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N Stefan

Publications and source records attributed to N Stefan.

11 recordsLinked to original sources
PubMed2001

Avoidance of hypoglycemia restores hypoglycemia awareness by increasing beta-adrenergic sensitivity in type 1 diabetes.

BACKGROUND: Lack of awareness of hypoglycemia is a major limiting factor in the management of type 1 diabetes. OBJECTIVE: To examine whether reduction in the number of episodes of hypoglycemia restores hypoglycemia awareness by influencing beta-adrenergic sensitivity in patients with type 1 diabetes. DESIGN: Controlled interventional study. SETTING: Research unit and outpatient diabetes clinic of a university hospital. PATIENTS: 10 men with type 1 diabetes and hypoglycemia unawareness (mean age [+/-SD], 46 +/- 16 years; mean duration of diabetes, 20 +/- 10 years). INTERVENTION: Strict avoidance of hypoglycemia. MEASUREMENTS: beta-Adrenergic sensitivity was measured by isoproterenol testing before and at 2 and 4 months after strict avoidance of hypoglycemia. Hypoglycemia awareness and catecholamine response were measured by performing hypoglycemic clamp (glucose level, 3 mmol/L [54 mg/dL]) before and after 4 months of avoidance of hypoglycemia. RESULTS: After 4 months, the mean (+/-SE) number of episodes of hypoglycemia (glucose level < 3.9 mmol/L [70 mg/dL]) decreased from 8.4 +/- 0.9 to 1.4 +/- 0.3 per week (P < 0.001). Hemoglobin A(1c) values increased from 0.068 +/- 0.003 (6.8% +/- 0.3%) to 0.077 +/- 0.003 (7.7% +/- 0.3%) (P < 0.001). Autonomic symptom scores during hypoglycemic clamp increased from 1.8 +/- 0.6 to 3.3 +/- 0.7 (P = 0.004) and did not significantly differ from those of normal participants (4.7 +/- 0.8) (P > 0.2). Although catecholamine responses to hypoglycemia were unchanged, the dose of isoproterenol necessary to increase heart rate by 25 beats/min (IC(25)) decreased from 1.96 +/- 0.43 microgram before treatment to 1.09 +/- 0.17 microgram after 4 months of treatment (P = 0.01), a value similar to that in normal participants (0.85 +/- 0.20 microgram) (P > 0.2). Improvements in beta-adrenergic sensitivity (change in IC(25)(-1)) were correlated with improvements in autonomic symptoms (r = 0.65; P = 0.04). CONCLUSIONS: Avoidance of hypoglycemia in patients with type 1 diabetes who have hypoglycemia unawareness seems to restore hypoglycemia awareness, primarily by increasing beta-adrenergic sensitivity.

Adult↗
PubMed2001

Acute stimulation of leptin concentrations in humans during hyperglycemic hyperinsulinemia. Influence of free fatty acids and fasting.

OBJECTIVE: To assess the acute regulation of leptin concentrations by insulin, glucose and free fatty acids (FFAs). DESIGN: Four protocols: saline control experiment (CON); hyperglycemic clamps (approximately 8.3 mmol/l, 120 min) after an overnight fast (12 FAST); after a 36 h fast (36 FAST); and after a 36 h fast during which Intralipid/heparin was given over the last 24 h (36 FAST+FFA). SUBJECTS: Lean, young, healthy volunteers; control group (n=6), experimental group (n=6). MEASUREMENTS: Serum leptin concentrations. RESULTS: Glucose and insulin concentrations were similar during the three clamp protocols. Average FFAs during the last 60 min of the clamp were 671+/-68 microM (CON),109+/-15 microM (12 FAST), 484+/-97 microM (36 FAST) and 1762+/-213 microM (36 FAST+FFA). Leptin concentrations decreased similarly during 36 FAST and 36 FAST+FFA. Leptin concentrations at 120 min (expressed as percentage of mean basal value) were 0.82+/-0.02 (CON), 0.93+/-0.08 (12 FAST) (P=0.29), 1.19+/-0.06 (36 FAST) (P<0.01) and 1.44+/-0.12 (36 FAST+FFA) (P<0.01). CONCLUSION: During a one-day fast leptin concentrations decrease regardless of maintainance of an isocaloric balance. During acute hyperinsulinemic hyperglycemia leptin concentrations increase only after a preceding fast. This increase was most pronounced during simultaneous elevation of FFAs. Overall, our findings are compatible with the hypothesis that leptin secretion may be coupled to triglyceride synthesis rather than to the absolute lipid content of the adipocyte. International Journal of Obesity (2001) 25, 138-142

Adult↗
PubMed2001

Evidence against a rate-limiting role of proinsulin processing for maximal insulin secretion in subjects with impaired glucose tolerance and beta-cell dysfunction.

In subjects with impaired glucose tolerance (IGT) insulin secretion is impaired. Increased proinsulin/insulin (PI/I) ratios suggest that there is also reduced processing of proinsulin to insulin in this condition. The PI/I ratio in the insulin secretory granule is ideally assessed by plasma measurements in response to acute stimulation of insulin secretion. In the present study we tested the hypothesis that maximal stimulation of insulin secretion results in exhaustion of the proinsulin conversion pathway to insulin. We therefore determined the PI/I ratio in 11 normal glucose-tolerant subjects (NGT) and 11 subjects with IGT in response to glucose (squarewave hyperglycemic clamp, 10 mmol/L), glucagon-like peptide-1 (GLP-1; primed-continuous infusion), and arginine given during the continued GLP-1 infusion. In IGT, insulin levels were significantly lower during the first phase (144 +/- 20 vs. 397 +/- 119 pmol/L; P = 0.02), at the end of the GLP infusion (2142 +/- 350 vs. 5430 +/- 1091 pmol/L; P: = 0.002), and in response to arginine (3983 +/- 375 vs. 8663 +/- 1430 pmol/L; P = 0.005). In response to glucose, the minimum PI/I ratio was significantly higher in IGT (3.4 +/- 0.6%) than in NGT (1.4 +/- 0.5%; P = 0.02), suggesting defective proinsulin processing in this condition. In subjects with IGT, the PI/I ratio decreased significantly after GLP-1 priming (1.7 +/- 0.2%; P = 0.02) and after arginine given during GLP-1 (1.4 +/- 0.2%; P = 0.007) and was not significantly different from those values in NGT (1.3 +/- 0.2% and 1.3 +/- 0.2%, respectively; both P = NS). In conclusion, during maximal stimulation of insulin secretion in subjects with IGT, the PI/I ratio in plasma decreased significantly and was not different from that in normal controls. This strongly argues against the hypothesis that defective processing of proinsulin to insulin represents a major component of the beta-cell dysfunction in IGT.

Adult↗
PubMed2001

The Gly972Arg polymorphism in the insulin receptor substrate-1 gene contributes to the variation in insulin secretion in normal glucose-tolerant humans.

The Gly972Arg polymorphism in the insulin receptor substrate (IRS)-1 was found in some studies to have a higher prevalence in type 2 diabetic subjects than in control subjects. Previously, transfection of IRS-1 with this polymorphism into insulin-secreting cells resulted in a marked reduction of glucose-stimulated insulin secretion compared with the wild-type transfected cells. In the present study, we compared insulin secretion in well-matched normal glucose-tolerant subjects with and without this polymorphism. Several validated indexes of beta-cell function from the oral glucose tolerance test were significantly lower in X/Arg (n = 31) compared with Gly/Gly (n = 181) (P between 0.002 and 0.05), whereas insulin sensitivity (measured with a euglycemic clamp) was not different. During a modified hyperglycemic clamp, insulin secretion rates were significantly lower in Gly/Arg (n = 8) compared with Gly/Gly (n = 36) during the first phase (1,711+/-142 vs. 3,014+/-328 pmol/min, P = 0.05) and after maximal stimulation with arginine (5,340+/-639 vs. 9,075+/-722 pmol/min, P = 0.03). In summary, our results suggest that the Gly972Arg polymorphism in IRS-1 is associated with decreased insulin secretion in response to glucose but not with insulin sensitivity. It is possible that this polymorphism causes insulin resistance at the level of the beta-cell and contributes to the polygenic etiology of type 2 diabetes.

Arginine↗
PubMed2001

Effect of experimental elevation of free fatty acids on insulin secretion and insulin sensitivity in healthy carriers of the Pro12Ala polymorphism of the peroxisome proliferator--activated receptor-gamma2 gene.

The transcription of many genes involved in lipid metabolism is regulated by the peroxisome proliferator-activated receptor-gamma (PPAR-gamma). The Pro12Ala polymorphism in the PPAR-gamma2 gene has been associated with reduced transcriptional activity in vitro and increased insulin sensitivity in vivo. Although PPAR-gamma has been demonstrated in human beta-cells, it is unknown whether the Pro12Ala polymorphism plays a role in insulin secretion. Moreover, it is also unknown if and how the effect of free fatty acids (FFAs) on insulin secretion and insulin sensitivity is modulated by the presence of this polymorphism. We therefore performed hyperglycemic clamps (8 mmol/l, 140 min, 5 g arginine bolus at min 120) in 10 healthy subjects with the (X/Ala) polymorphism and in 10 subjects without the polymorphism (Pro/Pro) basally and after 5 h infusion of Intralipid plus heparin. FFA concentrations increased from 473 +/- 61 micromol/l to 1,732 +/- 163 micromol/l in the Pro/Pro and from 372 +/- 46 micromol/l to 1,630 +/- 96 micromol/l in the X/Ala group (P = 0.68). Basally, neither insulin sensitivity nor insulin secretion were significantly different between the two groups. During infusion of Intralipid, first-phase insulin secretion remained unchanged in both groups (P = 0.21). In the Pro/Pro group, second-phase insulin secretion remained unchanged (444 +/- 67 vs. 471 +/- 93 pmol/min) and the response to arginine increased from 5,007 +/- 41 to 6,072 +/- 732 pmol/min. In contrast, in the X/Ala group, there was a decrease of both second-phase insulin secretion (533 +/- 58 to 427 +/- 48 pmol/min, P = 0.02 vs. Pro/Pro) and in the response to arginine (from 7,518 +/- 1,306 to 6,458 +/- 1,040 pmol/min, P = 0.014 vs. Pro/Pro). The insulin sensitivity index decreased comparably in Pro/Pro and X/Ala (to 71 +/- 8 vs. 74 +/- 9% of basal, P = 0.8). In conclusion, these results provide evidence that the Pro12Ala polymorphism in the PPAR-gamma2 gene might be involved in a differential regulation of insulin secretion in response to increased FFAs in humans.

Alanine↗
PubMed2000

Characterisation of beta-cell dysfunction of impaired glucose tolerance: evidence for impairment of incretin-induced insulin secretion.

AIMS/HYPOTHESIS: Our studies were undertaken to characterise the defective insulin secretion of impaired glucose tolerance (IGT). METHODS: We studied 13 normal glucose tolerant subjects (NGT) and 12 subjects with IGT carefully matched for age, sex, BMI and waist-to-hip ratio. A modified hyperglycaemic clamp (10 mmol/1) with a standard 2-h square-wave hyperglycaemia, an additional glucagon-like-peptide (GLP)-1 phase (1.5 pmol x kg(-1) x min(-1) over 80 min) and a final arginine bolus (5 g) was used to assess various phases of insulin secretion rate. RESULTS: Insulin sensitivity during the second phase of the hyperglycaemic clamp was low in both groups but not significantly different (0.12 +/- 0.021 in NGT vs 0.11 +/- 0.013 micromol x kg(-1) x min(-1) x pmol(-1) in IGT, p = 0.61). First-phase insulin secretion was lower in IGT (1467 +/- 252 vs 3198 +/- 527 pmol x min(-1), p = 0.008) whereas the second phase was not (677 +/- 61 vs 878 +/- 117 pmol x min(-1), p = 0.15). The acute insulin secretory peak in response to GLP-1 was absent in IGT subjects who only produced a late phase of GLP-1-induced insulin secretion rate which was lower (2228 +/- 188 pmol x min(-l)) than in NGT subjects (3056 +/- 327 pmol x min(-1), p = 0.043). Insulin secretion in response to arginine was considerably although not significantly lower in IGT subjects. The relative impairment (per cent of the mean rate for NGT subjects) was greatest for the GLP-1 peak (19 +/- 9%). CONCLUSION/INTERPRETATION: In this Caucasian cohort a defective insulin secretion rate is essential for the development of IGT. The variable degrees of impairment of different phases of the insulin secretion rate indicate that several defects contribute to its abnormality in IGT. Defects in the incretin signalling pathway of the beta cell could contribute to the pathogenesis of beta-cell dysfunction of IGT and thus Type II (non-insulin-dependent) diabetes mellitus.

Adult↗
PubMed2000

Stimulatory effect of increased non-esterified fatty acid concentrations on proinsulin processing in healthy humans.

AIMS/HYPOTHESIS: To assess the effect of increased concentrations of non-esterified fatty acids (NEFA) on proinsulin processing in healthy humans. METHODS: We did a hyperglycaemic clamp (130 min duration, 8 mmol/l glucose, with a 5-g arginine bolus at min 120) before and after a 5-h infusion of Intralipid/heparin in 14 healthy subjects. Of the subjects eight underwent a saline control experiment. The proinsulin:insulin (PI:I) ratio immediately after the arginine bolus (122.5 to 125 min) was considered to provide an estimate for the conversion of proinsulin to insulin in the beta cell. RESULTS: Concentrations of NEFA were 757 +/- 86 micromol/l and 1669 +/- 134 micromol/l (p < 0.001) after the 5-h infusion of saline or Intralipid, respectively. Insulin secretion rates were no different between the Intralipid and saline infusions (p = 0.73). There was no statistically significant difference for either the proinsulin concentration or the PI:I ratio during glucose stimulation alone (0 to 120 min). In response to arginine, in contrast, proinsulin remained unchanged during the saline infusion (from 31 +/- 6 to 29 +/- 7 pmol/l, p = 0.50) but decreased during 5 h of lipid infusion from (21 +/- 3 to 15 +/- 2 pmol/l, p = 0.02). The PI:I ratio in response to the arginine bolus was higher during the saline infusion (2.0 +/- 0.2% vs 1.7 +/- 0.2%, p = 0.04) but decreased during the Intralipid infusion (from 1.6 +/- 0.2% to 1.2 +/- 0.1%, p = 0.04). CONCLUSION/INTERPRETATION: The statistically significantly lower PI:I ratio in response to arginine during experimentally increased concentrations of NEFA suggests that NEFA increase the conversion of proinsulin to insulin in humans in vivo.

Adult↗
PubMed2000

A novel hyperglycaemic clamp for characterization of islet function in humans: assessment of three different secretagogues, maximal insulin response and reproducibility.

BACKGROUND: Characterization of beta-cell function in humans is essential for identifying genetic defects involved in abnormal insulin secretion and the pathogenesis of type 2 diabetes. MATERIALS AND METHODS: We designed a novel test assessing plasma insulin and C-peptide in response to 3 different secretagogues. Seven lean, healthy volunteers twice underwent a 200 min hyperglycaemic clamp (10 mmol L-1) with administration of GLP-1 (1.5 pmol. kg-1. min-1) starting at 120 min and an arginine bolus at 180 min. We determined glucose-induced first and second-phase insulin secretion, GLP-1-stimulated insulin secretion, arginine-stimulated insulin response (increase above prestimulus, DeltaIarg) and the maximal, i. e. highest absolute, insulin concentration (Imax). Insulin sensitivity was assessed during second-phase hyperglycaemia. On a third occasion 6 subjects additionally received an arginine bolus at > 25 mM blood glucose, a test hitherto claimed to provoke maximal insulin secretion. RESULTS: Insulin levels increased from 46 +/- 11 pM to 566 +/- 202 pM at 120 min, to 5104 +/- 1179 pM at 180 min and to maximally 8361 +/- 1368 pM after arginine (all P < 0.001). The within subject coefficients of variation of the different secretion parameters ranged from 10 +/- 3% to 16 +/- 6%. Except for second-phase which failed to correlate significantly with DeltaIarg (r = 0.52, P = 0.23) and Imax (r = 0.75, P = 0.053) all phases of insulin secretion correlated with one another. The insulin concentration after the arginine bolus at > 25 mM glucose (n = 6) was 2773 +/- 855 pM vs. 7562 +/- 1168 pM for Imax (P = 0.003). CONCLUSION: This novel insulin secretion test elicits a distinct pattern of plasma insulin concentrations in response to the secretagogues glucose, GLP-1 and arginine and is highly reproducible and can be used for differential characterization of islet function.

Adult↗
PubMed2000

A 60 minute hyperglycemic clamp is sufficient to assess both phases of insulin secretion.

The hyperglycemic clamp is considered to be the gold standard for determining both first and second phase insulin secretion. In order to achieve a reasonable insulin plateau for the second phase, it has become common practice to clamp for 120 or even 180 minutes at 10 mM. It is unknown whether earlier insulin determinations would be sufficient to predict second phase insulin secretion. We therefore reviewed the hyperglycemic clamp data of 58 subjects with different degrees of glucose tolerance to assess whether one or more insulin concentrations determined at earlier time points of the clamp could predict second phase insulin secretion (insulin and C-peptide concentration at 120 minutes). The correlation coefficients between second-phase insulin secretion and plasma insulin or C-peptide at 60 min were 0.95 and 0.96, respectively (both p<0.00005). Averaging plasma insulin or C-peptide over 2 or more adjacent time points did not improve the correlation. In conclusion, a one-hour hyperglycemic clamp can provide the standard measurement of first phase insulin secretion plus a good approximation of second phase insulin secretion.

Adult↗
PubMed1999

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