Postprandial Insulin Secretion Research Articles

Evaluating GIP and glucagon as key regulators of insulin secretion in the pancreatic islet.

The incretin axis is an essential component of postprandial insulin secretion and glucose homeostasis. There are two incretin hormones, glucagon-like peptide 1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP), which exert multiple actions throughout the body. A key cellular target for the incretins are pancreatic b-cells, where they potentiate nutrient-stimulated insulin secretion. This feature of incretins have made this system an attractive target for therapeutic interventions aimed at controlling glycemia. Here, we discuss the role of GIP in both b-cells and a-cells within the islet, to stimulate insulin and glucagon secretion, respectively. Moreover, we discuss how glucagon secretion from a-cells has important insulinotropic actions in b-cells through an axis termed a- to b-cell communication. These recent advances have elevated the potential of GIP and glucagon as a therapeutic targets, coinciding with emerging compounds that pharmacologically leverage the actions of these two peptides in the context of diabetes and obesity.

Glucagon-like peptide-1 analogs activate AMP kinase leading to reversal of the Warburg metabolic switch in breast cancer cells.

Breast cancer (BC) is associated with type 2 diabetes mellitus (T2DM) and obesity. Glucagon-like peptide (GLP)-1 regulates post-prandial insulin secretion, satiety, and gastric emptying. Several GLP-1 analogs have been FDA-approved for the treatment of T2DM and obesity. Moreover, GLP-1 regulates various metabolic activities across different tissues by activating metabolic signaling pathways like adenosine monophosphate (AMP) activated protein kinase (AMPK), and AKT. Rewiring metabolic pathways is a recognized hallmark of cancer, regulated by several cancer-related pathways, including AKT and AMPK. As GLP-1 regulates AKT and AMPK, we hypothesized that it alters BC cells' metabolism, thus inhibiting proliferation. The effect of the GLP-1 analogs exendin-4 (Ex4) and liraglutide on viability, AMPK signaling and metabolism of BC cell lines were assessed. Viability of BC cells was evaluated using colony formation and MTT/XTT assays. Activation of AMPK and related signaling effects were evaluated using western blot. Metabolism effects were measured for glucose, lactate and ATP. Exendin-4 and liraglutide activated AMPK in a cAMP-dependent manner. Blocking Ex4-induced activation of AMPK by inhibition of AMPK restored cell viability. Interestingly, Ex4 and liraglutide reduced the levels of glycolytic metabolites and decreased ATP production, suggesting that GLP-1 analogs impair glycolysis. Notably, inhibiting AMPK reversed the decline in ATP levels, highlighting the role of AMPK in this process. These results establish a novel signaling pathway for GLP-1 in BC cells through cAMP and AMPK modulation affecting proliferation and metabolism. This study suggests that GLP-1 analogs should be considered for diabetic patients with BC.

Evidence of Nesfatin-1 in Mouse Intestinal Enteroendocrine Cells

Objectives: Post-prandial insulin secretion is predominantly regulated by four intestinal hormones: glucagon-like peptide 1 (GLP-1), glucose-dependent insulinotropic polypeptide (GIP), Cholecystokinin (CCK) and peptide YY (PYY). Nesfatin-1, an insulinotropic and anorexigenic secreted peptide was reported in mouse hypothalamus. Data supporting nesfatin-1 expression in intestine is minimal. Is nesfatin-1 expressed in mouse intestinal cells? Does it affect intestinal hormones known to stimulate or inhibit insulin secretion? We present STC-1 cells as viable in vitro models to study nesfatin-1’s biological action in intestine. Methods: Immunofluorescence histochemistry (IHC) of intestinal sections from male C57BL/6 mice were carried out. STC-1 cells (n=8 wells/treatment) were dose-dependently treated with nesfatin-1, followed by RT-qPCR and immunoassay (ELISA) respectively. One-Way ANOVA followed by Tukey’s multiple comparison test using GraphPad Prism software was used for data analysis. p<0.01 was considered statistically significant. Results: IHC showed NUCB2/nesfatin-1 co-localizing CCK, PYY and GLP-1 in the intestinal mucosa of mice. Static incubation of STC-1 cells with nesfatin-1 upregulated both CCK, PYY and GLP-1 mRNA expression (1 and 10nM) and secretion at 1 hr post-incubation (0.1, 1 and 10nM). Conversely, nesfatin-1 downregulated PYY mRNA expression and secretion in STC-1 cells (all doses tested). Conclusion: The current data shows cell-specific localization of nesfatin-1 in the intestinal mucosa and establishes STC-1 cells as in vitro models to study nesfatin-1. This study adds a novel function for intestinal nesfatin-1 in stimulating insulinotropic intestinal hormones (GLP-1, GIP, CCK) and inhibit PYY which is insulinostatic.

Whole-Body Loss of NUCB2/Nesfatin-1 Alters Enteric Hormone Expression

Objectives: Post-prandial insulin secretion is predominantly regulated by four intestinal hormones: glucagon-like peptide 1 (GLP-1), glucose-dependent insulinotropic polypeptide (GIP) [collectively called incretins], Cholecystokinin (CCK) and peptide YY (PYY). Nesfatin-1, an insulinotropic and anorexigenic secreted peptide encoded by nucleobindin-2 (NUCB2) was reported in the mouse hypothalamus. We have earlier reported that nesfatin-1 stimulates incretins and CCK expression and secretion while being a potent inhibitor of PYY expression, both in vitro and vivo. We further this observation in this abstract by testing the incretin, CCK, and PYY expression in a mouse model of global Nesfatin-1/NUCB2 knockout (NKO). Methods: For the current study 6-8 weeks old male NKO mice and age-matched littermate C57BL/6J mice were used as controls (n=7). Total RNA extraction followed by Real-Time quantitative PCR (RT-qPCR) of small/large intestine samples was carried out. One-way ANOVA followed by Tukey’s multiple comparison test using GraphPad Prism software was used for data analysis. p<0.01 was considered statistically significant. Results: We found that whole-body knockout of NUCB2/Nesfatin-1 downregulated large and small intestinal expression of incretins, CCK, and increased expression of PYY. Conclusion: The current data extends our earlier observation in a mouse model lacking nesfatin-1. Lack of nesfatin-1 affects the healthy expression of incretins, CCK, and PYY in the intestine. These results highlight the importance of endogenous nesfatin-1 and its role in energy balance by modulating crucial enteroendocrine hormones known for their role in energy balance. Source of Support: Dr. Unniappan's lab (University of Saskatchewan) and Canadian Institutes of Health Research (CIHR).

Dietary insulin index, dietary insulin load and dietary patterns and the risk of metabolic syndrome in Hoveyzeh Cohort Study

Postprandial insulin secretion has been associated with metabolic disorders such as hyperlipidemia and type 2 diabetes. Therefore, we aimed to explore the relationship between dietary insulin indices and dietary pattern with the risk of Metabolic Syndrome (MetS). The participants of the present cross-sectional study were included among the individuals who participated in the Hoveyzeh Cohort Study (HCS). A total of 3905 Iranian adults, aged 35–70 years, are included in the current analysis. The Food Frequency Questionnaire (FFQ) is used to calculate the dietary Insulin Index (DII), Insulin Load (DIL), and dietary pattern. Dietary pattern was derived using Reduced-Rank Regression (RRR) based on intake of protein (g/day), fiber (g/day), fat (g/day), magnesium (mg/day), and dietary insulin index were considered as response variables. The Generalized Linear Model was used to obtain the odds ratio (OR) and 95% confidence interval (CI) for MetS based on gender, while considering quartiles of DIL, DII scores, and dietary pattern, adjusted for potential confounders. The mean ± SD of age and BMI of the participants in the top quartile of DIL were 45.72 ± 8.05 years and 28.25 ± 5.02 kg/m2, respectively. The mean ± SD of DII was 40.53 ± 4.06 and the mean ± SD of DIL was 117,986.1 ± 30,714.06. A significant positive association was observed between DIL and MetS in women after adjusting for confounding factors (OR: 1.51; 95% CI 1.16; 1.96). No significant association was seen between DIL, DII, and MetS among men. A derived dietary pattern characterized by high intakes of fruits, sugar, sweet deserts, Whole Grains, and dairy was associated with an increased risk of MetS in adjusted model2 among women (OR: 1.41; 95% CI 1.13; 1.75) and men in the same model (OR: 2.09; 95% CI 1.35; 3.21).However, the final model was significant just for men (OR: 2.08; 95% CI 1.35; 3.21) and not for women (OR: 1.24; 95% CI 0.96; 1.60). Our findings showed that adherence to a diet with a high insulin load can increase the risk of MetS in women. In addition, a derived dietary pattern by RRR indicated that a diet rich in fruits, sugar, sweet deserts, whole Grains, and dairy is related to increased risk of MetS in both men and women.

GLP-2 predicts cardiovascular outcomes in patients with myocardial infarction and increases atherosclerosis in mice

Abstract Background GLP-1 and GLP-2 (glucagon-like peptide-1/2) are incretin hormones that are co-secreted from intestinal L-cells in response to food intake and inflammatory stimuli. While GLP-1 is known to induce postprandial insulin secretion and to improve cardiovascular outcomes in patients with diabetes, GLP-2 enhances intestinal nutrient absorption. GLP-2 agonists are clinically used for the treatment of patients with short bowel syndrome. The relevance of GLP-2 beyond the gut is not well understood. The aim of this study was to investigate the role of GLP-2 for cardiovascular disease (CVD). Methods Total GLP-2 levels were assessed at time of admission in 918 patients with myocardial infarction presenting with acute chest pain, among them 597 patients with NSTEMI and 321 with STEMI. The primary composite outcome of the study was the first occurrence of all-cause death, nonfatal myocardial infarction, or nonfatal stroke (3-P-MACE) with a median follow-up of 311 days. To induce atherosclerosis, Glp2r−/− or WT mice were injected with PCSK9 virus and fed a diet high in cholesterol (HCD) for 12 weeks. Results Kaplan-Meier survival plots (separated by the median of GLP-2 with a cut-off value of 4.4 pM) and univariable cox regression analyses found GLP-2 values to be associated with adverse outcome (3-P-MACE and all-cause mortality; logarithmized GLP-2 values HR: 2.87; p<.0001). Further adjustment for age, sex, smoking, hypertension, hypercholesterinemia, previous CVD and diabetes mellitus did not affect this association (logarithmized GLP-2 values HR: 2.66; p=0.0055). Receiver operating characteristic curve (ROC) analyses illustrated that GLP-2 is a strong indicator for early events (area under the curve of the combined endpoint at 7 days: 0.74; 14 days: 0.76; 30 days: 0.76; 6 months: 0.72), which proved to be superior to Troponin T and hs-CRP. To asses the functional role of GLP-2 in CVD in an experimental approach we injected Glp2r−/− or WT mice PCSK9 virus (to induce functional Ldlr-deficiency and hypercholesterolemia) and fed these mice a HCD. After 12 weeks Glp2r−/− mice compared to WT littermates presented with a significant reduction in plaque volume and lesion size. While body weight and circulating leukocyte numbers (FACS analysis) were unaffected, Glp2r−/− mice had lower cholesterol levels. Conclusion Circulating GLP-2 levels are associated with cardiovascular events in patients with acute myocardial infarction while inactivation of the GLP-2 system reduces atherosclerosis in mice. Future studies are needed to investigate whether the GLP-2 receptor might provide a novel therapeutic target for cardiovascular disease.

261 Variations in Protein Deposition Might Be Associated with Insulin Resistance and Differences in Amino Acids Metabolism in Growing Gilts

Abstract Pigs with similar body weight (BW), same genetic background and sex vary in terms of protein deposition (PD) overgrowth. Insulin stimulates protein synthesis, and differences in PD could be associated with the variation among pigs in postprandial insulin secretion. Therefore, this study aimed to investigate if changes in preprandial and postprandial amino acids (AA) response and insulin resistance differ between pigs having Low or High PD. Seventy gilts (33 kg BW, ± 3.6; Alphagène) were assigned to a randomized complete block (BW) design and housed in the same pen equipped with automatic feeders. Pigs were fed ad libitum with a diet balanced to maximize PD. Dual X-Ray estimated body protein (BP) and lipid (BL) masses on d 1 and 21, and by difference, PD was calculated. On d 23, pigs were grouped in Low (157 g/d) and High (219 g/d) PD. Eight pigs per PD group were canulated in a jugular vein, and after 48h recovery receiving feed at 90% of the measured feed intake, they were fasted for eight hours to study preprandial metabolism (-5, -1 min before the meal). In sequence, all pigs received a 300 g meal and blood samples were collected at 10, 15, 20, 30, 40, 50, 60, 75, 90, 120, 150, 178, 178 min, relative to the meal, to measure AA, insulin and glucose concentrations. In addition, insulin resistance (HOMA-IR) was calculated based on fasting glucose and insulin concentrations. The AA response was modeled for each PD group based on the average group response using differential equations derived from the Erlang equation. Thus, the basal concentration, area under the curve (AUC) and AA flux could be compared among groups using the parameters obtained by the non-linear model. An F-test was used to compare the difference in the indexes between Low and High PD pigs. The basal concentration of methionine, valine and leucine were similar, whereas AUC was greater for Low PD pigs with no difference in flux, with the exception of methionine (P < 0.10; Table 1). Conversely, lysine (15%) and threonine (10%) basal concentrations were less in Low PD pigs. Lysine AUC was greater (8%), whereas others AA AUC were on average 27% less for High PD than for Low PD pigs. Lysine maximal concentration was 11% greater for High PD pigs and occurred later than for Low PD (1.15h vs 1.03h). Such differences in AA postprandial metabolism might be partially due to metabolic differences in response to anabolic hormones such as insulin. For instance, HOMA-IR differed (P < 0.05) among PD categories, with Low PD showing a 44% lower index for insulin resistance than high PD pigs. High PD pigs are less insulin-resistant and show differences in pre- and postprandial AA metabolism.

Insulin: The Journey Continues

Abstract In the history of medicine, the discovery of insulin marked a turning point. At first, the only form of insulin that could be administered to humans was this secretion from animal pancreas. Since its conception, technologies for purifying and altering insulin have been developed, although they are still a long way from simulating pancreatic-cells’ natural production. The precise structure of the insulin molecule had been uncovered by the late 1950s, and with the development of molecular biology and recombinant DNA techniques, it is now feasible to manipulate genes to produce recombinant human insulins. This opened the door for the creation of short-acting analogs to mimic postprandial insulin secretion and long-acting analogs to mimic basal or background insulin secretion. The patients can more closely mimic pancreatic insulin secretion thanks to the characteristics of the new basal and bolus analogs than they could with the earlier insulins. However, there are still issues with the absence of portal delivery, night-time dip, morning surge, and responsiveness to ambient blood glucose. There are a number of noninvasive methods being researched for the delivery of insulin, including transdermal, buccal, oral, and pulmonary routes. The hunt for insulin that precisely mirrors the physiological profile and has improved stability, less variability, and perhaps selective action, is still ongoing.

Signs of a Glucose- and Insulin-Independent Gut-Bone Axis and Aberrant Bone Homeostasis in Type 1 Diabetes.

Gut hormones seem to play an important role in postprandial bone turnover, which also may be affected by postprandial plasma glucose excursions and insulin secretion. To investigate the effect of an oral glucose tolerance test (OGTT) and an isoglycemic intravenous glucose infusion (IIGI) on bone resorption and formation markers in individuals with type 1 diabetes and healthy controls. This observational case-control study, conducted at the Center for Clinical Metabolic Research, Gentofte Hospital, Hellerup, Denmark, included 9 individuals with C-peptide negative type 1 diabetes and 8 healthy controls matched for gender, age, and body mass index. Subjects underwent an OGTT and a subsequent IIGI. We analyzed changes in bone resorption assessed by measurements of carboxy-terminal type I collagen crosslinks (CTX) and in bone formation as assessed by procollagen type I N-terminal propeptide (PINP) concentrations. Baseline CTX and PINP levels were similar in the 2 groups. Both groups exhibited significantly greater suppression of CTX during OGTT than IIGI. PINP levels were unaffected by OGTT and IIGI, respectively, in healthy controls. Participants with type 1 diabetes displayed impaired suppression of CTX-assessed bone resorption and inappropriate suppression of PINP-assessed bone formation during OGTT. Our data suggest the existence of a gut-bone axis reducing bone resorption in response to oral glucose independently of plasma glucose excursions and insulin secretion. Subjects with type 1 diabetes showed impaired suppression of bone resorption and reduced bone formation during OGTT, which may allude to the reduced bone mineral density and increased fracture risk characterizing these individuals.

221-LB: Identification of PAM as Novel Monogenic Diabetes Gene

Background/Objectives: Various biological mechanisms involved in type 2 diabetes (T2D) have been unveiled through converging evidence in common variants from Genome wide association studies (GWAS) and rare or low frequency variants (RV/LFV) from Exome wide association studies (EXWAS). We hypothesized that a two-pronged approach interrogating both RV/LFV and common variants could yield identification of new pathways involved in T2D. Methods: Protein-altering RV/LFV burden was tested for T2D association in an EXWAS of 11,731 cases and 149,613 controls in the UKBiobank. Significant encoded proteins were then investigated using 2-sample Mendelian randomization for causal association with T2D and related variables. Protein quantitative trait loci were estimated in the Prospective Urban and Rural Epidemiological study (N=11,020) and tested against GWAS-summary statistics of T2D and related traits from 10 consortia. Results: At the EXWAS significance threshold (P=0.05/19,589=2.55×10-6), we identified loss-of-function RV/LFV in GCK and PAM, which encode the proteins glucokinase and peptidylgycine α-amidating monooxygenase respectively, to be associated with T2D risk. Deleterious mutations in the PAM gene were associated with an 29% increase in T2D risk (OR per RV/LFV=1.29; 95%CI=1.17-1.43; P=7.17×10-7). This association was driven by a low frequency variant, rs78408340-G present in 2.6% of T2D cases and only in 1.8% of controls. MR analyses confirmed that 1 SD decrease in PAM circulating levels was consistently associated with increased T2D risk (OR=1.16; 95%CI=1.14-1.19; P=9.54×10-52) and HbA1c (%) (β=0.0047; 95%CI= 0.00051-0.0090; P=0.028), and decreased post-prandial insulin (mU/L) secretion (β=-0.060; 95% CI=-0.083(-)-0.036; P=8.32×10-7). Conclusion: We identified PAM variants as a novel cause of monogenic diabetes and demonstrated a strong causal effect of circulating PAM levels on T2D risk and post-prandial insulin secretion. This supports further investigation of PAM as a therapeutic T2D target. Disclosure J. Feiner: None. N. Perrot: None. M. Chong: Research Support; Bayer Inc. R. Lali: None. R. Morton: None. P. Mohammadi-Shemirani: None. S. Yusuf: None. H. C. Gerstein: Advisory Panel; Abbott Diagnostics, Eli Lilly and Company, Sanofi. Research Support; Novo Nordisk. Advisory Panel; Novo Nordisk. Research Support; Eli Lilly and Company, Sanofi. Advisory Panel; Kowa Company, Ltd., Hanmi Pharm. Co., Ltd. Other Relationship; Zuellig Pharma Holdings Pte. Ltd., DKSH, AstraZeneca. G. Pare: Research Support; Bayer Inc. Advisory Panel; Bayer Inc., Amgen Inc., Novartis AG. M. Pigeyre: None. Funding Bayer; Canadian Institutes of Health Research

278-LB: The Effect of Combining Very-Low-Calorie Diet with Semaglutide on Beta-Cell Function in Individuals with Type 2 Diabetes

Type 2 diabetes (T2D) is characterised by the loss of the first phase response of insulin-producing pancreatic beta cells. Recently, Very-low calorie diets (VLCD - defined as less than 800 kilocalories per day) have been shown to restore this first phase response to induce remission of T2D, while Glucagon-like peptide-1 agonists also improve the first phase response by enhancing postprandial insulin secretion. Here, we present interim results of an investigation exploring the effect of combining these two interventions on beta cell function, in individuals with T2D. Eighteen individuals with T2D and body mass index >27kg.m-2 were randomly allocated into 3 groups: i) Semaglutide (S), ii) VLCD (V), and iii) Semaglutide-plus-VLCD (SV). Semaglutide was administered once weekly gradually up titrated to a maximum dose of 1mg and VLCD regime was provided by LighterLife® total meal replacement. Beta cell function was assessed using intravenous glucose tolerance tests (IVGTT) performed at baseline and 12 weeks. First-phase insulin response was calculated as the incremental area under the suprabasal plasma insulin concentration curve during 0-10 minutes of the IVGTT (µU.min.ml-1). Data were analysed using GraphPad Prism 9.5.0 (La Jolla, USA). All groups were equally matched at baseline. Mean weight loss was 6.4, 14.1 and 14.9 kg in S, V and SV, respectively. A significant improvement in first phase response was observed in all groups (S: +398.5; V: +88.4; SV: +547.8 µU.min.ml-1, all p<0.05 vs. baseline). At 12 weeks, first phase response in SV was significantly higher than in V (583.9 vs. 169.2 µU.min.ml-1 respectively, p<0.05). These data suggest that combination of VLCD and Semaglutide results in a significantly greater improvement in first phase response than VLCD alone. This approach could result in a more robust remission of T2D in the longer-term, and may have important implications for the future design of interventions for the clinical management of T2D. Disclosure O. Anyiam: None. B. E. Phillips: None. D. J. Wilkinson: None. K. Smith: None. P. J. Atherton: None. I. R. Idris: None. Funding Medical Research Council Confidence in Concept Scheme

O155 Effects of oral feeding on gastric emptying and gastrointestinal hormone secretion in males with obesity compared with those of healthy weight

Abstract Introduction Hormones released in response to nutrients in the gastrointestinal (GI) tract, act as physiological signals to regulate appetite and play a role in feeding behaviours. Altered secretion of these ‘appetite’ hormones after feeding in those with obesity (‘Obese’), compared to those with healthy weight (‘Lean’), may drive over-consumption of energy. This study assessed whether gastric emptying rate was implicated in this altered response. Methods Twenty healthy males attended the laboratory once in the morning after an overnight fast. Volume of gastric contents (GCV) and small bowel water (SBW) were assessed using MRI (Philips 3T Ingenia and dStream Anterior Coil) pre, immediately post and every 30-minutes for 4-hours after a standard meal (2.5MJ, 78g Carbohydrate, 24g Protein, 21g Fat). Concurrently, arterialised-venous blood was taken for insulin, ghrelin, GLP-1 and PYY evaluation. Gastric emptying (T50) was derived from GCV. Data are presented as the mean (SD) or standardised effect size (ηp2). Results 10 Lean [38(14)y, 24(2) kg/m2] and 10 Obese [38(13)y, 34(3)kg/m2] were studied. Fasting insulin [12.5(5.8) vs. 17.6(11.3) mIU/l], Ghrelin [3.2(2.1) vs. 2.9(0.9) ng/ml], GLP-1 [7.2(11.5) vs. 13.3(2.5) pmol/l], PYY [102.3(46.7) vs. 88.4(32.4)pg/ml], SBW [121(96) vs. 168(125)ml] and GCV [59(33) vs. 59(30)ml] did not differ between ‘Lean’ and ‘Obese’. Response of Ghrelin (ηp2=0.005), GLP-1 (ηp2=0.103), PYY (ηp2=0.050) and SBWC (ηp2=0.145) to eating, and T50 [148(51) vs. 170(49) min] did not differ between groups. However, postprandial insulin secretion was greater in obese (ηp2=0.286; P<0.05). Conclusion Gastric emptying and incretin hormone secretion were not altered in participants with obesity. However, postprandial hyperinsulinemia, associated with insulin resistance, was observed.

Abstract 686: Glp-2 Predicts Cardiovascular Outcomes In Patients With Myocardial Infarction And Increases Atherosclerosis In Mice

Background: GLP-1 and GLP-2 (glucagon-like peptide-1/2) are incretin hormones that are co-secreted from intestinal L-cells in response to food. While GLP-1 is known to induce postprandial insulin secretion and to improve cardiovascular outcomes in patients with diabetes, GLP-2 is a local intestinal growth factor enhancing intestinal nutrient absorption. GLP-2 agonists are clinically used for the treatment of patients with short bowel syndrome. The relevance of GLP-2 beyond the gut is not well understood. The aim of this study was to investigate the role of GLP-2 for cardiovascular disease (CVD). Methods: Circulating GLP-2 levels were assessed at time of hospital admission in 1929 patients with myocardial infarction. The primary outcome of the study was the first occurrence of cardiovascular death, nonfatal myocardial infarction, or nonfatal stroke (3-P-MACE). To induce atherosclerosis, Glp2r –/– or WT mice were injected with PCSK9 virus and fed a HCD for 12 weeks. Results: Kaplan-Meier survival plots and univariable cox regression analyses found GLP-2 to be associated with adverse outcome (3-P-MACE and all-cause mortality; log. GLP-2 values HR: 2.87; p<.0001). Further adjustment for age, sex, smoking, hypertension, hypercholesterinemia, previous CVD and diabetes mellitus did not affect this association (log. GLP-2 values HR: 2.66; p=0.0055). Receiver operating characteristic curve (ROC) analyses illustrated that GLP-2 is a strong indicator for early events, which proved to be superior to Troponin T and hs-CRP. To asses the functional role of GLP-2 in CVD in an experimental approach we injected Glp2r –/– or WT mice PCSK9 virus and fed these mice a HCD. After 12 weeks Glp2r –/– mice compared to WT littermates presented with a significant reduction in plaque volume and lesion size. While body weight and leukocyte numbers in various organs were unaffected, Glp2r –/– mice had significantly lower cholesterol levels. Conclusion: Circulating GLP-2 levels are independently associated with cardiovascular events in patients with myocardial infarction while inactivation of the GLP-2 system reduces atherosclerosis in mice. Future studies are needed to investigate whether the GLP-2 receptor might provide a novel therapeutic target for cardiovascular disease.

Physiology, pharmacology and prospects for dipeptidilpeptidase-4 inhibitors use

Modern requirements for the treatment of type 2 diabetes mellitus (DM2) include not only achieving a glycemic control, but also reducing the risk of developing cardiovascular complications. Dipeptidyl peptidase 4 (DPP-4) inhibitors are inferior in the effectiveness to some other actively developing groups of hypoglycemic drugs (SGLT2 inhibitors and GLP-1 receptor agonists); however, they seem relevant at the present time.The aim of the study is to analyze the literature data on the therapeutic potential and results of the of DPP-4 inhibitors research.Materials and methods. When searching for the review article materials, the abstracting databases of PubMed, Google Scholar and e-Library were used. The search was carried out on the publications for the period from 2006 to 2022, using the following keywords: DPP-4 inhibitors; glucagonlike peptide-1 (GLP-1); glucose-dependent insulinotropic peptide (GIP); sitagliptin, and other drugs.Results. DPP-4 belongs to the serine proteases family and is involved in the degradation of various chemokines and peptide hormones, including incretins secreted by intestinal L- and K-cells – GLP-1 and GIP. They regulate a postprandial insulin secretion and a β-cell function, modulate a fasting and postprandial glucagon secretion, regulate the eating behavior and have many pleiotropic (immunomodulatory, anti-inflammatory, antifibrotic, etc.) effects. DPP-4 inhibitors reduce an enzyme activity by 70–90%, increasing plasma incretin levels by 2–4 times and have been used to treat DM2 since 2006. Now there are 13 DPP-4 inhibitors on the market in different countries, differing primarily in pharmacokinetic parameters. They are actively used in the combination therapy for type 2 diabetes, increasing the glycemic control effectiveness without increasing the risk of hypoglycemia. The evidence is emerging about the therapeutic potential of DPP-4 inhibitors in COVID-19.Conclusion. A peroral form, an ability to create effective combinations with other hypoglycemic drugs without increasing the risk of hypoglycemia, the pleiotropic effects of DPP-4 inhibitors, make this group relevant at the present time.

Glycemic index and obesity , , ,

Although weight loss can be achieved by any means of energy restriction, current dietary guidelines have not prevented weight regain or population-level increases in obesity and overweight. Many high-carbohydrate, low-fat diets may be counterproductive to weight control because they markedly increase postprandial hyperglycemia and hyperinsulinemia. Many high-carbohydrate foods common to Western diets produce a high glycemic response [high-glycemic-index (GI) foods], promoting postprandial carbohydrate oxidation at the expense of fat oxidation, thus altering fuel partitioning in a way that may be conducive to body fat gain. In contrast, diets based on low-fat foods that produce a low glycemic response (low-GI foods) may enhance weight control because they promote satiety, minimize postprandial insulin secretion, and maintain insulin sensitivity. This hypothesis is supported by several intervention studies in humans in which energy-restricted diets based on low-GI foods produced greater weight loss than did equivalent diets based on high-GI foods. Long-term studies in animal models have also shown that diets based on high-GI starches promote weight gain, visceral adiposity, and higher concentrations of lipogenic enzymes than do isoenergetic, macronutrientcontrolled, low-GI-starch diets. In a study of healthy pregnant women, a high-GI diet was associated with greater weight at term than was a nutrient-balanced, low-GI diet. In a study of diet and complications of type 1 diabetes, the GI of the overall diet was an independent predictor of waist circumference in men. These findings provide the scientific rationale to justify randomized, controlled, multicenter intervention studies comparing the effects of conventional and low-GI diets on weight control.

The incidence of insulin resistance based on indices calculated using the HOMA and Belfiore methods and its impact on the occurrence of metabolic complications in prepubertal children born small for gestational age.

Children born small for gestational age (SGA) are predisposed to obesity, insulin resistance (IR), and lipid disorders. TheHOMA-IR index is commonly used to assess IR (IRIHOMA), calculated from fasting glucose and insulin. However, sometimes, during the oral glucose tolerance test (OGTT), elevated and prolonged postprandial insulin secretion is observed despite normal fasting insulin levels. IRIBelfioreis an IR index that analyses glucose and insulin levels during OGTT according to the method proposed by Belfiore. was to assess the frequency of IR based on IRIHOMAand IRIBelfioreresults in SGA children aged 6-8 years, after catch-up phenomenon, to determine the usefulness of IRIBelfiorein diagnosis of IR and in predicting future metabolic complications. In 129 SGA normal-height children, aged 6-8 years, height, weight, waist circumference, blood pressure, as well as lipids, IGF-1, cortisol, C-peptide, leptin, adiponectin, and resistin concentrations were measured.The glucose and insulin concentrations were evaluated at 0, 60,and 120minutes of OGTT. IRIHOMAwas normal in all children, while elevated IRIBelfiorewas found in 22.5% of them. Children with IR diagnosed by IRIBelfiorewere taller, had higher blood pressure, higher leptin, and lower HDL-cholesterol concentrations. It seems worth recommending IRIBelfiore derived from OGTT asavaluable diagnostic tool for identifying IR in SGA prepubertal children. Abnormal IRIBelfiore is related to higher blood pressure and lower HDL-cholesterol concentration in this group.

Associations of low sex hormone-binding globulin and androgen excess in early pregnancy with fasting and post-prandial hyperglycaemia, gestational diabetes, and its severity.

We studied whether androgen excess and low sex hormone-binding globulin (SHBG) measured in early pregnancy are independently associated with fasting and post-prandial hyperglycaemia, gestational diabetes (GDM), and its severity. This nationwide case-control study included 1045 women with GDM and 963 non-diabetic pregnant controls. We measured testosterone (T) and SHBG from biobanked serum samples (mean 10.7 gestational weeks) and calculated the free androgen index (FAI). We first studied their associations with GDM and secondly with the type of hyperglycaemia (fasting, 1 and 2h glucose concentrations during the oral glucose tolerance test), early-onset GDM (<20 gestational weeks) and the need for anti-diabetic medication. After adjustments for gestational weeks at sampling, pre-pregnancy BMI, and age, women with GDM had 3.7% (95% CI 0.1%-7.3%) lower SHBG levels, 3.1% (95% CI 0.1%-6.2%) higher T levels, and 4.6% (95% CI 1.9%-7.3%) higher FAI levels than controls. SHBG was inversely associated with fasting glucose, whereas higher FAI and T were associated with higher post-prandial glucose concentrations. Women with early-onset GDM had 6.7% (95% CI 0.7%-12.7%) lower SHBG levels and women who needed insulin for fasting hyperglycaemia 8.7% (95% CI 1.8%-14.8%) lower SHBG levels than other women with GDM. Lower SHBG levels were associated especially with early-onset GDM, higher fasting glucose and insulin treatment, whereas androgen excess was associated with higher post-prandial glucose values. Thus, a low SHBG level may reflect the degree of existing insulin resistance, while androgen excess might impair post-prandial insulin secretion.

ODP173 Control of Alpelisib-Induced Hyperglycemia With DPP4- Inhibitors as add on to Metformin and Insulin

Abstract Context Alpelisib is an oral phosphatidylinositol-3-kinase alpha (PI3Ka) inhibitor approved in 2019 for treatment of ER/PR+, HER2-negative advanced breast cancer. The main side effect of PI3Ka inhibition is hyperglycemia. Case A 38 year-old woman was started on alpelisib and fulvestrant therapy for Stage IV bilateral breast carcinoma (ER+, PR+, HER2-negative) with multiple distant metastases. She had previously received multiple courses of systemic therapy with palbociclib, letrozole, and everolimus, in combination with fulvestrant. She was lean (BMI 20.6 kg/m 2), had a prior history of GDM only requiring diet control, and pre-existing pre-diabetes, with a baseline FPG of 5.6 mmol/L and HbA1c of 5.9%. She developed hyperglycemia after 2 months of Alpelisib 200 mg OD (FPG 138.6 mg/dL; HbA1c 5.8%) and was started on metformin 500 mg BD. Glucose levels remained under control (fasting BG of 108-126 mg/dL) until alpelisib dose was increased to 300 mg OD. Within 6 weeks of dose increment, her fasting BG markedly increased to 324 mg/dL and HbA1c to 10%. Metformin dose was increased to 1000 mg BD, linagliptin 5 mg OD and isophane insulin at 8 units once daily, was introduced in addition to lifestyle modifications. Due to the side effects resulting in diarrhea, alpelisib was discontinued temporarily for 3 weeks before subsequent reintroduction and titration to a maximum tolerable dose of 200 mg OD. Glycemic control subsequently improved with metformin, linagliptin and titration of insulin to 14units daily, with HbA1c reduction to 6. 0% and fasting BG of 84.6 mg/dL, without any hypoglycemia. Oncological assessment showed disease response, with smaller primary tumour and stable metastatic lesions. Discussion The PI3K/AKT pathway plays a central role in cellular growth and glucose metabolism. This pathway is a potent target of anticancer therapy. In physiological glucose homeostasis, postprandial insulin secretion activates the PI3Ka pathway, subsequently upregulating glucose transporters for cellular uptake and utilization of glucose. In the phase III clinical trial (SOLAR-1), the incidence of alpelisib-induced hyperglycemia was 63.7%, and was treated with insulin sensitizers such as metformin and pioglitazone. Subsequent case series have reported effective glycemic control using very low calorie diet (VLCD), SGLT2-inhibitors and insulin therapy 1 . In our patient, linagliptin, was chosen as an adjunct therapy in addition to metformin due to its mechanism of action that address insulin resistance and favourable safety profile. We also note that the severity of alpelisib side effects appeared to be dose-dependent, as seen in the clinical trial. Conclusion We demonstrated effective control of alpelisib-induced hyperglycemia using DPP4-inhibitors as an option, in combination with metformin and insulin.

Effects of an isoenergetic multifactorial diet on pancreatic fat and insulin secretion in patients with type 2 diabetes: A randomized controlled trial

Background and Aims : Pancreatic fat (PF) accumulation may impair beta-cell function. We investigated whether an isocaloric diet able to reduce liver fat in type 2 diabetes (T2D) also affected PF and postprandial insulin secretion.

High-Fat or High-Carbohydrate Meal-Does It Affect the Metabolism of Men with Excess Body Weight?

Excessive adipose tissue in the body may lead to adverse health effects, carbohydrate and lipid metabolism disorders, and cardiovascular diseases. The aim of this study was to analyze the effect of a standardized high-fat meal (HF) on changes in energy expenditure and changes in the oxidation of energy substrates as well as the concentration of glucose, insulin, triglycerides and homocysteine in blood serum in relation to a standardized high-carbohydrate (non-fat, HC) meal in men with different nutritional status. In this study, 26 men (aged 19–60) without carbohydrate disorders (study group GS = 13 overweight/obese; control group GC = 13 normal body weight) were examined. It was observed that following a high-fat or high-carbohydrate meal, men with excessive body weight metabolized the main nutrients differently than men with normal body weight, and postprandial insulin secretion was also different (even without any significant differences in glucose concentrations). Overweight/obesity, which is in itself a risk factor for cardiovascular disease, contributes to an increase in the concentration of other risk factors, such as the concentration of homocysteine and triglycerides, which is referred to as cardiometabolic risk. Consumption of a high-fat meal increased the number of potential risk factors for cardiovascular disease (homocysteine and triglycerides) compared to a high-carbohydrate meal.