Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0011849 (diabetes)
 277,896 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Diabetes-induced growth retardation in the rodent is associated with both reduced circulating insulin-like growth factor-I (IGF-I) and enhanced levels of inhibitors of somatomedin activity. IGF-binding proteins (IGFBPs) are present in the circulation and tissue fluids and are believed to modulate the actions of IGF-I. Since elevated concentrations of the IGFBPs may contribute to the enhanced somatomedin-inhibitor activity observed in serum from diabetic animals, we have examined the amounts of hepatic IGFBP-1, -2, -3 and -4 mRNA in the spontaneously diabetic BioBreeding/Worcester rat. The study used two types of diabetic animal: mildly diabetic animals, which received suboptimal insulin treatment (0.5-1 U/day) and diabetic animals, which received intensive insulin treatment (3-6 U/day). A significant increase in the amount of IGFBP-1 and IGFBP-2 mRNA was seen 1 month and 3 months after the onset of diabetes. Intensive insulin treatment for 3 weeks normalized the amount of IGFBP-1 mRNA in diabetic rats and resulted in a decrease in IGFBP-2 mRNA. In contrast to the increase in IGFBP-1 and IGFBP-2 mRNA, a significant decrease in IGFBP-3 mRNA was seen in diabetic rats (54.6% of control, P less than 0.0005 and 64.6% of control, P less than 0.005 for 1 and 3 months respectively) and intensive insulin treatment for 3 weeks did not restore the IGFBP-3 mRNA level in diabetic rats. No significant difference in IGFBP-4 mRNA levels was seen in diabetic compared with non-diabetic rats. When serum was analysed by ligand blotting the major finding was a reduction in the 39-42 kDa binding protein. No increase in 29-30 kDa IGFBP in the serum was detected in the diabetic rats. From these studies we conclude that the major change in IGFBPs in mildly hyperglycaemic spontaneously diabetic rats is a decrease in IGFBP-3. The changes in hepatic IGFBP-1 and -2 mRNA do not appear to be of sufficient magnitude to result in an increase in serum concentrations of these binding proteins.
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PMID:Differential expression of the insulin-like growth factor binding proteins in spontaneously diabetic rats. 138 Nov 81

Diabetes mellitus was induced using streptozotocin in five gilts between 8 and 12 weeks of age. Gilts were maintained with exogenous insulin (INS) except during experimental periods. Four litter-mate gilts served as controls. At 9 months of age, all gilts were ovariectomized, and 30 days after ovariectomy, Experiment (Exp) 1 was conducted. Jugular vein catheters were inserted and blood samples were collected every 10 min for 8 hr. Experiment 2 was conducted when gilts were 11 months of age. Venous blood and cerebrospinal fluid (CSF) samples were collected in the absence (Phase I) or presence (Phase II) of INS therapy. In Experiment 1, plasma glucose concentrations were greater (P < 0.05) in diabetic (465 +/- 17 mg/100 ml) than in control (82 mg +/- 17 mg/100 ml) gilts, whereas serum INS was lower (P < 0.0001) in diabetic gilts (0.3 +/- 0.02 vs 0.9 +/- 0.05 ng/ml) and insulin-like growth factor-I was similar in diabetic and control gilts (32 +/- 3 vs 43 +/- 4 ng/ml, respectively). Mean serum GH concentration was 2-fold greater (P < 0.02) in diabetics (2.8 +/- 0.4 ng/ml) than in control gilts (1.2 +/- 0.2 ng/ml). Diabetic gilts exhibited a greater (P < 0.05) number of GH pulses than control gilts (3.2 +/- 0.4 vs 1.5 +/- 0.3/8 hr, respectively). In addition, GH pulse magnitude was markedly elevated (P < 0.02) in diabetic (5.8 +/- 0.4 ng/ml) compared with control gilts (3.3 +/- 0.6 ng/ml). Mean basal serum GH concentrations were greater (P < 0.07) in diabetic (2.2 +/- 0.5 ng/ml) compared with control gilts (1.0 +/- .1 ng/ml). In Experiment 2, CSF concentrations of insulin-like growth factor-I, INS, GH, and protein were similar for diabetic and control gilts in both phases. Serum GH levels were similar for diabetics and controls in Phase I, but were greater (P < 0.05) in diabetics than in controls in Phase II. CSF glucose levels were greater in diabetic than in control gilts in both the presence (P < 0.003) and absence (P < 0.0002) of INS therapy, whereas plasma glucose was greater (P < 0.003) in diabetic than in control gilts in the absence of INS, but returned to control concentrations in the presence of INS. However, serum GH levels were unchanged after INS therapy in the diabetic gilts. In conclusion, altered GH secretion in the diabetic gilt may, in part, be due to elevated CSF glucose concentrations, which may alter GH-releasing hormone and/or somatostatin secretion from the hypothalamus.
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PMID:Growth hormone secretion, serum, and cerebral spinal fluid insulin and insulin-like growth factor-I concentrations in pigs with streptozotocin-induced diabetes mellitus. 140 37

The effects of continuous or acute administration of insulin or insulin-like growth factor-I (IGF-I) on IGF-I mRNA and IGF-I receptor mRNA were studied in the skeletal muscle (gastrocnemius), heart muscle and vascular smooth muscle (aorta) of non-diabetic and diabetic rats using a solution hybridization assay. The levels of IGF-I mRNA in the different types of muscle markedly decreased by diabetes, whereas changes in IGF-I receptor mRNA were less consistent. Continuous infusion of diabetic rats with insulin (28 or 35 nmol/day) for 4 days normalized the altered levels of IGF-I mRNA and IGF-1 receptor mRNA. Infusion of equimolar concentrations of IGF-I did not affect IGF-I mRNA, but decreased the level of IGF-I receptor mRNA in skeletal muscle. In acute experiments, rats were injected with equipotent blood glucose-lowering doses of insulin (14 nmol) or IGF-I (107 nmol). Insulin did not significantly affect levels of IGF-I mRNA, but decreased levels of IGF-I receptor mRNA in skeletal muscle and aorta. IGF-I increased levels of IGF-I mRNA in heart muscle, and markedly decreased levels of IGF-I receptor mRNA in skeletal muscle and heart muscle from non-diabetic and diabetic rats. In conclusion, exogenous IGF-I and insulin can increase IGF-I mRNA and decrease IGF-I receptor mRNA, indicating that both insulin and IGF-I can act as regulators of the IGF-I system in muscle in vivo.
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PMID:In-vivo regulation of messenger RNA encoding insulin-like growth factor-I (IGF-I) and its receptor by diabetes, insulin and IGF-I in rat muscle. 147 27

Two distinct GH-binding proteins (GHBP) are present in circulation in the human. The major GHBP (high affinity GHBP) is homologous to the extracellular portion of the GH receptor and the concentration of this protein in circulation may reflect the status of the GH receptor in the tissues. To gain information about the concentration of GHBPs in children with insulin-dependent diabetes mellitus (IDDM), we measured GHBP in the serum of 46 children with IDDM and compared it to that in 53 healthy control subjects matched for age and sexual maturity. The total GHBP concentration in the group of pubertal and postpubertal IDDM patients was lower than that measured in the control group (mean +/- SEM: 7.8 +/- 0.4 vs. 9.0 +/- 0.5%, P = 0.05). The diabetic children in stages II to IV of puberty had a lower GHBP level compared to their healthy controls (7.6 +/- 0.4 vs. 9.1 +/- 0.5%, P = 0.02), whereas the difference between the diabetic and control group of postpubertal children was not statistically different (8.3 +/- 0.7 vs. 9.7 +/- 0.7%, P = 0.1). In a randomly selected subset of eight patients and eight controls, the concentration of the individual GHBPs (i.e. high affinity and low affinity (GHBP) was estimated by gel chromatography. There was no difference in the low affinity GHBP between the two groups (9.9 +/- 0.6% vs. 9.9 +/- 0.4%), but the high affinity GHBP was less in the diabetic group than in the control group (10.5 +/- 0.9 vs. 15.6 +/- 1.0%, P less than 0.01). In the diabetic group, there was no correlation between the GHBP levels and age, duration of diabetes, hemoglobin A1, or insulin dose. We conclude that in IDDM there is less of the high affinity GHBP, suggesting a decrease in the number of GH receptors in these patients. This decrease may contribute to GH resistance manifesting as decreased insulin-like growth factor-I levels despite high GH levels in patients with IDDM.
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PMID:Diminished growth hormone-binding protein in children with insulin-dependent diabetes mellitus. 154 60

We have examined the effects of infusing recombinant human growth hormone (hGH), insulin-like growth factor-I (IGF-I), the truncated IGF-I analogue, des(1-3)IGF-I, and insulin over a 7-day period in streptozotocin-induced diabetic rats. IGF-I at a dose of 1.05 or 1.08 mg/kg per day in two experiments increased body weight and nitrogen retention above those of vehicle-infused controls to about 30% of the improvement achieved with 25 or 30 units of insulin/kg per day, but only in the second experiment were the differences statistically significant (P less than 0.05). A 2.5-fold higher IGF-I dose, or des(1-3)IGF-I at 1.08 mg/kg per day, gave effects that were approx. 70% of those obtained with insulin. hGH at 1.38 mg/kg per day was not effective. The IGF peptides, unlike insulin, did not ameliorate the diabetic glucosuria. The improvements in nitrogen balance could be accounted for in part by increases in muscle protein synthesis. Muscle protein breakdown, as assessed by 3-methylhistidine excretion, was inhibited by insulin, but not by the IGF peptides. Carcass fat increased substantially following insulin administration. This did not occur with the IGF peptides, suggesting that IGF predominantly stimulates the growth of lean tissue. IGF-I concentrations and IGF-I-binding proteins in plasma were increased by IGF-I, especially at the higher dose, whereas hGH produced only a transient increase in IGF-I. Des(1-3)IGF-I induced binding proteins, but had only a slight effect on measured IGF-I concentrations. We conclude that IGF peptides stimulate muscle protein synthesis and improve nitrogen balance in diabetes without obviously influencing the abnormal carbohydrate metabolism. Moreover, des(1-3)IGF-I is at least as potent as the full-length IGF-I.
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PMID:Increased weight gain, nitrogen retention and muscle protein synthesis following treatment of diabetic rats with insulin-like growth factor (IGF)-I and des(1-3)IGF-I. 171 Aug 92

Multiple factors contribute to the growth retardation which is a characteristic feature of uncontrolled diabetes. In this report we have examined the effects of streptozotocin-induced (STZ) diabetes on expression of insulin-like growth factor-I (IGF-I) and insulin-like growth factor binding protein-1 (IGFBP-1) in various tissues. As early as 7 days after STZ administration there was a modest reduction in IGF-I mRNA abundance. The reduction (10-30%) was of similar magnitude in each of the 7 tissues examined; liver, kidney, lung, diaphragm, quadraceps, heart and adipose tissue. However, the reduction achieved statistical significance only in the lung (p less than 0.05) and diaphragm (p less than 0.01). A further reduction in IGF-I mRNA abundance was seen in many tissues, 32 and 91 days after STZ administration. In contrast to the decrease in IGF-I mRNA, IGFBP-1 mRNA was significantly increased in the liver and kidney of diabetic rats. IGFBP-1 mRNA was detectable at only very low levels in other tissues but was increased in diabetic rats compared non-diabetic rats. In diabetic rats, a highly significant correlation (R = 0.75, p less than 0.001) between hepatic IGFBP-1 mRNA and glucose was observed whereas there was no significant correlation between serum glucose and hepatic IGF-I mRNA abundance (R = 0.24, p = NS). Treatment of diabetic rats with insulin resulted in a small, non significant increase in hepatic and renal IGF-I mRNA and a significant decrease in renal IGFBP-1 mRNA abundance. The observations reported here are consistent with the hypothesis that diminished IGF-I expression and inhibition of available IGF-I by increased levels of IGFBP-1 may explain the impaired growth seen in diabetic animals.
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PMID:Differential expression of insulin-like growth factor-I and insulin-like growth factor binding protein-1 in the diabetic rat. 171 93

Rat insulin-like growth factor-I (IGF-I) mRNAs with different 5'-untranslated region/prepeptide coding sequences result from transcription initiation in one of two leader exons. While not altering the mature IGF-I coding sequence, these different leaders potentially encode two distinct IGF-I prepeptides, one of 48 amino acids (exon 1) and one of 32 amino acids (exon 2). Within exon 1, transcription initiation is dispersed (i.e. occurs over a approximately 350-basepair region), while within exon 2, it is highly localized. A fourth exon 1 start site, residing only approximately 30 basepairs from its 3' end, is suggested on the basis of RNase protection assays; its use would produce an mRNA encoding a third distinct IGF-I leader peptide of 22 amino acids. We have determined that during postnatal development, and as a result of insulinopenic diabetes and fasting, choice of transcription start sites within exon 1 in the liver is coordinately regulated, i.e. use of all start sites increased during development and decreased in the two catabolic states. Transcription initiation at the single major site within exon 2 was also reduced in diabetes and fasting. Insulin replacement therapy and refeeding restored the levels of all transcripts coordinately. During postnatal development, however, transcripts initiating within exon 2 exhibited a different developmental profile than did exon 1 transcripts, increasing especially at the onset of GH-dependent linear growth. In liver, therefore, negative regulation of exon 1 and exon 2 transcription start site usage occurs in catabolic states, while in development, differential regulation of exon 1 and exon 2 transcription start sites occurs.
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PMID:Regulation of start site usage in the leader exons of the rat insulin-like growth factor-I gene by development, fasting, and diabetes. 177 70

Plasma insulin-like growth factor-I (IGF-I) concentrations and the effects of exogenous IGF-I administration were determined in 26 rhesus monkeys; each animal was well characterized regarding its degree of obesity, plasma glucose and insulin levels, and glucose tolerance (KG). Five separate groups were identified: lean normal, obese normoinsulinemic and normoglycemic, obese hyperinsulinemic with normal glucose tolerance, impaired glucose tolerant, and spontaneously diabetic (type II, non-insulin-dependent diabetes mellitus [NIDDM]). Basal plasma IGF-I levels in all monkeys ranged from 249 to 1,093 ng/mL and were strongly associated with age (r = -.66; P less than .001) and KG (r = .59; P less than .001), but not with body weight, body fat, or fasting plasma glucose or insulin levels. In addition, the acute insulin-like effects of exogenously administered IGF-I on glucose disappearance were studied in vivo in a dose-response comparison to insulin (subcutaneous administration of IGF-I at doses of 50, 100, or 200 micrograms/kg v insulin at 0.3 U/kg). Five hyperinsulinemic normoglycemic monkeys (fasting plasma glucose, 67 +/- 2 mg/dL; insulin, 163 +/- 42 microU/mL) and overt type II diabetic monkeys (fasting plasma glucose, 201 +/- 13 mg/dL; insulin, 38 +/- 6 microU/mL) each underwent a series of three to five experiments to determine the time course and degree of hypoglycemia induced by IGF-I as compared with insulin or with control (saline) injection.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Insulin-like growth factor-I in non-insulin-dependent diabetic monkeys: basal plasma concentrations and metabolic effects of exogenously administered biosynthetic hormone. 194 41

Diabetes mellitus is associated with a generalized defect in connective tissue metabolism. Since collagen is the major protein of connective tissues, we used collagen as a probe to examine the role of factors in diabetic rat serum (DRS) in the etiology of these defects. Serum and skin fibroblasts were isolated from nondiabetic rats, and serum was taken from rats 48 h after injection of 200 mg/kg streptozotocin. Within 24 h of confluency, the fibroblast medium was changed to experimental serum for 24 h, with 5 microCi [3H]proline added for the final 6 h. Collagen and noncollagen proteins were quantitated using purified collagenase. Compared to cells incubated in medium without serum, collagen fell to 58% with 0.5% DRS (P less than 0.05) and continued to decrease with increasing concentrations of DRS. Noncollagen protein decreased below levels in cells incubated in medium without serum only when concentrations of diabetic serum were 1% or greater and did not decrease further with higher concentrations of diabetic serum. Collagen was decreased to a greater degree than noncollagen protein at each concentration of DRS, such that collagen relative to total protein production was significantly reduced at 0.5% or more DRS. Addition of 10(-7)-10(-9) M insulin or insulin-like growth factor-I (0.1-1000 ng/ml) to DRS did not return collagen production to the level seen in cells incubated in medium with no added serum (basal production). After separation of serum components based on size, incubation of cells with the low mol wt fraction (less than 5000 daltons) of normal and diabetic rat serum resulted in equivalent collagen production, while incubation with the high mol wt fraction of DRS resulted in 200-fold less collagen compared to the similar fraction of normal serum. This decrease in collagen production appeared due to the presence of a high mol wt factor(s) in diabetic serum which had a direct inhibitory effect on collagen and was not due to deficiency of growth peptides. The degree and specificity of these changes in collagen production probably contribute to long term complications in diabetes through altered connective tissue metabolism.
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PMID:Inhibition of collagen production by diabetic rat serum: response to insulin and insulin-like growth factor-I added in vitro. 195 85

Endothelial cells are likely to play an important role in the development of diabetic vascular diseases since they are exposed directly to the abnormal circulating metabolites of diabetes and may be easily damaged early in the natural course of vascular complications. Recently, we have demonstrated a decrease of insulin binding and autophosphorylation of the insulin receptor in cultured capillary endothelial cells of diabetic rats. In this study, similar defects in insulin receptor of aortic endothelial cells cultured from diabetic BB rats were found. The specific insulin binding was 45% lower in cells from diabetic than from non-diabetic rats (3.9 +/- 1.3 vs 7.3 +/- 1.2% per mg protein, p less than 0.05), which was due to a decrease of cell surface binding sites. In contrast to the decrease in insulin binding, insulin-like growth factor-I binding was higher in cells of diabetic than control rats (20.6 +/- 5.6 vs 13.7 +/- 4.6% per mg protein). The decrease in insulin binding could not be induced by the two-week treatment of endothelial cells from non-diabetic rats with medium containing high concentration of glucose (400 mg/dl). Insulin-induced tyrosine kinase activity of partially purified insulin receptor measured using poly-glutyr as substrate was also lower in cells from diabetic rats (normal:1.4 +/- 0.6-fold; diabetic 0.5 +/- 0.3-fold above baseline; (p less than 0.05). These data suggest that the diabetic milieu in vivo can induce persistent defects in insulin receptor of aortic endothelial cells. Further studies are warranted to understand the potential pathophysiological role of these defects.
Diabetes Res 1990 May
PMID:Changes of insulin receptor in aortic endothelial cells from diabetic rats. 196 86


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