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Journal of Clinical Endocrinology & Metabolism , doi:10.1210/jc.2008-2838 Copyright © 2009 by The Endocrine Society Short-Term Effects of the Long-Acting Insulin Analog Detemir and Human Insulin on Plasma Levels of Insulin-Like Growth Factor-I and Its Binding Proteins in HumansFrancesca Porcellati, Paolo Rossetti, Paola Candeloro, Paola Lucidi, Patrizia Cioli, Anna Marinelli Andreoli, Ezio Ghigo, Geremia B. Bolli and Carmine G. FanelliDepartment of Internal Medicine (F.P., P.R., P.Ca., P.L., P.Ci., A.M.A., G.B.B., C.G.F.), Section of Internal Medicine, Endocrinology and Metabolism, University of Perugia, 06126 Perugia, Italy; and Division of Endocrinology and Metabolism (E.G.), Department of Internal Medicine, University of Torino, 10126 Torino, Italy Address all correspondence and requests for reprints to: Prof. Geremia B. Bolli, University of Perugia, Department of Internal Medicine, Via E. Dal Pozzo, 06126 Perugia, Italy. E-mail: gbolli{at}unipg.it.
Objective: The objective of the study was to compare responses of plasma levels of IGF-I and IGF binding proteins (IGFBP-1 and IGFBP-3) induced by human regular insulin (HI) and the long-acting insulin analog detemir (IDet) at doses equivalent with respect to the glucose-lowering effect. Experimental Design: Ten nondiabetic subjects (six males, four females; age, 36 ± 7 yr; body mass index, 22.9 ± 2.6 kg/m2) were studied on four randomized occasions with iv infusion of IDet (2 mU/kg · min for 4 h, followed by 4 mU/kg · min for 1 h) or HI (1 mU/kg · min for 4 h, followed by 2 mU/kg · min for 1 h) in euglycemia [plasma glucose (PG), 90 mg/dl] or during stepped hypoglycemia (PG, 90, 78, 66, 54, and 42 mg/dl). Results: PG was maintained at preselected plateaus, without any significant difference between IDet and HI (P > 0.2). Plasma insulin concentrations were on average approximately nine times greater with IDet than HI (749 ± 52 vs. 83 ± 19 µU/ml, respectively). Plasma IGF-I concentrations did not change from baseline during insulin infusion in euglycemia (IDet, 147 ± 16 ng/ml; HI, 155 ± 15 ng/ml) and hypoglycemia (IDet, 163 ± 14 ng/ml; HI, 165 ± 14 ng/ml) with no differences between the two insulins (P > 0.2). A similar pattern was observed for plasma IGFBP-3 levels. Insulin infusion resulted in a suppression of plasma IGFBP-1 concentrations with no differences between IDet (baseline, 16.6 ± 3.8 ng/ml; endpoint, 2.0 ± 0.6 ng/ml) and HI (baseline, 16.6 ± 4.1 ng/ml; endpoint, 2.6 ± 1.4 ng/ml) (P > 0.2) and study conditions (P > 0.2). Conclusions: The greater plasma insulin concentrations obtained with IDet exert effects on plasma levels of IGF-I, IGFBP-1, and IGFBP-3 similar to those of HI. Additional studies are needed to confirm these short-term results in patients with diabetes mellitus on long-term treatment with IDet.
The IGF-I is a mitogenic and antiapoptic factor involved in the regulation of several growth-related processes (1) and recently also deemed to be implicated in the pathophysiological mechanisms underlying the growth of neoplasms (2, 3, 4). Indeed, elevated circulating IGF-I concentrations have been associated with an increased risk of several among the most common forms of cancer (4, 5, 6, 7, 8). Among the factors involved in the regulation of the biological activity of IGF-I, the IGF binding proteins (IGFBPs) seem to play the most critical role. At least six different IGFBPs (IGFBP-1 to -6) have been isolated, cloned, and further characterized (1, 9). They bind more than 98% of IGF-I with high affinity and specificity, buffering IGF-I in the vascular system, thereby regulating IGF-I bioavailability, and ultimately enhancing or inhibiting IGF-I action at the cellular level, depending on whether they protect IGF-I from degradation or prevent its binding to the IGF-I-specific receptors. The IGFBPs are subjected to a complex regulation that has been only partially clarified (1, 10, 11). GH stimulates the hepatic production of IGFBP-3, which binds the majority of the circulating IGF in a large 150-kd ternary complex along with a non-IGF-binding glycoprotein, the acid-labile subunit, acting mainly as an IGF-I reservoir, not capable of passing through the capillary boundary. Conversely, insulin is the primary regulator of IGFBP-1, which is, among the six proteins, the only one whose levels, liver derived, are dynamically regulated with recurrent, rapid fluctuations within a few hours, thereby modulating the free fraction of IGF-I (1, 10, 11). Insulin-induced inhibition of IGFBP-1 production occurs at the molecular level, through inhibition of gene transcription via an insulin-responsive element (12, 13). As a consequence, IGFBP-1 levels are inversely correlated with plasma insulin concentrations, thus representing a marker of hepatic insulin effects. Indeed, whereas IGFBP-1 levels rise during fasting and exercise and are elevated in poorly controlled type 1 diabetes, reflecting low insulin concentrations, they are suppressed in those conditions characterized by elevated insulin levels, such as postprandial state, obesity, and insulinomas (13, 14, 15, 16). Interestingly, hypoglycemia, both as acute insulin-induced as well as after prolonged fasting, may stimulate a rise in IGFBP-1 levels, closely mimicking the counterregulatory hormonal responses, a finding that has been related to a possible implication of IGFBP-1 in glucose counterregulation (17, 18), although the specific role and the extent to which it may contribute to it have never been defined. The critical role of insulin in regulating IGF-I bioavailability through the modulation of IGFBP concentrations has led to the hypothesis that plasma insulin levels may play a role in promoting carcinogenesis (19). Indeed, several epidemiological studies, including cross-sectional and case control, along with prospective observations, have shown the association between colorectal adenomas and cancer with type 2 diabetes (20). Furthermore, studies evaluating prospectively collected serum samples have found an increased risk of colorectal cancer with increasing levels of serum insulin (21) and C-peptide concentration (22, 23), as well as of metabolic correlates of insulin resistance such as hypertriglyceridemia (20). Insulin detemir is a soluble, acylated, long-acting insulin analog, suitable to replace basal insulin needs in diabetic patients (24). This lipophilic molecule has been specifically designed to bind reversibly to albumin in interstitial fluid and in the circulation, thus leading to a delayed insulin absorption and a lower clearance rate from plasma and thereby protracting insulin’s effect. The lower affinity of insulin detemir for insulin receptors has required a 4-fold concentrated formulation to be used in diabetic patients to match the biological potency of human insulin (24). Therefore, administration of insulin detemir results in greater plasma insulin concentration than human NPH or glargine insulin (25, 26). Our group has recently shown that the physiological responses to hypoglycemia induced by the long-acting insulin analog detemir are unequivocally different from those induced by human insulin, with a delayed perception of symptoms and an earlier deterioration of cognitive function, thus suggesting a differential modulation of neuroendocrine counterregulation (27). So far, it is not known whether the greater plasma insulin levels after administration of insulin detemir also translate into different modulatory actions on plasma concentrations of IGF-I and IGFBPs compared with those following unmodified human insulin. The aim of the present study was to compare the responses of plasma levels of IGF-I, IGFBP-1, and IGFBP-3 induced by insulin detemir and human regular insulin at doses equivalent with respect to the glucose-lowering effect. Healthy subjects were studied in euglycemia and hypoglycemia in a randomized, double-blind study design with the glucose clamp technique, during iv infusion of either human insulin or insulin detemir, as previously reported (27).
The study was approved by the local ethics committee and carried out according to the Helsinki Declaration after obtaining written informed consent from all subjects. The study design and metabolic outcome measures have been reported in detail previously (27). Here we present the outcome measures regarding the responses of plasma levels of IGF-I, IGFBP-1, and IGFBP-3 recorded during the study on the 10 nonobese volunteers (six males, four females; age, 36 ± 7 yr; body mass index, 22.9 ± 2.6 kg/m2). All subjects were studied on four randomized occasions in a computer-generated sequence at 2- to 3-wk intervals with the hyperinsulinemic euglycemic and, on a separate occasion, the hypoglycemic glucose clamp technique. They received a 5-h iv infusion of either regular human insulin (Actrapid U 100, 1 U = 6 nmol; Novo Nordisk, Bagsværd, Denmark) or insulin detemir (Levemir, 1 U = 24 nmol; Novo Nordisk) in euglycemia (euglycemic clamps) or during a stepped hypoglycemic clamp (hypoglycemic clamps) (27). Briefly, the subjects were admitted to the investigator’s clinic at the University of Perugia at 0730 h on the day of study after an overnight fast. One iv cannula was placed into an antecubital vein of the nondominant forearm for the infusion of insulin, glucose, and saline. A second cannula was inserted retrogradely in a dorsal vein of the ipsilateral hand and kept in a thermoregulated box at about 65 C to obtain arterialized venous blood (28). This second cannula was used for intermittent blood sampling. After no less than 1 h for equilibration and baseline testing, at time "0 min" of study, an iv bolus of either 10 mU/kg of human insulin or 20 mU/kg of detemir insulin was given. Subsequently, a continuous iv infusion of 1 mU/kg · min (6 pmol/kg · min) of human insulin or 2 mU/kg · min (48 pmol/kg · min) detemir insulin was initiated and maintained unchanged until time 240 min, after which infusion rates were doubled for the last 60 min (time 240–300 min). These rates of infusion were selected from a series of pilot studies because they gave the best approximation in terms of equivalence in the glucose-lowering effects between the two insulins (8:1 molar ratio of insulin detemir to human insulin). Immediately after the insulin bolus, a variable infusion of 20% glucose was initiated by means of a syringe pump (Harvard Apparatus; Ealing Corp., South Natick, MA) and continued at a variable rate according to the principle of the eu- and hypoglycemic glucose clamp technique on all four study occasions. On two occasions, plasma glucose was maintained at the target value of 90 mg/dl (euglycemic clamps, henceforth indicated as Eu-HI and Eu-Det for human insulin and detemir insulin, respectively), whereas on the two other occasions plasma glucose was clamped at sequential target glucose concentrations of 90, 78, 66, 54, and 42 mg/dl (hypoglycemic clamps, indicated as Hypo-HI and Hypo-Det). Each step consisted of 60 min, with the initial 30 min used to reach the desired plasma glucose target and the subsequent 30 min used to maintain the plasma glucose plateau for measurement of variables. At time 300 min, the clamp procedure was terminated, the insulin infusion withdrawn, and the glucose infusion increased to quickly restore euglycemia. In all studies, arterialized venous blood samples were drawn at 5- to 10-min intervals for plasma glucose measurements and at hourly intervals for total IGF-I, IGFBP-1, and IGFBP-3 assays. In addition, at 30-min intervals measurement of metabolic, counterregulatory variables and nonglucose substrates was also performed as previously detailed (27). Analytical methods Bedside plasma glucose was measured using a Beckman Glucose Analyzer (Beckman Instruments, Palo Alto, CA). The measurement of insulin detemir and human insulin was performed using a commercial RIA kit (Linco Research Inc., Minneapolis, MN). Glucagon, GH, cortisol, adrenaline, and noradrenaline were measured by previously described assays (29). Plasma free fatty acid concentrations were measured using a commercial kit (NEFA C test kit; Wako Chemicals, Neuss, Germany). Plasma total IGF-I was determined by RIA after acid/ethanol extraction according to the manufacturer’s specification (BioSource, Nivelles, Belgium). IGFBP-1 and IGFBP-3 levels were measured by double-antibody RIA (Diagnostic System Laboratories, Webster, TX; and Immunotech, Praha, Czech Republic, respectively). Statistical analysis All data were subjected to repeated measures ANOVA with Huynh-Feldt adjustment for nonsphericity (30). The ANOVA model included the sequence of studies as between-subjects factor, whereas test condition (Eu vs. Hypo) and time were the within-subjects factors. Subjects were entered in the model as random factors. Post hoc comparisons (Newman-Keuls test) were carried out to pinpoint specific differences on significant interaction terms. Data are given as means ± SE. We considered differences to be statistically significant if the P value was 0.05 or less. We conducted the statistical analyses by using NCSS 2007 software (NCSS, Kaysville, UT) (31).
Plasma glucose, glucose infusion rate, plasma C-peptide, and insulin concentrations (Figs. 1  and 2)
Plasma glucose was maintained at the preselected plateaus without any significant difference between detemir and human insulin in either euglycemic or hypoglycemic studies (Fig. 1
The glucose infusion rate was higher in euglycemia compared with hypoglycemia with both insulins (P < 0.001). The glucose infusion rate was lower with detemir vs. human insulin from time 30 to 105 min (P < 0.05) in euglycemic studies (Fig. 1  ) and from time 30 to 75 min (P < 0.05) in hypoglycemic studies (Fig. 1), but it was no different thereafter.
C-peptide was similarly suppressed with both detemir and human insulin, with a greater degree of suppression in hypoglycemia (95%) than euglycemia (55%) (P < 0.001). However, at time 60 min, C-peptide was slightly but significantly less suppressed with detemir compared with human insulin in both study conditions (P < 0.05) (Fig. 2
Plasma insulin concentrations were nearly 9-fold greater in the detemir as compared with the human insulin studies (Eu-HI, 83 ± 5.9 µU/ml; Eu-Det, 748 ± 52.2 µU/ml) (Fig. 2 Indeed, no formal direct comparison between serum insulin levels across the two insulin preparations was applied, given the expected higher concentrations of insulin detemir compared with human insulin.
Plasma counterregulatory hormones (Table 1
In euglycemic studies, no significant changes in plasma concentrations of any of the counterregulatory hormones both with detemir and human insulin were observed, with the notable exception of glucagon whose plasma levels decreased significantly (P < 0.05) from baseline to the end of studies without differences between the two insulins (Table 1
Conversely, during hypoglycemic studies, all counterregulatory hormones increased significantly compared with the control euglycemic studies, both with detemir and human insulin with nearly identical time profiles and magnitude of responses. However, plasma GH concentration showed a greater increase from baseline values in the Hypo-Det study, compared with the Hypo-HI study (Table 1 ). Plasma free fatty acid concentrations decreased significantly from baseline in euglycemia and hypoglycemia without any difference between detemir and human insulin studies in the level of suppression (P > 0.2, data not shown).
Plasma total IGF-I concentrations, IGFBP-1, and IGFBP-3 concentrations (Fig. 3
In euglycemic studies, plasma total IGF-I concentrations did not change from baseline without differences between the two insulins (P > 0.2; Fig. 3
Plasma IGFBP-1 levels were similar at baseline in all study conditions (Table 2 ). In euglycemic studies, during insulin infusion plasma IGFBP-1 levels exhibited a significant decrease from baseline at 120 min (P < 0.05; Fig. 3), the extent of which was comparable for both insulin infusions (P > 0.2). With the doubling of insulin infusion rates at 240 min, although plasma IGFBP-I concentrations tended to decrease through the end of studies, no further significant suppression was observed, compared with that showing at 120 min (P > 0.2), without any differences between the two insulins (P > 0.2; Fig. 3). In hypoglycemic studies, the changes over time in IGFBP-1 plasma levels during insulin infusion were not different from the corresponding changes in euglycemic studies (P > 0.2), without any differences between the two insulins (P > 0.2; Table 2).
Plasma IGFBP-3 concentrations, similar at baseline in all four clamps (Table 2
The present study was undertaken to compare the responses of plasma levels of IGF-I, IGFBP-1, and IGFBP-3 to hyperinsulinemia induced by equivalent doses, with respect to the glucose-lowering potency, of insulin detemir and human regular insulin in euglycemia and hypoglycemia. The results demonstrate that there are no significant differences between detemir and human insulin on circulating levels of IGF-I, IGFBP-1, and IGFBP-3 in either study condition. Thus, the long-acting insulin analog detemir does not differ from human insulin in modulating these specific components of the IGF axis, at least under the experimental conditions of the present studies. Two additional findings deserve further comments: the delay in plasma C-peptide suppression, and the greater plasma GH responses in hypoglycemia observed with detemir compared with human insulin. Although the former is likely due to the delayed equilibration and pharmacodynamic action of detemir compared with human insulin (24, 25, 26, 27), the reason for the differences in GH response is less clear. As a hypothesis, this might be linked to insulin detemir-induced modulation of neuroendocrine counterregulation due to an easier access of detemir to brain tissue (27). In this context, it is intriguing to speculate a potential role of detemir in modulating locally generated ghrelin within the hypothalamus (32), given the well-known clinical finding of a lower weight gain associated with insulin detemir compared with other basal insulin formulations, which would suggest a potential anorexigenic effect related to its higher brain insulin levels (24). The rationale for studying insulin detemir with respect to its effects on IGF-I axis relies on the structural alterations of its molecule. Insulin detemir differs from human insulin in two ways: 1) for the omission of the amino acid threonine at position B30 of the B chain; and 2) for the presence of a 14C fatty acid chain covalently bound to the B29 lysine residue. The fatty acid molecule allows the association with specific free fatty acid binding sites on albumin in the sc, intravascular, and extracellular compartments, developing an equilibrium between free and albumin-bound analog (24). Therefore, its long-acting profile is based on slow release from albumin, along with a strong self-association at the injection site (24). Compared with human insulin, insulin detemir has a lower affinity for insulin receptor (33). This leads to the need for greater insulin levels to attain a comparable metabolic potency to that of human insulin, which explains why insulin detemir is being marketed 4-fold more concentrated than human insulin (24). Still, the 4-fold concentrated insulin detemir does not match the metabolic effect of human insulin in normal subjects (25) and in subjects with type 1 diabetes (26), whereas in the present study, to have valid comparisons with human insulin given iv, it was necessary to double the doses of insulin detemir to achieve similar glucose-lowering biological effects. Consequently, the average insulin detemir requirements in intervention trials in type 1 and type 2 diabetes are greater than those of human NPH and glargine (24). For these reasons, insulin detemir exposes diabetic patients to greater plasma insulin concentrations than those of other basal insulin formulations. Hyperinsulinemia, a reflection of insulin resistance (34), may modulate several biological functions, such as glucose counterregulation and carcinogenesis (19, 35). With respect to the former, the greater plasma insulin detemir concentration elicits substantial differences in the physiological responses to hypoglycemia (27), a finding likely linked to the easier access to brain tissues by the acylated insulin detemir (36), which is more lipophilic than human insulin, although it remains to be established whether attributable to insulin detemir per se or to insulin detemir-induced hyperinsulinemia. Evidence is accumulating in favor of a possible role of insulin in modulating the risk of carcinogenesis. Indeed, insulin may promote carcinogenesis through two main pathways: one involving a direct activation of its own receptor, the receptors for IGF-I, or hybrid insulin/IGF-I receptors (19, 23); and the second via inhibition of IGFBPs, leading to an increased bioavailability of IGF-I to the IGF-I receptor (19). However, because insulin has a low affinity for IGF-I receptor and a negligible competition with IGF-I for binding to hybrid insulin/IGF-I receptors, a direct action at receptor sites is quite implausible, occurring only when insulin is present at supraphysiological concentrations or, alternatively, in case of major structural changes in its molecule, as for insulin analogs, that could alter the binding to and activation of specific receptors (32). On the other hand, the finding that elevated circulating levels of insulin may lead to increased IGF-I bioavailability, as a result of hyperinsulinemia-induced suppression in IGFBP concentrations, supports the hypothesis of insulin as indirectly promoting carcinogenesis through pathophysiological changes in concentrations of circulating IGF-I and IGFBPs (19). Ultimately, this hypothesis has provided the rationale for our project. To our knowledge, our study is the first report comparing the effects of insulin detemir with human insulin at equivalent biological potency on circulating IGF-I and IGFBP-1 levels in humans. Indeed, whereas in vitro studies have documented a lower affinity of insulin detemir for IGF-I receptor, along with a two times faster dissociation from insulin receptor compared with human insulin (32), no studies have addressed the role of insulin detemir on plasma IGF-I and IGFBP-1 in humans. A previous study (37) measured IGF-I and IGFBP-1 responses induced with insulin detemir during hypoglycemia in subjects with type 1 diabetes. The study did not indicate any significant difference between detemir and human insulin on the IGF-I axis outcomes evaluated, but the responses were examined only during a single plateau of hypoglycemia without performing euglycemic control, and hence bioequivalence of the two insulins was not ensured. A potential implication of IGFBP-1 in glucose counterregulation has been broadly debated, mostly in the past few years, although never conclusively demonstrated (18). In this regard, the role of IGFBP-1 has been specifically related to the prevention of hypoglycemia, likely arising from high plasma levels of free IGFs (18). Indeed during hypoglycemia after prolonged fasting (14), a typical rise of IGFBP-1 levels has been described, a finding that has been attributable not only to the low endogenous insulin secretion state, but also to the lower availability of substrates (38). Interestingly also, acute insulin-induced hypoglycemia has been reported to induce an increase in IGFBP-1 levels (17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39). At first glance, this may appear surprising given the exquisite sensitivity of IGFBP-1 to the inhibitory effects of insulin, although teleologically, the rise of IGFBP-1 in these conditions would be elicited to counteract the insulin-like effect of IGF-I. Of note, some investigators have also hypothesized a role of cortisol (16), whereas others have postulated that it is the suppression of endogenous insulin secretion after hypoglycemia that may trigger the rise in IGFBP-1 (39). Finally, glucagon, adrenaline, and noradrenaline may all stimulate IGFBP-1 production in vivo (18), thereby affecting IGFBP-1 levels during hypoglycemia. In the present study, there were no differences between euglycemia and hypoglycemia with regard to plasma IGFBP-1 levels, showing a similar suppression with both insulins. Certainly this may be due to the design of study where the high rates of insulin infusion achieved during the last hour could have likely masked any counterregulatory hormone-induced increase in plasma IGFBP-1. However, the aim of our study was not to investigate IGFBP-1 responses to insulin-induced hypoglycemia, but rather to look at potential differences between insulin detemir and human insulin with regard to IGF-I and IGFBP plasma levels under euglycemia and hypoglycemia. Potential limitations of the present study need to be taken into account. Indeed, we specifically examined a limited aspect, moreover in acute conditions, of a more complex issue—namely, whether the greater plasma insulin detemir concentrations may, through an increased bioavailability of IGF-I to IGF-I receptor, lead to different responses at the cellular levels. Indeed, our study does not give insight on potential effect of high levels of detemir itself on the IGF-I receptor or on IGF-I production, which is regulated among other things by insulin action and GH action on the liver; the latter point is of particular interest, given the greater GH responses observed in the present studies with insulin detemir compared with human insulin in hypoglycemia. We intended to study healthy nondiabetic subjects under standardized hyperinsulinemic-euglycemic and hypoglycemic clamp conditions because in normal subjects, IGF-I and IGFBP responses to insulin are not influenced by confounding factors such as the degree of glucose control and insulin deficiency, insulin doses, the presence of insulin resistance and its metabolic correlates, which conversely may come into play in subjects with diabetes. The insulin dose infused was relatively high, as from previous dose-response studies the insulin concentrations at which plasma IGFBP-1 resulted in half-maximal suppression were about 50 µU/ml (40). In this regard, it is worth noting that the plasma human insulin concentrations obtained were in the physiological range of the postprandial condition in humans (80 µU/ml), which corresponded to (higher) plasma detemir concentrations demonstrated to be bioequivalent in euglycemia. On the other hand, if we had chosen a lower rate of insulin infusions, it would have not been possible to compare the effects of the two insulins on IGFBP-1 responses, given the fact that bioequivalence of the two insulins would not have been reached. In addition, previous studies have used correspondent insulin infusion rates (39) or rates notably close (38) to ours. The insulin assay used in our study to measure serum insulin detemir concentration deserves several comments. First, it does not distinguish the albumin-bound from the free form, the latter accounting for 1–2% of circulating levels (24), thus measuring the total serum insulin detemir concentration. Moreover, the assay has a cross-reactivity of 100% with human insulin. Certainly in the framework of such high peripheral plasma insulin the contribution of endogenous insulin secretion is quite negligible; therefore the cross-reactivity with human insulin does not play a major role in determining total insulin levels. This also explains why plasma detemir concentrations did not show any differences between euglycemia and hypoglycemia. Free IGF-I was not measured in the present study due to the lack of a reliable commercial method. However, a unanimous agreement highlights the strong inverse correlation between free IGF-I and IGFBP-1 (1, 9, 10, 41). Low levels of free IGF-I are therefore presumed in the presence of high levels of IGFBP-1. Thus IGFBP-1 is considered an unequivocal "indirect" index of the free IGF-I. Finally, one should use caution to extrapolate from the experimental situation of the present study, which analyzes normal, nondiabetic subjects with iv infusion of insulin detemir in acute experimental conditions, to the clinical situation of diabetic subjects who receive therapeutic insulin doses of detemir as sc injections. In conclusion, the results of our study indicate that in healthy subjects, short-term hyperinsulinemia induced by insulin detemir and human insulin, at doses equivalent with respect to the glucose-lowering effect, elicit comparable effects on plasma levels of IGF-I and its binding proteins, IGFBP-1 and IGFBP-3. A longer term effect on IGF-I levels with insulin detemir cannot be ruled out, especially given the different GH responses during hypoglycemia with the two insulins. Moreover, whether similar responses would occur during ongoing treatment of subjects with insulin-treated diabetes requires additional study.
We deeply thank Dr. Angela Bertagna (University of Turin, Turin, Italy) for measuring plasma IGF-I, IGFBP-1, and IGFBP-3 concentrations.
This is an investigator-initiated trial performed without financial support from drug companies. It has received Juvenile Diabetes Research Foundation Grant 1-2005-176. Disclosure Summary: F.P., P.R., P.Ca., P.L., P.Ci., A.M.A., E.G., and C.G.F. have nothing to declare. G.B.B. has received honoraria for scientific advising and consulting from Sanofi-Aventis, Novo Nordisk, and Eli Lilly and Co. First Published Online May 26, 2009 Abbreviations: Eu-Det, Detemir insulin euglycemic clamp; Eu-HI, human insulin euglycemic clamp; Hypo-Det, detemir insulin hypoglycemic clamp; Hypo-HI, human insulin hypoglycemic clamp; IGFBP, IGF binding protein. Received December 31, 2008. Accepted May 19, 2009.
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Abstract
Introduction
human insulin euglycemic clamp (Eu-HI); 
, detemir insulin hypoglycemic clamp (Hypo-Det) 
