Biphasic insulin secretion during intravenous glucose tolerance test promotes optimal interstitial insulin profile

We examined the hindlimb lymph insulin profile during simulated intravenous glucose tolerance tests (IVGTTs) in anesthetized dogs to test the following hypotheses: 1) the biphasic insulin response to intravenous glucose can be seen as a priming bolus and a secondary infusion that effect a rapid stepwise increase in the interstitial insulin concentration and 2) the activation of glucose utilization (rate of glucose uptake [Rd]) during an IVGTT is more similar to the dynamics of the interstitial insulin profile than that of the arterial plasma. Three insulin profiles were infused: a normal biphasic pattern, a second phase infusion only, and a biphasic pattern with a fourfold greater first phase and a normal second phase. During the normal biphasic infusion, lymph insulin quickly reached and maintained a steady-state concentration (10 min, 26.42 +/- 0.86 microU/ml). With second phase only, it took lymph insulin 35 min to reach a steady state of lower concentration (13.13 +/- 0.46 microU/ml) than the normal. And with a fourfold greater first phase, lymph insulin plateaued quickly (16 min, 140.87 +/- 1.68 microU/ml), but for a shorter duration than the normal. For each profile, the time course of activation of Rd did not follow the time course of insulin in the plasma, but was more similar to that of insulin in the interstitial fluid. These results show that the biphasic response allows interstitial insulin to rapidly reach and maintain a steady state beneficial to activation and maintenance of glucose utilization.     

Bromocriptine treatment over 12 years in acromegaly: effect on glucose tolerance and insulin secretion

It is not known whether the beneficial effect of bromocriptine on glucose homeostasis in acromegaly is limited by a certain duration of therapy. To elucidate this problem, oral glucose tolerance tests were performed in 12 acromegaly patients before bromocriptine medication, under therapy (15.0 +/- 6.8 mg/day for 12 +/- 3 years), and during a 2-week drug withdrawal after long-term treatment. Initially altered glucose tolerance was normalized in 4 of 5 patients under bromocriptine therapy. During drug withdrawal the mean fasting glucose level and the mean glucose concentration at 120 min after oral glucose load increased from 5.05 +/- 0.61 to 5.77 +/- 0.78 mmol/l and from 5.61 +/- 2.05 to 7.55 +/- 3.05 mmol/l, respectively. A deterioration in glucose homeostasis was observed in 9 patients, and impaired glucose tolerance was ameliorated (but not to normal range) in 2 when bromocriptine was withdrawn. The proportion of alterations in glucose tolerance during drug withdrawal corresponded to that before the beginning of long-term bromocriptine treatment. Impaired glucose tolerance, observed in 2 patients under bromocriptine treatment, seemed to be compensated because a distinct elevation of glycosylated hemoglobin A1c was not observed. Bromocriptine led to a significant decrease in basal as well as glucose-stimulated insulin levels, and growth hormone secretion during oral glucose load was reduced in all 12 patients.(ABSTRACT TRUNCATED AT 250 WORDS)     

Assessment of insulin sensitivity and secretion with the labelled intravenous glucose tolerance test: improved modelling analysis

A new modelling analysis was developed to assess insulin sensitivity with a tracer-modified intravenous glucose tolerance test (IVGTT). IVGTTs were performed in 5 normal (NGT) and 7 non-insulin-dependent diabetic (NIDDM) subjects. A 300 mg/kg glucose bolus containing [6,6-(2)H2]glucose was given at time 0. After 20 min, insulin was infused for 5 min (NGT, 0.03; NIDDM, 0.05 U/kg). Concentrations of tracer, glucose, insulin and C-peptide were measured for 240 min. A circulatory model for glucose kinetics was used. Glucose clearance was assumed to depend linearly on plasma insulin concentration delayed. Model parameters were: basal glucose clearance (Cl(b)), glucose clearance at 600 pmol/l insulin concentration (Cl600), basal glucose production (Pb), basal insulin sensitivity index (BSI = Cl(b)/basal insulin concentration); incremental insulin sensitivity index (ISI = slope of the relationship between insulin concentration and glucose clearance). Insulin secretion was calculated by deconvolution of C-peptide data. Indices of basal pancreatic sensitivity (PSIb) and first (PSI1) and second-phase (PSI2) sensitivity were calculated by normalizing insulin secretion to the prevailing glucose levels. Diabetic subjects were found to be insulin resistant (BSI: 2.3 +/- 0.6 vs 0.76 +/- 0.18 ml x min(-1) x m(-2) x pmol/l(-1), p < 0.02; ISI: 0.40 +/- 0.06 vs 0.13 +/- 0.05 ml x min(-1) x m(-2) x pmol/l(-1), p < 0.02; Cl600: 333 +/- 47 vs 137 +/- 26 ml x min(-1) x m(-2), p < 0.01; NGT vs NIDDM). Pb was not elevated in NIDDM (588 +/- 169 vs 606 +/- 123 micromol x min(-1) x m(-2), NGT vs NIDDM). Hepatic insulin resistance was however present as basal glucose and insulin were higher. PSI1 was impaired in NIDDM (67 +/- 15 vs 12 +/- 7 pmol x min x m(-2) x mmol/l(-1), p < 0.02; NGT vs NIDDM). In NGT and in a subset of NIDDM subjects (n = 4), PSIb was inversely correlated with BSI (r = 0.95, p < 0.0001, log transformation). This suggests the existence of a compensatory mechanism that increases pancreatic sensitivity in the presence of insulin resistance, which is normal in some NIDDM subjects and impaired in others. In conclusion, using a simple test the present analysis provides a rich set of parameters characterizing glucose metabolism and insulin secretion, agrees with the literature, and provides some new information on the relationship between insulin sensitivity and secretion.     

Conditioned insulin secretion and meal feeding in rats.

Previous researchers have reported that rats placed upon a feeding regimen such that they receive only 2 hrs of food/day (meal-fed rats) develop hyperinsulinemia at the time of the day associated with feeding, even in the absence of food. Controls fed ad lib show no such response. In the 3 experiments reported here, the 74 meal-fed Charles River rats had elevated insulin levels at only the specific time of the day associated with feeding, and the increment of insulin at that time could be eliminated with atropine. The 58 free-feeding controls, on the other hand, always had higher insulin levels than the meal-fed rats, did not have an elevation of insulin at the time of the day that the meal-fed rats normally ate, and had insulin values that were unaffected by atropine. Further experimentation showed that hyperinsulinemia could become associated with arbitrary stimuli always associated with eating for meal-fed rats. It is concluded that the hyperinsulinemia of meal-fed rats associated with their feeding time is a learned response. (19 ref) (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

A high biotin diet improves the impaired glucose tolerance of long-term spontaneously hyperglycemic rats with non-insulin-dependent diabetes mellitus

Event-related potentials (ERPs) were recorded in a continuous memory recognition task. Readable non-words and abstract geometric figures were presented in an alternating manner with an inter-stimulus interval of 2.1 s. Probability of item repetition was 0.25, a lag of one item lay between initial presentation and repetition. OLD/NEW distinction was indicated by the subject's motor response. Using linked-mastoid electrodes for reference, material-specific hemispheric asymmetries of ERPs started 150 ms after stimulus onset in temporo-lateral and parietal recordings with ERPs elicited by non-words being lateralized to the left and those by figures to the right. Clear OLD/NEW ERP effects were found with non-words: Starting about 200-250 ms after stimulus presentation, ERPs of formerly presented (OLD) items were more positive-going in recordings over the midline than ERPs of items that were new and to be repeated (NEW). In contrast, no local OLD/NEW ERP-difference was found with figures. In some brain regions, OLD/NEW ERP-differences were larger over the left hemisphere compared to the right. This finding, however, did not differ between non-words and figures.     

Intracerebroventricular insulin improves spatial learning and memory in male Wistar rats.

As one of the most studied protein hormones, insulin as well as its receptor have been known to play key roles in a variety of important biological processes. Detection of insulin and its receptor in the central nervous system (CNS) has led to a rapidly growing interest in the central effects of insulin. Insulin and its receptor are located in the specific area of the CNS with a diversity of region-specific functions different from its direct carbohydrate homeostasis in the periphery. The high density of insulin/insulin receptor in brain areas such as the hippocampus and cerebral cortex have shown to play an important role in higher cognitive functions, suggesting that insulin might be involved in the modulation of memory. Previous studies have offered controversial results regarding the effects of insulin on various types of memory. The aim of the present study is to determine whether intracerebroventricular (ICV) administration of insulin improves the water maze performance of rats. The experimental groups had pretraining insulin infusion (2, 4, 8, 16, and 32 mu) into the third ventricle, and then they were compared with a sham (saline) group. Insulin treatment caused an enhancing effect on spatial memory in a dose-dependent manner. The low doses (2, 4, and 8 mu) of insulin had no significant effect on the water maze achievement of rats, whereas higher doses (16 and 32 mu) significantly improved the rats’ performance. These results suggest that ICV administration of insulin may result in a dose-dependent improvement of memory function in rats. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Reference values for glucose tolerance and glucose tolerance status in cats

1. Disposition kinetics of florfenicol were studied in Pasteurella-free (control) and Pasturella-infected Muscovy ducks following intravenous and/or intramuscular injection in a single dose of 30 mg/kg body weight. In addition, the tissue distribution and residual pattern of the drug were determined in diseased ducks. 2. The maximum serum concentration of florfenicol in control healthy and infected ducks was reached 1 hour after intramuscular injection but the peak concentration in control ducks was higher than in infected birds. 3. The volume of distribution, total body clearance and systemic bioavailability were higher in infected ducks than in control birds 5.15 l/kg, 10.24 ml/kg/min and 73.03% respectively. Data relating to intravenous injection were analysed using a 2 compartment open model curve fit. 4. Florfenicol was not detected in the serum of infected ducks on the 7th day following intramuscular administration of 30 mg/kg body weight twice daily for 5 successive days but was detected in kidney, bile and liver.     

Modulation of insulin secretion by hepatic vagotomy in cirrhotic rats

A soluble protein kinase (PK) was purified from bovine and human follicular fluids (FF) by ultrafiltration through a PM-10 membrane followed by chromatography on heparin-agarose, DEAE-cellulose and cellulose phosphate columns. The PK phosphorylated calf thymus histones and endogenous FF proteins having estimated Mrs of 40, 62, 128 and 180 KD. cAMP enhanced PK activity; whereas protein kinase A (PKA)-inhibitor peptide blocked the activity. The present findings suggest that the enzyme is a cAMP-dependent PK.     

Intravenous infusion of glucose and insulin in relation to milk secretion in the sow

1. A comparison was made of the composition of milk from front and rear tetas in four sows. There were small and not significant differences in fat, protein and lactose contents, and in the fatty-acid composition of the milk fat with the exception of the 18:3 acid where the difference was also small but significant. 2. The effects of intravenous infusions of glucose and insulin in lactating sows on milk secretion and blood composition were investigated in two sows. 3. Intravenous infusion of glucose had no effect on blood plasma glucose concentration but increased the yields of lactose, protein and water. 4. Intravenous infusion of insulin depressed plasma glucose concentration and the yields of lactose and water. The yield of protein was unaffected. 5. It is concluded that differences between the non-ruminant (the sow) and the ruminant in the responses in milk secretion to glucose infusion may be related to differences in the sensitivity to insulin of mammary tissue.     

Interstitial muscle insulin and glucose levels in normal and insulin-resistant Zucker rats

Tumour angiogenesis (antifactor VIII-related antigen antibody), p53 overexpression (DO-1) and proliferative activity (MIB-1) were immunohistochemically analysed for the prediction of long-term survival in 113 patients with squamous cervical carcinoma. The median follow-up time was 82 months (range 72-99). In early stages (IB-IIA), neovascularisation was significantly related to tumour size. Significantly more patients in stage IIA had high tumour vascularity compared to stage IB (P < 0.01) but no significant difference was found between early and advanced stages (IIB-IVB) of cervical carcinoma. p53 overexpression was correlated to the stage of disease (P < 0.01). No relationship was found between tumour angiogenesis, p53 overexpression or MIB-1 and pelvic lymph node metastases, histological subtype or differentiation. Tumours with more than 50% p53 overexpression was significantly correlated with survival in the univariate analysis, but no independent predictive value was found. It is concluded that immunohistochemically detectable p53 overexpression as measured by DO-1 and proliferative activity as measured by MIB-1 seems of no clinical value for the prediction of long-term survival in squamous cervical carcinoma. The predictive value of tumour angiogenesis for survival outcome has still to be determined in squamous cervical carcinoma.     

Experimental benefit of moxonidine on glucose metabolism and insulin secretion in the fructose-fed rat

OBJECTIVE: Non-insulin-dependent diabetes mellitus (NIDDM) is often associated with hypertension leading to a specifically high cardiovascular risk in these patients. However, there is evidence that insulin resistance and hyperinsulinaemia are not only characteristic for diabetic patients but also for some non-diabetic populations in which a cluster of cardiovascular risk factors is observed (hypertension, hypertriglyceridaemia, obesity). Therefore, hyperinsulinaemia and insulin resistance have been suggested to be of major pathophysiological importance for the development of this syndrome (syndrome X). Since imidazoline receptors are currently considered to be a specific pharmacological target for blood pressure reduction, it is important to know whether and in which way these compounds affect the glucose homoeostasis and insulin release. DESIGN: The influence of moxonidine on glucose tolerance in vivo was determined in healthy control rats, in rats receiving a high fructose diet for 6 weeks to induce insulin resistance, hyperinsulinaemia and hypertension, and in rats receiving in addition to a high fructose diet moxonidine (1.5 mg/kg body weight daily). In vitro, using isolated pancreatic islets of mice, long-lasting effects (chronic) and immediate (acute) effects of moxonidine on beta-cell function were determined by basal and glucose stimulated insulin release in two different experimental systems: (1) islets were exposed for 24 h (37 degrees C) to various concentrations of moxonidine ranging from 1 nmol/l to 1 mmol/l, followed by a washing procedure to remove excess of moxonidine and then used for the beta-cell function test; (2) islet cultures were incubated again with moxonidine for 24 h (37 degrees C) with either 1 nmol/l or 1 micromol/l. In contrast to the first experiments, however, after the washing procedure moxonidine was added at the same concentration as used for preincubation to test its direct effect on beta-cell function. RESULTS: In healthy control rats acute administration of moxonidine in vivo impaired the glucose tolerance in high dosages, which effectively reduced the blood pressure (>1 mg/kg body weight). This effect was, however, smaller that that observed by clonidine. In fructose-fed rats, moxonidine completely prevented the development of insulin resistance, hyperinsulinaemia and hypertension. In vitro, pancreatic islets preincubated with moxonidine exhibited dose-dependently both stimulatory and inhibitory chronic effects on beta-cell function compared with that in controls. Preincubation of islet cultures with moxonidine at concentrations between 1 nmol/l and 1 mmol/l resulted in a reduction of basal insulin release which was very pronounced at concentrations higher than 100 nmol/l. The results obtained for glucose-stimulated insulin release opposed in part those for basal insulin release, since the preincubation with moxonidine up to 10 micromol/l gave rise to an increased insulin release. An additional direct effect of moxonidine with a marked reduction of glucose-stimulated insulin release was observed, however, when moxonidine was present during the preincubation (24 h) and the functional test at a concentration of 1 nmol/l or 1 micromol/l. CONCLUSIONS: Our data suggest that a causal linkage exist between the development of hypertension and insulin resistance/hyperinsulinaemia in the high fructose diet rat model. Since central activation of imidazoline receptors by moxonidine can prevent this syndrome, it follows that an overactivity of the sympathetic nervous system is of major importance. Suppression of this sympathetic overactivity might be an effective approach to reduce hypertension and the concomitant metabolic defect. Therefore, such an interventional strategy could contribute to reduce the cardiovascular risk of NIDDM patients and patients with other forms of insulin resistance/hyperinsulinaemia such as metabolic cardiovascular syndrome.     

The effect of acarbose on insulin sensitivity in subjects with impaired glucose tolerance

OBJECTIVE: To study the effect of acarbose, an alpha-glucosidase inhibitor, on postprandial plasma glucose and insulin and insulin sensitivity in subjects with impaired glucose tolerance (IGT). RESEARCH DESIGN AND METHODS: Subjects with IGT were randomly treated in a double-blind fashion with placebo (n = 10) or acarbose (n = 8) at 100 mg t.i.d. for 4 months. All subjects were submitted before randomization and at the end of the study to a standardized breakfast and a 12-h daytime plasma glucose and plasma insulin profile, and insulin sensitivity was measured as steady-state plasma glucose (SSPG) using the insulin suppression test. RESULTS: While placebo had no effect on postprandial plasma glucose and plasma insulin incremental area under the curve (AUC) (3.03 +/- 0.5 vs. 3.76 +/- 0.6 mmol.h-1.l-1, P = NS; 1,488 +/- 229 vs. 1,609 +/- 253 pmol.h-1.l-1, P = NS), acarbose resulted in a significant reduction for both glucose (1.44 +/- 0.3 vs. 4.45 +/- 0.9 mmol.h-1.l-1, P = 0.002) and insulin (626.7 +/- 104.3 vs. 1,338.3 +/- 220.5 pmol.h-1.l-1, P = 0.003). The reduction in 12-h plasma glucose and insulin AUC on acarbose (11.2 +/- 2.1 mmol.h-1.l-1 and 7.5 +/- 0.7 nmol.h-1.l-1) was significantly greater than that on placebo (4.0 +/- 1.6 mmol.h-1.l-1 and 0.8 +/- 0.4 nmol.h-1.l-1) (P = 0.014 and 0.041). While SSPG was not affected by placebo (13.9 +/- 0.4 vs. 13.8 +/- 0.3 mmol/l; P = NS), it was significantly improved by acarbose (10.9 +/- 1.4 vs. 13.1 +/- 1.5 mmol/l, P < 0.004) and was also significantly different from placebo at 4 months (P < 0.02). CONCLUSIONS: It is concluded that in subjects with IGT, acarbose treatment decreases postprandial plasma glucose and insulin and improves insulin sensitivity. Acarbose may therefore be potentially useful to prevent the progression of IGT to NIDDM.     

Neural modulation of glucose-dependent insulinotropic peptide (GIP) and insulin secretion in conscious dogs

Glucose-dependent insulinotropic peptide (GIP) is a potent incretin, but it remains unclear whether this effect is dependent upon intact vagal pathways. In four conscious dogs, plasma GIP, plasma insulin, and plasma glucose responses were measured after intraduodenal administration of a defined formula diet, after glucose was perfused intraduodenally, and after insulin-mediated hypoglycemia with and without bilateral cryogenic blockade of the cervical vagus nerves. Vagal blockade did not alter elevations of plasma GIP after the defined formula diet or after glucose. However, with the vagi blocked plasma insulin responses were suppressed after the enteral diet (-52 +/- 8%) and after intraduodenal glucose (-55 +/- 4%), without changes in plasma glucose. Intravenous atropine (50 micrograms/kg) did not modify the GIP responses to intraduodenal perfusions of the defined formula diet or to glucose, but did suppress plasma insulin responses to baseline values. Insulin hypoglycemia without or with vagal blockade had no effect on basal concentrations of plasma GIP. These results indicate that vagal muscarinic and nonvagal muscarinic pathways participate in the control of the intestinal phase of insulin secretion, but the regulation of GIP secretion is independent of vagal or muscarinic neural control mechanisms.     

Dietary fish oil does not alter glucose tolerance in conscious rats

We examined the effect of dietary fish oil (MaxEPA) and sunflower seed oil on glucose tolerance in male Wistar rats. Semipurified diets containing 100 g oil/kg diet were administered for 30 d. The fish oil diet contained 26 g (n-3) fatty acids, 16 g eicosapentaenoic acid and 10.4 g docosahexaenoic acid/kg diet. Phospholipids from liver, pancreas, and pancreatic islets were enriched in eicosapentaenoic and docosahexaenoic acids by the fish oil diet. In unfed pentobarbital-anesthetized rats, both basal plasma insulin concentration and insulin responses to intravenous glucose were significantly lower for fish oil-fed rats although glucose responses were similar; however, incremental excursions in plasma insulin over the basal concentrations did not differ. Intravenous glucose tolerance was also examined in conscious unfed rats under minimal restraint. Responses of plasma glucose and insulin were similar for fish oil- and sunflower oil-fed groups. Furthermore, in another experiment, intravenous glucose tolerance tests were similar for conscious rats provided with either 100 g fish oil or corn oil/kg nonpurified diet. Thus, glucose-induced insulin secretion is lower in rats fed fish oil than in rats fed sunflower oil, when tests are conducted in pentobarbital-anesthetized animals but not when tests are performed in conscious rats; there was no effect on plasma glucose in either anesthetized or nonanesthetized rats. Therefore, substitution of (n-3) for (n-6) polyunsaturated fatty acids in tissue phospholipids does not alter plasma glucose or insulin in conscious male Wistar rats.     

Treatment with the oral antidiabetic agent troglitazone improves beta cell responses to glucose in subjects with impaired glucose tolerance

Impaired glucose tolerance (IGT) is associated with defects in both insulin secretion and action and carries a high risk for conversion to non-insulin-dependent diabetes mellitus (NIDDM). Troglitazone, an insulin sensitizing agent, reduces glucose concentrations in subjects with NIDDM and IGT but is not known to affect insulin secretion. We sought to determine the role of beta cell function in mediating improved glucose tolerance. Obese subjects with IGT received 12 wk of either 400 mg daily of troglitazone (n = 14) or placebo (n = 7) in a randomized, double-blind design. Study measures at baseline and after treatment were glucose and insulin responses to a 75-g oral glucose tolerance test, insulin sensitivity index (SI) assessed by a frequently sampled intravenous glucose tolerance test, insulin secretion rates during a graded glucose infusion, and beta cell glucose-sensing ability during an oscillatory glucose infusion. Troglitazone reduced integrated glucose and insulin responses to oral glucose by 10% (P = 0.03) and 39% (P = 0.003), respectively. SI increased from 1.3+/-0.3 to 2.6+/-0.4 x 10(-)5min-1pM-1 (P = 0.005). Average insulin secretion rates adjusted for SI over the glucose interval 5-11 mmol/liter were increased by 52% (P = 0.02), and the ability of the beta cell to entrain to an exogenous oscillatory glucose infusion, as evaluated by analysis of spectral power, was improved by 49% (P = 0.04). No significant changes in these parameters were demonstrated in the placebo group. In addition to increasing insulin sensitivity, we demonstrate that troglitazone improves the reduced beta cell response to glucose characteristic of subjects with IGT. This appears to be an important factor in the observed improvement in glucose tolerance.