The insulin sensitivity index. Correlation in dogs between values determined from the intravenous glucose tolerance test and the euglycemic glucose clamp

We previously proposed the insulin sensitivity index, Sl, as an absolute measure of whole body tissue sensitivity to insulin. Sl is defined, in the physiologic range of insulin action, as the effect of insulin to augment glucose's ability to reduce its own plasma level. This parameter can be determined from the frequently sampled intravenous glucose tolerance test (IVGTT) by using a digital computer to find the coefficients of a minimal mathematical model of glucose kinetics. In the present study we compared, in normal dogs, Sl determined from the IVGTT to an analogous parameter [Sl(clamp)] calculated from the euglycemic glucose clamp (EGC). Fifteen pairs of experiments (1 IVGTT and 1 EGC) were performed on 12 animals. IVGTTs: After glucose injection (0.3 g/kg), frequent blood samples were taken over the subsequent 3 h. KG ranged from 1.7 to 4.7%/min, and integrated insulin from 0.4 to 5.9 (mU/ml) min for 0-60 min. Sl varied over a nine-fold range from 1.0 to 9.1 X 10(-4) (min-1)/(microU/ml), with a mean of 4.3 +/- 0.7 X 10(-4). Fractional glucose disappearance rate independent of insulin (p1) was 4.3 +/- 0.5%/min. EGCs: Low-rate insulin infusion (8 mU/min from 1 to 150 min) elevated plasma insulin (INS) from 15 +/- 4 to 43 +/- 10 microU/ml. Glucose was infused (GINF) at 119 +/- 20 mg/min to maintain euglycemia. Moderate insulin infusion (40 mU/min: 151-300 min) further elevated plasma insulin (to 176 +/- 37 microU/ml) and the requisite glucose infusion (to 372 +/- 36 mg/min).(ABSTRACT TRUNCATED AT 250 WORDS)     

Caffeine ingestion decreases glucose disposal during a hyperinsulinemic-euglycemic clamp in sedentary humans

The purpose of this investigation was to examine the effect of caffeine (an adenosine receptor antagonist) on whole-body insulin-mediated glucose disposal in resting humans. We hypothesized that glucose disposal would be lower after the administration of caffeine compared with placebo. Healthy, lean, sedentary (n = 9) men underwent two trial sessions, one after caffeine administration (5 mg/kg body wt) and one after placebo administration (dextrose) in a double-blind randomized design. Glucose disposal was assessed using a hyperinsulinemic-euglycemic clamp. Before the clamp, there were no differences in circulating levels of methylxanthines, catecholamines, or glucose. Euglycemia was maintained throughout the clamp with no difference in plasma glucose concentrations between trials. The insulin concentrations were also similar in the caffeine and placebo trials. After caffeine administration, glucose disposal was 6.38 +/- 0.76 mg/kg body wt compared with 8.42 +/- 0.63 mg/kg body wt after the placebo trial. This represents a significant (P < 0.05) decrease (24%) in glucose disposal after caffeine ingestion. In addition, carbohydrate storage was 35% lower (P < 0.05) in the caffeine trial than in the placebo trial. Furthermore, even when the difference in glucose disposal was normalized between the trials, there was a 23% difference in the amount of carbohydrate stored after caffeine administration compared with placebo administration. Caffeine ingestion also resulted in higher plasma epinephrine levels than placebo ingestion (P < 0.05). These data support our hypothesis that caffeine ingestion decreases glucose disposal and suggests that adenosine plays a role in regulating glucose disposal in resting humans.     

Kinin system responses in sepsis after trauma in man

We measured the level or activity of plasma kallikrein, kininase I (carboxypeptidase N), trypsin and kallikrein inhibitors. The concentration of kininogen substrate was established by activating plasma prekallikrein with an added insoluble prekallikrein activator preparation. The blood samples were collected from normal donors and from young men hospitalized with combat trauma complicated by gram-negative sepsis. Twelve of these patients survived and six died during the study. Some of the patients had no measurable kininogen at the beginning of the hospitalization. In those patients who survived, the kininogen levels declined profoundly toward the end. This drop was accompanied by a decrease in the prekallikrein level. The levels of the other three proteins were not significantly different between the two groups of patients. The results suggest the liberation of bradykinin in septic shock.     

The relationship of insulin production to glucose metabolism in severe sepsis

Basal glucose metabolism was evaluated in eight stable, infected patients by measuring hepatic glucose production rates in relation to stress endocrine profile and by comparing these data to five injured, noninfected patients. All patients exhibited normal total-body oxygen consumptions and cardiac indices. Fasting basal insulin values were similar in both groups (6 microU/cc) despite a significantly higher plasma glucose level in septic patients (106 +/- 14 mg/dL) compared to nonseptic patients (88 +/- 10 mg/dL). Septic patients exhibited splanchnic glucose production and calculated glucose clearance rates, 53% and 34% higher, than injured nonseptic patients, respectively. In addition, septic patients exhibited a decreased pancreatic insulin secretory response to an intravenous glucose tolerance test as evidenced by a significantly depressed peak insulin value (17 microU/cc) relative to injured patients (77 microU/cc). These findings indicate that insulin suppression is evident in sepsis even in the absence of shock and suggest that sepsis-related basal hyperglycemia does not appear to be associated with peripheral insulin resistance.     

Relation between glucose tolerance and serum insulin levels in man before and after thiopental intravenous administration.

A glucose-tolerance test was performed in a number of healthy volunteers before and after a single dose of intravenous sodium thiopental. During this test, serum insulin levels were determined at similar intervals. A small but significant decrease in glucose tolerance, not related to serum insulin levels, was seen.     

In vivo deactivation of proinsulin action on glucose disposal and hepatic glucose production in normal man

We have studied the deactivation of the in vivo actions of insulin and biosynthetic human proinsulin (recombinant DNA) to stimulate the glucose disposal rate (GDR) and to inhibit hepatic glucose output (HGO) in man. Twelve healthy, lean, young subjects were studied using a modification of the euglycemic glucose clamp technique. Subjects received 4-h infusions on separate occasions of insulin (15 mU/m2/min equivalent to 0.54 microgram/m2/min) or proinsulin (2.75 micrograms/m2/min), achieving steady-state serum levels of 32 +/- 3 microU/ml (equivalent to 0.23 +/- 0.02 pmol/ml) and 3.7 +/- 0.2 pmol/ml, respectively. Suppression of HGO was similar (83-84%) with proinsulin and insulin, but stimulation of GDR above basal was greater with insulin (3.41 +/- 0.43 versus 1.98 +/- 0.28 mg/kg/min, P less than 0.001). Following cessation of the hormone infusions, serum proinsulin concentration fell in a biphasic fashion with half-times of 25 and 146 min for the two phases. Serum half-disappearance time for insulin was 5 min. Deactivation of the hormone's effects to stimulate GDR was 50% complete by 35 min after insulin and 71 min after proinsulin. In contrast, 50% of the recovery times for the effect on suppression of HGO were 55 min after insulin and 188 min after proinsulin. Serum glucagon levels did not differ significantly after the insulin and proinsulin infusions. In summary: (1) Deactivation of proinsulin and insulin's effects to suppress HGO proceeds more slowly than deactivation of their effects to stimulate GDR; and (2) There is a markedly prolonged and disproportionately delayed deactivation of proinsulin's effects on suppression of HGO. This later finding may prove of therapeutic value in the treatment of diabetes mellitus.     

Glucose disposal is not proportional to plasma glucose level in man

Metabolic clearance rate (MCR) of glucose has been defined as the rate of glucose utilization divided by the glucose concentration. This model of glucose transport has been widely used as a measure of hormonally regulated glucose disposal, on the assumption that glucose disposal rate is proportional to glucose concentration. To test this assumption, the relationship between glucose concentration and disposal rate was studied in man during infusion of somatostatin +/- exogenous insulin to achieve fixed plasma insulin levels of 1, 18, and 46 microM/ml on separate days. When glucose concentration was increased to more than twice basal fasting levels, the glucose disposal rate increased significantly at all three insulin levels. However, the increase was not proportional to the rise in glucose concentration, and MCR fell by 38%, 16%, and 11% at the low, medium, and high insulin levels, respectively. These results are explained by an alternative model of glucose transport in which insulin-independent tissues such as brain have a relatively fixed glucose uptake, while other tissues have glucose transport systems which take up glucose at a rate proportional to its plasma concentration. We conclude that MCR of glucose is not a good measure of hormonally regulated glucose disposal because it is partially dependent on the glucose concentration, particularly at low insulin levels.     

The effect of intravenous glucose on pentagastrin-induced gastric acid secretion in man.

The effect of intravenous glucose on pentagastrin-induced submaximal gastric acid secretion was invesgated in 8 patients with uncomplicated duodenal ulcer and normal glucose tolerance. 50 ml of a 50% glucose solution, injected over approximately 3 minutes, was completely without effect on volume, acidity, and acid output. These findings seem to rule out the possibility that the marked inhibition earlier demonstrated after intrajejunal glucose is caused by hyperglycemia.     

手术创伤、胰岛素抵抗及血糖控制

外科手术创伤后常发生一系列代谢异常,胰岛素抵抗(in-sulin resistance,IR)作为机体对创伤应激的一种反应,会导致组织对胰岛素敏感性降低,引起糖、脂代谢紊乱,破坏机体内环境的稳定,影响患者的预后和恢复。近年来,IR的防治正日益受到关注,其在外科创伤后的作用已愈来愈引起临床医师的重视。一、IR的概念及影响因素IR是指胰岛素的外周靶组织(主要为骨骼肌、肝脏和脂肪组织)对胰岛素的敏感性和反应性降低,造成生理剂量的胰岛素产生低于正常的生理效应。除了导致病理性高血糖、糖耐量下降,IR还可引起机体分解代谢增加、负氮平衡、瘦组织群…     

The effect of pancreatic polypeptide infusion on glucose tolerance and insulin response in longitudinally studied pancreatitis-induced diabetes

Glucose intolerance is often associated with pancreatitis. Pancreatitis-induced diabetes represents a different clinical syndrome than type I and type II diabetes mellitus. Patients with pancreatitis-induced diabetes may be extremely sensitive to exogenous insulin, rarely develop ketoacidosis, and rarely exhibit classic diabetic complications, such as retinopathy, nephropathy, or accelerated vasculopathy. Pancreatic polypeptide (PP) deficiency has been implicated in the defect of glucose homeostasis found after pancreatitis. This study evaluated intravenous and oral glucose tolerance and insulin response to glucose loading, in the setting of pancreatitis, with and without short-term PP replacement. Dogs (n = 7) underwent pancreatic duct ligation (PDL) and were studied with and without PP infusion (2 micrograms/kg/hr) before PDL and at 1 week, 6 weeks, and 4 months after PDL by means of intravenous and oral glucose tolerance tests. Basal and bombesin-stimulated PP levels at 4 months after PDL were subnormal, verifying PP deficiency in these animals with pancreatitis. PP levels during PP infusion reproduced normal postcibal levels, averaging 897 +/- 40 pg/ml. Glucose tolerance, expressed as the glucose decay constant for the intravenous glucose tolerance tests and as the integrated glucose response for the oral glucose tolerance tests, deteriorated over time and was not improved by acute PP replacement. The integrated insulin response to glucose was not affected by PP. The acute infusion of PP at a dose that reproduces normal postprandial PP levels fails to improve glucose tolerance or augment insulin release in this model of pancreatitis-induced diabetes.     

The metabolic response to trauma and sepsis

The metabolic response of the body to trauma and sepsis is the summed response of the organs. Net catabolism of the muscles of ambulation is particularly important in providing the other organs with a source of amino acids for protein synthesis and, therefore, anabolism. This net catabolism of muscle is based upon decreased physical activity, the net effects of the neuroendocrine system, and the consequences of local amino acid concentration changes within muscle, particularly of leucine. Secondary to these changes, previously healthy humans sustaining acute short-term trauma of fairly major degree do not require exogenous supplies of amino acid even though the patient has a short-term negative nitrogen balance. In contrast, the septic patient has, in addition to the preceding changes, activation of phagocytosis with release of phagocytic factors that mobilize white cells, increase body temperature, and further modulate the metabolism of muscle and probably all other organs. Since these changes are induced by phagocytosis, which may be activated by retained dead tissues of all kinds, the basic attributes of the septic state may be activated in the absence of bacteria. The retained dead tissue makes bacterial growth much more likely. The septic state, therefore, has as its hallmark all of the changes of the trauma state, plus a prolonged enhanced catabolism of all amino acids, which leads to protein malnutrition with its overt manifestation of multiple systems organ failure. These patients require calories only 10 to 50% in excess of the requirement of normal humans, but a great increase in amino acid intake (up to 2.5% to 3 g/kg per day). This support will purchase more time in which to treat the underlying sepsis.     

Effect of surgical trauma on plasma insulin and somatostatin in response to glucose

The role of somatostatin for the suppression of insulin release in the early post-traumatic phase was investigated by measurement of somatostatin-like immunoreactivity in plasma during an intravenous glucose tolerance test. In accordance with previous findings the increase of insulin in response to glucose was significantly (p less than 0.001) reduced 2 hours after laparotomy as compared to control subjects. Simultaneously plasma somatostatin was decreased significantly (p less than 0.05). The present data with hormone determinations in peripheral blood does not support the hypothesis that somatostatin, a potent inhibitor of insulin release, mediates the insulin suppression in the early trauma phase.