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Biomedical subjects

M K Sinha

Publications and source records attributed to M K Sinha.

At least 19 recordsLinked to original sources
PubMed1998

Clinical aspects of leptin.

Hyperleptinemia is an essential feature of human obesity. Total body fat mass > % body fat > BMI are the best predictors of circulating leptin levels. Although ob gene is differentially expressed in different fat compartments, apart from total body fat, upper or lower body adiposity or visceral fat does not influence basal leptin levels. Similarly, age, basal glucose levels, and ethnicity do not influence circulating leptin levels. Only in insulin-sensitive individuals do basal levels of insulin and leptin correlate positively even after factoring in body fat. Diabetes does not influence leptin secretion in both lean and obese subjects per se. Independent of adiposity, leptin levels are higher in women than in men. This sexual dimorphism is also present in adolescent children. In eating disorders anorexia nervosa and bulimea nervosa, leptin levels are not upregulated but simply reflect BMI and probably body fat. In spite of strong correlation between body fat and leptin levels, there is great heterogeneity in leptin levels at any given index of body fat. About 5% of obese populations can be regarded as "relatively" leptin deficient which could benefit from leptin therapy. Leptin has dual regulation in human physiology. During the periods of weight maintenance, when energy intake and energy output are equal, leptin levels reflect total bodyfat mass. However, in conditions of negative (weight-loss programs) and positive (weight-gain programs) energy balances, the changes in leptin levels function as a sensor of energy imbalance. This latter phenomenon is best illustrated by short-term fasting and overfeeding experiments. Within 24 h of fasting leptin levels decline to approximately 30% of initial basal values. Massive overfeeding over a 12-h period increases leptin levels by approximately 50% of initial basal values. Meal ingestion does not acutely regulate serum leptin levels. A few studies have shown a modest increase in leptin secretion at supraphysiological insulin concentrations 4-6 h following insulin infusion. Under in vitro conditions, insulin stimulates leptin production only after four days in primary cultures of human adipocytes, which is apparently due to its trophic effects and an increased fat-cell size. Similar to other hormones, leptin secretion shows circadian rhythm and oscillatory pattern. The nocturnal rise of leptin secretion is entrained to mealtime probably due to cumulative hyperinsulinemia of the entire day. Like other growth factors and cytokines, leptin binding proteins including soluble leptin receptor are present in human serum. In lean subjects, the majority of leptin circulates in the bound form whereas in obese subjects, the majority of leptin is present in the free form. When free-leptin levels are compared between lean and obese subjects, even more pronounced hyperleptinemia in obesity is observed than that reported by measuring total leptin levels. During short-term fasting, free-leptin levels in lean subjects decrease in much greater proportion than those in obese subjects. In lean subjects with a relatively small energy store and particularly during food deprivation, leptin circulating predominantly in the bound form could be the mechanism to restrict its availability to hypothalamic leptin receptors for inhibiting leptin's effect on food intake and/or energy metabolism. Unlike marked changes in serum leptin, CSF leptin is only modestly increased in obese subjects and the CSF leptin/serum leptin ratio decreases logarithmically with increasing BMI. If CSF leptin levels are any indication of brain interstitial fluid levels, then hypothalami of obese subjects are not exposed to abnormally elevated leptin concentrations. In the presence of normal leptin receptor (functional long form, i.e., OB-Rb) mRNA expression and in the absence of leptin receptor gene mutations, it is logical to assume defective leptin signaling and/or impaired affector system(s) are the likely causes of leptin resistance in

Adipose Tissue↗
PubMed1997

Entrainment of the diurnal rhythm of plasma leptin to meal timing.

To identify the physiologic factor(s) that entrain the diurnal rhythm of plasma leptin, leptin levels were measured hourly after changes in light/dark cycle, sleep/wake cycle, and meal timing. Four young male subjects were studied during each of two protocols, those being a simulated 12-h time zone shift and a 6.5-h meal shift. During the baseline day, plasma leptin demonstrated a strong diurnal rhythm with an amplitude of 21%, zenith at 2400 h, and nadir between 0900 and 1200 h. Acute sleep deprivation did not alter plasma leptin, but day/night reversal (time zone shift) caused a 12+/-2 h shift (P < 0.01) in the timing of the zenith and nadir. When meals were shifted 6.5 h without changing the light or sleep cycles, the plasma leptin rhythm was shifted by 5-7 h (P < 0.01). The phase change occurred rapidly when compared with changes in the diurnal rhythm of cortisol, suggesting that leptin levels are not acutely entrained to the circadian clock. The leptin rhythm was altered by meal timing in a manner very similar to the rhythm of de novo cholesterol synthesis. We conclude that the diurnal rhythm of plasma leptin in young males is entrained to meal timing.

Adult↗
PubMed1997

Leptin plasma levels in healthy Spanish children and adolescents, children with obesity, and adolescents with anorexia nervosa and bulimia nervosa.

OBJECTIVES: (1) To investigate normal circulating levels of leptin in children at various stages of pubertal maturation (Tanner stages) according to sex; and (2) to analyze serum leptin levels in pediatric patients with eating disorders (obesity, anorexia nervosa, and bulimia nervosa). STUDY DESIGN: Fasting leptin levels were studied in normal healthy boys and girls throughout development. Obese pediatric subjects and patients with anorexia nervosa were studied at the time of diagnosis and after 6 months and 1 year of treatment for weight reduction or weight recuperation, respectively. Patients with bulimia nervosa were studied at the moment of diagnosis. RESULTS: Leptin levels in both boys and girls vary significantly depending on the maturational stage, being low in both sexes at Tanner stage I and rising significantly by Tanner stage III. In girls, there was a further increase by Tanner stage V and a significant decrease in boys, resulting in a sexual dimorphism in Tanner V subjects. In obese prepubertal patients, leptin levels were significantly elevated at the time of diagnosis and declined significantly with weight loss (ANOVA: p < 0.0001). In anorexia nervosa patients' leptin levels are significantly reduced compared with age- and sex-matched controls (p < 0.0001). These levels remain significantly lower even after recovery of at least 10% of the original body weight and 1 year later. In patients with bulimia leptin levels were reduced at the time of diagnosis but were significantly higher than in patients with anorexia. CONCLUSION: In normal pediatric subjects leptin levels are highly correlated with the body mass index, but this is not the case in eating disorders, where the body mass index is either significantly elevated or reduced. Both age and sex should be taken into consideration when analyzing serum leptin levels.

Adolescent↗
PubMed1996

Ultradian oscillations of leptin secretion in humans.

We have recently demonstrated the nocturnal increase in leptin secretion in humans. In the present study we have examined the pulsatile pattern of leptin secretion using two different experimental protocols. The first protocol utilized blood samples withdrawn at 30 minute intervals immediately after meals, at 1 hour intervals between meals, and at 2 hour intervals during the night from 4 lean, 11 obese, and 5 obese NIDDM subjects. Analysis of circulating leptin levels by ULTRA algorithmic program and using matched intra-assay coefficient of variations demonstrated 1 to 7 ultradian oscillations with a mean of 3.25 +/- 0.36 (SEM) pulses per 24 hour period (period: 10.0 +/- 1.5 hours; mean relative amplitude: 0.52 +/- 0.06, n = 20). Significant positive correlations were observed for changes in absolute amplitude with body mass index (p < 0.025) and fasting leptin levels (< 0.0001). In the second series of experiments utilizing 15 minute blood sampling from 10 overnight fasted obese subjects (BMI 35.9 +/- 2.0 kg/m2), ultradian oscillations for leptin were more frequent, i.e., 2 to 7 oscillations (4.20 +/- 0.59), over a 12 hour duration (period: 3.44 +/- 0.49; mean relative amplitude: 0.28 +/- 0.03). The number of oscillations over a 12 hour period correlated significantly with BMI (p < 0.001), fasting leptin levels (p < 0.01), and absolute amplitude (p < 0.005) in a 15 minute sampling protocol. In summary, similar to other hormones, ultradian oscillations of leptin are observed in humans, although the physiological significance in relation to obesity or feeding behavior is not yet understood.

Blood Glucose↗
PubMed1996

Evidence of free and bound leptin in human circulation. Studies in lean and obese subjects and during short-term fasting.

Little is known about leptin's interaction with other circulating proteins which could be important for its biological effects. Sephadex G-100 gel filtration elution profiles of 125I-leptin-serum complex demonstrated 125I-leptin eluting in significant proportion associated with macromolecules. The 125I-leptin binding to circulating macromolecules was specific, reversible, and displaceable with unlabeled leptin (ED50: 0.73 +/- 0.09 nM, mean +/- SEM, n = 3). Several putative leptin binding proteins were detected by leptin-affinity chromatography of which either 80- or 100-kD proteins could be the soluble leptin receptor as approximately 10% of the bound 125I-leptin was immunoprecipitable with leptin receptor antibodies. Significantly higher (P < 0.001) proportions of total leptin circulate in the bound form in lean (46.5 +/- 6.6%) compared with obese (21.4 +/- 3.4%) subjects. In lean subjects with 21% or less body fat, 60-98% of the total leptin was in the bound form. Short-term fasting significantly decreased basal leptin levels in three lean (P < 0.0005) and three obese (P < 0.005) subjects while refeeding restored it to basal levels. The effects of fasting on free leptin levels were more pronounced in lean subjects (basal vs. 24-h fasting: 19.6 +/- 1.9 vs. 1.3 +/- 0.4 ng/ml) compared with those in obese subjects (28.3 +/- 9.8 vs. 14.7 +/- 5.3). No significant (P > 0.05) decrease was observed in bound leptin in either group. These studies suggest that in obese individuals the majority of leptin circulates in free form, presumably bioactive protein, and thus obese subjects are resistant to free leptin. In lean subjects with relatively low adipose tissue, the majority of circulating leptin is in the bound form and thus may not be available to brain receptors for its inhibitory effects on food intake both under normal and food deprivation states.

Carrier Proteins↗
PubMed1996

Decreased cerebrospinal-fluid/serum leptin ratio in obesity: a possible mechanism for leptin resistance.

BACKGROUND: A receptor for leptin has been cloned from the choroid plexus, the site of cerebrospinal-fluid (CSF) production and the location of the blood/cerebrospinal-fluid barrier. Thus, this receptor might serve as a transporter for leptin. We have studied leptin concentrations in serum and (CSF). METHODS AND FINDINGS: We demonstrated by radioimmunoassay and western blot the presence of leptin in human CSF. We then measured leptin in CSF and serum in 31 individuals with a wide range of bodyweight. Mean serum leptin was 318% higher in 8 obese (40.2 [SE 8.6] ng/mL) than in 23 lean individuals (9.6 [1.5] ng/mL, p < 0.0005). However, the CSF leptin concentration in obese individuals (0.337 [0.04] ng/mL) was only 30% higher than in lean people (0.259 [0.26] ng/mL, p < 0.1). Consequently, the leptin CSF/serum ratio in lean individuals (0.047 [0.010]) was 4.3-fold higher than that in obese individuals (0.011 [0.002], p < 0.05). The relation between CSF leptin and serum leptin was best described by a logarithmic function (r = 0 x 52, p < 0.01). INTERPRETATION: Our data suggest that leptin enters the brain by a saturable transport system. The capacity of leptin transport is lower in obese individuals, and may provide a mechanism for leptin resistance.

Biological Transport↗
PubMed1996

Nocturnal rise of leptin in lean, obese, and non-insulin-dependent diabetes mellitus subjects.

We studied 24-h profiles of circulating leptin levels using a sensitive and specific RIA in lean controls and obese subjects with or without non-insulin-dependent diabetes mellitus (NIDDM) during normal routine activity. Serum leptin levels were significantly higher in obese (41.7 +/- 9.0 ng/ml; n = 11) and obese NIDDM (30.8 +/- 6.7; n = 9) subjects compared with those in lean controls (12.0 +/- 4.4, n = 6). In all the three groups, serum leptin levels were highest between midnight and early morning hours and lowest around noon to midafternoon. The nocturnal rise in leptin levels was significant when data were analyzed by ANOVA (lean: F = 3.17, P < 0.0001, n = 4; obese: F = 2.02, P < 0.005, n = 11; and obese NIDDM: F = 4.9, P < 0.0001, n = 5). The average circadian amplitude between acrophase and nadir was 75.6% in lean, 51.7%, in obese and 60.7% in obese NIDDM groups, respectively. No significant correlations (P > 0.05) were observed between circulating levels of leptin and either insulin or glucose levels in any of the 20 subjects studied for 24-h profiles. The nocturnal rise in leptin observed in the present study resembles those reported for prolactin, thyroid-stimulating hormone, and free fatty acids. We speculate that the nocturnal rise in leptin could have an effect in suppressing appetite during the night while sleeping.

Adult↗
PubMed1996

Serum immunoreactive-leptin concentrations in normal-weight and obese humans.

BACKGROUND: Leptin, the product of the ob gene, is a hormone secreted by adipocytes. Animals with mutations in the ob gene are obese and lose weight when given leptin, but little is known about the physiologic actions of leptin in humans. METHODS: Using a newly developed radioimmunoassay, wer measured serum concentrations of leptin in 136 normal-weight subjects and 139 obese subjects (body-mass index, > or = 27.3 for men and > or = 27.8 for women; the body-mass index was defined as the weight in kilograms divided by the square of the height in meters). The measurements were repeated in seven obese subjects after weight loss and during maintenance of the lower weight. The ob messenger RNA (mRNA) content of adipocytes was determined in 27 normal-weight and 27 obese subjects. RESULTS: The mean (+/- SD) serum leptin concentrations were 31.3 +/- 24.1 ng per milliliter in the obese subjects and 7.5 +/- 9.3 ng per milliliter in the normal-weight subjects (P < 0.001). There was a strong positive correlation between serum leptin concentrations and the percentage of body fat (r = 0.85, P < 0.001). The ob mRNA content of adipocytes was about twice as high in the obese subjects as in the normal-weight subjects (P < 0.001) and was correlated with the percentage of body fat (r = 0.68, P < 0.001) in the 54 subjects in whom it was measured. In the seven obese subjects studied after weight loss, both serum leptin concentrations and ob mRNA content of adipocytes declined, but these measures increased again during the maintenance of the lower weight. CONCLUSIONS: Serum leptin concentrations are correlated with the percentage of body fat, suggesting that most obese persons are insensitive to endogenous leptin production.

Adipocytes↗
PubMed1996

Relationship between weight loss maintenance and changes in serum leptin levels.

Serum leptin concentrations are higher in obese humans than in lean and are decreased by initial weight loss. This study examined the effects of maintenance of weight loss on leptin concentrations and tested whether leptin concentrations at baseline or after initial weight loss are related to the ability to maintain a reduced body weight. Fifty-two overweight women [body mass index (kg/m2) averaging 31.3] were studied before and after a 4 month weight loss program and at 6 month follow-up. Subjects lost 8.1 kg over the 4 month program, and leptin concentrations decreased from 30.1 to 20.4 ng/ml. Initial leptin level per unit body mass index (r = -0.61, p < 0.0001) and weight loss during months 0 to 4 (r = 0.39, p = 0.004) were both significantly associated with initial changes in leptin, and together explained 60% of the variance in change in leptin. Subjects who maintained their weight losses over the 6-month follow-up maintained their reductions in leptin levels; again, weight changes during follow-up were correlated with changes in serum leptin levels (r = 0.41, p = 0.003). There was no evidence that baseline leptin concentration (or leptin/body mass index) or the changes in leptin which accompanied initial weight loss were predictive of subsequent weight regain. Thus, changes in leptin concentration during weight loss track with changes in weight. However, neither baseline concentrations nor initial changes in leptin predict success at weight loss or maintenance.

Adult↗
PubMed1996

Paracrine stimulation of preadipocyte-enriched cell cultures by mature adipocytes.

We developed a double-chamber system in which to examine the effects of mature adipocytes on the growth and differentiation of preadipocytes and other cells in the adipose tissue. In the present study we found that mature adipocytes from both lean and obese subjects release a factor that stimulates the growth of preadipocyte-enriched and dedifferentiated adipocyte-enriched cell cultures. This growth stimulation was dependent on both time of exposure to mature cells and the number of mature cells in the coculture. Proliferation of the preadipocyte-enriched (n = 4) and dedifferentiated adipocyte-enriched cultures (n = 5) in the presence of mature adipocytes from obese subjects [body mass index (BMI) > 35] was 4.1- and 2.9-fold more (P < 0.05) than that in the presence of adipocytes from lean subjects (BMI < or = 25). There was no difference in the growth of cultures enriched in preadipocytes or dedifferentiated adipocytes from lean or obese subjects in the absence of mature adipocytes. These observations demonstrate that mature adipocytes from obese patients stimulate the growth of preadipocyte-enriched cultures to a greater extent than those from lean individuals.

Adipocytes↗
PubMed1994

High dose intravenous, but not low dose subcutaneous, insulin-like growth factor-I therapy induces sustained insulin sensitivity in severely resistant type I diabetes mellitus.

We have previously demonstrated weekly iv insulin-like growth factor-I (IGF-I; 500 micrograms/kg) bolus therapy to be effective in inducing sustained insulin sensitivity in a patient with type I diabetes mellitus and massive insulin resistance. The present study was undertaken to determine the efficacy of daily sc IGF-I in the treatment of two severely insulin-resistant type I diabetic patients (requiring in excess of 3500 U insulin/day) compared to weekly iv IGF-I therapy. Prolonged insulin sensitivity was achieved in both patients after weekly 500 micrograms/kg iv bolus infusions of IGF-I, with sc insulin requirements falling to approximately 1 U/kg.day. Smaller iv doses (250 micrograms/kg) of IGF-I were ineffective in acutely lowering serum glucose or inducing sustained insulin sensitivity. However, even this smaller IGF-I dose resulted in acute symptomatic hypophosphatemia, which could be prevented by coadministration of potassium phosphate. With sc administered IGF-I (up to 10 mg twice daily), insulin appeared to control patient glucose concentrations, but severe insulin resistance returned within 72 h of discontinuing IGF-I therapy. IGF-I dosing was decreased to the lowest concentration that maintained euglycemia (7.5 mg in the morning and 2.5 mg in the evening). However, severe arthropathy in both patients and neurological symptoms including multiple cranial nerve palsies in one patient were associated with chronic therapy. We conclude that both iv and sc administered IGF-I can precipitate acute symptomatic hypophosphatemia. Chronic low dose sc therapy may be associated with severe neuropathy and arthropathy, and does not induce the sustained insulin sensitivity associated with high dose intermittent bolus IGF-I therapy.

Adipocytes↗
PubMed1992

Surgical treatment of obesity and its effect on diabetes: 10-y follow-up.

Since 1980 we have performed the identical Greenville gastric bypass (GGB) procedure on 479 morbidly obese patients with an acceptable morbidity and a mortality rate of 1.2%. The weight loss in the series was well maintained over the follow-up period of 10 y. The GGB can control non-insulin-dependent diabetes mellitus (NIDDM) in most patients. The group of 479 patients included 101 (21%) with NIDDM and another 62 (13%) who were glucose impaired. Of these 163 individuals, 141 reverted to normal and only 22 (5%) remained with inadequate control of their carbohydrate metabolism. Those patients who were older or whose diabetes was of longer duration were less likely to revert to normal values. The gastric bypass operation is an effective approach for the treatment of morbid obesity. Along with its control of weight, the operation also controls the hyperglycemia, hyperinsulinemia, and insulin resistance of the majority of patients with either glucose impairment or frank NIDDM.

Adult↗