Glucose-induced Insulin Response Research Articles

Postpartum development of metabolic dysfunction-associated steatotic liver disease in a lean mouse model of gestational diabetes mellitus

Gestational diabetes mellitus (GDM) is associated with increased postpartum risk for metabolic dysfunction-associated steatotic liver disease (MASLD). GDM-related MASLD predisposes to advanced liver disease, necessitating a better understanding of its development in GDM. This preclinical study evaluated the MASLD development in a lean GDM mouse model with impaired insulin secretion capacity. Lean GDM was induced by short-term 60% high-fat diet and low-dose streptozotocin injections (60 mg/kg for 3 days) before mating in C57BL/6N mice. The control dams received only high-fat diet or low-fat diet. Glucose homeostasis was assessed during pregnancy and postpartum, whereas MASLD was assessed on postpartum day 30 (PP30). GDM dams exhibited a transient hyperglycemic phenotype during pregnancy, with hyperglycaemia reappearing after lactation. Lower insulin levels and impaired glucose-induced insulin response were observed in GDM mice during pregnancy and postpartum. At PP30, GDM dams displayed higher hepatic triglyceride content compared controls, along with increased MAS (MASLD) activity scores, indicating lipid accumulation, inflammation, and cell turnover indices. Additionally, at PP30, GDM dams showed elevated plasma liver injury markers. Given the absence of obesity in this double-hit GDM model, the results clearly indicate that impaired insulin secretion driven pregnancy hyperglycaemia has a distinct contribution to the development of postpartum MASLD.

Short-Term Oral Quercetin Supplementation Improves Post-exercise Insulin Sensitivity, Antioxidant Capacity and Enhances Subsequent Cycling Time to Exhaustion in Healthy Adults: A Pilot Study.

AimQuercetin has been reported to have antioxidant and anti-inflammatory properties on health promotion in human studies. The main purpose of this study was to investigate the effect of short-term oral quercetin supplementation on post-exercise whole-body energy metabolism. This study also aimed to determine the effects of supplementation on oxygen stress, inflammation, muscle damage, and high-intensity cycling exercise performance.MethodTwelve healthy participants, physically active students, were recruited to perform a randomized, single-blind crossover study. All subjects completed 7-days of quercetin (quercetin:1,000 mg per day for 7-days) and placebo supplementation in a randomized order. Supplement/placebo was combined with exercise consisting of 70% V̇O2max cycling for 60-min, followed by 3-h of recovery, then a subsequent single bout of cycling exercise with 75% V̇O2max to exhaustion. Time to exhaustion, indicators of muscle damage, as well as blood and gaseous parameters relating to energy metabolism, oxidative stress, inflammatory response, respectively, were determined.ResultsThe results showed that 7-day quercetin supplementation significantly attenuated the post-exercise glucose-induced insulin response, increased total antioxidant capacity (TAC) and superoxidase dismutase (SOD) activities, and mitigated malondialdehyde (MDA) levels during the recovery period (p < 0.05). While subsequent 75% V̇O2max cycling performance was significantly improved after quercetin treatment and accompanied by lower responses of interleukin 6 and creatine kinase at 24-h. However, it’s noted that there were no significant responses in glucose, respiratory exchange rate, tumor necrosis factor-α (TNF-α), myoglobin, and high sensitivity C-reactive protein between quercetin and placebo trials.ConclusionOur findings concluded that 7-day oral quercetin supplementation enhances high-intensity cycling time to exhaustion, which may be due in part to the increase in whole-body insulin-stimulated glucose uptake and attenuation of exercise-induced oxygen stress and pro-inflammation. Therefore, quercetin may be considered an effective ergogenic aid for enhancing high-intensity cycling performance among young adults.

A High Cell-Bearing Capacity Multibore Hollow Fiber Device for Macroencapsulation of Islets of Langerhans.

Macroencapsulation of islets of Langerhans is a promising strategy for transplantation of insulin-producing cells in the absence of immunosuppression to treat type 1 diabetes. Hollow fiber membranes are of interest there because they offer a large surface-to-volume ratio and can potentially be retrieved or refilled. However, current available fibers have limitations in exchange of nutrients, oxygen, and delivery of insulin potentially impacting graft survival. Here, multibore hollow fibers for islets encapsulation are designed and tested. They consist of seven bores and are prepared using nondegradable polymers with high mechanical stability and low cell adhesion properties. Human islets encapsulated there have a glucose induced insulin response (GIIS) similar to nonencapsulated islets. During 7 d of cell culture in vitro, the GIIS increases with graded doses of islets demonstrating the suitability of the microenvironment for islet survival. Moreover, first implantation studies in mice demonstrate device material biocompatibility with minimal tissue responses. Besides, formation of new blood vessels close to the implanted device is observed, an important requirement for maintaining islet viability and fast exchange of glucose and insulin. The results indicate that the developed fibers have high islet bearing capacity and can potentially be applied for a clinically applicable bioartificial pancreas.

Field Trial on Glucose-Induced Insulin Response in High-Yielding Dairy Cows under Different Environmental Temperatures

Abstract This study aimed to evaluate glucose-induced insulin response in cows exposed to different temperature-humidity index. Twenty early lactating Holstein-Friesian cows were divided into 2 equal groups based on season, as summer (SU) and spring (SP). SP cows were not exposed to heat stress, while SU cows were exposed to moderate or severe heat stress. Milk production was recorded daily. Starting from day 30 of lactation, intravenous glucose tolerance test (IVGTT) was carried out three times at 30-day intervals. Blood samples were taken before (basal) and after glucose infusion, and glucose and insulin were measured at each sample point. The homeostatic model assessment (HOMA) index was calculated. Milk yield from days 30 to 40 and 64 to 90 of lactation were higher in SP cows than in SU cows. Basal glucose did not differ on days 30 and 60 of lactation, while basal insulin and HOMA were lower in SU compared to SP cows. On day 90 of lactation, SU cows had higher basal glucose, whereas basal insulin and HOMA did not differ. IVGTT results revealed that glucose tolerance was affected by heat stress such that SU cows had higher glucose clearance. Insulin responses to IVGTT did not differ on days 30 and 60 of lactation. Heat stress had a marked effect on insulin secretion on day 90 of lactation, illustrated by higher increments, peak concentrations and area under the curve for insulin in SU cows. Overall, season differences in glucose tolerance depend not only on heat stress and milk production but also on the stage of lactation.

Chronic Intermittent Hypoxia Impairs Insulin Sensitivity but Improves Whole-Body Glucose Tolerance by Activating Skeletal Muscle AMPK.

Obstructive sleep apnea syndrome is a highly prevalent disease resulting in transient respiratory arrest and chronic intermittent hypoxia (cIH). cIH is associated with insulin resistance and impaired metabolic homeostasis in rodents and humans, but the exact underlying mechanisms remain unclear. In the current study, we investigated the effects of 2 weeks of cIH (1-min cycle, fraction of inspired oxygen 21-5%, 8 h/day) on whole-body insulin sensitivity and glucose tolerance in lean mice. Although food intake and body weight were reduced compared with normoxia, cIH induced systemic insulin resistance in a hypoxia-inducible factor 1-independent manner and impaired insulin signaling in liver, white adipose tissue, and skeletal muscle. Unexpectedly, cIH improved whole-body glucose tolerance independently of changes in body weight and glucose-induced insulin response. This effect was associated with elevated phosphorylation of Thr172-AMPK and Ser237-TBC1 domain family member 1 (TBC1D1) in skeletal muscle, suggesting a tissue-specific AMPK-dependent increase in TBC1D1-driven glucose uptake. Remarkably, although food intake, body weight, and systemic insulin sensitivity were still affected, the improvement in glucose tolerance by cIH was abolished in muscle-specific AMPKα1α2-deficient mice. We conclude that cIH impairs insulin sensitivity while improving whole-body glucose tolerance by promoting specific activation of the skeletal muscle AMPK pathway.

Prenatal Testosterone Exposure Leads to Gonadal Hormone-Dependent Hyperinsulinemia and Gonadal Hormone-Independent Glucose Intolerance in Adult Male Rat Offspring.

Elevated testosterone levels during prenatal life lead to hyperandrogenism and insulin resistance in adult females. This study evaluated whether prenatal testosterone exposure leads to the development of insulin resistance in adult male rats in order to assess the influence of gonadal hormones on glucose homeostasis in these animals. Male offspring of pregnant rats treated with testosterone propionate or its vehicle (control) were examined. A subset of male offspring was orchiectomized at 7 wk of age and reared to adulthood. At 24 wk of age, fat weights, plasma testosterone, glucose homeostasis, pancreas morphology, and gastrocnemius insulin receptor (IR) beta levels were examined. The pups born to testosterone-treated mothers were smaller at birth and remained smaller through adult life, with levels of fat deposition relatively similar to those in controls. Testosterone exposure during prenatal life induced hyperinsulinemia paralleled by an increased HOMA-IR index in a fasting state and glucose intolerance and exaggerated insulin responses following a glucose tolerance test. Prenatal androgen-exposed males had more circulating testosterone during adult life. Gonadectomy prevented hyperandrogenism, reversed hyperinsulinemia, and attenuated glucose-induced insulin responses but did not alter glucose intolerance in these rats. Prenatal androgen-exposed males had decreased pancreatic islet numbers, size, and beta-cell area along with decreased expression of IR in gastrocnemius muscles. Gonadectomy restored pancreatic islet numbers, size, and beta-cell area but did not normalize IRbeta expression. This study shows that prenatal testosterone exposure leads to a defective pancreas and skeletal muscle function in male offspring. Hyperinsulinemia during adult life is gonad-dependent, but glucose intolerance appears to be independent of postnatal testosterone levels.

Fatty acid binding proteins 4 and 5 in overweight prepubertal boys: effect of nutritional counselling and supplementation with an encapsulated fruit and vegetable juice concentrate.

Elevated fatty acid binding proteins (FABP) may play a role in obesity and co-morbidities. The role of nutritional interventions in modulating these levels remains unclear. The aim of this post hoc study was to determine the effect of overweight (OW) on FABP4 and FABP5 in boys in relation to indices of adiposity, insulin resistance and inflammation, and to investigate the effects of a 6-month supplementation with an encapsulated fruit and vegetable juice concentrate (FVJC) plus nutritional counselling (NC) on FABP levels. A post hoc analysis of a double-blind, randomised, placebo-controlled study of children recruited from the general paediatric population was performed. A total of thirty age-matched prepubertal boys (nine lean and twenty-one OW; aged 6-10 years) were studied. Patients received NC by a registered dietitian and were randomised to FVJC or placebo capsules for 6 months. FABP4, FABP5, glucose, insulin, homeostasis model assessment-insulin resistance (HOMA-IR), glucose-induced acute insulin response (AIR), lipid-corrected β-carotene (LCβC), adiponectin, leptin, high-sensitivity C-reactive protein (hs-CRP), IL-6 and body composition by dual-energy X-ray absorptiometry were determined before and after the intervention. FABP were higher (P<0·01) in the OW v. lean boys and correlated directly with HOMA-IR, abdominal fat mass (AFM), hs-CRP, IL-6, and LCβC (P<0·05 for all). FABP4 was associated with adiponectin and AIR (P<0·05). FVJC plus NC reduced FABP4, HOMA-IR and AFM (P<0·05 for all) but not FABP5. OW boys showed elevated FABP4 and FABP5, but only FABP4 was lowered by the FVJC supplement.

Adaptive human CDKAL1 variants underlie hormonal response variations at the enteroinsular axis.

Recent analyses have identified positively selected loci that explain differences in immune responses, body forms, and adaptations to extreme climates, but variants that describe adaptations in energy-balance regulation remain underexplored. To identify variants that confer adaptations in energy-balance regulation, we explored the evolutionary history and functional associations of candidate variants in 207 genes. We screened single nucleotide polymorphisms in genes that had been associated with energy-balance regulation for unusual genetic patterns in human populations, followed by studying associations among selected variants and serum levels of GIP, insulin, and C-peptide in pregnant women after an oral glucose tolerance test. Our analysis indicated that 5′ variants in CDKAL1, CYB5R4, GAD2, and PPARG are marked with statistically significant signals of gene–environment interactions. Importantly, studies of serum hormone levels showed that variants in CDKAL1 are associated with glucose-induced GIP and insulin responses (p<0.05). On the other hand, a GAD2 variant exhibited a significant association with glucose-induced C-peptide response. In addition, simulation analysis indicated that a type 2 diabetes risk variant in CDKAL1 (rs7754840) was selected in East Asians ∼6,900 years ago. Taken together, these data indicated that variants in CDKAL1 and GAD2 were targets of prior environmental selection. Because the selection of the CDKAL1 variant overlapped with the selection of a cluster of GIP variants in the same population ∼11,800 to 2,000 years ago, we speculate that these regulatory genes at the human enteroinsular axis could be highly responsive to environmental selection in recent human history.

Effects of a Combination of Alpha Lipoic Acid and Myo-Inositol on Insulin Dynamics in Overweight/Obese Patients with PCOS

Myo-inositol increases insulin sensitivity in insulin resistant patients with PCOS since it improves the insulin postreceptor pathways. Since previous reports suggested that also alpha lipoic acid has specific positive effects on glucose control, we aimed to evaluate the specific effects of a combination of alpha lipoic acid and myo-inositol on insulin resistance in obese patients with PCOS. We studied a group of obese PCOS patients (n=34, BMI= 30.1 ± 0.9) according to the revised 2003 Rotterdam consensus diagnostic criteria. Among the PCOS patients, 16 out of 34 had diabetic type II relatives (parents and/or grandparents). Patients were administered a combination of alpha lipoic acid (400 mg) and myo-inositol (1 gr.) (Sinopol, Laborest, Italy) every day for at least 12 weeks. Patients underwent to baseline hormone determination and to an oral glucose tolerance test (OGTT) before and at the 12th week of treatment. After the treatment interval, HOMA index decreased significantly as well as the glucose-induced insulin response with no changes of BMI. Interestingly the treatment did not change insulin dynamics in normo-insulinemic PCOS while significant insulin decrease was observed in hyperinsulinemic PCOS patients. 87.5% (14 out of 16) of the PCOS patients with diabetic relatives resulted to be among the hyperinsulinemic patients. Hyperinsulinemic PCOS patients showed the significant decrease of the insulin plasma levels (from 14 ± 2.1 to 9.5 ± 0.8 μU/ml, p<0.05), of HOMA index (from 3.3 ± 0.4 to 2.1 ± 0.1, p<0.05) and showed the significant decrease of insulin response to glucose load. In conclusion, the combination of alpha lipoic acid plus MYO was effective in improving insulin sensitivity in obese PCOS patients that resulted to be hyperinsulinemic under OGTT. Moreover the more peculiar and relevant positive changes were observed in obese PCOS with diabetic first grade relatives.

Species incompatibilities in the pig‐to‐macaque islet xenotransplant model affect transplant outcome: a comparison with allotransplantation

Porcine islet transplantation into diabetic non-human primates is considered most relevant in translational research supporting a clinical application. Most studies have focused on immunosuppressive protocols, while metabolic aspects have mainly been utilized in graft monitoring. We evaluated data from our group regarding human and non-human primate (NHP) allotransplantation and pig-to-NHP xenotransplantation to identify incompatibilities in metabolic factors and their consequences for transplant outcomes. Basic gluco-metabolic parameters (fasting blood glucose, C-peptide, and response to stimulation with arginine or glucose) were derived from literature (humans), 72 macaques, and 47 adult Landrace pigs. Islet preparations from 15 human deceased donors, 61 macaques, and 23 adult pigs were compared with respect to yield, fractional viability assessed by oxygen consumption normalized for DNA, and in vitro glucose-induced insulin release. Metabolic parameters at day 75 after a single islet transplantation in the liver were compared for 19 patients and 9 macaques receiving an allotransplant and 11 macaques receiving a porcine xenotransplant: recipients received chronic immunosuppression. Pigs differ from NHPs and humans by a much lower C-peptide level (0.42 vs. 1.3 to 2.0 ng/ml, respectively) and a 2- to 7-fold lower C-peptide response to arginine stimulation. In contrast, NHPs have the highest metabolic demand as evidenced by a high C-peptide and high C-peptide response to arginine stimulation; values are about twice higher than in humans. For manufactured islet preparations, these differences are reflected by glucose-stimulated insulin release (the stimulation index for pigs is 1.5, for humans 3.8, and for macaques 7.7), but not by fractional viability, which was in the same range. The day 75 outcome after transplantation assessed by C-peptide was similar for allotransplanted humans and NHPs (80 to 90% good graft function) and lower in xenografted NHPs (36% good graft function); gluco-metabolic parameters were in accordance with graft function, albeit different between species because normoglycemia under exogenous insulin is maintained more aggressively in patients than in NHPs. In xenografted NHPs, the shift in glycemic control with respect to normal values, combined with low values of circulating porcine C-peptide, resembled more the normal condition in a pig than that in a macaque. The substantially lower glucose-induced insulin response in adult porcine islet preparations as opposed to islets manufactured from humans or macaques combined with the much higher need for insulin in macaques than in humans creates an imbalance between the metabolic demand and the engrafted islet mass in the pig-to-NHP xenograft recipient. Engrafted islet mass is affected by dose, suggesting that a much higher dose level of islets is necessary in the xenogeneic setting than in human or NHP allotransplantation, and pig islets need to be given at a higher dose in macaques than the anticipated effective dose in humans. To cope with differences in metabolic demand and presumably also metabolic dynamics, a liberal regime in supportive exogenous insulin might be essential to achieve long-term survival. These intrinsic characteristics of the NHP model deserve consideration to optimally design experimental studies with the perspective of translational value of results.

Increased neuronal nitric oxide synthase dimerisation is involved in rat and human pancreatic beta cell hyperactivity in obesity

Pancreatic beta cell hyperactivity is known to occur in obesity, particularly in insulin-resistant states. Our aim was to investigate whether changes in neuronal nitric oxide synthase (nNOS) function affect beta cell compensation in two relevant models: the Zucker fa/fa rats and pancreatic islets from obese humans. Glucose-induced insulin response was evaluated in the isolated perfused rat pancreas and in human pancreatic islets from obese individuals. Expression of nNOS (also known as NOS1) and subcellular localisation of nNOS were studied by quantitative RT-PCR, immunoblotting, immunofluorescence and electron microscopy. Pancreatic beta cells from Zucker fa/fa rats and obese individuals were found to be hyper-responsive to glucose. Pharmacological blockade of nNOS was unable to modify beta cell response to glucose in fa/fa rats and in islets from obese individuals, suggesting an abnormal control of insulin secretion by the enzyme. In both cases, nNOS activity in islet cell extracts remained unchanged, despite a drastic increase in nNOS protein and an enhancement in the dimer/monomer ratio, pointing to the presence of high amounts of catalytically inactive enzyme. This relative decrease in activity could be mainly related to increases in islet asymmetric dimethyl-arginine content, an endogenous inhibitor of nNOS activity. In addition, mitochondrial nNOS level was decreased, which contrasts with a strongly increased association with insulin granules. Increased nNOS production and dimerisation, together with a relative decrease in catalytic activity and relocalisation, are involved in beta cell hyperactivity in insulin-resistant rats but also in human islets isolated from obese individuals.

Progress in the studies on extra-islet effects of incretin

Incretin is defined as an intestinal hormone released in response to nutrient ingestion, which potentiates the glucose-induced insulin response. In human body, the incretin's effect is mainly induced by two peptide hormones, glucagon-like peptide-I (GLP-I)and glucose-dependent insulinotropic polypeptide (GIP). In order to fully evaluate the clinical advantages of novel agents based on incretin, this review introduces the islet actions of incretin in brief, and mainly focuses on the extra-islet effect of incretin. Key words: Incretin; Glucagon-like peptide-I ; Glucose-dependent insulinotropic polypeptide; Diabetes mellitus, type 2

Milk performance and glucose metabolism in dairy cows fed rumen-protected fat during mid lactation

Feeding rumen-protected fat (RPF) can improve energy supply for dairy cows but it affects glucose metabolism. Glucose availability is a precondition for high milk production in dairy cows. Therefore, this study investigated endocrine regulation of glucose homeostasis and hepatic gene expression related to glucose production because of RPF feeding in lactating cows. Eighteen Holstein dairy cows during second lactation were fed either a diet containing RPF (mainly C16:0 and C18:1; FD; n=9) or a control diet based on corn starch (SD; n=9) for 4 wk starting at 98 d in milk (DIM). Feed intake and milk yield were measured daily and milk composition once a week. Blood samples were taken weekly for analyses of plasma triglyceride, nonesterified fatty acids (NEFA), β-hydroxybutyrate, bilirubin, urea, lactate, glucose, insulin, and glucagon. At 124 DIM, an intravenous glucose tolerance test (GTT; 1g/kg of BW0.75) was performed after a 12-h period without food. Blood samples were taken before and 7, 14, 21, and 28min after glucose administration, and plasma concentrations of glucose, insulin, and glucagon were measured. Glucose half-life as well as areas under the concentration curve for glucose, insulin, and glucagon were calculated. After slaughter at d 28 of treatment, liver samples were taken to measure mRNA abundance of pyruvate carboxylase, cytosolic phosphoenolpyruvate carboxykinase, glucose 6-phosphatase (G6Pase), and facilitative glucose transporter 2. Dry matter intake, but not energy and protein intake, was lower in FD than in SD. Milk yield during lactation decreased more in SD than in FD, and milk protein was lower in FD than in SD. Plasma concentrations of triglycerides and NEFA were higher in FD than in SD. Plasma insulin concentrations were lower and the glucagon:insulin ratios were higher in FD than in SD. Fasting glucose concentration before GTT was lower, and fasting glucagon concentrations tended to be higher in FD than in SD. In liver, fat content tended to be higher and G6Pase mRNA abundance was lower in FD than in SD. Lower hepatic G6Pase mRNA abundance was associated with reduced fasting plasma glucose concentrations, but the glucose-induced insulin response was not affected by RPF feeding. Hepatic G6Pase gene expression might be affected by DMI and might be involved in the regulation of glucose homeostasis in dairy cows, resulting in a lower hepatic glucose output after RPF feeding.

Effects of incretin in the treatment of type 2 diabetes

Incretin hormones are defined as intestinal hormones released in response to nutrient ingestion,and potentiate the glucose-induced insulin response. In humans, the incretin effect is mainly caused by two peptidehormones, glucagon-like peptide-1 ( GLP-1 ) and glucose-dependent insulin releasing polypeptide (GIP). According to the recently finished studies, the review focuses on the physiological actions of incretin, explains the different insulinotropic actions of GLP-1 and GIP in type 2 diabetic patients, and evaluates the clinical features of recently approved therapeutic agents based on incretin action. Key words: Incretin; Glucagon-like peptide-1; Glucose-dependent insulinotropic peptide; Diabetes mellitus, type 2

Nouveaux marqueurs dans l’homéostasie glucidique : physiologie et physiopathologie

The term diabetes mellitus describes a metabolic disorder resulting from defects in insulin secretion, insulin action, or both. People with diabetes are at increased risk of cardiovascular, peripheral and cerebrovascular disease. In consequence, it is important to better understand early step in this disease in order to prevent complications. Incretine hormones are defined as intestinal hormones released in response to nutrient ingestion, which potentiate the glucose-induced insulin response. The incretine effect is mainly caused by two peptide hormones, glucose-dependent insulin releasing polypeptide (GIP) and glucagons-like peptide-1 (GLP-1). Analogs of GLP-1 and dipeptidyl-peptidase IV (DPP-IV) inhibitors are actually used as antidiabetic drugs. Adiponectin is an adipokine, which is expressed in adipose tissue and is thought to play an important role in glucose metabolism. Hypoadiponectinemia was related to obesity, insulin-resistance and as a risk factor of diabetes, cardiovascular events and death. Plasmatic quantification of GLP-1 and adiponectin should improve insulin-resistance diagnosis and diabetes prevention.

Field trial on glucose-induced insulin and metabolite responses in Estonian Holstein and Estonian Red dairy cows in two herds

BackgroundInsulin secretion and tissue sensitivity to insulin is considered to be one of the factors controlling lipid metabolism post partum. The objective of this study was to compare glucose-induced blood insulin and metabolite responses in Estonian Holstein (EH, n = 14) and Estonian Red (ER, n = 14) cows.MethodsThe study was carried out using the glucose tolerance test (GTT) performed at 31 ± 1.9 days post partum during negative energy balance. Blood samples were obtained at -15, -5, 5, 10, 20, 30, 40, 50 and 60 min relative to infusion of 0.15 g/kg BW glucose and analysed for glucose, insulin, triglycerides (TG), non-esterified fatty acids (NEFA), cholesterol and β-hydroxybutyrate (BHB). Applying the MIXED Procedure with the SAS System the basal concentration of cholesterol, and basal concentration and concentrations at post-infusion time points for other metabolites, area under the curve (AUC) for glucose and insulin, clearance rate (CR) for glucose, and maximum increase from basal concentration for glucose and insulin were compared between breeds.ResultsThere was a breed effect on blood NEFA (P < 0.05) and a time effect on all metabolites concentration (P < 0.01). The following differences were observed in EH compared to ER: lower blood insulin concentration 5 min after glucose infusion (P < 0.05), higher glucose concentration 20 (P < 0.01) and 30 min (P < 0.05) after infusion, and higher NEFA concentration before (P < 0.01) and 5 min after infusion (P < 0.05). Blood TG concentration in ER remained stable, while in EH there was a decrease from the basal level to the 40th min nadir (P < 0.01), followed by an increase to the 60th min postinfusion (P < 0.01).ConclusionOur results imply that glucose-induced changes in insulin concentration and metabolite responses to insulin differ between EH and ER dairy cows.

Differences in the glucose-induced insulin response and the peripheral insulin responsiveness between neonatal calves of the Belgian Blue, Holstein-Friesian, and East Flemish breeds

Decreased insulin sensitivity (IS) in dairy cows supports milk yield but increases the risk for metabolic and reproductive disorders. Although several inducers of decreased IS are known, it is unclear to what extent it is congenitally determined. The main aim was to investigate differences in IS between neonatal calves of the Belgian Blue (BB) breed, reared for beef production, and the Holstein-Friesian (HF) breed, reared for milk yield. Additionally, a small number of East Flemish (EF) calves, a local dual-purpose breed, were compared with the 2 other breeds. Ten BB, 12 HF, and 4 EF calves with similar age, ration, and housing were selected. In the intravenous glucose tolerance test, blood samples were taken at regular intervals after an intravenous glucose bolus of 150mg/kg. Area under the curve (AUC), peak concentration, and elimination rate of insulin and glucose were computed. The quantitative insulin sensitivity check index (QUICKI) and revised QUICKI were computed using basal glucose, insulin, and nonesterified fatty acid concentrations. In the intravenous insulin tolerance test, blood samples were obtained from 4 calves of each breed at regular times after an intravenous insulin challenge of 0.05IU/kg. Based on the decline in glucose concentrations relative to basal levels, the insulin-stimulated blood glucose response was computed. Basal insulin concentrations were higher in HF (1.58±0.40μU/mL) than in BB calves (0.35±0.09mmol/L). Compared with BB calves, HF and EF calves had higher basal glucose concentrations (4.40±0.16 vs. 5.70±0.35 and 5.81±0.13mmol/L, respectively), insulin peak concentrations (4.62±1.09 vs. 9.70±1.45 and 16.44±5.58μU/mL, respectively), insulin AUC (86.71±18.81 vs. 222.65±45.00 and 293.69±109.22μU/mL·min, respectively), and glucose AUC (256.22±17.53 vs. 335.66±18.74 and 321.03±10.05mmol/L·min, respectively). Glucose elimination rates were lower in HF (1.37±0.22%/min) than in BB calves (2.35±0.25%/min). The QUICKI was lower in HF and EF than in BB calves (0.52±0.039 and 0.57±0.068 vs. 0.76±0.038, respectively), and the revised QUICKI was lower in HF (0.86±0.11) than in BB calves (1.59±0.17). The insulin-stimulated blood glucose response did not differ between breeds. Because management differences were negligible, our results suggest breed-specific differences in glucose partitioning and IS. These findings may reflect different rearing purposes of the breeds, although extrapolation of the data to adult animals should be done cautiously.

Zn2+‐transporter‐8: A dual role in diabetes

Diabetes mellitus arises from defects in insulin secretion or action, or both. In pancreatic islets, insulin production is linked with zinc transport mediated by zinc transporter ZnT-8, a product of the SLC30A8 gene. Therefore, altered activity of ZnT-8 is expected to be associated with impaired glucose-induced insulin response and promote progression from glucose intolerance to diabetes. Recent findings do emerge with a role of SLC30A8 in diabetes. Genome-wide association scans for type 2 diabetes (T2D) susceptibility loci revealed and then replicated a highly significant association between the R allele of the R325W variant of SLC30A8 (marker rs13266634) and susceptibility to T2D in Caucasians. A role of ZnT-8 as a new major self-antigenic determinant in type 1 diabetes (T1D) was found. Marker rs13266634 was also shown to modulate anti-ZnT-8 self-antibody specificity in islet autoimmunity. Hence, these findings suggest for a dual role of SLC30A8 in diabetes, which is consisted in conferring genetic susceptibility to T2D and being a major islet self-antigen in T1D as well. Here we characterize an emerging role of ZnT-8 in diabetes and discuss potential mechanisms of its involvement in the etiology of both forms of diabetes.

Interrelations Between Glucose-Induced Insulin Response, Metabolic Indicators, and Time of First Ovulation in High-Yielding Dairy Cows

High-yielding dairy cows are more susceptible to metabolic and reproductive disorders than low-yielding cows. Insulin plays a pivotal role in the development of both problems. In the present study, we aimed to assess the glucose-induced insulin responses of dairy cows at different time points relative to calving and to relate this to the metabolic status and the time of first ovulation. Twenty-three healthy, multiparous Holstein-Friesian cows with a high genetic merit for milk yield were studied from 14 d prepartum to 42 d postpartum. Intravenous glucose tolerance tests were performed on −14, 14, and 42 d relative to calving to evaluate the plasma insulin and glucose responses to a glucose load, as estimated by the peak concentration, the area under the curve (AUC), and the clearance rates of insulin and glucose. Blood samples were obtained at 3-d intervals and analyzed for glucose, insulin, and nonesterified fatty acids (NEFA). The time of first ovulation was defined by transrectal ultrasonography and plasma progesterone analysis. Glucose-induced insulin AUC and peak concentration decreased and glucose clearance increased during lactation compared with the dry period. Plasma NEFA concentrations were negatively related to insulin AUC and peak concentrations. Fourteen cows ovulated within 42 d postpartum, and the remaining 9 cows suffered from delayed resumption of ovarian function. Survival analysis demonstrated that cows with lower NEFA concentrations during the dry period tended to have earlier resumption of ovarian activity. In conclusion, our data suggest a decreased plasma insulin response to glucose postpartum in high-yielding dairy cows, possibly contributing to metabolic stress during the early postpartum period. It is hypothesized that NEFA impair glucose-induced insulin secretion in dairy cows. Additionally, our results suggest the importance of lipolysis during the transition period as a risk factor for delayed ovulation.

Insulin stimulates hepatic low density lipoprotein receptor-related protein 1 (LRP1) to increase postprandial lipoprotein clearance

Background While the role of insulin in glucose uptake and its aberration in diabetes are well established, the effect of insulin on lipoprotein clearance in the postprandial phase is not yet fully understood. The dietary lipids are carried in chylomicron remnants (CR) which are taken up into the liver mainly via LDLR-related protein 1 (LRP1). In this study, the effect of insulin on LRP1-mediated hepatic CR uptake was investigated. Methods The study was based on determining the subcellular localisation of LRP1 by subcellular fractionation and immunofluorescence microscopy and correlating those findings with the hepatic uptake of fluorescently or radioactively labelled LRP1-specific ligands and CR in hepatoma cells, primary hepatocytes and mouse models. Results and conclusion In vitro and in vivo, insulin stimulated the translocation of hepatic LRP1 from intracellular vesicles to the plasma membrane, which correlates with an increased uptake of LRP1-specific ligands. In wild-type mice, a glucose-induced insulin response increased the hepatic uptake of LRP1 ligands while in leptin-deficient obese mice ( ob/ ob), which are characterised by hepatic insulin resistance, insulin-inducible LRP1 ligand uptake was abolished. Finally, upon hepatic LRP1 knockdown, insulin no longer significantly enhanced CR uptake into the liver. The insulin-induced LRP1-mediated CR uptake, as demonstrated here, suggests that impaired hepatic LRP1 translocation can contribute to the postprandial lipaemia in insulin resistance.