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Biomedical subjects

C N Hales

Publications and source records attributed to C N Hales.

At least 19 recordsLinked to original sources
PubMed1992

Control of Hep G2-cell triacylglycerol and apolipoprotein B synthesis and secretion by polyunsaturated non-esterified fatty acids and insulin.

Non-esterified fatty acids (NEFAs) and insulin are important factors in the control of lipoprotein secretion, but the mechanism of action is unclear. The present study was undertaken to determine whether insulin and NEFAs modulated hepatic secretion of triacylglycerol and apolipoprotein B (apo-B) by regulation of hepatic intracellular apo-B content. The experiments were performed with the human hepatoblastoma cell line Hep G2, for periods of up to 72 h in the presence and absence of NEFAs and insulin. Higher concentrations of eicosapentanoate (EPA) sustained for 72 h decreased cellular protein content (at 250 microM) or caused cell death (at 750 microM), and this effect was not observed with the other NEFAs studied, whereas 75 microM-EPA did not affect cell viability. Compared with the absence of NEFA, 75 microM-EPA did not alter the intracellular triacylglycerol content, but decreased the intracellular content of apo-B by 47% (P < 0.01) and decreased secreted triacylglycerol and secreted apo-B by 13% (P < 0.05) and 21% (P < 0.01) respectively, after 72 h. However 250 microM-oleate increased the intracellular triacylglycerol by 36% (P < 0.01), intracellular apo-B by 22% (P < 0.05) and secreted triacylglycerol and apo-B by 20-30% (P < 0.05-0.01). Insulin decreased secreted triacylglycerol and apo-B in the presence of each NEFA studied by 20-30%. There was no correlation between the changes in intracellular triacylglycerol and the rate of secretion. However, when the secreted triacylglycerol or apo-B was plotted against intracellular apo-B content a significant correlation was observed (r = 0.89, P < 0.001 for both analyses). Apo-B mRNA levels did not change after 72 h incubation with oleate or EPA. These results demonstrate that EPA can be toxic to hepatocytes and that NEFAs and insulin control secretion of triacylglycerol and apo-B by regulation of the intracellular apo-B concentration, thus controlling assembly of apo-B with triacylglycerol to form lipoproteins.

Apolipoproteins B↗
PubMed1992

Relation of infant feeding to adult serum cholesterol concentration and death from ischaemic heart disease.

OBJECTIVE: To examine whether method of infant feeding is associated with adult serum lipid concentrations and mortality from ischaemic heart disease. DESIGN: Follow up study of men born during 1911-30. SETTING: Hertfordshire, England. SUBJECTS: 5718 men, for 5471 of whom information on infant feeding had been recorded by health visitors and 1314 of whom had died. 485 of the men born during 1920-30 and still living in Hertfordshire who had blood lipid measurements. MAIN OUTCOME MEASURES: Death from ischaemic heart disease; serum cholesterol and apolipoprotein concentrations. RESULTS: 474 men had died from ischaemic heart disease. Standardised mortality ratios were 97 (95% confidence interval 81 to 115) in men who had been breast fed and had not been weaned at 1 year, 79 (69 to 90) in breast fed men who had been weaned at 1 year, and 73 (59 to 89) in men who had been breast and bottle fed. Compared with men weaned before one year men not weaned had higher mean serum concentrations of total cholesterol (6.9 (not weaned) v 6.6 (weaned) mmol/l), low density lipoprotein cholesterol (5.0 v 4.6 mmol/l) and apolipoprotein B (1.14 v 1.08 g/l). Men who had been bottle fed also had a high standardised mortality ratio for ischaemic heart disease (95; 68 to 130) and high mean serum concentrations of total cholesterol (7.0 mmol/l), low density lipoprotein cholesterol (5.1 mmol/l), and apolipoprotein B (1.14 g/l). In all feeding groups serum apolipoprotein B concentrations were lower in men with higher birth weight and weight at 1 year. CONCLUSIONS: Age of weaning and method of infant feeding may influence adult serum low density lipoprotein cholesterol concentrations and mortality from ischaemic heart disease. Adult serum apolipoprotein B concentrations are related to growth in fetal life and infancy.

Age Factors↗
PubMed1992

The relation of fetal growth to plasma glucose in young men.

In a study of men aged 59 to 70 years plasma glucose levels 30 min and 2 h after a 75-g glucose load were inversely related to birthweight. To determine whether there are similar relations at a younger age the 30-min plasma glucose levels of 40 men aged 21 years, who were born in one hospital in the United Kingdom, were measured. Lower birthweight was associated with higher 30-min plasma glucose levels. This trend was independent of gestational age, and current body mass, height and social class.

Birth Weight↗
PubMed1992

Immunoradiometric assay of insulin, intact proinsulin and 32-33 split proinsulin and radioimmunoassay of insulin in diet-treated type 2 (non-insulin-dependent) diabetic subjects.

Plasma insulin, intact proinsulin and 32-33 split proinsulin measured by specific immunoradiometric assays and insulin and C-peptide measured by radioimmunoassay were measured during a constant infusion of glucose test in ten diet-treated subjects with a history of Type 2 (non-insulin-dependent) diabetes (termed diabetic subjects), mean fasting plasma glucose 6.0 +/- 1.0 mmol/l (mean +/- SD), and 12 non-diabetic control subjects. Immunoreactive insulin concentrations measured by radioimmunoassay were 33% higher than insulin and 16% higher than the sum of insulin and its precursors by immunoradiometric assay. The diabetic and non-diabetic subjects had similar fasting concentrations of insulin, intact proinsulin and 32-33 split proinsulin. The ratio of fasting intact proinsulin to total insulin was greater in the diabetic than the non-diabetic group 12.0% (6.8-21.0%, 1 SD range) and 6.3% (4.0-9.8%), respectively, p less than 0.01), though the groups overlapped substantially. After glucose infusion, diabetic and non-diabetic subjects had similar intact proinsulin concentrations (geometric mean 4.9 and 5.2 pmol/l, respectively), but the diabetic group had impaired insulin secretion by immunoradiometric assay (geometric means 55 and 101 pmol/l, p less than 0.05) or by radioimmunoassay C-peptide (geometric means 935 and 1410 pmol/l, p less than 0.05), though not by radioimmunoassay insulin (87 and 144 pmol/l, p = 0.12), respectively. Individual immunoradiometric assay insulin responses to glucose expressed in terms of obesity were subnormal in nine of ten diabetic subjects. Radioimmunoassay insulin and C-peptide gave less complete discrimination (subnormal responses in six of ten and eight of ten, respectively).(ABSTRACT TRUNCATED AT 250 WORDS)

Blood Glucose↗
PubMed1992

Difficulties in localization and treatment of insulinomas in type 1 multiple endocrine adenomatosis (MEA).

A 15 year old girl with a family history of type 1 multiple endocrine adenomatosis presented with reversible neurological disturbances, hypoglycaemia and hyperinsulinaemia. Initial radiology was normal, but portal venous sampling suggested an insulinoma in the tail of the pancreas which was removed with conservation of the spleen. Hypoglycaemia persisted despite high doses of diazoxide and intravenous dextrose. A second laparotomy revealed a pancreatic endocrine tumour and sub-total pancreatectomy was performed. Histology revealed islet cell microadenomatosis. Hypoglycaemia persisted despite treatment with somatostatin analogues and 40% intravenous dextrose was required to maintain normoglycaemia. A possible lesion near the splenic hilum on computed tomographic scan was reported as a splenunculus although further peripheral, hepatic and portal venous sampling suggested hepatic or systemic lesions. A positron emission scan and selective visceral angiography suggested a lesion in the left upper quadrant. Acute lactic acidosis, rhabdomyolysis and renal failure supervened. Post mortem revealed the putative 'splenunculus' to be a residual insulinoma, whilst the splenic vein was thrombosed, accounting in part for discrepant venous sampling data. Hyperinsulinaemia in type 1 multiple endocrine adenomatosis may require more aggressive surgical and hormonal intervention than when dealing with solitary insulinomas. Insulinomas may mimic developmental abnormalities on computed tomographic scanning.

Adolescent↗
PubMed1992

Dose-response characteristics of human proinsulin and insulin in non-insulin-dependent diabetic humans.

We compared the actions of human proinsulin and insulin on glucose turnover and on intermediary carbohydrate and lipid metabolism in non-insulin-dependent diabetes mellitus (NIDDM). Six diet-controlled weight-matched (25.4 +/- 1.0 kg/m2) NIDDM subjects underwent six separate isoglycemic clamps. Glucose turnover was measured using a primed continuous infusion of [6',6'-2H2]glucose. Each subject received three low-dose intravenous infusions of both insulin and proinsulin. Blood glucose was maintained at 6.7 +/- 0.3 mM during proinsulin and insulin infusion. Insulin (I) infusions gave steady-state levels of 0.12 +/- 0.001 (I1), 0.18 +/- 0.01 (I2), and 0.33 +/- 0.01 nM (I3). Steady-state proinsulin (P) levels were 2.5 +/- 0.1 (P1), 4.3 +/- 0.2 (P2), and 8.8 +/- 0.9 nM (P3). Hepatic glucose production was suppressed equally by proinsulin and insulin at all doses. The metabolic clearance rate of glucose was significantly increased during the insulin infusion compared with proinsulin. The use of [6',6'-2H2]glucose resulted in a mean underestimation of the glucose infusion rate of 10.0 +/- 4.0 and 6.0 +/- 2.5% during the two highest insulin and proinsulin doses, respectively. Proinsulin had a significantly weaker effect than insulin, at the lowest infusion dose, in percent suppression of plasma nonesterified fatty acids, blood glycerol, and beta-hydroxybutyrate levels (all P less than 0.05). Blood lactate levels were lower during the P1 (628 +/- 43 microM) and P2 (657 +/- 93 microM) infusions compared with I1 (776 +/- 60 microM) and I2 (878 +/- 44 microM; P less than 0.05, P less than 0.02), respectively.(ABSTRACT TRUNCATED AT 250 WORDS)

Diabetes Mellitus, Type 2↗
PubMed1992

The effects of human proinsulin on glucose turnover and intermediary metabolism in insulin-dependent-diabetes mellitus.

We have compared the action of human proinsulin and insulin on glucose turnover, intermediary carbohydrate, and lipid metabolism in insulin-dependent-diabetic (IDDM) subjects. Six, young, weight-matched (23 +/- 2 kg-2) IDDM subjects underwent separate hyperinsulinemic euglycemic clamps. Three, low dose, iv infusions of both insulin and proinsulin were used to construct dose response curves. The proinsulin infusions were chosen to give steady state levels approximately or equal to 20-fold higher on a molar basis than insulin, based on previous findings that proinsulin has only 5-10% the biological potency of insulin. Hepatic glucose production, measured using [6'6'2H2]glucose, was suppressed equally by proinsulin and insulin at the three dose levels; (I1) 2.8 +/- 0.7 (P1) 3.3 +/- 0.6, (I2) 2.3 +/- 0.9 (P2) 3.3 +/- 1.1, (I3) -2.0 +/- 1.7 (P3) -1.1 +/- 0.6 mumol/kg min-1. Percentage elevation of glucose disposal was significantly increased during the insulin infusions compared to proinsulin; (I1) 132 +/- 12 (P1) 78 +/- 4 p < 0.01; (I2) 157 +/- 18 (P2) 104 +/- 14; P < 0.05; (I3) 242 +/- 23 (P3) 159 +/- 24 p = 0.02. Dose response curve analysis demonstrated that proinsulin stimulated glucose disposal approximately or equal to 3.7% whereas suppression of HGP was congruent to 5.7% compared to insulin. Proinsulin had a significantly weaker effect than insulin, at the lowest infusion dose, in percent suppression of plasma nonesterified fatty acids (I1 34 +/- 4, P1 14 +/- 15%; P < 0.05), blood glycerol (I1 47 +/- 4, P1 30 +/- 3%; P < 0.01) and 3-hydroxybutyrate levels (I1 81 +/- 7, P1 42 +/- 17%; P < 0.05). Proinsulin caused significant net reductions in blood lactate levels compared to insulin at each infusion dose; (P1) -130 +/- 34, (I1) -32 +/- 30 mumol/L (P < 0.05) (P2) -139 +/- 76 (I2) +8 +/- 65 mumol/L (P < 0.05) (P3) 48 +/- 60 (I3) 230 +/- 64 mumol/L (P < 0.05). We conclude that in IDDM: 1) proinsulin has a preferential effect on the liver compared to muscle, in terms of glucose handling; 2) proinsulin may have a different effect on lactate metabolism compared to insulin; 3) proinsulin at the lowest dose resulted in an inability to suppress lipolysis and ketogenesis; 4) glucose turnover can be underestimated using [6'6'2H2]glucose.

Adult↗
PubMed1992

Sensitive amplified immunoenzymometric assays (IEMA) for human insulin and intact proinsulin.

Immunoenzymometric assays (IEMAs) for human insulin and intact proinsulin were developed using the amplification system developed by Johannsson et al. (Clin. Chim. Acta 148 (1985) 119-124) for the detection of the enzyme alkaline phosphatase. The detection limit of the assays was 0.8 pmol/l for proinsulin and 0.8 pmol/l for insulin whereas it was 1.8 pmol/l and 2.3 pmol/l respectively for the homologous immunoradiometric assays (IRMA). These assays are superior to immunoradiometric assays in terms of sensitivity, shelf-life of the labelled antibody and suitability for automation.

Alkaline Phosphatase↗
PubMed1991

Interaction of non-esterified fatty acid and insulin in control of triacylglycerol secretion by Hep G2 cells.

The role of insulin in the regulation of plasma triacylglycerol is poorly understood. Conflicting actions of insulin on rat liver cells have been reported, insulin inhibiting triacylglycerol secretion in short incubations (less than 24 h) and stimulating triacylglycerol secretion in longer incubations (48-72 h). The present study was undertaken to examine regulation of triacylglycerol secretion by insulin and investigate the interaction between insulin and non-esterified fatty acid over 72 h in human hepatoblastoma (Hep G2) cells. Insulin inhibited triacylglycerol secretion throughout the 72 h period. The inhibition increased from 66% in the first 24 h to 88% in the final 24 h. Increasing the initial concentration of oleic acid from 200 microM to 1000 microM resulted in a 358% increase in triacylglycerol secretion and a 712% increase in accumulation over 24 h. Oleic acid uptake by the cells was rapid, with only 2.4% of the initial concentration (500 microM) remaining after 24 h. Supplementation of the medium with oleic acid to maintain the concentration between 750 microM and 1000 microM throughout a 5 h period resulted in a 350% increase in triacylglycerol secretion. Supplementation also decreased the insulin-induced inhibition of triacylglycerol secretion (18.2 to 7.8%; P less than 0.001). These results demonstrate that there is not a biphasic action of insulin on triacylglycerol secretion by Hep G2 cells. Experiments of this nature have not previously taken into account the rapid uptake of non-esterified fatty acid by hepatocytes and have consequently underestimated the effect of a sustained concentration on triacylglycerol metabolism. Oleic acid is therefore an even more potent stimulus to triacylglycerol synthesis and secretion than has previously been recognized. In addition, in the presence of a sustained increase in oleic acid concentration, there is a decrease in the action of insulin to inhibit triacylglycerol secretion.

Biological Transport↗
PubMed1991

Fetal and infant growth and impaired glucose tolerance at age 64.

OBJECTIVE: To discover whether reduced fetal and infant growth is associated with non-insulin dependent diabetes and impaired glucose tolerance in adult life. DESIGN: Follow up study of men born during 1920-30 whose birth weights and weights at 1 year were known. SETTING: Hertfordshire, England. SUBJECTS: 468 men born in east Hertfordshire and still living there. MAIN OUTCOME MEASURES: Fasting plasma glucose, insulin, proinsulin, and 32-33 split pro-insulin concentrations and plasma glucose and insulin concentrations 30 and 120 minutes after a 75 g glucose drink. RESULTS: 93 men had impaired glucose tolerance or hitherto undiagnosed diabetes. They had had a lower mean birth weight and a lower weight at 1 year. The proportion of men with impaired glucose tolerance fell progressively from 26% (6/23) among those who had weighted 18 lb (8.16 kg) or less at 1 year to 13% (3/24) among those who had weighed 27 lb (12.25 kg) or more. Corresponding figures for diabetes were 17% (4/23) and nil (0/24). Plasma glucose concentrations at 30 and 120 minutes fell with increasing birth weight and weight at 1 year. Plasma 32-33 split proinsulin concentration fell with increasing weight at 1 year. All these trends were significant and independent of current body mass. Blood pressure was inversely related to birth weight and strongly related to plasma glucose and 32-33 split proinsulin concentrations. CONCLUSIONS: Reduced growth in early life is strongly linked with impaired glucose tolerance and non-insulin dependent diabetes. Reduced early growth is also related to a raised plasma concentration of 32-33 split proinsulin, which is interpreted as a sign of beta cell dysfunction. Reduced intrauterine growth is linked with high blood pressure, which may explain the association between hypertension and impaired glucose tolerance.

Aged↗
PubMed1991

UK clinical research.

Explore the source record for details and available documents.

National Health Programs↗
PubMed1991

Height and glucose tolerance in adult subjects.

In a prospective study concerning the pathogenesis of impaired glucose tolerance and Type 2 (non-insulin-dependent) diabetes mellitus, 346 subjects with no clinical history of diabetes were given a standard 75 g oral glucose tolerance test. The expected positive associations between 120-min plasma glucose concentration and age and body mass index were observed in both sexes and between 120-min plasma glucose and waist/hip ratio in male subjects. An unexpected negative correlation was found between 120-min plasma glucose and height in both sexes (r = -0.23, (95% confidence interval, -0.38 - -0.07) p less than 0.007 for male subjects and r = -0.24, (-0.37 - -0.11) p less than 0.006 for female subjects). These negative associations with height remained significant after controlling for age and body mass index in male subjects but not in female subjects. In the latter a highly significant negative relationship of height with age was recorded (r = -0.33, (-0.45 - -0.20) p less than 0.0001). Comparison between individuals with impaired glucose tolerance and control subjects matched for sex, age and body mass index showed that subjects with impaired glucose tolerance are significantly shorter. Mean (+/- SEM) height in the male subjects with impaired glucose tolerance (n = 29) was 173.4 +/- 1.1 cm vs 176.9 +/- 1.3 cm in control subjects, p = 0.02. In the female subjects (n = 39) mean (+/- SEM) height was 159.4 +/- 1.0 cm vs 162.4 +/- 1.0 cm in control subjects, p = 0.02. The negative relationship between height and glucose tolerance is a new epidemiological observation which has not been previously reported.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1991

The effects of human proinsulin on glucose turnover and intermediary metabolism.

We compared the effects of human proinsulin and human insulin on glucose disposal, suppression of hepatic glucose production (HGP), and intermediary carbohydrate and lipid metabolism. Six young, lean, subjects underwent eight separate euglycemic clamps with low-dose intravenous (IV) infusions of insulin and proinsulin (four each). The insulin infusions gave steady-state levels of 0.08 +/- 0.004 (I1), 0.12 +/- 0.003 (I2), 0.18 +/- 0.07 (I3), and 0.25 +/- 0.06 nmol/L (I4). The proinsulin infusions were chosen to give steady-state levels approximately 20-fold higher on a molar basis than insulin, based on previous findings that proinsulin has only 5% to 10% the biological potency of insulin. Steady-state proinsulin levels were 1.2 +/- 0.04 (P1), 2.8 +/- 0.07 (P2), 4.5 +/- 0.3 (P3), and 6.9 +/- 0.3 nmol/L (P4). HGP was suppressed equally by proinsulin and insulin at the four dose levels. Percentage elevation of glucose disposal was significantly increased during each of the insulin infusions compared with proinsulin: I1 107% +/- 4%, P1 87% +/- 4% (P = .03); I2 143% +/- 7%, P2 125% +/- 12% (P = .01); I3 238% +/- 38%, P3 173% +/- 22% (P = .03); I4 283% +/- 17%, P4 178% +/- 11% (P = .002). Dose-response curve analysis demonstrated that proinsulin stimulated glucose disposal approximately 3.3% compared with insulin. The effectiveness of proinsulin in suppressing HGP was approximately 5% compared with insulin. Plasma nonesterified fatty acids, blood glycerol, and 3-hydroxybutyrate were suppressed by similar amounts during each of the four insulin and proinsulin doses.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1991

Voltage-activated currents in the CRI-G1 rat insulin-secreting cell-line.

1. The whole-cell configuration of the patch-clamp recording technique was used to characterize the electrophysiological properties of CRI-G1 insulin-secreting cells. 2. Current-clamp recordings demonstrated the excitable nature of these cells. 3. Voltage-clamp recordings revealed the presence of an inward Na+ current, an inward Ca2+ current and a delayed outward K+ conductance. 4. The electrophysiological properties of CRI-G1 closely resemble those of pancreatic beta-cells, thereby rendering this cell-line as a useful alternative to freshly isolated cells for the study of pancreatic beta-cell electrophysiology and pharmacology.

Action Potentials↗