Intravenous Glucose Tolerance Test Research Articles

Association between insulin sensitivity and lean mass loss during weight loss.

The study objective was to assess the relationship between insulin sensitivity and changes in total lean mass (LM) and appendicular LM (ALM) during weight loss. Individuals were randomly assigned to either a standard or a moderately reduced carbohydrate diet for 16 weeks. Body composition was assessed using dual-energy x-ray absorptiometry and insulin sensitivity index (SI) using an intravenous glucose tolerance test. Multiple linear regression was used to determine whether baseline SI was predictive of changes in total LM and ALM. Participants (n = 57; baseline BMI 32.1 ± 3.8 kg/m2) lost an average of 6.8 ± 3.2 kg of body weight (p < 0.001), with 1.5 ± 2.6 kg coming from LM (p < 0.05) and 0.5 ± 0.73 kg from ALM (p < 0.05). Multiple regression analysis demonstrated that SI was inversely associated with changes in total LM (kilograms; β = 0.481, p < 0.001), after adjusting for baseline LM, fat mass, acute insulin response to glucose, and weight loss. Similar results were seen when assessing ALM loss (β = 0.359, p < 0.05). Identifying individuals with low insulin sensitivity prior to weight loss interventions may allow for a personalized approach aiming at minimizing LM loss.

Reanimating Pancreatic Grafts Subjected to Prolonged Cold Ischemic Injury Using Normothermic Ex Vivo Perfusion.

Pancreas transplant volumes are limited because of poor utilization of "extended criteria grafts." Prolonged cold ischemia is a risk factor associated with poor allograft survival. We aimed to establish the feasibility of transplantation using grafts subjected to prolonged cold ischemia and determine whether these grafts could be optimized using normothermic ex vivo perfusion (NEVP) in a porcine model. The study population consisted of 35 to 40 kg male Yorkshire pigs in an allotransplantation model with a 3-d survival plan for recipients. Control grafts were subjected to cold storage (CS) in a University of Wisconsin solution for 21 to 24 h (n = 6), whereas the test group received an additional 3 h NEVP after CS of 21 h (n = 5). The 3-d survival was 60% in the NEVP arm versus 0% in the control arm (P = 0.008; log rank). Graft parenchyma was 60% to 70% preserved in the NEVP arm at necropsy on gross appearance. In addition, the islet function was well preserved, and both the pancreas (including the islets) and the duodenal morphology were maintained histologically. The intravenous glucose tolerance test on the day of euthanasia was in the normoglycemic range for 80% of cases in the NEVP arm. Optimization of pancreas grafts exposed to extended CS with NEVP seems promising at rescuing and reanimating these grafts for transplantation, resulting in significantly improved survival in a porcine pancreas transplant model.

Impact of Physiological Fluctuations of Sex Hormones During the Menstrual Cycle on Glucose Metabolism and the Gut Microbiota.

Diabetes mellitus is one of the most prevalent chronic diseases. Previous studies have shown differences in glucose metabolism between males and females. Moreover, difficulties in medication adherence have been reported in females with type 2 diabetes. These observations are believed to be caused by fluctuations in sex hormone concentrations during the menstrual cycle. Furthermore, gut microbiota is linked to female host metabolism and sex hormone production. Understanding the interactions between fluctuating hormone concentrations during the menstrual cycle, gut microbiota, and glucose metabolism in humans is significant because of the increasing prevalence of diabetes and the consequent need to expand preventive efforts. A literature search was performed to determine and summarize the existing evidence, deduce future research needs to maintain female health, and investigate the relationship between the physiological menstrual cycle and glucose metabolism. Studies from 1967 to 2020 have already examined the relationship between variations during the menstrual cycle and glucose metabolism in healthy female subjects using an oral-glucose tolerance test or intravenous glucose tolerance test. However, the overall number of studies is rather small and the results are contradictory, as some studies detected differences in glucose concentrations depending on the different cycle phases, whereas others did not. Some studies reported lower glucose levels in the follicular phase than in the luteal phase, whereas another study detected the opposite. Data on gut microbiota in relation to the menstrual cycle are limited. Conflicting results exist when examining the effect of hormonal contraceptives on the gut microbiota and changes in the course of the menstrual cycle. The results indicate that the menstrual cycle, especially fluctuating sex hormones, might impact the gut microbiota composition.The menstrual cycle may affect the gut microbiota composition and glucose metabolism. These results indicate that glucose tolerance may be the greatest in the follicular phase; however, further well-conducted studies are needed to support this assumption.

Estimating insulin sensitivity and β-cell function from the oral glucose tolerance test: validation of a new insulin sensitivity and secretion (ISS) model.

Efficient and accurate methods to estimate insulin sensitivity (SI) and β-cell function (BCF) are of great importance for studying the pathogenesis and treatment effectiveness of type 2 diabetes (T2D). Existing methods range in sensitivity, input data, and technical requirements. Oral glucose tolerance tests (OGTTs) are preferred because they are simpler and more physiological than intravenous methods. However, current analytical methods for OGTT-derived SI and BCF also range in complexity; the oral minimal models require mathematical expertise for deconvolution and fitting differential equations, and simple algebraic surrogate indices (e.g., Matsuda index, insulinogenic index) may produce unphysiological values. We developed a new insulin secretion and sensitivity (ISS) model for clinical research that provides precise and accurate estimates of SI and BCF from a standard OGTT, focusing on effectiveness, ease of implementation, and pragmatism. This model was developed by fitting a pair of differential equations to glucose and insulin without need of deconvolution or C-peptide data. This model is derived from a published model for longitudinal simulation of T2D progression that represents glucose-insulin homeostasis, including postchallenge suppression of hepatic glucose production and first- and second-phase insulin secretion. The ISS model was evaluated in three diverse cohorts across the lifespan. The new model had a strong correlation with gold-standard estimates from intravenous glucose tolerance tests and insulin clamps. The ISS model has broad applicability among diverse populations because it balances performance, fidelity, and complexity to provide a reliable phenotype of T2D risk.NEW & NOTEWORTHY The pathogenesis of type 2 diabetes (T2D) is determined by a balance between insulin sensitivity (SI) and β-cell function (BCF), which can be determined by gold standard direct measurements or estimated by fitting differential equation models to oral glucose tolerance tests (OGTTs). We propose and validate a new differential equation model that is simpler to use than current models and requires less data while maintaining good correlation and agreement with gold standards. Matlab and Python code is freely available.

The importance of intravenous glucose tolerance test glucose stimulus for the evaluation of insulin secretion

For 100 years, the Intravenous glucose tolerance test (IVGTT) has been used extensively in researching the pathophysiology of diabetes mellitus and AIRg—the IVGTT-induced acute insulin response to the rapid rise in circulating glucose—is a key measure of insulin secretory capacity. For an effective evaluation of AIRg, IVGTT glucose loading should be adjusted for glucose distribution volume (gVOL) to provide an invariant, trend-free immediate rise in circulating glucose (ΔG0). Body weight-based glucose loads have been widely used but whether these achieve a trend-free ΔG0 does not appear to have been investigated. By analysing variation in AIRg, ΔG0 and gVOL with a range of IVGTT loads, both observed and simulated, we explored the hypothesis that there would be an optimum anthropometry-based IVGTT load calculation that, by achieving a trend-free ΔG0, would not compromise evaluation of AIRg as an index of beta cell function. Data derived from patient and research volunteer records for 3806 IVGTT glucose and insulin profiles. Among the non-obese, as gVOL rose, weight increased disproportionately rapidly. Consequently, the IVGTT glucose load needed for an invariant ΔG0 was progressively overestimated, accounting for 47% of variation in AIRg. Among the obese, ΔG0 was trend-free yet AIRg increased by 11.6% per unit body mass index, consistent with a more proportionate increase in weight with gVOL and a hyperinsulinaemic adaptation to adiposity-associated insulin resistance. Simulations further confirmed our hypothesis by demonstrating that a body surface area-based IVGTT load calculation could provide for a more generally invariant IVGTT ΔG0.

High fat diet is associated with gut microbiota dysbiosis and decreased gut microbial derived metabolites related to metabolic health in young Göttingen Minipigs.

The objectives were 1) to characterize a Göttingen Minipig model of metabolic syndrome regarding its colon microbiota and circulating microbial products, and 2) to assess whether ovariectomized female and castrated male minipigs show similar phenotypes. Twenty-four nine-week-old Göttingen Minipigs were allocated to four groups based on sex and diet: ovariectomized females and castrated males fed either chow or high-fat diet (HFD) for 12 weeks. At study end, body composition and plasma biomarkers were measured, and a mixed meal tolerance test (MMT) and an intravenous glucose tolerance test (IVGTT) were performed. The HFD groups had significantly higher weight gain, fat percentage, fasting plasma insulin and glucagon compared to the chow groups. Homeostatic model assessment of insulin resistance index (HOMA-IR) was increased and glucose effectiveness derived from the IVGTT and Matsuda´s insulin sensitivity index from the MMT were decreased in the HFD groups. The HFD groups displayed dyslipidemia, with significantly increased total-, LDL- and HDL-cholesterol, and decreased HDL/non-HDL cholesterol ratio. The colon microbiota of HFD minipigs clearly differed from the lean controls (GuniFrac distance matrix). The main bacteria families driving this separation were Clostridiaceae, Fibrobacteraceae, Flavobacteriaceae and Porphyromonadaceae. Moreover, the species richness was significantly decreased by HFD. In addition, HFD decreased the circulating level of short chain fatty acids and beneficial microbial metabolites hippuric acid, xanthine and trigonelline, while increasing the level of branched chain amino acids. Six and nine metabolically relevant genes were differentially expressed between chow-fed and HFD-fed animals in liver and omental adipose tissue, respectively. The HFD-fed pigs presented with metabolic syndrome, gut microbial dysbiosis and a marked decrease in healthy gut microbial products and thus displayed marked parallels to human obesity and insulin resistance. HFD-fed Göttingen Minipig therefore represents a relevant animal model for studying host-microbiota interactions. No significant differences between the castrated and ovariectomized minipigs were observed.

Insulin resistance before type 2 diabetes onset is associated with increased risk of albuminuria after diabetes onset: A prospective cohort study.

Reduced renal insulin signalling is implicated in the pathogenesis of albuminuria. We sought to investigate whether insulin action and secretion, measured before diabetes onset, are associated with the development of albuminuria after diabetes onset. Baseline body composition, insulin sensitivity by hyperinsulinaemic-euglycaemic clamp at submaximal and maximal insulin stimulation (240 and 2400 pmol/m2/min; M-low and M-high), and insulin secretion by intravenous glucose tolerance test [acute insulin response (AIR)] were measured in 170 Southwestern Indigenous American adults who subsequently developed diabetes. After diabetes onset and during the median follow-up of 13.6 years, 81 participants (48%) developed albuminuria (urine albumin-to-creatinine ratio ≥30 mg/g). Separate associations of M-low, M-high and AIR (per 1-SD change) with the risk of albuminuria were assessed by Cox regression models adjusted for age, sex and body fat (%). Participants who developed albuminuria were of similar age (26.4 ± 5.4 vs. 27.5 ± 6.1 years), sex (46% vs. 48% male), body fat (36.4 ± 7.5 vs. 35.7 ± 7.9%) and AIR [2.3 ± 0.3 vs. 2.3 ± 0.3, pmol/L (log)] as those who did not develop albuminuria but had lower insulin sensitivity [M-low: 0.33 ± 0.08 vs. 0.36 ± 0.12, p = .03; M-high: 0.87 ± 0.11 vs. 0.91 ± 0.12, p = .02; mg/kg-metabolic body size/min (log)]. In separate adjusted models, lower M-low and M-high were both associated with an increased risk for albuminuria [hazard ratio (HR) 1.51, 95% confidence interval (CI) 1.14, 2.00, p = .004; HR 1.31, 95% CI 1.06, 1.63, p = .01), whereas AIR was not (HR 1.15, 95% CI 0.87, 1.56, p = .3). Lower insulin sensitivity is associated with the development of albuminuria, suggesting a role for insulin signalling in the pathogenesis of proteinuria.

The Effects of Resistance Exercise Training on Skeletal Muscle Metabolism and Insulin Resistance Development in Female Rodents with Type 1 Diabetes.

The etiology of insulin resistance (IR) development in type 1 diabetes mellitus (T1DM) remains unclear; however, impaired skeletal muscle metabolism may play a role. While IR development has been established in male T1DM rodents, female rodents have yet to be examined in this context. Resistance exercise training (RT) has been shown to improve IR and is associated with a lower risk of hypoglycemia onset in T1DM compared to aerobic exercise. The purpose of this study was to investigate the effects of RT on IR development in female T1DM rodents. Forty Sprague Dawley eight-week-old female rats were divided into four groups: control sedentary (CS; n = 10), control trained (CT; n = 10), T1DM sedentary (DS; n = 10), and T1DM trained (DT; n = 10). Multiple low-dose streptozotocin injections were used to induce T1DM. Blood glucose levels were maintained in the 4-9 mmol/l range with intensive insulin therapy. CT and DT underwent weighted ladder climbing 5 days/week for six weeks. Intravenous glucose tolerance tests (IVGTT) were conducted on all animals following the six-week period. Results demonstrate that DS animals exhibited significantly increased weekly blood glucose measures compared to all groups including DT (p < 0.0001), despite similar insulin dosage levels. This was concomitant with a significant increase in insulin-adjusted area under the curve following IVGTT in DS (p < 0.05), indicative of a reduction in insulin sensitivity. Both DT and DS exhibited greater serum insulin concentrations compared to CT and CS (p < 0.05). DS animals also exhibited significantly greater glycogen content in white gastrocnemius muscle compared to CS and DT (p < 0.05), whereas DT and DS animals exhibited greater p-Akt: Akt ratio in the white vastus lateralis muscle and citrate synthase activity in the red vastus lateralis muscle compared to CS and CT (p < 0.05). These results indicate that female rodents with T1DM develop poor glycemic control and IR which can be attenuated with RT, possibly related to differences in intramyocellular glycogen content.

Glucose intolerance in acromegaly is driven by low insulin secretion; results from an intravenous glucose tolerance test.

Insulin sensitivity (Si) and its role in glucose intolerance of acromegaly has been extensively evaluated. However, data on insulin secretion is limited. We aimed to assess stimulated insulin secretion using an intravenous glucose tolerance test (IVGTT) in active acromegaly. We performed an IVGTT in 25 patients with active acromegaly (13 normal glucose tolerance [NGT], 6 impaired glucose tolerance [IGT] and 6 diabetes mellitus [DM]) and 23 controls (8 lean NGT, 8 obese NGT and 7 obese IGT). Serum glucose and insulin were measured at 20 time points along the test to calculate Si and acute insulin response (AIRg). Medical treatment for acromegaly or diabetes was not allowed. In acromegaly, patients with NGT had significantly (p for trend < 0.001) higher AIRg (3383 ± 1082 pmol*min/L) than IGT (1215 ± 1069) and DM (506 ± 600). AIRg was higher in NGT (4764 ± 1180 pmol*min/L) and IGT (3183 ± 3261) controls with obesity than NGT (p = 0.01) or IGT (p = 0.17) acromegaly. Si was not significantly lower in IGT (0.68 [0.37, 0.88] 106*L/pmol*min) and DM (0.60 [0.42, 0.84]) than in NGT (0.81 [0.58, 1.55]) patients with acromegaly. NGT (0.33 [0.30, 0.47] 106*L/pmol*min) and IGT (0.37 [0.21, 0.66]) controls with obesity had lower Si than NGT (p = 0.001) and IGT (p = 0.43) acromegaly. We demonstrated that low insulin secretion is the main driver behind glucose intolerance in acromegaly. Compared to NGT and IGT controls with obesity, patients with NGT or IGT acromegaly had higher Si. Together, these findings suggest that impaired insulin secretion might be a specific mechanism for glucose intolerance in acromegaly.

Glucose volume of distribution affects insulin sensitivity measured by intravenous glucose tolerance test.

To determine whether glucose volume of distribution (VdGLUCOSE ) affects the diagnosis of impaired insulin sensitivity (IS) when using an intravenous glucose tolerance test (IVGTT). Individuals with distinct levels of IS underwent IVGTT after an overnight fast. The prediabetic group (Prediab; n = 33) differed from the healthy group (Healthy; n = 14) in their larger glycosylated hemoglobin (HbA1c of 5.9 ± 0.3 vs. 5.4 ± 0.1%; 41 ± 4 vs. 36 ± 1 mmol/mol; p < 0.001), percent body fat (37 ± 6 vs. 24 ± 3%; p < 0.001) and cardiovascular fitness level (VO2MAX 22 ± 5 vs. 44 ± 5 mL of O2 ·kg-1 ·min-1 ; p < 0.001). Ten minutes after intravenous infusion of the glucose bolus (i.e., 35 g in a 30% solution), VdGLUCOSE was assessed from the increases in plasma glucose concentration. IS was calculated during the next 50 min using the slope of glucose disappearance and the insulin time-response curve. VdGLUCOSE was higher in Healthy than in Prediab (230 ± 49 vs. 185 ± 21 mL·kg-1 ; p < 0.001). VdGLUCOSE was a strong predictor of IS (β standardized coefficient 0.362; p = 0.004). VO2MAX was associated with VdGLUCOSE and IS (Pearson r = 0.582 and 0.704, respectively; p < 0.001). However, body fat was inversely associated with VdGLUCOSE and IS (r = -0.548 and -0.555, respectively; p < 0.001). Since fat mass is inversely related to VdGLUCOSE and in turn, VdGLUCOSE affects the calculations of IS, the IV glucose bolus dose should be calculated based on fat-free mass rather than body weight for a more accurate diagnosis of impaired IS.

Alterations in nonesterified free fatty acid trafficking rather than hyperandrogenism contribute to metabolic health in obese women with polycystic ovary syndrome

To determine whether alterations in non-esterified free fatty acids (NEFA) dynamics or degree of hyperandrogenism (HA) contribute to the difference in insulin sensitivity between metabolically healthy (MHO-PCOS) and metabolically unhealthy (MUO-PCOS) obese PCOS women. Prospective cross-sectional study. One hundred-and-twenty-five obese PCOS women. Consecutive obese (BMI≥30 kg/m2) oligo-ovulatory PCOS women (n=125) underwent oGTT and a subgroup of 16 participants underwent modified frequently samples intravenous glucose tolerance test (mFSIVGTT), to determine insulin action and NEFA dynamics. Degree of IR in adipose tissue (AT) basally (Adipo-IR) and dynamically (NEFAnadir, TIMEnadir, and %NEFAsupp); lipolysis rate (SNEFA) and NEFA uptake rate (KNEFA); whole-body insulin action (AIRg, Si, Sg, and DI); and HA (hirsutism score, testosterone [total, free], DHEAS). 85 (68%) subjects were MUO-PCOS and 40 (32%) MHO-PCOS by HOMA-IR. MUO-PCOS and MHO-PCOS did not differ in mean age, BMI, WHR, HA and lipoprotein levels. By mFSIVGTT, 8 MUO-PCOS subjects had lesser Si, KNEFA, and %NEFAsupp, and greater TIMEnidar, NEFAnidar and Adipo-IR, than 8 MHO-PCOS, but similar fasting NEFA and SNEFA. MUO-PCOS had higher HOMA-β% and fasting insulin than MHO-PCOS. In bivalent analysis, Si correlated strongly and negatively with NEFAnadir, weakly and negatively with TIMEnadir, and positively with KNEFA and NEFAsupp, in MUO-PCOS only. Independent of age and BMI, MUO-PCOS women have reduced NEFA uptake and altered insulin-mediated NEFA suppression, but no difference in HA, than MHO-PCOS. Altered insulin-mediated NEFA suppression, rather than HA or lipolysis rate, contributes to variations in insulin sensitivity among obese PCOS women.

Peri-Transplant Inflammation and Long-Term Diabetes Outcomes Were Not Impacted by Either Etanercept or Alpha-1-Antitrypsin Treatment in Islet Autotransplant Recipients.

The instant blood-mediated inflammatory response (IBMIR) causes islet loss and compromises diabetes outcomes after total pancreatectomy with islet autotransplant (TPIAT). We previously reported a possible benefit of etanercept in maintaining insulin secretion 3months post-TPIAT. Here, we report 2-year diabetes outcomes and peri-operative inflammatory profiles from a randomized trial of etanercept and alpha-1 antitrypsin (A1AT) in TPIAT. We randomized 43 TPIAT recipients to A1AT (90mg/kg IV x6 doses, n = 13), etanercept (50mg then 25mg SQ x 5 doses, n = 14), or standard care (n = 16). Inflammatory cytokines, serum A1AT and unmethylated insulin DNA were drawn multiple times in the perioperative period. Islet function was assessed 2years after TPIAT with mixed meal tolerance test, intravenous glucose tolerance test and glucose-potentiated arginine induced insulin secretion. Cytokines, especially IL-6, IL-8, IL-10, and MCP-1, were elevated during and after TPIAT. However, only TNFα differed significantly between groups, with highest levels in the etanercept group (p = 0.027). A1AT increased after IAT in all groups (p < 0.001), suggesting endogenous upregulation. Unmethylated insulin DNA ratios (a marker of islet loss) and 2years islet function testing were similar in the three groups. To conclude, we found no sustained benefit from administering etanercept or A1AT in the perioperative period.

Association of glucose metabolism and insulin resistance with feed efficiency and production traits of finishing beef steers.

Increasing nutrient utilization efficiency is an important component of enhancing the sustainability of beef cattle production. The objective of this experiment was to determine the association of glucose metabolism and insulin resistance with dry matter intake (DMI), average daily gain (ADG), gain:feed ratio (G:F), and residual feed intake (RFI). Steers (n = 54; initial body weight = 518 ± 27.0kg) were subjected to an intravenous glucose tolerance test (IVGTT) where glucose was dosed through a jugular catheter and serial blood samples were collected. Three days after the last group's IVGTT, steers began a 63-d DMI and ADG test. Body weight was measured on days 0, 1, 21, 42, 62, and 63, and DMI was measured using an Insentec Roughage Intake Control system (Hokofarm Group, Emmeloord, the Netherlands). To examine relationships between DMI, ADG, G:F, and RFI with IVGTT measurements, Pearson correlations were calculated using Proc Corr of SAS 9.4 (SAS Inst. Inc., Cary, NC). Additionally, cattle were classified based on DMI, ADG, RFI, and G:F, where the medium classification was set as mean ± 0.5 SD, the low classification was < 0.5 SD from the mean, and the high classification was > 0.5 SD from the mean. No associations between DMI and IVGTT parameters were observed, and no differences were detected when classifying cattle as having low, medium, or high DMI. Peak insulin concentration in response to the IVGTT tended to be correlated with ADG (r = 0.28; P = 0.07), indicating cattle with greater ADG tend to have a greater insulin release in response to glucose. Glucose nadir concentrations tended to be positively correlated with ADG (r = 0.26; P = 0.10). Additionally, the glucose nadir was greater in high-ADG steers (P = 0.003). The association of greater glucose nadir with high-ADG could indicate that high-ADG steers do not clear glucose as efficiently as low-ADG steers, potentially indicating increased insulin resistance. Further, RFI was not correlated with IVGTT measurements, but low RFI steers had a greater peak glucose concentration (P = 0.040) and tended to have a greater glucose area under the curve (P = 0.09). G:F was correlated with glucose area under the curve (r = 0.33; P = 0.050), glucose nadir (r = 0.35; P = 0.011), and insulin time to peak (r = 0.39; P = 0.010). These results indicate that glucose metabolism and insulin signaling are associated with growth and efficiency, but the molecular mechanisms that drive these effects need to be elucidated.

Adverse Metabolic Phenotypes in Parenterally Fed Neonatal Pigs Do Not Persist into Adolescence

BackgroundNutrition during fetal and neonatal life is an important determinant for the risk of adult-onset diseases, especially type 2 diabetes and obesity. ObjectivesWe aimed to determine whether total parenteral nutrition (TPN) compared with enteral formula feeding [enteral nutrition (EN)] in term piglets during the first 2 wk after birth would increase the long-term (5-mo) development of metabolic syndrome phenotypes with adverse glucose homeostasis, fatty liver disease, and obesity. MethodsNeonatal female pigs were administered TPN (n = 12) or fed enterally with a liquid enteral milk-replacer formula (EN, n = 12) for 14 d. After transitioning TPN pigs to enteral feeding of liquid formula (days 15–26), both groups were adapted to a solid high-fat diet (30% of the total diet) and sucrose (20% of the total diet) diet (days 27–33), which was fed until the end of the study (140 d). Body composition was measured by dual-energy X-ray absorptiometry at 14, 45, and 140 d. Serum biochemistry and glucose-insulin values (after a fasting intravenous glucose tolerance test) were obtained at 140 d. Liver and muscle were analyzed for insulin receptor signaling and triglycerides. ResultsBody weight was similar, but percent fat was higher, whereas percent lean and bone mineral density were lower in TPN than in EN pigs (P < 0.01) at 45 d of age but not at 140 d. At 140 d, there were no differences in serum markers of liver injury or lipidemia. Intravenous glucose tolerance test at 140 d showed a lower (P < 0.05) AUC for both glucose and insulin in TPN than in EN pigs, but the ratio of AUCs of insulin and glucose was not different between groups. ConclusionsAdministration of TPN during the neonatal period increased adipose deposition that transiently persisted in early adolescence when challenged with a high-fat diet but was not sustained or manifested as glucose intolerance.

Effects of poor maternal diet during gestation are detected in F2 offspring.

Poor maternal nutrition of F0 ewes impairs F1 offspring growth, with minimal differences in glucose tolerance or select metabolic circulating factors, and independent of differences in residual feed intake (RFI). To determine if poor maternal nutrition in F0 ewes alters F2 offspring growth, circulating leptin, feed efficiency, or glucose tolerance, F0 ewes (n = 46) pregnant with twins were fed 100% (control), 60% (restricted), or 140% (over) of National Research Council requirements from days 30 ± 0.02 of gestation until parturition. At 16 to 19 mo of age, female F1 (n = 36) offspring were bred to generate F2 offspring [CON-F2 (n = 12 ewes; 6 rams), RES-F2 (n = 7 ewes; 13 rams), or OVER-F2 (n = 13 ewes; 9 rams) corresponding to diets of the granddam (F0)]. Lamb body weights (BW) and blood samples were collected weekly from days 0 to 28 and every 14 d until day 252 of age. Circulating leptin was measured in serum at days 0, 7, 14, 56, 210, and 252. An intravenous glucose tolerance test was performed at days 133 ± 0.28. At days 167 ± 0.33, individual daily intake was recorded over a 77-d feeding period to determine RFI. Rams were euthanized at days 285 ± 0.93, and body morphometrics, loin eye area (LEA), back fat thickness, and organ weights were collected and bone mineral density (BMD) and length were determined in the right hind leg. During gestation, OVER-F1 ewes tended to be 8.6% smaller than CON-F1 ewes (P ≤ 0.06). F2 offspring were of similar BW from birth to day 70 (P ≥ 0.20). However, from days 84 to 252, RES-F2 offspring tended to be 7.3% smaller than CON-F2 (P ≤ 0.10). Granddam diet did not influence F2 ram body morphometrics, organ or muscle weights, LEA, adipose deposition, or leg BMD (P ≥ 0.84). RES-F2 (-0.20) and CON-F2 (-0.45) rams tended to be more feed efficient than CON-F2 ewes (0.31; P ≤ 0.08). No effects of granddam diet were observed on glucose or insulin average or baseline concentrations, area under the curve, first-phase response, or ratio (P ≥ 0.52). However, CON-F2 rams (297mg/dL ± 16.5) had a greater glucose peak compared with RES-F2 rams (239mg/dL ± 11.2; P = 0.05). Peak insulin concentrations were not influenced by granddam diet (P = 0.75). At d 56, RES-F2 and OVER-F2 offspring had 53.5% and 61.8% less leptin compared with CON-F2 offspring, respectively (P ≤ 0.02). These data indicate that poor maternal nutrition impacts offspring growth into the second generation with minimal impacts on offspring RFI, glucose tolerance, and circulating leptin.

Analysis of type 2 diabetes heterogeneity with a tree-like representation: insights from the prospective German Diabetes Study and the LURIC cohort

Heterogeneity in type 2 diabetes can be represented by a tree-like graph structure by use of reversed graph-embedded dimensionality reduction. We aimed to examine whether this approach can be used to stratify key pathophysiological components and diabetes-related complications during longitudinal follow-up of individuals with recent-onset type 2 diabetes. For this cohort analysis, 927 participants aged 18-69 years from the German Diabetes Study (GDS) with recent-onset type 2 diabetes were mapped onto a previously developed two-dimensional tree based on nine simple clinical and laboratory variables, residualised for age and sex. Insulin sensitivity was assessed by a hyperinsulinaemic-euglycaemic clamp, insulin secretion was assessed by intravenous glucose tolerance test, hepatic lipid content was assessed by 1 H magnetic resonance spectroscopy, serum interleukin (IL)-6 and IL-18 were assessed by ELISA, and peripheral and autonomic neuropathy were assessed by functional and clinical measures. Participants were followed up for up to 16 years. We also investigated heart failure and all-cause mortality in 794 individuals with type 2 diabetes undergoing invasive coronary diagnostics from the Ludwigshafen Risk and Cardiovascular Health (LURIC) cohort. There were gradients of clamp-measured insulin sensitivity (both dimensions: p<0·0001) and insulin secretion (pdim1<0·0001, pdim2=0·00097) across the tree. Individuals in the region with the lowest insulin sensitivity had the highest hepatic lipid content (n=205, pdim1<0·0001, pdim2=0·037), pro-inflammatory biomarkers (IL-6: n=348, pdim1<0·0001, pdim2=0·013; IL-18: n=350, pdim1<0·0001, pdim2=0·38), and elevated cardiovascular risk (nevents=143, pdim1=0·14, pdim2<0·00081), whereas individuals positioned in the branch with the lowest insulin secretion were more prone to require insulin therapy (nevents=85, pdim1=0·032, pdim2=0·12) and had the highest risk of diabetic sensorimotor polyneuropathy (nevents=184, pdim1=0·012, pdim2=0·044) and cardiac autonomic neuropathy (nevents=118, pdim1=0·0094, pdim2=0·06). In the LURIC cohort, all-cause mortality was highest in the tree branch showing insulin resistance (nevents=488, pdim1=0·12, pdim2=0·0032). Significant gradients differentiated individuals having heart failure with preserved ejection fraction from those who had heart failure with reduced ejection fraction. These data define the pathophysiological underpinnings of the tree structure, which has the potential to stratify diabetes-related complications on the basis of routinely available variables and thereby expand the toolbox of precision diabetes diagnosis. German Diabetes Center, German Federal Ministry of Health, Ministry of Culture and Science of the state of North Rhine-Westphalia, German Federal Ministry of Education and Research, German Diabetes Association, German Center for Diabetes Research, European Community, German Research Foundation, and Schmutzler Stiftung.

Insulin's Function in Health and Disease

Insulin is a polypeptide hormone that is primarily released by cells in the pancreatic islets of Langerhans. The hormone may work in tandem with glucagon to control blood sugar levels; glucagon has catabolic properties while insulin has anabolic ones. Insulin controls blood glucose levels and causes the liver, muscles, and adipose tissue to store glucose, which causes total weight gain. Insulin plays a crucial role in the initiation and development of many chronic diseases because it modulates a variety of physiological processes. Other techniques are based on the exogenous infusion of glucose or insulin, or both, either under steady-state (the insulin suppression test) or under dynamic conditions (the insulin tolerance test, intravenous glucose-tolerance test with minimal model analysis, and constant infusion of glucose with model analysis). Homeostatic model assessment uses fasting plasma glucose and insulin concentrations to derive indices of insulin sensitivity and secretion from a mathematical model.

Glucometabolic Alterations in Pregnant Women with Overweight or Obesity but without Gestational Diabetes Mellitus: An Observational Study

Introduction: Maternal overweight is a risk factor for gestational diabetes mellitus (GDM). However, emerging evidence suggests that an increased maternal body mass index (BMI) promotes the development of perinatal complications even in women who do not develop GDM. This study aims to assess physiological glucometabolic changes associated with increased BMI. Methods: Twenty-one women with overweight and 21 normal weight controls received a metabolic assessment at 13 weeks of gestation, including a 60-min frequently sampled intravenous glucose tolerance test. A further investigation was performed between 24 and 28 weeks in women who remained normal glucose tolerant. Results: At baseline, mothers with overweight showed impaired insulin action, whereby the calculated insulin sensitivity index (CSI) was lower as compared to normal weight controls (3.5 vs. 6.7 10^-4 min^-1 [microU/mL]^-1, p = 0.025). After excluding women who developed GDM, mothers with overweight showed higher average glucose during the oral glucose tolerance test (OGTT) at the third trimester. Moreover, early pregnancy insulin resistance and secretion were associated with increased placental weight in normal glucose-tolerant women. Conclusion: Mothers with overweight or obesity show an unfavorable metabolic environment already at the early stage of pregnancy, possibly associated with perinatal complications in women who remain normal glucose tolerant.

PSVIII-25 Investigating the Effects of Poor Maternal Nutrition on F2 Offspring Growth, Residual Feed Intake, and Glucose Tolerance

Abstract Poor maternal nutrition impairs F1 offspring growth independent of changes in feed efficiency and glucose tolerance. To determine if poor maternal nutrition in F0 ewes contributes to F2 offspring growth, feed efficiency, and glucose tolerance, multiparous Dorset ewes (F0; n = 46) pregnant with twins were fed 100% (control), 60% (restricted) or 140% (over) of NRC requirements from d 30 of gestation until parturition. At 16 to 19 mo of age, female F1 (n = 37) offspring were bred to one of two related Dorset rams to generate F2 offspring, identified as CON-F2 (n = 12 ewes; 6 rams), RES-F2 (n = 7 ewes; 13 rams), or OVER-F2 (n = 13 ewes; 9 rams), corresponding to diets of the granddam. F2 offspring body weight (BW) was measured weekly from birth (d 0) to d 28 and every 14 d until d 252. From d 0 to 70, granddam diet did not influence F2 BW (P ≥ 0.18). However, from d 84 to d 154, RES-F2 tended to be 9.42% lighter than CON-F2 with OVER-F2 intermediate (P ≤ 0.08), and from d 224 to d 252 RES-F2 tended to be 6.47% and 6.29% lighter than CON-F2 and OVER-F2, respectively (P ≤ 0.07). Overall, F2 rams were 8.36 kg heavier than F2 ewes (P &amp;lt; 0.0001). At d 133 ± 0.28 an intravenous glucose tolerance test (0.25 g/kg BW of a 50% dextrose solution) was performed. Glucose and insulin concentrations were determined using commercial kits. Granddam diet did not influence glucose or insulin average or baseline concentrations, area under the curve, first-phase response, or ratio (P ≥ 0.52). However, granddam diet influenced glucose peak response in rams, where CON-F2 rams (297 ± 16.5 mg/dL) had greater glucose peak compared with RES-F2 rams (239 ± 11.2 mg/dL; P = 0.05). At d 167 ± 0.33, daily intake of a complete pelleted feed was recorded using Super SmartFeeders over a 77-day feeding period. A treatment by sex interaction was detected for F2 offspring residual feed intake (RFI; P = 0.08) where CON-F2 ewes (0.31 ± 0.12 kg/d) tended to be less feed efficient than CON-F2 rams (-0.45 ± 0.20 kg/d) and RES-F2 rams (-0.20 ± 0.13 kg/d). Alternately, OVER-F2 ewes (0.16 ± 0.13 kg/d), OVER-F2 rams (0.02 ± 0.15 kg/d), RES-F2 ewes (-0.06 ± 0.18 kg/d), and RES-F2 rams were all of similar (P ≥ 0.34) feed efficiency. Rams were euthanized at d 285 ± 0.93 and body morphometrics, and organ weights were collected. No effect of granddam diet (P ≥ 0.25) on F2 ram morphometric measurements, organ weights, or muscle weights (P ≥ 0.15) were detected at time of necropsy. These data indicate that nutrient restriction during gestation decreases F2 offspring BW independent of RFI and glucose tolerance.

194 Functional Properties of Inositol in Canine Nutrition

Abstract Inositol is a natural extract mainly from Carob, a typical Mediterranean fruit, and small quantities of apples and grapes. Inositol has been associated with several benefits such as antioxidant, capacity, anti-cancer, and hyperglycemia reduction in type 2 diabetes mellitus. However, there is little information regarding the effects of inositol on canine nutrition. This study aimed to evaluate the longitudinal effects of daily supplementation of incremental doses of inositol on serum oxidative stress, inflammatory biomarkers, gut hormones, and postprandial glycemic and insulinemic responses in overweight dogs. Thirty adult dogs were used in a completely randomized study, with 10 animals per treatment. Dogs were fed a commercial dry extruded complete and balanced diet once daily to maintain body weight. Following a 15-d adaptation to the control diet, dogs were fed their respective treatment diets for 60 d. Three experimental treatments were used: 12 g/d of corn syrup (control), 8 g/d of inositol source, and 16 g/d of inositol source. The treatments supplementation had no detrimental effect on the overall health of the dogs and food intake. Throughout the experimental period, serum oxidative stress biomarkers did not differ among dogs fed different dietary treatments (P &amp;gt; 0.05). However, a linear increase across days of the serum cytokine CXCL1 with the supplementation of increasing inositol concentrations was observed (P = 0.0105). Although no differences were observed in the glycemic response to an intravenous glucose tolerance test with the supplementation of increasing concentrations of inositol (P &amp;gt; 0.05), a linear decrease in the average glucose for 24 h measured with interstitial glucose monitors was observed with the supplementation of increasing concentrations of inositol (P = 0.0215). These data suggest that the longitudinal supplementation of inositol may interact with inflammatory response and contribute to the regulation of glucose metabolism.