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 47,337 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Pancreatic function was investigated in neonatal suckling offspring of caffeine-ingesting dams, with or without maternal sucrose supplementation, throughout pregnancy and lactation. In offspring of rats ingesting caffeine without sucrose supplementation, there was initial hyperinsulinaemia, followed by a progressive fall of plasma insulin to subnormal levels. This fall in plasma insulin coincided with depletion of pancreatic insulin stores. Both the fall in plasma insulin and depletion of pancreatic insulin stores were prevented by sucrose supplementation of caffeine-ingesting dams. Offspring of dams fed sucrose alone and control offspring also maintained pancreatic insulin stores and circulating insulin levels over the first 14 days of postnatal life. Pancreases from offspring of caffeine-exposed animals tested in vitro showed enhanced sensitivity of the insulin release process to glucose. This was reflected in the glucose concentration required to elicit half-maximal insulin release (2.4 +/- 0.2 mmol/l for caffeine offspring, 2.3 +/- 0.2 mmol/l for caffeine with sucrose, 3.8 +/- 0.3 mmol/l for sucrose and 4.1 +/- 0.3 mmol/l for control offspring, mean +/- SEM). In contrast, offspring of sucrose-supplemented (with or without caffeine) dams showed increased sensitivity of the proinsulin biosynthetic process to glucose, whereas offspring of dams ingesting caffeine alone showed no significant enhancement of the biosynthetic process compared with control offspring. Thus enhanced sensitivity of the insulin secretory process to glucose without a change in the sensitivity of the biosynthetic process in the offspring of the caffeine ingesting (non-sucrose supplemented) dams could explain the progressive depletion of pancreatic insulin stores and eventual hypoinsulinaemia seen in this group.
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PMID:The effect of maternal caffeine ingestion on pancreatic function in the neonatal rat. 675 18

We describe a case of recurrent hypoglycaemia associated with a hepatoma. During hypoglycaemia serum insulin was undetectable. Plasma insulin-like growth factor II (IGF-II) was not elevated although 71% of plasma IGF-II was present as big IGF-II (molecular weight 11 kDa) which probably represents a non-glycated form of pro-IGF-II. The GH response to hypoglycaemia was impaired and plasma levels of both IGF-I and the GH-dependent IGF binding protein (IGFBP-3) were low. A recently described unextracted assay directed against the first 21 amino acids of the E-domain (E-21) of proinsulin-like growth factor-II (pro-IGF-II) allows direct plasma estimation (plasma E-21) of larger molecular forms of IGF-II without interference from normal IGF-II and IGF binding proteins. Basal values were grossly elevated (23.7 and 23.8 nmol/l). Treatment with GH led to an increase in the mean plasma glucose across 24 hours (4.25 +/- 0.21 mol/l (mean +/- SEM) before treatment, compared with 4.86 mmol/l +/- 0.17 following GH (P < 0.01)) and a reduction in hypoglycaemic attacks. The treatment was associated with a rise in IGFBP-3 and small increases in insulin like growth factors. Subsequent treatment with the somatostatin analogue octreotide did not produce a significant change in plasma glucose levels or insulin-like growth factors. Two courses of intrahepatic adriamycin restored elevated levels of E-21 to normal. Total IGF-II remained normal and IGF-I increased. GH treatment was successfully withdrawn with no effect on plasma glucose or growth factor levels. The patient remained free from hypoglycaemia.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:A case of hepatoma associated with hypoglycaemia and overproduction of IGF-II (E-21): beneficial effects of treatment with growth hormone and intrahepatic adriamycin. 752 21

Insulin-like growth factor (IGF)-binding protein-1 (IGFBP-1) modulates the metabolic and mitogenic effects of IGFs. Although IGFBP-1 levels are abnormally high in insulin-dependent diabetes (IDDM), relatively little is known in NIDDM; conflicting data have suggested both high and low levels. We investigated whether treatment modifies IGFBP-1 levels in two groups of NIDDM patients. Study 1 examined fasting concentrations in groups of patients with NIDDM, comparable except for treatment type (sulfonylurea, n = 23; once daily insulin, n = 15; sulfonylurea plus once daily insulin, n = 14; multiple insulin injections, n = 9) and 25 nondiabetic subjects. In sulfonylurea-treated patients there were markedly reduced plasma IGFBP-1 concentrations (median, interquartile range in parentheses): control, 61.0 (36-96) micrograms/L; sulfonylureas alone, 31.5 (21-61) micrograms/L (P < 0.01); and sulfonylureas plus insulin, 31.5 (9-53) micrograms/L (P < 0.01). Once daily insulin was associated with values similar to those in the control group [62.0 (27-103) micrograms/L; P = NS], whereas IGFBP-1 levels were higher with multiple insulin injection therapy [156.0 (71-184) micrograms/L; P < 0.05]. Proinsulin levels were higher in sulfonylurea-treated patients, but there was no significant correlation between IGFBP-1 and proinsulin within any individual group. Study 2 examined the effects of treatment on the dynamics of IGFBP-1 levels between 0800-1900 h. In control subjects (n = 8), levels fell from 0800 h (mean +/- SEM, 22.4 +/- 5.2 micrograms/L) to 1000 h (14 +/- 5.2 micrograms/L), followed by a rise, more rapid after food, to a peak at 1240 h (20.6 +/- 3.7 micrograms/L). Levels then declined until 1500 h (10.7 +/- 2.9 micrograms/L), with a further postprandial peak at 1840 h (23.1 +/- 3.2 micrograms/L). Sulfonylurea therapy (n = 6) resulted in a complete loss of this pattern, with a marked fall in IGFBP-1 from 0800 h (22 +/- 2.7 micrograms/L) to less than 7 micrograms/L for the remainder of the study (area under the curve, 1150-1400 h, P < 0.001 vs. control). By contrast, in metformin-treated patients (n = 7), neither IGFBP-1 levels nor postprandial peaks were significantly different from those in the control group. Our findings suggest that in patients with NIDDM, the regulation of IGFBP-1 is markedly influenced by the choice of treatment.
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PMID:Choice of treatment affects plasma levels of insulin-like growth factor-binding protein-1 in noninsulin-dependent diabetes mellitus. 753 8

Disproportionate elevation [increased proinsulin/insulin (PI/INS) ratio] of PI immunoreactivity is associated with noninsulin-dependent diabetes mellitus (NIDDM). The nature of this abnormality is not known. To address the question of whether genetic factors contribute to hyperproinsulinemia, we measured fasting levels of PI immunoreactivity, intact INS, and C peptide (CP) in 12 pairs of monozygotic twins discordant for NIDDM for a mean (+/- SEM) period of 9 +/- 3 yr. Thirteen age- and body mass index-matched healthy subjects without any family history of NIDDM acted as controls. The nondiabetic twins had levels of fasting INS, CP, PI, PI/CP, and PI/INS similar to those of control subjects. Fasting levels of PI, and PI/CP and PI/INS ratios were significantly 2- to 3-fold elevated in NIDDM twins compared to those in both nondiabetic twins and control subjects. To investigate whether hyperproinsulinemia in these NIDDM patients was due to a differential elevation of intact PI or conversion intermediates, we analyzed PI profiles in NIDDM twins and normal subjects by high pressure liquid chromatography. PI was heterogeneous and consisted mainly of des(31,32)-PI and intact PI in both NIDDM patients and normal subjects, with no major difference in composition between the groups. Small amounts of des(64,65)-PI (0-11%) were measured in some patients and normal subjects. The results suggest that hyperproinsulinemia is not a genetically determined trait per se in NIDDM. Disproportionately elevated PI levels seem to be related to the actual disease process. Further conversion of intact PI and des(31,32)-PI may be equally impaired in NIDDM.
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PMID:Proinsulin immunoreactivity in identical twins discordant for noninsulin-dependent diabetes mellitus. 762 30

The amounts of immunoreactive proinsulin (IRP), immunoreactive insulin (IRI), and C-peptidelike immunoreactivity (CPR) in six insulinomas and one nesidioblastosis lesion were determined together with those in the surrounding pancreatic tissue. Four non-insulinoma and nondiabetic human pancreases were used as the control. The IRP in the seven tumors ranged from 5.85 micrograms/g to 65.45 micrograms/g (mean +/- SEM, 28.70 +/- 8.01 micrograms/g), while the IRP in the surrounding pancreatic tissue ranged from 2.08 micrograms/g to 11.71 micrograms/g (5.32 +/- 1.76 micrograms/g). Control pancreases had an IRP content of 12.01 +/- 2.36 micrograms/g. The IRI in the seven tumors ranged from 4.02 U/g to 47.97 U/g (14.40 +/- 6.35 U/g), while that in the surrounding pancreatic tissue ranged from 0.28 U/g to 3.64 U/g (2.32 +/- 0.63 U/g). Mean tumor CPR was 206.84 +/- 81.6 micrograms/g and it was 29.16 +/- 9.15 micrograms/g in the surrounding pancreatic tissue. The molar ratio of the IRP to IRI content was 6.83 +/- 1.95% for tumor tissue and 6.24 +/- 2.18% for the surrounding pancreatic tissue. These levels were similar to the ratio in the control pancreases (7.67 +/- 1.88%), in contrast to the higher serum IRP/IRI ratio in the tumor patients.
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PMID:Tumor and serum levels of proinsulin and insulin in insulinoma patients. 795 10

Since insulin negatively controls its own secretion, we examined if insulin also inhibits the secretion of its precursor, proinsulin, in subjects with varying degrees of glucose tolerance. Under comparable hyperinsulinemia (50-70 microU/ml) achieved by the euglycemic insulin clamp technique, plasma C-peptide concentrations were equally suppressed to approximately 40-50% in nonobese subjects with normal glucose tolerance (NGT) (n = 13, 35.5 +/- 3.7%, M +/- SEM), borderline glucose intolerance (BGI) (n = 12, 46.7 +/- 5.6%), and non-insulin-dependent diabetes mellitus (NIDDM) (n = 12, 48.9 +/- 5.4%). In contrast, plasma proinsulin concentrations were slightly but significantly suppressed in NGT (4.1 +/- 0.2 to 3.7 +/- 0.2 pmol/L, P < 0.05), but not in patients with BGI (4.6 +/- 0.3 to 4.8 +/- 0.5 pmol/L, NS) and NIDDM (5.5 +/- 0.5 to 4.9 +/- 0.4 pmol/L, NS). The basal concentrations of proinsulin increased as glucose tolerance declined (P < 0.05 between NGT and NIDDM). These results suggest that the basal secretion of proinsulin by beta-cells seems relatively insensitive to insulin compared with C-peptide, and that the insulin-proinsulin feedback loop is disturbed in glucose-intolerant subjects. Therefore, a defective feedback inhibition of proinsulin secretion by insulin may be partly involved in the disproportionate increase of plasma proinsulin concentrations in patients with NIDDM.
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PMID:Physiological increase in plasma insulin concentration suppresses proinsulin secretion in normal controls but not in subjects with glucose intolerance. 795 67

1. Basal circulating concentrations of islet B cell products were measured using two-site monoclonal antibody-based immunoradiometric assays after a 10 h overnight fast in a group of non-obese subjects with recently diagnosed impaired glucose tolerance (World Health Organization criteria). A group of healthy subjects with normal oral glucose tolerance matched for age and body mass index served as normal controls. 2. Fasting blood glucose concentration was normal in all subjects with mean (+/- SEM) levels of 5.1 +/- 0.2 and 4.8 +/- 0.2 mmol/l (P > 0.1) for the group with impaired glucose tolerance and the healthy control group, respectively. 3. There was no significant difference (P > 0.1) in fasting plasma insulin or C-peptide concentrations between the groups. 4. By contrast, the fasting concentration of intact proinsulin was nearly four-fold higher in the subjects with impaired glucose tolerance than in the matched healthy control subjects (4.5 +/- 1.0 versus 1.2 +/- 0.2 pmol/l, P < 0.005). 5. Similarly, the fasting plasma concentration of 32-33 split proinsulin in the subjects with impaired glucose tolerance was almost twice that of the control subjects (7.4 +/- 1.3 versus 3.9 +/- 0.8 pmol/l, P < 0.02). 6. In conclusion, fasting concentrations of proinsulin-like molecules are elevated in non-obese subjects with newly diagnosed impaired glucose tolerance. This observation is consistent with defective islet B cell proinsulin processing in this syndrome.
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PMID:Hyperproinsulinaemia in impaired glucose tolerance. 814 2

This paper reports beta cell function as assessed during OGTT using specific IRMAs for insulin, intact and 32/33 split proinsulin in subjects with newly diagnosed Type 2 diabetes matched to normal controls. The relationships between insulin and the proinsulins to risk factors for cardiovascular disease were also examined. Similar fasting insulin concentrations but lower 30-min post-glucose-load insulin concentrations were found in diabetic subjects (mean +/- SEM 143 +/- 12 pmol-1 vs 304 +/- 19 (p < 0.001). Subjects with diabetes had increased fasting intact (10.6 +/- 1.1 pmol-1 vs 3.3 +/- 0.2, p < 0.001) and 32/33 split proinsulin concentrations (8.1 +/- 0.9 pmol-1 vs 2.2 +/- 0.3, p < 0.0001). Beta cell dysfunction, as expressed by a reduction in the 30-min insulin to glucose ratio (9.4 +/- 1 vs 34.8 +/- 2.3, p < 0.0001) and an increase in the fasting percentage of total proinsulin-like to total insulin-like molecules (24.5 +/- 9% vs 11.6 +/- 5, p < 0.001), was present in subjects with diabetes. In diabetic subjects beta cell dysfunction and insulin deficiency increased relative to the degree of fasting hyperglycaemia. It seems clear that beta cell dysfunction and insulin deficiency are major features of Type 2 diabetes. Only the fasting concentration of 32/33 split proinsulin positively correlated with both the waist/hip ratio (r = 0.36, p < 0.001), diastolic blood pressure (r = 0.23, p < 0.01) in addition to plasma triglyceride concentration (r = 0.46, p < 0.001). It is questionable whether hyperinsulinaemia plays a pathogenic role in cardiovascular disease in subjects with glucose intolerance.
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PMID:Insulin deficiency rather than hyperinsulinaemia in newly diagnosed type 2 diabetes mellitus. 850 11

This paper describes an immunofluorometric assay (IFMA) for insulin and compares it with the classical radioimmunoassay (RIA). Monoclonal antibodies against insulin were produced and used to develop the IFMA. One, immobilized on microtiter plates, was used for capture, the other, labelled with Europium, was used as tracer antibody. The IFMA presents sensitivity to an amount of insulin of 3 pmol/l and acceptable values for intra- and interassay error. The IFMA presented superimposable curves for human insulin, Arg65/Gly66-split proinsulin and des-Lys64,Arg65, and no cross-reactivity with human proinsulin, Arg32/Glu33-split and des-Arg31,Arg32. The RIA showed 100% cross-reactivity with human proinsulin, 90% with Arg32/Glu33-split, 193% with Arg65/Gly66-split, 340% with des-Arg31,Arg32 and 170% with des-Lys64,Arg65. The assays were used to measure insulin in 300 serum samples from 50 subjects submitted to an oral glucose tolerance test (OGTT). Twenty were normal, 10 had impaired glucose tolerance and 20 non-insulin-dependent diabetes mellitus. The mean value (+/- SEM) obtained by IFMA was 166.7 +/- 12.1 pmol/l and the mean value obtained by RIA was 339.6 +/- 18.6, with a correlation of r = 0.80 (P < 0.01). Comparison of basal insulin levels of the different groups of individuals using IFMA or RIA led to the same conclusions. The area under the curve showed statistically significant differences only for the comparison between normal lean subjects and individuals with impaired glucose tolerance, when measured by RIA. Our data stress the importance of methodology definition when comparing insulin results.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Comparison of the determination of insulin by a monoclonal antibody-based immunofluorometric assay and by radioimmunoassay. 855 73

GH-binding protein (GHBP) is increased in obesity. It is not known whether the increase in GHBP is reversible with weight loss or modulated by acute changes in nutritional intake. To address these questions, we measured GHBP in 18 obese subjects [body mass index (BMI), 40.9 +/- 1.1 kg/m2 (mean +/-SEM)] before and after an average weight loss of 30.3 +/- 4.6 kg and in 18 age- and sex matched normal subjects (BMI, 23.0 +/- 0.4 kg/m2) and studied the effects of a very low calorie diet over 4 days in 5 normal subjects and a subgroup of obese subjects before (n = 6) and after (n = 5) weight loss. GHBP was elevated in the obese subjects compared to levels in age- and sex-matched normal controls (1.48 +/- 0.1 vs. 0.53 +/- 0.1 nmol/L; P < 0.0001). GHBP was positively correlated to BMI and waist circumference (r = 0.71; P < 0.00001 and r = 0.73; P < 0.00001, respectively). In addition, GHBP was positively correlated to insulin as well as proinsulin levels (r = 0.60; P < 0.001 and r = 0.55; P < 0.001, respectively). After diet-induced massive weight loss, GHBP levels were restored to normal in obese subjects (BMI, 27.8 +/- 1.4 kg/m2). Multiple stepwise regression analysis revealed that changes in waist circumference and abdominal sagittal diameter during weight loss were the major determinants of and accounted for 54% of the fall in GHBP levels. Neither insulin nor proinsulin was an independent predictor. No changes were observed in GHBP in normal, obese, or reduced weight obese subjects after 4 days of a very low calorie diet, although mean insulin levels fell significantly in the normal subgroup as well as in the obese subgroup studied after weight loss. In summary, GHBP levels are elevated in obesity, are restored to normal by massive weight loss, and are unaffected by short term hypocaloric feeding. We conclude that GHBP may be regulated by the same or closely related factors that regulate fat mass and abdominal fat mass in particular, but not by insulin or acute changes in nutrition.
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PMID:Serum growth hormone-binding protein in obesity: effect of a short-term, very low calorie diet and diet-induced weight loss. 863 61


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