Oral glucose tolerance test indexes for insulin sensitivity and secretion based on various availabilities of sampling times.
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Administration, Oral↗
Biomedical subjects
A Fritsche
Publications and source records attributed to A Fritsche.
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↗
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↗
Intensive insulin therapy combined with metformin in obese type 2 diabetic patients.
Unlike other pharmacological therapies used in obese type 2 diabetic patients, metformin has been shown to improve glycemic control with lower insulin levels and not to involve weight gain. We therefore examined the effect of adjunct metformin in 13 severely obese type 2 diabetic patients (BMI 39.3 +/- 3.9 kg/m2) in suboptimal glycemic control pretreated with intensified insulin therapy. Patients were randomly assigned to either metformin or placebo treatment (double-blind) for 10 weeks and after a 2 week washout period received the opposite treatment, respectively, for 10 additional weeks. HbA1c decreased comparably during placebo (from 8.1 +/- 0.4 to 7.6 +/- 0.3%) and metformin (from 8.5 +/- 0.4 to 7.4 +/- 0.3%, p = 0.29 vs. placebo). Changes in fasting glucose levels were also not different between placebo (from 9.3 +/- 0.7 to 9.5 +/- 0.7 mM) and metformin (from 10.3 +/- 0.5 to 9.5 +/- 0.6 mM, p = 0.44 vs. placebo). Total exogenous insulin requirements decreased from 53 +/- 10 to 35 +/- 7 units during metformin treatment (p = 0.02 vs. placebo). Changes in fasting insulin levels during placebo and metformin treatments were not different (p = 0.11). Metformin had no effect on body weight and serum triglycerides but marginally decreased serum cholesterol levels (from 239 +/- 18 to 211 +/- 14 mg/dl, p = 0.005, p = 0.08 vs. placebo). During the oral glucose tolerance test no differences were observed in the areas under the curve for glucose and insulin while that for C-peptide showed a tendency to increase during metformin administration. We conclude that addition of metformin to insulin treatment in severely obese type 2 diabetic patients improves glycemia but not hyperinsulinemia in comparison to intensive insulin therapy alone. With adjunct metformin, approximately 30% less exogenous insulin is required. With respect to glycemia and lipids, adjunct metformin can be a reasonable treatment alternative in selected obese patients with type 2 diabetes already on intensive insulin therapy.
Body Mass Index↗
Leptin levels in humans are acutely suppressed by isoproterenol despite acipimox-induced inhibition of lipolysis, but not by free fatty acids.
Leptin secretion is complexly regulated in humans. Insulin has been shown to stimulate leptin secretion, whereas in vitro data suggest that catecholamines and free fatty acids (FFAs) inhibit leptin secretion. To dissect differential effects on leptin secretion, we performed two experimental protocols in 11 lean healthy subjects in addition to a saline infusion plus oral acipimox to suppress lipolysis (SAL + ACX) as a control experiment: (1) isoproterenol (approximately 30 ng/kg x min, to increase the heart rate by approximately 50 bpm) plus oral acipimox (ISO + ACX, 240 minutes) and (2) Intralipid (Pharmacia & Upjohn, Erlangen, Germany) plus heparin (LIP, 420 minutes). During SAL + ACX, FFAs decreased from 0.44 +/- 0.04 to 0.06 +/- 0.02 mmol/L (P = .001), while serum insulin and leptin remained unchanged. During ISO + ACX, FFAs decreased similarly from 0.41 +/- 0.13 to 0.09 +/- 0.02 mmol/L (P= .001), while insulin increased from 47 +/- 8 to a maximum of 116 +/- 15 pmol/L (P= .001) and serum leptin decreased acutely from 6.4 +/- 2.1 to a minimum of 5.4 +/- 1.8 ng/mL after 90 minutes (P = .003 vSAL + ACX). After 150 minutes, leptin returned to control levels. During LIP, the elevation of FFAs from 0.34 +/- 0.04 to 1.71 +/- 0.19 mmol/L (P = .001) had no effect on serum insulin or leptin concentrations (both P = nonsignificant). In conclusion, our results show that in humans, isoproterenol acutely suppresses leptin levels independently of increased FFAs, and elevated FFAs have no acute effect on leptin levels. The fact that an inhibition of leptin secretion occurred despite conditions that are known to suppress intracellular cyclic adenosine monophosphate (cAMP) levels, as demonstrated by suppressed lipolysis, suggests that signaling mechanisms other than those mediated by cAMP must be involved in modulating leptin secretion.
Adult↗
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↗
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↗
Reversal of hypoglycemia unawareness in a long-term type 1 diabetic patient by improvement of beta-adrenergic sensitivity after prevention of hypoglycemia.
The purpose of this study was to assess the effect of strict avoidance of hypoglycemia on beta-adrenergic sensitivity in a type 1 diabetic patient with hypoglycemia unawareness and a diabetes duration of 55 yr. beta-Adrenergic sensitivity was determined by an isoproterenol test and was expressed as the lowest dose of isoproterenol that increases the heart rate by 25 beats/min (IC25). Plasma epinephrine and symptom responses to hypoglycemia were determined during a 3-h hypoglycemic (3 mmol/L) clamp. Initially, the patient had a near-normal counterregulatory plasma epinephrine response to hypoglycemia but reduced beta-adrenergic sensitivity (IC25, 2 microg) compared to 10 hypoglycemia aware, type 1 diabetic patients (0.65 +/- 0.14 microg) and 10 normal control subjects (1.13 +/- 0.21 microg). After 1 yr of strict avoidance of blood glucose levels below 4 mmol/L, the IC25 decreased to 0.25 microg, reflecting improved beta-adrenergic sensitivity. In conclusion, the reduced beta-adrenergic sensitivity in this patient was probably the reason for hypoglycemia unawareness and was reversed by strict avoidance of hypoglycemia.
Adrenergic beta-Agonists↗
Assessment of insulin secretion from the oral glucose tolerance test in white patients with type 2 diabetes.
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Diabetes Mellitus, Type 2↗
Long term effect of a structured inpatient diabetes teaching and treatment programme in type 2 diabetic patients: influence of mode of follow-up.
Structured diabetes teaching and treatment programmes (STTP) are increasingly offered for patients with diabetes to improve metabolic control. We prospectively studied the long term-effect of STTP on metabolic control and knowledge of diabetes in patients with type 2 diabetes. In addition, differences in the mode of follow-up by a university diabetes centre (UDC) versus general practitioner (GP) were assessed. Of the 64 patients with type 2 diabetes (61 +/- 10 years old, diabetes duration 11 +/- 7 years) included in the study 52 could be reevaluated after 2 years. Of those, 31 were followed up by the UDC and 21 by their GPs who received detailed follow-up instructions from the UDC. In all patients, HbA1c decreased from 9.1 +/- 0.3% before the programme to 8.3 +/- 0.3% 2 years after the programme (P = 0.004), whereas body mass index increased from 28.8 +/- 0.8 to 30.3 +/- 0.9 kg/m2 (P < 0.001). Patients had a significantly better knowledge of diabetes and diet 2 years after the programme. For all parameters tested, none of the changes differed between patients managed by the UDC versus those managed by their GP. However, patients who chose follow-up by the UDC were more obese and had a better knowledge of diabetes. In conclusion, the STTP for patients with type 2 diabetes was effective in improving the long-term glycaemic control and knowledge of diabetes. Moreover, with precise therapeutic goals and follow-up instructions given to patient and GP this improvement was independent of the mode of outpatient follow-up.
Academic Medical Centers↗
Diabetes teaching program improves glycemic control and preserves perception of hypoglycemia.
Improvement of HbA1c is frequently accompanied by deteriorating awareness of hypoglycemia. We studied the effect of improved metabolic control on hypoglycemia perception in 33 type 1 diabetic patients during 3 months after an inpatient diabetes education program of 5 days. Patients were grouped according to the presence (H, n = 11) or the absence (N, n = 22) of a history of repeated severe hypoglycemia. To measure awareness of blood glucose (BG) and hypoglycemia, we calculated their accuracy of BG perception (error grid analysis) and sensitivity for BG levels < 3.9 mmol/l, respectively, during the first (I) and second (II) period of the 3 months using the method of BG estimation. HbA1c decreased from 8.0 +/- 0.3% before to 7.1 +/- 0.2% 3 months after the program (P < 0.001) with no difference between H and N. Neither accuracy of BG perception (40.6 +/- 3.8 (I) versus 43.6 +/- 4.1% (II), P = 0.25) nor sensitivity for low BG levels (49.1 +/- 4.2 (I) versus 54.9 +/- 4.9% (II), P = 0.12) changed significantly. Group H had a lower overall accuracy of BG estimation (P = 0.048) and a lower overall sensitivity for detecting BG levels < 3.9 mmol/l (P = 0.03) than group N. Group H was able to improve accuracy of BG estimation (H: 24.8 +/- 6.2 (I) versus 36.9 +/- 8.3% (II), P = 0.04) while group N was not (48.5 +/- 3.9 (I) versus 46.9 +/- 4.6% (II), P = 0.5). In conclusion, improvement of metabolic control after intensive diabetes education had no adverse effect on the perception of low BG levels. On the contrary, patients with a history of severe hypoglycemia improved their awareness of BG.
Adult↗
Evidence for inhibition of leptin secretion by catecholamines in man.
The regulation of leptin secretion is complex and not entirely understood in humans. Insulin has been shown to stimulate leptin secretion in humans, whereas in vitro data suggest that catecholamines inhibit leptin secretion. The present studies were therefore undertaken to examine the leptin response to hyperinsulinemia in the presence and absence of elevated plasma levels of endogenous catecholamines in humans. Leptin concentrations were determined during both a euglycemic and hypoglycemic hyperinsulinemic clamp study in 10 normal and 10 type I diabetic subjects. Serum leptin increased during the hyperinsulinemic euglycemic clamp in normal (from 6.1 +/- 0.9 to 7.2 +/- 1.1 ng/dl, p = 0.003) and diabetic subjects (from 6.2 +/- 1.4 to 7.8 +/- 1.8 ng/dl, p = 0.001). During hyperinsulinemic hypoglycemia leptin concentrations increased significantly in type 1 diabetic patients (from 5.6 +/- 1.1 to 7.6 +/- 1.7 ng/dl, p = 0.003) but remained unaltered in normals (from 5.5 +/- 0.7 to 5.7 +/- 0.9 ng/dl, p = 0.7). During hypoglycemia in all subjects the increase in leptin was negatively correlated with the increase in epinephrine (r = 0.60, p = 0.005) and positively with the decrease in free fatty acids (r = 0.71, p = 0.003). In conclusion our results indicate that catecholamines play a suppressive role in the regulation of leptin secretion.
Adult↗
Effect of hypoglycemia on beta-adrenergic sensitivity in normal and type 1 diabetic subjects.
OBJECTIVE: The purpose of this study was to assess the potential role of reduced tissue sensitivity to catecholamines in the pathogenesis of hypoglycemia unawareness in patients with type 1 diabetes. RESEARCH DESIGN AND METHODS: The effect of a single episode of hypoglycemia on beta-adrenergic sensitivity was studied in 10 type 1 diabetic patients with apparently normal awareness of hypoglycemia (age 29 +/- 5 years, diabetes duration 13 +/- 8 years, HbA1c 7.3 +/- 0.9%) and 10 age-matched healthy control subjects. Beta-adrenergic sensitivity was measured with the isoproterenol test after a hyperinsulinemic euglycemic clamp and after a hyperinsulinemic hypoglycemic clamp. Beta-adrenergic sensitivity was expressed as the dose of intravenous isoproterenol that increased the heart rate by 25 beats/min (IC25). RESULTS: During hypoglycemia, diabetic subjects had an impaired plasma epinephrine response compared with that of the control subjects (16.7 +/- 5.0 vs. 40.1 +/- 6.8 ng/ml, P = 0.02). In control subjects, the IC25 was lower after hypoglycemia than after euglycemia (0.83 +/- 0.22 vs. 1.13 +/- 0.21 microg, P = 0.02) indicating an increase in beta-adrenergic sensitivity. In diabetic subjects, on the other hand, the IC25 was greater after hypoglycemia than after euglycemia (1.00 +/- 0.26 vs. 0.65 +/- 0.14 microg, P = 0.04), indicating a decrease in beta-adrenergic sensitivity. CONCLUSIONS: In normal subjects, a single episode of hypoglycemia increases beta-adrenergic sensitivity. In diabetic subjects, in contrast, hypoglycemia reduces beta-adrenergic sensitivity. These results provide evidence that in type 1 diabetic patients, some maladaptation of tissue sensitivity to catecholamines contributes to the development of hypoglycemia unawareness. A unifying hypothesis is presented for the pathogenesis of hypoglycemia unawareness in type 1 diabetic patients incorporating the concepts of both a reduced catecholamine response and reduced adrenergic sensitivity
Adrenergic beta-Agonists↗
Necrotizing fasciitis caused by unencapsulated Haemophilus influenzae.
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Anti-Infective Agents↗
Features of malignancy in a benign pheochromocytoma.
Pheochromocytomas are rare conditions with a prevalence of 1-2/100,000 in the general population and 1/1,000 hypertensive subjects [1]. 10% of pheochromocytomas are malignant and various attempts have been made to find useful prognostic indicators of malignancy. In general, increased plasma or urine dopamine concentrations or increased homovanillic acid excretion and lack of 131-methyliodo-benzylguanidine uptake have been associated with malignancy [2]. However, to date no specific metabolic, radiologic or histopathologic features of either benign or malignant pheochromocytomas allowing the safe diagnosis of one or the other have been identified. The diagnosis of malignant pheochromocytoma can be made only in the presence of local tissue invasion or distant metastases. We present a benign pheochromocytoma exhibiting several features suggestive of malignant disease.
Adult↗
A functioning adrenocortical hemangioma.
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Adrenal Cortex Neoplasms↗
[Pharmacologic effects of biotin on epidermal cells].
Biotin deficiency in animals causes pathological changes of the skin and its appendages including, for example, exfoliative dermatitis, depigmentation, and alopecia. The hooves of biotin-deficient swine are weak, brittle, and often necrotic. These changes disappear after dietary biotin supplementation. Biotin supplementation also noticeably improves the hoof quality of horses, cattle and swine having no apparent biotin deficiency. In order to elucidate the molecular basis of these effects, the influence of biotin on cytokeratin expression in a keratinocyte cell line (Ha-CaT) was investigated using electrophoretic and immunological techniques. Pharmacological biotin concentrations of 1 microM, and 100 microM in the culture medium caused a specific increase in cytokeratins, which are normally induced upon terminal differentiation of epidermal cells in vivo. The expression of cytokeratins occurring in stratified epithelia independent of differentiation were not affected. These findings show that biotin directly stimulates the differentiation of epidermal cells. Such a molecular mechanism revealed in cell culture could provide an explanation for the therapeutic effects of pharmacological doses of biotin on hoof quality in farm animals.
Animals↗