Function of the hypothalamo-hypophyseal-adrenal system in mice with ectopic hyperproduction of the agouti protein

The agouti protein is known to compete with the melanocortin hormones (ACTH, melanocyte-stimulating hormone) at melanocortin receptors, which in turn are involved in controlling the central and peripheral components of the hypothalamo-hypophyseal-adrenal system. The aim of the present work was therefore to assess the effects of the dominant mutation Agouti yellow (A ^y/a), which induces ectopic hyperproduction of the agouti protein and yellow coat color, on the function of the hypothalamo-hypophyseal-adrenal system. Experiments were performed on male A ^y/a mice of the C57BI/6J line. Controls consisted of mice of the same line bearing the recessive mutation nonagouti (a/a), which leads to the absence of agouti protein and black coat color. The experimental results showed that mice with different agouti genotypes had identical basal corticosterone levels, though yellow mice, as compared with black mice, had increased corticosterone levels after restriction stress (p < 0.02), along with decreased stress reactivity after treatment with dexamethasone (p < 0.0007), and increased adrenal sensitivity to small doses of activity, both in vitro and in vivo.Translated from Rossiiskii Fiziologicheskii Zhurnal imeni I. M. Sechenova, Vol. 89, No. 7, pp. 851–857, July, 2003.     

Induction of receptor for advanced glycation end products by insufficient leptin action triggers pancreatic β‐cell failure in type 2 diabetes

Glucolipotoxicity, which is exerted by free fatty acids (FFA) and prolonged hyperglycemia, is implicated in pancreatic β‐cell failure in diabetes. Pattern recognition receptors such as receptor for advanced glycation end products (RAGE) and toll‐like receptors 2 and 4 could mediate danger signals in β‐cells. We examined whether RAGE contributes to β‐cell failure in a type 2 diabetes mouse model. Pancreatic islets were isolated from ob/ob, db/db, diet‐induced obesity (DIO), RAGE‐null (RAGE^−/−), and RAGE^+/+ wild‐type (WT) control mice and dispersed into single cells for flow cytometry. RAGE expression was detected in insulin‐positive β‐cells of ob/ob and db/db mice, but not of WT, DIO, or RAGE^−/− mice: thus, inadequate leptin receptor signaling and RAGE expression may be linked. Compared with RAGE^+/+ db/db mice, RAGE^−/− db/db mice showed higher β‐cell number and mass with less apoptosis as well as glucose tolerance with higher insulin secretion without any differences in serum levels of FFA and adiponectin. Palmitate or oleate pretreatment combined with a leptin antagonist induced RAGE expression, AGE‐elicited apoptosis, and impaired glucose‐stimulated insulin secretion by advanced glycation end products (AGE) in MIN6 cells. FFA elevation with concomitant AGE formation during prolonged hyperglycemia could cause β‐cell damage through insufficient leptin action and subsequent RAGE induction in type 2 diabetes.     

Diet‐induced obesity disrupts ductal development in the mammary glands of nonpregnant mice

Mammary glands develop postnatally in response to the hypothalamic‐pituitary‐gonadal axis. Obesity‐induced changes in the local environment, however, retard mammary gland development during late pregnancy and lactation. To clarify the effects of obesity on fundamental duct development, we compared the mammary glands of nulliparous nonpregnant obese mice fed a high‐fat diet with those of lean mice fed a normal diet. Obese mice had enlarged mammary glands, reflecting fat pad size, whereas the ducts in obese mice showed a less dense distribution with less frequent branching. Additionally, the ducts were surrounded by thick collagen layers, and were incompletely lined with myoepithelium. Because leptin receptors were localized in the epithelium region and leptin that was highly expressed in the obese glands suppressed mammary epithelial cell proliferation in vitro, the present results suggest that obesity disrupts mammary ductal development, possibly by remodeling the mammary microenvironment and promoting the expression of such paracrine factors as leptin. Developmental Dynamics 238:1092–1099, 2009. © 2009 Wiley‐Liss, Inc.     

Neonatal exposure to leptin reduces glucose tolerance in adult mice

Aim: The aim of this study was to evaluate the effect of leptin treatment in mouse neonates on glucose metabolism in adulthood. Methods: Leptin was administered subcutaneously to normally nourished neonates, from 5.5 to 10.5 days of age, to mimic the premature surge observed in neonates undernourished in utero. At 15–16 weeks of age, we measured blood glucose or insulin levels after the intraperitoneal administration of glucose or insulin. Results: After the intraperitoneal administration of glucose, the levels of blood glucose, but not insulin, in adult mice that received the neonatal leptin treatment were significantly higher than that of those which received vehicle control. After the intraperitoneal administration of insulin, the levels of blood glucose in adult mice that underwent neonatal leptin treatment were significantly higher than that of those which received vehicle control. Conclusion: These findings suggest that the premature leptin surge plays an essential role, as a programming signal during the early neonatal period, as well as in the developmental origins of impaired insulin sensitivity.     

Regulation of Food Consumption during Pregnancy and Lactation in Mice

The aim of the present work was to assess the expression of agouti-like protein and neuropeptide Y in pregnant and lactating mice and to compare this with the leptin level and food consumption. Food consumption, blood leptin levels, and agouti-like protein and neuropeptide Y mRNA levels in the hypothalamus of C57Bl/6J mice were assessed on days 7, 13, and 18 of pregnancy and on days 10 and 21 of lactation, and in virgin females of the same ages. During pregnancy, food consumption and leptin levels decreased on day 7 and increased in day 18 of pregnancy, while neuropeptide Y mRNA levels increased on day 13 and then remained unaltered, and the agouti-like protein level increased on day 18. After parturition, food consumption continued to increase, while leptin levels and neuropeptide Y mRNA levels decreased to normal. Thus, hyperphagia in pregnancy was due to sequential activation of the expression of neuropeptide Y and agouti-like protein, while in lactation hyperphagia resulted from mechanisms not associated with changes in the expression of these neuropeptides.     

The metabolic profile in patients with skin tags

Although skin tags are associated with diabetes mellitus, insulin resistance, hypertension, obesity, atherogenic lipid profile, no data in the literature show that the presence of skin tags is associated with serum high-sensitive C-reactive protein, uric acid, free fatty acid and leptin level. The purpose of this study was to evaluate the frequency of hypertension, dyslipidemia, insulin resistance and obesity in patients with skin tags and to compare patients with skin tags and normal healthy subjects for insulin resistance, serum lipids, insulin, glucose, leptin, high-sensitive C-reactive protein, free fatty acid levels. We evaluated 113 patients with skin tags and 31 healthy subjects. The two groups were compared with respect to BMI, lipid profile, blood pressure, insulin resistance, serum lipids, insulin, glucose, leptin, high-sensitive C-reactive protein, free fatty acid and homeostatic model assessment of insulin resistance (HOMA-IR). Total 53.9 and 33.6% of patients with skin tags were overweight and obese, respectively. The frequency of hypertension 30.1%, dyslipidemia 59.3% and insulin resistance 21.2% were detected. HOMA-IR (P < 0.001) and serum glucose (P < 0.001), insulin (P = 0.002), high-sensitive C-reactive protein (P = 0.001), uric acid (P = 0.001), free fatty acid (P = 0.002), HbA1c (P < 0.001), total cholesterol (P = 0.018), LDL-cholesterol (P = 0.023), and triglyceride levels (P = 0.001) were higher in patients with skin tags than control group. Overweight and/or obesity, dyslipidemia, hypertension, insulin resistance and elevated high-sensitive C-reactive protein are seen in patients with skin tags. Skin tags may be a marker of increased risk of atherosclerosis and cardiovascular disease.     

Plasma leptin and insulin in C57Bl/6J mice on a high-fat diet: relation to subsequent changes in body weight

It has been proposed that leptin and insulin through central effects are involved in the regulation of energy balance and body weight. Whether circulating leptin or insulin levels predict subsequent changes in body weight is, however, not known. We examined plasma leptin and insulin at 2, 3, 6, 9 and 12 months of age in C57Bl/6J mice given a normal diet (n = 12) or a high-fat diet (58% fat on a caloric base; n = 15). Plasma leptin levels increased by age and correlated with body weight in the entire material (r = 0.81, P < 0.001). Also plasma insulin increased by high-fat diet and correlated across all age periods with body weight (r = 0.56, P < 0.001). In mice, given normal diet, plasma leptin or insulin did not correlate to subsequent changes in body weight at any of the time points studied. However, in mice given the high-fat diet, plasma leptin at 6 (r = ?0.57, P = 0.027) and 9 months of age (r = ?0.56, P = 0.042) as well as plasma insulin at 6 (r = ? 0.51, P = 0.049) and 9 months (r = ?0.58, P = 0.037) correlated inversely to the change in body weight during the subsequent 3-month period. Hence, both leptin and insulin are negative predictors for future weight gain in high-fat fed mice. This suggests that when the regulation of body weight is challenged by a high-fat diet, leptin and insulin act to restrain or prevent future weight gain. This in turn may suggest that impairment of these (probably central) actions of leptin and insulin might underlie excessive increase in body weight under such conditions.     

Glucose and insulin responses during mixed meals or infusion of glucose in pregnant and lactating rats

We studied the glucose tolerance in freely moving rats throughout pregnancy and lactation and during the first week after weaning. Dioestrous virgin rats served as controls. Basal glucose and insulin levels were determined after a 2-hr fasting period. Subsequently, the changes of the insulin and the glucose levels were determined during ingestion of a mixed ad lib meal or a 2 g mixed test meal, or during infusion of glucose (7.4 mg/min for 20 min) into the vena cava. Basal glucose levels were high during early pregnancy, low during late pregnancy, and in the normal range throughout lactation and after weaning. Basal insulin levels were decreased at the end of lactation. The results of the ad lib meal and test meal experiments were essentially the same. Glucose tolerance during meals was somewhat decreased early in pregnancy. The corresponding insulin responses greatly increased during the last week of pregnancy. Glucose tolerance during IV infusion of glucose was normal during pregnancy, but increased during lactation. Insulin responses to the infusion were increased during pregnancy and decreased during lactation. We concluded that glucose tolerance is hardly affected by pregnancy and even increases in the course of lactation. This is effected by an increased responsiveness of the B-cells to glucose during late pregnancy and by an increased turnover of glucose during lactation. We discuss to what extent the actions of progesterone, placental lactogen and prolactin may explain these adaptions of maternal metabolism.     

Leptin and thermogenesis in humans

We examined changes in serum leptin concentrations and thermogenesis in 12 healthy men (39 ± 2 years, BMI 22.8 ± 0.3 kg m^?2) during a 4 h euglycaemic hyperinsulinaemia performed on a control day and after a day of a competitive marathon run. As compared with the control day, after the marathon, baseline FFA concentration (543 ± 0.73 vs. 955 ± 96 μmol L^?1, P < 0.05), lipid oxidation rate (0.8 ± 0.1 vs. 1.2 ± 0.1 mg kg^?1 min^?1}, P < 0.01) and energy expenditure (5.2 ± 0.1 vs. 5.5 ± 0.1 kJ min^?1}, P < 0.01) were elevated. Baseline serum leptin concentrations were similar on the control and postexercise days and increased during insulin infusion by 35–45% on both days (P ≤ 0.01). Baseline serum leptin concentration correlated directly with serum insulin ( r = 0.65, P < 0.05) and cortisol ( r = 0.64, P < 0.05), and inversely with serum growth hormone concentration ( r = ?0.66, P < 0.05). In the postexercise study, the rise in energy expenditure during insulin clamp correlated with serum leptin concentration as determined before ( r = 0.61, P < 0.05) or at the end of insulin infusion ( r = 0.55, P < 0.05). Thus, in healthy individuals with normal body weight: (1) hyperinsulinaemia increases serum leptin concentrations; (2) a rise in energy expenditure correlates with serum leptin concentration. These data suggest that leptin is involved in the regulation of energy expenditure in humans.     

Intermittent Hypoxia Increases Insulin Resistance in Genetically Obese Mice

Obstructive sleep apnoea, a syndrome that leads to recurrent intermittent hypoxia, is associated with insulin resistance in obese individuals, but the mechanisms underlying this association remain unknown. We utilized a mouse model to examine the effects of intermittent hypoxia on insulin resistance in lean C57BL/6J mice and leptin-deficient obese (C57BL/6J− Lep ^ob) mice. In lean mice, exposure to intermittent hypoxia for 5 days (short term) resulted in a decrease in fasting blood glucose levels (from 173 ± 11 mg dl⁻¹ on day 0 to 138 ± 10 mg dl⁻¹ on day 5, P < 0.01), improvement in glucose tolerance without a change in serum insulin levels and an increase in serum leptin levels in comparison with control (2.6 ± 0.3 vs. 1.7 ± 0.2 ng ml⁻¹, P < 0.05). Microarray mRNA analysis of adipose tissue revealed that leptin was the only upregulated gene affecting glucose uptake. In obese mice, short-term intermittent hypoxia led to a decrease in blood glucose levels accompanied by a 607 ± 136 % (   P < 0.01  ) increase in serum insulin levels. This increase in insulin secretion after 5 days of intermittent hypoxia was completely abolished by prior leptin infusion. Obese mice exposed to intermittent hypoxia for 12 weeks (long term) developed a time-dependent increase in fasting serum insulin levels (from 3.6 ± 1.1 ng ml⁻¹ at baseline to 9.8 ± 1.8 ng ml⁻¹ at week 12, P < 0.001) and worsening glucose tolerance, consistent with an increase in insulin resistance. We conclude that the increase in insulin resistance in response to intermittent hypoxia is dependent on the disruption of leptin pathways.     

Therapeutic Effect of Carboxymethylated and Quanternized Chitosan on Insulin Resistance in High-Fat-Diet-Induced Rats and 3T3-L1 Adipocytes

Abstract

Owing to their distinct biochemical properties, chitosan and its derivatives have a great potential in a range of bioapplications. One such application is as a dietary antilipidemic supplement to be used in reducing obesity and to improve insulin resistance. The lipid-binding efficiency of chitosan and its derivatives, however, remains debatable. Accordingly, in this study we investigated the interaction of chitosan and its two derivatives, O-carboxymethyl chitosan (O-CMCs) and N-[(2-hydroxy-3-N,N-dimethylhexadecyl ammonium)propyl]chitosan chloride (N-CQCs), with plasma leptin, glucose, insulin and total cholesterol in a diet-induced insulin-resistant rat model, and further interaction with mRNA expression of adipocytokines and its related molecule PPAR-γ. The experiments were performed using the RT-PCR technique in cultured 3T3-L1 adipocytes, in which the mRNA expression of leptin, adiponectin, resistin and PPAR-γ was recorded in the absence and presence of chitosan, O-CMCs and N-CQCs. The experimental results proved that chitosan, O-CMCs and N-CQCs not only lowered the level of plasma leptin, glucose, insulin and total cholesterol in vivo, but down-regulated mRNA expression of leptin and resistin, and up-regulated mRNA expression of adiponectin and PPAR-γ in vitro, to achieve the desired insulin resistance therapy.     

Improved insulin‐stimulated glucose uptake and glycogen synthase activation in rat skeletal muscles after adrenaline infusion: role of glycogen content and PKB phosphorylation

Aim: Effects of in vivo adrenaline infusion on subsequent insulin‐stimulated glucose uptake and glycogen synthase activation was investigated in slow‐twitch (soleus) and fast‐twitch (epitrochlearis) muscles. Furthermore, role of glycogen content and Protein kinase B (PKB) phosphorylation for modulation insulin sensitivity was investigated. Methods: Male Wistar rats received adrenaline from osmotic mini pumps (≈150 μg kg^?1 h^?1) for 1 or 12 days before muscles were removed for in vitro studies. Results: Glucose uptake at physiological insulin concentration was elevated in both muscles after 1 and 12 days of adrenaline infusion. Insulin‐stimulated glycogen synthase activation was also improved in both muscles. This elevated insulin sensitivity occurred despite the muscles were exposed to hyperglycaemia in vivo. After 1 day of adrenaline infusion, glycogen content was reduced in both muscles; insulin‐stimulated PKB ser⁴⁷³ phosphorylation was increased in both muscles only at the highest insulin concentration. After 12 days of adrenaline infusion, glycogen remained low in epitrochlearis, but returned to normal level in soleus; insulin‐stimulated PKB phosphorylation was normal in both muscles. Conclusion: Insulin‐stimulated glucose uptake and glycogen synthase activation were increased after adrenaline infusion. Increased insulin‐stimulated glucose uptake and glycogen synthase activation after adrenaline infusion cannot be explained by a reduction in glycogen content or an increase in PKB phosphorylation. The mechanisms for the improved insulin sensitivity after adrenaline treatment deserve particular attention as they occur in conjunction with hyperglycaemia.     

The roles of leptin receptors on POMC neurons in the regulation of sex-specific energy homeostasis

Leptin regulates energy homeostasis and reproduction. One key population of leptin receptors (Lepr) are found on proopiomelanocortin (POMC) neurons in the hypothalamic arcuate nucleus, and evidence links the action of gonadal estrogens to these same POMC neurons. To determine whether Lepr on POMC neurons are critical for reproductive capacity or for sex-specific energy and glucose homeostasis, we studied Cre/loxP mice lacking Lepr specifically on POMC neurons (Pomc-Cre, Lepr^flox/flox mice) and their controls with normal Lepr (Lepr^flox/flox mice). Pomc-Cre, Lepr^flox/flox mice maintained normal reproductive capacity and accumulated more body fat than their same sex controls. Ovariectomy (OVX) was performed to investigate the effects of the estrogens and Lepr on POMC neurons on body fat accumulation and glucose tolerance. OVX Pomc-Cre, Lepr^flox/flox females accumulated more fat than OVX Lepr^flox/flox females did. Pomc-Cre, Lepr^flox/flox males were glucose intolerant and insulin insensitive compared with control males. In contrast, control and Pomc-Cre, Lepr^flox/flox females had similar glucose tolerance before and after OVX. Therefore leptin's action on POMC neurons reduces body fat accumulation, but is not critical for regulation of reproduction. The sex difference in leptin signaling on POMC neurons on glucose tolerance appears independent of ovarian hormones.     

Reducing plasma free fatty acids by acipimox improves glucose tolerance in high‐fat fed mice

To study whether free fatty acids (FFAs) contribute to glucose intolerance in high‐fat fed mice, the derivative of nicotinic acid, acipimox, which inhibits lipolysis, was administered intraperitoneally (50 mg kg^?1) to C57BL/6J mice which had been on a high‐fat diet for 3 months. Four hours after administration of acipimox, plasma FFA levels were reduced to 0.46 ± 0.06 mmol L^?1 compared with 0.88 ± 0.10 mmol L^?1 in controls (P < 0.001). At this point, the glucose elimination rate after an intravenous glucose load (1 g kg^?1) was markedly improved. Thus, the elimination constant (K_G) for the glucose disposal between 1 and 50 min after the glucose challenge was increased from 0.54 ± 0.01% min^?1 in controls to 0.66 ± 0.01% min^?1 by acipimox (P < 0.001). In contrast, the acute insulin response to glucose (1–5 min) was not significantly different between the groups, although the area under the insulin for the entire 50‐min period after glucose administration was significantly reduced by acipimox from 32.1 ± 2.9 to 23.9 ± 1.2 nmol L^?1 × 50 min (P=0.036). This, however, was mainly because of lower insulin levels at 20 and 50 min because of the lowered glucose levels. In contrast, administration of acipimox to mice fed a normal diet did not affect plasma levels of FFA or the glucose elimination or insulin levels after the glucose load. It is concluded that reducing FFA levels by acipimox in glucose intolerant high‐fat fed mice improves glucose tolerance mainly by improving insulin sensitivity making the ambient islet function adequate, suggesting that increased FFA levels are of pathophysiological importance in this model of glucose intolerance.     

TRPM5 in the battle against diabetes and obesity

TRPM5 is a non‐selective monovalent cation channel activated by increases in intracellular Ca²⁺. It has a distinct expression pattern: expression is detected in chemosensitive tissues from solitary chemosensory cells to the taste receptor cells and in pancreatic β‐cells. The role of TRPM5 has been investigated with the use of knockout mouse models. Trpm5^?/? mice have a lack of type II taste perception and show reduced glucose‐induced insulin secretion. Expression levels of TRPM5 are reduced in obese, leptin‐signalling‐deficient mice, and mutations in TRPM5 have been associated with type II diabetes and metabolic syndrome. In this review, we aim to give an overview of the activation, selectivity, modulation and physiological roles of TRPM5.     

Glucagon-like peptide-1 reduces hepatic glucose production indirectly through insulin and glucagon in humans

The effect of glucagon-like peptide-1 (GLP-1) on hepatic glucose production and peripheral glucose utilization was investigated with or without infusion of somatostatin to inhibit insulin and glucagon secretion in 13 healthy, non-diabetic women aged 59 years. After 120 min 3-³H-glucose infusion, GLP-1 was added (4.5 pmol kg^?1 bolus + 1.5 pmol kg^?1 min^?1). Without somatostatin (n = 6), GLP-1 decreased plasma glucose (from 4.8 ± 0.2 to 4.2 ± 0.3 mmol L^?1, P = 0.007). Insulin levels were increased (48 ± 3 vs. 243 ± 67 pmol L^?1, P = 0.032), as was the insulin to glucagon ratio (P = 0.044). The rate of glucose appearance (R_a) was decreased (P = 0.003) and the metabolic clearance rate of glucose (MCR) was increased during the GLP-1 infusion (P = 0.024 vs. saline). Also, the rate of glucose disappearance (R_d) was reduced during the GLP-1 infusion (P = 0.004). Since R_a was reduced more than R_d, the net glucose flow was negative, which reduced plasma glucose. Somatostatin infusion (500 μg h^?1, n = 7) abolished the effects of GLP-1 on plasma glucose, serum insulin, insulin to glucagon ratio, R_a, R_d, MCR and net glucose flow. The results suggest that GLP-1 reduces plasma glucose levels mainly by reducing hepatic glucose production and increasing the metabolic clearance rate of glucose through indirectly increasing the insulin to glucagon ratio in healthy subjects.     

Effect of intraperitoneal injection of glucose on glucose oxidation and energy expenditure in the mdx mouse model of Duchenne muscular dystrophy

Previous studies suggesting that glucose metabolism could be impaired in the skeletal muscles of the mdx mouse led us to study the metabolic response to i.p. injection of either glucose or glucose and insulin in the free-moving mdx mouse. In the first study, changes in blood glucose and plasma insulin levels were measured in mice with chronic venous cannulae. In the second study, the thermogenic response to glucose and the changes induced on glucose oxidation (G _ox) and lipid oxidation (L _ox) were assessed by indirect calorimetry. The experiments showed that insulin response, as well as whole body glucose uptake, were normal in mdx mice. Addition of exogenous insulin abolished the increase in blood glucose level similarly in mdx and control mice. The thermogenic response to glucose was identical in mdx and control mice but, when insulin was injected with glucose, it increased significantly in mdx mice. Exogenous glucose increased G _ox less and decreased L _ox less in mdx than in control mice. Addition of exogenous insulin reduced the difference between mdx and control mice but affected G _ox and L _ox less in mdx than in control mice. Received: 6 November 1995/Received after revision: 13 February 1995/Accepted: 21 March 1996     

Plasma leptin and insulin levels in Aymara natives from Chile

The purpose of this study was to examine the relationship of plasma leptin levels with respect to obesity, gender, age and insulin levels in the native Aymara population. The Aymara natives live at high altitudes in isolated regions in the north of Chile, and they maintain distinctive genetic and cultural characteristics. Plasma leptin and insulin levels were correlated with body mass index (BMI), sex and age in a sample of 147 adult Aymara subjects who participated in a cross-sectional study. Multivariate analysis showed significant differences in leptin levels (dependent variable: natural log of leptin) by gender (p &lt; 0.0001), and by BMI (p &lt; 0.001), without significant statistical interaction between gender and BMI. The effect of age achieved statistical significance in the multivariate analysis (p = 0.02). Gender, BMI and insulin are independently associated with plasma leptin levels. On the other hand, the multivariate analysis of the plasma insulin concentration (dependent variable: natural log of insulin levels) shows that insulin is strongly associated with BMI (p &lt; 0.0001), although non-statistically significant differences of insulin levels by sex (p = 0.07) or age (p = 0.9) were detected at alpha 0.05 level. Thus, in the special ecosystem where the Aymara population live, a strong and independent association between sex, obesity and insulin levels with plasma leptin levels has been detected.     

Suckling increases insulin and glucagon levels in peripheral venous blood of lactating dogs

The aim of the present investigation was to study changes in insulin, glucagon and plasma glucose levels in response to suckling in lactating dogs. Blood samples were drawn from a peripheral vein during suckling in weeks 1 and 3 of lactation in 10 lactating beagles. Insulin- and glucagon-like immunoreactivity (below referred to as insulin and glucagon) were determined by radio-immunoassay, and plasma glucose levels by the glucose oxidase method. Insulin and glucagon levels rose following onset of suckling. However, only the rises recorded in week 3 of lactation were statistically significant. Plasma glucose levels were not affected. The mechanism by which suckling influences the levels of insulin and glucagon is not known. However, the release of both hormones is under vagal control and it is possible that touching of the teats reflexly elicits a vagally mediated release of these hormones. Alternatively, since oxytocin stimulates the secretion of insulin and glucagon, the effects might be secondary to the oxytocin released by suckling. The physiological function of the suckling-related release of insulin may be to stimulate milk production. Furthermore, since glucagon is also released, each suckling period may be accompanied by a transfer of glucose to the mammary glands from other maternal stores.     

Influence of hypo- and hyperglycaemia on plasma leptin concentrations in healthy women and in women with polycystic ovary syndrome

BACKGROUND: Insulin resistance and obesity play an important role in the pathogenesis of polycystic ovary syndrome (PCOS). It is known that experimentally induced insulin resistance diminishes the stimulatory effect of insulin on leptin secretion. It is not yet known whether the long-term insulin resistance as found in PCOS patients alters the leptin response to hypo- and hyperglycaemia. METHODS: We induced hyper- and hypoglycaemia by glucose clamp technique in 7 patients with PCOS and 20 healthy controls. After a plasma glucose level of 8.8 mmol/l was reached, the plasma glucose level was reduced stepwise to 6.8, 4.8 and 2.8 mmol/l. RESULTS: The PCOS patients required lower glucose infusion rates to reach the glycaemic targets (P < 0.05). Serum insulin and C-peptide concentrations increased significantly during the clamp compared with the baseline in both groups (P < 0.001 for insulin, and P < 0.001, P < 0.005 for C-peptide control and PCOS, respectively) and increased significantly more in PCOS patients compared with the control group (both P < 0.05). Basal leptin levels were significantly higher in the PCOS group than in the control group (P = 0.005). In the controls, the leptin concentration increased significantly during the clamp (P < 0.001 for each glycaemic target), whereas in the PCOS group, leptin secretion increased only during hypoglycaemia (P = 0.04). CONCLUSIONS: Compared with the healthy controls, the response of leptin secretion to hyper- and hypoglycaemia was diminished in PCOS patients. Changes in leptin secretion seem not to be caused by hyper- and hypoglycaemia, but rather by hyperinsulinaemia. Reduced insulin sensitivity seems to be responsible for the diminished leptin response, which might contribute to the obesity found in PCOS patients.