The relation between leptin and insulin remains when insulin secretion is disturbed

BACKGROUND: Serum insulin and leptin levels correlate positively. It is not known whether this relation remains the same in cases of severely disturbed insulin secretion and after rapid weight loss. We therefore studied the relation between insulin and leptin in obese type 2 diabetic patients before and after considerable weight loss. METHODS: In 17 obese type 2 diabetic patients, blood glucose-lowering medication was discontinued (day-1) and a 30-day very low calorie diet (VLCD, 450 kcal/day) was started. On days 0, 2, and 30, body weight, body fat mass [with bioelectrical impedance analysis (BIA)], fasting serum glucose, insulin, and leptin were determined. Homeostatic model assessment was used to estimate insulin resistance (HOMA-IR) and beta-cell function (HOMA-beta). On days 2 and 30, an intravenous glucose tolerance test (IVGTT) was performed. RESULTS: Fasting serum leptin levels correlated positively with fasting serum insulin levels (r=0.72, p=0.001 on day 2; r=0.78, p=0.001 on day 30) and area under the curve (AUC) of insulin (r=0.74, p=0.001 on day 2; r=0.84, p=0.0001 on day 30), as well as HOMA-beta, as a measure of insulin secretion, even after correction for body mass index (BMI) and body fat mass, with which leptin was also positively correlated. CONCLUSION: In a group of obese type 2 diabetic patients with a wide range of residual endogenous insulin secretion, we found a positive relation between fasting serum leptin and insulin levels, even after correction for BMI and body fat mass. This was true both before weight loss and during energy restriction with weight loss.     

Changes of leptin and metabolic hormones in preterm infants: a longitudinal study in early postnatal life

OBJECTIVES: Very little is known concerning the physiological role of leptin and growth in the early postnatal period and the association of leptin with other metabolic hormones in preterm infants. This study aims to investigate these relationships, and to explore the longitudinal and dynamic profile of leptin and metabolic hormones including insulin, ACTH, cortisol and FT4 in this category of patient. We also postulate that a rapid increase in body weight and body mass index in the first few weeks of life may be associated with a corresponding increase in serum leptin if the 'adipoinsular axis' is active at this stage. DESIGN: A longitudinal study in a cohort of preterm infants < 34 weeks gestation for the first five weeks of postnatal life. PATIENTS AND METHODS: Sixty-one preterm newborns < 34 weeks gestation were prospectively enrolled. Blood samples were collected in the morning when the newborns were 24 h of age (day 1), and on days 5, 14 and 35 of life. Serum leptin, insulin, cortisol, FT4, glucose and plasma ACTH concentrations were analysed using standard biochemical methods. Spearman's correlation coefficient was used to assess the inter-relationship of different metabolic hormones on the first day of life, and the relationship between metabolic hormones on day 1 and anthropometric or clinical parameters. The mixed-effects models were further used for analysing the multiple longitudinal measurements, and also for comparing the hormone concentrations between day 1 (baseline) and their corresponding levels on days 5, 14 and 35. RESULTS: Serum leptin on day 1 (baseline) was significantly associated with serum insulin (r = 0.30, P < 0.05) and insulin:glucose ratio (r = 0.29, P < 0.05) in infants < 34 weeks gestation. Female preterm infants had significantly higher serum leptin (P < 0.05) and insulin (P < 0.05) levels than male infants. In addition, the duration between the last dose of antenatal dexamethasone and delivery significantly influenced the serum concentrations of leptin (r = - 0.27, P < 0.05), cortisol (r = 0.52, P < 0.001), plasma ACTH (r = 0.28, P < 0.05) and insulin:glucose ratio (r = - 0.27, P < 0.05) on the first day of life. Despite significant increase in body weight (P < 0.00001) and body mass index (P < 0.00001) by day 35 when compared to birth weight, no corresponding significant changes were observed for serum leptin, insulin and FT4. However, there was an increasing though statistically nonsignificant trend in serum leptin after day 14 of life. CONCLUSION: This study characterized the longitudinal profile of leptin and metabolic hormones in preterm infants < 34 weeks gestation in the first 5 weeks of life. Serum leptin was significantly associated with serum insulin and insulin:glucose ratio supporting the hypothesis that an 'adipoinsular axis' exists and is likely to be functional before 34 weeks of gestation. Although a significant increase in body weight was demonstrated by day 35, no significant corresponding changes occurred with regard to serum leptin. We postulate that the limited quantity of adipose tissue at this stage of development might have contributed to this observation. Moreover, our results also showed that the duration between the last dose of antenatal corticosteroid and delivery could influence the postnatal concentrations of adipoinsular and pituitary-adrenal hormones. Thus, it is possible that antenatal dexamethasone might affect fetal growth and development via these neuroendocrine pathways in early intrauterine life.     

Leptin levels in patients with type 1 diabetes receiving intensive insulin therapy compared with those in patients receiving conventional insulin therapy

Several reports suggest that insulin may have a role in the regulation of serum leptin levels, and this is related to the fact that serum leptin levels generally indicate the amount of body fat. Studies show that leptin levels are low in newly diagnosed patients with Type-1 diabetes (T1 DM) and increase after institution of insulin therapy. This study was designed to test whether serum leptin levels are higher in patients receiving intensive insulin therapy (IIT) compared to conventional insulin therapy (CIT). Young patients with T1 DM were studied, 23 on IIT and 23 on CIT. The patients were matched for age (19+/-3 and 20+/-5 yr, respectively), duration of diabetes (8+/-5 and 10+/-6 yr, respectively) and BMI (24+/-4 and 23+/-3 kg/m2, respectively). Leptin levels were higher in IIT compared to CIT (13+/-12 vs 7+/-7 ng/ml, respectively, p<0.05). The results of this study demonstrate that patients on IIT have higher leptin levels than patients on CIT. This increase in leptin level in IIT patients is independent of changes in bw and is probably due to the stimulatory effect of insulin on leptin production.     

Effect of exercise training on serum leptin levels in type 2 diabetic patients

To evaluate the effect of exercise training on serum leptin levels 50 sedentary subjects with type 2 diabetes were enrolled in either 6 weeks of aerobic exercise training with diet therapy (n = 23) or diet therapy alone (n = 27). The training program consisted of walking and cycle ergometer exercise for 1 hour at least 5 times per week, with the intensity of exercise maintained at 50% of maximum oxygen uptake. Serum leptin levels decreased significantly in the exercise training (TR) group (7.2 +/- 3.6 to 4.6 +/- 2.5 ng/mL, P <.05), but not in the sedentary (SED) group (6.9 +/- 3.4 to 5.6 +/- 2.9 ng/mL). Leptin levels standardized for percentage body fat (dividing serum leptin level by percentage body fat) after treatment were lower in the TR subjects compared with the SED subjects. Body weight and percentage body fat decreased in all patients; however, no significant changes were observed in either group. Fasting concentrations of plasma insulin and cortisol and the urinary excretion of 17-hydroxycorticosteroid (17-OHCS) did not differ between the groups either before or after treatment. Fasting plasma glucose and hemoglobin A(1c) (HbA(1c)) improved significantly in both groups, although no significant differences were observed between the groups either before or after treatment. Ventilatory threshold increased significantly in the exercise training subjects. This study demonstrates that exercise training in type 2 diabetic subjects reduces serum leptin levels independent of changes in body fat mass, insulin, or glucocorticoids.     

Elevated leptin levels are associated with excess gains in fat mass in girls, but not boys, with type 1 diabetes: longitudinal study during adolescence

Adolescents, in particular girls, with type 1 diabetes may gain excessive weight during puberty. We present the results of a longitudinal study aimed to determine the roles of leptin and insulin in changes in body composition in subjects with type 1 diabetes and controls. Forty-six children (23 boys) with type 1 diabetes and 40 controls (20 boys) were followed from 8-17 yr of age. Height, weight, and sc skinfolds were assessed every 6 months, and a blood sample taken for leptin determination. Throughout the age range, body mass index (mean +/- SEM) was greater by 1.45 +/- 0.69 kg/m(2) in girls and 1.46 +/- 0.55 kg/m(2) in boys with type 1 diabetes compared with control values. In girls with type 1 diabetes, this reflected greater percent body fat (3.2 +/- 1.0%; P = 0.002), whereas in boys it related to differences in fat-free mass. Both boys and girls with type 1 diabetes had higher leptin levels adjusted for percent body fat than controls; in the girls this was related to insulin dose (regression coefficient B = 0.006 +/- 0.003; P = 0.04) and greater gains in fat mass. Hyperinsulinemia and raised leptin levels are associated with gains in fat mass throughout puberty in girls, but not boys, with type 1 diabetes.     

Leptin in children with newly diagnosed type 1 diabetes: effect of insulin therapy

Leptin, the gene product of adipose tissue that signals caloric plentitude via central nervous system receptors, may also have diverse peripheral metabolic actions. Of paramount interest has been the potential interaction(s) between leptin and insulin. Insofar as insulin alters leptin secretion/action (or vice versa), dysregulation of this system could contribute to disease states such as diabetes. The purpose of this study was to examine the effect of exogenous insulin on serum leptin in children with newly-diagnosed Type 1 diabetes. Since these patients are hypoinsulinemic (insulin-depleted) at diagnosis, they present an ideal opportunity to examine the effect of insulin repletion on serum leptin. Seventeen patients were enrolled. At baseline (prior to insulin therapy), leptin levels were 4.3 +/- 1.1 ng/ml; they were not statistically related to the baseline serum insulin or illness severity. There was no significant change in serum leptin before, shortly (1-6 days) or several weeks (3-26 weeks) after insulin treatment even when the data was corrected for changes in BMI, hemoglobin A1C, and daily insulin dose. Since repletion of the insulin deficiency that is present in non-acidotic, ambulatory patients with new onset Type 1 diabetes did not alter serum leptin, these results argue against an effect of insulin on serum leptin in the absence of the acute diabetic ketoacidosis. Because as the recuperative months following the diagnosis of new onset Type 1 diabetes are marked by weight gain, the absence of a rise in serum leptin might also indicate either an adaptive (weight permissive) or pathologic (impaired secretory) deficit.     

Effects of three antidiabetics on insulin and leptin in Chinese type 2 diabetes

AimsThis study was to investigate the effects of some different antidiabetics on circulating insulin and leptin levels in type 2 diabetes with or without overweight in a Chinese population.Methods80 type 2 diabetes men with overweight (body mass index BMI > 24 kg/m²) and 35 type 2 diabetes men with normal body weight (BMI ≤ 24 kg/m²) and 56 control subjects were enrolled in the study. We measured blood glucose, insulin, leptin, total cholesterol, LDL-C, HDL-C, triglycerides, fasting glucose, postprandial glycose, HbA1c and BMI before and after the administration of antidiabetic drugs.ResultsCompared with normal body weight, the levels of plasma insulin and leptin in overweight type 2 diabetes men were higher, after 3 months treatment, a significant increase in insulin and leptin levels was observed in overweight type 2 diabetes men in gliclazide group. Levels of leptin and insulin decreased in metformin and rosiglitazone groups, respectively.ConclusionsWe conclude that surfonylureas treatment leads to increased insulin and leptin levels in overweight type 2 diabetes men, metformin, or rosiglitazone treatment can reduce insulin and leptin levels, respectively, and effect of metformin on plasma leptin and insulin levels is more significant than that of rosiglitazone.     

Serum leptin concentrations in children with type 1 diabetes mellitus: relationship to body mass index, insulin dose, and glycemic control

Although obesity is a frequent feature of type 2 diabetes mellitus (DM), many patients with type 1 DM are prone to high body mass index (BMI). We measured serum leptin concentrations in a cohort of children (n = 55) with type 1 diabetes mellitus (DM), as well as their anthropometric parameters including BMI, skin fold thickness at multiple sites, and midarm circumference. Glycemic control was assessed by blood glucose (BG) monitoring before meals, and measurement of glycated hemoglobin (HbA1c) and insulin dose/kg/d was recorded. Dietary evaluation and assessment of caloric intake (kg/d) was performed by an expert dietitian. In the newly diagnosed children (n = 10) before initiation of insulin therapy, circulating leptin concentration was significantly lower (1.1 +/- 0.8 ng/dL) versus 5 days after insulin therapy (1.45 +/- 0.7 ng/dL). The decreased leptin level appears to be related to insulinopenia in these patients. In 45 children with type 1 DM on conventional therapy (2 doses of insulin mixture (NPH and regular) subcutaneous (SC) before breakfast and dinner for more than 2 years), serum leptin concentration was significantly higher (2.15 +/- 1 ng/dL) compared with age-matched normal children (1.3 +/- 1 ng/dL). Diabetic children were further divided into 2 groups according to their HbA1c level: group 1 with HbA1C less than 7.5% (less than 2 SD above the mean for normal population) (n = 29) and group 2 with HbA1c greater than 7.5%. (greater than 2 SD above the mean for normal population) (n = 16). Patients with a higher HbA1c level (group 2) had a higher leptin concentration (2.3 +/- 0.8 ng/dL), higher BMI (17.8 +/- 1.7), and were receiving higher insulin dose/kg (0.92 +/- 0.2 U/kg/d) compared with group 1 (lower HbA1c) (1.78 +/- 0.8 ng/dL, 16.7 +/- 1.5, and 0.59 +/- 0.2 U/kg/d, respectively). Group 2 patients had a higher incidence of late morning hypoglycemia (9/29) versus group 1 patients (2/16). Analysis of dietary intake showed that patients with a higher HbA1c (group 2) consumed more calories (73.5 +/- 10.5 kcal/kg/d) versus patients with lower HbA1c (64.2 +/- 8.7 kcal/kg/d). These findings pointed to the unphysiologic nature of injecting a mixture of insulin twice daily. To cover the relatively big lunch meal (40% to 50% of the total caloric intake in the Arab countries) and prevent afternoon hyperglycemia, there is a great tendency to increase NPH dose before breakfast. This, in turn, induces late-morning hypoglycemia and increases appetite and food intake at that time. Multiple regression analysis showed that circulating leptin concentrations (the dependent variable) were best correlated with the mean skinfold thickness (SFT), BMI, and caloric intake/kg/d (together they explained 65% of the variability in leptin concentrations). It appears that oversubstitution by insulin and increased food intake stimulate fat synthesis and subsequently BMI. Increased appetite and BMI contribute to increased leptin secretion and explains the higher leptin levels in undercontrolled diabetic children (higher circulating HbA1c concentrations) who were oversubstituted by insulin.     

Serum leptin levels in diabetic patients on hemodialysis: the relationship to parameters of diabetes metabolic control

Leptin is a protein hormone produced predominantly by adipocytes that affects food intake and energy expenditure. Its serum levels are significantly higher in patients with chronic renal failure compared to healthy subjects. The aim of this study was to compare serum leptin levels in hemodialyzed patients with type II diabetes mellitus (n=26) with body content-matched hemodialyzed patients without diabetes (n=26) and to explore the relationship between parameters of the long term diabetes metabolic control and serum leptin levels. Serum leptin levels in diabetic patients did not significantly differ from those of non-diabetic patients (25.3+/-8.8 vs 25.7+/-8.7 ng/ml). Serum leptin levels in diabetic patients positively correlated with body fat content, body mass index and predialysis serum insulin levels. No significant relationship were observed between serum leptin levels and blood glucose, glycated hemoglobin, glycated protein, serum urea, creatinine, leukocyte count and total hemoglobin respectively. The multiple stepwise regression analysis revealed that body fat content together with body mass index accounted for 77.8% of variations in predialysis serum leptin levels, while insulin levels and the parameters of diabetes metabolic control had only slight prediction value for leptin concentrations. We conclude that serum leptin levels in hemodialysed patients with type III diabetes mellitus do not significantly differ from those of hemodialysed non-diabetic patients. The body fat content and body mass index are the strongest predictors of serum leptin levels, while parameters of long term diabetes metabolic control play probably only minor direct role in its regulation.     

新诊断1型糖尿病患者血清瘦素质量浓度及短期胰岛素治疗对其影响

目的　观察新诊断 1型糖尿病患者血清瘦素质量浓度变化及胰岛素治疗对瘦素质量浓度的影响 ,进而探讨胰岛素和瘦素间的相互作用。方法　 1999- 0 7～ 2 0 0 0 - 0 7哈尔滨医科大学附属第二医院门诊和病房 2 9例新诊断的 1型糖尿病患者和 2 0名正常对照者彻夜空腹 14h后 ,第 2天早晨 8时采血检测血糖、HbA1c、甘油三酯、胆固醇、胰岛素、C肽及瘦素 ,然后对 1型糖尿病患者行皮下胰岛素注射治疗 ,2周后检测血糖、胰岛素、C肽和瘦素。结果　新诊断的 1型糖尿病患者血清瘦素质量浓度明显低于对照者 (P <0 0 5 ) ,胰岛素治疗 2周后 ,瘦素质量浓度无明显变化 (P >0 0 5 ) ;相关分析显示 ,对照组空腹血清瘦素质量浓度与性别、体重指数 (BMI)和胰岛素浓度具有相关性 ,新诊断 1型糖尿病组血清瘦素质量浓度仅与性别、胰岛素浓度具有相关性。结论　新诊断 1型糖尿病患者在胰岛素治疗前血清瘦素质量浓度低于对照者。短期胰岛素皮下注射治疗对血清瘦素质量浓度无明显影响。     

Potential causes of weight gain in type 1 diabetes mellitus

AIM: To investigate the potential causes of weight gain with insulin therapy and improved diabetic control in type 1 diabetes mellitus. METHODS: This was an open-label prospective study of insulin therapy of 6 months duration in an academic medical centre. Twenty-one subjects with type 1 diabetes were enrolled. The goal was to achieve an haemoglobin A1c (HbA1c) in the range of individuals without diabetes (<5.6%). At baseline, 3 and 6 months, weight, resting energy expenditure, appetite assessment, food intake, activity level, HbA1c and 24-h glycosuria and urea nitrogen were measured. Plasma leptin, ghrelin and adiponectin levels and body fat were measured at baseline and 6 months. RESULTS: At baseline, average weight was 73.7 +/- 17.4 kg and HbA1c was 10.0 +/- 2.2%. Weight increased by 2.15 kg (2.69% of baseline) by 6 months whereas the HbA1c dropped by 1.71% (16.3%) to 7.9%. Energy intake differences between 3 and 6 months had a negative correlation with weight gain, but the changes in glycosuria, appetite scores and the frequency of hypoglycaemia did not correlate with weight gain. Glycaemic control did not correlate with weight change but tended to correlate with fat mass increase (p = 0.064; r = -0.51). An increase in the activity levels between 3 and 6 months correlated with decreasing fat mass (p = 0.037; r = -0.74). The changes in the appetite scores had a negative correlation with fat mass gain (p = 0.035; r = -0.61). The changes in lean body mass correlated with protein and total energy intake (p = 0.007, r = 0.85 and p = 0.003, r = 0.73 respectively). The changes in leptin levels correlated with weight gain. CONCLUSIONS: The lipogenic effect of insulin with subsequent increase in fat mass may be the primary cause of this weight gain that can be attenuated by the increases in the activity levels. The negative correlation of energy intake and appetite scores with fat mass gain suggests that they do not play a significant role in fat mass gain whereas energy intake did correlate with lean body mass gain.     

Short-term effects of metformin in type 2 diabetes

BACKGROUND: Although metformin is widely used in the management of type 2 diabetes, its mechanism(s) of action is not fully known, and there have been remarkably few reports on short-term effects of the drug. Here, we examined early effects on glucose and lipid metabolism, and on certain adipose tissue and inflammatory markers during treatment for 28 days. METHODS: Twenty-one patients were randomized to metformin (n = 16) or placebo (n = 5) and studied at baseline, 1, 2 and 4 weeks with blood sampling and oral glucose tolerance tests (OGTT). The active group received 500 mg metformin daily in week 1, 500 mg twice daily in week 2 and 1000 mg twice daily in week 3 and 4. RESULTS: After 7 days of treatment, a reduced area under curve (AUC) for glucose at OGTT with no change in AUC for insulin levels was observed compared with baseline. Insulin sensitivity, as derived from the OGTT by Gutt's index, was increased. Reductions in fasting plasma glucose, total and LDL-cholesterol appeared after 14 days, and reductions in triglycerides, plasminogen activator inhibitor-1 (PAI-1) and leptin after 28 days of treatment. There were no changes in body weight, adiponectin or C-reactive protein. Compared with placebo, the changes between day 0 and day 28 differed significantly with regard to AUC for glucose at OGTT and Gutt's index, and showed strong trends for PAI-1 and leptin. CONCLUSIONS: The data demonstrate that in type 2 diabetes metformin rapidly affects glucose handling without changing the concentrations of insulin. Reductions in PAI-1 and leptin levels indicate that the early effects of metformin involve also the adipose tissue.     

Short-term effects of metformin in type 2 diabetes

BACKGROUND: Although metformin is widely used in the management of type 2 diabetes, its mechanism(s) of action is not fully known, and there have been remarkably few reports on short-term effects of the drug. Here, we examined the early effects on glucose and lipid metabolism and on certain adipose tissue and inflammatory markers during treatment for 28 days. METHODS: Twenty-one patients were randomized to metformin (n = 16) or placebo (n = 5) and studied at baseline, 1, 2 and 4 weeks with blood sampling and oral glucose tolerance tests (OGTT). The active group received 500 mg metformin daily in the first week, 500 mg twice daily during week 2 and 1000 mg twice daily during weeks 3 and 4. RESULTS: After 7 days of treatment, a reduced area under curve (AUC) for glucose at OGTT with no change in AUC for insulin levels was observed compared to baseline. Insulin sensitivity, as derived from the OGTT by Gutt's index, was increased. Reductions in fasting plasma glucose, total cholesterol and low-density lipoprotein cholesterol appeared after 14 days, and reductions in triglycerides, plasminogen activator inhibitor-1 (PAI-1) and leptin after 28 days of treatment. There were no changes in body weight, adiponectin or C-reactive protein. Compared with placebo, the changes between day 0 and day 28 differed significantly with regard to AUC for glucose at OGTT and Gutt's index, and showed strong trends for PAI-1 and leptin. CONCLUSIONS: The data demonstrate that in type 2 diabetes, metformin rapidly affects glucose handling without changing the concentrations of insulin. Reductions in PAI-1 and leptin levels indicate that the early effects of metformin involve also the adipose tissue.     

Evaluation of the effectiveness of extensive, ambulatory, non-pharmacological obesity treatment program

The aim of the study was an attempt to answer following questions: 1. Is extensive, non-pharmacological obesity treatment programme effective and is reduced body weight likely to be maintained in the long term? 2. What is the influence of the programme on some components of metabolic syndrome? 3. What is the effect of the programme on levels of leptin and insulin as indexes of weight reduction effectiveness? An informed consent to participate in the treatment was given by 37 women (GB) aged 19-47 yrs. (mean 36 +/- 7.7); with BMI 36 +/- 4.9 kg/m2. Control group (GK) was composed of 16 women aged 21-40 yrs. A 3-month extensive, ambulatory, non-pharmacological obesity treatment programme was offered to study subjects. Anthropometric, biochemical and hormonal assessment was performed before treatment (0), after 3 months--at the end of treatment (3), and after one year (R). After 3 months a reduction of body weight was observed in 34 persons (92%) whereas in 1 person (2.7%) body weight was stable and in 2 (5.4%) body weight increased. Body weight reduction was accompanied by beneficial changes in metabolic parameters. After one-year follow-up reduced body weight was maintained in 33 persons (89%), however, insulin and leptin levels and HOMA index increased significantly when compared to those observed during active treatment and were comparable with initial values. In the control group a significant increase in BMI, insulin and leptin levels and HOMA index was observed after one-year follow-up. Conclusions: 1. The extensive, non-pharmacological obesity treatment programme is effective because enables the reduction of body weight by 10% and patients are likely to maintain reduced body weight for one year. 2. The programme brings out metabolic benefits and enables to maintain them after its discontinuance. 3. The rebound increase in leptin and insulin levels after 9 months since active treatment has been discontinued may be an unfavourable prognostic factor in terms of maintenance of reduced body weight and indicates that the programme should be repeated in some patients groups.     

Recombinant human insulin-like growth factor-I (rhIGF-I) therapy in adults with type 1 diabetes mellitus: effects on IGFs, IGF-binding proteins, glucose levels and insulin treatment

OBJECTIVE: Insulin-like growth factor-I (IGF-I) has both insulin-like and anabolic actions but unlike insulin, IGF-I circulates bound to a number of specific binding proteins that regulate its availability and activity. Patients with type 1 diabetes mellitus have low levels of circulating IGF-I despite increased growth hormone (GH) secretion, and are a group that may benefit from rhIGF-I therapy. Understanding the relationship between IGF-I and its binding proteins is necessary to appreciate the actions of exogenously administered rhIGF-I. Therefore, we examined the effects of 19 days' subcutaneous administration of rhIGF-I (50 micrograms/kg BID) on the levels of IGF-I, IGF-II and the IGF-binding proteins (IGFBPs), as well as the daily dose of insulin necessary to maintain glycaemic control in patients with type 1 diabetes mellitus. DESIGN AND PATIENTS: This was an open study, and the patients were studied initially while resident (days 1-5) in the hospital and thereafter (days 6-24) as outpatients. Serum was collected at baseline and at intervals throughout the study for the measurement of total IGF-I, IGF-II, IGFBP-1, -2, -3, free insulin and growth hormone (GH). Daily insulin doses and glucometer readings were recorded throughout the study. The changes in each of these variables were examined. The subjects were six adults (35.3 +/- 4.0 years, mean +/- SE), with type 1 diabetes, and all had reasonable glycaemic control (HbA1c 7.2 +/- 0.5%). RESULTS: rhIGF-I administration increased circulating total IGF-I over two-fold (15.3 +/- 1.9 vs. 33.7 +/- 5.4 nmol/l, mean +/- SEM, P < 0.01, day 1 vs. day 20) and decreased plasma IGF-II concentration (85.0 +/- 4.7 vs. 50.6 +/- 4.7 nmol/l, P < 0.01, day 1 vs. day 20). The dose of insulin required for adequate glycaemic control decreased significantly during rhIGF-I therapy (46 +/- 7 vs. 31 +/- 8 U/day, P < 0.05, day -1 vs. day 19), as did the fasting free insulin concentration (8.4 +/- 1.5 vs. 5.0 +/- 0.8 mU/l, P < 0.05, baseline vs. day 5). IGFBP-2 concentration increased (388 +/- 115 vs. 758 +/- 219 micrograms/l, P < 0.05, day 1 vs. day 20), but IGFBP-1 and IGFBP-3 were unchanged during rhIGF-I treatment. Mean nocturnal GH concentration decreased (12.7 +/- 3.3 vs. 3.8 +/- 0.9 mU/l, P = 0.05) after 4 days' rhIGF-I therapy. CONCLUSION: Twice daily rhIGF-I therapy in adults with type 1 diabetes resulted in an increase in circulating IGF-I with a reciprocal decrease in IGF-II, and a marked elevation of IGFBP-2 concentration. The levels of IGFBP-1 and -3 were not dramatically changed despite a reduction in the concentration of serum free insulin, and a large decrease in the requirement for insulin. The mechanisms behind these changes remains unclear but alterations in circulating levels of of IGFBPs may alter IGF-I bioactivity. If rhIGF-I is to have an application in the management of adults with type 1 diabetes, further work is necessary to determine the metabolic consequences of the alterations seen in the IGFs and their binding proteins following rhIGF-I administration.     

Serum levels of leptin and changes during the course of recovery from diabetic ketoacidosis

Secretion of leptin, the obese gene product, is stimulated by insulin and glucocorticoids and reduced by fasting. In subjects with diabetic ketoacidosis (DKA), severe insulinopenia and prolonged fasting might cause a decrease in serum leptin levels, and subsequent insulin therapy would reverse the decrease. Otherwise, some other confounding factors, neither insulin nor fasting, might affect serum leptin levels in patients with DKA. The present study was undertaken to address these issues. Eleven patients with type 1 diabetes mellitus (seven males and four females, aged 44+/-6 years, mean +/- SEM), admitted to Jichi Medical School Hospital presenting DKA, were studied during the therapeutic period. Thirty-five sex-, age- and body mass index-matched healthy subjects served as controls. Serum leptin levels at the hospitalization were significantly greater than those of the matched control subjects (5.5+/-1.0 vs. 3.2+/-0.3 microg/l, P < 0.01). After the start of therapy with a small dose of short-acting insulin and a large volume of fluid infusion, serum leptin concentrations further increased to 10.6+/-3.6 microg/l at 24 h, and thereafter the concentrations gradually decreased and normalized at the discharge (3.3+/-0.7 microg/l, day 24+/-4). The peak levels at 24 h were significantly higher than the levels at the discharge (P < 0.05), and also +77+/-34% higher than those at the hospitalization (P < 0.005). Serum cortisol levels (1830+/-200 nmol/l) were markedly elevated at hospitalization. These results indicate that serum leptin levels are increased even under insulinopenia and fasting in the patients with DKA. Such a finding may be associated with marked hyperglycemia or enhanced secretion of glucocorticoid hormone, although the exact mechanisms remain to be elucidated. We speculate that leptin may serve as a stress peptide in DKA, but further analysis is necessary to explore a physiological role of leptin in DKA.     

Interrelationship between insulin, leptin and growth hormone in growth hormone-treated children

OBJECTIVES: The aim of the study was to examine insulin homeostasis during growth hormone (GH) therapy, and to investigate the effect of GH treatment on insulin and leptin concentration in obese children. SUBJECTS: Nineteen obese children (8 with Prader-Willi Syndrome (PWS)) were treated with GH 0.1 IU/kg/day dose for 3 months and were compared with 29 non-treated age and sex matched obese children (9 PWS) and 49 GH treated non-obese short children. Mean age of the children was 10.3+/-1.8 (6.7-13.8) y, with body mass index of 23.6+/-10.4 (11.5-47) kg/m2. RESULTS: Leptin concentration decreased and was correlated inversely with initial leptin value (r2=-0.374, P<0.001) and decreased body mass (r2=0.338, P=0.001). Insulin sensitivity index was not significantly changed during therapy. Leptin decrease after 3 months of GH administration was correlated inversely with the increase in first phase insulin response to intravenous glucose tolerance test (IVGTT) (r2=-0.595, P<0.001). Results of long-term follow-up of treated patients demonstrated a decrease in insulin concentration after cessation of therapy. In GH-treated subjects, the glucose increase in response to glucose load appeared to be higher than in untreated subjects. CONCLUSION: The high insulin response to glucose load seen in GH-treated subjects was appropriate to their glucose concentration and the insulin sensitivity index was unchanged relative to the pretreatment period. Increased insulin dosage in our patients did not induce an increase in leptin concentrations as had been hypothesised.     

High serum leptin levels in children with type 1 diabetes mellitus: contribution of age, BMI, pubertal development and metabolic status

OBJECTIVE: Children with diabetes mellitus are prone to develop obesity and to experience a delay in onset of the pubertal process. In order to understand the role of leptin in these abnormalities, serum leptin levels were analysed in children with type 1 diabetes mellitus. SUBJECTS: Twenty diabetic girls, 23 diabetic boys and 66 healthy children (selected from a reference population of 706 normal children), age-, sex- and BMI-matched with diabetic patients, were studied. MEASURMENTS: Standing height, weight and BMI were determined in each child. Serum testosterone, oestradiol and leptin were measured by specific radioimmunoassays, and HBA1c by high performance liquid chromatography. RESULTS: Both diabetic girls and boys showed higher leptin levels than the normative healthy population and a group of age-, sex- and BMI-matched normal children. In an age-related analysis, leptin levels in diabetic girls rose from 7.4 +/- 1.2 and 8.1 +/- 2.1 microg/l for the 5-7.99 and 8-10.99 year groups, to 12.6 +/- 2.4 microg/l for the 11-13.99 year group, and to 15.6 +/- 4.0 microg/l in the 14-15.99 year group in parallel with body weight. Leptin concentrations were parallel but higher (P < 0.05) than those of healthy girls. Diabetic boys had lower leptin levels than girls and, in contrast with normal boys, did not show a drop after the 10-year period. Leptin levels were 4.9 +/- 2.2, 3.9 +/- 0.2, 5.5 +/- 0.6 and 5.1 +/- 0.9 microg/l for the 5-7.99, 8-10. 99, 11-13.99 and 14-15.99 year groups, respectively. When divided by pubertal stage, leptin levels in the prepuberty stage of diabetic girls (8.6 +/- 1.0 microg/l) were higher (P < 0.05) than those in the controls (4.1 +/- 0.4 microg/l). In overt puberty girls, leptin was higher (P < 0.05) for diabetic (15.9 +/- 2.9 microg/l) than for healthy girls (9.2 +/- 1.1 microg/l). In prepubertal boys, differences were observed in leptin levels (4.9 +/- 0.5 microg/l for diabetic boys and 3.4 +/- 0.6 microg/l for healthy boys). In the overt puberty stage, diabetic boys showed higher (P < 0.05) levels of leptin (5.2 +/- 0.7 microg/l) than the healthy matched controls (2.1 +/- 0.2 microg/l). A multiple step regression analysis in the diabetic children revealed no associations between leptin and other relevant variables such as glycosylated haemoglobin, daily insulin dose, or years of suffering from the disease. CONCLUSION: Serum leptin levels were higher in diabetic than in healthy children. These differences were not attributable to age, adiposity or stage of pubertal development, and were probably conditioned by the metabolic perturbation intrinsic to the diabetic state, or the chronic hyperinsulinemia.     

Leptin and body fat in type 2 diabetes and monodrug therapy

To better understand the relations among leptin, insulin, and body fat during the metabolic progression to diabetes and during drug monotherapy, metabolic parameters were examined in subjects classified as 1) type 2 diabetes; 2) impaired fasting glucose or mild diabetes mellitus; 3) nondiabetic, matched for body mass index (BMI); and 4) nonobese, nondiabetic. Diabetic subjects were also studied during no pharmacological treatment, after 3 months of randomization to metformin or glyburide, and after 3 months of cross-over to the opposite drug. Log leptin correlated more with percent body fat (slope, 0.042; confidence interval, 0.036-0.047; r(2) = 0.826; P < 0.0001) than with total fat mass, percent truncal or nontruncal fat, or BMI. When normalized to percent fat, leptin did not differ by gender. Leptin normalized to percent fat was 35% less in untreated diabetes than that in BMI-matched controls (P < 0.001). Leptin normalized to percent fat was increased by 25% (P < 0.01) as a result of glyburide therapy compared with pretreatment values, but was unchanged by therapy with metformin. Across a spectrum of subjects with diabetes, impaired fasting glucose/mild diabetes, or BMI-matched nondiabetic controls, normalized leptin significantly correlated with glucose-induced insulin release, but not with insulin sensitivity. Our data suggest that plasma leptin is reduced in untreated type 2 diabetes probably as a consequence of reduced insulin secretion and that circulating leptin concentrations are differentially affected by monodrug therapy.     

Leptin levels as function of age, gender, auxological and hormonal parameters in 202 healthy neonates at birth and during the first month of life

Leptin signals to the brain energy stores and balance while integrating neuroendocrine functions. Leptin levels in adults are higher in females than in males, while a gender-related difference in newborns is controversial. To clarify this point, in 202 healthy neonates we measured dynamic changes in leptin levels over the first month of life and looked for correlation between leptin levels and auxological and hormonal parameters. Cord leptin concentration in females was higher (p < 0.001) than in males. IGF-I, IGF-II, insulin, testosterone and 17beta-estradiol levels were similar in both sexes while insulin-like growth factor binding protein 3 (IGF-BP3) levels in females were slightly higher than in males. Leptin levels were positively associated to body weight, gestational age, IGF-BP3 levels, insulin levels and maternal body mass index (BMI) at time of delivery. In a subset of subjects (no. = 65), in comparison with cord levels, serum leptin levels were decreased on the 5th day of life (p < 0.0001) and then increased at 1 month (p < 0.0001). Positive association between leptin and weight was lost on the 5th day of life but present again at 1 month. In conclusion, our findings in a large population of neonates definitely show that leptin levels at birth are functions of gender, body weight and gestational age but not of length, cranial circumference, IGF-I and IGF-II levels. These findings, coupled with weight-independent prompt decrease after birth followed by weight-dependent increase at one month of life, suggest that leptin secretion in neonates as well as in adults mainly signals the nutritional state to the brain.