Intravenous Glucose Load Research Articles

Quantifying the variability in the assessment of reproductive hormone levels

To quantify how representative a single measure of reproductive hormone level is of the daily hormonal profile using data from detailed hormonal sampling in the saline placebo-treated arm conducted over several hours. Retrospective analysis of data from previous interventional research studies evaluating reproductive hormones. Clinical Research Facility at a tertiary reproductive endocrinology centre at Imperial College Hospital NHS Foundation Trust. Overall, 266 individuals, including healthy men and women (n = 142) and those with reproductive disorders and states (n = 124 [11 with functional hypothalamic amenorrhoea, 6 with polycystic ovary syndrome, 62 women and 32 men with hypoactive sexual desire disorder, and 13 postmenopausal women]), were included in the analysis. Data from 266 individuals who had undergone detailed hormonal sampling in the saline placebo-treated arms of previous research studies was used to quantify the variability in reproductive hormones because of pulsatile secretion, diurnal variation, and feeding using coefficient of variation (CV) and entropy. The ability of a single measure of reproductive hormone level to quantify the variability in reproductive hormone levels because of pulsatile secretion, diurnal variation, and nutrient intake. The initial morning value of reproductive hormone levels was typically higher than the mean value throughout the day (percentage decrease from initial morning measure to daily mean: luteinizing hormone level 18.4%, follicle-stimulating hormone level 9.7%, testosterone level 9.2%, and estradiol level 2.1%). Luteinizing hormone level was the most variable (CV 28%), followed by sex-steroid hormone levels (testosterone level 12% and estradiol level 13%), whereas follicle-stimulating hormone level was the least variable reproductive hormone (CV 8%). In healthy men, testosterone levels fell between 9:00 am and 5:00 pm by 14.9% (95% confidence interval 4.2, 25.5%), although morning levels correlated with (and could be predicted from) late afternoon levels in the same individual (r2 = 0.53, P<.0001). Testosterone levels were reduced more after a mixed meal (by 34.3%) than during ad libitum feeding (9.5%), after an oral glucose load (6.0%), or an intravenous glucose load (7.4%). Quantification of the variability of a single measure of reproductive hormone levels informs the reliability of reproductive hormone assessment.

18F-FDG PET in Myocardial Viability Assessment: A Practical and Time-Efficient Protocol.

We assessed image quality using a practical and time-efficient protocol for intravenous glucose loading and insulin injection before administration of 18F-FDG for PET myocardial viability evaluation in patients with ischemic cardiomyopathy (ICM), with and without type 2 diabetes mellitus. Methods: The metabolic preparation period (MPP) or optimal cardiac 18F-FDG uptake was determined from the time of intravenous infusion of 12.5 or 25 g of 50% dextrose to the time of 18F-FDG injection. Cardiac 18F-FDG image quality was evaluated according to a 5-point scoring system (from 5, excellent, to 1, nondiagnostic) by 2 independent observers. In cases of disagreement, consensus was achieved in a joint reading. Fifteen patients with ICM who underwent oral glucose loading and intravenous insulin administration served as a reference for MPP comparisons. Results: Fifty-nine consecutive patients (age, 63 ± 10 y; 48 men and 11 women) underwent rest 99mTc-tetrofosmin SPECT/CT and 18F-FDG PET/CT for the evaluation of myocardial viability. 18F-FDG image quality was scored as excellent in 42%, very good in 36%, good in 17%, fair in 3%, and nondiagnostic in 2%. When diabetic and nondiabetic patients were compared, the quality scores were excellent in 29% versus 76%, very good in 41% versus 18%, good in 24% versus 6%, fair in 4% versus 0%, and nondiagnostic in 2% versus 0%. The mean (±SD) quality score was 4.12 ± 0.95, and overall it was better in nondiabetic than in diabetic patients (4.71 ± 0.59 vs. 3.88 ± 0.96; P < 0.0001). Notably, the average MPP was significantly less with intravenous glucose loading than with oral glucose loading (51 ± 15 min vs. 132 ± 29 min; P < 0.0001), paralleled by higher insulin doses (6.3 ± 2.2 U vs. 2.0 ± 1.69 U; P < 0.001). Conclusion: Using a practical and time-efficient protocol for intravenous glucose loading and insulin administration before 18F-FDG injection reduces the MPP by 61% as compared with an oral glucose challenge and affords good-to-excellent image quality in 95% of ICM patients.

When MINMOD Artifactually Interprets Strong Insulin Secretion as Weak Insulin Action

We address a problem with the Bergman-Cobelli Minimal Model, which has been used for 40 years to estimate SI during an intravenous glucose tolerance test (IVGTT). During the IVGTT blood glucose and insulin concentrations are measured in response to an acute intravenous glucose load. Insulin secretion is often assessed by the area under the insulin curve during the first few minutes (Acute Insulin Response, AIR). The issue addressed here is that we have found in simulated IVGTTs, representing certain contexts, Minimal Model estimates of SI are inversely related to AIR, resulting in artifactually lower SI. This may apply to Minimal Model studies reporting lower SI in Blacks than in Whites, a putative explanation for increased risk of T2D in Blacks. The hyperinsulinemic euglycemic clamp (HIEC), the reference method for assessing insulin sensitivity, by contrast generally does not show differences in insulin sensitivity between these groups. The reason for this difficulty is that glucose rises rapidly at the start of the IVGTT and reaches levels independent of SI, whereas insulin during this time is determined by AIR. The minimal model in effect interprets this combination as low insulin sensitivity even when actual insulin sensitivity is unchanged. This happens in particular when high AIR results from increased number of readily releasable insulin granules, which may occur in Blacks. We conclude that caution should be taken when comparing estimates of SI between Blacks and Whites.

An Analysis of Glucose Effectiveness in Subjects With or Without Type 2 Diabetes via Hierarchical Modeling.

Glucose effectiveness, defined as the ability of glucose itself to increase glucose utilization and inhibit hepatic glucose production, is an important mechanism maintaining normoglycemia. We conducted a minimal modeling analysis of glucose effectiveness at zero insulin (GEZI) using intravenous glucose tolerance test data from subjects with type 2 diabetes (T2D, n=154) and non-diabetic (ND) subjects (n=343). A hierarchical statistical analysis was performed, which provided a formal mechanism for pooling the data from all study subjects, to yield a single composite population model that quantifies the role of subject specific characteristics such as weight, height, age, sex, and glucose tolerance. Based on the resulting composite population model, GEZI was reduced from 0.021 min–1 (standard error – 0.00078 min–1) in the ND population to 0.011 min–1 (standard error – 0.00045 min–1) in T2D. The resulting model was also employed to calculate the proportion of the non–insulin-dependent net glucose uptake in each subject receiving an intravenous glucose load. Based on individual parameter estimates, the fraction of total glucose disposal independent of insulin was 72.8% ± 12.0% in the 238 ND subjects over the course of the experiment, indicating the major contribution to the whole-body glucose clearance under non-diabetic conditions. This fraction was significantly reduced to 48.8% ± 16.9% in the 30 T2D subjects, although still accounting for approximately half of the total in the T2D population based on our modeling analysis. Given the potential application of glucose effectiveness as a predictor of glucose intolerance and as a potential therapeutic target for treating diabetes, more investigations of glucose effectiveness in other disease conditions can be conducted using the hierarchical modeling framework reported herein.

Factors related to passing the safety fast test among neonates with hypoglycaemia in the neonatal intensive care unit.

To investigate the success rates and predictors of safety fast test among neonates admitted to the neonatal intensive care unit for hypoglycaemia. A retrospective review of neonates transferred from the newborn nursery unit to the neonatal intensive care unit for intravenous dextrose therapy for hypoglycaemia from January 2016 to June 2019. Neonatal clinical and demographic variables were abstracted from the medical records. A successful safety fast test was defined by blood glucose >60 mg/dL (3.3 mmol/L) at 3, 4, 5 and 6 h after a feed. Of the 76 neonates who had a safety fast test, 80% passed on their first attempt. Neonates who passed the safety fast test were less likely to be premature/small for gestational age (54.1% vs. 92.9%, P = 0.03), required less maximum glucose infusion rate (median 6 vs. 7 mg/kg/min; P = 0.04), and were younger at fasting challenge (median 5 vs. 9 days; P = 0.02), required lower overall intravenous glucose load (median 12 vs. 24 g/kg; P = 0.006). Safety fast test may be a useful tool evaluating discharge readiness of neonates with persistent hypoglycaemia.

A revised Sorensen model: Simulating glycemic and insulinemic response to oral and intra-venous glucose load.

In 1978, Thomas J. Sorensen defended a thesis in chemical engineering at the University of California, Berkeley, where he proposed an extensive model of glucose-insulin control, model which was thereafter widely employed for virtual patient simulation. The original model, and even more so its subsequent implementations by other Authors, presented however a few imprecisions in reporting the correct model equations and parameter values. The goal of the present work is to revise the original Sorensen’s model, to clearly summarize its defining equations, to supplement it with a missing gastrio-intestinal glucose absorption and to make an implementation of the revised model available on-line to the scientific community.

Acute glucose load induced islet β cells dysfunction in TLR4 dependent manner in male mice

Recent studies highlighted the significance of chronic inflammation, which is mediated in part by toll-like receptors 4 (TLR4), in islet β cell dysfunction by high-glucose exposure. However, about it is unclear whether islet β cell dysfunction in response to high glucose is associated with TLR4. This investigation was designed to address the effect of TLR4 deficiency on insulin secretion in mice in response to acute intravenous glucose load. Hyperglycemic clamp was used to impair insulin secretion, and intraperitoneal glucose tolerance test was carried out to analyze insulin secretion function of islet β cells. Our results showed that TLR4 deficiency repressed insulin secretion impairment in response to acute intravenous glucose load. Compared to wild-type mice, TLR4−/− mice did not exhibit increase of IL-1β and TNF-α level in plasma and pancreatic tissue in response to acute intravenous load of high glucose. However, recombinant IL-1β or TNF-α administration restored insulin secretion impairment induced by high glucose in TLR4−/− mice. Taken together, our results demonstrated that TLR4 activation and subsequent IL-1β and TNF-α production contribute to islet β cell dysfunction in mice in response to acute intravenous load of high glucose, which may provide a theoretical basis for diabetes complication improvement by physical exercise.

Glucose and Insulin Responses to an Intravenous Glucose Load in Thoroughbred and Paso Fino Horses

Certain breeds of horses may be genetically predisposed to developing insulin dysregulation, which is a risk factor for development of endocrinopathic laminitis in horses. This study was performed to test the hypotheses that Paso Fino horses exhibit evidence of insulin dysregulation compared with Thoroughbred horses and that obesity exaggerates the insulin dysregulation. Intravenous glucose tolerance tests were performed in 14 moderate-weight Thoroughbreds, 12 moderate-weight Paso Finos, and 12 overweight Paso Finos. Moderate Paso Finos had greater baseline serum insulin concentrations, area under the insulin concentration curve, peak insulin, insulin-to-glucose ratio, area under the insulin to glucose curve, and modified glucose-to-insulin ratio compared with moderate Thoroughbreds. The reciprocal inverse square of basal insulin (RISQI) and glucose-to-insulin ratio were significantly lower in moderate Paso Finos compared with moderate Thoroughbreds. Overweight Paso Finos had greater baseline insulin concentrations, area under the insulin concentration curve, time to peak insulin, baseline plasma glucose concentration, insulin-to-glucose ratio, and area under the insulin to glucose curve compared with moderate Paso Finos. The RISQI and glucose-to-insulin ratio were significantly lower in overweight Paso Finos compared with moderate Paso Finos. In conclusion, moderate-weight Paso Finos had higher baseline serum insulin concentrations and an excessive hyperinsulinemic response to an intravenous glucose load when compared with moderate-weight Thoroughbreds. Overweight Paso Finos had even greater baseline insulin concentrations and hyperinsulinemic responses to glucose compared with moderate Paso Finos, as well as greater baseline plasma glucose concentrations. Paso Finos exhibit insulin dysregulation compared with Thoroughbreds.

The effects of kisspeptin on β-cell function, serum metabolites and appetite in humans.

AimsTo investigate the effect of kisspeptin on glucose‐stimulated insulin secretion and appetite in humans.Materials and methodsIn 15 healthy men (age: 25.2 ± 1.1 years; BMI: 22.3 ± 0.5 kg m−2), we compared the effects of 1 nmol kg−1 h−1 kisspeptin versus vehicle administration on glucose‐stimulated insulin secretion, metabolites, gut hormones, appetite and food intake. In addition, we assessed the effect of kisspeptin on glucose‐stimulated insulin secretion in vitro in human pancreatic islets and a human β‐cell line (EndoC‐βH1 cells).ResultsKisspeptin administration to healthy men enhanced insulin secretion following an intravenous glucose load, and modulated serum metabolites. In keeping with this, kisspeptin increased glucose‐stimulated insulin secretion from human islets and a human pancreatic cell line in vitro. In addition, kisspeptin administration did not alter gut hormones, appetite or food intake in healthy men.ConclusionsCollectively, these data demonstrate for the first time a beneficial role for kisspeptin in insulin secretion in humans in vivo. This has important implications for our understanding of the links between reproduction and metabolism in humans, as well as for the ongoing translational development of kisspeptin‐based therapies for reproductive and potentially metabolic conditions.

Assessing the optimal preparation strategy to minimize the variability of cardiac pyruvate dehydrogenase flux measurements with hyperpolarized MRS.

Hyperpolarized [1‐13C] pyruvate MRS can measure cardiac pyruvate dehydrogenase (PDH) flux in vivo through 13C‐label incorporation into bicarbonate. Using this technology, substrate availability as well as pathology have been shown to modulate PDH flux. Clinical protocols attempt to standardize PDH flux with oral glucose loading prior to scanning, while rodents in preclinical studies are usually scanned in the fed state. We aimed to establish which strategy was optimal to maximize PDH flux and minimize its variability in both control and Type II diabetic rats, without affecting the pathological variation being assessed. We found similar variances in the bicarbonate to pyruvate ratio, reflecting PDH flux, in fed and fasted/glucose‐loaded animals, which showed no statistically significant differences. Furthermore, fasting/glucose loading did not alter the low PDH flux seen in Type II diabetic rats. Overall this suggests that preclinical cardiac hyperpolarized magnetic resonance studies could be performed either in the fed or in the fasted/glucose‐loaded state. Centres planning to start new clinical studies with cardiac hyperpolarized magnetic resonance in man may find it beneficial to run small proof‐of‐concept trials to determine whether metabolic standardizations by oral or intravenous glucose load are beneficial compared with scanning patients in the fed state.

Decline in Beta-Cell Function among Adolescents with Type 2 Diabetes Mellitus

It is well known that beta-cell function declines over time in adults with type 2 diabetes mellitus (T2DM). The beta-cell dysfunction, initially characterized by impairment in the first phase of insulin secretion following glucose stimulation, advances to a decline in second phase insulin secretion as the disease progresses. But whether this decline in beta-cell function occurs in adolescents with T2DM is uncertain. Investigators prospectively compared beta-cell functioning over time between 39 adolescents with newly diagnosed T2DM (mean age, 15 years; body-mass index z-score, 2.4) and 32 obese adolescents without T2DM of comparable body-mass index, gender, and race (mean age, 14) during a 2-year period. Recently, researchers from Duke University School of Medicine, Durham North Carolina reported that adolescents with newly diagnosed T2DM had a 25% annual decline in beta-cell function despite receiving treatment. In this study, the results of which were first presented at the American Diabetes Association (ADA), the participants were adolescents with T2DM, more than half of whom were being treated with insulin whereas 80% were taking oral anti-diabetes medications. Beta-cell function in this study, assessed at baseline and 6, 12, and 24 months was measured by insulin secretion in response to an intravenous glucose load adjusted for insulin sensitivity (disposition index). The authors observed that adolescents with T2DM had significantly higher levels of both insulin resistance and fasting glucose at baseline compared with controls. But during the two-year study, the study subjects experienced a significant increase in fasting glucose and a 25 percent annual decline in disposition index. Understandably, both these indicators remained unchanged among the controls. JMS 2017;20(2):116

Sympathetic nervous system activity and anti-lipolytic response to iv-glucose load in subcutaneous adipose tissue of obese and obese type 2 diabetic subjects.

The study aim was to investigate the effect of endogenous insulin release on lipolysis in subcutaneous adipose tissue after adrenergic stimulation in obese subjects diagnosed with type 2 diabetes (T2D). In 14 obese female T2D subjects, or 14 obese non-T2D controls, glycerol concentration was measured in response to the α1,2,ß-agonist norepinephrine, the α1-agonist norfenefrine and the ß2-agonist terbutaline (each 10−4 M), using the microdialysis technique. After 60 minutes of stimulation, an intravenous glucose load (0.5 g/kg lean body mass) was given. Local blood flow was monitored by means of the ethanol technique. Norepinephrine and norfenefrine induced a four and three fold rise in glycerol dialysate concentration (p<0.001, each), with a similar pattern in adipose tissue. Following agonist stimulation and glucose infusion, endogenous insulin release inhibited lipolysis in the presence of norepinephrine, which was more rapid and pronounced in healthy obese controls than in T2D subjects (p = 0.024 obese vs T2D subjects). Insulin-induced inhibition of lipolysis in the presence of norfenefrine was similar in all study participants. In the presence of terbutaline the lipolysis rate increased two fold until the effect of endogenous insulin (p<0.001). A similar insulin-induced decrease in lipolysis was observed for each of the norfenefrine groups and the terbutaline groups, respectively. Adipose tissue blood flow remained unchanged after the iv-glucose load. Both norepinephrine and norfenefrine diminished blood flow slightly, but insulin reversed this response (p<0.001 over the entire time). Terbutaline alone and terbutaline plus increased endogenous insulin augmented local blood flow (p<0.001 over the entire time). In conclusion, a difference in insulin-induced inhibition of lipolysis was observed in obese T2D subjects compared to obese healthy controls following modulation of sympathetic nervous system activity and is assumed to be due to ß1-adrenoceptor mediated stimulation by norepinephrine.

Insulin binding characteristics in canine muscle tissue: effects of the estrous cycle phases

Abstract: Hormonal fluctuations during the different estrous cycle are a well-recognized cause of insulin resistance in bitches, and little is known about insulin receptor binding or post-binding defects associated with insulin resistance in dogs. To evaluate insulin binding characteristics in muscle tissue of bitches during the estrous cycle, 17 owned bitches were used in the study (six in anestrus, five in estrus, and six in diestrus). An intravenous glucose tolerance test (IVGTT) was performed in all patients by means of injection of 1mL/kg of a glucose 50% solution (500mg/kg), with blood sample collection for glucose determination at 0, 3, 5, 7, 15, 30, 45 and 60 minutes after glucose infusion. Muscle samples, taken after spaying surgery, were immediately frozen in liquid nitrogen and then stored at -80 ºC until the membranes were prepared by sequential centrifugation after being homogenized. For binding studies, membranes were incubated in the presence of 20,000cpm of human 125I-insulin and in increasing concentrations of unlabeled human regular insulin for cold saturation. The IVGTT showed no differences among bitches during the estrous cycle regarding baseline glycemia or glycemic response after glucose infusion. Two insulin binding sites - high-affinity and low-affinity ones - were detected by Scatchard analysis, and significant statistical differences were observed in the dissociation constant (Kd1) and maximum binding capacity (Bmax1) of the high-affinity binding sites. The Kd1 for the anestrus group (6.54±2.77nM/mg of protein) was smaller (P&lt;0.001) than for the estrus (28.54±6.94nM/mg of protein) and diestrus (15.56±3.88nM/mg of protein) groups. Bmax1 in the estrus (0.83±0.42nM/mg of protein) and diestrus (1.24±0.24nM/mg of protein) groups were also higher (P&lt;0.001) than the values observed in anestrus (0.35±0.06nM/mg of protein). These results indicate modulation of insulin binding characteristics during different phases of the estrous cycle in dogs, showing that muscle insulin binding affinity for its receptor is reduced during estrus and diestrus. However, this poor hormone-receptor affinity is compensated for by a greater total binding capacity, once there is no difference in patients' glycemic response after an intravenous glucose load.

Anagliptin, a dipeptidyl peptidase-4 inhibitor, decreases macrophage infiltration and suppresses atherosclerosis in aortic and coronary arteries in cholesterol-fed rabbits

IntroductionSeveral studies have demonstrated suppression of aortic atherosclerosis by dipeptidyl peptidase-4 (DPP-4) inhibitors in hypercholesterolemic mice. However, it remains unknown whether DPP-4 inhibitors also exert anti-atherogenic effects in coronary arteries. We examined the effect of anagliptin, a DPP-4 inhibitor, on atherosclerosis development in the aorta and coronary arteries in a high-cholesterol diet-fed rabbits. MethodsJapanese white rabbits were fed either normal chow (n=8) or a diet containing 0.5% cholesterol (n=34) for 14weeks. Cholesterol-fed rabbits were given 0.3% anagliptin or not in drinking water (each n=16 and 18) for 12weeks. ResultsDietary cholesterol intake markedly increased serum total cholesterol (TC) levels (1464±150mg/dL, mean±SE), and the most striking increase was observed among the major lipoproteins in very low-density lipoprotein (VLDL) as determined by high-performance liquid chromatography. No significant changes were observed in body weight, water intake, hemoglobin A1c, or glucose response to intravenous glucose loading following anagliptin administration. Anagliptin decreased TC and VLDL-cholesterol as well as cholesterol absorption markers sitosterol and campesterol slightly, although not significantly. Serum DPP-4 activity was suppressed by 82%, and active glucagon-like peptide-1 and glucose-dependent insulinotropic polypeptide levels were increased 2- to 3-fold by anagliptin treatment. Severe hypercholesterolemia resulted in the development of atherosclerosis in the aorta, and the ratio of atherosclerotic lesions to the total aortic surface area was 22±2%. Anagliptin suppressed the lesion ratio to 9±2% (p<0.001). Atherosclerotic lesions were clearly observed in the coronary arteries, where the mean intima-media area was enlarged, and intimal formation was developed. Anagliptin treatment attenuated the intima-media area and the intimal area by 43%. Alpha-smooth muscle actin-positive and macrophage-positive areas in the coronary arteries were suppressed by 66 and 75%, respectively, after anagliptin treatment. The aortic lesion ratio and the coronary intima area were correlated with each other (r=0.506, p<0.01), and each lesion correlated with TC in the whole cholesterol-fed rabbits. Gene expression of the proinflammatory cytokines tumor necrosis factor-alpha and interleukin-6 in the carotid arteries was markedly reduced by approximately 90%, and vascular DPP-4 activity was reduced by 66% after anagliptin treatment. ConclusionsWe demonstrated for the first time that a DPP-4 inhibitor can substantially suppress plaque formation in coronary arteries with a marked reduction in macrophage accumulation likely via its anti-inflammatory properties.

Serum Leptin and Adiponectin Concentration in Type 2 Diabetes Patients in the Short and Long Term Following Biliopancreatic Diversion.

A deranged adipokine system is implicated in obesity and in type 2 diabetes mellitus (T2DM), and the lack of remission of T2DM after bariatric surgery could be also accounted for by the postoperative persistence of this condition. Thirty T2DM patients undergoing biliopancreatic diversion (BPD) with a wide range of baseline body mass index (BMI) were evaluated prior to and at 1 and 5years following BPD. Besides the usual clinical evaluations, acute insulin response (AIR) to intravenous glucose load as a parameter of insulin secretion and the serum leptin and adiponectin concentration were measured throughout the follow-up period in all patients. A long-term T2DM remission was observed in 21 patients (70%). Serum leptin level reduced at the first year and remained substantially unchanged at a long term in both the remitter and non-remitter patients, while following the operation, a progressive significant increase of serum adiponectin level was observed only in remitter patients (from 9.2 to 12.3μg/mL at 1year and to 15.18μg/mL at 5years in the remitters and from 8.8 to 8.75μg/mL at 1year and to 11.8μg/mL at 5years in the non-remitters). Serum leptin mean values were positively associated with the BMI ones both prior to and following BPD (p < 0.005), while serum adiponectin values were positively related (p < 0.04) to the postoperative AIR data. The improvement of the pattern of cytokine production, as evidenced by postoperative rise in serum adiponectin concentration, might play a role in T2DM remission after bariatric surgery.

Comment on Jakubowicz et al. Fasting Until Noon Triggers Increased Postprandial Hyperglycemia and Impaired Insulin Response After Lunch and Dinner in Individuals With Type 2 Diabetes: A Randomized Clinical Trial. Diabetes Care 2015;38:1820–1826

More than 100 years ago, it was shown that oral ingestion of two successive carbohydrate meals results in an improved glucose tolerance in healthy people, a phenomenon known as the “Staub-Traugott” effect. In 1970, Metz and Friedenberg (1) reported that an improvement in glucose tolerance to sequential intravenous glucose loads could be seen in both subjects with normal glucose tolerance and with glucose intolerance after a second or even a third isocaloric glucose load. Much work was subsequently carried out to study the metabolic …

Acute intravenous glucose load impairs early insulin secretion and insulin content in islet β cells in mice.

To investigate insulin secretion and content in islet β cells after intravenous glucose load in mice. Acute hyperglycemia (≥16.7 mmol/L) in C57BL/J6 mice was achieved by hyperglycemic clamp. Mice were divided into four groups: a 2-hour and a 4-hour high glucose-infusion (2 h-HG and 4 h-HG) with 25% dextrose groups and control groups with saline infusion of the same duration. Insulin levels and response were measured using intraperitoneal glucose tolerance test (IPGTT) in mice and glucose-stimulated insulin secretion (GSIS) for isolated islets after overnight culture. Immunohistochemistry and electron microscopy (EM) for islet β cells were used after the hyperglycemic clamp to study morphologic changes of insulin granules and to assess the impact of acute glucose load on islet histology. Blood glucose at 15, 30, 60 and 120 min was significantly higher in 4 h-HG compared with the other groups. Serum plasma insulin significantly decreased only at 15 min as a first-phase insulin response (FPIR). Insulin secretion at 2.8 and 16.7 mmol/L glucose stimulus in 4 h-HG group decreased 77% and 64% more than those in 2 h-HG, respectively (P<0.05). Similarly, residual insulin content in islet β cells after 2.8 and 16.7 mmol/L glucose challenge decreased 30% and 43% more than those in 2 h-HG, respectively (P<0.05). EM showed decreased insulin granules in islet cells and swollen mitochondria only in 4 h-HG. Short time intravenous glucose load blunted FPIRs and decreased insulin content of islet β cells.

Simplified protocol of cardiac 18F-fluorodeoxyglucose positron emission tomography viability study in normoglycemic patients with known coronary artery disease

PurposeThe purpose was to evaluate quality of 18F-fluorodeoxyglucose positron emission tomography (18F-FDG-PET) myocardial scans and its correlation with background glucose (BG) after simplified 5% intravenous glucose load protocol. MethodsAn intravenous glucose load protocol was applied in 69 normoglycemic patients with confirmed coronary artery disease. The blood glucose level was measured every 15min. ResultsEighty-four percent of images were optimal, 8.7% suboptimal, and 7.3% uninterpretable. The quality of 18F-FDG-PET was BG independent and body mass index dependent (P=.0007). ConclusionsSimplified glucose load protocol is a safe and efficient method of preparation for FDG cardiac viability study in patients with normoglycemia.

Incretin Effect and Glucagon Responses to Oral and Intravenous Glucose in Patients With Maturity-Onset Diabetes of the Young—Type 2 and Type 3

Maturity-onset diabetes of the young (MODY) is a clinically and genetically heterogeneous subgroup of nonautoimmune diabetes, constituting 1-2% of all diabetes. Because little is known about incretin function in patients with MODY, we studied the incretin effect and hormone responses to oral and intravenous glucose loads in patients with glucokinase (GCK)-diabetes (MODY2) and hepatocyte nuclear factor 1α (HNF1A)-diabetes (MODY3), respectively, and in matched healthy control subjects. Both MODY groups exhibited glucose intolerance after oral glucose (most pronounced in patients with HNF1A-diabetes), but only patients with HNF1A-diabetes had impaired incretin effect and inappropriate glucagon responses to OGTT. Both groups of patients with diabetes showed normal suppression of glucagon in response to intravenous glucose. Thus, HNF1A-diabetes, similar to type 2 diabetes, is characterized by an impaired incretin effect and inappropriate glucagon responses, whereas incretin effect and glucagon response to oral glucose remain unaffected in GCK-diabetes, reflecting important pathogenetic differences between the two MODY forms.

The dipeptidyl peptidase-4 inhibitor vildagliptin has the capacity to repair β-cell dysfunction and insulin resistance.

The aim of the present study was to determine whether the dipeptidyl peptidase (DPP)-4 inhibitor could repair pancreatic β-cell dysfunction and insulin resistance. Ten subjects with type 2 diabetes who had never received DPP-4 inhibitor treatment were enrolled in the study. Just before and 3 months after twice-daily administration of vildagliptin (50 mg tablets), insulin secretion and insulin sensitivity were estimated using 2-compartment model analysis of C-peptide kinetics and insulin-modified minimal model parameters, respectively. The first-phase insulin secretion (CS1) was determined as the sum of the C-peptide secretion rate (CSR) from 0 to 5 min (normal range 6.8-18.5 ng/ml/min). The whole-body insulin sensitivity index (SI) was calculated using a minimal model software program (normal range 2.6-7.6×10(-4)/min/μU/ml). After vildagliptin treatment, reductions in mean (± SE) HbA1c were noted (43.28±1.53 vs. 40.98±1.77 mmol/mol; p=0.019). Vildagliptin treatment increased the area under the curve for the C peptide reactivity (CPR) (AUCCPR; 26.66±5.15 vs. 33.02±6.12 ng/ml · 20 min; p=0.003) and CS1 (0.80±0.20 vs. 1.35±0.38 ng/ml/min; p=0.037) in response to an intravenous glucose load. -Vildagliptin treatment significantly increased SI (0.46±0.27 vs. 1.21±0.48×10(-4)/min/μU/ml; p=0.037). The long-term administration of vildagliptin improved CS1 and Si suggesting that this drug has the capacity to repair impairments in pancreatic β-cell function and insulin resistance in type 2 diabetes.