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Biomedical subjects

P M Clark

Publications and source records attributed to P M Clark.

At least 19 recordsLinked to original sources
PubMed1996

Hyperproinsulinemia is associated with increased beta cell demand after hemipancreatectomy in humans.

The cause of disproportionate hyperproinsulinemia in patients with type II diabetes is controversial. To examine whether increased beta cell demand might contribute, we measured proinsulin and insulin concentrations in clinically healthy humans who had undergone hemipancreatectomy for the purpose of organ donation, a procedure previously demonstrated to increase beta cell demand and diminish insulin secretory reserve capacity. Subjects were studied at least 1 yr after hemipancreatectomy. Seven donors were followed prospectively and serves as their own controls. Nine additional donors were matched with normal controls (cross-sectional group). Fasting serum concentrations of intact proinsulin and conversion intermediates (total) were measured by a two-step radioimmunoassay; independent determinations of intact proinsulin and 32,33 split proinsulin were performed using an immunoradiometric assay. Serum total proinsulin values were significantly greater in hemipancreatectomized groups than controls (prospective group: predonation = 6.24 +/- 1.14 pM, postdonation = 34.63 +/- 17.47 pM, P < 0.005; cross-sectional group: controls = 5.78 +/- 1.12 pM, donors = 15.22 +/- 5.20 pM, P < 0.025). The ratio of total proinsulin to immunoreactive insulin was directly correlated with fasting plasma glucose and showed a significant inverse relationship to secretory reserve capacity. Both absolute and relative hyperproinsulinemia is found in hemipancreatectomized donors. These data demonstrate that partial pancreatectomy with its associated increase in beta cell demand raises measures of proinsulin in humans.

Adult↗
PubMed1995

Fetal and infant growth and cardiovascular risk factors in women.

OBJECTIVE: To examine whether cardiovascular risk factors in women are related to fetal and infant growth. DESIGN: Follow up study of women born 1923-30 whose birth weights and weights at one year were recorded. SETTING: Hertfordshire. SUBJECTS: 297 women born and still living in East Hertfordshire. MAIN OUTCOME MEASURES: Plasma glucose and insulin concentrations during a standard oral glucose tolerance test; fasting plasma proinsulin and 32-33 split proinsulin concentrations; blood pressure; fasting serum total, low density lipoprotein and high density lipoprotein cholesterol, triglyceride, and apolipoprotein A I and B concentrations; and plasma fibrinogen and factor VII concentrations. RESULTS: Fasting plasma concentrations of glucose, insulin, and 32-33 split proinsulin fell with increasing birth weight (P = 0.04, P = 0.002, and P = 0.0002 respectively, when current body mass index was allowed for). Glucose and insulin concentrations 120 minutes after an oral glucose load showed similar trends (P = 0.03 and P = 0.02). Systolic blood pressure, waist:hip ratio, and serum triglyceride concentrations also fell with increasing birth weight (P = 0.08, P = 0.07, and P = 0.07 respectively), while serum high density lipoprotein cholesterol concentrations rose (P = 0.04). At each birth weight women who currently had a higher body mass index had higher levels of risk factors. CONCLUSION: In women, as in men, reduced fetal growth leads to insulin resistance and the associated disorders: raised blood pressure and high serum triglyceride and low serum high density lipoprotein cholesterol concentrations. The highest values of these coronary risk factors occur in people who were small at birth and became obese. In contrast with men, low rates of infant growth did not predict levels of risk factors in women.

Apolipoproteins↗
PubMed1995

Insulin-like growth factor (IGF) and IGF binding proteins in growth hormone dysregulation and abnormal glucose tolerance in small cell lung cancer patients.

Growth hormone (GH) regulation, glucose tolerance and serum concentrations of insulin-like growth factor (IGF) and IGF binding proteins (IGFBP) have been investigated in small cell lung cancer (SCLC) patients. Elevated serum GH was observed in the patient and smoking control groups but not in non-smoking control subjects. Glucose suppression of GH was observed in the few SCLC patients with raised basal GH but most SCLC patients exhibited a paradoxical increase in GH following oral glucose. Abnormal glucose tolerance and insulin resistance with respect to plasma glucose was observed in most patients. Patients showing GH dysregulation exhibited higher serum concentrations of IGFBP-2 than those showing no increase in GH. Abnormal glucose tolerance was associated with decreased serum concentrations of IGF-I. Given reports of elevated IGFBP secretion in SCLC and inhibition of IGF-I bioactivity by IGFBPs, these findings may indicate that increased serum IGFBPs disrupt IGF-I regulation of GH secretion and glucose homeostasis.

Adult↗
PubMed1995

Undiagnosed glucose intolerance in the community: the Isle of Ely Diabetes Project.

The Isle of Ely Diabetes Project is a prospective population-based study of the aetiology and pathogenesis of Type 2 diabetes mellitus. Between 1990 and 1992, 1156 subjects aged between 40 and 65 years underwent a standard 75 g oral glucose tolerance test (OGTT). A total of 1122 individuals who were not known to have diabetes completed the test and were classified according to WHO criteria; 51 subjects (4.5%) had previously undiagnosed diabetes and 188 (16.7%) had impaired glucose tolerance. The subjects with newly diagnosed glucose intolerance were significantly older, more obese, and shorter than those with normal glucose tolerance. Blood pressure, cholesterol, triglyceride, and LDL-cholesterol concentrations were elevated and HDL-cholesterol levels were lower among those with abnormal rather than normal glucose tolerance. In multiple regression analyses stratified by gender and including age, body mass index, and the waist-hip ratio as covariates, there were significant differences between those with normal and abnormal glucose intolerance in blood pressure, triglyceride, and HDL-cholesterol, but not total or LDL-cholesterol. In both male and female subjects, height had a significant independent negative association with the plasma glucose at 120 min after administration of oral glucose (standardized beta coefficient = -0.12, p < 0.01).

Adult↗
PubMed1995

Size at birth and plasma insulin-like growth factor-1 concentrations.

OBJECTIVE: To test the hypothesis that reduced fetal growth leads to altered plasma insulin-like growth factor-1 (IGF-1) concentrations in childhood. DESIGN: A follow up study of 4 year old children whose birth weights were recorded, and of 7 year old children whose weight, length, head circumference, and placental weight were measured at birth. SETTING: Pune, India, and Salisbury, England. SUBJECTS: 200 children born during October 1987 to April 1989 in the King Edward Memorial Hospital, Pune, weighing over 2.0 kg at birth and not requiring special care, and 244 children born during July 1984 to February 1985 in the Salisbury Health District and still living there. MAIN OUTCOME MEASURE: Plasma IGF-1 concentrations. RESULTS: In both groups of children, and consistent with findings in other studies, plasma IGF-1 concentrations were higher in taller and heavier children, and higher in girls than boys. Allowing for sex and current size, concentrations were inversely related to birth weight (Pune p = 0.002; Salisbury p = 0.003). Thus at any level of weight or height, children of lower birth weight had higher IGF-1 concentrations. The highest concentrations were in children who were below average birth weight and above average weight or height when studied. Systolic blood pressures were higher in children with higher IGF-1 concentrations (Pune p = 0.01; Salisbury p = 0.04). CONCLUSIONS: Children of lower birth weight develop higher circulating concentrations of IGF-1 than expected for their height and weight. This is consistent with the hypothesis that under-nutrition in utero leads to reprogramming of the IGF-1 axis. The increase of plasma IGF-1 concentrations in low birthweight children may also be linked to postnatal catch-up growth. High IGF-1 concentrations may be one of the mechanisms linking reduced fetal growth and high blood pressure in later life.

Anthropometry↗
PubMed1995

Use of specific immunoradiometric assay to determine preterm neonatal insulin-glucose relations.

Highly specific immunoradiometric assays were used to measure plasma concentrations of insulin, proinsulin, and 32-33 split proinsulin in neonates (n = 16). Neonatal plasma insulin concentrations were high relative to blood glucose concentrations and compared with adult insulin-glucose relations. Concentrations of proinsulin and 32-33 split proinsulin together accounted for 34-70% of the total concentration of insulin and pro-peptides. This study confirms the need to use a specific assay and neonatal reference data in the diagnosis of neonatal hyperinsulinism, and shows that neonatal pancreatic beta cell function may differ from that of older subjects.

Blood Glucose↗
PubMed1995

Measurement of proinsulin and intermediates. Validation of immunoassay methods by high-performance liquid chromatography.

Human proinsulin and 32-33 split proinsulin have been measured in the peripheral circulation by immunoradiometric assays (IRMAs) and have been shown to be elevated in impaired glucose tolerance and non-insulin-dependent diabetes mellitus (NIDDM). The IRMA for 32-33 split proinsulin did not discriminate between this molecule and des-32 or des-31,32 split proinsulin. We describe the comparison of IRMA for human plasma proinsulin and 32-33 split proinsulins with assays combined with high-performance liquid chromatography (HPLC), which can discriminate between 32-33 split, des-32 split, and des-31,32 split proinsulin. Subjects were those with normal glucose tolerance (n = 8) and those with NIDDM (n = 17), who were studied while fasting and 30 min after a glucose load. After collection, blood was centrifuged promptly, and the serum/plasma was stored frozen until assay. Both IRMA and HPLC methods were calibrated against synthetic peptides. Interassay coefficients of variation for the IRMA for proinsulin and 32-33 split proinsulin were < 13% over the ranges 3.8-65 pmol/l and 6.4-65 pmol/l, respectively. The following regression lines were obtained: proinsulin IRMA = -0.143 + 1.066 HPLC, r = 0.860; 32-33 split proinsulin IRMA = 0.048 + 1.051 HPLC; and des-31,32 split proinsulin, r = 0.814. For both analytes, there was no significant difference in the relationship of IRMA to HPLC results between the various subject groups and various time points. Thus, the IRMA for proinsulin has been validated by an independent method.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1995

Excessive secretion of insulin precursors characterizes and predicts gestational diabetes.

Using assays that specifically measure insulin, intact proinsulin, and 32,33 split proinsulin, we examined the beta-cell secretory response to an oral glucose tolerance test (OGTT) in 64 women with gestational diabetes mellitus (GDM) and 154 pregnant normoglycemic control subjects of comparable age and body mass index. Women with GDM were characterized by a lower 30-min insulin increment (40.8 [34.9-47.6] vs. 58.6 [53.6-64] pmol insulin/mmol glucose, P < 0.001; geometric mean [95% confidence interval]) and a higher plasma insulin level at 120 min (702 [610-808] vs. 444 [400-492] pmol/l, P < 0.001). 32,33 split proinsulin levels were elevated in GDM patients in both fasting (9.1 [7.3-11.4] vs. 6.7 [6.0-7.5] pmol/l, P < 0.02) and 120-min (75.2 [62.9-90.0] vs. 52.2 [46.7-58.3] pmol/l, P < 0.001) samples, respectively. Intact proinsulin levels were significantly elevated at 120 min in the women with GDM (21.3 [18.1-25.1] vs. 14.8 [13.4-16.3] pmol/l, P < 0.001). Thus, the qualitative abnormalities of insulin secretion in GDM patients (low 30-min insulin increment, high 120-min plasma insulin, and elevated 32,33 split proinsulin) are similar to those seen in nonpregnant subjects with impaired glucose tolerance. To determine whether measures of proinsulin-like molecules (PLMs) might assist in the prediction of GDM, women who had a 1-h glucose level of > 7.7 mmol/l after a 50-g glucose challenge at 28-32 weeks' gestation had insulin and PLMs measured in the 1-h sample.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1995

Breast cancer: what the primary care provider needs to know.

Breast cancer is the most frequently encountered cancer in women today. It is estimated that more than 180,000 women will be diagnosed with breast cancer this year. However, somewhere between 900,000 and 1.8 million women will undergo breast biopsy. The primary care provider will most likely be the first to identify a local problem in the breast and is often the initial source of information regarding diagnosis and treatment. Hundreds of thousands of women are currently undergoing local, as well as systemic treatment for their breast cancer. In addition, a large number of women are living with breast cancer that has metastasized to other organs. It is estimated that the clinical courses for these women ranges from 5-40 years. During this long block of time, the women will work intimately with her oncology center, as well as her primary care provider. In order to provide knowledgeable, comprehensive health care to all women, primary care providers must possess a basic understanding of the risk factors, diagnosis, treatment, and natural history of breast cancer.

Adult↗
PubMed1994

Hypertriglyceridaemia in subjects with normal and abnormal glucose tolerance: relative contributions of insulin secretion, insulin resistance and suppression of plasma non-esterified fatty acids.

Although plasma insulin and triglyceride concentrations are positively correlated in many studies, the relationships between insulin resistance, insulin secretion and hypertriglyceridaemia remain unclear. To study these associations, subjects between the ages of 40 and 64 were randomly selected from a general practice register and invited to attend for a standard oral glucose tolerance test for measurement of insulin, triglyceride and non-esterified fatty acid concentrations. The study comprised 1122 subjects who were not previously known to have diabetes and who completed the test. Using the World Health Organisation criteria, 51 subjects were classified to have non-insulin-dependent diabetes mellitus, 188 had impaired glucose tolerance and 883 subjects had normal glucose tolerance. Triglyceride concentrations in subjects with glucose intolerance were elevated compared to those in control subjects, even after adjustment for age, obesity and gender (p < 0.001 for subjects with diabetes and p < 0.01 for those with impaired glucose tolerance compared to normal subjects). In separate multiple regression analyses for males and females, the most important determinants of the plasma triglyceride concentration were the area under the non-esterified fatty acid suppression curve (p < 0.001 in both genders) and the waist-hip ratio (p < 0.001 for men and < 0.01 for women). The fasting insulin concentration was independently associated with triglyceride concentration in women only (p < 0.01). The most important determinant of the area under the non-esterified fatty acid suppression curve in men was the 30-min insulin increment, a measure of insulin secretion, (p < 0.001) whereas for women age (p < 0.001) and the body mass index (p < 0.01) were the most important.

Adult↗
PubMed1994

Fetal growth and insulin secretion in adult life.

Recent studies suggest that NIDDM is linked with reduced fetal and infant growth. Observations on malnourished infants and studies of experimental animals exposed to protein energy or protein deficiency in fetal or early neonatal life suggest that the basis of this link could lie in the detrimental effects of poor early nutrition on the development of the beta cells of the islets of Langerhans. To test this hypothesis we have measured insulin secretion following an IVGTT in a sample of 82 normoglycaemic and 23 glucose intolerant subjects who were born in Preston, England, and whose birthweight and body size had been recorded at birth. The subjects with impaired glucose tolerance had lower first phase insulin secretion than the normoglycaemic subjects (mean plasma insulin concentrations 3 min after intravenous glucose 416 vs 564 pmol/l, p = 0.04). Insulin secretion was higher in men than women (601 vs 457 pmol/l, p = 0.02) and correlated with fasting insulin level (p = 0.04). However, there was no relationship between insulin secretion and the measurements of prenatal growth in either the normoglycaemic or glucose intolerant subjects. These results argue against a major role for defective insulin secretion as a cause of glucose intolerance in adults who were growth retarded in prenatal life.

Blood Glucose↗
PubMed1994

Understanding oral glucose tolerance: comparison of glucose or insulin measurements during the oral glucose tolerance test with specific measurements of insulin resistance and insulin secretion.

The extent to which the oral glucose tolerance test can be used to estimate insulin secretion and insulin resistance has been evaluated by comparing glucose and insulin concentrations during an oral glucose tolerance test with specific measurements of insulin secretion and insulin resistance in 85 normoglycaemic subjects and 23 subjects with impaired glucose tolerance (IGT). Insulin secretion was measured by the first phase insulin response to intravenous glucose and insulin resistance by the insulin tolerance test which measures the decline of plasma glucose after the injection of a bolus of insulin. The best measure of insulin secretion was the ratio of the 30 min increment in insulin concentration to the 30 min increment in glucose concentration following oral glucose loading. This correlated with the first phase insulin release following intravenous glucose (r = 0.61, p < 0.001) but not insulin resistance (r = -0.05, p > 0.05). Insulin resistance could be estimated by the fasting insulin, proinsulin, or split proinsulin concentrations. However, fasting split proinsulin appeared to discriminate best between insulin resistance (r = -0.53, p < 0.001) and insulin secretion (r = 0.07, p > 0.05). Relative insulin resistance estimated by homeostasis model assessment (HOMA) also correlated well with insulin resistance (r = -0.57, p < 0.001) but not insulin secretion (r = 0.01, p > 0.05). We conclude that the oral glucose tolerance test can be used to derive estimates of the relative roles of insulin secretion and insulin resistance in population studies of glucose tolerance.

Blood Glucose↗
PubMed1994

Clinical experience with the Greenfield filter in 193 patients and description of a new technique for operative insertion.

Transvenous inferior vena cava (IVC) interruption using the Greenfield filter was performed upon 193 patients from January 1982 to December 1988. Placement of a filter in the IVC was indicated for prophylaxis (23.8 percent), contraindication to anticoagulation (22.8 percent), pulmonary embolism despite anticoagulation (18.7 percent), complications of anticoagulation (26.9 percent) and free-floating thrombus (7.8 percent). Filters were placed in an infrarenal location in 92 percent of the patients. The remaining 8 percent of patients had placement of a suprarenal filter for specific indications, without complication. Most (97.4 percent) of the patients had filters placed through internal jugular or femoral vein cutdown. Five patients required filter placement through a retroperitoneal approach to the right common iliac vein and IVC junction. This new technique of filter insertion is described. The operative morbidity rate was 4.7 percent, with an additional 8.8 percent having postoperative thrombotic complications. The 30 day operative mortality rate (6.7 percent) was related to preexisting associated disease. Nonfatal, late, recurrent pulmonary embolism occurred in 2.6 percent of the patients despite filter placement. Caval patency remains at 97.9 percent in long term follow-up evaluation. The Greenfield filter is an effective and safe adjunct in the treatment of venous thromboembolic disease and a satisfactory prophylactic measure in specific high-risk patients.

Adolescent↗
PubMed1993

Type 2 (non-insulin-dependent) diabetes mellitus, hypertension and hyperlipidaemia (syndrome X): relation to reduced fetal growth.

Two follow-up studies were carried out to determine whether lower birthweight is related to the occurrence of syndrome X-Type 2 (non-insulin-dependent) diabetes mellitus, hypertension and hyperlipidaemia. The first study included 407 men born in Hertfordshire, England between 1920 and 1930 whose weights at birth and at 1 year of age had been recorded by health visitors. The second study included 266 men and women born in Preston, UK, between 1935 and 1943 whose size at birth had been measured in detail. The prevalence of syndrome X fell progressively in both men and women, from those who had the lowest to those who had the highest birthweights. Of 64-year-old men whose birthweights were 2.95 kg (6.5 pounds) or less, 22% had syndrome X. Their risk of developing syndrome X was more than 10 times greater than that of men whose birthweights were more than 4.31 kg (9.5 pounds). The association between syndrome X and low birthweight was independent of duration of gestation and of possible confounding variables including cigarette smoking, alcohol consumption and social class currently or at birth. In addition to low birthweight, subjects with syndrome X had small head circumference and low ponderal index at birth, and low weight and below-average dental eruption at 1 year of age. It is concluded that Type 2 diabetes and hypertension have a common origin in sub-optimal development in utero, and that syndrome X should perhaps be re-named "the small-baby syndrome".

Aged↗
PubMed1993

Fetal growth and impaired glucose tolerance in men and women.

A follow-up study was carried out to determine whether reduced fetal growth is associated with the development of impaired glucose tolerance in men and women aged 50 years. Standard oral glucose tolerance tests were carried out on 140 men and 126 women born in Preston (Lancashire, UK) between 1935 and 1943, whose size at birth had been measured in detail. Those subjects found to have impaired glucose tolerance or non-insulin-dependent diabetes mellitus had lower birthweight, a smaller head circumference and were thinner at birth. They also had a higher ratio of placental weight to birthweight. The prevalence of impaired glucose tolerance or diabetes fell from 27% in subjects who weighed 2.50 kg (5.5 pounds) or less at birth to 6% in those who weighed more than 3.41 kg (7.5 pounds) (p < 0.002 after adjusting for body mass index). Plasma glucose concentrations taken at 2-h in the glucose tolerance test fell progressively as birthweight increased (p < 0.004), as did 2-h plasma insulin concentrations (p < 0.001). The trends with birthweight were independent of duration of gestation and must therefore be related to reduced rates of fetal growth. These findings confirm the association between impaired glucose tolerance in adult life and low birthweight previously reported in Hertfordshire (UK), and demonstrate it in women as well as men. It is suggested that the association reflects the long-term effects of reduced growth of the endocrine pancreas and other tissues in utero. This may be a consequence of maternal undernutrition.

Birth Weight↗
PubMed1993

Hyperproinsulinaemia in impaired glucose tolerance.

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

Glucose Intolerance↗