Plasma concentrations of fibrinogen and factor VII in adult life and their relation to intra-uterine growth

To examine the relation between fetal development and plasma concentrations of fibrinogen and factor VII in adult life we followed up 202 men and women, now aged around 50 years, who had been measured in detail at birth. Plasma concentrations of fibrinogen were related to weight and abdominal circumference at birth. In men, after adjustment for cigarette smoking and current obesity, plasma concentrations of fibrinogen fell by 0.12 g/l (95% CI 0.05-0.19) for each pound increase in birthweight and by 0.10 g/l (95% CI 0.03-0.17) for each inch increase in abdominal circumference. In contrast, analysis of the data for women showed no statistically significant relation between plasma fibrinogen concentration and weight or abdominal circumference at birth. No relation was seen between concentrations of factor VII and measurements made at birth in either sex. These findings suggest that, in men, reduced growth of the liver in fetal life has a long-term influence on fibrinogen metabolism.     

Circulating proinsulin levels in insulin-dependent diabetic patients after whole pancreas-kidney transplantation

Disproportional hyperproinsulinemia is a sensitive marker for beta-cell dysfunction. The objective of this study was to assess the proinsulin profile in persons with insulin-dependent diabetes mellitus (IDDM) after pancreas-kidney transplantation. We determined serum insulin, C-peptide, and proinsulin concentrations during an oral glucose challenge in five pancreas-kidney transplant recipients, nine nondiabetic kidney transplant recipients, and 17 normal subjects. Basal proinsulin concentrations were significantly increased in pancreas-kidney recipients (geometric mean [+/-1 SE range], 6.0 [5.5 to 6.4] pmol/L) and kidney recipients (6.4 [5.4 to 7.5] pmol/L) compared with the normal subjects (2.8 [2.5 to 3.2] pmol/L). Integrated proinsulin concentrations during the oral glucose load were also higher in pancreas-kidney recipients (1.4 [1.1 to 1.8] nmol/L x min) and kidney recipients (1.5 [1.2 to 2.0] nmol/L x min) versus normal subjects (0.8 [0.7 to 0.9] nmol/L x min). There was no difference in basal or integrated proinsulin concentrations between the two transplant groups. Even after adjustment for the glomerular filtration rate (GFR), basal and incremental proinsulin concentrations continued to be higher in the transplant groups than in the normal subjects. Proinsulin to C-peptide molar ratios both before and after the glucose load were similar in the three groups. From these findings, we conclude that pancreas-kidney transplantation provokes proportional hyperproinsulinemia, which is closely associated with its reduced clearance in the kidneys.     

Deficient counterregulation: a possible risk factor for excessive fetal growth in IDDM pregnancies

OBJECTIVE: The rate of macrosomia in infants born to women with IDDM remains high despite intensive insulin therapy and good glycemic control. We hypothesized that one of the factors contributing to this high rate of macrosomia is deficient counterregulatory hormonal responses to hypoglycemia. RESEARCH DESIGN AND METHODS: Hypoglycemia was induced in 17 women with IDDM and 10 normal control subjects at 24-28 and at 32-34 weeks' gestation, using the hypoglycemic clamp technique. Plasma glucose concentrations were decreased to 3.3 mmol/l and maintained at this level for 1 h. Blood samples were drawn every 15 min for measurement of counterregulatory hormone concentrations. RESULTS: All 17 women with IDDM had diminished epinephrine responses to hypoglycemia, compared with control subjects. Eight of the women with IDDM (nonresponders) had minimal or no responses (< 165 pmol/l above baseline) and nine women (responders) had a moderate response (244-764 pmol/l). Of the eight nonresponders, seven had large infants (birth weight in the upper quartile), while only three of the nine responders had large infants (P < 0.05). CONCLUSIONS: Severely impaired counterregulatory epinephrine responses to hypoglycemia in pregnant women with IDDM may be a factor contributing to excessive fetal growth. We speculate that in these women, recurrent episodes of hypoglycemia may result in frequent bouts of increased caloric intake, with repeated episodes of transient hyperglycemia leading to fetal hyperinsulinism and excessive fetal growth.     

Biomedical imaging and the evolution of medical informatics

BACKGROUND: Data concerning the insulin status in the early phase of NIDDM are controversial. PATIENTS AND METHOD: Since this has therapeutical implications, ten patients were identified with new-onset type 2 diabetes, defined by fasting blood glucose concentrations below 120 mg/dl, no previous history of diabetes and venous blood glucose concentrations at 120 min of an oral glucose tolerance test above 200 mg/dl (x 262 +/- 15 mg/dl) ("diabetic glucose tolerance"). Ten subjects with normal glucose tolerance and no familial history of NIDDM, who were matched for gender, age (n: 56 +/- 2 years, D: 61 +/- 5) and BMI (n: 28 +/- 1, D: 28 +/- 1), served as control group. Serum insulin was measured using a double-antibody sandwich-test (no cross-reaction with proinsulin and C-peptide) at 0, 30 and 120 min of an oGTT. RESULT: In the diabetic group, basal insulin levels were found to be elevated 1.7-fold (n: 7.9 +/- 1.4 uU/ml, D: 13.3 +/- 1.4, p = 0.03), 30 min values were the same in both groups and the 120 min value was 4.6-fold higher in the diabetic group (n: 33.9 +/- 8.7, D: 156.2 +/- 27.4, p = 0.0008). CONCLUSION: Thus, in new-onset diabetes, in the early phase of an oGTT (30 min) both insulin secretion and action are reduced, in the second phase (120 min) severe insulin resistance predominates at maximally stimulated secretion. These findings underline the therapeutical strategy in these patients, to reduce postprandial blood glucose increments and improve insulin resistance by diet and, if necessary, pharmacologically.     

Transport of paraquat by isolated renal proximal tubular segments from rabbits

In order to evaluate somatostatin (SRIH) secretion in uremia, plasma SRIH concentrations were determined in basal conditions and after an oral glucose tolerance test (OGTT) in 14 non-dialysed patients with chronic renal failure (CRF), seven of whom had normal glucose tolerance (NGT) and seven impaired glucose tolerance (IGT). Plasma insulin, C-peptide and glucagon and blood glucose concentrations were also evaluated. The results were compared with those obtained in a group of age- and sex-matched normal subjects. In CRF patients, plasma SRIH fasting values (8.6 +/- 0.6 and 7.8 +/- 0.6 pmol/L in NGT and IGT patients, respectively) were comparable to those recorded in controls (7.7 +/- 0.5 pmol/L). SRIH response to OGTT, evaluated as area under curves (AUC) above basal, was similar in both groups of CRF patients (412.9 +/- 84.5 and 415.6 +/- 51.9 pmol/L per min), and significantly lower than in controls (660.1 +/- 58.5 pmol/L per min). Data indicate that chronic uremia induces a loss of SRIH secretory cell responsiveness to glucose. A possible effect of impaired SRIH secretion on glucose metabolism in CRF is discussed.     

Plasma concentrations of inactive renin in adult life are related to indicators of foetal growth

OBJECTIVES: To determine whether plasma concentrations of inactive and active renin in adult life are related to foetal development. DESIGN: A follow-up study of a group of men and women whose weight and other measurements of body size had been recorded at birth. SETTING: Sheffield, England. SUBJECTS: In total 148 men and women born in the Jessop Hospital, Sheffield, during 1939-40 and now aged 50-53 years. MAIN OUTCOME MEASUREMENT: Plasma concentrations of inactive and active renin in adult life. RESULTS: Plasma concentrations of inactive and active renin in adult life tended to be higher in people who had been large at birth. The strongest relationship was between concentrations of inactive renin and abdominal circumference at birth; the median plasma concentration of inactive renin was 88.5 mu/ml in people whose abdominal circumference at birth had been 13 inches (33.02 cm) or more compared with 61 mu/ml in people whose abdomens had measured 11.5 inches (29.21 cm) or less. CONCLUSION: Impairment of foetal growth is associated with lower plasma concentrations of inactive renin in adult life. Alterations in the activity of the renin-angiotensin system may be a mechanism by which reduced foetal growth leads to raised adult blood pressure.     

Effect of glibenclamide on insulin release at moderate and high blood glucose levels in normal man

Insulin release occurs in two phases; sulphonylurea derivatives may have different potencies in stimulating first- and second-phase insulin release. We studied the effect of glibenclamide on insulin secretion at submaximally and maximally stimulating blood glucose levels with a primed hyperglycaemic glucose clamp. Twelve healthy male subjects, age (mean +/- SEM) 22.5 +/- 0.5 years, body mass index (BMI) 21.7 +/- 0.6 kgm-2, were studied in a randomized, double-blind study design. Glibenclamide 10 mg or placebo was taken before a 4-h hyperglycaemic clamp (blood glucose 8 mmol L-1 during the first 2 h and 32 mmol L-1 during the next 2 h). During hyperglycaemic clamp at 8 mmol L-1, the areas under the delta insulin curve (AUC delta insulin, mean +/- SEM) from 0 to 10 min (first phase) were not different: 1007 +/- 235 vs. 1059 +/- 261 pmol L-1 x 10 min (with and without glibenclamide, P = 0.81). However, glibenclamide led to a significantly larger increase in AUC delta insulin from 30 to 120 min (second phase): 16087 +/- 4489 vs. 7107 +/- 1533 pmol L-1 x 90 min (with and without glibenclamide respectively, P < 0.03). The same was true for AUC delta C-peptide no difference from 0 to 10 min but a significantly higher AUC delta C-peptide from 30 to 120 min on the glibenclamide day (P < 0.01). The M/I ratio (mean glucose infusion rate divided by mean plasma insulin concentration) from 60 to 120 min, a measure of insulin sensitivity, did not change: 0.26 +/- 0.05 vs. 0.22 +/- 0.03 mumol kg-1 min-1 pmol L-1 (with and without glibenclamide, P = 0.64). During hyperglycaemic clamp at 32 mmol L-1, the AUC delta insulin from 120 to 130 min (first phase) was not different on both study days: 2411 +/- 640 vs. 3193 +/- 866 pmol L-1 x 10 min (with and without glibenclamide, P = 0.29). AUC delta insulin from 150 to 240 min (second phase) also showed no difference: 59623 +/- 8735 vs. 77389 +/- 15161 pmol L-1 x 90 min (with and without glibenclamide, P = 0.24). AUC delta C-peptide from 120 to 130 min and from 150 to 240 min were slightly lower on the glibenclamide study day (both P < 0.04). The M/I ratio from 180 to 240 min did not change: 0.24 +/- 0.04 vs. 0.30 +/- 0.07 mumol kg-1 min-1 pmol L-1 (with and without glibenclamide, P = 0.25). In conclusion, glibenclamide increases second-phase insulin secretion only at a submaximally stimulating blood glucose level without enhancement of first-phase insulin release and has no additive effect on insulin secretion at maximally stimulating blood glucose levels. Glibenclamide did not change insulin sensitivity in this acute experiment.     

Preliminary characterization of glial-secreted factors responsible for the induction of high electrical resistances across endothelial monolayers in a blood-brain barrier model

Low levels of sex hormone-binding globulin (SHBG) are considered to be an indirect index of hyperinsulinemia, predicting the later onset of diabetes mellitus type 2. In the insulin resistance state and in the presence of an increased pancreatic beta-cell demand (e.g. obesity) both absolute and relative increases in proinsulin secretion occur. In the present study we investigated the correlation between SHBG and pancreatic beta-cell secretion in men with different body compositions. Eighteen young men (30.0 +/- 2.4 years) with normal glucose tolerance and body mass indexes (BMI) ranging from 22.6 to 43.2 kg/m2 were submitted to an oral glucose tolerance test (75 g) and baseline and 120-min blood samples were used to determine insulin, proinsulin and C-peptide by specific immunoassays. Baseline SHBG values were significantly correlated with baseline insulin (r = -0.58, P < 0.05), proinsulin (r = -0.47, P < 0.05), C-peptide (r = -0.55, P < 0.05) and also with proinsulin at 120 min after glucose load (r = -0.58, P < 0.05). Stepwise regression analysis revealed that proinsulin values at 120 min were the strongest predictor of SHBG (r = -0.58, P < 0.05). When subjects were divided into obese (BMI > 28 kg/m2, N = 8) and nonobese (BMI < or = 25 kg/m2, N = 10) groups, significantly lower levels of SHBG were found in the obese subjects. The obese group had significantly higher baseline proinsulin, C-peptide and 120-min proinsulin and insulin levels. For the first time using a specific assay for insulin determination, a strong inverse correlation between insulinemia and SHBG levels was confirmed. The finding of a strong negative correlation between SHBG levels and pancreatic beta-cell secretion, mainly for the 120-min post-glucose load proinsulin levels, reinforces the concept that low SHBG levels are a suitable marker of increased pancreatic beta-cell demand.     

The effect of acarbose on insulin sensitivity in subjects with impaired glucose tolerance

OBJECTIVE: To study the effect of acarbose, an alpha-glucosidase inhibitor, on postprandial plasma glucose and insulin and insulin sensitivity in subjects with impaired glucose tolerance (IGT). RESEARCH DESIGN AND METHODS: Subjects with IGT were randomly treated in a double-blind fashion with placebo (n = 10) or acarbose (n = 8) at 100 mg t.i.d. for 4 months. All subjects were submitted before randomization and at the end of the study to a standardized breakfast and a 12-h daytime plasma glucose and plasma insulin profile, and insulin sensitivity was measured as steady-state plasma glucose (SSPG) using the insulin suppression test. RESULTS: While placebo had no effect on postprandial plasma glucose and plasma insulin incremental area under the curve (AUC) (3.03 +/- 0.5 vs. 3.76 +/- 0.6 mmol.h-1.l-1, P = NS; 1,488 +/- 229 vs. 1,609 +/- 253 pmol.h-1.l-1, P = NS), acarbose resulted in a significant reduction for both glucose (1.44 +/- 0.3 vs. 4.45 +/- 0.9 mmol.h-1.l-1, P = 0.002) and insulin (626.7 +/- 104.3 vs. 1,338.3 +/- 220.5 pmol.h-1.l-1, P = 0.003). The reduction in 12-h plasma glucose and insulin AUC on acarbose (11.2 +/- 2.1 mmol.h-1.l-1 and 7.5 +/- 0.7 nmol.h-1.l-1) was significantly greater than that on placebo (4.0 +/- 1.6 mmol.h-1.l-1 and 0.8 +/- 0.4 nmol.h-1.l-1) (P = 0.014 and 0.041). While SSPG was not affected by placebo (13.9 +/- 0.4 vs. 13.8 +/- 0.3 mmol/l; P = NS), it was significantly improved by acarbose (10.9 +/- 1.4 vs. 13.1 +/- 1.5 mmol/l, P < 0.004) and was also significantly different from placebo at 4 months (P < 0.02). CONCLUSIONS: It is concluded that in subjects with IGT, acarbose treatment decreases postprandial plasma glucose and insulin and improves insulin sensitivity. Acarbose may therefore be potentially useful to prevent the progression of IGT to NIDDM.     

Mothers' pelvic size, fetal growth, and death from stroke and coronary heart disease in men in the UK

BACKGROUND: People who have a low birthweight show increased death rates from coronary heart disease and a higher prevalence for its risk factors. These findings have led to the hypothesis that the disease is programmed in fetal life. The aim of this study was to explore whether risk of stroke in adult life was linked to impaired fetal growth. METHODS: We ascertained deaths from stroke and coronary heart disease in 13 249 men in two cohorts from Hertfordshire and Sheffield, UK. We related death rates from these disease to body size at birth, weight at 1 year, and to measurements of the mothers' pelvises. FINDINGS: Death rates from both stroke and coronary heart disease tended to be highest in men whose birthweight had been low. Standardised mortality ratios (SMRs) for stroke fell by 12% (95% Cl 1-22) and for coronary heart disease by 10% (6-14) between each of five groupings of increasing birthweight (< or = 5.5 lb, 5.6-6.5 lb, 6.6-7.5 lb, 7.6-8.5 lb, and > 8.5 lb). Mortality from stroke was most strongly associated with low birthweight in relation to head size, and low placental weight in relation to head size. These patterns of growth occurred in offspring of mothers with flat bony pelvises. The SMR in sons of these women was 184 (67-396) compared with 104 (78-138) in the remainder of the cohort. In contrast, mortality from coronary heart disease was associated with small head circumference, thinness or shortness at birth and an altered ratio of placental weight to birthweight. INTERPRETATION: Stroke may originate in poor nutrition during the mother's childhood, which deforms the bony pelvis and subsequently impairs her ability to sustain the growth of the placenta and fetus in late pregnancy. Coronary heart disease, on the other hand, seems to originate in adaptations made by the fetus to inadequate delivery of nutrients when it occurs for reasons other than failure of placental growth.     

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.     

Relationship of hepatic and peripheral insulin resistance with plasminogen activator inhibitor-1 in Pima Indians

Plasminogen activator inhibitor-1 (PAI-1) is related to insulin resistance and several components of the insulin resistance syndrome, and PAI-1 levels are elevated in subjects with non-insulin-dependent diabetes mellitus. Many Pima Indians are obese, insulin-resistant, and hyperinsulinemic, and they have high rates of diabetes but a low risk of ischemic heart disease. In contrast to whites and Asians, PAI-1 activity is similar between nondiabetic and diabetic Pima Indians. We therefore examined the association of PAI-1 with hepatic and peripheral insulin action measured using the hyperinsulinemic-euglycemic clamp. To investigate if insulin per se has any effect on PAI-1 in vivo, we also assessed the effects of endogenous (during a 75-g oral glucose load) and exogenous (during hyperinsulinemic clamp) insulin on PAI-1 antigen. Twenty-one (14 men and seven women; mean age, 26.3 +/- 4.8 years) Pima Indians underwent a 75-g oral glucose tolerance test (OGTT) and a sequential hyperinsulinemic-euglycemic clamp. Peripheral insulin action was measured as absolute glucose uptake (M value) and normalized to estimated metabolic body size (EMBS). Hepatic insulin action was measured as percent suppression of basal hepatic glucose output during hyperinsulinemia. PAI-1 antigen was determined using a two-site enzyme-linked immunosorbent assay that detects only free PAI-1. PAI-1 antigen concentrations were significantly related to body mass index ([BMI] rs = .54, P = .012), waist (rs=.52, P=.016) and thigh (rs=.63, P=.002) circumference, and fasting plasma insulin concentration (rs=.59, P=.004). PAI-1 antigen concentrations were not significantly associated with peripheral glucose uptake (M value) during either low-dose (rs= -.01, P=NS) or high-dose (rs= -.11, P=NS) insulin infusion. PAI-1 antigen was negatively correlated with basal hepatic glucose output (rs= -.57, P=.013) and percent suppression of hepatic glucose output during hyperinsulinemia (rs= -.69, P=.005). However, this relationship was largely due to the confounding effects of BMI, waist and thigh girth, fasting insulin, and 2-hour postload glucose concentrations, and was not significant when controlled for these variables (partial rs= -.30, P=NS). There was no significant relationship of PAI-1 antigen concentration with glucose storage or glucose oxidation. Despite a threefold increase in plasma insulin concentrations during the OGTT, there were no significant changes in PAI-1 antigen concentrations (median, 57, 61, 55, and 44 ng/mL at 0, 60, 120, and 180 minutes, respectively; P=NS by ANOVA). During the hyperinsulinemic clamp, mean plasma insulin concentrations at the end of low-dose (240 pmol/m2/min) and high-dose (2,400 pmol/m2/min) infusions were 1,005 and 14,230 pmol/L, respectively. However, PAI-1 antigen concentrations at the end of low-dose and high-dose insulin infusions were similar to those at baseline (median, 63, 43, and 58 ng/mL, respectively; P=NS by ANOVA). PAI-1 antigen in Pima Indians is related to several components of the insulin resistance syndrome. However, direct measurement of insulin resistance indicates that hepatic but not peripheral insulin resistance is related to PAI-1 antigen. Neither endogenous nor exogenous hyperinsulinemia for short periods had any significant effect on PAI-1 antigen concentrations. Short-term hyperinsulinemia is unlikely to be an important regulator of PAI-1 in Pima Indians. The relationship of PAI-1 antigen to hepatic insulin resistance is largely dependent on the relationship of PAI-1 to indices of obesity and fasting insulin concentrations.     

Osteopontin is strongly expressed by histiocytes in granulomas of diverse etiology

It is generally assumed that exercise and shivering are analogous processes with regard to substrate utilisation and that, as a consequence, exercise can be used as a model for shivering. In the present study, substrate utilisation during exercise and shivering at the same oxygen consumption (VO2) were compared. Following an overnight fast, eight male subjects undertook a 2-h immersion in cold water, designed to evoke three different intensities of shivering. At least 1 week later they undertook a 2-h period of bicycle ergometry during which the exercise intensity was varied to match the VO2 recorded during shivering. During both activities hepatic glucose output (HGO), the rate of glucose utilisation (Rd), blood glucose, plasma insulin, free fatty acid (FFA) and beta-hydroxybutyrate (B-HBA) concentrations were measured. The VO2 measured during the different levels of shivering averaged 0.49 l.min-1 (level 1: low), 0.6 l.min-1 (level 2: low-moderate), and 0.9 l.min-1 (level 3: moderate), and corresponded closely to the levels measured during exercise. HGO and Rd were greater (P < 0.05) during exercise than during shivering at the same VO2 (9.5% and 14.7%, respectively). The average (SD). HGO during level 3 exercise was 3.0 (0.91) mg.kg-1.min-1 compared to 2.76 (1.0) mg.kg-1.min-1 during shivering. The values for Rd were 3.06 (0.98) mg.kg-1.min-1 during level 3 exercise and 2.68 (0.82) mg.kg-1.min-1 during shivering. Blood glucose levels did not differ between conditions averaging 5.4 (0.3) mmol.l-1 over all levels of shivering and 5.2 (0.3) mmol.l-1 during exercise. Plasma FFA and B-HBA were higher (P < 0.01) during shivering than during corresponding exercise (12.3% and 33.3%, respectively). FFA averaged 0.61 (0.2) mmol.l-1 over all levels of shivering and 0.47 (0.16) mmol.l-1 during exercise. The figures for L-HBA were 0.44 (0.13) mmol. l-1 during all levels of shivering and 0.32 (0.1) mmol.l-1 during exercise. Plasma insulin was higher (P < 0.05) during level 2 and 3 shivering compared to corresponding exercise; at these levels the average value for plasma insulin was 95.9 (21.9) pmol.l-1 during shivering and 80.6 (16.1) pmol.l-1 during exercise. On the basis of the present findings it is concluded that, with regard to substrate utilisation, shivering and exercise of up to 2 h duration should not be regarded as analogous processes.     

Tinnitus after head injury: evidence from otoacoustic emissions

The ability of portal vein insulin to control hepatic glucose production (HGP) is debated. The aim of the present study was to determine, therefore, if the liver can respond to a selective decrease in portal vein insulin. Isotopic ([3H]glucose) and arteriovenous difference methods were used to measure HGP in conscious overnight fasted dogs. A pancreatic clamp (somatostatin plus basal portal insulin and glucagon) was used to control the endocrine pancreas. A 40-min control period was followed by a 180-min test period. During the latter, the portal vein insulin level was selectively decreased while the arterial insulin level was not changed. This was accomplished by stopping the portal insulin infusion and giving insulin peripherally at half the basal portal rate (PID, n=5). In a control group (n=5), the portal insulin infusion was not changed and glucose was infused to match the hyperglycemia that occurred in the PID group. A selective decrease of 120 pmol/l in portal vein insulin was achieved (basal, 150+/-36 to last 30 min, 30+/-12 pmol/l) in the absence of a change in the arterial insulin level (basal, 30+/-3 to last 30 min, 36+/-4 pmol/l). Neither arterial nor portal insulin levels changed in the control group (30+/-6 and 126+/-30 pmol/l, respectively). In response to the selective decrease in portal vein insulin, net hepatic glucose output (NHGO) increased significantly, from 8+/-1 (basal) to 30+/-6 and 14+/-2 micromol x kg(-1) x min(-1) by 15 min and the last 30 min (P < 0.05) of the experimental period, respectively. Arterial plasma glucose increased from 5.9+/-0.2 (basal) to 10.5+/-0.4 micromol/l (last 30 min). Three-carbon gluconeogenic precursor uptake fell from 11.2+/-2.9 (basal) to 5.9+/-0.7 micromol x kg(-1) x min(-1) (last 30 min), and thus a change in gluconeogenesis could not account for any of the increase in NHGO. With matched hyperglycemia (basal, 5.5+/-0.3 to last 30 min, 10.5+/-0.8 micromol/l) but no change in insulin, NHGO decreased from 12+/-1 (basal) to 0 (-1+/-6 micromol x kg(-1) x min(-1), last 30 min, P < 0.05) and hepatic gluconeogenic precursor uptake did not change (basal, 8.0+/-1.7 to last 30 min, 8.9+/-2.2 micromol x kg[-1] x min[-1]). Thus, the liver responds rapidly to a selective decrease in portal vein insulin by markedly increasing HGP as a result of increased glycogenolysis. These studies indicate that after an overnight fast, basal HGP (glycogenolysis) is highly sensitive to the hepatic sinusoidal insulin level.     

Assessment of insulin sensitivity and secretion with the labelled intravenous glucose tolerance test: improved modelling analysis

A new modelling analysis was developed to assess insulin sensitivity with a tracer-modified intravenous glucose tolerance test (IVGTT). IVGTTs were performed in 5 normal (NGT) and 7 non-insulin-dependent diabetic (NIDDM) subjects. A 300 mg/kg glucose bolus containing [6,6-(2)H2]glucose was given at time 0. After 20 min, insulin was infused for 5 min (NGT, 0.03; NIDDM, 0.05 U/kg). Concentrations of tracer, glucose, insulin and C-peptide were measured for 240 min. A circulatory model for glucose kinetics was used. Glucose clearance was assumed to depend linearly on plasma insulin concentration delayed. Model parameters were: basal glucose clearance (Cl(b)), glucose clearance at 600 pmol/l insulin concentration (Cl600), basal glucose production (Pb), basal insulin sensitivity index (BSI = Cl(b)/basal insulin concentration); incremental insulin sensitivity index (ISI = slope of the relationship between insulin concentration and glucose clearance). Insulin secretion was calculated by deconvolution of C-peptide data. Indices of basal pancreatic sensitivity (PSIb) and first (PSI1) and second-phase (PSI2) sensitivity were calculated by normalizing insulin secretion to the prevailing glucose levels. Diabetic subjects were found to be insulin resistant (BSI: 2.3 +/- 0.6 vs 0.76 +/- 0.18 ml x min(-1) x m(-2) x pmol/l(-1), p < 0.02; ISI: 0.40 +/- 0.06 vs 0.13 +/- 0.05 ml x min(-1) x m(-2) x pmol/l(-1), p < 0.02; Cl600: 333 +/- 47 vs 137 +/- 26 ml x min(-1) x m(-2), p < 0.01; NGT vs NIDDM). Pb was not elevated in NIDDM (588 +/- 169 vs 606 +/- 123 micromol x min(-1) x m(-2), NGT vs NIDDM). Hepatic insulin resistance was however present as basal glucose and insulin were higher. PSI1 was impaired in NIDDM (67 +/- 15 vs 12 +/- 7 pmol x min x m(-2) x mmol/l(-1), p < 0.02; NGT vs NIDDM). In NGT and in a subset of NIDDM subjects (n = 4), PSIb was inversely correlated with BSI (r = 0.95, p < 0.0001, log transformation). This suggests the existence of a compensatory mechanism that increases pancreatic sensitivity in the presence of insulin resistance, which is normal in some NIDDM subjects and impaired in others. In conclusion, using a simple test the present analysis provides a rich set of parameters characterizing glucose metabolism and insulin secretion, agrees with the literature, and provides some new information on the relationship between insulin sensitivity and secretion.     

Low birth weight is associated with non-insulin-dependent diabetes mellitus in discordant monozygotic and dizygotic twins

Previous studies have demonstrated an association between low weight at birth and risk of later development of non-insulin dependent diabetes mellitus (NIDDM). It is unknown whether this association may be due to an impact of intrauterine malnutrition per se, or whether it may be due to a coincidence between the putative "NIDDM susceptibility genotype" and a genetically determined low weight at birth. We traced original midwife birthweight record determinations in a group of monozygotic (n = 14 pairs) and dizygotic (n = 14 pairs) twins who phenotypically appeared discordant for NIDDM at a mean age of 67 and 64 years respectively. Birthweights were lower in the NIDDM twins compared with both their identical and non-identical non-diabetic co-twins respectively (p < 0.02 both). Using a similar approach in twin pairs discordant for impaired glucose tolerance (IGT) per se, no significantly decreased birthweight was detected in the IGT twins compared with their non-diabetic co-twins. However, when a larger group of twins with different glucose tolerances were considered, birthweights were lower in twins with abnormal glucose tolerance including both NIDDM and IGT. Furthermore, the twins with the lowest birthweights among the two co-twins had the highest plasma glucose concentrations 120 min after the 75 g oral glucose load (n = 86 pairs, p = 0.02). The study supports the hypothesis that low birthweight and a non-genetically determined intrauterine component such af malnutrition may play a role for the development of NIDDM in twins.     

Glucose homeostasis during spontaneous labor in normal human pregnancy

Using stable isotope, glucose turnover was measured in six normal pregnant women during the various stages of labor; during the latent (A1) and active (A2) phases of cervical dilatation, during fetal expulsion (B), and during placental expulsion (C). These data were compared to measurements made in five postpartum women. Pancreatic hormones and cortisol were also measured. In four other normal women undergoing spontaneous labor, catecholamines and free fatty acids were measured. Plasma glucose increased throughout labor from 4.0 +/- 0.2 (A1) to 5.5 +/- 0.5 mmol/L (C) (P < 0.01), compared to 4.7 +/- 0.1 in the postpartum women. Glucose utilization and production were increased throughout labor at 33.4 +/- 3.1 and 32.8 +/- 3.1 mumol/kg min, respectively, compared to 8.2 +/- 0.9 in postpartum women. Glucose metabolic clearance was also increased to 7.5 +/- 0.8 mL/kg.min compared to that in nonpregnant women (1.8 +/- 0.3). Plasma insulin remained at 59 +/- 5 pmol/L during stages A1, A2, and B, but increased to 115 +/- 15 pmol/L during stage C. Plasma glucagon was increased throughout labor at 127 +/- 7 pg/mL, compared to 90 +/- 4 pg/mL in control postpartum women. Plasma cortisol increased during labor from 921 +/- 136 to 2018 +/- 160 nmol/L, compared to 645 +/- 355 during the postpartum period. Epinephrine and norepinephrine also increased during labor from 218 +/- 132 pmol/L and 1.09 +/- 0.16 nmol/L to 1119 +/- 158 and 3.61 +/- 1.04, respectively. It is concluded that labor is associated with a marked increase in glucose utilization and production. These findings suggest that muscle contraction (uterus and skeletal) independent of insulin is a major regulator of glucose utilization during labor. Furthermore, the increase in hepatic glucose production could be favored by an increase in glucagon, catecholamines, and cortisol.     

Effect of fluoxetine on the plasma concentrations of clozapine and its major metabolites in patients with schizophrenia

Triglyceride levels and free fatty acid metabolism are influenced by body fat distribution. To test whether the pattern of fat distribution in obese subjects results in distinct insulin mediated suppression of non-esterified fatty acids which could account for differences in plasma triglycerides, we studied 59 obese subjects who were classified according to waist-to-hip ratio. Non-esterified fatty acids and insulin response to a 75 g oral glucose tolerance test were higher in abdominal obesity. Total non-esterified fatty acids response, after adjustment for sex, showed a positive association with waist-to hip ratio (r = 0.292; p < 0.05). The abdominal obese group had higher fasting triglycerides (1.74+/-0.83 versus 1.11+/-0.71 mmol/L; p = 0.003) and lower glucose/insulin ratio (5.2+/-2.3 versus 7.1+/-2.4; p = 0.003). Stepwise multiple regression analysis showed that triglyceride levels are explained by fasting and 120 min non-esterified fatty acids and by glucose/insulin ratio. We conclude that abdominal obesity is associated with a higher resistance to insulin mediated suppression of non-esterified fatty acids in obese subjects. Variation of triglyceride concentrations in obesity is dependent on both fasting and 120 min non-esterified fatty acids as well as on insulin sensitivity to glucose utilization.     

Plasma leptin is not associated with insulin resistance and proinsulin in non-diabetic South Asian Indians

In an earlier study, we observed only a weak association between plasma insulin (non-specific assay) and leptin in South Asian Indians. This was in contrast to the observations in many other ethnic groups. With the availability of measurements of specific insulin (SI) and proinsulin (PI) in the same study group, we have reanalysed the data to look for possible correlation of leptin with proinsulin and with insulin resistance calculated from the fasting values of specific insulin and glucose using the HOMA model. Subjects with normoglycaemia (n = 117) and impaired glucose tolerance (n = 27, WHO criteria) were included in the analysis. Leptin values were higher in women. Multiple linear regression analysis showed that the variations in leptin concentrations in men were associated with BMI, WHR, and 2 h SI values (R2 = 56.2%) while fasting SI and proinsulin concentrations had no significant association. In women BMI and age showed a significant association with serum leptin values (R2 = 40.1%). Univariate and multivariate analyses using insulin resistance as the dependent variable showed that it had no association with leptin in both genders. Leptin had no correlation with proinsulin also. This study confirmed that in Asian Indians the association between plasma leptin and insulin concentrations is weak and that leptin has no influence on insulin resistance. Proinsulin and leptin are also not correlated in this population. Insulin resistance shows correlation with the beta-cell function both in men and women.     

Boomerang flap. A true single-stage pedicled cross finger flap

We investigated the efficacy of intrapulmonary administration of short-acting porcine insulin in anaesthetized pigs (n = 14) in a randomized intervention study. Insulin was administered by a new jet nebulizer (Maxin) in a random order at different doses, 0 (saline), 10 or 40 U. The hypoglycaemic effect was compared to control (0.9% saline). Blood glucose and serum insulin concentrations were followed at specified time intervals for 90 min. Plasma catecholamine concentrations were measured in order to estimate the concurrent stress. Nebulized insulin caused a significant decrease in blood glucose concentrations (p < 0.0001) (n = 28) at all doses used. The decrease in mean blood glucose concentration from the start of nebulization was 39 +/- 3% (mean +/- SEM), falling from 4.6 +/- 0.1 to 2.8 +/- 0.2 mmol 1(-1), with a nadir at 40 min after the 40 U insulin dose (n = 10). Serum insulin concentration rose from (mean +/- SEM) 5.2 +/- 0.1 to 25 +/- 9 mU 1(-1) after the insulin dose of 40 U (n = 10), the peak value occurred at 30 min. The plasma catecholamine concentrations increased significantly (p < 0.0001) (n = 28) from 0 to 60 min, this increase was similar for control and for different insulin doses. We conclude that intrapulmonary administration of insulin can cause a significant decrease in blood glucose concentrations in anaesthetized and mechanically ventilated pigs and results in clinically relevant serum insulin levels. Similar effects in humans would make inhaled insulin possible for clinical use.