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The Journal of Clinical Endocrinology & Metabolism Vol. 89, No. 12 6305-6309
Copyright © 2004 by The Endocrine Society

Residual ß-Cell Function More than Glycemic Control Determines Abnormalities of the Insulin-Like Growth Factor System in Type 1 Diabetes

Christina A. Hedman, Jan Frystyk, Torbjörn Lindström, Jian-Wen Chen, Allan Flyvbjerg, Hans Ørskov and Hans J Arnqvist

Division of Internal Medicine (C.A.H., T.L., H.J.A.), Department of Medicine and Care and Division of Cell Biology (H.J.A.), Department of Biomedicine and Surgery, Diabetes Research Centre, Faculty of Health Sciences, Linkoping University, S-581 83 Linkoping, Sweden; and Medical Research Laboratories, Aarhus University Hospital (J.F., J.-W.C., A.F., H.Ø.), DK-8000 Aarhus, Denmark

Address all correspondence and requests for reprints to: Dr. Christina Hedman, Division of Internal Medicine, Department of Medicine and Care, Linkoping University, S-581 83 Linkoping, Sweden. E-mail: christina.hedman{at}lio.se.


   Abstract
Top
 Abstract
Introduction
 Patients and Methods
 Results
 Discussion
 References
 
The GH-IGF-I axis is disturbed in patients with type 1 diabetes. Our aim was to investigate whether abnormalities are found in patients in very good glycemic control and, if so, to estimate the role of residual ß-cell function. Patients with hemoglobin A1c (HbA1c) less than 6% (reference range, 3.6–5.4%) were selected for the study. Twenty-two men and 24 women, aged 41.3 ± 13.8 yr (mean ± SD), with a diabetes duration of 17.8 ± 14.6 yr participated. Healthy controls (15 women and nine men), aged 41.3 ± 13.0 yr, were also studied. Overnight fasting serum samples were analyzed for HbA1c, C peptide, free and total IGFs, IGF-binding proteins (IGFBPs), GH-binding protein, and IGFBP-3 proteolysis. HbA1c was 5.6 ± 0.5% in patients and 4.4 ± 0.3% in controls. Total IGF-I was 148 ± 7 µg/liter in patients and 178 ± 9 µg/liter in controls (P < 0.001). Free IGF-I, total IGF-II, IGFBP-3, and GH-binding protein were lower, whereas IGFBP-1, IGFBP-1-bound IGF-I, and IGFBP-2 were elevated compared with control values. Patients with detectable C peptide (≥100 pmol/liter) had higher levels of total IGF-I, free IGF-I, and total IGF-II and lower levels of IGFBP-1 and IGFBP-2 than those with an undetectable C peptide level despite having identical average HbA1c. IGFBP-3 proteolysis did not differ between patients and controls. Despite very good glycemic control, patients with type 1 diabetes and no endogenous insulin production have low free and total IGF-I. Residual ß-cell function, therefore, seems more important for the disturbances in the IGF system than good metabolic control per se, suggesting that portal insulin delivery is needed to normalize the IGF system.


   Introduction
Top
 Abstract
 Introduction
Patients and Methods
 Results
 Discussion
 References
 
PATIENTS WITH TYPE 1 diabetes show abnormalities in the GH-IGF system (1, 2, 3, 4, 5, 6). IGF-I mediates most of GH’s anabolic effects on muscle, skeleton, and other tissues (7). Local and circulating IGF-I and its binding proteins (IGFBPs) have been associated with the metabolic and vascular manifestations of diabetes as well as those of insulin resistance and atherosclerosis (8, 9, 10, 11, 12, 13).

Free and total IGF-I and IGFBP-3 levels are low in patients with type 1 diabetes, whereas circulating GH is increased (5, 6, 14). Low serum IGF-I levels despite high circulating GH levels indicate hepatic GH resistance. These abnormalities and the well established increase in IGFBP-1 are probably dependent on glycemic control and portal insulinopenia (6, 14, 15). However, it is not clear to what degree a low portal insulin level or hyperglycemia per se is the main actor in these abnormalities.

We recently reported that low serum total IGF-I levels in type 1 diabetes of 6 yr duration or more were not correlated to glycemic control, indicating that the abnormalities in the IGF system persist even if glycemic control is good (16). To further investigate this, the aim of the present study was to examine the IGF system in patients with excellent glycemic control. Therefore, we selected subjects with hemoglobin A1c (HbA1c) levels less than 6% during the preceding period. In 46 patients with type 1 diabetes, with or without endogenous insulin production, we examined the impact of glycemic control and C peptide levels on the circulating IGF system.


   Patients and Methods
Top
 Abstract
 Introduction
 Patients and Methods
Results
 Discussion
 References
 
Patients

Forty-six patients with type 1 diabetes, according to WHO criteria 1998 (17), and HbA1c less than 6% (reference range, 3.6–5.4%) recorded at the last previous visit to our out-patient clinic were recruited for the study. Twenty-two men and 24 women, aged 41.3 ± 13.8 yr (mean ± SD), with a body mass index of 24.4 ± 6.5 kg/m2, a duration of diabetes of 17.8 ± 14.6 yr (range, 4 months to 52 yr), and a present HbA1c of 5.6 ± 0.5% participated. For comparison, a nondiabetic control group of 24 subjects was included (nine men and 15 women). The background characteristics of the patients and the controls are given in Table 1Go. All patients were treated with multiple injection therapy or continuous sc insulin infusion. None of the patients had elevated serum creatinine levels, and only one patient had microalbuminuria (20–200 µg/min). Ten patients had background retinopathy, one had preproliferative retinopathy, and six had proliferative retinopathy. Four patients had polyneuropathy symptoms. Hypertension was found in seven patients, and cardiovascular disease was present in three patients. The study was performed according to the Declaration of Helsinki, and the protocol was approved by the local ethical committee. All patients gave their informed consent.


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  		TABLE 1. Characteristics of patients and controls

 
Methods

Patients and controls were admitted to our out-patient clinic at 0700–0900 h after an overnight fast. Height and body weight were measured. Blood samples were drawn from an antecubital vein. Plasma and serum samples were frozen at –70 C for additional analysis, whereas blood glucose and HbA1c were analyzed in unfrozen samples. HbA1c was analyzed using our hospital routine method (reference range, 3.2–5.4%). This method gives about 1% lower values than the Diabetes Control and Complications Trial method (18). Blood glucose was analyzed with HemoCue (HemoCue, Inc., Mission Viejo, CA). Serum total (extractable) IGF-I and IGF-II were determined with noncompetitive time-resolved immunofluorometric assays (TR-IFMAs) in acid-ethanol extracts, and serum free IGF-I was measured by ultrafiltration by centrifugation as previously described (19, 20). Total IGFBP-1 was determined by an in-house RIA performed as described by Westwood et al. (21) with modifications (22). IGFBP-2 was determined by a novel in-house TR-IFMA as recently described (22). The binary complex of IGF-I and IGFBP-1 was determined using a TR-IFMA specific for IGFBP-1-bound IGF-I (23). IGFBP-3 was measured with a commercial immunoradiometric assay (Diagnostic Systems Laboratories, Webster, TX) calibrated against recombinant nonglycosylated human IGFBP-3. Proteolysis of IGFBP-3 was determined as previously described (24). GH-binding protein (GHBP) was determined by an in-house TR-IFMA as previously described (25). All samples were analyzed in duplicate, with the exception of free IGF-I, which was analyzed in triplicate. Plasma free insulin was measured with a Mercodia Iso-Insulin ELISA (Mercodia AB, Uppsala, Sweden), a two-site enzyme immunoassay containing two monoclonal antibodies against insulin. Human insulin was used for the standard curve. The assay has 100% cross-reactivity with lispro and insulin aspart. C Peptide was measured with an ELISA (DakoCytomation, Ely, UK) based on two monoclonal antibodies against C peptide. The limit of detection of the C peptide assay is 100 pmol/liter. Intra- and interassay coefficients of variation for the method were both 5%.

Statistics

Statistical analyses were made using StatView 4.5 software (Abacus Concepts, Inc., Berkeley, CA). Results are given as the mean ± SD. Differences between groups were tested with ANOVA and unpaired t tests. P < 0.05 was considered statistically significant. Linear simple regression analysis and multiple regression analysis with total and free IGF-I as dependent factors were performed. All comparisons with IGFBP-1 were performed after log transformation due to a skewed distribution (right tail).


   Results
Top
 Abstract
 Introduction
 Patients and Methods
 Results
Discussion
 References
 
Comparison between patients with type 1 diabetes and nondiabetic control subjects

Age and body mass index did not differ between the groups, as shown in Table 1Go. Although the patients had a very good glycemic control with HbA1c of 5.6 ± 0.5% (range, 4.8–6.8%), it was significantly higher than in the controls (4.4 ± 0.3%; range, 3.9–4.8%; P < 0.001). Only patients with HbA1c less than 6% at the previous visit to the clinic were included in the study, but 13 of these patients had HbA1c between 6.0–6.8% at the time of the study. As expected, fasting C peptide was much lower in patients than in controls (Table 1Go). Free and total IGF-I were significantly lower in the patient group, whereas IGFBP-1 as well as IGFBP-1-bound IGF-I were elevated compared with control values. Total IGF-II, IGFBP-3, and GHBP were lower, but IGFBP-2 was elevated, compared with control values (Table 1Go). IGFBP-3 proteolysis was 42.7 ± 8.2% in the patients with type 1 diabetes and 42.9 ± 7.8% in the controls (not significantly different), implying that the comparison of IGFBP-3 measurements was reliable.

Comparison between patients with type 1 diabetes with detectable or undetectable C peptide and with normal or elevated HbA1c

To evaluate the importance of endogenous insulin secretion for the IGF system, the patient group was divided according to detectable or undetectable C peptide and also compared with the nondiabetic control group (Table 2Go). Patients with preserved endogenous insulin secretion (C peptide, ≥100 pmol/liter) had shorter diabetes duration, but there were no significant differences in age or HbA1c. The fasting blood glucose concentration was slightly lower in patients with detectable C peptide. There were several significant differences in the IGF system, as shown in Table 2Go. In fact, serum free and total IGF-I as well as total IGF-II levels were significantly lower in individuals with undetectable C peptide compared with individuals with detectable C peptide and controls, whereas differences in total IGF-I and IGF-II were not seen when comparing the two latter groups. GHBP was lower in patients with undetectable C peptide than in patients with detectable C peptide (P = 0.024, by unpaired t test).


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  		TABLE 2. Comparison of patients with undetectable C peptide (<100 pmol/liter), patients with detectable C peptide, and a control group

 
We also divided the patients into two groups according to glycemic control, one with normal (HbA1c, ≤5.4%) and one with elevated HbA1c (Table 3Go) and found no significant differences in total and free IGF-I concentrations or in other variables.


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  		TABLE 3. Comparison of patients with HbA1c within the normal range (3.2–5.4%), patients with slightly elevated HbA1c (>5.4%), and controls

 
Associations among total IGF-I, free IGF, age, and HbA1c in the patient group

Simple regression analysis showed no significant association between total IGF-I and HbA1c, C peptide, or plasma free insulin levels in the patient group (Table 4Go). However, a weak, but significant, association between free IGF-I and HbA1c (r = –0.29; P = 0.048) was found. There was a positive association between total IGF-I and free IGF-I with GHBP. We also found a positive association between total and free IGF-I (r = 0.68; P < 0.0001). There was a significant negative association between total IGF-I and age (r = –0.63; P < 0.001) as well as for IGF-I and duration of diabetes (r = –0.57; P < 0.001). No significant association was seen between age and free IGF-I (r = –0.23; P = 0.12), but free IGF-I was associated with duration of diabetes (r = –0.45; P = 0.002). In simple regression analysis, log IGFBP-1 was associated with C peptide, free IGF-I (Table 4Go), and fasting blood glucose. IGFBP-2 was associated with C peptide, free IGF-I, and total IGF-I (Table 4Go).


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  		TABLE 4. Associations of different variables in 46 patients with type 1 diabetes

 
In multiple regression analysis with total IGF-I as the dependent variable and including age, HbA1c, and categorized C peptide (detectable or undetectable C peptide) as independent variables, age (P < 0.001; standard coefficient, –0.60) and C peptide (P = 0.004; standard coefficient, 0.33) showed significant associations with total IGF-I. When adding diabetes duration as an independent variable to this analysis, there was still a significance for C peptide, but not for duration of diabetes. The above multiple regression analysis with free IGF-I as dependent variable including the dependent variables, age, HbA1c, and categorized C peptide was significant for HbA1c (P = 0.024; standard coefficient, –0.31) and C peptide (P = 0.010; standard coefficient, 0.36), whereas age was not significant. When diabetes duration was included in this model, only HbA1c remained statistically significant.


   Discussion
Top
 Abstract
 Introduction
 Patients and Methods
 Results
 Discussion
References
 
In the present study we investigated the circulating IGF system in patients with type 1 diabetes and very good glycemic control. Our results show that even in this group of patients, with either normal or slightly elevated HbA1c, total and free IGF-I levels were significantly lower than those in nondiabetic controls. This is the first study, to our knowledge, showing that patients with very good glycemic control have an abnormal circulating IGF system.

There is little information on the relationship between glycemic control and the IGF system in adults with type 1 diabetes, because most studies have focused on the relationship between the GH-IGF-I axis and growth in children and adolescents with diabetes. In one study of patients, aged 30–60 yr, with severely deranged diabetes, including diabetic ketoacidosis, plasma levels of IGF-I were low (26). Amiel et al. (3) reported that intensified insulin therapy in adolescents, aged 13–22 yr, improved metabolic control and increased total IGF-I levels. Attia et al. (27) showed that acute insulin withdrawal and the subsequent rise in blood glucose in C peptide-negative adults with type 1 diabetes resulted in modestly lowered total IGF-I levels and markedly suppressed free IGF-I. Tan and Baxter (4) found a negative correlation between HbA1c and total IGF-I only in younger patients, aged 21–40 yr, with type 1 diabetes, but not in older patients. In patients with type 1 diabetes and diabetes duration of 6 yr or longer, which indicates that the endogenous insulin secretion is very low or lacking, we found no correlation between IGF-I and HbA1c (16). In the present study there was no correlation between IGF-I and HbA1c, but a slight negative correlation was found between free IGF-I and HbA1c. It is conceivable that patients with undetectable C peptide have more pronounced glycemic excursions than patients with detectable C peptide even though they have the same HbA1c (28). There is, however, little information regarding the IGF system in relation to glycemic excursions in patients with good HbA1c levels. In one study in well controlled, C peptide-negative patients, total IGF-I levels were low and did not change during 24 h of hyperglycemia and unchanged insulinization (29). These results suggest little influence of glycemic control on the IGF system in patients with good metabolic control, whereas pronounced disturbances are found in severely decompensated type 1 diabetes.

In the present study we found that patients with undetectable C peptide had markedly lower free and total IGF-I levels than patients with detectable C peptide levels despite no significant difference in glycemic control or plasma free insulin. Accordingly, multiple regression analysis showed a significant correlation between detectable and undetectable C peptide and IGF-I. We measured endogenous insulin secretion as overnight fasting C peptide. It should be mentioned that there is a positive correlation between overnight fasting and stimulated C peptide levels in both type 1 and type 2 diabetes (30, 31). There are few data comparing IGF-I levels in C peptide-positive and -negative adults with type 1 diabetes. In one small study, patients with measurable C peptide were found to have a greater IGF-I response to GH treatment than patients with unmeasurable C peptide (32).

Under normal conditions, insulin is secreted from the ß-cells into the portal vein, and the liver cells are exposed to a several-fold higher insulin concentration than other tissues (33). In human liver, insulin regulates IGF-I and IGFBP-1 production (34) and probably also the number of GH receptors (35). In rat hepatocytes, insulin regulates IGFBP-2 (36, 37). In the diabetic state with absent ß-cells and sc insulin administration, liver cells are subjected to a relative hypoinsulinemia, which could explain most of the present findings, including high IGFBP-1 and -2 levels in patients with undetectable C peptide levels. Another finding that suggests a role for portal insulin is that ip insulin delivery has been shown to raise IGF-I levels compared with sc administration of insulin even if there is no change in HbA1c (15). Acutely restored insulin infusion in patients with type 1 diabetes in whom insulin was withheld for 12 h has also been shown to lower IGFBP-1 levels and elevate IGF-I levels (34).

GHBP, which is considered to reflect the number of GH receptors, was lower in patients compared with controls in agreement with previous studies (14, 38), and the group of patients with undetectable C peptide had lower levels than those with detectable levels, suggesting that endogenous insulin is of importance for GHBP levels. A positive correlation between GHBP and plasma insulin levels has been found by Kratzsch et al. (38) in patients with type 1 diabetes.

We found a strong correlation between free IGF-I and total IGF-I. Although free and total IGF-I are closely associated, they represent different entities. Free IGF-I levels in our patients with type 1 diabetes were low, in accordance with previous reports (39, 40), but in this study they did not correlate with age, in contrast to total IGF-I. IGFBP-1 is regulated within hours, whereas total IGF-I requires days to change (14). Free IGF-I is inversely correlated to IGFBP-1 and is considered to reflect bioactive IGF-I (19, 40).

The clinical consequences of low free and total IGF-I in diabetes are not clear. IGF-I mediates the anabolic effects of GH on skeleton and muscles (7). The reduction in especially free IGF-I, which increases with the disappearance of endogenous insulin, probably has consequences for the metabolic state as well as for the regeneration and repair of tissues. Patients with low circulating IGF-I levels due to GH deficiency are characterized by increased mortality attributable to cardiovascular diseases (41, 42).

In conclusion, the circulating IGF system exhibits several highly significant aberrations even in well controlled patients with type 1 diabetes and normal or slightly elevated HbA1c. These abnormalities are only weakly related to this long-term estimate of glycemic control. In contrast, they are dependent on the presence of residual ß-cell function, indicating that portal insulin delivery is required to normalize the IGF system.


   Footnotes
 
This work was supported by the Swedish Medical Research Council (Grant 4952), the Swedish Diabetes Association, Barndiabetesfonden and the County of Östergötland, the Danish Health Research Council, the Danish Diabetes Association and The Hørslev Foundation.

Abbreviations: GHBP, GH-binding protein; HbA1c, hemoglobin A1c; IGFBP, IGF-binding protein; TR-IFMA, time-resolved immunofluorometric assay.

Received March 26, 2004.

Accepted September 13, 2004.


   References
Top
 Abstract
 Introduction
 Patients and Methods
 Results
 Discussion
 References
 

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