The association of metabolic disorders with the metabolic syndrome is different in men and women.

AIMS: Metabolic disorders depend on genetic, hormonal and environmental factors, whose relations may differ between genders. Therefore, we compared the contribution of metabolic disorders to the metabolic syndrome in women and men. METHODS: To this end, we used a hierarchical classification statistical method to classify subjects into similarity groups according to clinical and biological parameters. Data were collected from 3,508 men and women aged 35-64 years, from a cardiovascular disease survey. RESULTS: In both women and men, hierarchical classification identified a cluster corresponding to the metabolic syndrome representing 14 and 15% of the women's and men's sample, respectively. In women, elevated body weight (women's Z-score: 1.59 vs. men's Z-score: 1.29; p < 0.005), waist girth (1.62 vs. 1.30; p < 0.001) and low HDL cholesterol (-0.95 vs. -0.75; p < 0.05) were significantly larger contributors to the metabolic syndrome than in men. In contrast, systolic (0.59 vs. 0.95; p < 0.0001) and diastolic (0.55 vs. 0.99; p < 0.0001) blood pressure and apolipoprotein B (0.51 vs. 0.71; p < 0.0001) contributed significantly less in women than in men. Finally, insulin (n.s.), glucose (n.s.), triglycerides (n.s.) and LDL-cholesterol (n.s.) contributions were not different between genders. CONCLUSION: These results are consistent with the concept that a clustering of metabolic disorders occurs frequently in both women and men. However, the contribution of several metabolic disorders to the metabolic syndrome is different in men and women. This finding supports the concept that different criteria are necessary to define the metabolic syndrome in women and men.

Evaluation of microcomputer nutritional teaching games in 1,876 children at school.

OBJECTIVE: We evaluated in a prospective study microcomputer nutritional teaching games and their contribution to the children's acquisition of nutritional knowledge and improvement of eating habits. MATERIAL AND METHODS: One thousand eight hundred seventy-six children aged 7-12 years took part in this study at school. All 16 schools of the same school district were randomized into two groups: games group and control group, both receiving conventional nutritional teaching by their teachers. The children in the games group played computer games during the conventional nutritional teaching period (2 hours a week for 5 weeks). At completion of the study, dietetic knowledge and dietary records were evaluated in both groups. RESULTS: Dietary knowledge tests results were better in the games group (p<0.001). The children in the games group had a significantly better balanced diet for an energy intake of about 1900 kilocalories: more carbohydrate (46.4 +/- 0.2% vs 45.7 +/- 0.2%, p<0.05), less fat (37.1 +/- 0.1% vs 37.6 +/- 0.2%, p<0.05), less protein (16.5 +/- 0.1% vs 16.7 +/- 0.1%, p<0.05), less saccharose (11.5 +/- 0.1% vs 12.2 +/- 0.2%, p<0.001), more calcium (p<0.001) and more fiber (p<0.05). The games group had a better snack at 10 a.m., a less copious lunch and less nibbling (p<0.001). CONCLUSION: The children in the games group had slightly but significantly better nutritional knowledge and dietary intake compared to children in the control group. Using our micro computer nutritional teaching games at school provides an additional and modern support to conventional teaching.

Impact of sulfonylurea receptor 1 genetic variability on non-insulin-dependent diabetes mellitus prevalence and treatment: a population study.

The high affinity sulfonylurea receptor 1 (SUR1) is involved in the metabolism of glucose in pancreatic beta-cells. We investigated the impact of the SUR1 intron 16-3t-->c polymorphism on non-insulin-dependent diabetes mellitus (NIDDM) prevalence in a large representative sample of French men and women, 35-64 years old, and explored potential relationships between the SUR1 intron 16 -t-->c polymorphism and sulfonylurea therapy efficiency. This study took place in Lille (northern), Strasbourg (eastern), and Toulouse (southern France). One hundred and twenty-two subjects with NIDDM were registered. We stratified NIDDM subjects according to their medical treatment: sulfonylureas (n = 70) versus other treatments (n = 50). From the three populations, a control group was selected (n = 1,250). Subjects carrying the cc intron 16 genotype had an increased risk of NIDDM [odds ratio (OR) = 1.76, 95% confidence interval (CI) 1.10-2.80; P = 0.017]. Subjects bearing at least one -3c allele and treated with sulfonylurea agents had fasting plasma triglyceride concentrations 35% lower than subjects that were tt homozygous (P = 0.026), whereas no difference could be detected between genotypes in NIDDM subjects treated with other treatments. The SUR1 intron 16 -3t-->c polymorphism was associated with an increased susceptibility to NIDDM in this population study, and seems to modulate the sulfonylurea therapy efficiency on hypertriglyceridemia reduction. This observation may help to better target the various therapies available for treatment of NIDDM.

Multicenter randomized evaluation of a nutritional education software in obese patients.

OBJECTIVE: To study the efficacy of the nutritional education software, Nutri-Expert, in the management of obese adult patients. MATERIAL AND METHODS: Two groups of obese patients were followed up over one year in a randomized study: the first group received close traditional management (seven nutritional visits over the year, with physicians and dietitians conjointly) and the second one also used at home by Minitel the Nutri-Expert system. 557 patients were enrolled in the study by 16 French centers of diabetology and nutrition. Body mass index (BMI), tests of dietetic knowledge, dietary records and centralized biological measurements were assessed at inclusion, 6 and 12 months. 341 patients were evaluable at the end of the year. RESULTS: The group using Nutri-Expert scored significantly better in the tests of dietetic knowledge than the control group. For all patients, nutritional education led to a significant improvement in BMI, dietary records and biological measurements, without significant difference between the two groups. Five years after the end of the study, the weight of 148 patients was recorded; mean BMI was significantly lower than the initial value but there was no significant difference between the two groups. CONCLUSION: In the management of obese patients, Nutri-Expert system has a role to play in reinforcing nutritional knowledge; if regular follow-up is not possible, or if a large series of obese patients is to be treated, Nutri-Expert could partly replace traditional management, for example between visits.

Comparison of continuous subcutaneous insulin infusion and multiple daily injection regimens using insulin lispro in type 1 diabetic patients on intensified treatment: a randomized study. The Study Group for the Development of Pump Therapy in Diabetes.

OBJECTIVE: To compare the efficacy of 2 intensified insulin regimens, continuous subcutaneous insulin infusion (CSII) and multiple daily injections (MDI), by using the short-acting insulin analog lispro in type 1 diabetic patients. RESEARCH DESIGN AND METHODS: A total of 41 C-peptide-negative type 1 diabetic patients (age 43.5+/-10.3 years; 21 men and 20 women, BMI 24.0+/-2.4 kg/m2, diabetes duration 20.0+/-11.3 years) on intensified insulin therapy (MDI with regular insulin or lispro, n = 9, CSII with regular insulin, n = 32) were included in an open-label randomized crossover study comparing two 4-month periods of intensified insulin therapy with lispro: one period by MDI and the other by CSII. Blood glucose (BG) was monitored before and after each of the 3 meals each day. RESULTS: The basal insulin regimen had to be optimized in 75% of the patients during the MDI period (mean number of NPH injections per day = 2.65). HbA1c values were lower when lispro was used in CSII than in MDI (7.89+/-0.77 vs. 8.24+/-0.77%, P<0.001). BG levels were lower with CSII (165+/-27 vs. 175+/-33 mg/dl, P<0.05). The SD of all the BG values (73+/-15 vs. 82+/-18 mg/dl, P<0.01) was lower with CSII. The frequency of hypoglycemic events, defined as BG levels <60 mg/dl, did not differ significantly between the 2 modalities (CSII 3.9+/-4.2 per 14 days vs. MDI 4.3+/-3.9 per 14 days). Mean insulin doses were significantly lower with CSII than with MDI (38.5+/-9.8 vs. 47.3+/-14.9 U/day. respectively, P< 0.0001). CONCLUSIONS: When used with external pumps versus MDI, lispro provides better glycemic control and stability with much lower doses of insulin and does not increase the frequency of hypoglycemic episodes.

Polymorphism of the 5' untranslated region of NHE1 gene associated with type-I diabetes.

The ubiquitous form of the sodium-hydrogen exchanger, NHE1, is devoted to the regulation of intracellular pH and cell volume. In addition, NHE1 activity is stimulated by growth factors and increased NHE rates are found in both circulating and immortalized cells during diabetes or diabetic nephropathy. In this context, we searched for polymorphisms of the 5'-flanking regulatory region of NHE1 gene in subjects with type-I diabetes. We identified a C/T transition 696 bases upstream the translation initiation start site which disrupts a repeated palindromic GC sequence. The TT genotype was significantly more frequent in type-1 diabetics and may have functional importance. Genetic linkage between NHE1 and diabetes has been previously described in NOD mice strains with consequences on NHE rates. Hence, the polymorphism described hereby may act as a predisposition factor to type-I diabetes or to diabetic complications, and may be useful to investigate the genetic involvement of NHE1 in human pathophysiology.

Normal reproductive function in leptin-deficient patients with lipoatropic diabetes.

To further examine the relationships between leptin and female reproductive axis, we conducted hormonal studies in two patients with lipoatropic diabetes that occurred before puberty. Despite complete atrophy of sc and visceral adipose tissue, menarche occurred in these two patients between 11-12 yr of age, followed by regular menstrual cycles. One patient had been pregnant three times, giving birth to children who did not develop the disease. In our two patients, repeated analysis revealed leptin levels below 1 ng/mL (normal range for 20 insulin-treated diabetic women, 2-23 ng/mL for body mass index of 14-39 kg/m2; personal data). We measured peripheral levels of estradiol, progesterone, FSH, LH, free testosterone, and androstenedione within the first 5 days of the menstrual cycle, and we tested the reactivity of pituitary after iv injection of 100 microg GnRH. The variation in body temperature in the morning before arising was also analyzed. We showed that 1) all measured levels of hormones were in the normal range for both patients; and 2) low levels of leptin did not impair the development of reproductive function in one patient and was associated with normal gonadal function in both patients. We conclude that puberty and fertility can occur despite chronic low serum levels of leptin. This suggests that leptin is not fundamental to the maintenance of normal reproductive function in humans.

Contrasting renal functional reserve in very long-term Type I diabetic patients with and without nephropathy.

AIMS: This study was to determine whether renal functional reserve (RFR) is present in patients who have suffered long-lasting Type I (insulin-dependent) diabetes mellitus. METHODS: Renal functional reserve was elicited by a 3-h amino acid infusion (4.5 mg x kg(-1) x min(-1)) in 10 patients with nephropathy (DN+) and 10 patients without nephropathy (DN-) who had lived with diabetes for 24 +/- 3 and 27 +/- 3 years, respectively and in 15 healthy control subjects. Renal functional reserve was calculated as the difference between amino acid-stimulated and baseline glomerular filtration rates (GFR). RESULTS: Baseline glomerular filtration rate in DN- patients (106 +/- 8) and control subjects (112 +/- 3 ml x min(-1) x (1.73m2)(-1)) was significantly higher (p < 0.01) than in DN+ patients (79 +/- 7 ml x min(-1) x (1.73m2)(-1)). Renal functional reserve was absent in DN+ patients, whereas it represented 26 +/- 4% of the baseline in DN- patients and 23 +/- 2% in control subjects. Renal vascular resistance decreased statistically significantly during amino acid infusion in DN- patients and control subjects but not in DN+ patients. CONCLUSIONS/HYPOTHESIS: These results indicate that very long-term Type I diabetic patients without diabetic nephropathy still have a normal renal functional reserve. In contrast, this reserve is suppressed in similarly long-term macroalbuminuric and hypertensive patients with overt nephropathy in spite of their remarkably maintained glomerular filtration rate. This opposite impairment supports the interpretation that glomerular hyperfiltration is a determining mechanism in human diabetic nephropathy.

GH deficiency in adults: an epidemiological approach.

OBJECTIVE: The prevalence of adult onset GH deficiency (GH-D) is poorly documented. Epidemiological data are now required to estimate the financial cost of GH treatment in adults. The aim of the present study was to estimate the prevalence of GH-D, from a cohort of 1652 adult patients with hypothalamo-pituitary diseases. DESIGN: The hormonal status of all patients presenting with pituitary diseaseand observed during the year 1994 in 15 endocrine units was retrospectively analyzed, irrespective of the date of disease onset, of the nature and date of pituitary investigations, and whether or not they included specific testing of the GH axis. Of the whole population of 1652 patients, a selected group (RG2) was chosen after exclusion of patients with active acromegaly (n=1414). RESULTS: GH stimulation tests had been performed in 549 patients of the RG2 group and a documented GH-D was found in 301. A relationship between the value of the GH peak and the number of pituitary deficits was evaluated. For instance, it was shown that 93% of patients with three deficits had GH-D. These results constituted the basis for estimating the number of GH-D in the group of untested patients. The number of GH-D deduced from the number of established GH-D (n=301) and from the number of GH-D hypothesized from other pituitary deficits (n=406) was 707 cases. Prevalence and annual incidence were calculated from data recorded in a referral center with a well-defined catchment area, Marseilles (Bouches du Rhône department). We projected a prevalence of 2638 for France and an annual incidence of 12 GH-D per million of the adult population.

GH replacement in 1034 growth hormone deficient hypopituitary adults: demographic and clinical characteristics, dosing and safety.

OBJECTIVE: Long-term experience of growth hormone (GH) replacement therapy in a large population of hypopituitary adults with GH deficiency (GHD) is limited, and safety surveillance is clearly essential. KIMS, the Pharmacia & Upjohn International Metabolic Database, is a long-term, open, outcomes research programme of hypopituitary adult patients with GHD who are treated in a conventional clinical setting. PATIENTS: The present analysis encompasses data from 1034 hypopituitary adult GHD patients treated with GH for a total of 818 patient years. RESULTS: Prior to GH therapy, the KIMS patient population exhibited an increased prevalence of obesity, diabetes mellitus (in females) and hyperlipidaemia, compared with normal populations described in published studies. Quality of life, assessed using a disease-specific questionnaire (QoL-AGHDA), was also reduced in KIMS patients. The maintenance dose of GH was significantly higher in patients who were receiving GH prior to enrolment into KIMS (non-naive patients) compared with patients who commenced GH at the time of enrolment (naive patients). In addition, dose of GH correlated significantly with body weight in the former group of patients. Analysis of serum levels of IGF-I indicated that overtreatment with GH was markedly more common in non-naive than in naive patients. The frequency of adverse events in KIMS patients was no higher than that reported in patients receiving placebo in previous clinical trials. Recurrence of pituitary or CNS tumours was reported in six patients, a rate consistent with data from control series. Three deaths were reported, none of which was obviously associated with GH treatment. CONCLUSIONS: Our data, drawn from a large population of hypopituitary adults treated with GH for a total of more than 800 patient years, confirm previous reports that untreated GHD in hypopituitary adults is associated with a number of important clinical problems. In addition, the results suggest that there has been a shift in recent years from determination of GH dose on the basis of body weight to dose titration of individual patients, and indicate that the latter technique has important advantages. The data provide further evidence that GH replacement therapy is well-tolerated in adults. However, it is possible that some adverse events may not become evident over the time scale covered by the present analysis, and continued surveillance therefore remains mandatory.

[Oral antidiabetic drugs]. / Médicaments antidiabétiques oraux.

Type II diabetes includes various pathophysiologic entities. Glycoregulatory disorders are due to multiple mechanisms, associated to different degrees. Identical response to treatment is not observed among patients or at different times of treatment, early or later in the disease. Until very recently, the treatment available was insufficient. It now has gained new classes of drugs that act on the secretion of insulin, the sensitivity to insulin and the rate of intestinal glucide absorption. Approaches to treatment are often complementary and oral antidiabetic drugs can be associated. Hygienic and dietary measures remain indispensable to reinforce drug efficacity and to prevent complications in these patients.

Improvement of HbA1c and blood glucose stability in IDDM patients treated with lispro insulin analog in external pumps.

OBJECTIVE: To compare the efficacy of the short-acting insulin analog lispro (LP) with that of regular insulin in IDDM patients treated with an external pump. RESEARCH DESIGN AND METHODS: Thirty-nine IDDM patients (age, 39.4 +/- 1.5 years; sex ratio, 22M/17W; BMI, 24.4 +/- 0.4 kg/m2; diabetes duration, 22.5 +/- 1.6 years) who were treated by external pump for 5.1 +/- 0.5 years were involved in an open-label, randomized, crossover multicenter study comparing two periods of 3 months of continuous subcutaneous insulin infusion with LP or with Actrapid HM, U-100 (ACT). Boluses were given 0-5 min (LP) or 20-30 min (ACT) before meals. Blood glucose (BG) was monitored before and after the three meals every day. RESULTS: The decrease in HbA1c was more pronounced with LP than with ACT (-0.62 +/- 0.13 vs. -0.09 +/- 0.15%, P = 0.01). BG levels were lower with LP (7.93 +/- 0.15 vs. 8.61 +/- 0.18 mmol/l, P < 0.0001), particularly postprandial BG levels (8.26 +/- 0.19 vs. 9.90 +/- 0.20 mmol/l, P < 0.0001). Standard deviations of all the BG values (3.44 +/- 0.10 vs. 3.80 +/- 0.10 mmol/l, P = 0.0001) and of postprandial BG values (3.58 +/- 0.10 vs. 3.84 +/- 0.10 mmol/l. P < 0.02) were lower with LP. The rate of hypoglycemic events defined by BG < 3.0 mmol/l did not significantly differ between LP and ACT (7.03 +/- 0.94 vs. 7.94 +/- 0.88 per month, respectively), but the rate of occurrences of very low BG, defined as BG < 2.0 mmol/l, were significantly reduced with LP (0.05 +/- 0.05 vs. 0.47 +/- 0.19 per month, P < 0.05). At the end of the study, all but two (95%) of the patients chose LP for the extension phase. CONCLUSIONS: When used in external pumps, LP provides better glycemic control and stability than regular insulin and does not increase the frequency of hypoglycemic episodes.

Renal functional reserve in IDDM patients.

The aim of this study was to determine whether renal functional reserve (RFR) is altered in insulin-dependent diabetic (IDDM) patients according to the stage of diabetic nephropathy. RFR was examined in 33 IDDM patients in similar glycaemic and metabolic control and compared to 12 healthy control subjects, during eight 1 h clearance periods prior to, during and after a 3-h stimulation by amino acid infusion (4.5 mg x kg(-1) x min[-1]). RFR was calculated as the difference between stimulated and baseline glomerular filtration rates (GFR). In 14 early normotensive diabetic patients with normal urinary albumin excretion, mean baseline GFR (133 +/- 3 ml x min(-1) x 1.73 m[-2]) was higher whereas RFR (10 +/- 4 ml x min(-1) x 1.73 m[-2]) was lower (p < 0.05) than in control subjects (113 +/- 4 and 28 +/- 2 ml x min(-1) x 1.73 m(-2), respectively). In 10 normotensive patients who had lived with IDDM for 16 years and who had microalbuminuria, baseline GFR and RFR (109 +/- 7 and 24 +/- 6 ml x min(-1) x 1.73 m(-2), respectively) were similar to those in control subjects. In 9 patients who had suffered IDDM for 23 years and had developed macroalbuminuria and hypertension, baseline GFR (78 +/- 8 ml x min(-1) x 1.73 m[-2]) was lower than in control subjects (p < 0.05) and RFR (8 +/- 4 ml x min(-1) x 1.73 m[-2]) was not significant. In addition, renal vascular resistance decreased significantly during infusion (p < 0.05) in microalbuminuric normotensive patients as well as in control subjects (by 9 +/- 4 and 11 +/- 4 mmHg x l(-1) x min(-1) x 1.73 m(-2), respectively) but not in normoalbuminuric normotensive or macroalbuminuric hypertensive patients. These results indicate that microalbuminuric normotensive patients retain a normal RFR, whereas RFR is reduced or suppressed at two opposite stages of the disease: in normoalbuminuric normotensive patients with a high GFR and in macroalbuminuric hypertensive patients with a decreased GFR. This dissimilar impairment reveals permanent glomerular hyperfiltration in both early IDDM without nephropathy and IDDM with overt diabetic nephropathy, but not in IDDM with incipient nephropathy.

[The insulin analog, Humalog, in discontinuous: from pharmacology to clinical use]. / L'analogue de l'insuline, Humalog, en injections discontinues: de la pharmacologie a la clinique.

Humalog is the first analog of human insulin to be evaluated on a large scale in clinical conditions by discontinuous subcutaneous administration. Eight international multicentric studies have investigated the efficacy and tolerance of Humalog in protocols with 3 daily insulin injections (3 preprandial injections of Humalog associated with 1 or 2 injections of Umuline NPH or Umuline Zinc). A total of 2834 patients participated in these studies, including 2,277 who used Humalog. In addition to these trials, more than 5,000 patients had used Humalog by 1996, in some cases for more than 3 years. In insulin-dependent diabetes (IDDM), glycaemic control at the time of inclusion of patients in these protocols, as evaluated by HbA1C, was generally moderate (8 to 9%) despite 3 daily injections. This did not constitute intensive care since basal insulin for half of these patients was ensured by only a single daily injection. In these conditions, the results obtained showing significant postprandial improvement in glycaemic control and a significant reduction of the number of hypoglycaemic episodes, particularly at night, are important even though HbA1C levels were not significantly decreased. In a more recent crossover study (1996), 199 well-controlled IDDM patients (HbA1C = 7.3%) were treated intensively by multiple injections. The number of severe hypoglycaemic episodes with coma was only one-fifth that of the group treated by Humalog (equivalent to a reduction of 26 comas per 100 patients/year) in the absence of any significant modification of HbA1C. No differences were noted for lipids, adverse side effects or severe events (except hypoglycaemic episodes) and immunogenicity. In non-insulin-dependent diabetes, the results were similar but less impressive concerning the improvement in postprandial glycaemic control and the reduction in hypoglycaemic episodes. In addition to the significant results obtained in these studies, Humalog was favoured by the vast majority of patients. It is likely that Humalog will allow intensified treatment of diabetes in very favourable conditions, and that more patients will achieve the difficult goal of normalising glycaemia. However, a single injection of NPH or prolonged insulin is not sufficient for that purpose. Two daily injections will generally be necessary.

[Quality of life and non-insulin-dependent diabetes]. / Qualité de vie et diabète non-insulino-dépendant.

In diabetes, the links between long-term complications and chronic hyperglycaemia and the risk of hypoglycaemia during intensive treatment have been well-documented. However, the potential short- or long-term benefits of glycaemic control on quality of life and cognitive functions have generally been reported as minimal or nil. Patients do not perceive the connection between better glycaemic control and quality of life. The potential advantages of Ozidia, whether in terms of glycaemic control, tolerance or ease of use, suggest that this treatment may provide improved quality of life. Two studies have investigated this possibility. The first, carried out over a 16-week period in the United States, was a randomised double-blind Ozidia vs placebo study in 594 non-insulin-dependent (NIDDM) diabetic patients to evaluate the respective influences of glycaemic control, symptoms of hyperglycaemia and side-effects of treatment on quality of life. The results were important, indicating a decrease in short-term clinical symptoms and an improvement in the quality of life, in correlation with decreased HbA1C. The quality of life of NIDDM patients can be improved by stricter glycaemic control, and thus can modify in the choice of therapeutic strategies and cost-benefit evaluation of intensive glycaemic control. The second study now under way in France concerns an evaluation of the quality of life of NIDDM patients before and after treatment with Ozidia. More than 600 diabetologists are involved, and the study should include 1,500 patients. The purpose is to show that Ozidia effectively improves quality of life by encouraging treatment compliance and improving treatment effectiveness. Thanks to self-monitoring of glycaemia, patients can measure the efficacy of their treatment regularly at various times of the day. A dose 5 to 15 mg/day of Ozidia is administered in this open 12-week study. The results will not be available before the end of 1997.

Effect of intraperitoneal insulin delivery on growth hormone binding protein, insulin-like growth factor (IGF)-I, and IGF-binding protein-3 in IDDM.

Low plasma insulin-like growth factor (IGF)-I despite high circulating growth hormone (GH) in insulin-dependent diabetes mellitus (IDDM) indicate a hepatic GH resistance. This state may be reflected by the reduction of the circulating GH binding protein (GHBP), corresponding to the extracellular domain of the GH receptor, and the reduction of insulin-like growth factor binding protein (IGFBP)-3, major IGF-I binding protein, upregulated by GH. We carried out two studies. In the first, plasma GHBP activity was compared in patients with IDDM on continuous subcutaneous insulin infusion (CSII) or on conventional therapy and in healthy subjects. In the second study, the 18 patients on CSII at baseline were then treated by continuous intraperitoneal insulin infusion with an implantable pump (CPII) and prospectively studied for GH-IGF-I axis. Although HbA1c was lower in patients on CSII than in those on conventional therapy, GHBP was similarly reduced in both when compared to control subjects (10.2 +/- 0.8 and 11.6 +/- 0.9% vs 21.0 +/- 1.3, p < 0.01). CPII for 12 months resulted in: a slight and transient improvement in HbA1c (Time (T)0: 7.6 +/- 0.2%, T3: 7.1 +/- 0.2%, T12: 7.5 +/- 0.2%, p < 0.02), improvement in GHBP (T0: 10.2 +/- 0.8%, T12: 15.5 +/- 1.5, p < 0.0001), near-normalization of IGF-I (T0: 89.4 +/- 8.8 ng/ml, T12: 146.9 +/- 15.6, p < 0.002) and normalization of IGFBP-3 (T0: 1974 +/- 121 ng/ml, T12: 3534 +/- 305, p < 0.0001). The hepatic GH resistance profile in IDDM does not seem to be related to glycaemic control, but partly to insufficient portal insulinization. Intraperitoneal insulin delivery, allowing primary portal venous absorption, may influence GH sensitivity, and improve hepatic IGF-I and IGFBP-3 generation.

Insulin therapy and GH-IGF-I axis disorders in diabetes: impact of glycaemic control and hepatic insulinization.

In Type 1 diabetes, high circulating growth hormone (GH) in conjunction with low plasma insulin-like growth factor-I (IGF-I) is indicative of a hepatic GH-resistance profile since the liver is the main source of circulating IGF-I. The reduction in specific growth hormone binding protein (GHBP), corresponding to the extracellular domain of the GH receptor, provides an indirect indication of the hepatic density of GH receptors, as does the reduction in IGFBP-3, the major IGF binding protein, which is GH-dependent. Type 1 diabetes is also associated with high levels of IGFBP-1, a binding protein down-regulated by insulin. Although most of these abnormalities have been described in situations of poor glycaemic control, hyperglycaemia does not seem to be the predominant factor in their pathogenesis. Even intensified subcutaneous insulin therapy does not normalize GH, IGF-I, GHBP and IGFBP-3 plasma levels. Some indirect evidence suggests that portal insulinopenia plays a role in the hepatic GH-resistance profile of Type 1 diabetes, i.e. discrepancies between the abnormalities reported in Type 1 and Type 2 diabetes, and the inverse relationship between residual insulin secretion in Type 1 diabetes and some of these abnormalities. Intraperitoneal insulin therapy administered to Type 1 diabetic patients by implantable pumps (without modification of glycaemic control) can improve GHBP activity, practically normalize plasma IGF-I and normalize IGFBP-3. The improvement in GH-IGF-I axis disorders obtained with intraperitoneal insulin therapy (which allows primary portal insulin absorption) provides direct evidence of the central role of portal insulin in the regulation of this system.