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  • 1
    ISSN: 1432-0428
    Keywords: Proinsulin ; split proinsulin ; immunoradiometric assay ; Type 2 (non-insulin-dependent) diabetes mellitus ; impaired Beta-cell function
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary 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 〈 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/1,p 〈 0.05) or by radioimmunoassay C-peptide (geometric means 935 and 1410 pmol/1,p 〈 0.05), though not by radioimmunoassay insulin (87 and 144 pmol/1,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). Thus, raised proinsulin and proinsulin:total insulin ratio are not necessarily a feature of mild diet-treated Type 2 diabetic patients with subnormal insulin responses to glucose.
    Type of Medium: Electronic Resource
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  • 2
    ISSN: 1432-0428
    Keywords: Keywords Insulin resistance ; fetal growth ; non-insulin-dependent diabetes mellitus ; desaturase activity.
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary Numerous studies show an association between poor fetal growth and adult insulin resistance. Recent studies have shown relation between the long chain polyunsaturated fatty acid composition of skeletal muscle membranes and insulin sensitivity. More detailed analysis has indicated that the activity of Δ5 desaturase is inversely correlated to insulin resistance. The amount of docosahexaenoic acid (C22:6n3) is also thought to play a part in determining insulin sensitivity. The purpose of this study was to test the hypothesis that early growth retardation in the rat, as a result of maternal protein restriction, would lead to alterations in desaturase activities similar to those observed in human insulin resistance. There were no differences in phospholipid fatty acid composition in liver or muscle from control and low protein rats. In both muscle and liver the ratio of docosahexaenoic acid to docosapentaenoic acid was, however, reduced in low protein offspring. Direct measurement of Δ5 desaturase activity in hepatic microsomes showed a reduction (p 〈 0.03) in the low protein offspring which was negatively corrrelated (r = – 0.855) with fasting plasma insulin. No correlation was observed in controls. These results show that it is possible to programme the activity of key enzymes involved in the desaturation of long chain polyunsaturated fatty acids. This is possibly a mechanism linking fetal growth retardation to insulin resistance. [Diabetologia (1998) 41: 1337–1342]
    Type of Medium: Electronic Resource
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  • 3
    ISSN: 1432-0428
    Keywords: Impaired glucose tolerance ; non-insulin-dependent diabetes mellitus ; fetal growth ; ponderal index at birth ; placental weight to birthweight ratio
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary 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.
    Type of Medium: Electronic Resource
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  • 4
    ISSN: 1432-0428
    Keywords: Proinsulin ; insulin ; insulin secretion ; non-insulin-dependent diabetes mellitus ; epidemiology ; follow-up study
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary Insulin resistance and impaired insulin secretion are thought to be the primary defects in the pathogenesis of non-insulin-dependent diabetes mellitus (NIDDM). Disproportionately increased proinsulin relative to insulin levels are suggested to be an early indicator of a failing pancreas. We examined the relationship of fasting specific insulin, proinsulin, and 32, 33 split proinsulin concentrations, and the proinsulin: insulin ratio to the risk of developing NIDDM 3.5 years later in 65–74-year-old non-diabetic Finnish subjects participating in a populationbased study (n=892) on diabetes and heart disease. Altogether 69 subjects developed NIDDM over a 3.5-year follow-up (cases). The cases were compared to randomly-selected gender-matched control subjects (n=69) and control subjects matched for gender, glucose tolerance status (normal or impaired), and body mass index (n=69). There were no differences in insulin concentrations between cases and random or matched control subjects [median and interquartile range; 123 (77–154), 108 (74–143), 118 (83–145) pmol/l, p=0.271]. Random control subjects had lower proinsulin and 32,33 split proinsulin concentrations and split proinsulin: insulin ratios compared to cases [5.7 (3.8–9.0) vs 7.3 (4.8–10.0) pmol/l, p=0.005; 7.3 (4.5–13.0) vs 10.4 (7.1–18.0) pmol/l, p=0.002; 0.073 (0.057–0.110) vs 0.097 (0.060–0.135), p=0.003]. Matched control subjects had lower proinsulin concentrations and proinsulin: insulin ratios compared to cases [5.9 (4.0–7.7) vs 7.3 (4.8–10.0) pmol/l, p=0.019; 0.048 (0.035–0.071) vs 0.064 (0.045–0.100), p=0.008]. When cases were compared to matched control subjects a 1 SD increase in baseline proinsulin: insulin ratio was associated with a 1.37-fold risk (p=0.020) of developing diabetes. Moreover, this association was independent of fasting glucose concentration at baseline. Thus, in elderly prediabetic subjects disproportionately increased proinsulin concentration, an indicator of defective insulin secretion, is associated with conversion to diabetes over a short time period.
    Type of Medium: Electronic Resource
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  • 5
    Electronic Resource
    Electronic Resource
    Springer
    Diabetologia 37 (1994), S. 592-596 
    ISSN: 1432-0428
    Keywords: NIDDM ; insulin secretion ; fetal growth ; programming
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary 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 pre-natal life.
    Type of Medium: Electronic Resource
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  • 6
    ISSN: 1432-0428
    Keywords: Proinsulin ; insulin ; C-peptide ; identical twins ; Type 1 (insulin-dependent) diabetes
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary Glucose tolerance and insulin secretion were studied in two groups of non-diabetic identical twins of recently-diagnosed Type 1 (insulin-dependent) diabetic patients: (1) a group of 5 twins with islet cell antibodies, and (2) a group of 6 twins without. Despite similar fasting glucose, insulin and C-peptide concentrations both groups of twins had significantly higher fasting proinsulin concentrations than the control group (p〈0.05). The twins with complement-fixing islet cell antibodies had reduced glucose tolerance and clearance, whilst the twins without islet cell antibodies did not. Neither group of twins showed any abnormality in insulin, C-peptide or proinsulin response to oral or intravenous glucose. We conclude that increased fasting proinsulin levels precede abnormalities of insulin secretion, and are an early indication of minor B-cell damage in these twins irrespective of their risk of developing diabetes.
    Type of Medium: Electronic Resource
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  • 7
    ISSN: 1432-5233
    Keywords: Forearm ; Lactate ; Man ; Proinsulin
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract We have compared the effects of human proinsulin and insulin on forearm metabolism. Seven normal, non-obese subjects were infused with 386 pmol/kg per hour of proinsulin and 180 pmol/kg per hour of insulin using the euglycaemic clamp technique. Glucose appearance and utilization rates were quantified using a primed continuous infusion of [6′,6′-2H2]glucose. Mean blood glucose was 4.1±0.1 and 4.1±0.2 mmol/l during proinsulin and insulin infusions respectively. Basal insulin concentrations increased from 0.02±0.01 to 0.25±0.03 nmol/l. The proinsulin infusion was chosen to give steady-state levels approximately 20-fold higher on a molar basis than those of insulin, based on previous findings that proinsulin has only 5% the biological potency of insulin. Basal proinsulin concentrations increased from 0.003 to 5.4±0.3 nmol/l. Hepatic glucose production was suppressed similarly during the last hour of each hormone infusion: 0.07±0.16 (proinsulin, P), and 0.01±0.13 (insulin, I) mg/kg per minute. Glucose disposal, however, was significantly increased during the final hour of the insulin infusion: 4.7±0.4 (I) and 3.4±0.2 (P) mg/kg per minute (P=0.025). Net forearm glucose uptake (FGU) increased by a greater amount during insulin compared with proinsulin infusion: 1.44±0.02 (I) and 0.71±0.01 (P) μmol/100 ml forearm per minute (P〈0.02). There was a small but significant net drop in arterialized blood lactate and pyruvate concentrations during proinsulin compared with insulin infusion: lactate −43±29 (P) and +63±35 (I) μmol/l (P〈0.01); pyruvate −8±3 (P) and +6±2 (I) μmol/l (P〈0.02). Arterialized blood alanine concentrations were similar during both series of hormone infusions. Forearm production and arterialized concentrations of glycerol were suppressed by equal amounts during the last hour of each hormone infusion. Despite greater FGU during insulin infusion, forearm production of lactate, pyruvate and alanine were similar during the last hour of each glucose clamp. These results indicate that in overnight fasted normal man: (1) proinsulin may have a preferential effect on the liver compared with muscle in terms of glucose handling; (2) proinsulin is less effective in stimulating FGU than is insulin; (3) from calculation of carbon flux across the forearm, proportionally less glucose was oxidized or stored during infusion of proinsulin compared with insulin; (4) proinsulin has similar effects on forearm lipolysis compared with insulin; (5) proinsulin may have a differential effect on splanchnic lactate metabolism compared with insulin.
    Type of Medium: Electronic Resource
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