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  • 1
    ISSN: 1432-0428
    Keywords: Keywords Fatty acid acylated insulin ; glucose turnover ; hindlimb lymph ; transendothelial transport ; albumin binding.
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Aims/hypothesis. The provision of stable, reproducible basal insulin is crucial to diabetes management. This study in dogs examined the metabolic effects and interstitial fluid (ISF) profiles of fatty acid acylated insulin, LysB29-tetradecanoyl, des-(B30) human insulin (NN304). Methods. Euglycaemic clamps were carried out under inhalant anaesthesia during equimolar intravenous infusions (3.6 pmol · min–1· kg–1 for 480 min) of human insulin or NN304 (n = 8 per group). Results. Steady-state total NN304 (albumin-bound and unbound) was considerably higher in plasma compared with human insulin (1895 ± 127 vs 181 ± 10 pmol/l, p 〈 0.001) and increased in interstitial fluid (163 ± 14 vs 106 ± 9 pmol/l, p 〈 0.01). The halftime for appearance of NN304 in interstitial fluid was slower than human insulin (92 vs 29 min, p 〈 0.001). Yet, equivalency of action was shown for glucose turnover; steady-state glucose uptake (Rd) of 7.28 ± 0.55 and 6.76 ± 0.24 mg · min–1· kg–1 and endogenous glucose production of 0.11 ± 0.12 and 0.22 ± 0.03 mg · min–1· kg–1 (p 〉 0.40; NN304 and human insulin, respectively). Similar to interstitial fluid, half times for Rd and endogenous glucose production were delayed during NN304 infusion (162 vs 46 min and 80 vs 31 min, respectively; p 〈 0.01 vs human insulin). Conclusion/interpretation. Firstly equivalency of steady-state action is found at equimolar physiologic infusions of human insulin and NN304. Secondly NN304 binding to plasma albumin results in slower NN304 appearance in the interstitial compartment compared with human insulin. Thirdly the delay in appearance of NN304 in interstitial fluid may not in itself be a source of the protracted action of this insulin analogue. The protracted effect is due primarily to albumin binding of the insulin analogue NN304. [Diabetologia (1999) 42: 1254–1263]
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  • 2
    ISSN: 1432-0428
    Keywords: Keywords Insulin transport ; experimental diabetes ; insulin action
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary To determine whether long-term insulin deficiency alters insulin movement across the endothelium, plasma and lymph dynamics were assessed in dogs after alloxan (50 mg/kg; n = 8) or saline injection (n = 6). Glucose tolerance (KG) and acute insulin response were assessed by glucose injection before and 18 days after treatment. Two days later, hyperglycaemic (16.7 mmol/l) hyperinsulinaemic (60 pmol · min−1· kg−1) glucose clamps were carried out in a subset of dogs (n = 5 for each group), with simultaneous sampling of arterial blood and hindlimb lymph. Alloxan induced fasting hyperglycaemia (12.9 ± 2.3 vs 5.7 ± 0.2 mmol/l; p = 0.018 vs pre-treatment) and variable insulinopenia (62 ± 14 vs 107 ± 19 pmol/l; p = 0.079). The acute insulin response, however, was suppressed by alloxan (integrated insulin from 0–10 min: 155 ± 113 vs 2745 ± 541 pmol · l−1· 10 min−1; p = 0.0027), resulting in pronounced glucose intolerance (KG: 0.99 ± 0.19 vs 3.14 ± 0.38 min−1; p = 0.0002 vs dogs treated with saline). During clamps, steady state arterial insulin was higher in dogs treated with alloxan (688 ± 60 vs 502 ± 38 pmol/l; p = 0.023) due to a 25 % reduction in insulin clearance (p = 0.045). Lymph insulin concentrations were also raised (361 ± 15 vs 266 ± 27 pmol/l; p = 0.023), such that the lymph to arterial ratio was unchanged by alloxan (0.539 ± 0.022 vs 0.533 ± 0.033; p = 0.87). Despite higher lymph insulin, glucose uptake (Rd) was significantly diminished after injection of alloxan (45.4 ± 2.5 vs 64.3 ± 6.5 μmol · min−1· kg−1; p = 0.042). This was reflected in resistance of target tissues to the lymph insulin signal (ΔRd/Δlymph insulin: 3.389 ± 1.093 vs 11.635 ± 2.057 · 10−6· l · min−1· kg–1· pmol−1· l−1; p = 0.012) which correlated strongly with the KG (r = 0.86; p = 0.0001). In conclusion, alloxan induces insulinopenic diabetes, with glucose intolerance and insulin resistance at the target tissue level. Alloxan treatment, however, does not alter lymph insulin kinetics, indicating that insulin resistance of Type 1 (insulin-dependent) diabetes mellitus reflects direct impairment at the cellular level. [Diabetologia (1998) 41: 1327–1336]
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  • 3
    Electronic Resource
    Electronic Resource
    Springer
    Diabetologia 43 (2000), S. 946-952 
    ISSN: 1432-0428
    Keywords: Keywords Adipocyte, liver, gluconeogenesis, central adiposity, single gateway hypothesis.
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Aims/hypothesis. Insulin control of glucose output is a major mechanism by which appropriate amounts of glucose are produced to supply energy to the central nervous system, without causing long-term increases of the plasma glucose concentration. It is hypothesised that the primary route by which insulin maintains control over glucose production is indirect and is mediated by regulation of non-esterified fatty acid release from the adipocyte. The question arises as to why evolution has chosen insulin to be secreted into the portal vein, if control of the liver is partially or primarily indirect. It is suggested that alterations in hepatic insulin clearance which attend increases in central adiposity are an important part of the compensation for insulin resistance and limit the necessity for up-regulation of insulin secretion in insulin resistance secondary to central adiposity.¶Methods. Review of research from author's group and other laboratories.¶Results. Data over the previous decade indicate that suppression of glucose output by increased insulin is a relatively slow process, much slower than the rate of binding of insulin to hepatocytes. One explanation is that insulin acts on an extrahepatic tissue, which in turn alters a signal to the liver, reducing glucose output. Additional evidence for an extrahepatic primary effect of insulin emerges from experiments in which insulin was given portally or peripherally at half the portal dose. Endogenous glucose production was related to systemic, not portal insulin, supporting the concept that the primary step in insulin's action on liver is on some other tissue, altering signalling to the liver itself. Strong correlation between plasma non-esterified fatty acids (NEFA) and liver glucose output suggests that the primary effect is on the adipocyte. The primacy of the adipocyte locus for the insulin effect included data that insulin's action on liver is prevented when plasma NEFA are maintained, as well as data showing proportional decline in glucose production and fatty acids when antilipolysis is induced by an adenosine agonist.¶Why then, from an evolutionary point of view is insulin secreted into the portal vein? Institution of central adiposity in dogs with fat feeding causes hepatic insulin resistance, at least partially due to the provision of NEFA in portal blood. The initial response to resistance is enhanced beta-cell sensitivity to glucose; a secondary compensation is, however, a substantial reduction in liver clearance, allowing for a greater proportion of secreted insulin to reach muscle, where it can more efficiently stimulate glucose utilisation.¶Conclusion/interpretation. Non-esterified fatty acids act as a signal as well as a metabolic substrate. They can regulate glucose utilisation in muscle and apparently are important signals to the liver and the beta cells as well. The importance of portal vein NEFA concentrations to the function of the liver could explain insulin resistance of the liver with central pattern obesity. [Diabetologia (2000) 43: 946–952]
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  • 4
    ISSN: 1432-0428
    Keywords: Glucose intolerance ; diabetes mellitus ; cirrhosis ; “minimal model” ; insulin ; insulin sensitivity ; insulin secretion ; glucose effectiveness ; tolbutamide
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary In cirrhotic patients with normal fasting glucose levels both insulin insensitivity and a blunted early insulin response to oral glucose are important determinants of the degree of intolerance to oral glucose. It is not known whether the ability of hyperglycaemia per se to enhance glucose disposal (glucose effectiveness) is also impaired. It is also unclear whether overt diabetes is due to (1) more marked insulin insensitivity; (2) impaired insulin secretion; (3) reduced glucose effectiveness; or (4) a combination of these mechanisms. We used the “minimal model” to analyse the results of a 3-h intravenous glucose tolerance test to assess glucose effectiveness, insulin sensitivity and insulin responses in 12 non-diabetic cirrhotic patients, 8 diabetic cirrhotic patients and 10 normal control subjects. Fasting blood glucose levels were 4.8±0.2, 7.5±0.6 and 4.7±0.1 mmol/l, respectively. Fasting insulin and C-peptide levels were higher in both cirrhotic patient groups compared with control subjects. The glucose clearance between 6 and 19 min after i.v. glucose was lower in both cirrhotic groups (non-diabetic, 1.56±0.14, diabetic, 0.76±0.06, control subjects, 2.49±0.16 min−1%, both p〈0.001 vs control subjects). Serum insulin peaked at 3 and 23 min in the non-diabetic cirrhotic patients and control subjects; both peaks were higher in the non-diabetic cirrhotic patients and showed a delayed return to basal levels. In the diabetic cirrhotic patients, the first phase insulin and C-peptide response to i.v. glucose was absent; their early (22–27 min) incremental insulin response to i. v. tolbutamide was however similar to that of control subjects but 43% lower than in the non-diabetic cirrhotic patients (p〈0.05). Insulin sensitivity was markedly reduced in both cirrhotic groups (non-diabetic, 1.11±0.24×10−4, diabetic, 0.33±0.53×10−4, control subjects, 4.37±0.53×10−4 min−1 per mU·l−1, both p〈0.001 vs controls). Glucose effectiveness was normal in the non-diabetic cirrhotic patients but 29% lower in the diabetic group. It would appear that overt diabetes develops in those cirrhotic patients who in addition to insulin insensitivity have a marked impairment of insulin secretion. An associated reduction in glucose effectiveness may be a contributory factor.
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  • 5
    ISSN: 1432-0428
    Keywords: Keywordsβ3-Adrenergic receptor ; Type II diabetes ; obesity ; association.
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary Recent studies have suggested an association between Type II (non-insulin-dependent) diabetes mellitus-related phenotypes and a cytosine-to-thymidine substitution that results in the replacement of tryptophan by arginine at codon 64 (Trp64Arg or W64R) of the β 3-adrenergic receptor gene. Here, we present the results of possibly the largest association study to date on the variant in a sample of 526 families with a total of 1725 subjects, 1053 of whom had Type II diabetes. Preliminary calculations suggested that we had excellent power to detect the moderate associations which were reported in previous studies. No associations were found between the W64R variant and the following phenotypes in our sample: Type II diabetes, age at diagnosis for Type II diabetes, measures of obesity, fasting glucose, fasting insulin, minimal model variables, and systolic and diastolic blood pressures. In the analysis of plasma lipids, we detected an association between the variant and HDL ratios (HDL cholesterol/total cholesterol) (p = 0.013), which remained significant even after adjusting for sex, affection status and age. Since W64R homozygotes (n = 11) had the highest HDL ratios, however, heterozygotes had the lowest and the wild-type subjects had intermediate values, we conclude that the W64R variant is unlikely to reduce HDL ratios in a dose-dependent, pathogenic manner. [Diabetologia (1999) 42: 238–244]
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  • 6
    ISSN: 1573-2878
    Keywords: Parameter estimation ; least-square estimation ; glucose tolerance test ; blood glucose regulation ; empirical data
    Source: Springer Online Journal Archives 1860-2000
    Topics: Mathematics
    Notes: Abstract A glucose tolerance test was performed on dogs by injecting glucose intravenously and measuring the plasma glucose and insulin concentrations versus time. Various analytical and computational techniques were utilized to fit the data to a minimal model and to estimate the parameters of the blood glucose regulation process. A relatively good fit was obtained in spite of the rather simple model.
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  • 7
    Electronic Resource
    Electronic Resource
    Palo Alto, Calif. : Annual Reviews
    Annual Review of Physiology 54 (1992), S. 861-883 
    ISSN: 0066-4278
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Medicine , Biology
    Type of Medium: Electronic Resource
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