Ghrelin is an orexigenic gastric hormone that decreases in peripheral blood after carbohydrate-rich meals but increases after protein ingestion. In the present study plasma ghrelin was determined together with hunger and satiety ratings and with insulin and glucose concentrations after the ingestion of satiating quantities of carbohydrate-, fat-, protein-, fruit-, and vegetable-rich meals in 14 healthy subjects. Four hours later, standardized sandwiches were consumed. After carbohydrate, ghrelin decreased, whereas fat, protein, fruit, and vegetable ingestion significantly increased ghrelin levels. Considering all test meals, no significant correlation existed between changes of ghrelin levels and satiety ratings (r = 0.05; not significant), whereas a significant inverse relationship was observed between plasma ghrelin and insulin levels (r = -0.44; P < 0.001). During the second meal, sandwich consumption was significantly greater after the preceding fruit and vegetable meals, which was significantly correlated with the fourth-hour increase of ghrelin (r = 0.44; P < 0.001). In conclusion, after an overnight fast, ghrelin release depends on the ingested macronutrients and is most likely not a major regulator of acute food intake, although it is of greater importance for the recurrence of hunger and subsequent meal size.

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To gain further insight into the regulatory role of insulin and leptin on plasma ghrelin, 56 normal weight, 128 normoinsulinemic obese, 121 hyperinsulinemic obese, and 30 type 2 diabetic normoinsulinemic and 75 type 2 diabetic hyperinsulinemic obese patients were examined. In the obese subjects, basal hyperinsulinemia was associated with significantly lower ghrelin independent of BMI, age, and leptin. In normoinsulinemic (normal weight and normoinsulinemic obese) subjects, ghrelin was inversely related to stepwise increasing leptin. Multiple regression analysis and matching for insulin revealed a significant negative interaction of ghrelin with leptin but not insulin. In type 2 diabetic normoinsulinemic subjects, ghrelin was significantly lower compared with that in normoinsulinemic obese subjects. In type 2 diabetic hyperinsulinemic subjects, ghrelin was significantly lower than in normoinsulinemic subjects, whereas no further reduction was observed compared with hyperinsulinemic obese subjects. The postprandial decrease was significantly attenuated in normoinsulinemic obese and hyperinsulinemic obese subjects (؊214.8 ؎ 247 pg/ml [normal weight], ؊137.6 ؎ 107 pg/ml [normoinsulinemic obese], ؊85.5 ؎ 69 pg/ml [hyperinsulinemic obese], P < 0.001; mean ؎ SD), whereas type 2 diabetes had no independent postprandial effect. In conclusion, the present data support the concept that leptin could be of importance for suppression of basal ghrelin during moderate weight gain in normoinsulinemic subjects, whereas hyperinsulinemia but not leptin is responsible in more severe obesity. Postprandial suppression of ghrelin is attenuated by as yet unknown mechanisms that are related to body weight but not to insulin or type 2 diabetes. Diabetes

-Obesity is associated with insulin resistance and hyperinsulinemia, which is considered to be a core component in the pathophysiology of obesity-related comorbidities. As yet it is unknown whether insulin resistance and hyperinsulinemia already develop during weight gain within the normal range. In 10 healthy male subjects the effect of intentional weight gain by 2 BMI points was examined on insulin. C-peptide and glucose levels following a meal, 75 g of glucose, and a two-step hyperglycemic clamp increased plasma glucose by 1.38 and 2.75 mmol/l, respectively. Baseline insulin, C-peptide, and glucose concentrations were significantly higher after weight gain from 21.8 to 23.8 kg/m 2 BMI within 41/2 mo. Calculations of insulin secretion and clearance indicate that reduced insulin clearance contributes more to post-weight gain basal hyperinsulinemia than insulin secretion. Following oral or intravenous stimulation insulin concentrations were significantly higher postweight gain during all three test conditions, whereas C-peptide and glucose levels did not differ. Calculations of insulin secretion and clearance demonstrated that higher stimulated insulin concentrations are entirely due to clearance but not secretion. Despite significantly higher insulin levels, the rate of intravenous glucose required to maintain the defined elevation of glucose levels was either identical (1.38 mmol/l) or even significantly lower (2.75 mmol/l) following weight gain. The present study demonstrates for the first time that insulin resistance already develops during weight gain within the normal range of body weight. The associated basal and stimulated hyperinsulinemia is the result of differentiated changes of insulin secretion and clearance, respectively. insulin secretion; obesity; insulin clearance OVERWEIGHT AND OBESITY represent a worldwide increasing problem that greatly raises the risk of the development of cardiovascular disease, severe metabolic disorders such as type 2 diabetes mellitus or various malignances (22), and related mortality (5). Obesity is associated with insulin resistance and subsequent hyperinsulinemia, which has been known for more than 40 years (21, 35), and it is considered to be a core component in the pathophysiology of obesity-related comorbidities (19).Increased peripheral plasma insulin concentrations can be attributed to stimulation of pancreatic insulin secretion. On the other hand, insulin is extracted to a considerable and varying degree during its passage through the liver, which is an important physiological mechanism for the postprandial increase of peripheral plasma insulin concentrations (29, 39). Several studies have reported that both mechanisms of action contribute to the pathophysiologically relevant hyperinsulinemia of overweight and obese subjects. In the basal state, hypersecretion (3, 13, 14, 31) as well as decreased hepatic insulin clearance (38) have been demonstrated. Similarly, both mechanisms are relevant during stimulation by a meal (31, 37), an oral glucose load (3, 13, 28), ...

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Transforming growth factor ␤ (TGF-␤) is thought to play an important role in bone metabolism, but its relationship to human bone turnover and bone mass has not been examined yet. In this study, we measured the concentration of TGF-␤ in 811 samples of male and female bone from four representative sites of the human skeleton and in the supernatants of 72 short-term human bone marrow cultures from the iliac crest. The concentrations of TGF-␤1 and TGF-␤2 in the bone matrix were positively correlated with histomorphometric indices of bone resorption and bone formation and with serum levels of osteocalcin and bone-specific alkaline phosphatase. We also observed a positive association between the release of TGF-␤ in the bone marrow cultures and serum osteocalcin. Changes in the rate of cancellous or cortical bone remodeling with age or menopause were accompanied by corresponding changes in skeletal TGF-␤. In contrast, there was no significant relationship between the concentration of TGF-␤ and bone volume at any skeletal site. In conclusion, our study supports the hypothesis that TGF-␤ plays an important role in human bone remodeling, but fails to demonstrate an association between the skeletal concentration of TGF-␤ and human bone mass. (J Bone Miner Res 1998;13:716-730)