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  • 1
    Electronic Resource
    Electronic Resource
    Assessment of proinsulin's effects on intermediary metabolism using the forearm technique in normal man (1993)
    Springer
    Acta diabetologica 30 (1993), S. 29-35 
    Details
    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
    URL: http://dx.doi.org/10.1007/BF00572871
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  • 2
    Electronic Resource
    Electronic Resource
    Measurement of human proinsulin by an indirect two-site immunoradiometric assay (1979)
    Springer
    Diabetologia 17 (1979), S. 229-234 
    Details
    ISSN: 1432-0428
    Keywords: Indirect two-site immunoradiometric assay ; human proinsulin ; insulin ; C-peptide ; diabetes ; insulinoma
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary An indirect two-site immunoradiometric assay is described for the measurement of human proinsulin in plasma. Polyethylene tubes coated with purified guinea-pig antibodies to insulin were used to extract proinsulin and insulin from plasma. Rabbit antibody to human C peptide was then added to react with the C-peptide moiety of the bound proinsulin. The uptake of this antibody was measured by the subsequent binding of125I-sheep antibody to rabbit IgG. The binding of radioactivity to the tubes was a function of the proinsulin concentration in the sample. The sensitivity of the assay was 0.006 pmol/ml. Only 200 μl of plasma was required in the assay and the125I-labelled antibody was produced from readily available reagents. The polyethylene tubes remained stable for at least 5 months after coating. The mean fasting proinsulin level was 0.009 pmol/ml in sixteen normal subjects and 0.025 pmol/ml in twelve maturity onset diabetics. Oral glucose produced an 8 fold increase in proinsulin concentration but a decline in the plasma proinsulin/insulin molar ratio. Four patients with insulinoma had extremely elevated proinsulin levels and proinsulin/insulin ratios.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF01235859
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  • 3
    Electronic Resource
    Electronic Resource
    Height and glucose tolerance in adult subjects (1991)
    Springer
    Diabetologia 34 (1991), S. 531-533 
    Details
    ISSN: 1432-0428
    Keywords: Type 2 (non-insulin-dependent) diabetes mellitus ; impaired glucose tolerance ; glucose tolerance ; oral glucose tolerance test ; epidemiology ; height ; body mass index ; waist/hip ratio
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary In a prospective study concerning the pathogenesis of impaired glucose tolerance and Type 2 (non-insulindependent) 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〈0.007 for male subjects and r = − 0.24, (− 0.37− − 0.11) p〈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〈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. One possible reason for this is that the most commonly used anthropometric index, body mass index, eliminates height as an independent analytical variable.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00403292
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  • 4
    Electronic Resource
    Electronic Resource
    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 (1992)
    Springer
    Diabetologia 35 (1992), S. 469-474 
    Details
    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
    URL: http://dx.doi.org/10.1007/BF02342446
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  • 5
    Electronic Resource
    Electronic Resource
    Increased proinsulin levels as an early indicator of B-cell dysfunction in non-diabetic twins of Type 1 (insulin-dependent) diabetic patients (1988)
    Springer
    Diabetologia 31 (1988), S. 182-184 
    Details
    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
    URL: http://dx.doi.org/10.1007/BF00276853
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  • 6
    Electronic Resource
    Electronic Resource
    Serum proinsulin levels are disproportionately increased in elderly prediabetic subjects (1995)
    Springer
    Diabetologia 38 (1995), S. 1176-1182 
    Details
    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
    URL: http://dx.doi.org/10.1007/BF00422366
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  • 7
    Electronic Resource
    Electronic Resource
    Indirect two-site immunoradiometric assay of rat and mouse proinsulin (1979)
    Springer
    Diabetologia 17 (1979), S. 235-242 
    Details
    ISSN: 1432-0428
    Keywords: Indirect two-site immunoradiometric assay ; rat proinsulin ; mouse proinsulin ; islets ; proinsulin/insulin ratio
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary An indirect two-site immunoradiometric assay for rat and mouse proinsulin using a rabbit antibody to synthetic rat C-peptide has been developed. The sensitivity of the assay is 0.006 pmol/ml. Proinsulin was 4.95% of the total proinsulin and insulin in extracts of rat pancreas and 5.45% in extracts of isolated rat islets. The mean fasting rat insulin and proinsulin concentrations were 0.13±0.09 pmol/ml (n=5) and 0.008±0.002 pmol/ml (n=5) respectively. The mean fasting mouse proinsulin concentration was 0.019±0.006 pmol/ml (n=8). In rats intravenous glucose produced a biphasic insulin response but proinsulin rose progressively to 0.021±0.011 pmol/ml at 45 min. In mouse oral glucose increased the proinsulin concentration to 0.13 pmol/ ml at 30 min. Proinsulin release from isolated rat islets was studied during intermittent or continuous high glucose (20 mmol/l) stimulation in static incubation. Significant increases in proinsulin release were only observed 90 min after initial exposure to high glucose whether glucose stimulation was continuous or intermittent. Both in vivo and in vitro glucose stimulation led initially to a fall in the proinsulin/ insulin molar ratio but later upon prolonged stimulation this progessively increased to above the basal value.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF01235860
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  • 8
    Electronic Resource
    Electronic Resource
    Serum proinsulin levels are disproportionately increased in elderly prediabetic subjects (1995)
    Springer
    Diabetologia 38 (1995), S. 1176-1182 
    Details
    ISSN: 1432-0428
    Keywords: Key words 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 population-based 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. [Diabetologia (1995) 38: 1176–1182]
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00422366
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