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Databases, Bibliographic↗
Biomedical subjects
S G Hartling
Publications and source records attributed to S G Hartling.
Proinsulin immunoreactivity in identical twins discordant for noninsulin-dependent diabetes mellitus.
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.
Adult↗
Disproportionately elevated proinsulin levels precede the onset of insulin-dependent diabetes mellitus in siblings with low first phase insulin responses. The Childhood Diabetes in Finland Study Group.
The objective of this study was to test whether levels of proinsulin immunoreactivity (PIM) relative to those of insulin immunoreactivity (IRI) or C-peptide are changed and related to subclinical beta-cell dysfunction in siblings of insulin-dependent diabetes mellitus (IDDM) patients. Twenty-three siblings, previously found positive for islet cell antibodies and/or insulin autoantibodies, were divided into 2 groups according to their first phase insulin response (FPIR) to i.v. glucose tolerance tests (IVGTTs) sequentially performed during an observation period of 2 yr. Eleven siblings had diminished FPIR on at least 1 occasion (group 1), whereas 12 siblings had a normal FPIR on all occasions studied (group 2). All underwent a further IVGTT (0.5 g glucose/kg BW), and serum samples were taken at 0, 1, 3, 6, 10, 20, 30, 40, 50, and 60 min. The 2 groups had comparable median age, female/male ratio, weight, height, fasting blood glucose, immunoreactive insulin, C-peptide, and insulin autoantibodies levels, but group 1 had significantly higher islet cell antibodies levels. Fasting median PIM/IRI and PIM/C-peptide ratios were 2- to 3-fold higher in group 1 [10.5% (range, 1.8-93.8%) vs. 5.2% (range, 1.9-14.3%) and 3.3% (range, 0.4-23.1%) vs. 1.3% (range, 0.7-2.6%; P < 0.05]. Fasting PIM/C-peptide ratios correlated inversely with FPIRs (rs = -0.68; P < 0.01). During glucose stimulation, maximal responses of IRI and C-peptide were 4-fold lower in group 1, and the time of maximal responses of IRI and C-peptide occurred later in group 1 than in group 2. In contrast, no difference in maximal responses of PIM was found, but the time of maximal responses of PIM occurred later in group 1. Nine of 11 siblings in group 1 presented with IDDM 1-28 months after the test, compared to none in group 2. In group 1 a paradoxical inhibitory response of PIM was observed during the first 6 min of the IVGTT. These data indicate that fasting PIM/IRI and/or PIM/C-peptide ratio reflects subclinical beta-cell dysfunction in prediabetic subjects with evidence of immunological beta-cell assault and suggests that an elevated ratio may be an additional marker for later development of IDDM.
Adolescent↗
Proportional proinsulin responses in first-degree relatives of patients with type 2 diabetes mellitus.
Elevated fasting proinsulin immunoreactive material (PIM) has previously been found in patients with type 2 (non-insulin-dependent) diabetes mellitus. It is not known whether this is a genetic trait or whether it is related to the manifestation of type 2 diabetes. Neither is it clear whether the raised fasting insulin immunoreactivity previously observed in first-degree relatives of patients with type 2 diabetes is due to raised PIM. Furthermore, it has not been investigated whether first-degree relatives have altered PIM responses to different secretagogues. To study this, PIM, insulin and C-peptide were measured in patients with type 2 diabetes, in their first-degree relatives and in healthy control subjects in the fasting state and in relatives and controls during a hyperglycemic clamp. At the end of the hyperglycemic clamp, 0.5 mg of glucagon was given intravenously to stress the beta cells further. Fasting PIM concentrations were significantly higher in patients with type 2 diabetes (P < 0.05). These patients did not have significantly elevated fasting insulin levels when corrected for PIM. In the relatives, fasting insulin concentrations were elevated but PIM levels were normal suggesting that the increase in fasting insulin concentrations reflected an increase in true insulin. The incremental PIM, insulin and C-peptide responses to glucose and glucagon in the relatives were not different from those in the controls. We conclude that elevated fasting PIM levels in patients with type 2 diabetes seem not to be a genetic trait.(ABSTRACT TRUNCATED AT 250 WORDS)
Adult↗
Proinsulin levels in newborn siblings of type 1 (insulin-dependent) diabetic children and their mothers.
Elevated proinsulin levels have been observed in healthy first degree relatives of Type 1 (insulin-dependent) diabetic patients. This elevation could reflect a sequele after a previous attack on the beta-cells not necessarily leading to diabetes, or represent a family trait related to the development of diabetes. When cord plasma levels of proinsulin, insulin and C-peptide from 14 newborn siblings of Type 1 diabetic patients were compared with 21 newborn control siblings unrelated to diabetic subjects, no differences were observed. Neither were any differences observed between their mothers at delivery when comparing the same parameters. In cord plasma the proinsulin levels (median and range) were higher than those in plasma from 35 adult fasting women unrelated to diabetic subjects (10, 5-83 pmol/l vs 4, 2-33 pmol/l; p < 0.001) whereas the C-peptide levels (median and range) were lower (0.20, 0.11-0.56 nmol/l vs 0.37, 0.21-0.69 nmol/l; p < 0.001). No differences in insulin levels using a highly specific insulin assay were observed. The results suggest that newborn children have high proinsulin and low C-peptide levels unrelated to heredity of diabetes and that the previously described elevated proinsulin level observed in older first degree relatives of diabetic subjects occurs later in life.
Adult↗
Elevated proinsulin levels related to islet cell antibodies in first-degree relatives of IDDM patients.
OBJECTIVE: To assess whether proinsulin levels are elevated in first-degree relatives of insulin-dependent diabetes mellitus (IDDM) patients and whether there is a relationship between proinsulin levels and the occurrence of immunological markers. RESEARCH DESIGN AND METHODS: Fasting proinsulin concentrations were measured in 85 first-degree relatives (54 siblings, 20 parents, 11 children) of IDDM patients and in 90 age- and weight-matched control subjects with no family history of diabetes mellitus. RESULTS: Fasting proinsulin levels (median, 25th, and 75th percentiles) were 8 pM (range 3.2-14 pM) in first-degree relatives and 1.7 pM (range 1.7-4 pM) in control subjects (P less than 0.0001). Proinsulin was significantly elevated in siblings (7.2 pM, range 3.8-15 pM; P less than 0.0001), parents (9.8 pM, range 6.4-13 pM; P less than 0.0001), and children (6.6 pM, range 1.8-12 pM, P = 0.04) compared with control subjects but without differences between these groups. Islet cell antibody positive (ICA+) IDDM relatives had significantly higher proinsulin levels than ICA- (16 pM; range 7.2-25 vs. 6.9 pM, range 3.1-12 pM; P = 0.02). There was no difference between individuals with and without insulin autoantibodies. No difference in proinsulin levels was observed if the relatives were subdivided according to HLA-DR sharing with the diabetic proband. CONCLUSIONS: Fasting proinsulin concentrations were raised not only in siblings but also in parents and children of IDDM patients. Because proinsulin is more elevated in ICA+ than in ICA- subjects, increased proinsulin levels could reflect minor beta-cell damage due to previous immunological attack.
Adult↗
Separation and quantitation of serum proinsulin and proinsulin intermediates in humans.
Two reversed-phase high-performance liquid chromatographic (RP-HPLC) systems were developed for the separation of human insulin, proinsulin and the major proinsulin intermediates. The individual components were quantified using two enzyme-linked immunosorbent assays for insulin and proinsulin immunore-active material (PIM) after (passive) evaporation of the organic modifier. Serum samples from normal subjects and patients with non-insulin-dependent diabetes mellitus were immunopurified and analysed in one of the RP-HPLC systems. The proportion of PIM relative to insulin immunoreactive material was higher in the diabetic patient compared with that in the normal subject. In both, PIM was heterogeneous, consisting of intact proinsulin and des-proinsulin intermediates.
Chromatography, High Pressure Liquid↗
Follow-up of women with previous GDM. Insulin, C-peptide, and proinsulin responses to oral glucose load.
Gestational diabetes mellitus (GDM) is a strong predictor of glucose intolerance later in life. Former GDM (n = 145) and control (n = 41) subjects were studied 3-4 yr after the index pregnancy. They were subjected to a 75-g oral glucose tolerance test (OGTT) with measurements of insulin, C-peptide, and proinsulin in the basal state and every 30 min for 180 min. In the former GDM group, 5 subjects (3.4%) had developed non-insulin-dependent diabetes mellitus (NIDDM), and 32 (22%) had developed impaired glucose tolerance (IGT; by World Health Organization criteria). In the control group, 2 (4%) had IGT. In the GDM group, IGT or NIDDM was significantly associated with obesity (body mass index [BMI] greater than or equal to 25 kg/m2) and earlier diagnosis of GDM during pregnancy (P less than 0.001). Nonobese (BMI less than 25 kg/m2) GDM subjects with normal glucose tolerance at follow-up had significantly higher mean glucose (P less than 0.01), insulin (P less than 0.05), and proinsulin (P less than 0.001) values during the OGTT than control subjects, whereas there was no significant difference in C-peptide values. A comparison between control subjects with normal OGTT and BMI less than 25 kg/m2 (n = 39) and GDM subjects (n = 39) selected to have a comparable area under the glucose curve, BMI, and age demonstrated no group differences in glucose, C-peptide, or insulin levels, whereas the proinsulin levels were significantly higher (P less than 0.001) during the glucose load. The molar ratio between proinsulin and insulin was also significantly higher among the former GDM subjects.(ABSTRACT TRUNCATED AT 250 WORDS)
Adult↗
Proinsulin and C-peptide at onset and during 12 months cyclosporin treatment of type 1 (insulin-dependent) diabetes mellitus.
An increased proinsulin to C-peptide molar ratio at the onset of Type 1 (insulin-dependent) diabetes mellitus has been suggested. We studied fasting proinsulin levels and proinsulin/C-peptide ratios in the newly diagnosed diabetic subjects participating in the Canadian/European placebo controlled cyclosporin study at entry, during the one year treatment period and six months of follow-up. Available entry data from 176 out of the 188 allocated patients were compared to 60 age and weight matched control subjects. Fasting proinsulin was significantly elevated in male patients compared to male control subjects (p less than 0.01), whereas the levels only tended to be elevated in female patients. The proinsulin/C-peptide ratio was three to fourfold elevated in the diabetic groups of both sexes, (p less than 0.001). Further, proinsulin and C-peptide were studied in 83 cyclosporin and 86 placebo-treated subjects during the trial and follow-up. An additional increase of proinsulin/C-peptide ratio was observed during the first three months of placebo treatment. It remained constantly high for nine months and then declined to entry level. This pattern was not seen in the cyclosporin-treated group, where the ratio was unchanged during the 12 months trial and follow-up. The effect of cyclosporin on the induction of non-insulin requiring remission was unrelated to fasting and glucagon stimulated C-peptide levels at entry, whereas 64% of the cyclosporin-treated against 28% of the placebo-treated subjects (p less than 0.01) went into remission if the proinsulin/C-peptide ratio at entry was above 0.024.(ABSTRACT TRUNCATED AT 250 WORDS)
Adult↗
Effects of dexamethasone on glucose-induced insulin and proinsulin release in low and high insulin responders.
We compared the effects of dexamethasone-induced insulin resistance on B-cell secretory performance in 12 low insulin responders (LIR) and in eight high insulin responders (HIR). A hyperglycemic clamp (120 minutes) was performed before and after the subjects had ingested dexamethasone 3 mg x 2 for 2 1/2 days. Fasting levels of blood glucose increased from 4.60 +/- 0.13 to 5.74 +/- 0.23 mmol/L after dexamethasone in LIR and from 4.37 +/- 0.18 to 5.26 +/- 0.13 mmol/L in HIR. Dexamethasone treatment increased fasting levels of total immunoreactive insulin (IRI), C-peptide, and proinsulin, as well as the proinsulin to IRI ratio to a similar degree in LIR and HIR. The amount of glucose infused to uphold hyperglycemia during the clamp decreased by 54% after dexamethasone in LIR and by 46% in HIR. Mean level of stimulated IRI during the clamp increased after dexamethasone by 43% in LIR and by 53% in HIR. Mean level of stimulated C-peptide increased by 11% (not significant) in LIR and by 24% in HIR. Mean level of stimulated proinsulin increased by 86% in LIR and by 93% in HIR. The effects of dexamethasone on insulin secretion varied among individuals, since steroid treatment failed to affect IRI responses to glucose in two LIR and two HIR. The magnitude of dexamethasone effects on secretion was not correlated to pre-dexamethasone insulin sensitivity as assessed by a somatostatin-insulin-glucose infusion test (SIGIT) or by M/I (glucose infused/insulin level) ratios of the control clamp.(ABSTRACT TRUNCATED AT 250 WORDS)
Adult↗
Elevated proinsulin in healthy siblings of IDDM patients independent of HLA identity.
Based on the recent demonstration of elevated serum proinsulin levels in cystic fibrosis patients with impaired glucose tolerance, it was hypothesized that proinsulin could be an indicator of altered beta-cell function. We therefore analyzed fasting proinsulin levels in 99 siblings of insulin-dependent diabetes mellitus (IDDM) patients, most of them discordant for diabetes for greater than 6 yr. The results from this group were compared with the results from 41 healthy age- and sex-matched control subjects with no family history of diabetes. Median (range) fasting proinsulin in siblings was 8.9 pM (1.7-58 pM) vs. 3.8 pM (less than 1.2-28 pM) in control subjects (P less than .00001). There was no difference between the groups in fasting blood glucose concentrations. Both groups had fasting insulin concentrations within the normal range with a tendency toward lower values in the siblings: 108 pM (60-237 pM) vs. 118 pM (71-175 pM) (P = .07). The 99 siblings were subdivided into groups according to HLA sharing with their diabetic proband. The concentration of proinsulin, insulin, and blood glucose among the groups of 33 HLA-identical, 40 HLA-haploidentical, and 26 nonidentical siblings did not differ significantly. The fasting proinsulin level did not correlate with fasting levels of insulin, blood glucose, age, or body weight. We conclude that fasting proinsulin is elevated in healthy siblings of IDDM patients, whereas fasting insulin is normal or slightly decreased independent of HLA identity with their diabetic sibling. Elevated proinsulin levels could represent a family trait, perhaps mirroring a beta-cell more vulnerable to destruction, or it could reflect previous beta-cell damage that does not lead to IDDM.
Adolescent↗
A nation-wide cross-sectional study of glycosylated haemoglobin in Danish children with type 1 diabetes.
A nation-wide screening for HbA1c was carried out in Denmark. Twenty-one paediatric departments treating children with Type 1 diabetes participated. During a period of 4 months 884 children were included, 93% of all those followed at these centres, representing approximately 70-80% of all children and adolescents with Type 1 diabetes in Denmark. Among the children 351 were less than or equal to 12 years and 533 were adolescents between 12 and 18 years. Children less than or equal to 12 years had a HbA1c concentration of 8.9 +/- 1.5 (+/- SD)% and an insulin dose of 0.71 +/- 0.3 U kg-1 24-h-1. For adolescents HbA1c was significantly higher 9.7 +/- 2.0% (p less than 0.001) and insulin dose significantly increased 0.85 +/- 0.3 U kg-1 24-h-1 (p less than 0.001). Normal range for HbA1c is 4.0-6.5 (mean 5.3)% of total haemoglobin. Boys and girls less than or equal to 12 years had similar HbA1c, but girls received 13% more insulin (p less than 0.001). In the group of adolescents, girls had a HbA1c 4% higher than boys (9.9 +/- 2.0 vs 9.5 +/- 2.0%, p less than 0.025), received 11% more insulin (p less than 0.001), and had 6% higher body mass index (p less than 0.001). A weak correlation was found between insulin dose and the HbA1c level (r = 0.29, p less than 0.001).(ABSTRACT TRUNCATED AT 250 WORDS)
Adolescent↗
Proinsulin, insulin, and C-peptide in cystic fibrosis after an oral glucose tolerance test.
The beta-cell response to an oral glucose load was studied in 22 patients with cystic fibrosis (CF) by means of insulin, C-peptide and proinsulin, and the results compared with those from 20 healthy sex and age matched controls. According to WHO criteria two had diabetes mellitus, eight had impaired glucose tolerance and twelve had normal glucose tolerance. All patients showed lower insulin and C-peptide levels than the controls at 30 minutes. However the insulin and C-peptide responses were sustained so that the areas under the curves were comparable between controls, CF patients with normal glucose tolerance, and CF patients with impaired glucose tolerance. By contrast, the area under the proinsulin curve was significantly higher in the CF patients with impaired glucose tolerance compared with both controls (p less than 0.05) and with the CF normal glucose tolerance group (p less than 0.02). In the CF patients with impaired glucose tolerance the proinsulin level was significantly elevated at 120 minutes (median 50 pmol/l) and at 180 minutes (29 pmol/l) as compared with the controls (24 and 19 pmol/l p less than 0.01) and with the CF patients with normal glucose tolerance (21 and 16 pmol/l p less than 0.01). These data confirm that impaired glucose tolerance and diabetes is frequent in cystic fibrosis. The elevated proinsulin immunoreactive material in CF patients with impaired glucose tolerance may partly compensate for the relative insufficient insulin response found in these patients.
Adolescent↗
Twenty-four hour urinary C-peptide and fasting plasma C-peptide as indicators of metabolic control in 83 insulin dependent diabetic patients.
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Adolescent↗
ELISA for human proinsulin.
A micro enzyme-linked-immunosorbent-assay (ELISA) for monitoring circulating human proinsulin (hPI) was developed. A micro test plate was coated with guinea pig anti-insulin antibody. As labelling system peroxidase-labelled F(ab1)2-fragments of a guinea pig anti-human-C-peptide was used. The detection limit in buffer (95% level) was 0.6 pmol/l corresponding to 0.06 fmol/incubation well and to 1.2 pmol/l in serum, since samples were diluted 50%. Standard operating range was from 0-160 pmol/l. Interassay variation was 9% estimated from two human control materials (assayed within the range 6-9 pmol/l and 9-14 pmol/l, respectively). Insulin in samples did not interfere in concentrations below 400 pmol/l. Human C-peptide, porcine, and bovine proinsulins did not cross-react even at 10 000 pmol/l. In 38 healthy fasting subjects a reference range less than 1.2-13 pmol/l with a median of 4.1 pmol/l was found. Serum from total pancreatectomised patients showed values below the detection limit. The value from a patient with an insulinoma was 263 pmol/l. When stored at -20 degrees C human proinsulin appeared stable in serum or plasma for at least 9 mth. This ELISA, although among the most sensitive immunoassays for human proinsulin, is still not sensitive enough to measure the concentrations expected in samples from IDDM patients in the fasting state. In spite of this the method is useful in characterising beta-cell function in stimulated situations, as well as in the diagnosis of insulinoma.
Animals↗
The effect of exogenous hyperinsulinemia on proinsulin secretion in normal man, obese subjects, and patients with insulinoma.
To examine possible feedback inhibition of insulin on proinsulin secretion, we measured serum proinsulin levels before and after 120 min of euglycemic hyperinsulinemia (90-100 mU/liter) in 11 normal and 7 obese hyperinsulinemic subjects and 6 patients with beta-cell adenoma (n = 4), carcinoma, or hyperplasia. Baseline proinsulin levels accounted for 19%, 14%, and 56% of the total immunoreactive insulin in the 3 groups, respectively. Compared to normal subjects, baseline proinsulin levels were elevated (P less than 0.02) by 4- and 6-fold in obese subjects and patients with autonomous insulin secretion, respectively, but there was an overlap between the groups. In both normal and obese subjects, hyperinsulinemia suppressed proinsulin secretion by 45-50% (P less than 0.02), whereas no response occurred in the patients. Thus, the 120 min values were clearly different in the patients and the normal or obese subjects. After removal of the adenoma in 4 patients, baseline proinsulin levels and the response to hyperinsulinemia were normalized, but they remained elevated after a partial pancreatectomy or tumor removal in the patients with beta-cell hyperplasia or carcinoma. Thus, proinsulin secretion is under negative feedback control of insulin in both normal man and hyperinsulinemic obese subjects. In patients with insulinoma or beta-cell hyperplasia, this control is lost.
Adenoma, Islet Cell↗
Glucose-induced insulin response is reduced and proinsulin response increased in healthy siblings of type 1 diabetic patients.
Glucose-stimulated insulin and proinsulin responses, and insulin sensitivity, were studied in 30 HLA identical, 38 HLA haplo-identical, and 25 HLA non-identical, healthy islet-cell-antibody negative siblings of Type 1 diabetic patients. The results were compared with 41 age- and sex-matched healthy subjects with no diabetes in the family. The proinsulin-corrected insulin response to an intravenous glucose infusion test was significantly lower among siblings when insulin sensitivity was taken into account (1.65 (inter-quartile range 1.20-2.64) vs 2.18 (1.65-3.28) nmol mmol-1 min, p = 0.04). Proinsulin values were consistently higher among siblings than among control subjects (peak values 50.0 vs 38.0 pmol l-1 (p = 0.004)). When proinsulin release was corrected for individual insulin sensitivity this difference remained. The results suggest disturbed islet B-cell function, unrelated to HLA identity or the presence of circulating islet cell antibodies.
Adolescent↗
Interaction of ethanol and glipizide in humans.
The hypoglycemic effect of 2.5 mg glipizide and the potentiation of this effect by ethanol were studied in 10 normal-weight nondiabetic subjects. The reductions in blood glucose concentrations were similar in time of onset and extent (2 mM) whether glipizide was taken alone or in combination with ethanol. However, the return of blood glucose toward fasting level was delayed by ethanol. Beta-Cell secretory activity, evaluated from the concentrations of insulin and C-peptide, was unchanged by ethanol. The serum glipizide concentrations were reproducible within subjects, whereas there was a considerable interindividual variation. This heterogeneity in the rise in glipizide concentration was strongly correlated with blood glucose fall and insulin secretion. Thus, ethanol can prolong but does not augment the hypoglycemia induced by glipizide. The heterogeneity in glipizide concentration seems to be caused by an interindividual variation in kinetics.
Adult↗