Intravenous Glucose Tolerance Research Articles

Dietary Betaine Impacts Metabolic Responses to Moderate Heat Exposure in Sheep.

Dietary betaine supplementation can ameliorate physiological responses to heat exposure (HE) in sheep. This experiment measured metabolic responses to glucose (intravenous glucose tolerance, IVGTT), insulin (insulin tolerance test, ITT), and adrenocorticotropic hormone (ACTH) challenges in Merino ewes (n = 36, 39.7 kg) maintained at thermoneutral (TN, 21 °C) or HE (18-43 °C) and supplemented with either 0, 2, or 4 g/day dietary betaine (n = 6 per group). Sheep had ad libitum access to water and were pair-fed such that the intake of the TN sheep mimicked that of the HE sheep. After 21 days of treatment, sheep were fitted with jugular catheters and subjected to consecutive daily challenges (IVGTT, ITT, and ACTH, d 21-23, respectively), followed by skeletal muscle and subcutaneous adipose tissue biopsy collections for gene expression analysis (d 24). The HE-treated sheep had a greater insulin:glucose ratio (p = 0.033), a greater estimated homeostatic model assessment of insulin resistance (HOMAIR; p = 0.029), and a reduced revised quantitative insulin sensitivity check index (RQUICKI; p = 0.015). Sheep fed betaine (2 + 4 g/day) had a greater basal plasma insulin (p = 0.017) and a reduced basal non-esterified fatty acid (NEFA; p = 0.036) concentration, while the RQUICKI was reduced (p = 0.001) in sheep fed betaine. The results suggested that betaine supplementation alters lipid metabolism by potentially improving insulin signaling, although these responses differ between TN and HE conditions. There was no other impact of temperature or dietary treatments on the tissue gene expressions measured. Our results support the notion that betaine, in part, acts to modify lipid metabolism.

Bioluminescence Imaging In Vivo Confirms the Viability of Pancreatic Islets Transplanted into the Greater Omentum.

The liver is the most widely used site for pancreatic islet transplantation. However, several site-specific limitations impair functional success, with instant blood-mediated inflammatory reaction being the most important. The aim of this study was to develop a preclinical model for placement of the islet graft into a highly vascularized omental flap using a fibrin gel. For this purpose, we tested islet viability by bioluminescence imaging (BLI). Pancreatic islets were isolated from luciferase-positive and luciferase-negative rats, mixed at a 1:1 ratio, placed into a plasma-thrombin bioscaffold, and transplanted in standard (10 pancreatic islets/g wt; n = 10) and marginal (4 pancreatic islets/g wt; n = 7) numbers into the omentums of syngeneic diabetic animals. For the control, 4 pancreatic islets/g were transplanted into the liver using the standard procedure (n = 7). Graft viability was tested by bioluminescence at days 14, 30, 60, and 90 post transplant. Glucose levels, intravenous glucose tolerance, and serum C-peptide were assessed regularly. Nonfasting glucose levels < 10 mmol/l were restored in all animals. While islet viability in the omentum was clearly detected by stable luminescence signals throughout the whole study period, no signals were detected from islets transplanted into the liver. The bioluminescence signals were highly correlated with stimulated C-peptide levels detected at 80 days post transplant. Glucose tolerance did not differ among the 3 groups. We successfully tested a preclinical model of islet transplantation into the greater omentum using a biocompatible scaffold made from autologous plasma and human thrombin. Both standard and marginal pancreatic islet numbers in a gel-form bioscaffold placed in the omentum restored glucose homeostasis in recipients with diabetes. Bioluminescence was shown promising as a direct proof of islet viability.

Mathematical model of blood glucose dynamics by emulating the pathophysiology of glucose metabolism in type 2 diabetes mellitus

Mathematical modelling has established itself as a theoretical tool to understand fundamental aspects of a variety of medical-biological phenomena. The predictive power of mathematical models on some chronic conditions has been helpful in its proper prevention, diagnosis, and treatment. Such is the case of the modelling of glycaemic dynamics in type 2 diabetes mellitus (T2DM), whose physiology-based mathematical models have captured the metabolic abnormalities of this disease. Through a physiology-based pharmacokinetic-pharmacodynamic approach, this work addresses a mathematical model whose structure starts from a model of blood glucose dynamics in healthy humans. This proposal is capable of emulating the pathophysiology of T2DM metabolism, including the effect of gastric emptying and insulin enhancing effect due to incretin hormones. The incorporation of these effects lies in the implemented methodology since the mathematical functions that represent metabolic rates, with a relevant contribution to hyperglycaemia, are adjusting individually to the clinical data of patients with T2DM. Numerically, the resulting model successfully simulates a scheduled graded intravenous glucose test and oral glucose tolerance tests at different doses. The comparison between simulations and clinical data shows an acceptable description of the blood glucose dynamics in T2DM. It opens the possibility of using this model to develop model-based controllers for the regulation of blood glucose in T2DM.

1343-P: A Comparison of C-Peptide and Glucose Responses between Children and Adolescents Who Progress to Type 1 Diabetes (T1D)

Type 1 diabetes is a heterogeneous disease with differences in β-cell dysfunction and rates of progression. We thus assessed whether there are differences in C-peptide and glucose responses during 2-hour oral (OGTTs) and intravenous (IVGTTs) glucose tolerance tests between children and adolescents at high risk for T1D. Data from the Diabetes Prevention Trial-type 1 (DPT-1) study participants who progressed to T1D was used for the analysis. We compared C-peptide and glucose responses between children (&amp;lt;10.0 years old; 7.1±1.9 years; n=125) and adolescents (10.0 years to &amp;lt;18.0 years old; 12.8±2.2 years; n=94). The risks for T1D were similar between the children and adolescents (mean 3-year T1D estimates from DPT-1 Risk Score: 63% and 56% respectively), as was the time to diagnosis (2.4±2.1 years vs. 2.5±2.2 years, respectively). Adolescents had higher OGTT derived AUC C-peptide levels (3.8±1.5 ng/ml vs. 1.9±1.4 ng/ml; p&amp;lt;0.001 with BMIZ adjustment), whereas their AUC glucose levels were similar to children (138.6±25.1 mg/dl vs. 139.6±22.8 mg/dl). The 0 to 30 minute C-peptide response from baseline OGTTs was significantly higher among adolescents compared to children (2.6±1.6 vs. 2.1±1.2, p=0.004 with BMIZ adjustment). However, C-peptide and glucose changes for each subsequent 30-minute OGTT interval were nearly identical between the children and adolescents. Similar to the 0 to 30 minute C-peptide response, the first-phase insulin response from baseline IVGTTs was higher in adolescents (114.1±74.0 µU/ml vs. 88.6±59.9 µU/ml; p&amp;lt;0.001 with BMIZ adjustment). In conclusion, the findings showed that despite a lower early insulin response in children, OGTT glucose levels were not higher. This suggests increased insulin sensitivity. The findings also showed that despite the lower early insulin response, the time to diagnosis did not differ. Other aspects of insulin responsiveness, and perhaps sensitivity, appear to also determine the progression rate to T1D. Disclosure H.M. Ismail: None. B.M. Nathan: None. J.P. Palmer: None. L. DiMeglio: Research Support; Self; Amgen Inc., Caladrius Biosciences, Inc., Janssen Research &amp; Development, Medtronic, Sanofi. Other Relationship; Self; Dexcom, Inc. J.M. Sosenko: None. Funding National Institutes of Health

Consistency of compact and extended models of glucose-insulin homeostasis: The role of variable pancreatic reserve.

Published compact and extended models of the glucose-insulin physiologic control system are compared, in order to understand why a specific functional form of the compact model proved to be necessary for a satisfactory representation of acute perturbation experiments such as the Intra Venous Glucose Tolerance Test (IVGTT). A spectrum of IVGTT’s of virtual subjects ranging from normal to IFG to IGT to frank T2DM were simulated using an extended model incorporating the population-of-controllers paradigm originally hypothesized by Grodsky, and proven to be able to capture a wide array of experimental results from heterogeneous perturbation procedures. The simulated IVGTT’s were then fitted with the Single-Delay Model (SDM), a compact model with only six free parameters, previously shown to be very effective in delivering precise estimates of insulin sensitivity and secretion during an IVGTT. Comparison of the generating, extended-model parameter values with the obtained compact model estimates shows that the functional form of the nonlinear insulin-secretion term, empirically found to be necessary for the compact model to satisfactorily fit clinical observations, captures the pancreatic reserve level of the simulated virtual patients. This result supports the validity of the compact model as a meaningful analysis tool for the clinical assessment of insulin sensitivity.

Steroid-Free Immune Suppression Impairs Glycemic Control in a Healthy Cynomolgus Monkey.

The need for chronic immune suppression (IS) is one of the hurdles precluding widespread use of islet cell transplantation to restore glycemic control in patients with type 1 diabetes. We report the case of a healthy nonhuman primate (NHP) treated on and off for over 2.5 years with steroid-free IS, consisting of daclizumab induction and maintenance therapy with rapamycin and low dose tacrolimus. Treatment for 1 year resulted in a striking destabilization of glycemic control, with concomitant decreases in fasting c-peptide and insulin levels. Although these changes gradually reversed during a wash out period of 7 months, retreatment with the same therapy led to accelerated deterioration in glycemic control. Intravenous glucose tolerance and percentage of glycosylated hemoglobin testing further supported a dramatic effect on metabolic control. IS also led to decreases in weight during treatment. Histological evaluation of the pancreas revealed islet hyperplasia, with varying sizes and endocrine cell ratios that differed from normal islet composition, and parenchymal infiltration with adipose tissue. These deleterious effects of IS on glucose control and endocrine components in the native pancreas of a healthy NHP suggest that IS agents commonly utilized for islet transplantation may contribute to failure in islet allograft function in long-term transplant patients.

Metabolic syndrome and extensive adipose tissue inflammation in morbidly obese Göttingen minipigs

ObjectiveThe worldwide prevalence of obesity has increased to 10% in men and 15% in women and is associated with severe comorbidities such as diabetes, cancer, and cardiovascular disease. Animal models of obesity are central to experimental studies of disease mechanisms and therapeutic strategies. Diet-induced obesity (DIO) models in rodents have provided important insights into the pathophysiology of obesity and, in most instances, are the first in line for exploratory pharmacology studies. To deepen the relevance towards translation to human patients, we established a corresponding DIO model in Göttingen minipigs (GM). MethodsYoung adult female ovariectomized GM were fed a high-fat/high-energy diet for a period of 70 weeks. The ration was calculated to meet the requirements and maintain body weight (BW) of lean adult minipigs (L-GM group) or increased stepwise to achieve an obese state (DIO-GM group). Body composition, blood parameters and intravenous glucose tolerance were determined at regular intervals. A pilot chronic treatment trial with a GLP1 receptor agonist was conducted in DIO-GM. At the end of the study, the animals were necropsied and a biobank of selected tissues was established. ResultsDIO-GM developed severe subcutaneous and visceral adiposity (body fat >50% of body mass vs. 22% in L-GM), increased plasma cholesterol, triglyceride, and free fatty acid levels, insulin resistance (HOMA-IR >5 vs. 2 in L-GM), impaired glucose tolerance and increased heart rate when resting and active. However, fasting glucose concentrations stayed within normal range throughout the study. Treatment with a long-acting GLP1 receptor agonist revealed substantial reduction of food intake and body weight within four weeks, with increased drug sensitivity relative to observations in other DIO animal models. Extensive adipose tissue inflammation and adipocyte necrosis was observed in visceral, but not subcutaneous, adipose tissue of DIO-GM. ConclusionsThe Munich DIO-GM model resembles hallmarks of the human metabolic syndrome with extensive adipose tissue inflammation and adipocyte necrosis reported for the first time. DIO-GM may be used for evaluating novel treatments of obesity and associated comorbidities. They may help to identify triggers and mechanisms of fat tissue inflammation and mechanisms preventing complete metabolic decompensation despite morbid obesity.

Cohort profile: the German Diabetes Study (GDS).

BackgroundThe German Diabetes Study (GDS) is a prospective longitudinal cohort study describing the impact of subphenotypes on the course of the disease. GDS aims at identifying prognostic factors and mechanisms underlying the development of related comorbidities.Study design and methodsThe study comprises intensive phenotyping within 12 months after clinical diagnosis, at 5-year intervals for 20 years and annual telephone interviews in between. Dynamic tests, including glucagon, mixed meal, intravenous glucose tolerance and hyperinsulinemic clamp tests, serve to assess beta-cell function and tissue-specific insulin sensitivity. Magnetic resonance imaging and multinuclei spectroscopy allow quantifying whole-body fat distribution, tissue-specific lipid deposition and energy metabolism. Comprehensive analyses of microvascular (nerve, eye, kidney) and macrovascular (endothelial, cardiorespiratory) morphology and function enable identification and monitoring of comorbidities. The GDS biobank stores specimens from blood, stool, skeletal muscle, subcutaneous adipose tissue and skin for future analyses including multiomics, expression profiles and histology. Repeated questionnaires on socioeconomic conditions, patient-reported outcomes as quality of life, health-related behavior as physical activity and nutritional habits are a specific asset of GDS. This study will recruit 3000 patients and a group of humans without familiy history of diabetes. 237 type 1 and 456 type 2 diabetes patients have been already included.Electronic supplementary materialThe online version of this article (doi:10.1186/s12933-016-0374-9) contains supplementary material, which is available to authorized users.

Skeletal muscle phosphatidylcholine and phosphatidylethanolamine are related to insulin sensitivity and respond to acute exercise in humans.

Several recent reports indicate that the balance of skeletal muscle phosphatidylcholine (PC) and phosphatidylethanolamine (PE) is a key determinant of muscle contractile function and metabolism. The purpose of this study was to determine relationships between skeletal muscle PC, PE and insulin sensitivity, and whether PC and PE are dynamically regulated in response to acute exercise in humans. Insulin sensitivity was measured via intravenous glucose tolerance in sedentary obese adults (OB; n = 14), individuals with type 2 diabetes (T2D; n = 15), and endurance-trained athletes (ATH; n = 15). Vastus lateralis muscle biopsies were obtained at rest, immediately after 90 min of cycle ergometry at 50% maximal oxygen consumption (V̇o2 max), and 2-h postexercise (recovery). Skeletal muscle PC and PE were measured via infusion-based mass spectrometry/mass spectrometry analysis. ATH had greater levels of muscle PC and PE compared with OB and T2D (P < 0.05), with total PC and PE positively relating to insulin sensitivity (both P < 0.05). Skeletal muscle PC:PE ratio was elevated in T2D compared with OB and ATH (P < 0.05), tended to be elevated in OB vs. ATH (P = 0.07), and was inversely related to insulin sensitivity among the entire cohort (r = -0.43, P = 0.01). Muscle PC and PE were altered by exercise, particularly after 2 h of recovery, in a highly group-specific manner. However, muscle PC:PE ratio remained unchanged in all groups. In summary, total muscle PC and PE are positively related to insulin sensitivity while PC:PE ratio is inversely related to insulin sensitivity in humans. A single session of exercise significantly alters skeletal muscle PC and PE levels, but not PC:PE ratio.

Short-Term Estrogen Replacement Effects on Insulin Sensitivity and Glucose Tolerance in At-Risk Cats for Feline Diabetes Mellitus.

Male domestic cats that are neutered and overweight are at an increased risk for developing a type-2-like diabetes mellitus. Beneficial effects of 17β-estradiol (E2) on glucose homeostasis may be lost with neutering and thereby account for increased diabetes risk. To evaluate this, adult male neutered overweight cats (n=6) were given daily E2 (1.0 μg/kg) or vehicle (Vh; ethanol, 1.0μL/kg) in a single crossover trial of 14-day periods with a 7-day washout. The E2 and Vh were voluntarily ingested on food. The E2 dosage was determined in a pre-trial to significantly and transiently reduce food intake with no measurable change in plasma E2 concentration. During treatments, physical activity was assessed with collar-mounted accelerometers on days 9-11, and tests of intravenous insulin tolerance and intravenous glucose tolerance were conducted on days 13 and 14, respectively. Over the 14 days, E2 compared to Vh treatment reduced (p=0.03) food intake (- 22%) but not enough to significantly reduce body weight; activity counts were not significantly changed. With E2 compared to Vh treatment, the late-phase plasma insulin response of the glucose tolerance test was less (p=0.03) by 31%, while glucose tolerance and insulin sensitivity indexes were not significantly changed. The results indicate that oral E2 at a dosage that moderately affects food intake may reduce insulin requirement for achieving glucose homeostasis in neutered male cats. Further investigation is needed to identify the mechanism underlying the E2 effect.

Shorter sleep duration is associated with decreased insulin sensitivity in healthy white men.

Short sleep has been linked to increased risk for type 2 diabetes and incident cardiovascular disease and acute sleep restriction impairs insulin-mediated glucose disposal. Here, we examined whether indices of glucose metabolism vary with naturally occurring differences in sleep duration. Subjects were midlife, nondiabetic community volunteers (N = 224; mean age 44.5 ± 6.6 y [range: 30-54]; 52% female; 89% white). Laboratory measures of insulin sensitivity (Si) and acute secretion (AIRg), glucose effectiveness (Sg), and disposition index (Di) were obtained from a 180-min, intravenous glucose tolerance test. Shorter self-reported sleep duration (in hours) was associated with lower Si (P = 0.043), although an interaction of sleep duration with participant race (β = -0.81, P = 0.002) showed this association significant only in whites. Moreover, sex-stratified analyses revealed that shorter sleep duration predicted lower Si in white men (β = 0.29, P = 0.003) but not in white women (P = 0.22). Findings were similar for AIRg. The relationship between sleep duration and AIRg was moderated by race as well as sex, such that shorter sleep duration associated with greater insulin release only in white men (β = -0.28, P = 0.004). Sleep duration was unrelated to Sg and Di (P's > 0.05). Our findings suggest that shorter sleep duration may impair insulin sensitivity and beta-cell function in nondiabetic white men, possibly contributing to later type 2 diabetes and cardiovascular disease.

Abstract 605: Association of Apolipoprotein B with Impaired Insulin Sensitivity and Secretion Is Mediated by Reduced Fat Clearance in Obese Subjects

OBJECTIVE: Human data from our lab and others have demonstrated that elevated concentrations of apoB-lipoproteins, measured as plasma apoB, are associated with insulin resistance (IR), hyperinsulinemia and the development of type 2 diabetes. However, the underlying mechanism to date remains unknown. We recently reported that LDL, the major form of apoB-lipoproteins, directly impairs the hydrolysis and storage of triglyceride-rich lipoproteins ex vivo in human white adipose tissue. Therefore, we hypothesized that the association between apoB and IR and compensatory increase in insulin secretion (IS) is mediated by delayed postprandial TG clearance in vivo in obese subjects. METHODS: We performed a Botnia clamp on normoglycemic obese men (N=14) and postmenopausal women (N=16) (BMI ≥ 27 kg/m2, age ≥ 45 years). First phase, 2 nd phase and total IS were measured during a 1-hour intravenous-glucose tolerance test (IVGTT) while insulin sensitivity was measured during a 3-hours hyperinsulinemic euglycemic clamp that followed. On a separate date, postprandial plasma clearance of TG was measured over 6 hours following the ingestion of a 13 C-triolein-labeled high-fat meal. RESULTS: Plasma apoB correlated positively with IR (r=0.15, p=0.037), 2 nd phase IS (r=0.15, p=0.039) and delayed TG clearance (AUC 6hrs of total plasma TG: r=0.64, p&lt;0.001; AUC 6hrs of 13 C-plasma TG: r=0.77, p&lt;0.001). Moreover, AUC 6hr of total plasma TG was associated with higher IR (r=0.16, p=0.042), 1 st phase IS (r=0.20, p=0.023), 2 nd phase IS (r=0.16, p=0.044) and total IS (r=0.16, p=0.046). Similarly, a positive association existed between delayed 13 C-labeled plasma TG clearance (AUC 6hrs ) and IR (r=0.41, p=0.046). A gender difference existed as TG clearance was mainly associated with IR in women (r=0.41, p=0.046) whereas it was mainly associated with 2 nd phase IS in men (r=0.41, p=0.046). As hypothesized, correcting for TG clearance eliminated the association of plasma apoB with IR and IS. CONCLUSION: The association of apoB with insulin resistance and secretion may be secondary to LDL-mediated delayed TG clearance by adipose tissue in humans.

Intrahepatic lipid, not visceral or muscle fat, is correlated with insulin resistance in older, female rhesus macaques

ObjectiveLittle is known of the effect of body composition on glucose metabolism in the aging female non-human primate. We studied these variables in older female Rhesus macaques.Design and MethodsFemale Rhesus macaques (Macacamulatta, n = 19, age range 23–30 yrs) underwent magnetic resonance imaging and 1H spectroscopy to quantify total abdominal fat, visceral fat (VF), subcutaneous fat (SF) area, extramyocellular lipid (EMCL), intramyocellular lipid (IMCL) and intrahepatic lipid (IHL) content, and DEXA scan for whole body composition. A subgroup (n=12) underwent a fasting blood draw and intravenous glucose tolerance test.ResultsSF correlated with homeostatic model assessment of insulin resistance (HOMAIR) and quantitative insulin sensitivity check index (QUICKI), but not after adjustment for fat mass. IHL demonstrated the strongest correlation with HOMAIR, QUICKI and calculated insulin sensitivity index (CSI), and remained significant after adjustment for fat mass. VF, IMCL, and EMCL did not correlate with any of our measures of insulin sensitivity.ConclusionsDespite a greater amount of VF compared to SF, VF was not associated with markers of insulin resistance (IR) in the older female monkey. Instead, IHL is a marker for IR in the fasting and post-prandial state in these animals.

The young göttingen minipig as a model of childhood and adolescent obesity: Influence of diet and gender

Gender and sex hormones influence the development of obesity and metabolic syndrome in humans and Göttingen minipigs. The aim of this study was to investigate possible gender differences in the metabolic response to a high energy diet in young Göttingen minipigs as a model of childhood/adolescent obesity. Nine-week-old male and female Göttingen minipigs were fed restrictedly on either a low energy diet (LED) or a high energy diet (HED) for 4 months (n = 5-7). Parameters of interest were fat percentage, visceral fat mass, plasma lipids and glucose tolerance, insulin resistance, and β-cell function measured by oral and intravenous glucose tolerance tests. At 11 to 12 weeks of age, after 2 weeks diet feeding, both genders on HED had increased fat percentage, glucose intolerance, decreased insulin sensitivity, and increased plasma levels of cholesterol and triglycerides (TGs). There was no gender difference in body weight (BW) or fat percentage, but males had lower glucose tolerance than females. After 3.5 to 4 months on the diets, the pigs on HED had increased BW, fat percentage, and visceral fat mass and were more glucose intolerant and insulin resistant than pigs on LED. Also increases in plasma cholesterol and TG levels were observed in the pigs on HED. Females had higher fat percentage and more visceral fat, were more insulin resistant, and had a more unfavorable lipid profile compared with males independent of diet. In conclusion, the young Göttingen minipig, and especially the female gender, seems to be a potential model for diet induced childhood/adolescent obesity and metabolic syndrome.

Serum metabolic variables associated with impaired glucose tolerance induced by high-fat-high-cholesterol diet in Macaca mulatta

Dyslipidemia caused by 'Western-diet pattern' is a strong risk factor for the onset of diabetes. This study aimed to disclose the relationship between the serum metabolite changes induced by habitual intake of high-fat and high-cholesterol (HFHC) diet and the development of impaired glucose tolerance (IGT) and insulin resistance through animal models of Macaca mulatta. Sixteen M. mulatta (six months old) were fed a control diet or a HFHC diet for 18 months. The diet effect on serum metabolic profiles was investigated by longitudinal research. Islet function was assessed by intravenous glucose tolerance and hyperinsulinemic-euglycemic clamp test. Metabonomics were determined by (1)H proton nuclear magnetic resonance spectroscopy. Prolonged diet-dependent hyperlipidemia facilitated visceral fat accumulation in liver and skeletal muscle and disorder of glucose homeostasis in juvenile monkeys. Glucose disappearance rate (K(Glu)) and insulin response to the glucose challenge effects in HFHC monkeys were significantly lower than in control monkeys. Otherwise, serum trimethylamine-N-oxide (TMAO), lactate and leucine/isoleucine were significantly higher in HFHC monkeys. Sphingomyelin and choline were the most positively correlated with K(Glu) (R(2) = 0.778), as well as negative correlation (R(2) = 0.64) with total cholesterol. The HFHC diet induced visceral fat, abnormal lipid metabolism and IGT prior to weight gain and body fat content increase in juvenile monkeys. We suggest that increased serum metabolites, such as TMAO, lactate, branched-chain amino acids and decreased sphingomyelin and choline, may serve as possible predictors for the evaluation of IGT and insulin resistance risks in the prediabetic state.

Colesevelam Improves Oral but Not Intravenous Glucose Tolerance by a Mechanism Independent of Insulin Sensitivity and β-Cell Function

OBJECTIVETo determine the mechanism by which the bile acid sequestrant colesevelam improves glycemic control.RESEARCH DESIGN AND METHODSWe performed a frequently sampled intravenous glucose tolerance test (FSIGT) with minimal model analysis and a meal tolerance test (MTT) in 20 subjects with impaired fasting glucose (11 men, 9 women; mean age 60.7 ± 1.9 years, BMI 29.4 ± 0.9 kg/m2) in a single-blind study after 2 weeks of placebo treatment and 8 weeks of colesevelam 3.75 g daily. From these tests, insulin sensitivity, β-cell function, and glucose tolerance were determined, along with gastrointestinal peptide levels during the MTT.RESULTSFasting plasma glucose and HbA1c decreased with colesevelam (from 5.9 ± 0.1 to 5.7 ± 0.1 mmol/L, P < 0.05, and from 5.86 ± 0.06 to 5.76 ± 0.06%, P = 0.01, respectively), but fasting insulin did not change. Colesevelam had no effect on any FSIGT measures. In contrast, the MTT incremental area under the curve (iAUC) for both glucose (from 249.3 ± 28.5 to 198.8 ± 23.6 mmol/L ⋅ min, P < 0.01) and insulin (from 20,130 [13,542–35,292] to 13,086 [9,804–21,138] pmol/L ⋅ min, P < 0.05) decreased with colesevelam. However, the ratio of iAUC insulin to iAUC glucose was not changed. iAUC for cholecystokinin (CCK) increased (from 43.2 [0–130.1] to 127.1 [47.2–295.2] pmol/L ⋅ min, P < 0.01), while iAUC for fibroblast growth factor 19 decreased (from 11,185 [1,346–17,661] to 2,093 [673–6,707] pg/mL ⋅ min, P < 0.01) with colesevelam. However, iAUC for glucagon, glucose-dependent insulinotropic peptide, and glucagon-like peptide 1 did not change.CONCLUSIONSColesevelam improves oral but not intravenous glucose tolerance without changing insulin sensitivity, β-cell function, or incretins. This effect may be at least partially explained by the colesevelam-induced increase in CCK.

Increased fat and simple carbohydrate consumption results in obese prepubertal pigs without an increase in body weight

The objective was to determine how carbohydrate (CHO) source affects body adiposity, intravenous glucose tolerance (IVGT) and insulin levels in female prepubertal pigs. Pigs (28‐d‐old) were used in an 8‐wk trial. Diets were Control or high‐fat (HF), which was further divided into containing complex (Corn) or simple CHO (SC, Glucose or Fructose). Control pigs were pair‐fed to HF pigs resulting in similar weight gain and final body weight across treatments (P=0.81). Compared to Controls, metabolizable energy intakes were higher for HF (37%, P&lt;0.001) and SC (14%, P&lt;0.03) diets. Plasma cholesterol was higher (P&lt;0.02) in pigs fed Corn and Fructose compared to those fed Glucose or Control diets. Ultrasound backfat depth, an indicator of body adiposity, was 84% higher (P&lt;0.001) in HF, and SC tended to increase fat (P=0.11). HF intake increased (P&lt;0.001) fasting blood glucose levels but lowered insulin, HOMA‐B, and HOMA‐IR (P&lt;0.01). SC intake tended to reduce (P=0.08) fasting insulin and lowered HOMA‐B and HOMA‐IR (P&lt;0.05). Glucose area under the curve (AUC) was higher (P&lt;0.05) in HF and SC pigs compared to Control, but insulin AUC was not different (P=0.14) across all treatment combinations. No differences between Glucose and Fructose were found for any measured parameter. Consumption of SC increases body adiposity and alters glucose homeostasis without changes in weight gain.Grant Funding Source : College of Agriculture and Life Sciences

A report of anticipated benefits of functional electrical stimulation after spinal cord injury

BackgroundFunctional electrical stimulation (FES) has been regularly used to offset several negative body composition and metabolic adaptations following spinal cord injury (SCI). However, the outcomes of many FES trials appear to be controversial and incoherent.ObjectiveTo document the potential consequences of several factors (e.g. pain, spasms, stress and lack of dietary control) that may have attenuated the effects on body composition and metabolic profile despite participation in 21 weeks of FES training.ParticipantA 29-year-old man with T6 complete SCI participated in 21 weeks of FES, 4 days per week.MethodsPrior to and following training, the participant performed arm-crank-graded exercise testing to measure peak VO2. Tests conducted included anthropometrics and dual energy X-ray absorptiometry body composition assessments, resting energy expenditure, plasma lipid profiles and intravenous glucose tolerance tests.ResultsThe participant frequently reported increasing pain, stress and poor eating habits. VO2 peak decreased by 2.4 ml/kg/minute, body mass increased by 8.5 kg, and body mass index increased from 25 to 28 kg/m2. Waist and abdominal circumferences increased by 2–4 cm, while %fat mass increased by 5.5%. Absolute increases in fat mass and fat-free mass of 8.4 and 1 kg, respectively, were reported. Fasting and peak plasma glucose increased by 12 and 14.5%, while lipid panel profiles were negatively impacted.ConclusionFailure to control for the listed negative emerging factors may obscure the expected body composition and metabolic profile adaptations anticipated from FES training.

Acute activation of central GLP-1 receptors enhances hepatic insulin action and insulin secretion in high-fat-fed, insulin resistant mice

Glucagon-like peptide-1 (GLP-1) receptor knockout (Glp1r(-/-)) mice exhibit impaired hepatic insulin action. High fat (HF)-fed Glp1r(-/-) mice exhibit improved, rather than the expected impaired, hepatic insulin action. This is due to decreased lipogenic gene expression and triglyceride accumulation. The present studies overcome these secondary adaptations by acutely modulating GLP-1R action in HF-fed wild-type mice. The central GLP-1R was targeted given its role as a regulator of hepatic insulin action. We hypothesized that acute inhibition of the central GLP-1R impairs hepatic insulin action beyond the effects of HF feeding. We further hypothesized that activation of the central GLP-1R improves hepatic insulin action in HF-fed mice. Insulin action was assessed in conscious, unrestrained mice using the hyperinsulinemic euglycemic clamp. Mice received intracerebroventricular (icv) infusions of artificial cerebrospinal fluid, GLP-1, or the GLP-1R antagonist exendin-9 (Ex-9) during the clamp. Intracerebroventricular Ex-9 impaired the suppression of hepatic glucose production by insulin, whereas icv GLP-1 improved it. Neither treatment affected tissue glucose uptake. Intracerebroventricular GLP-1 enhanced activation of hepatic Akt and suppressed hypothalamic AMP-activated protein kinase. Central GLP-1R activation resulted in lower hepatic triglyceride levels but did not affect muscle, white adipose tissue, or plasma triglyceride levels during hyperinsulinemia. In response to oral but not intravenous glucose challenges, activation of the central GLP-1R improved glucose tolerance. This was associated with higher insulin levels. Inhibition of the central GLP-1R had no effect on oral or intravenous glucose tolerance. These results show that inhibition of the central GLP-1R deteriorates hepatic insulin action in HF-fed mice but does not affect whole body glucose homeostasis. Contrasting this, activation of the central GLP-1R improves glucose homeostasis in HF-fed mice by increasing insulin levels and enhancing hepatic insulin action.

Gastroduodenal feeding after gastric bypass: a response to the comment by Jorgensen et al.

we appreciate the constructive comments by Jorgensen et al. in their Letter to the Editor ([8][1]) regarding our recent paper comparing post-Roux-en-Y gastric bypass (RYGB) metabolic responses to a mixed meal delivered to the jejunum (orally) or the gastroduodenum via a gastrostomy tube ([6][2]).