Oral Glucose Research Articles

Metabolic response to sodium-glucose cotransporter 2 inhibition in type 2 diabetic patients

Sodium-glucose cotransporter 2 (SGLT2) inhibitors lower glycemia by enhancing urinary glucose excretion. The physiologic response to pharmacologically induced acute or chronic glycosuria has not been investigated in human diabetes. We evaluated 66 patients with type 2 diabetes (62 ± 7 years, BMI = 31.6 ± 4.6 kg/m(2), HbA1c = 55 ± 8 mmol/mol, mean ± SD) at baseline, after a single dose, and following 4-week treatment with empagliflozin (25 mg). At each time point, patients received a mixed meal coupled with dual-tracer glucose administration and indirect calorimetry. Both single-dose and chronic empagliflozin treatment caused glycosuria during fasting (median, 7.8 [interquartile range {IQR}, 4.4] g/3 hours and 9.2 [IQR, 5.2] g/3 hours) and after meal ingestion (median, 29.0 [IQR, 12.5] g/5 hours and 28.2 [IQR, 15.4] g/5 hours). After 3 hours of fasting, endogenous glucose production (EGP) was increased 25%, while glycemia was 0.9 ± 0.7 mmol/l lower (P < 0.0001 vs. baseline). After meal ingestion, glucose and insulin AUC decreased, whereas the glucagon response increased (all P < 0.001). While oral glucose appearance was unchanged, EGP was increased (median, 40 [IQR, 14] g and 37 [IQR, 11] g vs. 34 [IQR, 11] g, both P < 0.01). Tissue glucose disposal was reduced (median, 75 [IQR, 16] g and 70 [IQR, 21] g vs. 93 [IQR, 18] g, P < 0.0001), due to a decrease in both glucose oxidation and nonoxidative glucose disposal, with a concomitant rise in lipid oxidation after chronic administration (all P < 0.01). β Cell glucose sensitivity increased (median, 55 [IQR, 35] pmol • min(-1) • m(-2) • mM(-1) and 55 [IQR, 39] pmol • min(-1) • m(-2) • mM(-1) vs. 44 [IQR, 32] pmol • min(-1) • m(-2) • mM(-1), P < 0.0001), and insulin sensitivity was improved. Resting energy expenditure rates and those after meal ingestion were unchanged. In patients with type 2 diabetes, empagliflozin-induced glycosuria improved β cell function and insulin sensitivity, despite the fall in insulin secretion and tissue glucose disposal and the rise in EGP after one dose, thereby lowering fasting and postprandial glycemia. Chronic dosing shifted substrate utilization from carbohydrate to lipid. Trial registration. ClinicalTrials.Gov NCT01248364 (EudraCT no. 2010-018708-99). Funding. This study was funded by Boehringer Ingelheim.

Effects of Sitagliptin and Metformin Treatment on Incretin Hormone and Insulin Secretory Responses to Oral and “Isoglycemic” Intravenous Glucose

Dipeptidyl peptidase-4 (DPP-4) inhibitors prevent degradation of incretin hormones (glucagon-like peptide 1 [GLP-1] and glucose-dependent insulinotropic polypeptide [GIP]), whereas metformin may increase GLP-1 levels. We examined, in a four-period crossover trial, the influence of metformin (2,000 mg/day), sitagliptin (100 mg/day), or their combination, on GLP-1 responses and on the incretin effect in 20 patients with type 2 diabetes, comparing an oral glucose challenge (75 g, day 5) and an "isoglycemic" intravenous glucose infusion (day 6). Fasting total GLP-1 was significantly increased by metformin and not changed by sitagliptin. After oral glucose, metformin increased and sitagliptin significantly decreased (by 53%) total GLP-1. Fasting and postload intact GLP-1 increased with sitagliptin but not with metformin. After oral glucose, only sitagliptin, but not metformin, significantly augmented insulin secretion, in monotherapy and as an add-on to metformin. The incretin effect was not changed numerically with any of the treatments. In conclusion, sitagliptin increased intact GLP-1 and GIP through DPP-4 inhibition but reduced total GLP-1 and GIP (feedback inhibition) without affecting the numerical contribution of the incretin effect. Insulin secretion with sitagliptin treatment was similarly stimulated with oral and "isoglycemic" intravenous glucose. This points to an important contribution of small changes in incretin concentrations within the basal range or to additional insulinotropic agents besides GLP mediating the antidiabetic effects of DPP-4 inhibition.

Phenological and geographical influence in the concentration of selected bioactive 4-phenylcoumarins and chlorogenic acid in Hintonia latiflora leaves

Ethnopharmacological relevanceHintonia latiflora is a Mexican medicinal plant with well-documented ethnomedical record comprising more than 400 years; in modern Mexico is used for treating several maladies such as diabetes and gastric ulcers. Although the pharmacological actions of the stem-bark and leaves have been demonstrated, the phenological and geographical effect on the concentration of active principles remains unexplored. Aim of the studyThe main goals of this study were to analyze the amount of selected 4-phenylcoumarins and chlorogenic acid in the leaves in order to assess the best harvesting period, and consequently their pharmacological efficacy. In addition, the preclinical antidiabetic efficacy of the infusion of the leaves was corroborated using standard pharmacological tests. Materials and methodsThe aqueous extracts from the leaves of Hintonia latiflora were prepared by infusion. For phenological and geographical comparison, leaves of Hintonia latiflora were collected in two different regions in Chihuahua and Michoacán. The material was analyzed by UPLC applying an analytical method that developed and validated for this purpose following the ICH guidelines. Investigation of the antidiabetic action was accomplished using an acute hypoglycemic test and oral glucose and sucrose tolerance tests. ResultsThe validated analytical method was successfully applied for quantifying chlorogenic acid (1) and 4-phenylcoumarins (2–5) in the leaves of 12 different batches (1–12) during one-year period, and seven different batches for each geographical region; the concentration of the metabolites at the phenological cycle was significantly different, their concentration increased during the pre-senescence phase whereas in the leaf renovation stage the highest concentration of 2–5 was reached. The overall analysis of the active compounds concentration between the two populations investigated seems to be less important than the phenological variations. The aqueous extract of the leaves of Hintonia latiflora exerted its antidiabetic effect by different mechanisms showing comparable effect to the organic extract. ConclusionsThe findings of the present investigation reveal that the best harvest season for the leaves of Hintonia latiflora is between the leaves renovation and senescence stages avoiding the flowering period. In addition, no significant differences were found among the two different geographical populations analyzed. The infusions of the leaves, rich in 4-phenylcoumarins and chlorogenic acid, showed comparable antidiabetic action than the organic extract.

Oral glucose- and pH-sensitive nanocarriers for simulating insulin release in vivo

We design novel oral glucose sensitive nanocarriers for simulating insulin release using a modification of mesoporous silica nanoparticles (MSN) surfaces with a sensitive shell and conduct in vivo testing of these nanocarriers in diabetic rats. Here, MSN are coated with pH-sensitive dextran–maleic acid (Dex–Ma) and then grafted with glucose-sensitive 3-amidophenylboronic acid (APBA). These core–shell nanocarriers are confirmed by FT-IR, TEM, TGA, N2 adsorption–desorption method and elemental analysis. The results indicate that the MSN core can efficiently increase the loading capacity of insulin. In vitro insulin release shows good glucose-trigged behavior, in addition the rate of insulin release can be easily adjusted by changing the shell thickness. The cell viability of the nanocarriers against calu-3 cells demonstrates excellent cytocompatibility, and the nanocarriers can be internalized into cells. According to the studies of diabetic rats in vivo, the oral insulin-loaded nanocarriers produce an obvious hypoglycemic effect compared with insulin directly given orally. Study of the ligated intestinal loops absorption indicates that the material can enhance the permeation of insulin across the epidermis of intestine and facilitate the uptake of insulin. Therefore, the simple and effective pH- and glucose-sensitive nanocarrier can be regarded as a potential self-regulated tool to simulate insulin release in vivo.

Protection from vascular endothelial dysfunction in acute glycemic load-induced primary hypertension by vitamin C and E.

This study aimed to investigate the influence of acute glycemic load on vascular endothelial function in patients with hypertension and to evaluate the protective effect of vitamins C and E during the acute glycemic phase. We randomly selected 39 hypertensive patients and 21 normal subjects and divided them into 3 groups: 75 g oral glucose (glycemic load group), 75 g glucose+0.9 g vitamin C (VC group), 75 g glucose+2 g vitamin C+0.8 g vitamin E (VC+VE group). Extravascular color Doppler ultrasound was used to detect brachial artery flow-mediated vasodilation at 0, 1, 2, and 3 h, and, at the same time, serum anti-oxidant products were measured. Basic endothelial functions in patients with hypertension were decreased in the glycemic load group (9.48±3.33 versus 13.09±6.78%, P<0.05), and was even more depressed in the hypertensive group (9.48±3.33 versus 14.20±6.48%, P<0.05). Antioxidant vitamins played a dose-dependent protective role on acute damage of endothelial function due to glycemic load. Acute high blood sugar damaged vascular endothelial functions, especially in hypertensive patients, but this effect can be reversed by large doses of vitamin C and E.

Evaluation of Intragastric Vs Intraperitoneal Glucose Tolerance Tests in the Evaluation of Insulin Resistance in a Rodent Model of Burn Injury and Glucagon-Like Polypeptide-1 Treatment

Evaluation of glucose tolerance in rodent models is usually performed after intraperitroneal administration of glucose (intraperitoneal glucose tolerance test [IPGTT]), whereas in humans the test is performed with oral glucose. Hyperglycemia is a major clinical manifestation of burn injury. Our previous studies using IPGTT have demonstrated burn injury-induced insulin resistance and the beneficial effects of glucagon-like polypeptide-1 (GLP-1) in improving insulin resistance. The goal of the present study is to compare the results of these two procedures under 1) burn injury-induced insulin resistance and 2) GLP-1 treatment after burn. Male CD rats were divided into three groups: sham burn, burn, and burn with GLP-1. Blood glucose and plasma insulin levels were measured during intragastric glucose tolerance test (IGGTT) on day 6 after 40% of full-thickness burn injury. The results were compared with our previous IPGTT. Blood glucose curves for IGGTT and IPGTT showed a similar pattern. However, IGGTT demonstrated a significant lower level of maximal blood glucose when compared with IPGTT. This was accompanied by higher peak insulin levels in sham burn and burn groups. In contrast, peak insulin levels of each burn with GLP-1 group were similar. 1) Both IPGTT and IGGTT demonstrated burn injury-induced insulin resistance and the efficacy of GLP-1 for reducing hyperglycemia after burn injury. 2) The observed differences in the plasma glucose and insulin levels between IGGTT and IPGTT suggest that endogenously produced GLP-1 during the IGGTT may play a role in ameliorating insulin resistance after burn injury.

Clustering effects on postprandial insulin secretion and sensitivity in response to meals with different fatty acid compositions.

Dietary fatty acids play a role in glucose homeostasis. The aim of this study was to assess the individual relationship between dietary saturated (SFA), monounsaturated (MUFA) and polyunsaturated (PUFA) fatty acids with postprandial β-cell function and insulin sensitivity in subjects with normal and high fasting triglycerides. We assessed postprandial β-cell function (by the insulinogenic index and the ratio of the insulin to glucose areas under the time-concentration curve) and insulin sensitivity (by the oral glucose and the minimal model insulin sensitivity indices) over four nonconsecutive, randomly assigned, high-fat meals containing a panel of SFA (palmitic and stearic acids), MUFA (palmitoleic and oleic acids) and PUFA (linoleic and α-linolenic acids) in 14 subjects with normal and in 14 subjects with high fasting triglycerides. The proportions of each fatty acid in the meals and the values for surrogate measures of postprandial β-cell function and insulin sensitivity were subjected to a Pearson correlation and hierarchical cluster analysis, which revealed two classes of dietary fatty acids for regulating postprandial glucose homeostasis. We successfully discriminated the adverse effects of SFA palmitic acid from the beneficial effects of MUFA oleic acid on postprandial β-cell function (r ≥ 0.84 for SFA palmitic acid and r ≥ -0.71 for MUFA oleic acid; P < 0.05) and insulin sensitivity (r ≥ -0.92 for SFA palmitic acid and r ≥ 0.89 for MUFA oleic acid; P < 0.001) both in subjects with normal and high fasting triglycerides. In conclusion, dietary MUFA oleic acid, in contrast to SFA palmitic acid, favours the tuning towards better postprandial glycaemic control in subjects with normal and high fasting triglycerides.

Continuous positive airway pressure therapy decreases plasma glucose levels after the glucose load even in non-diabetic patients with obstructive sleep apnea

Introduction Although much attention has been paid to a positive association between obstructive sleep apnea (OSA) and impaired glucose metabolism, no information is available on the effect of continuous positive airway pressure (CPAP) on plasma glucose levels in oral 75-g glucose tolerance tests (75-g OGTTs) in patients with OSA. Materials and methods A total of 47 non-diabetic patients who underwent full polysomnography for suspected OSA and who were newly diagnosed as having OSA with an apnea–hypopnea index (AHI) ⩾20 were prospectively enrolled in this study. The patients were divided into the following 2 groups: 29 patients in whom CPAP could be introduced (CPAP group) and 18 patients in whom CPAP could not be introduced (non-CPAP group). All patients underwent 75-g OGTTs at baseline and after 6months. Results There were no significant differences in age, body mass index, prevalence of men, hypertension, dyslipidemia or current smokers, medications and polysomnographic parameters between the 2 groups. In the CPAP group, AHI decreased significantly (51.8±15.7–5.6±5.5, p p =0.009), whereas the levels did not change significantly in the non-CPAP group (141.7±28.9–151.8±46.9mg/dl, p =0.33). The body mass index, fasting plasma glucose level and homeostasis model assessment for insulin resistance did not change in the both groups. Conclusion This study indicates that CPAP therapy can decrease the plasma glucose level after glucose load in non-diabetic patients with OSA, suggesting that CPAP therapy has a favorable effect on glucose metabolism even in non-diabetic patients with OSA.

The Resist Diabetes trial: Rationale, design, and methods of a hybrid efficacy/effectiveness intervention trial for resistance training maintenance to improve glucose homeostasis in older prediabetic adults

Advancing age is associated with reduced levels of physical activity, increased body weight and fat, decreased lean body mass, and a high prevalence of type 2 diabetes (T2D). Resistance training (RT) increases muscle strength and lean body mass, and reduces risk of T2D among older adults. The Resist Diabetes trial will determine if a social cognitive theory (SCT)-based intervention improves RT maintenance in older, prediabetic adults, using a hybrid efficacy/effectiveness approach. Sedentary, overweight/obese (BMI: 25–39.9kg/m2) adults aged 50–69 (N=170) with prediabetes (impaired fasting glucose and/or impaired glucose tolerance) completed a supervised 3-month RT (2×/wk) initiation phase and were then randomly assigned (N=159; 94% retention) to one of two 6-month maintenance conditions: SCT or standard care. The SCT intervention consisted of faded contacts compared to standard care. Participants continue RT at an approved, self-selected community facility during maintenance. A subsequent 6-month period involves no contact for both conditions. Assessments occur at baseline and months 3 (post-initiation), 9 (post-intervention), and 15 (six months after no contact). Primary outcomes are prediabetes indices (i.e., impaired fasting and 2-hour glucose concentration) and strength. Secondary measures include insulin sensitivity, beta-cell responsiveness, and disposition index (oral glucose and C-peptide minimal model); adherence; body composition; and SCT measures. Resist Diabetes is the first trial to examine the effectiveness of a high fidelity SCT-based intervention for maintaining RT in older adults with prediabetes to improve glucose homeostasis. Successful application of SCT constructs for RT maintenance may support translation of our RT program for diabetes prevention into community settings.

Dipeptidyl peptidase-4 inhibitors: their role in the management of type 2 diabetes

The production of glucagon-like peptide 1 (GLP-1), an incretin hormone, has been shown to be abnormally low in patients with type 2 diabetes, suggesting that GLP-1 may be a contributor in the pathogenesis of the disease. New type 2 diabetic medications target incretin hormones in their mechanism of action. The incretin effect is based on the understanding that oral glucose has a greater stimulatory effect on insulin secretion than that of intravenous glucose. Over the past few years, a number of therapeutic agents, acting either as incretin mimetics, e.g. GLP-1 agonists, or inhibitors of the breakdown of GLP-1, e.g. dipeptidyl peptidase-4 inhibitors, have become available as treatment options for the management of type 2 diabetes.

Novel soy germ pasta enriched in isoflavones ameliorates gastroparesis in type 2 diabetes: a pilot study.

OBJECTIVETo determine the effect of soy germ pasta enriched in biologically active isoflavone aglycons on gastric emptying in type 2 diabetic patients with gastroparesis.RESEARCH DESIGN AND METHODSThis randomized double-blind, placebo-controlled study compared soy germ pasta with conventional pasta for effects on gastric emptying. Patients (n = 10) with delayed gastric emptying consumed one serving per day of each pasta for 8 weeks, with a 4-week washout. Gastric emptying time (t1/2) was measured using the [13C]octanoic acid breath test at baseline and after each period, and blood glucose and insulin concentrations were determined after oral glucose load.RESULTSSoy germ pasta significantly accelerated the t1/2 in these patients (161.2 ± 17.5 min at baseline vs. 112.6 ± 11.2 min after treatment, P = 0.009). Such change differed significantly (P = 0.009) from that for conventional pasta (153.6 ± 24.2 vs. 156.2 ± 27.4 min), without affecting glucose or insulin concentrations.CONCLUSIONSThese findings suggest that soy germ pasta may offer a simple dietary approach to managing diabetic gastropathy.

Nutrient-adjusted high-fat diet is associated with absence of periepididymal adipose tissue inflammation: is there a link with adequate micronutrient levels?

The aim of this study was to investigate the real impact of dietary lipids on metabolic and inflammatory response in rat white adipose tissue. Male healthy Wistar rats were fed ad libitum with a control diet (CON, n=12) or with an adjusted high-fat diet (HFD, n=12) for 12 weeks. Oral glucose and insulin tolerance tests were performed during the last week of the protocol. Plasma fatty acid, lipid profile, body adiposity, and carcass chemical composition were analyzed. Plasma concentration of leptin, adiponectin, C-reactive protein (CRP), TNF-α, IL-6, and monocyte chemotactic protein (MCP-1) was measured. Periepididymal adipose tissue was employed to evaluate TNF-α, MCP-1, and adiponectin gene expression as well as NF-κB pathway and AKT proteins. Isocaloric intake of the adjusted HFD did not induce hyperphagia, but promoted an increase in periepididymal (HFD = 2.94 ± 0.77 vs. CON = 1.99 ± 0.26 g/100 g body weight, p = 0.01) and retroperitoneal adiposity (HFD = 3.11 ± 0.81 vs. CON = 2.08 ± 0.39 g/100 g body weight, p = 0.01) and total body lipid content (HFD = 105.3 ± 20.8 vs. CON = 80.5 ± 7.6 g carcass, p = 0.03). Compared with control rats, HFD rats developed glucose intolerance (p=0.01), dyslipidemia (p = 0.02) and exhibited higher C-reactive protein levels in response to the HFD (HFD = 1002 ± 168 vs. CON = 611 ± 260 ng/mL, p = 0.01). The adjusted HFD did not affect adipokine gene expression or proteins involved in inflammatory signaling, but decreased AKT phosphorylation after insulin stimulation in periepididymal adipose tissue (p = 0.01). In this study, nutrient-adjusted HFD did not induce periepididymal adipose tissue inflammation in rats, suggesting that the composition of HFD differently modulates inflammation in rats, and adequate micronutrient levels may also influence inflammatory pathways.

Improved Plasma FFA/Insulin Homeostasis Is Independently Associated With Improved Glucose Tolerance After a 1-Year Lifestyle Intervention in Viscerally Obese Men

OBJECTIVEElevated plasma free fatty acids (FFAs) are one important link between excess visceral adiposity, insulin resistance, and the development of type 2 diabetes. Effects of lifestyle interventions on FFA metabolism are poorly known. This open-label study was conducted to test the effects of a 1-year healthy eating/physical activity intervention program on plasma FFA homeostasis in 117 viscerally obese men with dyslipidemia associated with insulin resistance (waist circumference ≥90 cm, triglycerides ≥1.69 mmol/L, and/or HDL-cholesterol <1.03 mmol/L).RESEARCH DESIGN AND METHODSBody weight, body composition, and fat distribution were assessed by dual-energy X-ray absorptiometry/computed tomography. Oral loads of lipid (60 g fat/m2 body surface area) and glucose (75 g) were measured before and after the intervention.RESULTSAfter 1 year of lifestyle intervention, visceral adiposity was reduced by −26% (95% CI −29 to −23), whereas cardiorespiratory fitness improved by +20% (95% CI +16 to +24). After 1 year, the suppression of FFAs after the glucose load improved, whereas insulin concentrations were drastically reduced. After the oral lipid load, the late increase in FFA was reduced together with reduced circulating insulin. We calculated an insulin sensitivity index to reflect the concentration of insulin needed to manage plasma FFAs after the oral lipid load, which increased after the intervention and was associated with improved glucose tolerance, independent of changes in visceral or total adiposity.CONCLUSIONSA 1-year healthy eating/physical activity intervention improved the suppression of FFAs after oral glucose and lipid load tests in viscerally obese men, possibly due to improved responsiveness to insulin. This insulin-mediated regulation of postprandial plasma FFA levels could be a link between visceral obesity and impaired glucose homeostasis.

Effects of Intraduodenal Glutamine on Incretin Hormone and Insulin Release, the Glycemic Response to an Intraduodenal Glucose Infusion, and Antropyloroduodenal Motility in Health and Type 2 Diabetes

OBJECTIVEGlutamine reduces postprandial glycemia when given before oral glucose. We evaluated whether this is mediated by stimulation of insulin and/or slowing of gastric emptying.RESEARCH DESIGN AND METHODSTen healthy subjects were studied during intraduodenal (ID) infusion of glutamine (7.5 or 15 g) or saline over 30 min, followed by glucose (75 g over 100 min), while recording antropyloroduodenal pressures. Ten patients with type 2 diabetes mellitus (T2DM) were also studied with 15 g glutamine or saline.RESULTSID glutamine stimulated glucagon-like peptide 1 (GLP-1; healthy: P < 0.05; T2DM: P < 0.05), glucose-dependent insulinotropic polypeptide (GIP; P = 0.098; P < 0.05), glucagon (P < 0.01; P < 0.001), insulin (P = 0.05; P < 0.01), and phasic pyloric pressures (P < 0.05; P < 0.05), but did not lower blood glucose (P = 0.077; P = 0.5).CONCLUSIONSGlutamine does not lower glycemia after ID glucose, despite stimulating GLP-1, GIP, and insulin, probably due to increased glucagon. Its capacity for pyloric stimulation suggests that delayed gastric emptying is a major mechanism for lowering glycemia when glutamine is given before oral glucose.

In vivo Effect of Insulin to Decrease Matrix Metalloproteinase-2 and -9 Activity after Arterial Injury

In vitro, insulin has both growth-promoting and vasculoprotective effects. In vivo, the effect of insulin is mainly protective. Insulin treatment (3 U/day) decreases smooth muscle cell (SMC) migration and neointimal growth after carotid angioplasty in normal rats maintained at normoglycemia by oral glucose. SMC migration requires limited proteolysis of the extracellular matrix, which is mediated by matrix metalloproteinases (MMPs). In this study, we investigated the effects of normoglycemic hyperinsulinemia on MMP activity after balloon angioplasty. Rats were divided into three groups: (1) control implants and tap water; (2) control implants and oral glucose, and (3) insulin implants (3 U/day) and oral glucose. Results: Gelatin zymography revealed that insulin reduced the gelatinolytic activity of pro-MMP-2 by 46% (p < 0.05), MMP-2 by 44% (p < 0.05) and MMP-9 by 51% (p < 0.05) compared to controls after arterial injury. Insulin also reduced mRNA levels of MMP-2 (p < 0.05) and MMP-9 (p < 0.05) and protein levels of MMP-2 (p < 0.05). In contrast, there were no significant changes in membrane-type 1 MMP protein and tissue inhibitors of MMP activity after insulin treatment. Thus, these results suggest a mechanism by which insulin inhibits SMC migration and supports a vasculoprotective role for insulin in vivo.

Bioactive Constituents from Hydrangea seemannii and Identification in the Fingerprint of the Infusion Development by UPLC-PDA

Hydrangea seemannii L. Riley (Hydrangeaceae) is used in Mexican traditional medicine for the treatment type II diabetes mellitus. An aqueous extract from the aerial parts of the plant, orally administered to normal and diabetic mice, showed significant hypoglycemic effect. The extract attenuated postprandial hyperglycemia in diabetic mice during oral glucose and sucrose tolerance tests. These results demonstrated that H. seemannii is effective for controlling fasting and postprandial blood glucose levels in animal models. Phytochemical investigation of the active extract led to the isolation of quercetin (1), kaempferol (2), isoquercetin (3), astragalin (4), quercetin 3-O-β-L-arabinopyranoside (5), rutin (6), nicotiflorin (7), chlorogenic acid (8), 3,4-di-O-caffeoylquinic acid (9) and 3,5-di-O-caffeoylquinic acid (10). Most of the isolated compounds have demonstrated significant hypoglycemic or antihyperglycemic effects; therefore, they are the active principles of the plant.

Experimental diabetes treated with trigonelline: effect on key enzymes related to diabetes and hypertension, β-cell and liver function

Type 2 diabetes is quite diverse, including the improvement of insulin sensitivity by dipeptidylpeptidase-4 (DPP-4) inhibitor, α-glucosidase inhibitors, and the protection of β-cells islet. The aim of this study was to search the effect of trigonelline (Trig) on DPP-4, α-glucosidase and angiotensin converting enzyme (ACE) activities as well as β-cells architecture, and starch and glucose tolerance test. In surviving diabetic rats, the supplement of Trig potentially inhibited DPP-4 and α-glucosidase activities in both plasma and small intestine. The pancreas islet and less β-cells damage were observed after the administration of trig to diabetic rats. The increase of GLP-1 in surviving diabetic rats suppressed the increase of blood glucose level and improved results in the oral glucose and starch tolerance test. Trig also normalized key enzyme related to hypertension as ACE and improved the hemoglobin A1c and lipid profiles (plasma triglyceride, HDL-cholesterol, LDL-cholesterol, and total cholesterol), and liver indices toxicity. Therefore, these results revealed that Trig was successful in improving glycemic control, metabolic parameters, and liver function in diabetic rats. It is therefore suggested that Trig may be a potential agent for the treatment of type 2 diabetes.

Phenobarbitone in Rh Hemolytic Disease of the Newborn: A Randomized Double-Blinded Placebo-Controlled Trial

To evaluate the efficacy of prophylactic oral phenobarbitone (PB) in neonates with Rh hemolytic disease of the newborn. In this double-blind randomized trial conducted in a tertiary care unit, we randomly allocated neonates with Rh hemolytic disease of the newborn born at or after 32 weeks' gestation to PB (10 mg/kg/day on day 1 followed by 5 mg/kg/day on days 2-5) (n = 23) or oral glucose (n = 21). The primary outcome was the duration of phototherapy. Baseline variables were comparable. There was no difference in the median duration of phototherapy [54 (range: 0-180) vs. 35 h (0-127); p = 0.39] and in the incidences of failure of phototherapy or significant rebounds of serum bilirubin. However, the proportion of infants with cholestasis was significantly lower in the PB group (0 vs. 19%; p = 0.04). PB does not reduce duration of phototherapy or its episodes. Its potential to reduce cholestasis needs validation in larger studies.

Postprandial lipid responses to standard carbohydrates used to determine glycaemic index values

Prior studies assessing the metabolic effects of different types of carbohydrates have focused on their glycaemic response. However, the response of postprandial cardiometabolic risk indicators has not been considered in these studies. The present study assessed postprandial lipid responses to two forms of carbohydrates used as reference foods for glycaemic index determinations, white bread (50 g available carbohydrate) and glucose (50 g), under controlled conditions and with intra-individual replicate determinations. A total of twenty adults (20–70 years) underwent two cycles of challenges with each pair of reference foods (four challenges/person), administered in a random order on separate days under standard conditions. Serum lipids (total cholesterol, LDL-cholesterol, HDL-cholesterol, TAG and NEFA), glucose and insulin were monitored for 5 h post-ingestion. Oral glucose resulted in greater glycaemic and insulinaemic responses than white bread for the first 90 min and a greater subsequent decline after 120 min (P =0·0001). The initial decline in serum NEFA concentrations was greater after the oral glucose than after the white bread challenge, as was the rebound after 150 min (P = 0·001). Nevertheless, the type of carbohydrate had no significant effect on postprandial total cholesterol, LDL-cholesterol and HDL-cholesterol concentrations. Following an initial modest rise in TAG concentrations in response to both challenges, the values dropped below the fasting values for oral glucose but not for the white bread challenge. These data suggest that the type of carbohydrate used to determine the glycaemic index, bread or glucose, has little or modest effects on postprandial plasma cholesterol concentrations. Differences in TAG and NEFA concentrations over the 5 h time period were modest, and their clinical relevance is unclear.

Pituitary carcinoma with endolymphatic sac metastasis

Pituitary carcinoma is characterized by the presence of a metastatic lesion(s) in a location non-contiguous with the original pituitary tumor. The mechanism(s) of malignant transformation are not known. A 15 year-old male was diagnosed in 1982 with a pituitary macroadenoma and acromegaly (random GH 67 ng/ml and no suppression by oral glucose). His prolactin was normal between 18 and 23 ng/ml. Transcranial resection in July 1983 was followed by radiation therapy. The tumor was immunopositive for GH and prolactin. The proliferation MIB-1 index was 0-1%. With aqueous Octreotide 100 mcg 4× daily both GH and IGF-1 became normal. The patient was lost to follow-up and was treated by his local physician. In 2001, his IGF-1 level was 1271 ng/ml, and his random GH was 1.8-2.4 ng/ml by ILMA despite progressive increase in the dose of Sandostatin LAR to 140 mg/month in divided doses. Prolactin remained normal or minimally increased between 15 and 25 ng/ml. In 2009 he was diagnosed with the tumor in the location of left endolymphatic sac. Histological examination showed low grade pituitary carcinoma strongly immunopositive for prolactin but negative for GH. MIB-1 antibody labeled 0-5% cells. In 2012 endoscopic resection of the pituitary tumor remnant was attempted. Immunohistochemical stains were strongly immunopositive for both prolactin and GH, similar to his original pituitary tumor. The MIB-1 proliferation index was low from 0 to 1%. To our knowledge this is the first case of pituitary carcinoma in the endolymphatic sac region. The dichotomy between the cell population of the pituitary lesion (GH/prolactin producing) and the metastasis (purely prolactin-producing) may suggest that the metastatic pituitary lesion derived from a clone distinct from the original one.