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  • 1
    ISSN: 1432-1041
    Keywords: Nicotine ; Insulin resistance ; Type 2 diabetes mellitus ; cigarette smoking ; insulin action
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The effect of nicotine absorbed transdermally from a patch (TNS) and. from cigarette smoking on insulin secretion and action in Type 2 diabetes has been compared. Twelve Type 2 diabetic smoking patients, aged 51 y, with diabetes for 9 y, treated either with diet and/or oral hypoglycaemic agents, were studied on three occasions according to a double-blind, placebo-controlled cross-over design. The subjects were investigated 12 h after their last cigarette or application of one patch of TNS 30 cm2 or TNS placebo, or whilst smoking their usual cigarette. Insulin secretion was assessed by a glucagon (1 mg IV) stimulation test. On a second occasion, insulin action was assessed by a hyperglycaemic-hyperinsulinaemic clamp, the spontaneous hyperglycaemia of the fasting state (8.61 mmol·l−1) being maintained during a 4 h insulin infusion (at 0.1 mU · kg−1 · min−1 for the initial 2 h, and 1 mU · kg−1 . min−1 during the last 2 h). TNS and the cigarette did not affect endogenous insulin secretion as compared to placebo. During the initial 2 h of the clamp study, plasma insulin increased from 88 to 155 pmol · l−1, hepatic glucose production (3-3H-glucose) was less suppressed after TNS (4.31 μmol · kg−1 · min−1) than after placebo (2.5 μmol · kg−1 min−1), but was more suppressed than after cigarette smoking (5.61 μmol · kg−1 · min−1). In the last 2 h of the clamp (plasma insulin 646 pmol · l−1), glucose utilization was less stimulated after TNS (36.1 μmol · kg−1 · min−1) vs placebo (39.8 μmol · kg−1 · min−1), but more than after cigarette smoking (33.6 μmol · kg−1 · min−1), primarily because of a decrease in glucose storage. Free fatty acid and lipid oxidation were significantly less suppressed by hyperinsulinaemia after TNS and cigarette smoking vs placebo. Nicotine impairs insulin action on the liver, adipose tissue and muscle and may contribute to hyperglycaemia in Type 2 diabetes. TNS diminishes the action of insulin to a lesser extent than cigarette smoking. Thus, TNS may represent a “metabolically” safe measure to help patients with Type 2 diabetes to quit smoking.
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  • 2
    ISSN: 1432-0614
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology , Process Engineering, Biotechnology, Nutrition Technology
    Notes: Summary Lipoperoxidation appears to play a role in inducing aflatoxin biosynthesis. In vitro, synthetic lipoperoxides greatly stimulate aflatoxin production when added to cultures of toxigenic strains of Aspergillus parasiticus or A. flavus. In vivo, the amount of toxin formed in sunflower seeds of different ages inoculated with A. parasiticus is directly related to the peroxide number of their oil content: the higher the peroxide number, the higher the aflatoxin production. In cultures of A. parasiticus carbon tetrachloride (CCl4) greatly stimulates aflatoxin biosynthesis. This effect might be due to the peroxidation of lipids of the endoplasmic reticulum of Aspergillus by the highly reactive CCl . 3 radicals formed by interaction with the NADPH-cytochrome P-450 system.
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  • 3
    ISSN: 1432-0428
    Keywords: Insulin pharmacokinetics ; insulin pharmacodynamics ; insulin mixtures ; glucose clamp ; insulin absorption ; regular insulin ; lente insulin ; NPH insulin
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary These studies were undertaken to assess the influence of storage temperature of insulin vials on pharmacokinetics and pharmacodynamics of a mixture of lente insulin (Monotard HM) and regular insulin (Actrapid HM) injected subcutaneously. Seven subjects with Type 1 (insulin-dependent) diabetes mellitus were studied twice after overnight normalization of plasma glucose. A mixture of lente insulin (0.22 U/kg) and regular insulin (0.11 U/kg) was prepared from insulin vials kept either refrigerated (∼4 °C) or at room temperature (∼18 °C) and injected subcutaneoulsy (abdomen). Euglycaemia was maintained for the following 16 h by glucose infusion at variable rate. With refrigerated insulin, the plasma free insulin peak was greater (53±5 versus 45±6 mU/l) and occurred earlier (2.5±0.2 versus 6±0.3 h), and the glucose infusion rate showed a greater (16.5±1.2 versus 14.5±0.9 μmol·kg−1·min−1) and earlier peak (3.2±0.2 versus 6±0.4 h) as compared to that occurring with the non-refrigerated insulin (p〈0.05). However, 6 h after insulin injection, both plasma free insulin and glucose infusion rate were 30% lower with the mixture of refrigerated as compared to that of non-refrigerated insulin (p〈0.05). In contrast, when NPH-insulin (Protaphane HM) was mixed with regular insulin and injected in 4 out of the 7 diabetic patients, the storage temperature of insulin vials had no effect on the pharmacokinetics and pharmacodynamics of the mixture. Thus, the storage temperature of insulin vials profoundly influences the effects of the mixture lente/regular insulin, but does not affect the pharmacokinetics and pharmacodynamics of the mixture NPH/regular insulin.
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  • 4
    ISSN: 1432-0428
    Keywords: Dawn phenomenon ; growth hormone ; Type 1 (insulin-dependent) diabetes mellitus ; insulin sensitivity ; hepatic glucose production ; peripheral glucose utilisation
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary The aim of the present studies was to test the hypothesis that the dawn phenomenon in Type 1 (insulin-de-pendent) diabetes mellitus is due to a decrease in insulin sensitivity caused by nocturnal spikes of growth hormone. Twelve subjects with Type 1 diabetes were studied on two different occasions, from 24.00 to 02.00 hours, and from 06.00 to 08.00 hours with the euglycaemic clamp technique at two plasma free insulin levels (≈25 mU/l,n=7; ≈80 mU/l,n=5). To eliminate the confounding factor of insulin waning of previous Biostator studies, prior to clamp experiments the diabetic subjects were infused with i.v. insulin by means of a syringe pump according to their minute-to-minute insulin requirements. Insulin sensitivity decreased at dawn as compared to the early night hours (≈30% increase in the rate of hepatic glucose production, ≈25% decrease in the rate of peripheral glucose utilisation). Plasma insulin clearance did not change overnight. In seven Type 1 diabetic subjects, suppression of nocturnal spikes of growth hormone secretion by somatostatin during basal glucagon and growth hormone replacement resulted in complete abolition of the increased rate of hepatic glucose production at dawn. Replacement of nocturnal spikes of growth hormone faithfully reproduced the increase in hepatic glucose production at dawn of the control study. It is concluded that the dawn phenomenon in Type 1 diabetes mellitus examined during optimal insulin replacement, first, is due solely to a decrease in insulin sensitivity and not to an increase in insulin clearance; second, that the decrease in insulin sensitivity at dawn takes place both in the liver and peripheral tissues; third, that the decrease in hepatic (and most likely extrahepatic) insulin sensitivity at dawn is caused by nocturnal spikes of growth hormone secretion.
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  • 5
    ISSN: 1432-0428
    Keywords: Hypoglycaemia ; counterregulatory hormones ; symptoms ; cognitive function ; brain fuel ; ketone bodies
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary It is controversial as to whether ketone bodies are utilized by the human brain as a fuel alternative to glucose during hypoglycaemia. To clarify the issue, we studied 10 normal volunteers during an experimental hypoglycaemia closely mimicking the clinical hypoglycaemia of patients with Type 1 (insulin-dependent) diabetes mellitus or insulinoma. Hypoglycaemia was induced by a continuous infusion of insulin (0.40 mU·kg−1·min−1 for 8 h, plasma insulin ≈180 pmol/l) which decreased the plasma glucose concentration to approximately 3.1 mmol/l during the last 3 h of the studies. Subjects were studied on two occasions, i. e. spontaneous, counterregulatory-induced post-hypoglycaemic increase in 3-β-hydroxybutyrate (from ≈ 0.2 to ≈ 1.1 mmol/l at 8 h), or prevention of post-hypoglycaemic hyperketonaemia (plasma β-hydroxybutyrate ≈ 0.1 mmol/l throughout the study) after administration of acipimox, a potent inhibitor of lipolysis. In the latter study, glucose was infused to match the hypoglycaemia observed in the former study. The glycaemic thresholds and overall responses of counterregulatory hormones, symptoms (both autonomic and neuroglycopenic), and deterioration of cognitive function (psychomotor tests) were superimposable in the control study in which ketones increased spontaneously after onset of hypoglycaemic counterregulation, as compared to the study in which ketones were suppressed (p=NS). The fact that responses of counterregulatory hormones, symptoms and deterioration in cognitive function were not exaggerated when posthypoglycaemic hyperketonaemia was prevented, indicate that during hypoglycaemia, the counterregulatory-induced endogenous hyperketonaemia does not provide the human brain with an alternative substrate to glucose. Thus, it is concluded that during hypoglycaemia, endogenous hyperketonaemia does not contribute to brain metabolism and function.
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  • 6
    ISSN: 1432-0428
    Keywords: Key words Autonomic neuropathy ; intensive insulin therapy ; hypoglycaemia unawareness ; glucose counterregulation ; catecholamines.
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary Hypoglycaemia unawareness, is a major risk factor for severe hypoglycaemia and a contraindication to the therapeutic goal of near-normoglycaemia in IDDM. We tested two hypotheses, first, that hypoglycaemia unawareness is reversible as long as hypoglycaemia is meticulously prevented by careful intensive insulin therapy in patients with short and long IDDM duration, and that such a result can be maintained long-term. Second, that intensive insulin therapy which strictly prevents hypoglycaemia, can maintain long-term near-normoglycaemia. We studied 21 IDDM patients with hypoglycaemia unawareness and frequent mild/severe hypoglycaemia episodes while on “conventional” insulin therapy, and 20 non-diabetic control subjects. Neuroendocrine and symptom responses, and deterioration in cognitive function were assessed in a stepped hypoglycaemia clamp before, and again after 2 weeks, 3 months and 1 year of either intensive insulin therapy which meticulously prevented hypoglycaemia (based on physiologic insulin replacement and continuous education, experimental group, EXP, n = 16), or maintenance of the original “conventional” therapy (control group, CON, n = 5). At entry to the study, all 21 IDDM-patients had subnormal neuroendocrine and symptom responses, and less deterioration of cognitive function during hypoglycaemia. After intensive insulin therapy in EXP, the frequency of hypoglycaemia decreased from 0.5 ± 0.05 to 0.045 ± 0.02 episodes/patient-day; HbA1 c increased from 5.83 ± 0.18 to 6.94 ± 0.13 % (range in non-diabetic subjects 3.8–5.5 %) over a 1-year period; all counterregulatory hormone and symptom responses to hypoglycaemia improved between 2 weeks and 3 months, with the exception of glucagon which improved at 1 year; and cognitive function deteriorated further as early as 2 weeks (p 〈 0.05). The improvement in responses was maintained at 1 year. The improvement in plasma adrenaline and symptom responses inversely correlated with IDDM duration. In contrast, in CON, neither frequency of hypoglycaemia, nor neuroendocrine responses to hypoglycaemia improved. Thus, meticulous prevention of hypoglycaemia by intensive insulin therapy reverses hypoglycaemia unawareness even in patients with long-term IDDM, and is compatible with long-term near-normoglycaemia. Because carefully conducted intensive insulin therapy reduces, not increases the frequency of moderate/severe hypoglycaemia, intensive insulin therapy should be extended to the majority of IDDM patients in whom it is desirable to prevent/delay the onset/progression of microvascular complications. [Diabetologia (1994) 37: 1265–1276]
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  • 7
    ISSN: 1432-0428
    Keywords: Hypoglycaemia ; counterregulation ; insulin analogues ; catecholamines ; hypoglycaemic symptoms ; monomeric insulin
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary The aim of these studies was to compare the pharmacokinetics, pharmacodynamics, counterregulatory hormone and symptom responses, as well as cognitive function during hypoglycaemia induced by s. c. injection of 0.15 IU/kg of regular human insulin (HI) and the monomeric insulin analogue [Lys(B28),Pro (B29)] (MI) in insulin-dependent-diabetic (IDDM) subjects. In these studies glucose was infused whenever needed to prevent decreases in plasma glucose below 3 mmol/l. After MI, plasma insulin increased earlier to a peak (60 vs 90 min) which was greater than after HI (294±24 vs 255±24 pmol/l), and plasma glucose decreased earlier to a 3 mmol/l plateau (60 vs 120 min) (p〈0.05). The amount of glucose infused to prevent plasma glucose falling below 3 mmol/l was ∼three times greater after MI than HI (293±26 vs 90±25 μmol · kg−1 · 60–375 min−1, p〈0.05). After MI, hepatic glucose production was more suppressed (0.7±1 vs 5.9±0.54 μmol · kg−1 · min−1) and glucose utilization was less suppressed than after HI (11.6±0.65 vs 9.1±0.11μmol · kg−1 · min−1) (p〈0.05). Similarly, plasma NEFA, glycerol, and β-OH-butyrate were more suppressed after MI than HI (p〈0.05), whereas plasma lactate increased only after MI, but not after HI. Responses of counterregulatory hormones, symptoms and deterioration in cognitive function during plasma glucose plateau of 3 mmol/l were superimposable after MI and HI (p=NS). Post-hypoglycaemia hyperglycaemia was greater after MI than HI (at 480 min 12.1±1 vs 11±1 mmol/l) because of greater hepatic glucose production during insulin waning which occurred at least 135 min earlier with MI as compared to HI (p〈0.05). It is concluded that counterregulatory hormones, symptoms and deterioration in cognitive function during hypoglycaemia respond similarly after MI and HI. The biological effect of MI appears greater than that of HI for at least 4 h after the s.c. injection and appears as a good candidate for achieving optimal post-prandial glucose control in IDDM.
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  • 8
    ISSN: 1432-0428
    Keywords: Key words Hypoglycaemia, counterregulatory hormones, symptoms, cognitive function, sympathetic nervous system, glycaemic thresholds, pancreatic polypeptide, gender.
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary To assess the relative roles of insulin and hypoglycaemia on induction of neuroendocrine responses, symptoms and deterioration of cognitive function (12 cognitive tests) during progressive decreases in plasma glucose, and to quantitate glycaemic thresholds, 22 normal, non-diabetic subjects (11 males, 11 females) were studied on four occasions: prolonged fast (n =8, saline euglycaemia study, SA-EU), stepped hypoglycaemia (plasma glucose plateaus of 4.3, 3.7, 3 and 2.3 mmol/l) or euglycaemia during insulin infusion at 1 and 2 mU·kg–1·min–1 (n =22, high-insulin hypoglycaemia and euglycaemia studies, HI-INS-HYPO and HI-INS-EU, respectively), and stepped hypoglycaemia during infusion of insulin at 0.35 mU· kg–1·min–1 (n =9, low-insulin hypoglycaemia study, LO-INS-HYPO). Insulin per se (SA-EU vs HI-INS-EU), suppressed plasma glucagon (∼20 %) and pancreatic polypeptide (∼30 %), whereas it increased plasma noradrenaline (∼10 %, p〈0.05). Hypoglycaemia per se (HI-INS-HYPO vs HI-INS-EU) induced responses of counterregulatory hormones (CR-HORM), symptoms and deteriorated cognitive function. With the exception of suppression of endogenous insulin secretion, which had the lowest glycaemic threshold of 4.44±0.06 mmol/l, pancreatic polypeptide, glucagon, growth hormone, adrenaline and cortisol had similar glycaemic thresholds (∼3.8–3.6 mmol/l); noradrenaline (3.1±0.0 mmol/l), autonomic (3.05± 0.06 mmol/l) and neuroglycopenic (3.05±0.05 mmol/l) symptoms had higher thresholds. All 12 tests of cognitive function deteriorated at a glycaemic threshold of 2.45±0.06 mmol/l, but 7 out of 12 tests were already abnormal at a glycaemic threshold of 2.89±0.06 mmol/l. Although all CR-HORM had a similar glycaemic threshold, the lag time of response (the time required for a given parameter to increase) of glucagon (15±1 min) and growth hormone (14±3 min) was shorter than adrenaline (19±3 min) and cortisol (39±4 min) (p〈0.05). With the exception of glucagon (which was suppressed) and noradrenaline (which was stimulated), insulin per se (HI-INS-HYPO vs LO-INS-HYPO) did not affect the responses of CR-HORM, and did not influence the symptoms or the cognitve function during hypoglycaemia. Despite lower responses of glucagon, adrenaline and growth hormone (but not thresholds) in females than males, females were less insulin sensitive than males during stepped hypoglycaemia. [Diabetologia (1994) 37: 797–807]
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  • 9
    ISSN: 1432-0428
    Keywords: Hypoglycaemia ; intensive insulin therapy ; hypoglycaemia unawareness ; counterregulation ; IDDM ; glycaemic thresholds
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary The present studies were designed to assess the percentage of HbA1c, frequency, and awareness of hypoglycaemia (H) during long-term intensive therapy (IT) of insulin-dependent diabetes mellitus (IDDM). From 1981 to 1994, 112 IDDM patients were on IT. HbA1c was 7.17±0.16% (non-diabetic subjects 3.8–5.5%), the frequency of severe H 0.01±0.009 episodes/patient-year, frequency of mild symptomatic H 35.6±2.9 episodes/patient-year. IDDM patients with HbA1c ≤ 5.5% (Group I, n=10), between 6.1–7.0% (Group II, n=12), and ≥ 7.6% (Group III, n=11) were studied to assess responses of counterregulatory hormones, symptoms and cognitive function during experimental, stepped H. Compared to 18 non-diabetic subjects, Group I exhibited high thresholds (plasma glucose had to decrease more than normal to evoke responses), and impaired responses of adrenaline, unawareness of H and delayed onset of cognitive dysfunction at the lowest glycaemic plateau (2.3 mmol/l). Group II had normal thresholds and responses, whereas Group III had low thresholds. Frequency of mild H was higher in Group I (54.5±1.9 episodes/patient-year) than in Group II and III (33.7±3.5 and 20.4±2.5 episodes/ patient-year, respectively, p〈0.001) and correlated with percentage of HbA1c (r=−0.82). In conclusion: IT can maintain near-normal HbA1c and is compatible with low frequency of severe H. However, if HbA1c is less than 6.0%, mild, symptomatic H is excessively frequent and causes impaired counterregulation and H unawareness. Efforts should be made not only to maintain HbA1c ≤ 7.0%, but also to prevent, recognize and reverse iatrogenic H unawarenes during long-term IT of IDDM by maintaining HbA1c〉6.0%.
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  • 10
    ISSN: 1432-0428
    Keywords: Dawn phenomenon ; Type 1 (insulin-dependent) diabetes mellitus ; insulin-sensitivity ; glucose counterregulation ; glucose turnover ; growth hormone
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary In 114 subjects with Type 1 (insulin-dependent) diabetes mellitus the nocturnal insulin requirements to maintain euglycaemia were assessed by means of i. v. insulin infusion by a Harvard pump. The insulin requirements decreased after midnight to a nadir of 0.102±0.03 mU·kg−1·min−1 at 02.40 hours. Thereafter, the insulin requirements increased to a peak of 0.135±0.06mU·kg−1·min−1 at 06.40 hours (p〈0.05). The dawn phenomenon (increase in insulin requirements by more than 20% after 02.40 hours lasting for at least 90 min) was present in 101 out of the 114 diabetic subjects, and its magnitude (% increase in insulin requirements between 05.00–07.00 hours vs that between 01.00–03.00 hours) was 19.4±0.54% and correlated inversely with the duration of diabetes (r = −0.72, p〈0.001), but not with age. The nocturnal insulin requirements and the dawn phenomenon were highly reproducible on three separate nights. In addition, glycaemic control, state of counterregulation to hypoglycaemia and insulin sensitivity all influenced the magnitude of the dawn phenomenon as follows. In a subgroup of 84 subjects with Type 1 diabetes, the multiple correlation analysis showed that not only duration of diabetes (t = −9.76, p〈0.0001), but also % HbA1 significantly influenced the magnitude of the dawn phenomenon (t = 2.03, p〈0.05). After 5–9 months of intensive therapy, the magnitude of the dawn phenomenon decreased from 24+-2% to 18±2% (p〈0.05) in seven Type 1 diabetic subjects with initially poor glycaemic control, whereas it increased from 17±2% to 24±3% (p〈0.05) in five Type 1 diabetic subjects in whom glycaemic control had deteriorated for 2 weeks. In 18 Type 1 diabetic subjects the magnitude of the dawn phenomenon correlated with the indices of adequate glucose counterregulation, namely plasma glucose concentration at the hypoglycaemic nadir (r = −0.79) and the rate of plasma glucose recovery from hypoglycaemia (r = −0.74) (both p〈0.01). Finally, in 10 diabetic subjects in whom insulin sensitivity was examined by the euglycaemic glucose clamp technique, there was a correlation between the residual rate of hepatic glucose production (r = 0.78, p〈0.005) as well as between the rate of peripheral glucose utilization and the magnitude of the dawn phenomenon (r = −0.70, p〈0.025). In conclusion, the dawn phenomenon is a very frequent event in Type 1 diabetes; its magnitude (∼20%) is much lower than that indicated by previous Biostator studies; it is highly reproducible from day to day; it is influenced by the duration of diabetes, glycaemic control, state of the counterregulation system to hypoglycaemia and insulin sensitivity.
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