Mechanisms of insulin resistance in man. Assessment using the insulin dose-response curve in conjunction with insulin-receptor binding

During the past few years it has become increasingly apparent that insulin resistance may be a more frequent cause of carbohydrate intolerance or contributing factor in carbohydrate intolerance than was hitherto appreciated. Abnormal insulin action may result from prereceptor, receptor or postreceptor defects. These may be manifested by an increase in the concentration of insulin necessary for a half-maximal effect (decreased sensitivity) or a decrease in the maximal response to insulin (decreased responsiveness), or both. Alterations in sensitivity and responsiveness to insulin can be distinguished only by evaluating insulin dose-response curves. When used in conjunction with measurements of insulin binding to its receptor, the characteristics of these curves can provide insight into the mechanism or mechanisms responsible for insulin resistance.     

Validation of a practical in vivo insulin dose-response curve in man

To adequately investigate the state of insulin resistance, an insulin dose-response curve should be constructed so that insulin sensitivity (right shift of dose-response curve) and insulin responsiveness (maximal response) can be determined. This paper describes and validates in man a practical in vivo insulin dose-response curve technique, using a modification of the euglycaemic clamp described by De Fronzo et al. Insulin action at steady state was expressed as metabolic clearance rate of glucose (MCR_G) rather than overall rate of glucose disappearance (M or Rd). MCR_G was chosen because at plasma insulin concentrations >25μU/ml it was shown (n = 5) not to be altered by changes in blood glucose concentration (MCR_G 379 ± 23 and 408 ± 19 ml/m²/min; at plasma glucose concentrations 5.4 ± 0.3 and 10.2 ± 0.7 respectively), whereas Rd was critically dependent on the prevailing blood glucose concentration (Rd 2007 ± 128 and 4124 ± 219μmol m²/min respectively). MCR_G was demonstrated to be stable over a 6 hr period (n = 7) and to be reproducible (n = 4). Insulin dose-response curves (MCR_G Versus insulin concentration) were performed on two obese and seven normal weight individuals. The insulin dose-response curves were linearized, allowing accurate prediction of the maximal MCR_G, as compared to the experimentally determined maximal response (r = 0.953 p < 0.01). The use of this transformation obviates the need to employ very high insulin infusion rates to determine the maximal insulin response. In conclusion, the technique permits, in a single 6 hr study, a precise insulin dose-response curve to be constructed for accurately determining insulin sensitivity and responsiveness.     

Glucagon dose-response curve for hepatic glucose production and glucose disposal in type 2 diabetic patients and normal individuals

This study sought to examine whether enhanced hepatic sensitivity to glucagon contributes to impaired glucose homeostasis in subjects with type 2 diabetes mellitus (T2DM). Eight T2DM and 9 age-, weight-, and gender-matched nondiabetic subjects received a 4-hour glucagon infusion at the rates of 0.2, 0.5, 2, 6, and 8 ng. kg(-1). min(-1) while maintaining the plasma insulin concentration constant at the basal level with exogenous infusions of somatostatin and insulin. On the evening prior to study, diabetic subjects received a low-dose insulin infusion at a rate designed to maintain euglycemia and this infusion rate was continued until the end of the glucagon infusion study on the following day. Each glucagon infusion study was performed on a separate day and in random order. 3-(3)H-glucose was infused in all studies to measure endogenous glucose production (EGP) and the rate of whole body glucose disposal. During the first 2 hours (0 to 120 minutes) of glucagon infusion, EGP increased sharply in both groups, and the initial rate of rise in EGP was higher in control versus diabetic subjects. During the last 2 hours (120 to 240 minutes) of glucagon infusion, EGP in the diabetics tended to be higher than controls during the 3 lower glucagon infusion rates and this difference reached statistical significance (P <.05 to.01) during the 6 and 8 ng. kg(-1). min(-1) infusions. During the 2 hours following cessation of glucagon (240- to 360-minute time period), the stimulation of glucose disappearance from plasma was impaired (P <.05) during all 5 glucagon infusion rates in the diabetics compared to controls. We conclude that in T2DM patients, the initial (0 to 120 minutes) stimulation of hepatic glucose output (which primarily reflects glycogenolysis) by glucagon is not enhanced in T2DM patients. The late (120 to 240 minutes) stimulation of hepatic glucose output (which primarily reflects gluconeogenesis) by glucagon tends to be increased, especially at supraphysiologic plasma glucagon concentrations.     

Cerebrospinal fluid insulin levels increase during intravenous insulin infusions in man

We hypothesized that plasma insulin crosses the blood-cerebrospinal fluid (CSF) barrier and, as people gain weight, provides a physiological feedback signal to the central nervous system to inhibit food intake and further weight gain. However, it has not been demonstrated in man that insulin can enter the CSF from peripheral blood. To test whether increases in plasma insulin result in elevated CSF immunoreactive insulin (IRI) levels, we infused insulin iv in varying amounts approximating postprandial levels in eight normal subjects for 4.5 h. Euglycemia was maintained [88 +/- 3 (+/- SEM) mg/dl] by means of a variable glucose infusion. Samples were obtained every 30 min for measurements of insulin in peripheral plasma and insulin in lumbar CSF. Plasma IRI increased from a mean basal level of 12 +/- 1.2 microU/ml to a mean (during the 180- to 270-minute period) of 268 +/- 35 microU/ml. CSF IRI increased in all subjects during the infusion from a mean basal level of 0.9 +/- 0.1 microU/ml to a mean (during the 180- to 270-min period) of 2.8 +/- 0.4 microU/ml (P less than 0.006). By contrast, CSF IRI in two subjects who received an infusion of 0.9% saline did not increase. In summary, CSF insulin concentrations increased during peripheral infusions of insulin. This is the first demonstration in man that plasma insulin gains access to CSF and indicates a mechanism whereby peripheral insulin could provide a feedback signal to the central nervous system.     

Effect of breathing pattern during inhalation challenge on the shape and position of the dose-response curve

To examine the effect of breathing pattern on the dose-response curve, 4 mild asthmatic and 9 normal subjects inhaled increasing concentrations of methacholine (0.03–256 mg/ml) using a quiet tidal breathing pattern or tidal breathing with a forced expiratory phase. The provocative concentration of methacholine causing a 20% decrease in the forced expired volume in 1 s (PC₂₀FEV₁) or a 200% increase in pulmonary resistance (PC 200R_L) was determined. In addition, the maximal change in FEV₁ and R_L and the slopes of the dose-response curves were measured. The forced expiratory pattern caused an increase in the central/peripheral deposition ratio of a [99^m]technetium-labeled aerosol (n=3). There were no differences in mean tidal volume, minute ventilation, inspiratory flow rates, or baseline FEV₁ or R_L between the quiet breathing or forced expiration studies, although mean expiratory flows were increased in the latter (p<0.001). PC₂₀FEV₁ and PC₂₀₀ R_L decreased (p<0.001) but the maximal change in FEV₁ and R_L was unchanged in the forced expiration studies. Forced expiration during inhalation challenge did not alter the slope of FEV₁ or R_L dose-response curves. These results suggest that the sensitivity (PC₂₀, PC₂₀₀) and maximal response of in vivo dose-response curves may be affected independently by factors such as aerosol deposition.     

Effect of breathing pattern during inhalation challenge on the shape and position of the dose-response curve

To examine the effect of breathing pattern on the dose-response curve, 4 mild asthmatic and 9 normal subjects inhaled increasing concentrations of methacholine (0.03-256 mg/ml) using a quiet tidal breathing pattern or tidal breathing with a forced expiratory phase. The provocative concentration of methacholine causing a 20% decrease in the forced expired volume in 1 s (PC20FEV1) or a 200% increase in pulmonary resistance (PC 200RL) was determined. In addition, the maximal change in FEV1 and RL and the slopes of the dose-response curves were measured. The forced expiratory pattern caused an increase in the central/peripheral deposition ratio of a [99m]technetium-labeled aerosol (n = 3). There were no differences in mean tidal volume, minute ventilation, inspiratory flow rates, or baseline FEV1 or RL between the quiet breathing or forced expiration studies, although mean expiratory flows were increased in the latter (p less than 0.001). PC20FEV1 and PC200 RL decreased (p less than 0.001) but the maximal change in FEV1 and RL was unchanged in the forced expiration studies. Forced expiration during inhalation challenge did not alter the slope of FEV1 or RL dose-response curves. These results suggest that the sensitivity (PC20, PC200) and maximal response of in vivo dose-response curves may be affected independently by factors such as aerosol deposition.     

Influence of ambient glucose and insulin concentrations on adipocyte insulin binding

To elucidate factors of importance for insulin binding, fat cells from humans and rats were incubated under various experimental conditions for different periods of time. Human adipocytes incubated for 24 hours in the absence of insulin showed no significant difference in insulin binding compared with cells from freshly excised tissue. After 48 hours, however, an increased rate of binding (average 54%; P less than 0.05) was obtained. The addition of insulin (2000 microU/ml) to the culture medium resulted in a decrease in insulin binding (average 33%; P less than 0.05) compared with cells maintained in the absence of insulin. There was no apparent difference in receptor affinity, indicating that the altered binding was due to a change in receptor number. In the absence of insulin, elevating the glucose concentration of the medium from 0.8 mM to 22.4 mM did not significantly influence insulin binding. Rat adipocytes showed similar but more rapid changes. Thus, incubation for 24 hours without insulin caused an increase in insulin binding (average 37%; P less than 0.05). This up-regulation was seen even in a high glucose concentration (28 mM) but was completely prevented by the presence of insulin in the medium. Furthermore, when rat adipocytes were incubated with insulin in the presence of a high glucose concentration (28 mM) there was a significant further decrease in insulin binding compared with that of parallel incubations performed in 5.6 mM glucose. Thus, even in the absence of TRIS buffer, insulin-dependent regulation of the number of binding sites is shown for both human and rat adipocyte tissue in vitro. Although this perturbation could be directly due to hormone-receptor interaction at the membrane level, the finding of rat adipocytes that the ambient glucose concentration can modulate this effect suggests the importance of post-receptor events.     

Oscillations in insulin secretion during constant glucose infusion in normal man: relationship to changes in plasma glucose

Peripheral plasma or serum concentrations of glucose, insulin, C-peptide, glucagon, and cortisol and insulin secretory rates (ISR) were determined at 15-min intervals in eight normal subjects during a constant iv infusion of 4.5 mg glucose/kg.min for a 24-h period. During each sampling interval, the secretory rate of insulin was calculated by deconvolution of the peripheral plasma C-peptide concentration using C-peptide kinetic parameters derived after bolus injections of C-peptide in individual subjects. Periodogram analysis of the individual glucose curves demonstrated a circadian rhythm in all subjects, with a major nocturnal acrophase occurring at an average clock time of 0228 h (range, 0045-0350 h). In five of the eight subjects, a minor acrophase occurred at an average time of 1774 h (range, 1530-2045 h). This diurnal variation in plasma glucose levels was not paralleled by a similar pattern in insulin secretion. Although glucose was infused at a constant rate, significant pulses were found in glucose, insulin, and C-peptide levels and ISR; the pulse durations of these parameters were 182 +/- 30 (+/- SE), 89 +/- 5, 100 +/- 8, and 85 +/- 5 min, respectively, and their periodicities were 208 +/- 33, 106 +/- 7, 114 +/- 10, and 106 +/- 7 min. The durations and frequencies for pulses of insulin, C-peptide, and ISR were not significantly different, whereas glucose pulses had a longer duration and were less frequent (P less than 0.05, by analysis of variance). On the average, 54 +/- 9% of the C-peptide pulses and 47 +/- 8% of the ISR pulses were concomitant with a pulse in glucose levels. Moreover, approximately half of the C-peptide and ISR pulses that were not concomitant with a glucose pulse occurred in synchrony with a shoulder on the up-stroke or down-stroke of glucose pulses. Analysis of glucagon and cortisol profiles revealed no significant associations with the insulin and glucose oscillations. In conclusion, during a constant glucose infusion in normal subjects, regular oscillations of insulin secretion occur at 80- to 120-min intervals. Their tight coupling with glucose oscillations and the lack of association with fluctuations of glucagon and cortisol suggest that these oscillations represent a dynamic property of the insulin-glucose feedback loop.     

The effect of intraportal and peripheral infusions of glucagon on insulin and glucose concentrations and glucose tolerance in normal man

Summary The effect of peripheral and intraportal infusions of 0.86 pmol/kg · min^–1 of glucagon on plasma glucose, plasma insulin, and glucose tolerance was examined in four normal subjects. Peripheral glucagon concentrations increased by 60–90 pmol/l during intraportal and 70–180 pmol/l during peripheral infusions. The infusions caused increases in plasma glucose levels of approximately 1 mmol/l, and in plasma insulin levels of 75–100%, regardless of route of administration. Intravenous glucose tolerance tests carried out during the glucagon infusions showed that glucose tolerance remained within the normal range and was uninfluenced by the route of administration.     

Disassociation of the plasma insulin response from the blood glucose concentration during glucose infusions in normal dogs

Twenty-two anesthetized dogs were given a constant glucose infusion (14 mg/kg/min) for 360 min, while blood glucose concentration was continuously monitored. Plasma insulin concentration was measured every 30 min. The blood glucose peaked at 60 min and then steadily fell (mean fall, $\text{56}\text{mg}\text{100}\text{ml}$), while plasma insulin continuously rose (mean rise, 65 μU/ml). This suggests that blood glucose concentratiion was not the primary stimulus for insulin secretion. In a second series of experiments, five dogs received glucose infusions as described above. One week later, each dog was reinfused with a larger total glucose load, regulated by continuous blood glucose monitoring to exactly reproduce the blood glucose response observed during the first infusion. Plasma insulin concentrations during the high load infusions were significantly higher than during the low load infusions. Thus, changes in glucose load produced changes in plasma insulin concentration, even though blood glucose levels were held constant. Thus, using two different approaches, we have demonstrated that plasma insulin levels can be dissociated from the coexisting blood glucose concentration. These results suggest that the level of blood glucose may not be the primary determinant of the insulin response to glucose during the chronic phase of insulin secretion.     

Assessing 1-h plasma glucose and shape of the glucose curve during oral glucose tolerance test

OBJECTIVE: To assess the cutoff values at different time points for impaired glucose regulation (IGR) and diabetes, the glucose curve and isolated 1-h hyperglycemia were monitored during an oral glucose tolerance test (OGTT). METHODS: Two thousand eight hundred and eighty-six subjects (1300 men and 1586 women) were recruited to have an OGTT. Plasma was collected at 0, 30, 60, 120, and 180 min to analyze glucose and insulin. The diagnosis of impaired fasting glucose, impaired glucose tolerance, and diabetes was based on World Health Organization and American Diabetes Association's criteria. Those with fasting plasma glucose (FPG) < 5.6 and 2-h plasma glucose (PG) < 7.8, but 1-h PG > or = 7.8 and < 11.1 mmol/l were defined as 1h-High7.8, and those with FPG < 7.0 and 2-h PG < 11.1, but 1-h PG > or =11.1 mmol/l as 1h-High11.1. The cutoff values were calculated by receiver operating characteristic (ROC) curve. The correlation between beta-cell function and the area under the curve of glucose (AUCg) and the shape index was analyzed with linear regression. RESULTS: The cutoff values for IGR were 5.6, 9.7, 10.1, 7.8 and 6.1 mmol/l for blood glucose at 0, 30, 60, 120 and 180 min, 24 for AUCg and 1.3 mmol/l for the shape index. The cutoff values for diabetes were 6.8, 11.2, 13, 11.1 and 7 mmol/l for 0, 30, 60, 120 and 180 min, 30.9 for AUCg and 2 mmol/l for the shape index. Both AUCg and the shape index were inversely related to beta-cell function. The profiles of glucose and insulin in the subgroup with isolated 1-h hyperglycemia were very different from those seen in subjects with normal glucose tolerance or IGR. CONCLUSIONS: The present study provides new information on measures other than the fasting and 2-h PG to evaluate glucose metabolism in vivo and stimulates further research aimed at assessing the value of the OGTT 1-h PG concentration prospectively.     

Plasma leptin concentrations during extended fasting and graded glucose infusions: relationships with changes in glucose, insulin, and FFA

Despite numerous studies, the in vivo regulation of plasma leptin levels in response to nutritional factors continues to remain unclear. We investigated temporal and dose-response relationships of plasma leptin in response to physiological changes in insulin/glucose. After an overnight fast of 10 h, lean, healthy subjects were investigated for an additional 16 h of either extended fasting or one of three levels of glycemia/insulinemia induced by stepwise increasing iv glucose infusions. During extended fasting, plasma leptin values declined steadily and significantly. Plasma leptin levels remained constant at glucose concentrations between 5.8-6.5 mmol/liter, which maintained normoinsulinemia at 41.5-45.4 pmol/liter and FFA at 106-123 mg/liter, but leptin concentrations were increased at higher rates of glucose infusion (with plasma glucose rising to 8.7 mmol/liter). Concentrations of serum leptin were inversely related to FFA levels during extended fasting and at all levels of glycemia. Our data indicate that in lean healthy subjects, physiological changes in glycemia and insulinemia significantly alter plasma FFA and leptin concentrations. The increases in leptin concentrations demonstrate dose-dependent relationships that appear to relate to changes in FFA levels as well as to changes in glycemia/insulinemia.     

正常糖耐量者口服葡萄糖-胰岛素释放试验的胰岛素分泌曲线特点的研究

目的研究口服葡萄糖一胰岛素释放试验（OGIRT）的胰岛素（Ins）分泌曲线特点,初步探讨适用于I临床评价个体胰岛素敏感性和8细胞分泌功能的方法。方法对12例正常糖耐量者行OGIRT和静脉糖耐量试验（IVGTT）,观察OGIRT、IVGTT血浆Ins分泌峰值时间分布频数,分析胰岛素敏感性和B细胞功能各指标相关指数。结果OGIRT血浆Ins分泌高峰出现于35-45min,无明显第二分泌峰。经多因素线性回归分析表明20、30、35minIns增值与葡萄糖增值的比值（ΔI20／ΔG20、ΔI30／ΔG30、ΔI35／ΔG35）与第一相（1PH）胰岛素分泌、葡萄糖及胰岛素曲线下面积比值（SGI）、胰岛素作用指数（IAI）、HOMA—IR、胰岛素分泌指数均不相关（P〉0．05）,ΔI40／ΔG40与SGI、IAI、HOMA-IR显著相关（P均〈0．01）。结论OGIRT可能不能反映1PH;OGIRTΔI40／ΔG40比I20／ΔG20、△I30／ΔG30能更好地评估β细胞功能。     

Influence of adrenergic receptor stimulation on glucose metabolism during starvation in man: effects on circulating levels of insulin growth hormone and free fatty acids

Three days of starvation in 23 healthy, non-diabetic volunteers produced a “diabetic-like” state characterized by ketonuria, glucose intolerance, and diminished insulin secretion in response to i.v. glucose. The serum concentration of growth hormone and free fatty acids, and the urinary excretion of free catecholamines were also elevated. Free plasma cortisol remained unchanged. To investigate the influence of adrnergic receptor stimulation on these metabolic alterations, fasting subjects were divided into three groups, 40 min before an i.v. glucose tolerance test (IVGTT). One group received a saline infusion and served as controls. A second group (α-adrenergic blockade) received an infusion of phentolamine beginning 40 min before and lasting throughout the fasting IVGTT; the third group received phentolamine and propranolol (total adrenergic blockade). All subjects were glucose intolerant after fasting, and by comparison with the prefasting IVGTT, it was found that adrenergic blockade had no effect on the change in glucose tolerance after starvation. Control subjects exhibited a 45% (p < .03) decline in glucose-stimulated insulin secretion, while subjects under α blockade exhibited a 110% increase (p < .03) in insulin secretion. Subjects under total adrenergic blockade showed a modest decline that was not statistically significant (p > .30). Alpha adrenergic blockade returned growth hormone levels to prefasting values in three subjects, and total blockade partially restored the free fatty acid concentration to prefasting levels. These results indicate that sympathetic tone, as reflected by catecholamine excretion, is increased during starvation and may play a role in the regulation of insulin, growth hormone, and free fatty acid release; that acute reversal of insulin deficiency after fasting does not restore normal glucose tolerance; and that peripheral insulin antagonism due to growth hormone and free fatty acids does not appear to be a major cause of glucose intolerance during starvation.     

The shape of the dose-response curve to histamine in asthmatic and normal subjects

In order to determine the shape of the dose-response curves of the human airways to bronchial challenge, changes in forced expiratory volume in one second (FEV1) after inhaled histamine were measured in 8 current asthmatic, 2 mildly asthmatic, and 10 normal subjects. The challenges were continued until a plateau was reached (in all the normal and in the 2 mildly asthmatic subjects), or the FEV1 had fallen by 60%. A sigmoidal equation was fitted to the data points to obtain values for alpha (the position constant) and beta (the slope constant). All the normal and the 2 mildly asthmatic subjects reached a plateau value for fall in FEV1. Current asthmatics were differentiated from normal and mildly asthmatic subjects by the failure to reach a plateau at a 60% fall in FEV1 by higher values for alpha (greater sensitivity to histamine) and by higher values for beta. Ipratropium bromide (an atropinelike drug), in doses that completely inhibited the effects of methacholine, caused no change in the shape or position of the curves in normal or asthmatic subjects. It is concluded that the nature of the airway response to histamine is different in asthmatic from that in normal subjects. It is possible that asthmatics lack a normal mechanism that inhibits severe airway narrowing during histamine challenge.     

A comparison of the activity and disposal of semi-synthetic human insulin and porcine insulin in normal man by the glucose clamp technique

Summary The activity of semi-synthetic human insulin has been compared with porcine insulin in normal man using an euglycaemic glucose clamp at two different insulin infusion rates. In a two hour infusion insulin levels plateaued for both types of insulin at 44–48 mU/l (infusion rate 0.05 U kg body weight^-1 h^-1) and 22–24 mU/l (0.02 U kg^-1 h^-1), giving identical metabolic clearance rates. The glucose delivery required to maintain euglycaemia in the second hour of insulin infusion was 13.9±2.1 g (mean±SEM) and 14.7±1.5 g (NS) at the lower dose for porcine and human insulins respectively, and 27.1±2.5 and 28.0±2.9 g (NS) at the higher dose. The potency ratio for human, compared with porcine, insulin was 1.06 ±0.12. No differences were seen in the time of onset of action of the insulins, serum half-life or distribution space. The responses of blood lactate, pyruvate, alanine, glycerol and 3-hydroxybutyrate were identical. No untoward reactions occurred. The activity and disposal of this semi-synthetic human insulin are indistinguishable from porcine insulin in normal euglycaemic man.     

Changes in the concentrations of glucose,free fatty acids,insulin and ketone bodies in the blood during sodium \-hydroxybutyrate infusions in man

Summary Sodium -hydroxybutyrate was infused for 1.5 h in 8 normal subjects, at a constant rate of 5 mmoles/ kg/h. Equimolar amounts of sodium chloride were infused in 5 control subjects. — The induced hyperketonaemia provoked the following changes in peripheral blood: a fall in glycaemia (15 mg/100 ml) and in plasma NEFA concentration (50%) without concomitant modifications of insulin concentrations. These results indicate that the glucose and NEFA changes observed are not mediated by a pancreatic stimulation.

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Änderungen der Glucose-, FFS-, Insulin- und Ketokörper-Konzentrationen unter einer Natrium--hydroxybutyrat-Infusion beim Menschen

Zusammenfassung Natrium--hydroxy-butyrat wurde 8 Normalpersonen während 1.5 Std bei konstanter Geschwindigkeit von 5 mMol/kg/Std infundiert. 5 Kontrollpersonen erhielten äquimolekulare Mengen einer Kochsalzlösung. — Die so bewirkte Erhöhung der Ketokörper-Spiegel führte im peripheren Blut zu folgenden Veränderungen: Absinken des Blutzuckers um 15 mg %, Abfall der Plasma-FFS auf die Hälfte ohne gleichzeitige Änderung der Insulinspiegel. Diese Ergebnisse sprechen dafür, daß die Änderung der Glucose- und FFS-Konzentrationen nicht durch eine Stimulierung des Pankreas ausgelöst wird.

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Modifications des concentrations de glucose, d'acides gras libres, d'insuline et de corps cétoniques dans le sang pendant des perfusions de -hydroxybutyrate de sodium chez l'homme

Résumé Les auteurs ont étudié chez 8 sujets normaux les effets d'une perfusion de -hydroxy-butyrate de sodium (5 m mol/kg/h pendant 1.6 h) sur la concentration sanguine en glucose, en acides gras libres, en corps cétoniques et en insuline dans le sang veineux périphérique. Cinq sujets témoins ont été perfuses à l'aide de solution équimolaires de NaCl. — L'hypercétonémie provoque une chute de la glycémie d'environ 15 mg/100 ml, une chute des NEFA atteignant 50%, sans modifications concommitantes de l'insulinémie. Ces résultats plaident contre l'intervention d'une stimulation pancréatique dans la chute de la glycémie et des NEFA.

     

The shape of the glucose concentration curve during an oral glucose tolerance test predicts risk for type 1 diabetes

Aims/hypothesis

We aimed to examine: (1) whether specific glucose-response curve shapes during OGTTs are predictive of type 1 diabetes development; and (2) the extent to which the glucose-response curve is influenced by insulin secretion.

Methods

Autoantibody-positive relatives of people with type 1 diabetes whose baseline OGTT met the definition of a monophasic or biphasic glucose-response curve were followed for the development of type 1 diabetes (n = 2627). A monophasic curve was defined as an increase in OGTT glucose between 30 and 90 min followed by a decline of ≥ 0.25 mmol/l between 90 and 120 min. A biphasic response curve was defined as a decrease in glucose after an initial increase, followed by a second increase of ≥ 0.25 mmol/l. Associations of type 1 diabetes risk with glucose curve shapes were examined using cumulative incidence curve comparisons and proportional hazards regression. C-peptide responses were compared with and without adjustments for potential confounders.

Results

The majority of participants had a monophasic curve at baseline (n = 1732 [66%] vs n = 895 [34%]). The biphasic group had a lower cumulative incidence of type 1 diabetes (p < 0.001), which persisted after adjustments for age, sex, BMI z score and number of autoantibodies (p < 0.001). Among the monophasic group, the risk of type 1 diabetes was greater for those with a glucose peak at 90 min than for those with a peak at 30 min; the difference persisted after adjustments (p < 0.001). Compared with the biphasic group, the monophasic group had a lower early C-peptide (30–0 min) response, a lower C-peptide index (30–0 min C-peptide/30–0 min glucose), as well as a greater 2 h C-peptide level (p < 0.001 for all).

Conclusions/interpretation

Those with biphasic glucose curves have a lower risk of progression to type 1 diabetes than those with monophasic curves, and the risk among the monophasic group is increased when the glucose peak occurs at 90 min than at 30 min. Differences in glucose curve shapes between the monophasic and biphasic groups appear to be related to C-peptide responses.