Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0011854 (type 1 diabetes)
 20,749 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Leptin circulates in serum bound to high molecular weight proteins. Hypothesizing that leptin binding proteins may regulate the functional efficiency of leptin, we characterized auxologic and hormonal factors that influence leptin binding in three disparate groups: normal adolescents, obese children, and teenagers with type I diabetes mellitus (IDDM). Specific leptin binding activity (sLBA) was assessed by column chromatography after incubation of serum with 125I-leptin in the presence and absence of excess unlabeled leptin. Mean sLBA was 17.0 +/- 7% (SD) in the healthy adolescents (n=41), 6.6 +/-4.3% in the obese children (n=26), and 14.9 +/-7.3% in the diabetic teenagers (n=17). At any value of sLBA, obese children had higher serum leptin levels than non-obese adolescents or diabetic teenagers, consistent with "leptin resistance" in the obese group. sLBA was higher in males than in females only in those with diabetes (18.6 +/- 7.3 vs 10.9 +/- 5.1%, p<0.05). sLBA correlated inversely with serum insulin-like growth factor-I values in the normal group (r= -0.45, p<0.01) and with insulin in the obese children (r= -0.53, p<0.01). There was no correlation between sLBA or serum leptin values and HbA1c, in the diabetic group. The serum leptin concentration was the principal determinant explaining the total variability of sLBA in all three cohorts. However, body mass index (BMI = weight/ height2) accounted for more of the total variability of percent specific binding in the healthy adolescents than in the other groups. We conclude that sLBA reflects circulating leptin levels, body composition, and hormonal milieu. Thus, in addition to leptin, qualitative and quantitative characteristics of leptin binding may play a physiological role in the regulation of appetite and in the "leptin resistance" of obesity.
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PMID:Leptin binding activity (LBA) in plasma of nondiabetic and diabetic adolescents and obese children: relation to auxologic and hormonal data. 1071 58

Insulin-like growth factor-I (IGF-I) enhances insulin action in normal subjects and in patients with both type 1 and 2 diabetes; however, its administration is associated with significant side effects in a high percentage of patients. The coadministration of IGF binding protein-3 (IGFBP-3, the predominant IGF binding protein in serum) with IGF-I limits IGF-I inducible side effects, but it does not attenuate the ability of IGF-I to enhance protein synthesis and bone accretion; therefore, we determined whether IGF-I/IGFBP-3 would retain biological activity in type 1 DM and limit side effects associated with free IGF-I administration. Twelve patients received recombinant human IGF-I plus IGFBP-3 (2 mg/kg-day) by continuous sc infusion for 2 weeks. Each subject served as his own control; and, during a paired 2-week period, each received a placebo infusion. The order of the treatments was randomized. Subjects were placed on a constant caloric intake but were allowed to adjust insulin doses to maintain appropriate levels of glycemic control. Subjects measured blood glucose four times per day at home and kept a log of their insulin use. Frequent sampling for glucose, insulin, and GH was conducted during four inpatient study periods, one at the beginning and one at the end of each 2-week study interval. During IGF-I/IGFBP-3, insulin doses were reduced by 49%, and mean serum glucose was reduced by 23%. Free insulin levels obtained during frequent sampling in hospital fell 47% on IGF-I/IGFBP-3, compared with control, but showed no change with placebo. Concomitant glucose measurements did not differ in the two treatment groups. There was no change in body weight. Fructosamine levels decreased by 12%, but this was not significant (P < 0.1). Fasting triglyceride was unchanged, but cholesterol declined from 170 +/- 24 to 149 +/- 31 mg/dL (P < 0.05). IGFBP-2 (an IGF-I-dependent responsive variable) rose from 141 +/- 56 to 251 +/- 98 ng/mL (P < 0.01) on IGF-I/IGFBP-3. To analyze the mechanism by which IGF-I/IGFBP-3 might reduce insulin requirements, the change in serum GH was quantified. Mean GH levels were reduced by 72%, from 2.48 to 0.55 ng/mL (P < 0.001). An equal number (40%) of drug- and placebo-treated subjects had minor hypoglycemic episodes at home that required adjustment of insulin doses. No episode was classified as severe. In contrast to previous studies with free IGF-I, there were no cases of edema, headache, jaw pain, retinal edema, or Bell's palsy. No subject withdrew because of drug complications. These findings indicate that IGF-I/IGFBP-3 is biologically active on carbohydrate metabolism, as measured by a decrease in insulin requirements in patients with type 1 diabetes. Further studies will be required to determine the long-term safety and efficacy of this combination in patients with insulin resistance and diabetes.
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PMID:The combination of insulin-like growth factor I and insulin-like growth factor-binding protein-3 reduces insulin requirements in insulin-dependent type 1 diabetes: evidence for in vivo biological activity. 1077 Jan 91

Diabetes mellitus and glucose dysregulation have significant effects on the circulating level of insulin-like growth factor-I (IGF-I) and IGF binding proteins (IGFBPs). In the present study, serum and urine IGFBP (IGFBP-1, -2, and -3) and serum IGF-I and -II levels were measured by radioimmunoassay (RIA) in 27 patients with type 1 diabetes aged 9 to 48 years compared with 9 healthy subjects aged 10 to 28 years. The patients were divided into 3 groups according to the amount of albumin excreted in 24 hours. The macroalbuminuria group (>500 mg/24 h) had elevated serum IGFBP-1 and -2 and decreased IGF-I levels (P < .01 v normal controls). Serum IGFBP-3 and IGF-II were not different among the patient groups and controls (P > .05). The mean urinary IGFBP-1 was decreased in all 3 patient groups compared with the controls (P < .05). Urinary IGFBP-2 and IGFBP-3 were increased in patients with macroalbuminuria. Immunoblot analysis showed increased low-molecular-weight fragments of urinary IGFBP-2 in the poorly controlled diabetics, and direct evidence for increased urinary IGFBP-2 proteolytic activity could be demonstrated in both the microalbuminuric and macroalbuminuric groups. Low-molecular-weight fragments of urinary IGFBP-3 were also increased in both the microalbuminuric and macroalbuminuric groups. In conclusion, alterations of IGFBPs in urine and serum are related to metabolic control in diabetic patients, and there is an increase of urinary IGFBP-2 protease activity in poorly controlled diabetics. The changes in serum IGFBP concentrations (eg, increases in IGFBP-1 and IGFBP-2) may lead to alterations in the availability of IGF-I to peripheral tissues.
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PMID:Insulin-like growth factor binding proteins (IGFBPs) in serum and urine and IGFBP-2 protease activity in patients with insulin-dependent diabetes mellitus. 1083 Nov 74

It has been hypothesized that a decreased amount of the free form of insulin-like growth factor-I (fIGF-I) results in morning hyperglycemia in patients with type 1 diabetes mellitus. In this study, we attempted to clarify the role of fIGF-I in relation to total IGF-I (tIGF-I) and its related peptides or proteins in type 1 diabetes. Forty-seven patients with type 1 diabetes, mean age 13.7 years, were evaluated. Blood samples were obtained for the measurement of BG at 0200, 0400 and 0700, and of insulin, total IGF-I (tIGF-I), fIGF-I, IGFBP-1 and IGFBP-3 at 0700. The SD scores (SDS) were determined for the levels of tIGF-I, flGF-I, IGFBP-1 and IGFBP-3 by using Japanese reference data. The morning increase in BG (deltaBG(4-7)) correlated significantly with fIGF-I SDS (r=-0.352, p=0.0152) and IGFBP-1 SDS (r=0.438, p=0.0021), but did not correlate significantly with the fIGF-I level itself or the ratio of fIGF-I to tIGF-I (f/t IGF-I ratio). Hereupon, the f/t IGF-I ratio correlated positively with fIGF-I SDS (r=0.541, p=0.0003). The mean+/-SD in the f/t IGF-I ratio was 0.94+/-0.43%, and that in fIGF-I SDS was -0.50+/-1.32. The level of IGFBP-I SDS correlated negatively with fIGF-I SDS (r=-0.472, p=0.0008) and insulin (r=-0.365, p=0.0116). We suggest that the morning level of fIGF-I SDS, rather than the fIGF-I level itself, may be a useful marker of decreased insulin-like bioactivity in the dawn phenomenon in type 1 diabetes mellitus.
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PMID:A role of free insulin-like growth factor-I in dawn phenomenon in children and adolescents with type 1 diabetes mellitus. 1089 Jan 93

Hyperglycaemia and increased variability of blood glucose in pubertal children with type 1 diabetes may be related to increased growth hormone (GH) secretion and insulin resistance. The role of changes in insulin-like growth factor-I (IGF-I) bioavailability for the glycaemic control in these patients has not been completely elucidated. In particular, the possible role of increased IGF binding protein-3 (IGFBP-3) proteolysis reported in other insulin resistant states awaits further characterization. The aims of this study were to assess if hyperglycaemia in children with type 1 diabetes was associated with changes in free dissociable IGF-I (fdIGF-I) and IGF binding protein-3 protease activity (IGFBP-3-PA) and if increased insulin resistance during puberty was associated with changes in IGFBP-3-PA in healthy and diabetic children. In diabetic boys in the period of maximal linear growth (Tanner stage 3, n = 5), the mean level and the variability of IGFBP-3-PA, determined every second hour throughout 24 h, were significantly higher both compared to postpubertal diabetic boys (n = 6; P = 0.003 and P = 0.001, respectively), and to age matched healthy boys (n = 4; P = 0.006 and P < 0.001 respectively). This activation of IGFBP-3-PA was most prominent during the day time. The mean 24 h blood glucose level (determined hourly) was the only parameter studied that significantly predicted the changes in mean 24 h IGFBP-3-PA in the diabetes group. The mean 24 h concentrations of fdIGF-I were decreased in the diabetic boys compared to the healthy controls but statistical significance was only achieved in Tanner Stage 5 (p = 0.03). We speculate that the elevated levels of IGFBP-3-PA in Tanner 3 diabetic boys are related to deteriorated glucose homeostasis and that it may be a compensatory mechanism to attenuate the decrease in fdIGF-I in order to partly restore insulin sensitivity and glycemic control.
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PMID:Increased 24 h mean insulin-like growth factor binding protein-3 proteolytic activity in pubertal type 1 diabetic boys. 1116 63

Type 1 diabetes mellitus (DM) is a disease of insulin deficiency, resulting from the autoimmune-mediated destruction of pancreatic beta cells. However, as a likely consequence of intraportal insulin deficiency, patients with type 1 DM also exhibit abnormalities of the growth hormone (GH)/IGF/IGF-binding protein (IGFBP) axis, including GH hypersecretion, reduced circulating levels of insulin-like growth factor-I (IGF-I) and IGFBP-3, and elevated levels of IGFBP-1. These abnormalities not only exacerbate hyperglycemia in patients with type 1 DM, but may contribute to the pathogenesis of diabetes-specific complications, including diabetic neuropathy, nephropathy, and retinopathy. Therefore, therapeutic modalities aimed at restoring the GH-IGF-IGFBP axis are being considered. Herein, we review the efficacy of one such therapy, specifically IGF-I replacement therapy. To date, short-term beneficial metabolic effects of recombinant human IGF (rhIGF)-I therapy have been demonstrated in numerous diabetic conditions, including type 1 DM, type 2 DM, and type A insulin resistance. However, the long- term safety and metabolic efficacy of rhIGF-I therapy remains to be established. Moreover, the potential impact of rhIGF-I on the natural history of diabetic complications has yet to be explored.
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PMID:Insulin-like growth factor-I in diabetes mellitus: its physiology, metabolic effects, and potential clinical utility. 1146 25

Dysfunction of the autonomic nervous system is a recognized complication of diabetes, ranging in severity from relatively minor sweating and pupillomotor abnormality to debilitating interference with cardiovascular, genitourinary, and alimentary dysfunction. Neuroaxonal dystrophy (NAD), a distinctive distal axonopathy involving terminal axons and synapses, represents the neuropathologic hallmark of diabetic sympathetic autonomic neuropathy in man and several insulinopenic experimental rodent models. Although the pathogenesis of diabetic sympathetic NAD is unknown, recent studies have suggested that loss of the neurotrophic effects of insulin and/or insulin-like growth factor-I (IGF-I) on sympathetic neurons rather than hyperglycemia per se, may be critical to its development. Therefore, in our current investigation we have compared the sympathetic neuropathology developing after 8 months of diabetes in the streptozotocin (STZ)-induced diabetic rat and BB/ Wor rat, both models of hypoinsulinemic type 1 diabetes, with the BBZDR/Wor rat, a hyperglycemic and hyperinsulinemic type 2 diabetes model. Both STZ- and BB/Wor-diabetic rats reproducibly developed NAD in nerve terminals in the prevertebral superior mesenteric sympathetic ganglia (SMG) and ileal mesenteric nerves. The BBZDR/Wor-diabetic rat, in comparison, failed to develop superior mesenteric ganglionic NAD in excess of that of age-matched controls. Similarly, NAD which developed in axons of ileal mesenteric nerves of BBZDR/Wor rats was substantially less frequent than in BB/Wor- and STZ-rats. These data, considered in the light of the results of previous experiments, argue that hyperglycemia alone is not sufficient to produce sympathetic ganglionic NAD, but rather that it may be the diabetes-induced superimposed loss of trophic support, likely of IGF-I, insulin, or C-peptide, that ultimately causes NAD.
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PMID:Experimental rat models of types 1 and 2 diabetes differ in sympathetic neuroaxonal dystrophy. 1519 24

Insmed is developing mecasermin rinfabate, a recombinant complex of insulin-like growth factor-I (rhIGF-I) and binding protein-3 (rhIGFBP-3) [insulin-like growth factor-I/insulin-like growth factor binding protein-3, rhIGF-I/rhIGFBP-3, SomatoKine], for a number of metabolic and endocrine indications. In the human body, IGF-I circulates in the blood bound to a binding protein-3 (IGFBP-3), which regulates the delivery of IGF-I to target tissues, and particular proteases clip them apart in response to stresses and release IGF-I as needed. IGF-I, a naturally occurring hormone, is necessary for normal growth and metabolism. For the treatment of IGF-I deficiency, it is desirable to administer IGF-I bound to IGFBP-3 to maintain the normal equilibrium of these proteins in the blood. Mecasermin rinfabate (rhIGF-I/rhIGFBP-3) mimics the effects of the natural protein complex in the bloodstream and would augment the natural supply of these linked compounds. The most advanced indication in development of mecasermin rinfabate is the treatment of severe growth disorders due to growth hormone insensitivity syndrome (GHIS), also called Laron syndrome. GHIS is a genetic condition in which patients do not produce adequate quantities of IGF because of a failure to respond to the growth hormone signal. This results in a slower growth rate and short stature. Mecasermin rinfabate also has potential as replacement therapy for IGF-I, which may become depleted in indications such as major surgery, organ damage/failure, traumatic injury, cachexia and severe burn trauma. It also has potential for the treatment of osteoporosis. Mecasermin rinfabate was developed by Celtrix using its proprietary recombinant protein production technology. Subsequently, Celtrix was acquired by Insmed Pharmaceuticals on 1 June 2000. Insmed and Avecia of the UK have signed an agreement for manufacturing mecasermin rinfabate and its components, rhIGF-1 and rhIGFBP-3. CGMP clinical production of mecasermin rinfabate and its components will be carried out in Avecia's Advanced Biologics Centre, Billingham, UK, which manufactures recombinant-based medicines and vaccines at the capacity of up to 1000L. In April 2004, Insmed announced that it acquired a lease to operate the manufacturing facility formerly operated by Baxter for the commercial production of SomatoKine in Boulder, CO, USA. With the two manufacturing facilities for SomatoKine, Insmed plans to meet the development and commercial demands for the product over the next several years. In its 2003 Form-10K, Insmed announced plans to conduct comparative studies with the previously used drug substance and the new substance produced by Avecia. The comparative data will be included in the regulatory filing for mecasermin rinfabate. Mecasermin rinfabate was originally licensed to Welfide for Japan. On 1 October 2001, Welfide Corporation merged with Mitsubishi-Tokyo Pharmaceuticals to form Mitsubishi Pharma Corporation. The new company is a subsidiary of Mitsubishi Chemical. In October 2004, Insmed announced that Tzamal Pharma has been granted exclusive distribution and marketing rights for mecasermin rinfabate in certain Middle Eastern territories including Israel. Tzamal Pharma also acquired exclusive rights to Insmed's named patient programme for the agent in these territories. Tzamal Pharma intends to begin the appropriate registration activities for mecasermin rinfabate in the treatment of children with growth hormone-insensitivity syndrome. This pivotal, 12-month, multicentre, open-label trial in 30 children with GHIS was initiated in June 2003 and was designed to evaluate the safety and efficacy of the agent in prepubescent children with GHIS. The 6-month endpoint data analysis showed that mecasermin rinfabate given as a once-daily injection was safe and well tolerated. The agent demonstrated a significant increase in height velocity in children with GHIS similar to that observed by Pfizer in their pivotal study with twice-daily injections of rhIGF-I. The full results from the pivotal trial are expected in 2005. In April 2003 Insmed initiated a named patient programme in Europe that will make available mecasermin rinfabate for the treatment of GHIS-Laron syndrome. The treatment of patients was initiated in Scandinavia, with authorisation pending in several other European countries. Mecasermin rinfabate will be made available to those GHIS patients who, in the opinion of their doctor, may benefit from IGF-I therapy. At precommercial scale quantities, the drug will be available on a limited basis.A phase II dose-ranging study in children with GHIS was completed at Saint Bartholomew's and the Royal London School of Medicine, London, UK. A single dose of mecasermin rinfabate delivered the same amount of IGF-1 as two daily injections of unbound IGF-1. No adverse events were reported. Insmed has acquired an exclusive licence to Pharmacia's regulatory filings concerning yeast-derived insulin-like growth factor 1 (IGF-1). These filings were used by Pharmacia to receive marketing approvals in several European countries and also in the IND application with the US FDA. Insmed believes that this licence will facilitate the development of mecasermin rinfabate for the treatment of children with GHIS. In January 2003, Insmed announced positive results from a double-blind, placebo-controlled, dose-ranging study of mecasermin rinfabate in adolescent patients with type 1 diabetes receiving insulin therapy. The study was conducted at the University of Cambridge, Cambridge, UK, under supervision of Prof. D. Dunger. The researchers from The Robarts Research Institute and the University of Western Ontario, Canada (leading investigator T.L. Delovitch, the Sheldon H. Weinstein scientist in Diabetes at the University of Western Ontario) have found that mecasermin rinfabate complex was significantly more effective than IGF-1 in reducing the severity of insulitis, beta cell destruction and delaying the onset of type 1 diabetes. The study was supported by grants from Canadian Institutes of Health and the Juvenile Diabetes Research Foundation. Insmed plans to initiate large-scale phase II clinical studies in this indication. At the BIO 2004 Annual International Convention (BIO-2004) in June 2004, Insmed announced that it has received a grant from the US National Institutes of Health (NIH)/Muscular Dystrophy Association (MDA) worth USD $6.5 million to investigate the efficacy of mecasermin rinfabate for the treatment of myotonic dystrophy. It has also been granted orphan drug status for the treatment of GHIS-Laron syndrome in the US and Europe. In December 2003, Insmed announced that mecasermin rinfabate was designated orphan drug status by the FDA for the treatment of extreme insulin resistance. This provides Insmed with 7 years of market exclusivity following approval of mecasermin rinfabate for this indication. Insmed has received orphan drug designation for mecasermin rinfabate in the treatment of extreme insulin resistance in Europe (October 2004). In November 2004, Insmed was granted the European patent EP1183042 entitled "Methods for Treating Diabetes". This patent corresponds with the US patent US 6,040,292 also entitled "Methods for Treating Diabetes". Both patents cover type 1 and type 2 diabetes mellitus and insulin resistant diabetes including type A insulin resistance (the least severe form of extreme insulin resistance syndromes). In January 2004, Insmed obtained a non-exclusive licence to the patents for use of IGF-I for the treatment of extreme or severe insulin-resistant diabetes from Fujisawa Pharmaceutical. Insmed will have worldwide rights in territories (excluding Japan) with existing valid patent claims including the US and Europe. Insmed holds 28 US issued or allowed patents for the composition, production, antibodies and methods of use of mecasermin rinfabate. These US patents expire at various times between the years 2010 and 2019. Insmed through their lawyers filed its defense and counterclaim to the alleged patent infringement brought by Tercica against Insmed in the London High Court of Justice. Insmed asserted that it did not infringe any valid patent claims as none of the claims of the patent were patentable because the subject matter was not new. Insmed also stated that the patent did not involve an inventive step, did not have capability of industrial application and had no clear description of the invention so that invention can be performed by the person skilled in the art. Insmed is seeking revocation of the patent on these grounds.
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PMID:Mecasermin rinfabate: insulin-like growth factor-I/insulin-like growth factor binding protein-3, mecaserimin rinfibate, rhIGF-I/rhIGFBP-3. 1577 6

Circulating levels of insulin-like growth factor-I (IGF-I) and its principal binding protein IGFBP-3 are reduced, whereas those of the inhibitory binding protein, IGFBP-1, tend to be high in children and adolescents with type 1 diabetes mellitus (T1DM). These abnormalities are thought to arise because of relative portal hypoinsulinaemia and partial resistance at the hepatic growth hormone (GH) receptor. During adolescence, reductions in IGF-I and IGF bioactivity lead to feedback for GH hypersecretion and the elevated GH and low IGF-I levels lead to an increase of the normal insulin resistance encountered during puberty. Low IGF-I levels, but in particular elevated GH levels, have been implicated in the pathogenesis of diabetic microangiopathic complications, in particular, renal hypertrophy, glomerular hyperfiltration and the development of microalbuminuria. Early study of IGF-I replacement with recombinant human IGF-I (rhIGF-I) demonstrated, in the short term, reductions in GH hypersecretion with improved insulin sensitivity and, in the longer term, reductions in insulin requirements and improvements in HbA1c levels. However, larger doses of rhIGF-I were associated with retinopathy either due to rapid improvements in glycaemic control or direct effects of high levels of 'free' IGF-I. More recently, pilot studies using the combination of rhIGF-I/rhIGFBP-3 have confirmed the physiological efficacy of IGF-I replacement in T1DM. The combined treatment is better tolerated and may result in reduced tissue exposure to high levels of 'free' IGF-I. Longer term clinical studies with this IGF-I/IGFBP-3 combination are needed.
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PMID:Childhood and adolescent diabetes. 1587 93

The relationship between diabetes and bone disease is complex. While low bone mineral density (BMD) is consistently observed in type 1 diabetes (T1DM), in type 2 diabetes (T2DM) bone mineral density is similar to or higher than in non diabetic subjects. Yet, for both types of diabetes bone appears to be more fragile for a given density. Recent meta-analyses and cohort studies confirm that T1DM and T2DM are associated with higher fracture risk. Many factors influence the probability of fractures. Diabetes can affect bone through multiple pathways including obesity, changes in insulin levels, higher concentrations of advanced glycation end products in collagen, increased urinary excretion coupled with lower intestinal absorption of calcium, inappropriate homeostatic response of parathyroid hormone secretion, complex alterations of vitamin D regulation, reduced renal function, lower insulin-like growth factor-I, microangiopathy, and inflammation. Data on cellular mechanisms and experimental models are extensive, but the relevance of each one of these factors to the clinical situation is unclear. In this article we review the pathophysiological mechanisms potentially involved in the altered BMD found in diabetic patients, show data on the increased risk of fractures, and speculate on the potential causes of the increased risk of fractures in this context. Finally, we comment on the prevention and treatment of osteoporosis in diabetes, although the lack of trials testing the use of pharmacotherapy on preventing fractures in this context is emphasized.
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PMID:Bone disease in diabetes. 2038 Jun 29


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