Ablation of capsaicin-sensitive afferent nerves affects insulin response during an intravenous glucose tolerance test

We investigated the role of sensory nerves in glucose tolerance in conscious Wistar rats neonatally treated with neurotoxin capsaicin or vehicle. Intravenous glucose tolerance tests (IVGTT, 150, 300 and 450 mg in 30 min) were performed to measure glucose tolerance, and glucose, insulin and glucagon levels were measured. Higher glucose concentration resulted in a greater insulin response in both capsaicin- and vehicle-treated rats. However, glucose-stimulated insulin secretion was attenuated in capsaicin-treated animals, even though glucose levels did not differ. Glucagon levels did not differ between both groups. These results show that capsaicin-sensitive nerves are involved in glucose-stimulated insulin secretion, but are not directly involved in the regulation of blood glucose levels. Moreover, they suggest that capsaicin-sensitive nerves could be involved in the regulation of insulin sensitivity. We hypothesize that sensory afferents could play a role in the aetiology of pathologies where glucohomeostatic mechanisms are disturbed, as is in type 2 diabetes mellitus.     

Mathematical modelling of the intravenous glucose tolerance test

 Several attempts at building a satisfactory model of the glucose-insulin system are recorded in the literature. The minimal model, which is the model currently mostly used in physiological research on the metabolism of glucose, was proposed in the early eighties for the interpretation of the glucose and insulin plasma concentrations following the intravenous glucose tolerance test. It is composed of two parts: the first consists of two differential equations and describes the glucose plasma concentration time-course treating insulin plasma concentration as a known forcing function; the second consists of a single equation and describes the time course of plasma insulin concentration treating glucose plasma concentration as a known forcing function. The two parts are to be separately estimated on the available data. In order to study glucose-insulin homeostasis as a single dynamical system, a unified model would be desirable. To this end, the simple coupling of the original two parts of the minimal model is not appropriate, since it can be shown that, for commonly observed combinations of parameter values, the coupled model would not admit an equilibrium and the concentration of active insulin in the “distant” compartment would be predicted to increase without bounds. For comparison, a simple delay-differential model is introduced, is demonstrated to be globally asymptotically stable around a unique equilibrium point corresponding to the pre-bolus conditions, and is shown to have positive and bounded solutions for all times. The results of fitting the delay-differential model to experimental data from ten healthy volunteers are also shown. It is concluded that a global unified model is both theoretically desirable and practically usable, and that any such model ought to undergo formal analysis to establish its appropriateness and to exclude conflicts with accepted physiological notions. Received: 22 June 1998 / Revised version: 24 February 1999     

Variations in the level of human serum albumin during glucose tolerance test

The serum protein level in patients taking the glucose tolerance test was found to vary. This variation was accounted for by changes in the level of serum albumin which dropped an average of 17% one hour after the administration of glucose. The serum albumin level returned to its normal value when blood glucose and non-esterified fatty acid levels returned to their initial levels. It is suggested that this variation is the result of a shift of albumin between the intravascular and extravascular compartments.     

Simplification of the intravenous glucose tolerance test (ivGTT) in rats

A simplified technique was established for the intravenous glucose tolerance test (ivGTT) in unanesthetized rats. In order to evaluate the relation between insulin secretion, glucose load and glucose disappearance rate, precatheterized rats were given glucose ranging in dose from 0.25 to 2.0 g/kg bw by intravenous injection. A highly linear correlation was observed in glucose disappearance rate during a period of 4-32 min. A glucose load greater than 0.5 g/kg ow induced a maximum response in insulin secretion. Small blood samples were collected using the orbital bleeding technique at 4, 16 and 28 minutes after a glucose load of 1.0 g/kg bw had been given and then T1/2, the time taken for the glucose level to fall by one half, was calculated. The mean T1/2 was significantly longer in alloxan- or cyproheptadin-diabetic rats than that in the intacts. These data indicate that a glucose load of 1.0 g/kg administered by intravenous injection with the T1/2 calculated between 4 and 32 minutes would provide an accurate means of assessing pancreatic endocrine function.     

Positive correlation of galanin with glucose in healthy volunteers during an oral glucose tolerance test.

Galanin has been found in increased amounts in subjects with type 2 diabetes. The purpose of the present study was to determine the levels of galanin in healthy volunteers during an oral glucose tolerance test (OGTT). We enrolled 11 healthy volunteers, 4 males aged 48+/-3.56 years with BMI 27+/-0.5 kg/m (2) and 7 females aged 41.3+/-3.05 years with BMI 27.6+/-0.9 kg/m (2). All were in good health without cardiac, hepatic, renal or other chronic disease. None were taking any medication affecting glucose tolerance (beta-blockers, thiazide diuretics, and corticoids) and none had a first degree relative with type 2 diabetes. Glucose tolerance was determined by using the International Expert Committee criteria. Blood samples were collected at 0, 30, 60, 90, 120 and 180 minutes for the measurement of plasma glucose, insulin, C-peptide and human galanin (hGal). During the OGTT, hGal exhibited a significant increase from time 0 to 90 minutes (p < 0.001) and returned to the basal values at 180 minutes, while a positive correlation of blood glucose with hGal was observed during the time scale of OGTT. A significant increase was detected both in insulin and C-peptide from the early beginning of the test at 30 minutes, which remained steady until 90 minutes, and returned gradually to the basal values at 180 minutes. No relationship was found either between hGal and serum insulin, or between hGal and serum C-peptide among the healthy subjects, during the OGTT.     

Caffeine ingestion elevates plasma insulin response in humans during an oral glucose tolerance test

We tested the hypothesis that caffeine ingestion results in an exaggerated response in blood glucose and (or) insulin during an oral glucose tolerance test (OGTT). Young, fit adult males (n = 18) underwent 2 OGTT. The subjects ingested caffeine (5 mg/kg) or placebo (double blind) and 1 h later ingested 75 g of dextrose. There were no differences between the fasted levels of serum insulin, C peptide, blood glucose, or lactate and there were no differences within or between trials in these measures prior to the OGTT. Following the OGTT, all of these parameters increased (P < or = 0.05) for the duration of the OGTT. Caffeine ingestion resulted in an increase (P < or = 0.05) in serum fatty acids, glycerol, and plasma epinephrine prior to the OGTT. During the OGTT, these parameters decreased to match those of the placebo trial. In the caffeine trial the serum insulin and C peptide concentrations were significantly greater (P < or = 0.001) than for placebo for the last 90 min of the OGTT and the area under the curve (AUC) for both measures were 60 and 37% greater (P < or = 0.001), respectively. This prolonged, increased elevation in insulin did not result in a lower blood glucose level; in fact, the AUC for blood glucose was 24% greater (P = 0.20) in the caffeine treatment group. The data support our hypothesis that caffeine ingestion results in a greater increase in insulin concentration during an OGTT. This, together with a trend towards a greater rather than a more modest response in blood glucose, suggests that caffeine ingestion may have resulted in insulin resistance.     

Effect of repaglinide on endothelial dysfunction during a glucose tolerance test in subjects with impaired glucose tolerance

Background

Secondary treatment of arteriosclerosis may be applicable for the primary prevention of atherosclerosis in diabetic patients. This prospective, 2-year follow-up study was designed to determine the efficacy and safety of antiplatelet therapy in the prevention of atherosclerosis of diabetic subjects.

Methods

Patients with type 2 diabetes and arteriosclerosis obliterans from the Eastern Asian countries were registered online and randomly assigned either to the aspirin group (81–100 mg/day) or the cilostazol group (100–200 mg/day) in this international, 2-year, prospective follow-up interventional study.

Results

The primary study endpoint was changes in right and left maximum intima-media thickness of the common carotid artery. Secondary endpoints include changes in right and left maximum intima-media thickness of the internal carotid artery; semiquantitative evaluation of cerebral infarction by magnetic resonance imaging; cardiovascular events including sudden death, stroke, transient cerebral ischemic attacks, acute myocardial infarction, angina, and progression of arteriosclerosis obliterans; overall death; withdrawal; and change in ankle-brachial pressure index.

Conclusion

This is the first study to use an online system that was developed in Asian countries for pooling data from an international clinical trial. These findings are expected to help in the prevention of diabetic atherosclerosis and subsequent cardiovascular and cerebrovascular disease.     

Evaluating the glucose tolerance test in mice

The objective of this study was to determine the optimal conditions under which to assess glucose tolerance in chow- and high-fat-fed C57BL/6J mice. Mice were fed either chow or high-fat diet for 8 wk. Variables tested were fasting duration (0-, 3-, 6-, and 24-h and overnight fasting), route of administration (intraperitoneal vs. oral) load of glucose given (2, 1, or 0.5 g/kg and fixed 50-mg dose), and state of consciousness. Basal glucose concentrations were increased in high-fat- compared with chow-fed mice following 6 h of fasting (9.1 +/- 0.3 vs. 7.9 +/- 0.4 mmol/l P = 0.01). Glucose tolerance was most different and therefore significant (P = 0.001) in high-fat-fed mice after 6 h of fasting (1,973 +/- 96 vs. 1,248 +/- 83 mmol.l(-1).120 min(-1)). The difference in glucose tolerance was greater following an OGTT (142%), in contrast to an IPGTT, with a 127% difference between high fat and chow. We also found that administering 2 g/kg of glucose resulted in a greater level of significance (P = 0.0008) in glucose intolerance in high-fat- compared with chow-fed mice. A fixed dose of 50 mg glucose regardless of body weight was enough to show glucose intolerance in high-fat- vs. chow-fed mice. Finally, high-fat-fed mice showed glucose intolerance compared with their chow-fed counterparts whether they were tested under conscious or anesthetized conditions. We conclude that 2 g/kg glucose administered orally following 6 h of fasting is best to assess glucose tolerance in mice under these conditions.