Circulating Plasma Insulin Concentrations Research Articles

Antidiabetic Effects of Hispidulin in Streptozotocin‐Induced Insulin Deficient Mice

In both Type 1 and type 2 diabetes, pancreatic beta‐cell failure plays an important role in the deterioration of glycemic control. In this study, we investigated whether hispidulin, a naturally occurring flavone, can be used to ameliorate diabetes in an animal model of insulin deficiency. Here, we report that oral administration of hispidulin (20 mg/kg) alleviates streptozotocin‐induced hyperglycemia in C57/BL6 male mice. Hispidulin effectively mitigates postprandial and fasting hyperglycemia and glucose tolerance, which was associated with higher circulating plasma insulin concentrations and improved glucose stimulated‐insulin secretion (GSIS). In addition, treatment with hispidulin reduced expression of pyruvate carboxylase and glucose 6‐phosphatase in the livers. In vitro, hispidulin suppressed glucose production in mouse primary hepatocytes, but potentiated GSIS in insulin‐secreting cells and mouse islets. These findings suggest that hispidulin could be a dual action, natural compound that exerts antidiabetic action via promoting beta‐cell function and suppressing hepatic glucose production.Support or Funding InformationThe work was supported by grants from NCCIH of NIH (1R01AT007077, 1R01AT007566)This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Biological Activity and Antidiabetic Potential of C-Terminal Octapeptide Fragments of the Gut-Derived Hormone Xenin.

Xenin is a peptide that is co-secreted with the incretin hormone, glucose-dependent insulinotropic polypeptide (GIP), from intestinal K-cells in response to feeding. Studies demonstrate that xenin has appetite suppressive effects and modulates glucose-induced insulin secretion. The present study was undertaken to determine the bioactivity and antidiabetic properties of two C-terminal fragment xenin peptides, namely xenin 18–25 and xenin 18–25 Gln. In BRIN-BD11 cells, both xenin fragment peptides concentration-dependently stimulated insulin secretion, with similar efficacy as the parent peptide. Neither fragment peptide had any effect on acute feeding behaviour at elevated doses of 500 nmol/kg bw. When administered together with glucose to normal mice at 25 nmol/kg bw, the overall insulin secretory effect was significantly enhanced in both xenin 18–25 and xenin 18–25 Gln treated mice, with better moderation of blood glucose levels. Twice daily administration of xenin 18–25 or xenin 18–25 Gln for 21 days in high fat fed mice did not affect energy intake, body weight, circulating blood glucose or body fat stores. However, circulating plasma insulin concentrations had a tendency to be elevated, particularly in xenin 18–25 Gln mice. Both treatment regimens significantly improved insulin sensitivity by the end of the treatment period. In addition, sustained treatment with xenin 18–25 Gln significantly reduced the overall glycaemic excursion and augmented the insulinotropic response to an exogenous glucose challenge on day 21. In harmony with this, GIP-mediated glucose-lowering and insulin-releasing effects were substantially improved by twice daily xenin 18–25 Gln treatment. Overall, these data provide evidence that C-terminal octapeptide fragments of xenin, such as xenin 18–25 Gln, have potential therapeutic utility for type 2 diabetes.

Ablation of glucagon receptor signaling by peptide-based glucagon antagonists improves glucose tolerance in high fat fed mice

Modification to the structure of glucagon has provided a number of glucagon receptor antagonists with possible therapeutic application for diabetes. These novel peptide analogs include desHis1Pro4Glu9-glucagon and desHis1Pro4Glu9(Lys30PAL)-glucagon. This study has evaluated the metabolic benefits of once daily administration of desHis1Pro4Glu9-glucagon and desHis1Pro4Glu9(Lys30PAL)-glucagon in high fat (45%) fed mice for 15 days. Administration of desHis1Pro4Glu9-glucagon and desHis1Pro4Glu9(Lys30PAL)-glucagon had no significant effect on body weight, food intake or circulating glucose concentrations during the treatment period. However, both peptides significantly (P<0.05 to P<0.01) reduced circulating plasma insulin concentrations from day 6 onwards. Oral glucose tolerance and insulin sensitivity, as assessed by exogenous insulin administration, were significantly (P<0.01 to P<0.001) improved by both desHis1Pro4Glu9-glucagon and desHis1Pro4Glu9(Lys30PAL)-glucagon. These metabolic benefits were accompanied by significantly (P<0.01) increased pancreatic insulin stores. No significant differences in blood triacylglycerol or cholesterol levels were noted with desHis1Pro4Glu9-glucagon, however desHis1Pro4Glu9(Lys30PAL)-glucagon treatment significantly (P<0.01) increased HDL-cholesterol levels. Glucagon-mediated elevations of glucose and insulin were effectively (P<0.01 to P<0.001) annulled in both treatment groups on day 15. Interestingly, glucose levels during an intraperitoneal glucose tolerance test were not altered by either desHis1Pro4Glu9-glucagon or desHis1Pro4Glu9(Lys30PAL)-glucagon treatment. These data provide further evidence that glucagon antagonism could provide an effective means of treating T2DM.

A Novel Glucagon-like Peptide-1 (GLP-1)/Glucagon Hybrid Peptide with Triple-acting Agonist Activity at Glucose-dependent Insulinotropic Polypeptide, GLP-1, and Glucagon Receptors and Therapeutic Potential in High Fat-fed Mice

Glucagon-like peptide-1 (GLP-1), glucose-dependent insulinotropic polypeptide (GIP), and glucagon bind to related members of the same receptor superfamily and exert important effects on glucose homeostasis, insulin secretion, and energy regulation. The present study assessed the biological actions and therapeutic utility of novel GIP/glucagon/GLP-1 hybrid peptides. Nine novel peptides were synthesized and exhibited complete DPP-IV resistance and enhanced in vitro insulin secretion. The most promising peptide, [dA(2)]GLP-1/GcG, stimulated cAMP production in GIP, GLP-1, and glucagon receptor-transfected cells. Acute administration of [dA(2)]GLP-1/GcG in combination with glucose significantly lowered plasma glucose and increased plasma insulin in normal and obese diabetic (ob/ob) mice. Furthermore, [dA(2)]GLP-1/GcG elicited a protracted glucose-lowering and insulinotropic effect in high fat-fed mice. Twice daily administration of [dA(2)]GLP-1/GcG for 21 days decreased body weight and nonfasting plasma glucose and increased circulating plasma insulin concentrations in high fat-fed mice. Furthermore, [dA(2)]GLP-1/GcG significantly improved glucose tolerance and insulin sensitivity by day 21. Interestingly, locomotor activity was increased in [dA(2)]GLP-1/GcG mice, without appreciable changes in aspects of metabolic rate. Studies in knock-out mice confirmed the biological action of [dA(2)]GLP-1/GcG via multiple targets including GIP, GLP-1, and glucagon receptors. The data suggest significant promise for novel triple-acting hybrid peptides as therapeutic options for obesity and diabetes.

The glucose lowering effect of an oral insulin (Capsulin) during an isoglycaemic clamp study in persons with type 2 diabetes

Randomized, open, single-centre, two-way crossover study comparing the pharmacokinetic (PK) and pharmacodynamic (PD) properties of subcutaneous (sc) regular human insulin (Actrapid) and oral insulin in a capsule form (Capsulin). Sixteen persons (12 males) with type 2 diabetes on oral hypoglycaemic agents (OHAs) participated. Mean (s.d.) age 60.2 (5.5) years, BMI 28.3 (3.4) kg/m(2), haemoglobin A(1c) (HbA(1c)) 7.4% (1.1). Two 6-h isoglycaemic glucose clamp studies were conducted 11 days apart. All subjects received in random order 12U sc Actrapid on one clamp study day and either 150U or 300U Capsulin (Cap) on the other day. Glucose infusion rates (GIRs), plasma insulin and C-peptide concentrations were determined throughout each 6-h isoglycaemic clamp. Between the clamp study days, all patients received 150U Capsulin twice daily, dropping all their standard OHAs apart from metformin. Self-monitored blood glucose (SMBG) levels were taken four times a day between the clamp study days. Administration of either Actrapid or Capsulin (150 and 300U) increased GIRs reaching a maximum values at approximately 280-330 min. Overall values for maximum GIR values were higher for Actrapid than either dose of Capsulin (p < 0.05). The significantly greater systemic insulin concentrations following Actrapid were reflected in the AUC(0-6 h) (910 +/- 270 vs. 472 +/- 245 pmol h/L; 950 +/- 446 vs. 433 +/- 218 pmol h/L; both p < 0.05 for Actrapid vs. 150U Capsulin and 300U Capsulin respectively). No difference was observed between 150U and 300U Capsulin. During the repeat-dosing period, good safety and tolerability were observed with Capsulin, and SMBG levels remained stable. At the poststudy visit, significant falls in HbA(1c), weight and triglycerides were observed. Administration of the oral insulin Capsulin preparation demonstrated a significant hypoglycaemic action over a period of 6 h associated with only a small increase in circulating plasma insulin concentrations.

Oral glutamine increases circulating glucagon-like peptide 1, glucagon, and insulin concentrations in lean, obese, and type 2 diabetic subjects

BackgroundIncretin hormones, such as glucagon-like peptide 1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP), play an important role in meal-related insulin secretion. We previously demonstrated that glutamine is a potent stimulus of GLP-1 secretion in vitro. ObjectiveOur objective was to determine whether glutamine increases circulating GLP-1 and GIP concentrations in vivo and, if so, whether this is associated with an increase in plasma insulin. DesignWe recruited 8 healthy normal-weight volunteers (LEAN), 8 obese individuals with type 2 diabetes or impaired glucose tolerance (OB-DIAB) and 8 obese nondiabetic control subjects (OB-CON). Oral glucose (75 g), glutamine (30 g), and water were administered on 3 separate days in random order, and plasma concentrations of GLP-1, GIP, insulin, glucagon, and glucose were measured over 120 min. ResultsOral glucose led to increases in circulating GLP-1 concentrations, which peaked at 30 min in LEAN (31.9 ± 5.7 pmol/L) and OB-CON (24.3 ± 2.1 pmol/L) subjects and at 45 min in OB-DIAB subjects (19.5 ± 1.8 pmol/L). Circulating GLP-1 concentrations increased in all study groups after glutamine ingestion, with peak concentrations at 30 min of 22.5 ± 3.4, 17.9 ± 1.1, and 17.3 ± 3.4 pmol/L in LEAN, OB-CON, and OB-DIAB subjects, respectively. Glutamine also increased plasma GIP concentrations but less effectively than glucose. Consistent with the increases in GLP-1 and GIP, glutamine significantly increased circulating plasma insulin concentrations. Glutamine stimulated glucagon secretion in all 3 study groups. ConclusionGlutamine effectively increases circulating GLP-1, GIP, and insulin concentrations in vivo and may represent a novel therapeutic approach to stimulating insulin secretion in obesity and type 2 diabetes.

Different responses of protein synthesis to refeeding in various muscles of fasted chicks

1. The change in the rate of protein synthesis of different muscles, concentrations of plasma insulin, plasma insulin-like growth factor-I (IGF-I) and other plasma components were investigated after refeeding in fasted chicks. 5.2 g of the complete diet was refed. This was the maximum that could be force-fed with water. 2. The fractional synthesis rates (FSR) of breast (M. pectoralis major) and leg (M. gastrocnemius) muscles were measured after injection of L-\\[2, 6-3H]phenylalanine. Plasma insulin and IGF-I concentration were determined by radioimmunoassay. 3. In the breast muscle, FSR was significantly reduced by 2-d fasting. The FSR had recovered completely after 1 h of refeeding and was maintained until 6 h. The change in FSR after refeeding was associated with the change in ribosomal efficiency (K RNA ; absolute synthesis rate per unit RNA), while no change in ribosomal capacity (C S ; RNA: protein ratio) was observed. 4. In the leg muscle, FSR was decreased by 2-d fasting and increased gradually toward 6 h after refeeding but did not reach the level of the fed control. In contrast to the breast muscle, no significant changes in C S and K RNA in the leg muscle were observed. 5. Plasma glucose concentration increased significantly at 1 h after refeeding but returned to the fasted level after 24 h. Plasma insulin concentration in chicks refed for 1 h was higher than in the fasted group. There was no significant change in plasma IGF-I concentration. 6. These results suggest that the FSR of breast muscle was more sensitive to refeeding than that of leg muscle which may be explained, in part, by differences in sensitivity to the change in circulating plasma insulin concentration after refeeding.

The effect of ruminal starch degradability in the diet of Booroola crossbred ewes on induced ovulation rate and prolificacy

The effect of ruminally degradable starch on the reproductive performance of sheep was studied in 50 Booroola x Assaf crossbred ewes, of which 32 were carriers of the FeC B (Booroola) allele and 18 were not carriers. The sheep were group-fed, according to body weight (BW), diets composed of pea straw, soybean concentrate and corn grain offered in two meals per day. Dietary differences in ruminally undegradable starch (RUS) were obtained during the 29 day treatment period by feeding grain as whole corn (WC, 1.4 g RUS day −1 kg −1 BW) or extruded (EC, 0.4 g RUS day −1 kg −1 BW ). Oestrus was synchronized by inserting progestagen pessaries at Day 8, and withdrawing pessaries and injecting 400 IU of pregnant mare serum gondaotrophin at Day 20 after initiation of dietary treatments (Day 0). Ovulation rate (OR) was estimated by laparoscopy. The Fec B allele was associated with a significant increase in OR (2.88 vs. 1.40, P⪕ 0.0001) and prolificacy (1.85 vs. 1.32 lamb born per ewe lambing, P⪕0.09). Within Fec B allele carriers, all WC-fed ewes had multiple ovulations, compared with 61% of EC-fed ewes ( P⪕0.005). OR values were 3.29±0.27 and 2.46±0.31 corpora lutea (CL) per ewe ovulating and prolificacy was 2.13±0.22 and 1.57±0.23 lamb per ewe lambing in WC- and EC-fed ewes, respectively ( P⪕ 0.09). In non-carrier ewes, dietary treatments did not affect OR (1.44 and 1.36 CL per ewe ovulating in WC- and EC-fed ewes) or prolificacy (1.20 and 1.44 lamb per ewe lambing, in the same order). In a second experiment, aimed to assess the effect of dietary RUS on circulating insulin levels, blood was sampled before and at hourly intervals for 10 h after a meal from ten ewes fed rations with WC or EC. Insulin levels were higher in EC than in WC-fed ewes before and 3 h after a meal ( P⪕ 0.05). EC feeding may be associated with higher peripheral insulin concentration but does not enhance OR. Data are used to show that: (1) provision of about 100 g RUS day −1 exerts a positive effect on the OR and prolificacy of Fec B carriers; (2) dietary treatments may affect OR in sheep of different ovulation potential differently; (3) no positive relationship was found between circulating plasma insulin concentration and OR.

Oscillations of circulating plasma insulin concentrations in the rat

In previous studies, we found that insulin is secreted in a pulsatile fashion in vitro in isolated rat pancreatic islets. This study evaluated whether similar plasma insulin fluctuations occur in the rat in vivo. Freely moving rats were implanted with a chronic jugular catheter and serial blood samples were obtained 48–72 hrs post surgery. Blood was sampled at 3 min intervals for 60 mins with volume replacement using a red cell preparation. Plasma insulin concentrations were observed to fluctuate around a mean of 10.6 ± 1.1 uU/ml, with an amplitude of 4.7 ± 0.5 uU/ml and a period of 13.3 ± 1 mins (n=6). This was similar to the cycling observed in isolated islets at similar glucose concentrations. Sampling during the dark phase of the light-dark cycle in the rat was associated with an increase in the mean plasma level, amplitude and period of insulin oscillations compared with values obtained during the light phase (n=3). These data are the first in vivo demonstration of oscillatory circulating insulin concentrations in the rat and show that the pulsatility in this species is similar to that observed in other mammals incuding man. We conclude that the chronically catheterised rat is a useful model for the evaluation of oscillating insulin concentrations in vivo, and may provide interesting insights by comparison with in vitro data in the same species.

Effect of Central Obesity on Regulation of Carbohydrate Metabolism in Obese Patients with Varying Degrees of Glucose Tolerance*

It has been proposed that central obesity, by virtue of the enhanced lipolytic activity of abdominal adipose tissue, leads to higher plasma FFA concentrations, which, in turn, decrease both hepatic removal of insulin and insulin-stimulated glucose uptake by peripheral tissues. In short, the predicted consequences of abdominal obesity are elevations in circulating FFA and insulin levels as well as insulin resistance. The goal of this study was to evaluate the relationships predicted by the overall hypothesis; this study was carried out in 31 obese females, defined as having normal glucose tolerance (n = 12), impaired glucose tolerance (n = 8), or noninsulin-dependent diabetes mellitus (n = 11). Abdominal obesity was estimated by determining the ratio of waist to hip girth, fasting and postprandial plasma FFA and insulin concentrations were measured at hourly intervals from 0800-1600 h, and insulin-stimulated glucose disposal was quantified by the euglycemic hyperinsulinemic clamp technique. The first step in the postulated sequence of events to be tested was that the greater the WHR, the higher the total integrated plasma FFA response. The correlation coefficient between these two variables was 0.29, indicating that the results did not support the prediction. Furthermore, we could not demonstrate any relationship between the magnitude of the plasma FFA and insulin responses (r = 0.20; P = NS). However, there was a modest inverse relationship between height of circulating plasma insulin concentration and a decrease in insulin-stimulated glucose uptake (r = -0.43; P less than 0.03) in the group as a whole. On the other hand, when the three groups were analyzed individually, a significant inverse relationship was only seen in the control group (r = -0.67), and a direct relationship was actually seen in patients with impaired glucose tolerance (r = 0.88). Furthermore, when the mean responses for the variables in each of the three groups were compared, it was apparent that the postulated relationships between abdominal obesity, plasma FFA concentration, and insulin secretion and action were not present. Thus, the data presented do not support the hypothesis that differences in the degree of central obesity play an important role in regulation of plasma concentrations of either FFA or insulin or in modulation of insulin-stimulated glucose uptake in the patients we studied.

Effect of Metformin on Carbohydrate and Lipoprotein Metabolism in NIDDM Patients

The effect of metformin treatment on various aspects of carbohydrate and lipoprotein metabolism has been defined in 12 patients with non-insulin-dependent diabetes mellitus (NIDDM). Patients were studied before and after approximately 4 mo of metformin therapy. Treatment was initiated with a single dose of 500 mg/day, increased at weekly intervals, and maintained at a final dose of 2.5 g/day (given at divided intervals) for the last 3 mo of the treatment program. Results demonstrated that both fasting and postprandial glucose concentrations were significantly lower after metformin administration, with the greatest change seen after meals. As a result, the total incremental plasma glucose response above basal measured from 0800 to 1600 after metformin was less than 25% of that seen initially. The improvement in ambient plasma glucose concentration in association with metformin occurred despite a modest but statistically significant decrease in circulating plasma insulin concentration. In addition, insulin-stimulated glucose uptake measured during hyperinsulinemic clamp studies was similar before and after metformin treatment. Furthermore, changes in insulin binding and insulin internalization by isolated monocytes did not correlate with the improvement in glycemic control. Thus, the ability of metformin to lower plasma glucose concentration in NIDDM does not appear to be secondary to an improvement in insulin action. Finally, metformin treatment was associated with a significant (P less than 0.01) decrease in plasma triglyceride concentration and an increase in plasma high-density lipoprotein cholesterol concentration. These results indicate that metformin treatment of patients with NIDDM led to an improvement in both glycemic control and lipoprotein metabolism.

Age-Related Changes in Tissue Metabolic Rates and Sensitivity to Insulin in the Chicken

In-vitro metabolic studies were conducted with tissues from broiler pullets at 4, 8, and 12 weeks of age. In order to accurately assess plasma insulin at each of these ages, blood samples were withdrawn via indwelling venous catheters at 30-min intervals for 6 hr, and plasma was assayed by a homologous chicken insulin (clns) radioimmunoassay. Birds (n=6) were sacrificed 24 hr following blood sampling and livers, hearts, and abdominal fat pads removed for metabolic studies. Tissue slices of removed organs were incubated in Krebs-Ringer Bicarbonate buffer containing 13.9 mM glucose, .25 mM leucine, and .35 mM palmitate with either 0.0, 0.1, 1.0, or 100 ng/ml clns. Carbon-14 labelled substrates were added to appropriate slice incubations and oxidation and incorporation into endproducts assessed.Plasma insulin decreased with age from 4 to 12 weeks (area under 6-hr concentration curve = 172.0 vs 56.9 ng·min·ml–1) to a degree approaching significance (P<.10), in conjunction with decreased feed intake per unit of body weight. Palmitate oxidation and incorporation into cell lipid by adipose tissue, glucose oxidation and incorporation into lipid by liver and incorporation of leucine into trichloroacetic acid (TCA)-precipitable protein by cardiac muscle decreased substantially with age from 4 to 8 weeks (P<.05) . Oxidation of the branched-chain amino acid by cardiac muscle did not change significantly with age. Insulin enhanced the rate of leucine oxidation by cardiac muscle approximately 100% at 12 weeks but had no significant effect at earlier ages. For all other tissue × substrate combinations, insulin had no significant effect upon oxidation or synthetic rates, at any age measured.The early period of most rapid growth in commercial meat-type poultry is characterized by high rates of tissue metabolism including protein and lipid synthesis, in relation to later ages. The relative increase in cardiac muscle sensitivity to insulin at a later age, associated with a trend of decreased circulating plasma insulin concentrations, raises the possibility of down-regulation of tissue receptors by insulin in this species.

Diabetes and Exercise

The abnormal metabolic responses to exercise in insulin-dependent diabetes are in great part related to abnormal circulating plasma insulin concentrations. Exercising during relative insulin deprivation results in an increase in glycemia and ketosis. Exercise during insulin excess results in inhibition of hepatic glucose production and accelerated muscle glucose utilization and results in hypoglycemia. These responses can be significantly improved when insulin is administered more appropriately, as is the case with insulin infusion pumps. Self blood glucose monitoring before, during, and after exercise can provide important information that can be used to optimize the metabolic response to exercise in individual patients. A better understanding of the metabolic response to exercise in patients with diabetes will serve as the basis for developing specific recommendations to enable these individuals to have the freedom to take part in all forms of exercise with minimal restriction. However, the demonstration that exercise will have a long-term beneficial effect on the metabolic control of diabetes or prevent the development of the complications of diabetes remains to be established.

Glycemic response to glucagon during fasting hypoglycemia: An aid in the diagnosis of hyperinsulinism

ORGANIC HYPERINSULINISM, once felt to be rare in the pediatric age range, is now recognized more frequently in infants and children with recurrent hypoglycemia. At the Children's Hospital of Philadelphia, hyperinsulinism is the most common cause of recurrent hypoglycemia in infants under one year of age? The diagnosis of hyperinsulinism must be made rapidly so that specific therapy may be instituted, particularly in young infants, to minimize the risk of brain damage from hypoglycemia. Inappropriate elevation of circulating plasma insulin concentration during an episode of hypoglycemia is diagnostic. However, measurement of single or multiple circulating insulin levels may fail to define the disorder since insulin levels at times of spontaneous hypoglycemia in patients with hyperinsulinism are not always diagnostically elevated. For this reason, other physiologic manifestations of excessive insuliri secretion have been utilized to help verify this diagnosis. The demonstration of low serum levels of beta-hydroxybutyrate at the time of fasting hypoglycemia is valuable in establishing the diagnosis of hyperinsulinism? Another predictable effect of hyperinsulinism is an inappropriate conservation of liver glycogen during fasting. The present study examined whether the glycemic response to glucagon at the time of fasting

Dose response to insulin in man: differential effects on glucose and ketone body regulation.

This prospective study was undertaken to elucidate the relationship between progressive log increments in plasma free insulin concentration and the resultant changes in the concentrations of plasma glucose, potassium, ketones, and free fatty acids in man. We attempted to define both the maximal and minimal threshold for substrate response relative to circulating concentrations of plasma insulin. Hyperglycemia and hyperketonemia were experimentally induced with dexamethasone in six diabetic subjects. Circulating plasma insulin concentration was acutely elevated by the continuous iv infusion of insulin in order to attain ten-fold increments in circulating plasma insulin concentration. Specifically, following a progressive elevation above basal concentration, maximal increments in circulating plasma insulin of 7 μU/ml, 90μU/ml, and 1, 621 μU/ml were obtained. The differential effects of these acute alterations in plasma insulin concentration on plasma substrate concentrations were compared to a controlsaline...