Regional variations in definitions and rates of hypoglycaemia: findings from the global HAT observational study of 27 585 people with Type 1 and insulin-treated Type 2 diabetes mellitus.

AIM: To determine participant knowledge and reporting of hypoglycaemia in the non-interventional Hypoglycaemia Assessment Tool (HAT) study. METHODS: HAT was conducted in 24 countries over a 6-month retrospective/4-week prospective period in 27 585 adults with Type 1 or insulin-treated Type 2 diabetes mellitus. Participants recorded whether hypoglycaemia was based on blood glucose levels, symptoms or both. RESULTS: Hypoglycaemia rates were consistently higher in the prospective compared with the retrospective period. Most respondents (96.8% Type 1 diabetes; 85.6% Type 2 diabetes) knew the American Diabetes Association/European Association for the Study of Diabetes hypoglycaemia definition, but there were regional differences in the use of blood glucose measurements and/or symptoms to define events. Confirmed symptomatic hypoglycaemia rates were highest in Northern Europe/Canada for Type 1 diabetes (63.9 events/year) and in Eastern Europe for Type 2 diabetes (19.4 events/year), and lowest in South East Asia (Type 1 diabetes: 6.0 events/year; Type 2 diabetes: 3.2 events/year). Unconfirmed symptomatic hypoglycaemia rates were highest in Eastern Europe for Type 1 diabetes (5.6 events/year) and South East Asia for Type 2 diabetes (4.7 events/year), and lowest for both in Russia (Type 1 diabetes: 2.1 events/year; Type 2 diabetes: 0.4 events/year). Participants in Latin America reported the highest rates of severe hypoglycaemia (Type 1 diabetes: 10.8 events/year; Type 2 diabetes 3.7 events/year) and severe hypoglycaemia requiring hospitalization (Type 1 diabetes: 0.56 events/year; Type 2 diabetes: 0.44 events/year). The lowest rates of severe hypoglycaemia were reported in South East Asia (Type 1 diabetes: 2.0 events/year) and Northern Europe/Canada (Type 2 diabetes: 1.3 events/year), and the lowest rates of severe hypoglycaemia requiring hospitalization were in Russia (Type 1 diabetes: 0.15 events/year; Type 2 diabetes: 0.09 events/year). The blood glucose cut-off used to define hypoglycaemia varied between regions (Type 1 diabetes: 3.1-3.6 mmol/l; Type 2 diabetes: 3.5-3.8 mmol/l). CONCLUSIONS: Under-reporting of hypoglycaemia rates in retrospective recall and regional variations in participant definitions of hypoglycaemia may contribute to the global differences in reported rates. Discrepancies between participant definitions and guidelines may highlight a need to redefine hypoglycaemia criteria. (Clinical Trials Registry No: NCT01696266).

Rates and predictors of hypoglycaemia in 27 585 people from 24 countries with insulin-treated type 1 and type 2 diabetes: the global HAT study.

AIMS: To determine the global extent of hypoglycaemia experienced by patients with diabetes using insulin, as there is a lack of data on the prevalence of hypoglycaemia in developed and developing countries. METHODS: This non-interventional, multicentre, 6-month retrospective and 4-week prospective study using self-assessment questionnaire and patient diaries included 27 585 patients, aged ≥18 years, with type 1 diabetes (T1D; n = 8022) or type 2 diabetes (T2D; n = 19 563) treated with insulin for >12 months, at 2004 sites in 24 countries worldwide. The primary endpoint was the proportion of patients experiencing at least one hypoglycaemic event during the observational period. RESULTS: During the prospective period, 83.0% of patients with T1D and 46.5% of patients with T2D reported hypoglycaemia. Rates of any, nocturnal and severe hypoglycaemia were 73.3 [95% confidence interval (CI) 72.6-74.0], 11.3 (95% CI 11.0-11.6) and 4.9 (95% CI 4.7-5.1) events/patient-year for T1D and 19.3 (95% CI 19.1-19.6), 3.7 (95% CI 3.6-3.8) and 2.5 events/patient-year (95% CI 2.4-2.5) for T2D, respectively. The highest rates of any hypoglycaemia were observed in Latin America for T1D and Russia for T2D. Glycated haemoglobin level was not a significant predictor of hypoglycaemia. CONCLUSIONS: We report hypoglycaemia rates in a global population, including those in countries without previous data. Overall hypoglycaemia rates were high, with large variations between geographical regions. Further investigation into these differences may help to optimize therapy and reduce the risk of hypoglycaemia.

Fear of hypoglycaemia in adults with Type 1 diabetes.

AIMS: The aim of this study was to examine the fear of hypoglycaemia and its association with demographic and disease-specific variables in a large and unselective population of adult patients with Type 1 diabetes. METHODS: Questionnaires were sent by post to all patients with Type 1 diabetes who were identified in the local diabetes registries of two hospitals in Stockholm, Sweden (n=1387). Fear of hypoglycaemia was measured using the Swedish Hypoglycaemia Fear Survey, the Worry subscale and the Aloneness subscale. Demographic variables and disease-specific factors were collected from patients' self reports and medical records. Univariate analysis and multiple stepwise linear regression analysis were used in the statistical analyses of the data. RESULTS: Seven hundred and sixty-four (55%) patients participated in the study (mean age 43.3 years and mean HbA(1c) 7.0%, normal <5.0%). The Hypoglycaemia Fear Survey - Worry subscale was significantly associated with frequency of severe hypoglycaemia, number of symptoms during mild hypoglycaemia, gender, hypoglycaemic symptoms during hyperglycaemia and hypoglycaemic unawareness. The Hypoglycaemia Fear Survey - Aloneness subscale was significantly associated with frequency of severe hypoglycaemia, number of symptoms during mild hypoglycaemia, gender, frequency of mild hypoglycaemia, HbA(1c) , hypoglycaemic unawareness and visits to the emergency room because of severe hypoglycaemia. Fear of hypoglycaemia proved to be more prevalent in females and indicated a different pattern between genders in relation to factors associated with fear of hypoglycaemia. CONCLUSIONS: This study identifies the frequency of severe hypoglycaemia as the most important factor associated with fear of hypoglycaemia. Moreover, for the first time, we document gender differences in fear of hypoglycaemia, suggesting that females are more affected by fear of hypoglycaemia than men.

Can glycaemic variability, as calculated from blood glucose self-monitoring, predict the development of complications in type 1 diabetes over a decade?

AIMS: Is glycaemic variability an independent risk factor for the development of microvascular complications in addition to average glycaemia, as assessed by glycated haemoglobin (HbA(1c))? In this study, an 11-year follow-up was carried out in patients with type 1 diabetes. The standard deviation of blood glucose (SDBG) concentration, an index of glycaemic variability, was calculated from self-monitored blood glucose data at baseline. METHODS: A total of 100 patients were randomly selected from 442 consecutive type 1 diabetic patients attending our outpatients clinic. SDBG was calculated from 70 measurements taken over a period of four weeks. Onset and progression of micro- and macrovascular complications were recorded over the 11-year follow-up. RESULTS: As expected, the prevalence of complications increased over time. Statistical analyses showed that HbA(1c) was an independent predictor of the incidence (P=0.004) and prevalence (P=0.01) of nephropathy. SDBG was found to be a predictor of the prevalence of peripheral neuropathy (P=0.03), and showed borderline significance in predicting the incidence of peripheral neuropathy (P=0.07). SDBG was also a highly significant predictor of hypoglycaemic unawareness (P=0.001). CONCLUSIONS: We conclude that variability of blood glucose may be important in the development of peripheral neuropathy in patients with type 1 diabetes, and that the nervous system may be particularly vulnerable to glycaemic variability.

Effects of treatment with a 5-HT4 receptor antagonist in heart failure.

BACKGROUND AND PURPOSE: Positive inotropic responses (PIR) to 5-hydroxytryptamine (5-HT) are induced in the left ventricle (LV) in rats with congestive heart failure (CHF); this is associated with upregulation of the G(s)-coupled 5-HT(4) receptor. We investigated whether chronic 5-HT(4) receptor blockade improved cardiac function in CHF rats. EXPERIMENTAL APPROACH: Rats were given either the 5-HT(4) antagonist SB207266 (0.5 mg kg(-1) 24h(-1); MI(int)) or placebo (MI(pl)) through mini-osmotic pumps for 6 weeks subsequent to induction of post-infarction CHF. In vivo cardiac function and ex vivo responses to isoprenaline or 5-HT were evaluated using echocardiography and isolated LV papillary muscles, respectively. mRNA levels were investigated using real-time quantitative RT-PCR. KEY RESULTS: LV diastolic function improved, with 4.6% lower LV diastolic diameter and 24.2% lower mitral flow deceleration in MI(int) compared to MI(pl). SB207266 reduced LV systolic diameter by 6.1%, heart weight by 10.2% and lung weight by 13.1%. The changes in posterior wall thickening and shortening velocity, cardiac output, LV systolic pressure and (dP/dt)(max), parameters of LV systolic function, did not reach statistical significance. The PIR to isoprenaline (10 microM) increased by 36% and the response to 5-HT (10 microM) decreased by 57% in MI(int) compared to MI(pl). mRNA levels for ANP, 5-HT(4(b)) and 5-HT(2A) receptors, MHCbeta, and the MHCbeta/MHCalpha -ratio were not significantly changed in MI(int) compared to MI(pl). CONCLUSIONS AND IMPLICATIONS: Treatment with SB207266 to some extent improved in vivo cardiac function and ex vivo myocardial function, suggesting a possible beneficial effect of treatment with a 5-HT(4) receptor antagonist in CHF.

Analgesic effect of dextromethorphan in neuropathic pain.

BACKGROUND: Dextromethorphan, a clinically available N-methyl-D-aspartic acid (NMDA) receptor antagonist, has an analgesic effect in patients with diabetic neuropathy. The aim of this study was to evaluate the analgesic and adverse effects of a single high dose of dextromethorphan on spontaneous pain in patients suffering long-term neuropathic pain of traumatic origin. METHODS: Fifteen patients with post-traumatic neuropathic pain participated in this placebo-controlled, double-blind, randomized crossover study. On two separate occasions, the participants received 270 mg of dextromethorphan hydrobromide or placebo. Pain intensity, adverse effects and serum concentrations of dextromethorphan and metabolites were registered. RESULTS: Dextromethorphan had a statistically significant analgesic effect compared with placebo, but the effect varied markedly among the patients. Light-headedness was the most important adverse effect reported. Extensive metabolizers of dextromethorphan had an apparently better analgesic effect than poor metabolizers. CONCLUSION: This report indicates that a single high dose of dextromethorphan has an analgesic effect in patients with neuropathic pain of traumatic origin. The main metabolite dextrorphan seems to be important for the analgesic effect. At the relatively high dose studied, the clinical usefulness of dextromethorphan is limited to that portion of the patient population experiencing analgesia without an unacceptable level of adverse effects.

Evidence for a major role of skeletal muscle lipolysis in the regulation of lipid oxidation during caloric restriction in vivo.

A lipolytic process in skeletal muscle has recently been demonstrated. However, the physiological importance of this process is unknown. We investigated the role of skeletal muscle lipolysis for lipid utilization during caloric restriction in eight obese women before and after 11 days of very low-calorie diet (VLCD) (2.2 MJ per day). Subjects were studied with indirect calorimetry and microdialysis of skeletal muscle and adipose tissue in order to analyze substrate utilization and glycerol (lipolysis index) in connection with a two-step euglycemic-hyperinsulinemic (12 and 80 mU/m(2). min) clamp. Local blood flow rates in the two tissues were determined with (133)Xe-clearance. Circulating free fatty acids and glycerol decreased to a similar extent during insulin infusion before and during VLCD, and there was a less marked insulin-induced reduction in lipid oxidation during VLCD. Adipose tissue glycerol release was hampered by insulin infusion to the same extent ( approximately 40%) before and during VLCD. Skeletal muscle glycerol release was not influenced by insulin before VLCD. However, during VLCD insulin caused a marked (fivefold) (P < 0.01) increase in skeletal muscle glycerol release. The effect was accompanied by a fourfold stimulation of skeletal muscle blood flow (P < 0.01). We propose that, during short-term caloric restriction, the reduced ability of insulin to inhibit lipids, despite a preserved antilipolytic effect of the hormone in adipose tissue, is caused by an augmented mobilization of fat from skeletal muscle, and that a physiological role of muscle lipolysis provides a local source of fatty acids.

Rates of skeletal muscle and adipose tissue glycerol release in nonobese and obese subjects.

Skeletal muscle and adipose tissue lipolysis rates were quantitatively compared in 12 healthy nonobese and 14 insulin-resistant obese subjects for 3.5 h after an oral glucose load using microdialysis measurements of interstitial glycerol concentrations and determinations of local blood flow with 133Xe clearance in the gastrocnemius muscle and in abdominal subcutaneous adipose tissue. Together with measurements of arterialized venous plasma glycerol, the absolute rates of glycerol mobilization were estimated. In the basal state, skeletal muscle and adipose tissue glycerol levels were 50% higher (P < 0.05-0.01) and adipose tissue blood flow (ATBF) and muscle blood flow (MBF) rates were 30-40% lower (P < 0.02-0.05) in obese versus nonobese subjects. After glucose ingestion, adipose tissue glycerol levels were rapidly and transiently reduced, whereas in muscle, a progressive and less pronounced fall in glycerol levels was evident. MBF remained unchanged in both study groups, whereas ATBF increased more markedly (P < 0.01) in the nonobese versus obese subjects after the oral glucose load. The fasting rates of glycerol release per unit of tissue weight from skeletal muscle were between 20 and 25% of that from adipose tissue in both groups. After glucose ingestion, the rates of glycerol release from skeletal muscle and from adipose tissue were almost identical in nonobese and obese subjects. However, the kinetic patterns differed markedly between tissues; in adipose tissue, the rate of glycerol mobilization was suppressed by 25-30% (P < 0.05) after glucose ingestion, whereas no significant reduction was registered in skeletal muscle. We conclude that significant amounts of glycerol are released from skeletal muscle, which suggests that muscle lipolysis provides an important endogenous energy source in humans. In response to glucose ingestion, the regulation of skeletal muscle glycerol release differs from that in adipose tissue; although the rate of glycerol release from adipose tissue is clearly suppressed, the rate of glycerol mobilization from skeletal muscle remains unaltered. In quantitative terms, the rate of glycerol release per unit of tissue weight in adipose tissue and in skeletal muscle is similar in nonobese and obese subjects in both the postabsorptive state and after glucose ingestion.

beta-Adrenergic regulation of lipolysis and blood flow in human skeletal muscle in vivo.

Little is known about the regulation of catecholamine-stimulated lipolysis in human skeletal muscle. Therefore, beta-adrenergic regulation of lipolysis and blood flow was investigated in healthy subjects in vivo by use of microdialysis of the gastrocnemius muscle. First, during a hypoglycemic, hyperinsulinemic clamp, which induces a lipolytic response in skeletal muscle tissue, the muscle was locally perfused with beta-adrenoceptor blocking agents. Perfusion with nonselective (propranolol) and beta2-selective (ICI-118551) blocking agents counteracted the hypoglycemia-induced lipolysis (P < 0.01), but perfusion with metoprolol (beta1-blocker) did not affect the glycerol response. Second, selective beta-adrenoceptor agonists were perfused in situ into skeletal muscle during resting conditions. beta2-Adrenoceptor stimulation with terbutaline induced a concentration-dependent increase in skeletal muscle glycerol levels and in tissue blood flow, whereas perfusion with beta1- or beta3-adrenoceptor agonists (dobutamine or CGP-12177) did not influence the glycerol concentration or blood flow. In conclusion, in skeletal muscle tissue, only the beta2-subtype is of importance among beta-adrenoceptors for regulation of lipolysis and blood flow. This is in contrast to adipose tissue, where beta1- and beta3-adrenoceptors are also involved.

Lipolytic response during spontaneous hypoglycaemia in insulin-dependent diabetic subjects.

The adipose tissue lipolytic response to spontaneous, non-experimental hypoglycaemic episodes was investigated in patients with IDDM during ordinary life conditions. The absolute concentration of glucose and glycerol in subcutaneous adipose tissue was monitored in mobile patients with microdialysis in 16 IDDM subjects. The absolute glycerol level in adipose tissue was about five times as high as in venous plasma, whereas the glucose concentration was almost the same in the two compartments. Fourteen hypoglycaemic episodes (glucose < 3.5 mmol/l) were recorded. Adipose tissue glycerol increased markedly by 75 % in response to hypoglycaemia and remained increased during at least 4 hours following glucose nadir (F = 3.70, p = 0.003). The circulating levels of free fatty acids increased about three-fold in parallel to the in situ lipolytic response (F = 2.98, p = 0.025). The same lipolytic response was observed whether or not the hypoglycaemic event was perceived by the patient. A rapid decrease in glucose concentration above hypoglycaemic levels did not affect the adipose tissue dialysate glycerol. It is concluded that spontaneous hypoglycaemia elicits a long-term lipolytic response in adipose tissue as evidenced by increased levels of glycerol in adipose tissue with a parallel increase in serum free fatty acids. However, lipolysis is not activated by a rapid glucose decrease per se. The microdialysis method can be used to characterise the lipolytic response to hypoglycaemic episodes in every day life of IDDM patients.

Importance of phosphodiesterase 3 for the lipolytic response in adipose tissue during insulin-induced hypoglycemia in normal man.

The present investigation aimed to clarify the role of phosphodiesterase (PDE) type 3 for in vivo lipolysis in human adipose tissue during simultaneous insulin and catecholamine stimulation. Therefore, ten healthy subjects were investigated during insulin-induced hypoglycemia. Microdialysis probes were implanted in the subcutaneous adipose tissue and perfused by solvents with or without addition of the specific PDE 3 antagonist amrinone. Furthermore, changes in the local blood flow surrounding the dialysis probes were assessed by the ethanol escape technique. During the 60 min period before the start of the insulin infusion, adipose tissue glycerol levels (lipolysis index) increased significantly when amrinone was added to the perfusate (p = 0.0006, one-factor ANOVA). The antilipolytic response to the early phase of insulin infusion decreased (delta glycerol 9.0+/-3.5 vs. 29.9+/-6.0 micromol/l, p = 0.04) and the lipolytic response after hypoglycemia increased (AUC 122.4+/-18.0 vs. 13.4+/-16.3 micromol x l(-1) x h, p = 0.0001) comparing the experiments with or without amrinone, respectively. When amrinone was excluded from the perfusate, there was an increase in the nutritive blood flow during hypoglycemia, whereas there were no significant changes in the local blood flow surrounding the probe when amrinone was added to the perfusate. In conclusion, during insulin-induced hypoglycemia, PDE 3 activation clearly counteracts the lipolytic effect of catecholamines. When PDE 3 is specifically blocked, lipolysis increases greatly. Thus, PDE 3 is important for the in vivo regulation of the antilipolytic and lipolytic responses to hormones in human adipose tissue.

Protracted glucose fall in subcutaneous adipose tissue and skeletal muscle compared with blood during insulin-induced hypoglycaemia.

The absolute glucose concentrations in subcutaneous adipose tissue and skeletal muscle were determined with microdialysis in 10 normal-weight, healthy subjects during a standardized hyperinsulinaemic hypoglycaemic clamp. The concentration of tissue dialysate glucose was measured in 15-min fractions and compared with that in arterialized venous plasma. Insulin (0.15 U x kg(-1) x h[-1]) was infused i.v. to lower the plasma glucose level to 2.5 mmol/l over 30 min. This level was maintained for 30 min by using a variable glucose infusion. Thereafter, the insulin infusion was stopped and the plasma glucose level was gradually increased to baseline levels over 120 min. During a 60-min basal period, the glucose levels in muscle were 0.6 mmol/l lower than those in plasma (p = 0.002), whereas the levels in adipose tissue and plasma were similar. The glucose nadirs in muscle (1.6 +/- 0.1 mmol/l) and adipose tissue (2.0 +/- 0.1 mmol/l) were significantly lower than that in plasma (2.4 +/- 0.1 mmol/l) (p = 0.001 and 0.02, respectively), and the time-to-nadir was substantially longer in muscle (69 +/- 5 min) and adipose tissue (57 +/- 2 min) than in plasma (39 +/- 3 min) (p = 0.0004). When the insulin infusion was stopped, the increases in adipose tissue and muscle glucose concentrations were delayed by approximately 25 and 45 min, respectively, as compared to the increase in plasma glucose. Thus, it seems that glucose measurements in adipose tissue and muscle more adequately reflect overall tissue homeostasis than do measurements in blood and that clinically relevant tissue glucopenia may be overlooked by conventional blood glucose measurements.

Detection of hypoglycaemia by microdialysis measurements of glucose in subcutaneous adipose tissue.

The aim of the present investigation was to study how various fractional sampling times affect the detection of hypoglycaemia, using microdialysis of the adipose tissue. We therefore studied eight healthy subjects during a standardized hyperinsulinaemic hypoglycaemic clamp. The glucose concentration in the adipose tissue dialysate was determined in timed fractions of 15 min, 30 min and 60 min and compared to those in arterialized venous plasma. Before and after hypoglycaemia, the plasma and adipose tissue glucose concentrations were similar. However, during hypoglycaemia, the adipose tissue glucose nadir, as measured in 15-min fractions of the tissue dialysate, was significantly lower than that in plasma (2.1 +/- 0.1 vs. 2.4 +/- 0.1 mmol/l, p = 0.05) and during the increase in plasma glucose, the corresponding increase in adipose tissue glucose was delayed by approximately 20 min (p = 0.004). When the microdialysate was sampled over 30 or 60 min periods, there was a close agreement between the plasma and adipose tissue glucose nadirs. We conclude that there is a protracted fall in subcutaneous adipose tissue glucose levels in response to insulin-induced hypoglycaemia. While shorter microdialysis sampling periods improve the resolution of the hypoglycaemic event, 30-min fractions seem sufficient to detect hypoglycaemia in a clinically relevant way.

Absolute concentrations of glycerol and lactate in human skeletal muscle, adipose tissue, and blood.

The absolute concentrations of glycerol and lactate were studied with microdialysis of adipose tissue and skeletal muscle in normal-weight subjects. The basal interstitial glycerol concentration was 232 +/- 33, 96 +/- 8, and 59 +/- 6 mumol/l in fat, muscle, and arterialized plasma, respectively (P = 0.0002). This relationship was maintained during both euglycemic hyperinsulinemia, when glycerol decreased in all three compartments, and hypoglycemia, when glycerol first decreased and then increased in fat, muscle, and blood (P = 0.0001 for both). Basal interstitial lactate concentrations were similar in adipose tissue (1.1 +/- 0.2 mmol/l) and skeletal muscle (1.9 +/- 0.4 mmol/l) and higher than in arterialized blood (0.6 +/- 0.1 mmol/l, P = 0.002). During hyperinsulinemia and hypoglycemia, lactate increased (P = 0.0001) and the tissue-blood relationship was maintained (P = 0.04). In conclusion, adipose tissue and skeletal muscle mobilize glycerol and lactate at rest. Glycerol and lactate production are influenced by hyperinsulinemia and hypoglycemia in both tissues. Adipose tissue appears to be the major site of glycerol production, whereas skeletal muscle and fat may be equally important for lactate production.

Acute effects of the alpha 2-adrenoreceptor antagonist idazoxan on hormonal responses and symptoms of hypoglycaemia in patients with type 1 diabetes mellitus.

The aim of the present study was to evaluate the effect of the alpha 2-adrenoceptor antagonist idazoxan on hormonal responses and hypoglycaemia symptoms in patients with insulin-dependent (Type 1) diabetes mellitus. Six male Type 1 diabetic patients were studied with and without intravenous infusion of idazoxan. Hypoglycaemia was induced by an intravenous infusion of insulin (100 mU.kg-1.h-1), together with a glucose clamp, to obtain an arterialised venous blood glucose level of 2.3 mmol/l. Idazoxan was given at a dose of 295 micrograms/kg. Venous blood samples were obtained for analyses of free insulin, growth hormone (GH), glucagon and catecholamines. Symptoms were scored on a visual-analogue rating scale. Areas under the curves with and without idazoxan were respectively 22.4 +/- 7.0 vs 33.0 +/- 9.6 micrograms.l-1.h (p = 0.17) for GH, 4.1 +/- 1.1 vs 2.4 +/- 0.9 nmol.l-1h (p < 0.05) for adrenaline, 5.6 +/- 0.9 vs 1.3 +/- 0.5 nmol.l-1.h (p < 0.05) for noradrenaline and 51 +/- 38 vs -40 +/- 11 ng.l-1.h (p < 0.05) for glucagon. Sweating and palpitations were more pronounced during idazoxan infusion than during the control test. It is concluded that idazoxan increases catecholamine and glucagon responses as well as some of the warning signals of hypoglycaemia in Type 1 diabetic patients, whereas the GH response seems less affected by idazoxan.

Epidermal growth factor behaves as a partial agonist in hepatocytes: effects on DNA synthesis in primary culture and competition with transforming growth factor alpha.

The structurally related mitogens epidermal growth factor (EGF) and transforming growth factor (alpha (TGFalpha) are believed to exert all their effects via the same receptor. We have compared the effects of EGF and TGFalpha, and examined their interaction, on DNA synthesis in cultured rat hepatocytes. The potency of the two agents was similar, or slightly higher for EGF, but TGFalpha stimulated the DNA synthesis more efficiently, producing at high levels a rate of S phase entry that clearly exceeded (two to threefold) that obtained with maximally effective concentrations of EGF. While the hepatocytes became more sensitive both to TGFalpha and EGF when addition of the agents was postponed until late in the prereplicative period, TGFalpha exhibited higher efficacy than EGF both at early and late exposure. When EGF and TGFalpha were added together at 24 h, TGFalpha further enhanced the DNA synthesis in the presence of a saturating concentration (5 nM) of EGF, while EGF dose-dependently reduced the DNA synthesis in the presence of a high concentration (10 nM) of TGFalpha. The results show a lower efficacy of EGF than of TGFalpha, and, therefore, EGF displays the characteristics of a partial agonist in its EGF receptor-mediated growth stimulation in hepatocytes.

Day-to-day variation of insulin sensitivity in patients with type 1 diabetes: role of gender and menstrual cycle.

The aim of the present study was to compare the day-to-day variations of the insulin sensitivity in male and female Type 1 diabetic patients and to assess the insulin sensitivity in the follicular and luteal phases of the menstrual cycle. Ten male and 20 female Type 1 diabetic patients participated in the study. The insulin sensitivity was assessed by the insulin (0.4 mU kg-1 min-1)-glucose/(4.5 mg kg-1 min-1)-infusion test (IGIT). In 5 of the female patients, a simultaneous i.v. influsion of somatostatin (100 micrograms h-1) was given (SIGIT). Each patient was studied twice, with 2 weeks separating the two tests. The day-to-day variations of the insulin sensitivity were almost identical in the male and female patients, the coefficients of variation being 13% in both groups. In 15 of the female patients, ovulation occurred. In these women, the mean blood-glucose levels between 120 and 240 min after the onset of the IGIT/SIGIT were 9.8 +/- 1.1 mmol l-1 in the follicular phase and 10.3 +/- 1.0 mmol l-1 in the luteal phase, n.s. (95% confidence interval for the difference (luteal-follicular) -0.8-1.9 mmol l-1). Although the present study cannot exclude minor changes of insulin sensitivity during the menstrual cycle, our results suggest that the changes of the metabolic control during the menstrual cycle, experienced by many women with Type 1 diabetes, are largely attributable to mechanisms other than variations of insulin sensitivity.

Variability of blood glucose levels in patients with type 1 diabetes mellitus on intensified insulin regimens.

The aim of the present study was to look for possible associations between the blood glucose variability and twenty-four clinical parameters in ninety-eight patients with Type 1 diabetes mellitus treated with multiple injections of insulin or insulin pumps and practising self-monitoring of blood glucose. The blood glucose variability was measured as the standard deviation of glucose values obtained by self-monitoring at five specified time points every two days for four weeks. The blood glucose variability significantly correlated with the mean blood glucose level (r = 0.48, p = 0.0001) and with the number of hypoglycaemic events (r = 0.31, p = 0.002), but not with HbA1c (r = 0.19, p = 0.07). Significant correlations were also found between glucose variability and patients' variations of insulin dosage (r = 0.31, p = 0.004), duration of diabetes (r = 0.22, p = 0.03), and body-mass index (r = 0.20, p = 0.04). Patients with incipient or clinical nephropathy had more variable blood glucose values, compared with patients without signs of nephropathy (p = 0.03). Other parameters studied, such as other late diabetic complications, the C-peptide level, the insulin dose and the level of insulin-binding to antibodies did not relate significantly to the blood glucose variability.

Brain kinetics of (R)- and (S)-[N-methyl-11C]ketamine in the rhesus monkey studied by positron emission tomography (PET).

The regional brain kinetics of the two enantiomers of the NMDA channel blocker ketamine radiolabelled with 11C was studied in the Rhesus monkey by means of positron emission tomography (PET). The uptake in brain areas which showed high radioactivities was blocked in a dose-dependent manner for both 11C-labelled enantiomers with simultaneous doses of the respective unlabelled (S)- or (R)-ketamine, indicating specific binding. The binding in the striatum and cortical areas of (S)-[N-methyl-11C]ketamine was selective and displaceable by the (R)-enantiomer and by MK-801.