and does not carry these diseases associations.
The insulin resistance has been demonstrated in obese patients using hyperglycemic and
euglycemic insulin clamp technique. The insulin mediated glucose metabolism is decreased by 50% in obesity. Fatty acid metabolisms is enhanced in obesity and NIDDM and this may interfere with glucose utilization. Overweight is a super imposed factor which perhaps by demanding excessive insulin secretion to overcome insulin resistance contributes to Beta cell exhaustion and a final decline to NIDDM. This is supported by the demonstration that insulin secretion is impaired in all patients with NIDDM.
Adipose Tissue As an "Endocrine Organ".
I. Leptin - It is a 16-Kdalton protein produced exclusively in the adipocyte.
II. Tumor Necrosis factor alpha - Secreted by not only the classic inflammatory cells but
also by adipocyte. It has been postulated to be responsible for insulin resistance by
alteration in the phospharylation status of insulin receptors substrate one (IRS-1) and to
alter insulin receptor activity.
The relationship between body mass index and risk of diabetes was shown by the Health
Professionals study. It was found that when body mass index was less than 24Kg/m2. The risk was lowest. At a body mass index of 35Kg/m2. The relative risk increased 40 fold or
4000%.
Management of Diabetes with Obesity
(a) Effect of weight reduction on glucose tolerance -
Trial Body Index Mass
1. Health Professionals 24 kg/m2 35 mg/m2
Low risk of DM Risk increase
.40 fold or 4000%
2. Nurses Health Total 22 kg/m2 >35 kg/m2
Low risk of DM Risk increase by 5=60
fold or >6000%
Using the body mass index at age 15yrs, Colditz and Cowerkers showed that a 20kg
weight gain increased risk for diabetes by 15 fold where as a weight reduction of 20kg decreased risk to almost zero.
In the Swedish obesity study, Sizostrone and colleagues observed that diabetes was
present in 13% to 16% of their obese subjects. Of those who underwent gastric by pass and subsequently lost weight 69% of subjects with diabetes were cured and diabetes developed in only 0.5% of those who did not have diabetes baseline. In contrast in the obese control group who lost no weight there was a small (16%) cure rate and a 7.8% incidence of new cases of diabetes.
Thus we see that weight reduction decreases the incidence of diabetes.
(b) Role of Diet and Exercise
Diet - The standard weight reduction diet is of 1200 to 1500 . cal/day. This diet helps
patient to loose 1 to 2 pound/'wk. Under very careful medical supervision in hospitalized patient 200 cal.
Semistarvation diets can be used for 1 week followed either by diet containing 1200 cal or very low protein sparing diet 600 to 800 cal/day.
Very low calories (protein sparing) modified diet (600 to 800 cal/day) includes
(i) l.Sgm protein/kg or 75gms protein 50gms carbohydrates.
(ii) Potassium 30mEg/day.
(iii) Multivitamins and minerals.
(iv) Sodium Chloride 5gms.
(v) Calcium Carbonate 4 tab/day.
(vi) 1.5L fluids.
Patients on very low caloric diet should monitor urine for ketosis biweekly electrolyte
estimaton. Electrocardiography after every 3 months, particularly after lossing 50 Ibs. (22.5kg) to check cardiac irregularities.
Exercise : From their meta analysis Epstein and Wing reported that exercise training was
modestly effective at reducing body weight (0.09Kg/wk). Exercise induced weight loss was dependent on weekly exercise energy expenditure/ initial body mass and frequency of exercise.
Other studies
| Metd analysis |
Mode |
Frequency |
Duration |
Weight loss |
| Fpstein &r Wing |
Walk/ run |
2.5 times/wk |
6-20 vvks |
0.09 kg/wk |
| Bailor & Keesay |
Walk/run Cycle |
3-4 times/wk. |
Ave 6.8 wks |
0.1 kg/vvk |
Ctirrow & Suinmerbell
|
Walk /run Cycle
|
3-4 times/wk |
8-52 wks |
0.1 kg/wk |
Original investigations
| Hadjijolovaetal |
Sports |
daily |
45 days |
0.6 kg/wk |
| Lee at al |
Military Training |
5 days/wk |
5 mth |
1.8 kg/wk |
Recently it has been found that hiity exercise but not prolonged endurance type training
increase skeletal muscle beta hydroxyacyl CoA dehydrogenase activity, a key enzyme in beta oxidation pathway of fatty acid metabolism. This can promote the oxidation of fatty acids not only during exercise but during non exercising periods, thereby promoting further fat loss.
Use of Metformin
Metformin is a methylbigmanide. It belongs to the class of bignamides, Mech of action - Metformin therapy improves insulin sensitivity as shown by a reduction of fasting plasma glucose and insulin concentration. It is not effective in absence of insulin. In patients of NIDDM glucose lowering is attributed mainly to low hepatic glucose output and increased peripheral glucose uptake. Several other action may contribute such as increased intestinal use of glucose and decreased fatty acid oxidation. Metformin also increases translocation of GLUT-1 and GLUT-4 isofarm of glucose transporters in different types of cells, and it prevents the development of insulin resistance iii cultured hepatocytes and adepocytes for long periods to high insulin concentrations.
Comparison of Sulphonylurea and Metformin Therapy
Metformin and Sulphonylurea cause similar decrease in fasting plasma glucose
concentration in patients with NIDDM.
Both Sulphonylurea and insulin can cause weight gain but this does not occur with
metformin Sulphonylurea can induce hypoglycemia, whereas this is rare with metformin therapy. Therefore metformin has a antihypoglycemia action where as Sulphonylurea and insulin have hypoglycemic action. Sulphonylurea increase fasting plasma insulin concentration where as metformin may decrease it. In theory, the reduced plasma concentration of insulin or plasminogen activator inhibitor type I could decrease the risk of macrovascular disease.
Thus we see that metformin is complimentary to sulphonylurea and dietary therapy and
represents a useful additional drug for management of NIDDM.
Appetite reducing agents in obesity.
There are several groups of drugs used as appetite suppressants-Bulk eg - psyllium - promotes gastric filling Psychogenic eg - impramine and amitryptyline
Anorexia (amphetamines) - most effective anorexics eg -Dextroamphethemine and methamphetamin.
Anticonvulsant - Phenytoin
Anti Hestamines - Chlorphiniramine
Grape fruit Pill
Carbohydrate wafers
Hormones
(a) Antirior pituitary hormones. Human chorrionic gonadatropin
(b) Vasopressin -
(c) Starch blockers (alpha amylase inhibitors)
(d) Thyroid hormones.
Hypolipidemic agents - Gemfibrozil - 600mg twice daily.
Antidepressive drugs like fluoxitine hydrochloride may be usefull in some and help in
weight reduction. Oral sustained release fenfluramine 20mg was used to suppress appetite. Now the drug is banned due to its side effect pulmonary hypertension.
Insulin Required in NIDDM only when
(1) Oral Hypoglycemic Agent failure
(2) Intercurrent illnesses
MI
Surgical disease
Occult infection
roblem of insulin therapyin obese DM
(1) As seen earlier due to insulin resistance they require a higher dose of insulin. With
hyperinsulinemia patient gets weight gain
Conclusion
Pathogenesis hazards of obesity and its indices are discussed. Type 2 DM patient may be
obese. If they loose weight diabetes status may be improved. When diet fails metformin is the drug of choice. Obese type 2 Diabetics may need insulin occasionally due to sepsis or during surgery. When insulin is used it is required in higher dose due to peripheral insulin resistance.
REFERENCE
1. Parks textbook of PSM - 14th edition. M/s. Banarsidas Bhanot Publishers, 1167
Prem Nagar, Jabalpur (M.P.)
2. Endocrinology and Metabolism Clinics of North America - Obesity, 1996.
3. NEJM. Vol. 334; 29th February, 1996.
4. API Textbook of Medicine - 5th edition, 1992. Association of Physicians of India,
Bombay.
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