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Gestational Diabetes Mellitus (GDM) is a highly prevalent maternal pathology characterized by maternal glucose intolerance during pregnancy that is, associated with severe complications for both mother and offspring. Several risk factors have been related to GDM; one of the most important among them is genetic predisposition. Numerous single nucleotide polymorphisms (SNPs) in genes that act at different levels on various tissues, could cause changes in the expression levels and activity of proteins, which result in glucose and insulin metabolism dysfunction. In this review, we describe various SNPs; which according to literature, increase the risk of developing GDM. These SNPs include: (1) those associated with transcription factors that regulate insulin production and excretion, such as rs7903146 (TCF7L2) and rs5015480 (HHEX); (2) others that cause a decrease in protective hormones against insulin resistance such as rs2241766 (ADIPOQ) and rs6257 (SHBG); (3) SNPs that cause modifications in membrane proteins, generating dysfunction in insulin signaling or cell transport in the case of rs5443 (GNB3) and rs2237892 (KCNQ1); (4) those associated with enzymes such as rs225014 (DIO2) and rs9939609 (FTO) which cause an impaired metabolism, resulting in an insulin resistance state; and (5) other polymorphisms, those are associated with growth factors such as rs2146323 (VEGFA) and rs755622 (MIF) which could cause changes in the expression levels of these proteins, producing endothelial dysfunction and an increase of pro-inflammatory cytokines, characteristic on GDM. While the pathophysiological mechanism is unclear, this review describes various potential effects of these polymorphisms on the predisposition to develop GDM. [ABSTRACT FROM AUTHOR]

The human insulin receptor (IR) exists in two isoforms that differ by the absence (IR-A) or the presence (IR-B) of a 12-amino acid segment encoded by exon 11. Both isoforms are functionally distinct regarding their binding affinities and intracellular signalling. However, the underlying mechanisms related to their cellular functions in several tissues are only partially understood. In this review, we summarize the current knowledge in this field regarding the alternative splicing of IR isoform, tissue-specific distribution and signalling both in physiology and disease, with an emphasis on the human placenta in gestational diabetes mellitus (GDM). Furthermore, we discuss the clinical relevance of IR isoforms highlighted by findings that show altered insulin signalling due to differential IR-A and IR-B expression in human placental endothelium in GDM pregnancies. Future research and clinical studies focused on the role of IR isoform signalling might provide novel therapeutic targets for treating GDM to improve the adverse maternal and neonatal outcomes. [ABSTRACT FROM AUTHOR]

The effects of a double replacement of fish oil (FO) and fish meal (FM) by dietary vegetable ingredients in juvenile gilthead sea bream ( Sparus aurata L. 1758) on some indices of lipid metabolism and plasma insulin levels were analysed. Four experimental diets with a replacement of 75% of FM by plant proteins (PP) were administered. Added oil was either FO (75PP/FO diet), or a vegetable oil mix (VO), replacing 33%, 66% or 100% of FO (75PP/33VO, 75PP/66VO, 75PP/100VO diets). Another diet with 50% of substitution of FM by PP and with 100% of VO was also tested (50PP/100VO diet). Final body weight was similar in all diet groups, except for the 75PP/100VO group, which presented lower values. Circulating insulin levels increased with feed administration in all groups and no differences between diets were observed, with the exception of the 75PP/FO group, which presented higher plasma insulin values. In adipose tissue, glucose-6-phosphate dehydrogenase and malic enzyme activities decreased with the inclusion of vegetable oil, especially 5 h after feeding. Diet had no significant effect on the hepatic activity of either enzyme. Lipoprotein lipase activity decreased in white muscle and adipose tissue with the replacement of fish oil in 75PP diets, 5 h after feeding. In conclusion, the use of a combined replacement of fish oil and fish meal by vegetable ingredients in gilthead sea bream permits satisfactory growth, with moderate changes in tissue lipogenesis and lipid uptake. [ABSTRACT FROM AUTHOR]

Primary cultures of rainbow trout (Oncorhynchus mykiss) adipocytes were used to examine the main signaling pathways of insulin and insulin-like growth factor I (IGF-I) during adipogenesis. We first determined the presence of IGF-I receptors (IGF-IR) and insulin receptors (IR) in trout preadipocytes (day 5) and adipocytes (day 14). IGF-IRs were more abundant and appeared to be in higher levels in differentiated cells than in preadipocytes, whereas IRs were detected in lower but constant levels throughout the culture. The cells were immunoreactive against ERK1/2 MAPK, and AKT/PI3K, components of the two main signal transduction pathways for insulin and IGF-I receptors. Stimulation of MAPK phosphorylation by IGF-I was higher in preadipocytes than in adipocytes, while no effects were observed in MAPK phosphorylation after incubation of cells with insulin. AKT phosphorylation increased in the presence of both insulin and IGF-I, with higher levels of stimulation in adipocytes than in preadipocytes. Activation of both pathways was blocked by the use of specific inhibitors of MAPK (PD98059) and AKT (wortmannin). We describe here, for the first time, the effects of IGF-I and insulin on 2-deoxyglucose uptake in primary culture of trout adipocytes. IGF-I was more potent in stimulating glucose uptake than insulin, and PD98059 and wortmannin inhibited the stimulation of glucose uptake by this growth factor, suggesting that IGF-I plays an important metabolic role in trout adipocytes. Our results suggest that differential activation of the MAPK and AKT pathways are involved in the IGF-I- and insulin-induced effects of trout adipocytes during the various stages of adipogenesis. [ABSTRACT FROM AUTHOR]

The effects of dietary amino acid profile (based on muscle (M) or whole body composition (WB) and the balance between indispensable (IAA) and dispensable amino acids (DAA) in the diet, on plasma levels of insulin and glucagon, were analysed in rainbow trout and gilthead sea bream. Plasma insulin values (baseline and 6 h postfeeding) were higher in trout than in sea bream, but the relative postfeeding increase was more pronounced in sea bream. Within the same dietary amino acid profile, diets with lower IAA/DAA, had a lower effect on the postfeeding secretion of insulin in both species. Circulating levels of glucagon (baseline and postfeeding relative increases) were higher in sea bream. In trout, diets with WB amino acid profile had a greater secretory effect on postfeeding glucagon than did diets with M profile, while gilthead sea bream showed an inverse response to circulating glucagon with respect to diet. Muscle insulin and insulin growth factor-I binding parameters were not affected by the dietary regimen. The postfeeding glucagon response depends on both the dietary AA profile and the fish species, while that of insulin seems to be more uniform, and is affected in a similar way regardless of the species. [ABSTRACT FROM AUTHOR]

We examined the effects of diet composition and fasting on lipolysis of freshly isolated adipocytes from gilthead seabream (Sparus aurata). We also analyzed the effects of insulin, glucagon, and growth hormone (GH) in adipocytes isolated from fish fed with different diets. Basal lipolysis, measured as glycerol release, increased proportionally with cell concentration and time of incubation, which validates the suitability of these cell preparations for the study of hormonal regulation of this metabolic process. Gilthead seabream were fed two different diets, FM (100% of fish meal) and PP (100% of plant protein supplied by plant sources) for 6 wk. After this period, each diet group was divided into two groups: fed and fasted (for 11 days). Lipolysis was significantly higher in adipocytes from PP-fed fish than in adipocytes from FM-fed fish. Fasting provoked a significant increase in the lipolytic rate, about threefold in isolated adipocytes regardless of nutritional history. Hormone effects were similar in the different groups: glucagon increased the lipolytic rate, whereas insulin had almost no effect. GH was clearly lipolytic, although the relative increase in glycerol over control was lower in isolated adipocytes from fasted fish compared with fed fish. Together, we demonstrate for the first time that lipolysis, measured in isolated seabream adipocytes, is affected by the nutritional state of the fish. Furthermore, our data suggest that glucagon and especially GH play a major role in the control of adipocyte lipolysis. [ABSTRACT FROM AUTHOR]

Abstract: A preadipocyte primary cell culture was established to gain knowledge about adipose tissue development in gilthead sea bream (Sparus aurata), one of the most extensively produced marine aquaculture species in the Mediterranean. The preadipocytes obtained from the stromal-vascular cell fraction of adipose tissue proliferated in culture, reaching confluence around day 8. At that time, the addition of an adipogenic medium promoted differentiation of the cells into mature adipocytes, which showed an enlarged cytoplasm filled with lipid droplets. First, cell proliferation and differentiation were analyzed under control and adipogenic conditions during culture development. Next, the effects of insulin, GH, and IGF-I on cell proliferation were evaluated at day 8. All peptides significantly stimulated proliferation of the cells after 48 h of incubation (P < 0.002 for GH and IGF-I and P < 0.05 for insulin), despite no differences were observed between the different doses tested. Subsequently, the effects of insulin and IGF-I maintaining differentiation when added to growth medium were studied at day 11, after 3 d of induction with adipogenic medium. The results showed that IGF-I is more potent than insulin enhancing differentiation (P < 0.01 for IGF-I compared with the control). In summary, a primary culture of gilthead sea bream preadipocytes has been characterized and the effects of several regulators of growth and development have been evaluated. This cellular system can be a good model to study the process of adipogenesis in fish, which may help improve the quality of the product in aquaculture. [Copyright &y& Elsevier]

Abstract: Adipose tissue plays a central role regulating the balance between deposition and mobilization of lipid reserves. Lipoprotein lipase (LPL) is a key enzyme controlling lipid accumulation in mammals and fish. In the present study, we have examined the expression of LPL in rainbow trout cultured adipocytes and we have investigated the effect of troglitazone, a member of thiazolidinediones (TZDs), and insulin on its expression. LPL gene expression increased from day 1 until day 12 of culture, and the level was maintained up to day 21. The addition of insulin at 10 nM and 1.7μM increased significantly LPL gene expression in undifferentiated cells (days 7 to 12 maintained in growth medium). Nevertheless, treatment of day 7 cells incubated in growth medium with troglitazone (5μM) or troglitazone plus insulin (1μM each), tended to enhance LPL expression. In addition, LPL mRNA levels increased significantly in the presence of 1μM and 5μM of troglitazone (days 7 to 12) when the cells were induced to differentiate by addition of differentiation medium. Although troglitazone alone (1μM) did not stimulate lipid accumulation in the cells neither in growth nor in differentiation medium, the simultaneous presence of troglitazone (1μM) and insulin (1μM) increased significantly the content of triglycerides in adipocyte cells maintained in growth medium (days 7 to 12). These results indicate that insulin and troglitazone regulate LPL gene expression during adipocyte differentiation and suggest that both factors may have combined effects in the modulation of adipogenesis. [Copyright &y& Elsevier]

The aim of this study was to determine the effects of growth hormone (GH) and insulin-like growth factor (IGF)-I on glycerol release and the regulation of IGF-I and IGF-II expression by GH in isolated rainbow trout adipocytes. Cells were also incubated with GH, tumor necrosis factor α (TNFα), or insulin to analyze the gene expression of peroxisome proliferator-activated receptors (PPARs) and lipid metabolism markers: hormone sensitive lipase, fatty acid synthase (FAS), and lipoprotein lipase. Complimentary in vivo experiments were performed by intraperitoneally administering insulin, TNFα, or lipopolysaccharide and subjecting the animals to fasting and refeeding periods. The results showed that IGF-I had an antilipolytic effect and GH had a lipolytic effect; the latter occurred independently of IGF modulation and in conjunction with a reduction in PPARα expression in adipocytes. The anabolic action of insulin was demonstrated through its upregulation of lipogenic genes such as lipoprotein lipase, FAS, and PPARγ, whereas GH, by contrast, inhibited FAS expression in adipose tissue. The gene transcription levels of PPARs changed differentially during fasting and refeeding, and the TNFα and/or lipopolysaccharide administration suggested that the regulation of PPARs helps maintain metabolic adipose tissue homeostasis in rainbow trout. [ABSTRACT FROM AUTHOR]

Abstract: A glucose tolerance test was performed in European sea bass juveniles to evaluate the effect of a glucose load on plasma insulin and insulin-like growth factor-I (IGF-I) levels. Interaction between these hormones, plasma triacylglycerides and liver glycogen was also determined. After being fasted for 48h, fish were intraperitoneally injected with either 1g of glucose per kg body weight or a saline solution. Plasma glucose levels peaked at 23–25mmoll−1, 2–6h after the glucose injection and fish exhibited hyperglycemia until 12h, when plasma glucose recovered to basal levels. Plasma insulin levels did not change significantly between sampling points, but insulin level was higher in the glucose group than in the control 4–6h and 24h after injection. Though plasma IGF-I levels remained constant for a long time (except at time 12h) in the glucose injected fish, at times 6–9h, 24h and 48h IGF-I levels were higher in the glucose group than in the control. Glucose administration led to lower plasma triacylglyceride levels than saline solution at times 9–12h. Although liver glycogen content was not affected by the glucose injection (except at times 4h and 48h), comparative to saline solution injection, there was a significant increase of liver glycogen at 6h and 9h. Results of this study indicate that under these experimental conditions glucose is probably not the most important stimulator of insulin release. Insulin may have contributed to the increase of IGF-I levels and to the enhancement of glucose uptake by the liver in glucose injected fish. [Copyright &y& Elsevier]

Abstract: The roles of insulin and insulin-like growth factor-I (IGF-I) in the regulation of glucose metabolism were assessed in European sea bass juveniles fed with distinct dietary carbohydrate levels. Three isonitrogenous diets were formulated to contain 10% (10%PGS) or 30% (30%PGS) pregelatinized starch or no starch (control). The highest plasma glucose and insulin levels were observed 6h after feeding in fish receiving the 30%PGS diet. Although plasma IGF-I was higher at 6h than at 24h after feeding, no effect of dietary carbohydrate level was noticed within each sampling time. Increasing dietary carbohydrate level resulted in an increase of liver but not of muscle glycogen content. Hepatic glucokinase (GK) and glucose-6-phosphate dehydrogenase (G6PD) activities increased with the dietary carbohydrate content, whereas pyruvate kinase (PK) activity was higher in fish fed the carbohydrate containing diets than the carbohydrate-free diet. GK activity was higher 6h than 24h after feeding, whereas the opposite was observed for G6PD activity. Data suggest that under the nutritional conditions assayed plasma glucose is an insulin secretagogue. Furthermore, insulin appears to have a more important role than IGF-I in stimulating hepatic glucose uptake, thus enhancing GK activity and leading to an increase in liver glycogen content to maintain glucose homeostasis. [ABSTRACT FROM AUTHOR]

Abstract: Lipoprotein lipase (LPL) is a key enzyme in lipoprotein metabolism by virtue of its capacity to hydrolyze triglycerides circulating in the form of lipoprotein particles. Here we analyzed the fasting effects of LPL in gilthead sea bream (Sparus aurata) and also present the first study in fish of the role of insulin as a potential modulator of both LPL activity and expression. Fasting for 2 weeks provoked a clear decrease in adipose tissue LPL activity, concomitant with lower levels of plasma insulin, while no effects were observed in red muscle. To elucidate the specific role of insulin, increases of plasma insulin were experimentally induced by arginine and insulin injections. However, arginine predominantly stimulated glucagon over insulin secretion in this fish species while LPL activity did not change significantly in adipose tissue. Instead, insulin administration induced an increase in adipose tissue LPL activity 3 h after the injection, whereas LPL activity in red muscle was not affected. Changes in LPL activity were accompanied by an increase in LPL mRNA levels in the adipose tissue of insulin-injected gilthead sea bream, although changes in LPL expression were delayed in time with respect to variations in LPL activity. Finally, LPL mRNA levels in red muscle were similar between control and insulin-injected gilthead sea bream, suggesting that insulin does not play a direct role in the regulation of LPL in this tissue. The current study shows that LPL activity is regulated by nutritional condition and underscores the importance of insulin as a modulator of LPL activity and expression in the adipose tissue of gilthead sea bream. [Copyright &y& Elsevier]

Metabolic changes during the transition from post-feeding to fasting were studied in Brycon cephalus, an omnivorous teleost from the Amazon Basin in Brazil. Body weight and somatic indices (liver and digestive tract), glycogen and glucose content in liver and muscle, as well as plasma glucose, free fatty acids (FFA), insulin and glucagon levels of B. cephalus, were measured at 0, 12, 24, 48, 72, 120, 168 and 336 h after the last feeding. At time 0 h (the moment of food administration, 09.00 h) plasma levels of insulin and glucagon were already high, and relatively high values were maintained until 24 h post-feeding. Glycemia was 6.42±0.82 mM immediately after food ingestion and 7.53±1.12 mM at 12 h. Simultaneously, a postprandial replenishment of liver and muscle glycogen reserves was observed. Subsequently, a sharp decrease of plasma insulin occurred, from 7.19±0.83 ng/ml at 24 h of fasting to 5.27±0.58 ng/ml at 48 h. This decrease coincided with the drop in liver glucose and liver glycogen, which reached the lowest value at 72 h of fasting (328.56±192.13 and 70.33±14.13 μmol/g, respectively). Liver glucose increased after 120 h and reached a peak 168 h post-feeding, which suggests that hepatic gluconeogenesis is occurring. Plasma FFA levels were low after 120 and 168 h and increased again at 336 h of fasting. During the transition from post-feeding to fast condition in B. cephalus, the balance between circulating insulin and glucagon quickly adjust its metabolism to the ingestion or deprivation of food. [Copyright &y& Elsevier]