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)

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

Although diabetes is a heterogeneous condition, IGF-I has been shown to improve glycaemic control and reduce insulin requirements in both IDDM and NIDDM. In IDDM, the therapeutic rationale for IGF-I is as a replacement therapy "topping up" low circulating IGF-I levels. There is now convincing evidence that this is associated with a reduction in GH secretion resulting in an improvement in insulin sensitivity and glycaemic control. The mechanism may simply be reduced GH-secretion, but pre- and post-receptor effects on insulin sensitivity are also likely. It is not clear what effect IGF-I treatment has on IGF binding proteins, but with the restoration of a more normal GH/IGF-I axis they are likely to be restored to normal concentrations which may in turn have a direct effect on glucose metabolism. In NIDDM, the mechanism of action of IGF-I remains unclear. At high doses, IGF-I may mimic insulin, but at levels resulting in unacceptable "acromegalic" IGF-I levels and side-effects. The most exciting data concerning IGF-I is with a low dose where IGF-I improves insulin sensitivity by an unknown mechanism. This may be mediated via the IGF-I receptor, by cross-reactivity with the insulin receptor, or by activation of hybrid receptors. The exact mechanism and interaction remains to be elucidated. In severe insulin-resistant states, IGF-I-treatment appears to be effective, and may be the only realistic therapeutic measure in the near future, and warrants further investigation. Detailed genetic characterization of these syndromes following treatment with IGF-I may also help to characterize the mechanism of action of IGF-I and its interactions with the insulin receptor. Thus, IGF-I appears to have a future as a therapeutic agent in treating diabetes, but long-term studies addressing safety and short-term studies addressing mechanisms are essential. With only a few pharmaceutical companies having the capability to produce IGF-I for scientific and therapeutic investigation, it is important that short-term marketing strategy does not prevent the proper exploration of this exciting peptide hormone as a therapeutic agent for all types of diabetes.
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PMID:Insulin-like growth factor-I and diabetes. A review. 1098 75

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

IGF-I regulates islet beta-cell growth, survival, and metabolism and protects against type 1 diabetes (T1D). However, the therapeutic efficacy of free IGF-I may be limited by its biological half-life in vivo. We investigated whether prolongation of its half-life as an IGF-I/IGF binding protein (IGFBP)-3 complex affords increased protection against T1D and whether this occurs by influencing T cell function and/or islet beta-cell growth and survival. Administration of IGF-I either alone or as an IGF-I/IGFBP-3 complex reduced the severity of insulitis and delayed the onset of T1D in nonobese diabetic mice, but IGF-I/IGFBP-3 was significantly more effective. Protection from T1D elicited by IGF-I/IGFBP-3 was mediated by up-regulated CCL4 and down-regulated CCL3 gene expression in pancreatic draining lymph nodes, activation of the phosphatidylinositol 3-kinase and Akt/protein kinase B signaling pathway of beta-cells, reduced beta-cell apoptosis, and stimulation of beta-cell replication. Reduced beta-cell apoptosis resulted from elevated Bcl-2 and Bcl-X(L) activity and diminished caspase-9 activity, indicating a novel role for a mitochondrial-dependent pathway of beta-cell death. Thus, IGF-I/IGFBP-3 affords more efficient protection from insulitis, beta-cell destruction, and T1D than IGF-I, and this complex may represent an efficacious therapeutic treatment for the prevention of T1D.
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PMID:Insulin-like growth factor (IGF)-I/IGF-binding protein-3 complex: therapeutic efficacy and mechanism of protection against type 1 diabetes. 1461 76

Ghrelin is secreted primarily by the stomach, although other tissues such as the pancreas synthesize a minor proportion. The discovery of a new cell type that produces ghrelin in the human pancreas and that this organ expresses GHS-R opens new perspectives in the understanding of the control of glucose metabolism. We have studied 22 children with newly diagnosed type 1 diabetes mellitus at four different points: at diagnosis before insulin therapy, after 48-60 h of insulin therapy, and after 1 and 4 mo of insulin treatment. At each point circulating levels of ghrelin, leptin, IGF-I, IGF binding protein (IGFBP)-1, IGFBP-2, IGFBP-3, and glucose were determined. Ghrelin levels were significantly decreased at diagnosis (573 +/- 68 pg/mL, p < 0.01) compared with controls (867 +/- 38 pg/mL) and remained decreased after insulin therapy (d 2: 595 +/- 68 pg/mL; 1 mo: 590 +/- 61 pg/mL; 4 mo: 538 +/- 67 pg/mL) with no differences before or after insulin treatment. There was a negative correlation between ghrelin levels and body mass index at all of the study points, whereas a negative correlation between ghrelin and glucose concentrations was only observed after insulin therapy. No correlation between ghrelin and HbA1c was found at any point. A positive correlation between ghrelin and IGFBP-1 was found after insulin therapy, but no correlation with other members of the IGF system or leptin was found. In conclusion, these data could indicate a possible link between glucose concentrations and ghrelin; hence, the persisting low ghrelin levels in diabetic children may suggest a defensive mechanism against hyperglycemia.
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PMID:Response of circulating ghrelin levels to insulin therapy in children with newly diagnosed type 1 diabetes mellitus. 1497 81

Understanding mechanisms underlying apoptotic destruction of insulin-secreting cells is critical to validate therapeutic targets for type 1 diabetes mellitus. We recently reported insulin-like growth factor binding protein-3 (IGFBP-3) as a novel mediator of apoptosis in insulin-secreting cells. In light of emerging IGF-independent roles for IGFBP-3, we investigated the mechanisms underlying actions of the novel, recombinant human mutant G(56)G(80)G(81)-IGFBP-3, which lacks intrinsic IGF binding affinity. Using the rat insulinoma RINm5F cell line, we report the first studies in insulin-secreting cells that IGFBP-3 selectively suppresses multiple, key intracellular phosphorelays. By immunoblot, we demonstrate that G(56)G(80)G(81)-IGFBP-3 suppresses phosphorylation of c-raf-MEK-ERK pathway and p38 kinase in time-dependent and dose-dependent manners. SAPK/JNK signaling was unaffected. These data delineate several novel intracellular sites of action for IGFBP-3 in insulin-secreting cells.
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PMID:Novel actions of IGFBP-3 on intracellular signaling pathways of insulin-secreting cells. 1627 48

Though children with type 1 diabetes mellitus (T1DM) are often tall at the time of diagnosis, they may experience growth retardation, pubertal delay or both, which may be due to poor glycemic control, associated diseases or chronic complications. Factors affecting growth include: gender, genetic environment, age at diagnosis, diabetes duration, puberty, metabolic control, and status of growth hormone (GH), insulin-like growth factors (IGFs), and IGF binding proteins (IGFBPs). Insulin regulates expression of hepatic GH receptors, affects IGFs and IGFBPs synthesis by modulating GH postreceptor events, and significantly increases IGF-I bioactivity. Low portal insulin seen in T1DM leads to GH hypersecretion, low circulating IGF-I and IGFBP-3, and high circulating IGFBP-1. Newly diagnosed T1DM patients have decreased GHBP which can be restored with insulin therapy. Growth velocity should be appropriate for the age of the child/adolescent, and the mid-parental height. Height, weight and blood pressure (BP) should be measured and plotted on a growth chart at least 2-3 times a year. Puberty should also be assessed annually. Following precautions are to be taken in T1DM children: checking for pubertal onset and ensuring it is not delayed, testing early when growth falters (hypothyroidism/celiac disease/puberty/other conditions), aiming for best possible metabolic control (multidose regimens, regardless of type of insulin), and encouraging dietary calcium and protein, exposure to sunlight, Vitamin D supplements and exercise.
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PMID:Growth disorders in type 1 diabetes: an Indian experience. 2594 56

Increasing evidence suggests an important role of the insulin-like growth factor (IGF)-IGF binding protein (IGFBP) axis in the maintenance of normal glucose and lipid metabolism. Significant changes occur in the local IGF-I-IGFBPs environment in response to the diabetic milieu. A significant reduction of serum IGF-I levels was observed in patients with type 1 diabetes mellitus (T1DM). Inversely, considerably increased serum levels of IGF-I and IGFBP-3 levels were detected in individuals with glucose intolerance including T2DM. Recently, several prospective studies indicated that baseline levels of IGF-I and IGFBPs are associated with the development of diabetes. These findings suggest that disturbances in insulin and IGF-I-IGFBP axis can affect the development of glucose intolerance including diabetes.
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PMID:Insulin-like growth factor (IGF)-I and IGF binding proteins axis in diabetes mellitus. 2619 9

The precise mechanisms relating type 1 diabetes (T1D) and poor glycemic control to the axis of growth hormone (GH), insulin like growth factor- I (IGF-I), and IGF binding protein-3 (IGFBP-3) remain to be definitively determined. GH resistance with low IGF-I as is frequently seen in patients with T1D is often related to portal hypoinsulization, and lack of upregulation of GH receptors. There are conflicting reports of the effect of a dysregulated GH/IGF-I axis on height in children and adolescents with T1D, as well as on chronic complications. This brief review discusses some of the interactions between the GH/IGF-I axis and T1D pathology, and vice-versa.
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PMID:Growth hormone and insulin-like growth factor-I axis in type 1 diabetes. 2924 23


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