Pain trajectories and neuropathic pain symptoms following lung cancer surgery: A prospective cohort study.

BACKGROUND: Persistent postsurgical pain (PPSP) after lung cancer surgery is common and current definitions are based on evaluations at a single time point after surgery. Pain intensity and symptoms may however fluctuate and change over time, and be impacted by multiple and shifting factors. Studies of postoperative recovery patterns and transition from acute to chronic pain are needed for further investigation of preventive measures and treatments to modify unfavourable recovery paths. METHODS: In this explorative study, 85 patients undergoing surgery due to either presumptive or confirmed lung cancer reported pain intensities bi-monthly for 12 months. Pain trajectories during recovery were investigated, using group-based trajectory modelling. Associations with possible risk factors for PPSP, including clinical variables and anxiety and depression score (HADS), were also explored. RESULTS: A trajectory model containing three 12-month pain recovery groups was computed. One group without PPSP fully recovered (50%) within two to three months. Another group with mild-intensity PPSP followed a protracted recovery trajectory (37%), while incomplete recovery was observed in the last group (13%). Acute postoperative pain and younger age were associated with a less favourable recovery trajectory. More neuropathic pain symptoms were observed in patients with incomplete recovery. CONCLUSIONS: Three clinically relevant recovery trajectories were identified, based on comprehensive pain tracking. Higher acute postoperative pain intensity was associated with an unfavourable pain recovery trajectory. SIGNIFICANCE STATEMENT: Understanding the transition from acute to chronic postoperative pain and identifying preoperative risk factors is essential for the development of targeted treatments and the implementation of preventive measures. This study (1) identified distinct recovery trajectories based on frequent pain assessment follow-ups for 12 months after surgery and (2) evaluated risk factors for unfavourable postoperative pain recovery paths. Findings suggest that early higher postoperative pain intensity is associated with an unfavourable long-term recovery path.

Low level of tissue plasminogen activator activity in non-diabetic patients with a first myocardial infarction.

OBJECTIVE: To explore the role of tissue plasminogen activator (tPA) activity and plasminogen activator inhibitor type 1 (PAI-1) in survivors of a first myocardial infarction (MI). Insulin and proinsulin were analysed as potential risk factors. DESIGN: Case-control study in northern Sweden. SUBJECTS: A total of 115 patients under 65 years of age with a first MI were enrolled and recalled for further examination 3 months later. Twenty-seven patients were excluded, 17 with known diabetes and 10 who did not come to the follow-up, giving a final number of 88 patients, 73 men and 15 women. Patients were age- and sex-matched with control subjects drawn from the local cohort in the MONICA population survey 1994. MAIN OUTCOME MEASURES: We compared MI patients and controls using univariate and multiple regression analyses including odds ratios (OR). RESULTS: PAI-1 activity, fibrinogen, postload insulin and -proinsulin were significantly higher and tPA activity significantly lower in MI patients in the univariate analysis. In a multiple regression analysis, including also age, sex and cardiovascular risk factors, these parameters were divided in quartiles. The lowest quartile of tPA activity was significantly associated with MI (OR = 19.1; CI 3.0-123) together with the highest quartiles of fibrinogen (OR = 25; CI 5.2-120) but other variables were not. CONCLUSION: Low tPA activity, i.e. low fibrinolytic activity, characterized nondiabetic subjects after a first MI which is not explained by concomitant disturbances in metabolic and anthropometric variables.

Effects of soy supplementation on blood lipids and arterial function in hypercholesterolaemic subjects.

BACKGROUND: Studies on soy supplementation suggest a cardioprotective potential. OBJECTIVE: To examine the effects on LDL cholesterol and arterial function as a result of dietary enrichment with soy supplementation. DESIGN: A Randomized, double blind, parallel intervention trial. SETTING: Department of Endocrinology and Metabolism C, Aarhus University Hospital, and Department of Human Nutrition, The Royal Veterinary and Agricultural University, Denmark. SUBJECTS: In all, 100 hypercholesterolaemic but otherwise healthy subjects were included in the study of which 89 completed it. INTERVENTIONS: Subjects were randomly assigned to 24 weeks of daily intake of either a soy supplement, Abalon (30 g soy protein, 9 g cotyledon fibre and 100 mg isoflavones) or placebo (30 g of casein). The soy supplement and placebo were provided in two sachets daily that were stirred in water. Fasting plasma lipids, TNF-alpha, homocysteine, insulin sensitivity, homeostasis model assessment (HOMA-IR), serum insulin, serum glucose, blood pressure as well as Glucagon-like peptide 1 (GLP-1), glucose-dependent insulinotropic peptide (GIP) and plasma lipids to a fat-rich meal were recorded before and after the intervention. In a sub study in 32 subjects, arterial dilatory capacity, compliance, and distensibility were recorded before and after the intervention. RESULTS: In the main study, no difference in fasting plasma lipid levels or insulin sensitivity was found between soy-based supplement and placebo. A significant postprandial increase in GIP to the meal test was observed in the soy group (P < 0.05). In a substudy, no difference between the groups in changes in flow-mediated vasodilatation (P = 0.84) was detected, while the soy supplementation caused a reduction in LDL and total cholesterol. CONCLUSIONS: No significant effects on blood lipids were observed in the main study to a soy supplementation in hypercholesterolaemic subjects after 24 weeks. In the substudy, the soy supplementation, however, reduced LDL and total cholesterol but did not influence markers of arterial function.

The effect of a rapid weight loss on lipid profile and glycemic control in obese type 2 diabetic patients.

OBJECTIVE: To test the effect of low calorie diet (LCD) on body weight, lipid profile, and glycemic control in obese type 2 diabetes mellitus (DM) patients. DESIGN: Dietary intervention. SETTING: Department of Human Nutrition, Copenhagen. SUBJECTS: Outpatients: 11 type 2 DM patients (three males/eight females) (10 completed), four on oral hypoglycemic agents (OHA). Body mass index (BMI) 36.8 +/- 5.5 kg/m2 and age 62 +/- 5.7 y. INTERVENTIONS: In all, 8 weeks full meal-replacement diet: eight sachets of a nutrition powder (Nutrilett, 850 kcal/day). Lipid profile assessed by NMR spectroscopy. RESULTS: Mean body weight fell by 10.9 kg (approximately 11%, P<0.001). Fasting insulin, fasting blood glucose, hemoglobin A1c, fasting plasma triglycerides, total cholesterol, and low-density lipoprotein (LDL) cholesterol fell significantly. There were large positive changes (statistically insignificant) in LDL subclass distribution and a similar shift in high-density lipoprotein subclass distribution. Medication was discontinued in all four subjects taking OHA for 2 weeks prior to the intervention and throughout the whole 8-week intervention period. CONCLUSION: LCD is effective in improving glycemic control and blood lipids through weight loss in overweight type 2 DM patients.

The association between leptin and proinsulin is lost with central obesity.

OBJECTIVE: Hyperproinsulinaemia and hyperleptinaemia are interrelated features of the insulin resistance syndrome that are linked to the prospective risk of cardiovascular diseases. Whether the association between leptin and proinsulin is different between groups displaying different degrees of risk for cardiovascular diseases is not known. We therefore examined this association in men versus women and in pre- versus postmenopausal women from a population-based sample. DESIGN AND SUBJECTS: Healthy subjects (n = 158; 85 men and 73 pre- and postmenopausal women) from the Northern Sweden Monitoring of Trends and Determinants in Cardiovascular Disease population were studied with a cross-sectional design. METHODS: Anthropometric measurements (body mass index and waist circumference) and oral glucose tolerance tests were performed. Enzyme-linked immunosorbent assays were used for the analyses of specific insulin and proinsulin, and radioimmunoassay for leptin. Insulin resistance and beta-cell function were calculated according to the homeostasis assessment model. Partial correlation coefficients adjusted for age and measures of adiposity were calculated and multiple linear regression analyses were performed with leptin as dependent variable. RESULTS: In nonobese men and premenopausal women and in obese postmenopausal women, leptin was significantly associated with proinsulin after stratification for waist circumference. Furthermore, a multivariate analyses taking age and measures of adiposity into account, showed that high fasting proinsulin was a significant predictor of high leptin in these groups. In contrast, this association was lost with increasing central obesity in men and premenopausal women. CONCLUSIONS: This study shows that both the degree of adiposity and the hormonal milieu influence the association between circulating leptin and proinsulin in a normal population. Therefore, the insulin resistance syndrome seems to be characterized by lost association between leptin and proinsulin, which may be explained by dysfunction in the adipoinsular axis.

Hyperproinsulinemia and proinsulin-to-insulin ratios in Swedish middle-aged men: association with glycemia and insulin resistance but not with family history of diabetes.

Elevated proinsulin and proinsulin/insulin ratios are features of abnormal beta-cell function in type 2 diabetes. The participation of genetic factors is disputed. The authors wished to investigate relations between family history of diabetes on one hand and proinsulin as well as proinsulin/immunoreactive insulin ratios on the other. A large, population-based sample of Swedish men aged 35-54 years in 1992 was studied. Subjects without known diabetes were selected either to have a strong family history of diabetes (n = 1,619) or no history of the disease (n = 1,495). An oral glucose tolerance test detected 172 subjects with impaired glucose tolerance and 55 subjects with previously unknown diabetes according to World Health Organization 1985 criteria. In multiple regression analysis, fasting levels of proinsulin and proinsulin/insulin ratios were positively associated both with the 2-hour glucose level (as a continuous variable) and with obesity, whereas a negative association was found with birth weight. No association was found with family history of diabetes or with chronologic age. These findings indicate that elevated proinsulin and proinsulin/insulin ratios are secondary to increased demands on beta-cell secretion induced by hyperglycemia and insulin resistance with no discernible influence of family history of diabetes.

Circulating IGF binding protein-1 is inversely associated with leptin in non-obese men and obese postmenopausal women.

OBJECTIVE: Hyperleptinaemia and hyperinsulinaemia interrelate to insulin-like growth factor binding protein 1 (IGFBP-1), and disturbances in the growth hormone-IGF-I axis are linked to obesity and cardiovascular diseases. However, whether the association between leptin and the GH-IGF-I axis is altered with increasing obesity is not known. We therefore examined the relationship between leptin, IGF-I, IGFBP-1, insulin and proinsulin in men and women with or without obesity in a population study. DESIGN AND SUBJECTS: Healthy subjects (n=158; 85 men and 73 pre- and postmenopausal women) from the Northern Sweden MONICA (Monitoring of Trends and Determinants in Cardiovascular Disease) population were studied with a cross-sectional design. METHODS: Anthropometric measurements (body mass index (BMI) and waist circumference) and oral glucose tolerance tests were performed. Radioimmunoassays were used for the analyses of leptin, IGF-I and IGFBP-1, and ELISAs for specific insulin and proinsulin. RESULTS: Leptin inversely correlated to IGFBP-1 in non-obese men (P<0.05) and obese postmenopausal women (P<0.05). In contrast, leptin did not correlate to IGF-I. IGFBP-1 was also significantly associated with proinsulin in non-obese men (P<0.01) and non-obese premenopausal women (P<0.05). The association between leptin and IGFBP-1 was lost after adjustment for insulin. In multivariate analyses taking measures of adiposity into account, low proinsulin, and IGF-I in combination with old age, but not leptin, predicted high IGFBP-1 levels. CONCLUSIONS: Leptin was inversely associated with IGFBP-1 in non-obese men and obese postmenopausal women, and proinsulin was inversely associated with IGFBP-1 in non-obese men and premenopausal women. However, these associations were lost with increasing central obesity in men and premenopausal women and after control for insulin. Therefore, this study suggests (i) that leptin is of minor importance for regulation of IGFBP-1 levels and (ii) that the insulin resistance syndrome is characterised by an altered relationship between leptin, IGFBP-1 and insulin.

Neonatal Type I diabetes associated with maternal echovirus 6 infection: a case report.

AIMS/HYPOTHESIS: Neonatal diabetes mellitus is rare, and it has not been associated with beta-cell autoimmunity. Enteroviral infections during pregnancy have been implicated as a risk factor for the later development of Type I (insulin-dependent) diabetes mellitus. We now report of a baby girl who was born severely growth-retarded with neonatal insulin-deficient diabetes, and look for evidence of intrauterine enteroviral infections and beta-cell targeted autoimmunity. METHODS: Diabetes-associated autoimmunity was studied by measurement of several types of islet cell reactive autoantibodies. The infant's T-cell responses to insulin and enterovirus antigens were recorded and enterovirus antibodies were measured both from the mother and the child. RESULTS: Several types of diabetes-associated autoantibodies were detected postnatally, including insulin autoantibodies, conventional islet cell autoantibodies and glutamic acid decarboxylase antibodies, whereas no autoantibodies were observed in the mother. The infant's T-cells showed reactivity to insulin and purified enterovirus particles. Based on serological studies, the pathogenetic process could have been triggered by an echovirus 6 infection during pregnancy. The patient's diabetes has been permanent, although there were signs of endogenous insulin production for several months. Exocrine pancreatic insufficiency was diagnosed at the age of 1 year. CONCLUSION/INTERPRETATION: These observations suggests that enteroviral infections may induce beta-cell autoimmunity even in utero.

Evaluation of beta-cell secretory capacity using glucagon-like peptide 1.

OBJECTIVE: Beta-cell secretory capacity is often evaluated with a glucagon test or a meal test. However, glucagon-like peptide 1 (GLP-1) is the most insulinotropic hormone known, and the effect is preserved in type 2 diabetic patients. RESEARCH DESIGN AND METHODS: We first compared the effects of intravenous bolus injections of 2.5, 5, 15, and 25 nmol GLP-1 with glucagon (1 mg intravenous) and a standard meal (566 kcal) in 6 type 2 diabetic patients and 6 matched control subjects. Next, we studied another 6 patients and 6 control subjects and, in addition to the above procedure, performed a combined glucose plus GLP-1 stimulation, where plasma glucose was increased to 15 mmol/l before injection of 2.5 nmol GLP-1. Finally, we compared the insulin response to glucose plus GLP-1 stimulation with that observed during a hyperglycemic arginine clamp (30 mmol/l) in 8 patients and 8 control subjects. RESULTS: Peak insulin and C-peptide concentrations were similar after the meal, after 2.5 nmol GLP-1, and after glucagon. Side effects were less with GLP-1 than with glucagon. Peak insulin and C-peptide concentrations were as follows (C-peptide concentrations are given in parentheses): for patients (n = 12): meal, 277 +/- 42 pmol/l (2,181 +/- 261 pmol/l); GLP-1 (2.5 nmol), 390 +/- 74 pmol/l (2,144 +/- 254 pmol/l); glucagon, 329 +/- 50 pmol/l (1,780 +/- 160 pmol/l); glucose plus GLP-1, 465 +/- 87 pmol/l (2,384 +/- 299 pmol/l); for control subjects (n = 12): meal, 543 +/- 89 pmol/l (2,873 +/- 210 pmol/l); GLP-1, 356 +/- 51 pmol/l (2,001 +/- 130 pmol/l); glucagon, 420 +/- 61 pmol/l (1,995 +/- 99 pmol/l); glucose plus GLP-1, 1,412 +/- 187 pmol/l (4,391 +/- 416 pmol/l). Peak insulin and C-peptide concentrations during the hyperglycemic arginine clamp and during glucose plus GLP-1 injection were as follows: for patients: 475 +/- 141 pmol/l (2,295 +/- 379 pmol/l) and 816 +/- 268 pmol/l (3,043 +/- 508 pmol/l), respectively; for control subjects: 1,403 +/- 308 pmol/l (4,053 +/- 533 pmol/l) and 2,384 +/- 452 pmol/l (6,047 +/- 652 pmol/l), respectively. CONCLUSIONS: GLP-1 (2.5 nmol = 9 microg) elicits similar secretory responses to 1 mg glucagon (but has fewer side effects) and a standard meal. Additional elevation of plasma glucose to 15 mmol/l did not enhance the response further. The incremental response was similar to that elicited by arginine, but hyperglycemia had an additional effect on the response to arginine.

High proinsulin levels precede first-ever stroke in a nondiabetic population.

BACKGROUND AND PURPOSE: Diabetic subjects have a 3- to 6-fold increased risk for stroke compared with nondiabetic subjects, and hyperinsulinemia shows strong and consistent associations with a cluster of cardiovascular risk factors. Methods separating proinsulin from (true) insulin have demonstrated proinsulin to be more strongly associated with cardiovascular disease than insulin. The present study evaluates the associations between first-ever stroke, proinsulin, and insulin. METHODS: In this incident case-referent study of a nondiabetic population, 94 cases of first-ever stroke (59 men and 35 women) were individually age- and sex-matched to 178 referents. Blood sampling was collected before the stroke event. Proinsulin and insulin were measured with highly sensitive 2-site sandwich enzyme-linked immunosorbent assays. RESULTS: In the study population, high proinsulin concentration more than tripled the risk for first-ever stroke after adjustments for total cholesterol, systolic blood pressure, smoking, body mass index, and insulin, with an odds ratio of 3.4 (95% CI, 1.4 to 8.4). In women the risk was even more pronounced, with an odds ratio of 13.7 (95% CI, 1.3 to 146). Synergy was found between proinsulin and systolic blood pressure. In women, synergy was also found between proinsulin and diastolic blood pressure as well as between insulin and both blood pressures. CONCLUSIONS: High levels of proinsulin may predict later occurrence of first-ever stroke in a nondiabetic population.

High proinsulin concentration precedes acute myocardial infarction in a nondiabetic population.

Hyperinsulinemia has been shown to have strong and consistent associations with a cluster of cardiovascular risk factors. Yet the associations between hyperinsulinemia and coronary heart disease (CHD) have been weak, at best, and often inconsistent. Most previous studies have analyzed the insulin level using a radioimmunoassay method, which does not separate proinsulin from intact (true) insulin. New methods separating the two have demonstrated that proinsulin may be at least as strongly or even more strongly associated than intact insulin with a CHD-promoting risk factor profile. In this incident case-control study of a nondiabetic population, 67 cases of first acute myocardial infarction (AMI) were compared with 127 individually age- and sex-matched controls. Blood sampling was collected prior to disease outcome. Proinsulin and intact insulin levels were measured using highly sensitive two-site sandwich enzyme-linked immunosorbent assays (ELISAs). The highest quartile of proinsulin, in contrast to intact insulin, showed a greater than threefold increase in AMI compared with the lowest quartile, with an odds ratio (OR) and 95% confidence interval (CI) of 3.5 and 1.2 to 9.9, respectively. The increased risk of AMI persisted after controlling for total cholesterol, smoking status, diastolic blood pressure, and antihypertensive medication, and disappeared after additional control was used for the body mass index. High levels of proinsulin, even in a nondiabetic population, seem to be a strong and independent risk factor for AMI. The mechanism underlying the relationship may be direct via effects on fibrinolysis or, probably more plausibly, indirect, where proinsulin is a marker of an underlying metabolic disturbance.

The effect of the deterioration of insulin sensitivity on beta-cell function in growth-hormone-deficient adults following 4-month growth hormone replacement therapy.

The purpose of the present study was to evaluate the combined effect of GH treatment on body composition and glucose metabolism, with special focus on beta-cell function in adult GHD patients. In a double-blind placebo-controlled design, 24 GHD adults (18M/6F), were randomized to 4 months treatment with biosynthetic GH 2 IU/m2s.c. daily (n =13) or placebo (n =11). At inclusion and 4 months later an oral glucose tolerance test (OGTT), a frequently sampled intravenous glucose tolerance test (FSIGT) and dual-energy X-ray absorptiometry (DXA) whole-body scanning were performed. During the study period, body weight decreased 1.6 kg from 94.0 +/- 18.7 to 92.4 +/- 19.4 kg (mean +/- SD) (P<0.05) in the GH-treated group, but remained unchanged in the placebo group. Fat mass decreased from 32.4 +/- 9.6 to 28.1 +/- 10.5 kg (P<0.001), whereas lean body mass increased from 58.3 +/- 11.5 to 61.0 +/- 11.7 kg (P<0.01) in the GH-treated group. Treatment with GH for 4 months resulted in a significant increase in fasting blood glucose (before GH 5.0 +/- 0.3 and after 5.4 +/- 0.6 mmol/l, P<0.05), fasting plasma insulin (before GH 38.4 +/- 30.2 and after 55.3 +/- 34.7 pmol/l, P<0.02) and fasting proinsulin (before 8. 1 +/- 6.7 and after 14.6 +/- 16.1 pmol/l, P<0.05). The insulin sensitivity index SI, estimated by Bergmans Minimal Model, decreased significantly [before GH 1.1 +/- 0.7 and after 0.4 +/- 0.2 10(-4)(min x pmol/l), P<0.003]. The non-insulin-dependent glucose uptake (glucose effectiveness SG did not change (before GH 0.017 +/- 0.005 and after 0.015 +/- 0.006 min-1, NS). Insulin secretion was enhanced during GH therapy, but insufficiently to match the changes in SI, resulting in a higher blood glucose level during an OGTT. Blood glucose at 120 min was 5.5 and 6.3 mmol/l before and after GH treatment, respectively (P = 0.07). One patient developed impaired glucose tolerance. Short-term GH replacement therapy in a dose of about 2 IU/m2 daily in GHD adults induces a reduction in insulin sensitivity, despite favourable changes in body composition, and an inadequate enhancement of insulin secretion.

Intact proinsulin and beta-cell function in lean and obese subjects with and without type 2 diabetes.

OBJECTIVE: Type 2 diabetes is a heterogeneous disease in which both beta-cell dysfunction and insulin resistance are pathogenetic factors. Disproportionate hyperproinsulinemia (elevated proinsulin/insulin) is another abnormality in type 2 diabetes whose mechanism is unknown. Increased demand due to obesity and/or insulin resistance may result in secretion of immature beta-cell granules with a higher content of intact proinsulin. RESEARCH DESIGN AND METHODS: We investigated the impact of obesity on beta-cell secretion in normal subjects and in type 2 diabetic patients by measuring intact proinsulin, total proinsulin immunoreactivity (PIM), intact insulin, and C-peptide (by radioimmunoassay) by specific enzyme-linked immunosorbent assays in the fasting state and during a 120-min glucagon (1 mg i.v.) stimulation test. Lean (BMI 23.5 +/- 0.3 kg/m2) (LD) and obese (30.1 +/- 0.4 kg/m2) (OD) type 2 diabetic patients matched for fasting glucose (10.2 +/- 0.6 vs. 10.3 +/- 0.4 mmol/l) were compared with age- and BMI-matched lean (22.4 +/- 0.6 kg/m2) (LC) and obese (30.8 +/- 0.9 kg/m2) (OC) normal control subjects. RESULTS: Diabetic patients (LD vs. LC and OD vs. OC) had elevated fasting levels of intact proinsulin 6.6 +/- 1.0 vs. 1.6 +/- 0.3 pmol/l and 7.7 +/- 2.0 vs. 1.2 +/- 0.2 pmol/l; PIM: 19.9 +/- 2.5 vs. 5.4 +/- 1.0 pmol/l and 29.6 +/- 6.1 vs. 6.1 +/- 0.9 pmol/l; and total PIM/intact insulin: 39 +/- 4 vs. 15 +/- 2% and 35 +/- 5 vs. 13 +/- 2%, all P < 0.01. After glucagon stimulation, PIM levels were disproportionately elevated (PIM/intact insulin based on area under the curve analysis) in diabetic patients (LD vs. LC and OD vs. OC): 32.6 +/- 6.7 vs. 9.2 +/- 1.1% and 22.7 +/- 5.2 vs. 9.1 +/- 1.1%, both P < 0.05. Intact insulin and C-peptide net responses were significantly reduced in type 2 diabetic patients, most pronounced in the lean group. The ratio of intact proinsulin to PIM was higher in diabetic patients after stimulation in both LD versus LC: 32 +/- 3 vs. 23 +/- 2%, and OD versus OC: 28 +/- 4 vs. 16 +/- 2%, both P < 0.01. In obese normal subjects, intact proinsulin/PIM was lower both in the fasting state and after glucagon stimulation: OC versus LC: 22 +/- 3 vs. 33 +/- 3% (fasting) and 16 +/- 2 vs. 23 +/- 2% (stimulated), both P < 0.05. CONCLUSIONS: Increased secretory demand from obesity-associated insulin resistance cannot explain elevated intact proinsulin and disproportionate hyperproinsulinemia in type 2 diabetes. This abnormality may be an integrated part of pancreatic beta-cell dysfunction in this disease.

Analysis of the relationship between fasting serum leptin levels and estimates of beta-cell function and insulin sensitivity in a population sample of 380 healthy young Caucasians.

OBJECTIVE: Circulating leptin levels correlate positively with the degree of obesity and prolonged hyperinsulinaemia increases serum leptin levels. Moreover, insulin secreting beta-cells express functional leptin receptors indicating a functional relationship between leptin and insulin. The aim of this study was to examine the relationship between fasting serum leptin levels and measures of insulin sensitivity and beta-cell function in a population-based sample of 380 young healthy Caucasians. DESIGN AND METHODS: Multiple regression analysis was employed to analyse the relationship between fasting serum leptin levels and levels of fasting serum insulin, insulin sensitivity index and acute insulin response (AIR) in a population-based study of 380 young healthy Caucasians who underwent a combined intravenous glucose and tolbutamide tolerance test. RESULTS AND CONCLUSION: Serum leptin levels were positively correlated to measures of adiposity and were 3.2 times higher in women than in men (P<0.00001). In multiple regression analyses adjusting for age, percentage body fat, waist circumference and maximal aerobic capacity, a significant positive correlation was observed between the fasting serum leptin concentrations and both fasting serum insulin levels (P<0.0001) and AIR (P = 0.014) for women. No significant interrelation of these variables was found in men. However, for both genders a significant negative correlation was observed between fasting serum leptin levels and measures of insulin sensitivity index (P = 0.007).

Insulin management and metabolic control of type 1 diabetes mellitus in childhood and adolescence in 18 countries. Hvidøre Study Group on Childhood Diabetes.

Insulin regimens and metabolic control in children and adolescents with Type 1 diabetes mellitus were evaluated in a cross-sectional, non-population-based investigation, involving 22 paediatric departments, from 18 countries in Europe, Japan, and North America. Blood samples and information were collected from 2873 children from March to August 1995. HbA1c was determined once and analysed centrally (normal range 4.4-6.3%, mean 5.4%). Year of birth, sex, duration of diabetes, height, body weight, number of daily insulin injections, types and doses of insulin were recorded. Average HbA1c in children under 11 years was 8.3 +/- 1.3% (mean +/- SD) compared with 8.9 +/- 1.8% in those aged 12-18 years. The average insulin dose per kg body weight was almost constant (0.65 U kg(-1) 24 h(-1)) in children aged 2-9 years for both sexes, but there was a sharp increase during the pubertal years, particularly in girls. The increase in BMI of children with diabetes was much faster during adolescence compared to healthy children, especially in females. Sixty per cent of the children (n = 1707) used two daily insulin injections while 37% (n = 1071) used three or more. Of those on two or three injections daily, 37% used pre-mixed insulins, either alone or in combination with short- and intermediate-acting insulin. Pre-adolescent children on pre-mixed insulin showed similar HbA1c levels to those on a combination of short- and long-acting insulins, whereas in adolescents significantly better HbA1c values were achieved with individual combinations. Very young children were treated with a higher proportion of long-acting insulin. Among adolescent boys, lower HbA1c was related to use of more short-acting insulin. This association was not found in girls. We conclude that numerous insulin injection regimens are currently used in paediatric diabetes centres around the world, with an increasing tendency towards intensive diabetes management, particularly in older adolescents. Nevertheless, the goal of near normoglycaemia is achieved in only a few.

[Autoimmune insulin syndrome. The first Danish case report]. / Autoimmunt insulinsyndrom. Forste danske tilfoelde.

This is the first case published in Denmark of autoimmune insulin syndrome (mb. Hirata). The patient, a 53 year old female suffering from a rheumatoid systemic disease, demonstrated high concentrations of autoimmune insulin antibodies in serum, a diabetic glucose tolerance test and recurrent postprandial hypoglycaemic attacks.

First direct assay for intact human proinsulin.

We describe a sensitive two-site sandwich enzyme-linked immunosorbent assay for the measurement of intact human proinsulin in 100 microL of serum or plasma. The assay is based on the use of two monoclonal antibodies specific for epitopes at the C-peptide/insulin A chain junction and at the insulin B chain/C-peptide junction, respectively. Cross-reactivities with insulin, C-peptide, and the four proinsulin conversion intermediates were negligible. The detection limit in buffer was 0.2 pmol/L (3 standard deviations from zero). The working range was 0.2-100 pmol/L. The mean intra- and interassay coefficients of variation were 2.4% and 8.9%, respectively. The mean recovery of added proinsulin was 103%. Dilution curves of 40 serum samples are parallel to the proinsulin calibration curve. Proinsulin concentrations in 20 fasting healthy subjects were all above the limit of detection: median (range), 2.7 pmol/L (1.1-6.9 pmol/L). Six fasting non-insulin-dependent diabetes mellitus and five insulinoma patients had proinsulin concentrations significantly higher than healthy subjects: median (range), 7.7 pmol/L (3.2-18 pmol/L) and 153 pmol/L (98-320 pmol/L), respectively.

Longitudinal study of fasting proinsulin in 148 siblings of patients with insulin-dependent diabetes mellitus. Study Group on Childhood Diabetes in Finland.

OBJECTIVE: To follow proinsulin immunoreactive material (PIM) in healthy siblings from the time of diagnosis of insulin-dependent diabetes mellitus (IDDM) in the proband, for at least 2 years. DESIGN AND METHODS: The study comprised 148 siblings representing 112 families. The siblings were recruited from the nationwide 'Childhood Diabetes in Finland' study and tested for immunological markers. If a sibling was found positive for islet cell antibodies (ICA) or insulin autoantibodies (IAA), PIM sampling was extended beyond 2 years. RESULTS: Of the 148 siblings, 12 developed IDDM 3-53 months after the diagnosis in the proband. Eleven of these siblings exhibited initially normal PIM concentrations. In nine siblings, samples were available both more than 6 months and during the last 6 months before the diagnosis of IDDM; PIM concentrations increased in seven, remained unchanged in one, and decreased in one in the period up to the diagnosis of IDDM (P < 0.05). Median PIM concentration did not change significantly during the examination period of 2 years in the 136 siblings who did not contract IDDM. Constantly increased PIM concentrations were found in 12 of the 136 siblings who did not develop IDDM. These 12 siblings were all ICA negative. CONCLUSION: In healthy siblings of IDDM patients exhibiting an initially low PIM concentration, an abrupt increase in PIM seems to precede the clinical manifestation of IDDM within 0-6 months. However, there were too few patients available to close follow-up to allow calculation of any predictive value of this increase. Persistently increased PIM concentrations were present in some healthy siblings who did not develop IDDM. The reason for that finding remains unclear, but it could be associated with previous B cell damage.

Proinsulin, intact insulin, and fibrinolytic variables and fibrinogen in healthy subjects. A population study.

OBJECTIVE: As high serum insulin predicts impaired fibrinolysis and proinsulin reacts in most conventional insulin assays, we hypothesized that proinsulin could link low fibrinolytic activity and hyperinsulinemic conditions. RESEARCH DESIGN AND METHODS: We explored the relationship between fibrinolysis and plasma fibrinogen on the one hand and specific insulin and proinsulin on the other, in a healthy population sample of 165 men and women, 25-74 years of age, from the Northern Sweden MONICA (Monitoring of Trends and Determinants in Cardiovascular Disease) Study. Specific insulin and proinsulin were measured by enzyme-linked immunosorbent assay. Partial correlation coefficients, adjusted for age and sex, were calculated. RESULTS: Plasma fibrinogen levels were related to insulin (r = 0.25, P < 0.01) and proinsulin (r = 0.29, P < 0.001), as was plasminogen activator inhibitor (PAI)-1 activity (r = 0.36 and r = 0.29, respectively; P < 0.001). Tissue Plasminogen activator (tPA) activity correlated inversely to insulin (r = 0.35, P < 0.001) and proinsulin (r = - 0.36, P < 0.001). In a multivariate analysis taking also smoking and anthropometric and metabolic measurements into account, fasting proinsulin was a significant predictor of high plasma fibrinogen level. Insulin and proinsulin levels were not related to tPA activity. High levels of postload insulin, triglycerides, and diastolic blood pressure, but not proinsulin, predicted high PAI-l activity. CONCLUSIONS: In a healthy population, the relationship previously described between high insulin levels and impaired fibrinolysis is not attributable to confounding from proinsulin. Elevated proinsulin levels are associated with high fibrinogen levels.

A hyperinsulinaemic, sequentially eu- and hypoglycaemic clamp test to characterize autonomous insulin secretion in patients with insulinoma.

To better characterize autonomous insulin secretory behaviour in insulinoma patients and to establish diagnostic criteria with high accuracy, hyper-insulinaemic, sequentially eu- and hypoglycaemic clamp tests were performed in insulinoma patients and control subjects. Ten patients with insulinoma (benign in nine, histologically proven in nine) and 10 patients with suspected episodes of hypoglycaemia, in whom thorough clinical evaluation excluded an insulinoma, were examined. Five insulinoma patients were restudied after successful extirpation of the tumour. Suppression of C-peptide during low-dose [2 pmol kg-1 min-1 (20 mU kg-1 h-1) for 90 min, plasma insulin approximately 120 pmol L-1 (20 mUL-1)] and high-dose [8 pmol kg-1 h-1 (80 mU kg-1 h-1) for 90 min, plasma insulin approximately 450 pmol L-1 (75 mU L-1)] insulin infusion under euglycaemic conditions [plasma glucose 4.4-5.0 mmol L-1 (80-90 mg dL-1)] and during high-dose insulin infusion under hypoglycaemic conditions [glucose 2-2.2 mmol L-1 (40-45 mg dL-1)] was evaluated by radioimmunoassay (RIA). Euglycaemic hyper-insulinaemia suppressed C-peptide in control subjects (P < 0.0001), whereas in insulinoma patients apparently irregular changes in C-peptide concentrations (with spontaneous or paradoxical increments, P = 0.0006 vs. controls) were observed. The combination of hyper-insulinaemia and controlled hypoglycaemia led to a nearly complete suppression of C-peptide in normal subjects (from basal, 0.76 +/- 0.08-0.06 +/- 0.01 nmol L-1; maximum observed value 0.10 nmol L-1), which was more pronounced than at the point of discontinuation of prolonged fasting (> 48 h; 0.26 +/- 0.16 nmol L-1; P = 0.005). In insulinoma patients, C-peptide remained elevated under all conditions (P = 0.51 vs. prolonged fasting). All these findings were reversible after successful surgical removal of the insulinoma. Insulinoma patients could be identified as abnormal by (a) non-suppression of C-peptide even under hyperinsulinaemic/hypoglycaemic conditions (10 out of 10 patients) and (b) irregular increments in C-peptide under conditions that led to at least partial suppression in all normal subjects (9 out of 10 patients) and/or by an apparent shift to the left of insulin secretion relative to glucose concentrations (7 out of 10 patients). Controlled exposure to hyperinsulinaemic/hypoglycaemic conditions can help to characterize autonomous secretion in insulinoma patients and may be used as a diagnostic procedure when conventional methods yield equivocal results.