Short-term effects of liraglutide on kidney function and vasoactive hormones in type 2 diabetes: a randomized clinical trial.

AIMS: To investigate the effects of a single dose of 1.2 mg liraglutide, a once-daily glucagon-like peptide-1 (GLP-1) receptor agonist, on key renal variables in patients with type 2 diabetes. METHODS: The study was a placebo-controlled, double-blind, crossover trial in 11 male patients with type 2 diabetes. Measurements included (51) Cr-EDTA plasma clearance estimated glomerular filtration rate (GFR) and MRI-based renal blood flow (RBF), tissue perfusion and oxygenation. RESULTS: Liraglutide had no effect on GFR [95% confidence interval (CI) -6.8 to 3.6 ml/min/1.73 m(2) ] or on RBF (95% CI -39 to 30 ml/min) and did not change local renal blood perfusion or oxygenation. The fractional excretion of lithium increased by 14% (p = 0.01) and sodium clearance tended to increase (p = 0.06). Liraglutide increased diastolic and systolic blood pressure (3 and 6 mm Hg) and heart rate (2 beats per min; all p < 0.05). Angiotensin II (ANG II) concentration decreased by 21% (p = 0.02), but there were no effects on other renin-angiotensin system components, atrial natriuretic peptides (ANPs), methanephrines or excretion of catecholamines. CONCLUSIONS: Short-term liraglutide treatment did not affect renal haemodynamics but decreased the proximal tubular sodium reabsorption. Blood pressure increased with short-term as opposed to long-term treatment. Catecholamine levels were unchanged and the results did not support a GLP-1-ANP axis. ANG II levels decreased, which may contribute to renal protection by GLP-1 receptor agonists.

Insulin X10 revisited: a super-mitogenic insulin analogue.

The molecular safety of insulin analogues has received a great deal of attention over the last year. In particular, attention has been directed to the mitogenic properties of insulin analogues as compared with human insulin. Understanding the mechanisms implicated in mediating mitogenic effects of insulin is therefore of particular interest. In this review we detail the story of the rapid-acting insulin analogue known as X10, which was the first insulin analogue in clinical development, but ended up being discontinued at an early clinical development stage following findings of mammary tumours in female Sprague-Dawley rats. The molecular characteristics of insulin X10, along with its interaction at both the IGF-1 receptor and the insulin receptor, have provided us with important insights into mechanisms implicated in metabolic and mitogenic signalling of insulin analogues.

No evidence of increased risk of malignancies in patients with diabetes treated with insulin detemir: a meta-analysis.

AIMS/HYPOTHESIS: Recent epidemiological studies suggest that treatment with insulin glargine (A21Gly,B31Arg,B32Arg human insulin) may promote cancer growth. The present meta-analysis was performed to assess the risk of cancer during treatment with insulin detemir (B29Lys(epsilon-tetradecanoyl),desB30 human insulin), another long-acting insulin analogue. METHODS: This meta-analysis was performed in a population of 8,693 patients with type 1 or type 2 diabetes, who were included in Novo Nordisk-sponsored, randomised and controlled diabetes trials of at least 12 weeks in duration that compared insulin detemir with NPH insulin or insulin glargine. In a blinded manner, the adverse events with suspected treatment-emergent malignant tumours were obtained from these studies under three system-organ classes: 'Neoplasms benign, malignant and unspecified (including cysts and polyps)', 'Neoplasm' and 'Surgical and medical procedures'. Conditional ORs were estimated applying both the Mantel-Haenzel and Peto methods to ensure robustness of results. RESULTS: Separate analyses were performed for trials comparing insulin detemir with NPH insulin and insulin detemir with insulin glargine. In the first analysis, 16 studies were included with a total of 3,983 patients treated with insulin detemir and 2,661 patients treated with NPH insulin. In the second analysis, five studies were included with a total of 1,219 patients treated with insulin detemir and 830 patients treated with insulin glargine. The estimated OR for a cancer diagnosis between NPH insulin and insulin detemir was statistically significantly >1, with the ratio favouring insulin detemir. There was a more than twofold higher cancer occurrence in the NPH insulin-treated population. For the insulin detemir comparison with insulin glargine, there was a non-significant difference in ORs in favour of insulin detemir. CONCLUSIONS/INTERPRETATION: In these randomised controlled diabetes trials, patients treated with insulin detemir had a lower or similar occurrence of a cancer diagnosis compared with patients treated with NPH insulin or insulin glargine, respectively.

Repaglinide acutely amplifies pulsatile insulin secretion by augmentation of burst mass with no effect on burst frequency.

OBJECTIVE: Repaglinide is a new oral hypoglycemic agent that acts as a prandial glucose regulator proposed for the treatment of type 2 diabetes by stimulating insulin secretion. The aim of this study was to explore actions of repaglinide on the rapid pulsatile insulin release by high-frequency insulin sampling and analysis of insulin-concentration time series. RESEARCH DESIGN AND METHODS: We examined 8 healthy lean male subjects in a single-dose double-blind placebo-controlled crossover design. After the subjects underwent an overnight fast, blood sampling was initiated and continued every minute for 120 min. After 40 min, a single dose (0.5 mg) of repaglinide or placebo was given. Serum insulin-concentration time series were assessed by deconvolution analyses and the regularity statistic by approximate entropy (ApEn). RESULTS: Average insulin concentration was increased after repaglinide administration (basal vs. stimulated period, P values are placebo vs. repaglinide) (25.1 +/- 3.6 vs. 33.5 +/- 4.1 pmol/l, P < 0.001). Insulin secretory burst mass (15.8 +/- 2.2 vs. 19.6 +/- 2.8 pmol x l(-1) x pulse(-1), P = 0.02) and amplitude (6.1 +/- 0.9 vs. 7.7 +/- 1.2 pmol x l(-1) x min(-1), P = 0.008) were augmented after repaglinide administration. A concomitant trend toward an increase in basal insulin secretion was observed (2.5 +/- 0.3 vs. 3.2 +/- 0.4 pmol x l(-1) x min(-1), p = 0.06), while the interpulse interval was unaltered (6.8 +/- 1.0 vs. 5.4 +/- 0.4 min/pulse, P = 0.38). ApEn increased significantly after repaglinide administration (0.623 +/- 0.045 vs. 0.670 +/- 0.034, P = 0.04), suggesting less orderly oscillatory patterns of insulin release. CONCLUSIONS: In conclusion, a single dose of repaglinide amplifies insulin secretory burst mass (and basal secretion) with no change in burst frequency. The possible importance of these mechanisms in the treatment of type 2 diabetes characterized by disrupted pulsatile insulin secretion remains to be clarified.

Histamine regulation of prolactin secretion through H1- and H2-receptors.

Histamine (HA) regulates PRL secretion in the rat by a stimulatory effect through H1-receptors and an inhibitory effect through H2-receptors. The effect of HA antagonists on basal and TRH-stimulated PRL secretion was investigated in five normal men. During saline infusion, serum PRL declined, as seen normally after sleep. HA infusion caused a significantly higher PRL secretion than that observed during the saline infusion [maximum change in PRL (delta PRL), 28 +/- 20 vs. -71 +/- 30 microIU/ml; P less than 0.05]. This effect of HA on PRL secretion was inhibited during the combined infusion of HA and the H1-antagonist mepyramine (delta PRL, 28 +/- 20 vs. -77 +/- 13 microIU/ml; P less than 0.025). The PRL-stimulating effect of HA was strongly enhanced during the combined infusion of HA and the H2-antagonist cimetidine (delta PRL, -28 +/- 20 vs. 132 +/- 57 microIU/ml; P less than 0.0125). This effect of HA and cimetidine on PRL secretion was higher than the effect of cimetidine alone (delta PRL, 132 +/- 57 vs. 17 +/- 22 microIU/ml; P less than 0.05). This shows that the H2-antagonist is not the only stimulator of PRL secretion. During the different infusions, serum PRL concentrations were in the following rank order: mepyramine less than saline less than HA less than cimetidine less than HA plus cimetidine. The same rank order was found for the PRL responses to TRH during the different infusions. These data indicate a HA stimulatory effect through H1-receptors and an inhibitory effect through H2-receptors on PRL secretion in human males.

Histamine-induced paradoxical growth hormone response to thyrotropin-releasing hormone in normal men.

GH responses to TRH occur in patients with certain diseases, such as acromegaly, severe liver disease, uremia, and mental disorders, and presumably reflect disruption of normal hypothalamic control of GH secretion. Since histamine (HA) inhibits hypothalamic stimulation of GH secretion, we investigated the combined effect of HA receptor activation and TRH administration on GH secretion in normal men. Eight men were given 4-h infusions of the following: saline, HA, HA plus mepyramine (Me; and H1-antagonist), HA plus cimetidine (C; an H2-antagonist), and C alone. TRH (200 micrograms) was injected iv 2 h after the start of each infusion. HA alone or in combination with either antagonist had no effect on basal or TRH-stimulated TSH secretion and no effect on basal GH secretion. However, when TRH was injected during H1 stimulation by HA plus C, GH secretion increased significantly [from 0.7 +/- 0.1 to 7.1 +/- 1.8 (+/- SEM) ng/ml; P less than 0.01] in seven of eight subjects. This GH response was reproducible and did not occur when saline was administered instead of TRH. A smaller and delayed GH response to TRH occurred during infusions of HA alone (from 0.8 +/- 0.1 to 4.9 +/- 1.0 ng/ml; P less than 0.05). No effect of TRH on GH secretion occurred during the infusion of saline (1.2 +/- 0.3 ng/ml), HA plus Me (0.9 +/- 0.1 ng/ml), or C (2.2 +/- 1.0 ng/ml). There was a significant increase in GH secretion after cessation of the infusions of HA (from 3.4 +/- 1.1 to 7.5 +/- 2.2 ng/ml) and HA plus Me (from 0.8 +/- 0.1 to 5.1 +/- 1.8 ng/ml). This rebound in GH secretion might indicate an inhibitory effect of TRH during H2-receptor stimulation. This concept is supported by the significantly smaller GH response to TRH during HA infusion than during HA plus C infusion (P less than 0.01). The study indicates that H1-receptor stimulation induces a stimulatory effect of TRH on GH secretion in normal men and that H2-receptor stimulation possibly induces an inhibitory effect of TRH on GH secretion.

The selective serotonin reuptake inhibitor citalopram relieves the symptoms of diabetic neuropathy.

The effect of the selective serotonin reuptake inhibitor citalopram on diabetic neuropathy symptoms was examined in a double-blind, placebo-controlled, crossover study for two 3-week periods. Citalopram was given as a fixed dose of 40 mg/day. Data from 15 patients could be included in the statistical analysis. Citalopram significantly relieved the symptoms of neuropathy as measured by both observer- and self-rating in comparison with placebo. The steady-state plasma concentration of citalopram was 10 to 890 nmol/L. There was no significant relationship between the plasma concentration of citalopram and the effect of treatment as measured by observer- or self-rating. Two of 17 patients, both receiving citalopram, left the study because of side effects (nausea and vomiting or gastric upset and diarrhea). Side-effect ratings were significantly higher during administration of citalopram than during administration of placebo, but citalopram was generally well tolerated. Compared with earlier results obtained with imipramine administered on the basis of plasma level monitoring, citalopram appeared to be less effective, but seemed to be better tolerated.

Improved postprandial glycaemic control with insulin Aspart in type 2 diabetic patients treated with insulin.

The effect on postprandial blood glucose control of an immediately pre-meal injection of the rapid acting insulin analogue Aspart (IAsp) was compared with that of human insulin Actrapid injected immediately or 30 minutes before a test meal in insulin-treated type 2 diabetic patients with residual beta-cell function. In a double-blind, double dummy crossover design, patients attended three study days where the following insulin injections in combination with placebo were given in a random order: IAsp (0.15 IU/kg body weight) immediately before the meal, or insulin Actrapid (0.15 IU/kg) immediately (Act0) or 30 minutes before (Act-30) a test meal. We studied 25 insulin-requiring type 2 diabetic patients, including 14 males and 11 females, with a mean age of 59.7 years (range, 43-71), body mass index 28.3 kg/m2 (range, 21.9-35.0), HbA1c 8.5% (range, 6.8-10.0), glucagon-stimulated C-peptide 1.0 nmol/l (range, 0.3-2.5) and diabetes duration 12.5 years (range, 3.0-26.0). Twenty-two patients completed the study. A significantly improved postprandial glucose control was demonstrated with IAsp as compared to Act0, based on a significantly smaller postprandial blood glucose excursion (IAsp, 899 +/- 609 (SD) mmol/l.min versus Act0, 1102 +/- 497 mmol/l min, p < 0.01) and supported by a significantly lower maximum serum glucose concentration (Cmax) up to 360 min after dosing (IAsp, 10.8 +/- 2.2 mmol/l vs. Act0, 12.0 +/- 2.4 mmol/l, p < 0.02). No difference was demonstrated in glucose endpoints between IAsp, administered with a meal and Actrapid injected 30 minutes before the meal (AUCglucose IAsp, 899 +/- 609 mmol/l min vs. Act-30, 868 +/- 374 mmol/l min; Cmax IAsp, 10.8 +/- 2.2 mmol/l vs. Act-30, 11.1 +/- 1.8 mmol/l). No concerns about the safety of IAsp were raised. Immediate pre-meal administration of the rapid-acting insulin analogue Aspart in patients with type 2 diabetes resulted in an improved postprandial glucose control compared to Actrapid injected immediately before the meal, but showed similar control compared to Actrapid injected 30 minutes before the meal. These results indicate that the improved glucose control previously demonstrated with insulin Aspart compared to human insulin in healthy subjects and type 1 diabetic patients also applies to insulin-treated type 2 diabetic patients.

Optimal dose and timing of insulin Aspart to mimic first phase insulin response in patients with recently onset type 2 diabetes.

OBJECTIVE: To assess the optimal dose and timing of subcutaneous injection of insulin Aspart (IAsp) in relation to meal to mimic first phase insulin response in patients with recently diagnosed type 2 diabetes. DESIGN AND METHODS: Twenty patients were randomised in a double blind, double dummy design to four standard meal tests with pre-meal injection of insulin Aspart 0.08 IU/kg BW 30 min before the meal, insulin Aspart 0.04 IU/kg BW 30 or 15 min before the meal and placebo. RESULTS: All three insulin regimes significantly reduced postprandial glucose increment (area under the curve AUC(-30 to 240 min)) and peak plasma glucose increment (DeltaC(max)) compared with placebo. Postprandial glucose increment AUC(-30 to 240 min) but not DeltaC(max) was significantly lower with IAsp 0.08 IU/kg BW as compared to IAsp 0.04IU/kg BW, (p<0.03 and p=0.18). One patient experienced hypoglycaemia after injection of IAsp 0.08 IU/kg BW. No difference in postprandial glucose profile was demonstrated whether IAsp 0.04 IU/kg BW was administrated 15 or 30 min before mealtime. CONCLUSIONS: IAsp 0.04IU/kg BW injected subcutaneously 15 or 30 min before meal reduced the postprandial blood glucose increment without risk of hypoglycaemia in patients with recently diagnosed type 2 diabetes. Doubling of the IAsp dose significantly reduced the postprandial glucose increment but increased the risk of hypoglycaemia.

Impaired first-phase insulin response predicts postprandial blood glucose increment in patients with recently diagnosed type 2 diabetes.

OBJECTIVE: The aim of the study was to evaluate the relationship between postprandial blood glucose and first-phase insulin response and, furthermore, to assess whether the intravenous glucagon stimulation test can be used as a predictor for increased postprandial glucose in patients with recently diagnosed type 2 diabetes. MATERIAL AND METHODS: Twenty patients with diet-treated type 2 diabetes, diagnosed within the past 5 years, were included. In random order, on three different days, the patients underwent: 1) a standardized meal tolerance test, 2) an intravenous glucose tolerance test, and 3) an intravenous glucagon stimulation test. The postprandial blood glucose response was defined as the incremental area under the blood glucose curve 0-240 min after the meal. RESULTS: The first-phase insulin response at an intravenous glucose stimulation test was significantly correlated to the postprandial blood glucose increment (R(2)=0.21, p<0.05) and the maximal increment in plasma glucose concentration (R(2)=0.40, p<0.01) during the meal tolerance test. However, the incremental C-peptide value at 6 min in response to intravenous glucagon stimulation did not correlate to the postprandial blood glucose increment (R(2)=0.09, p=0.14). CONCLUSION: Impaired first-phase insulin response is a significant predictor of the increase in postprandial blood glucose in patients with type 2 diabetes in near normal metabolic control, whereas beta-cell function, assessed by glucagon stimulation test, is not.

Pathophysiology and treatment of diabetic neuropathy.

The scope of the present review is to describe epidemiology, classification, symptomatology and treatment of diabetic peripheral somatic neuropathy and autonomic neuropathy. Special attention is paid to the use of local anaesthetic agents in painful diabetic neuropathy. Denervation hypersensitivity is a characteristic of autonomic neuropathy in diabetic patients. The pathophysiology behind this phenomenon is elucidated in this review and most recent studies related to diabetic encephalopathy are reviewed. References for this review were acquired via a MedLine and MedLars literature search.

Comparison of glycaemic control in diabetic patients treated with morning or evening human ultratard insulin.

To investigate whether morning or evening injection of a long-acting insulin preparation (Ultratard HM, Novo) affects the glycaemic control in insulin-dependent diabetic (IDDM) patients, 24-hour blood glucose and plasma free insulin profiles were obtained in nine C-peptide negative IDDMs after one daily injection of insulin Ultratard HM either before breakfast (0800 h) or at 2200 h during the preceding 14 days. There was a tendency towards higher plasma free insulin levels and lower blood glucose values from 0100 h to 1300 h when Ultratard HM insulin was injected at 2200 h as compared to the morning injection. There was, however, only a significant difference between the corresponding plasma free insulin values at 1200 h, and blood glucose levels did not differ significantly at any time point investigated. The number of blood glucose values below 3 mmol/l in the study periods was 6 when insulin Ultratrad HM was injected at 2200 h as opposed to 2 when insulin was given at 0800 h, but this difference was not significant.

Plasma fibronectin concentrations in patients with liver diseases.

Plasma, obtained just prior to diagnostic liver biopsy in 71 patients with various liver diseases, was examined by electroimmunoassay using immunoglobulin against human fibronectin and purified plasma fibronectin as standard. The plasma fibronectin concentration was not significantly different from age- and sex-matched healthy controls in patients with chronic persistent or chronic active hepatitis (n = 7), primary biliary cirrhosis (n = 8), alcoholic fatty liver (n = 9), alcoholic hepatitis (n = 10), and alcoholic cirrhosis (n = 16). Patients with acute viral hepatitis (type A (n = 2); type B (n = 7); type non A, non B (n = 1] had significantly (P less than 0.01) raised plasma fibronectin concentrations (median 506 mg/l (range 339-804] compared to controls (median 399 mg/l (range 304-462]. Morbidly obese patients with fatty liver (n = 11) had significantly (P less than 0.001) raised plasma fibronectin concentrations (median 610 mg/l (range 429-862] compared to controls (median 361 mg/l (range 303-419].

Veno-occlusive disease and peliosis of the liver after thorotrast administration.

A case of veno-occlusive disease and peliosis of the liver without coexisting liver malignancy 35 years after thorotrast administration is presented. In the liver four main widely distributed lesions were found: Veno-occlusive disease (VOD), peliosis, fibrosis and thorotrast deposits. Whether the VOD and the peliotic lesions are pathogenetically related or totally independent cannot be determined in the present case. However, the VOD and the peliosis are possibly related to the protracted alpha-emitting effect of thorotrast deposited in the liver parenchyma.

Plasma dihydroxyphenylglycol (DHPG) as an index of diabetic autonomic neuropathy.

Forearm venous plasma noradrenalin and dihydroxyphenylglycol (DHPG) concentrations were measured in eight diabetic patients with and eight diabetic patients without neuropathy. Plasma noradrenalin was on average the same in patients with and without neuropathy and correlated to serum creatinine. Plasma DHPG concentrations were significantly reduced in patients with autonomic neuropathy as compared to patients without neuropathy (P less than 0.05). A low plasma DHPG/noradrenalin ratio in forearm venous blood identified all patients with autonomic neuropathy except one (P less than 0.02). Measuring the plasma DHPG/noradrenalin ratio may circumvent the problem of unrepresentative noradrenalin release from the forearm.

Insulin infusion normalizes cardiovascular responses and plasma noradrenaline after oral glucose in type 1 (insulin-dependent) diabetes.

We examined whether the abnormal regulation of the cardiovascular system and plasma noradrenaline observed after oral glucose in insulin-dependent diabetic patients could be normalized by intravenous infusion of insulin. Eight patients with type 1 (insulin-dependent) diabetes were examined after an oral glucose load with and without simultaneous infusion of insulin. Insulin infusion increased plasma insulin from 0.07 to 0.31 nmol/l. In the control experiment (glucose only), mean heart rate and mean arterial systolic blood pressure remained unchanged and plasma noradrenaline (NA) decreased (p less than 0.05). After oral glucose plus intravenous insulin, mean heart rate increased by 11% and mean systolic blood pressure by 5% (p less than 0.05, p less than 0.01), whereas plasma NA did not change significantly. The present study indicates that physiologic increments in plasma insulin concentration are of importance in the regulation of the cardiovascular system and plasma NA following an oral glucose load.

Noradrenaline and isoproterenol kinetics in diabetic patients with and without autonomic neuropathy.

Noradrenaline and isoproterenol kinetics using intravenous infusion of L-3H-NA and of 3H-isoproterenol were investigated in eight Type 1 (insulin-dependent) diabetic patients without neuropathy and in eight Type 1 diabetic patients with autonomic neuropathy matched for age, sex and duration of diabetes. Resting plasma noradrenaline and adrenaline concentrations were reduced in patients with autonomic failure (p less than 0.05). The metabolic clearance rate of noradrenaline was similar in both groups of patients, and the appearance rate of noradrenaline in plasma was reduced in patients with autonomic failure (p less than 0.01). The disappearance of L-3H-noradrenaline from plasma after the infusion of L-3H-noradrenaline had been stopped was not different in patients with and without neuropathy. The metabolic clearance of isoproterenol was not influenced by the presence of autonomic failure and mean values were similar to the corresponding values for noradrenaline. Isoproterenol was only taken up by a non-neuronal uptake; this finding may indicate that neuronal uptake is not important for the inactivation of circulating catecholamines. Alternatively, because the non-neuronal uptake of isoproterenol is probably greater than that of noradrenaline, we cannot exclude the possibility that a small decrease in the neuronal uptake of noradrenaline was compensated for by a slightly higher non-neuronal uptake.

Different percentages of CD8+ lymphocytes in long-term type 1 diabetics with and without residual beta cell function.

About 15% of Type 1 diabetics display residual beta cell function after more than 10 yr duration of diabetes, indicating that the disease mechanisms have stopped before all beta cells are destroyed. Peripheral blood lymphocytes were studied from such patients, 11 females and 12 males, 29 +/- 1 yr old, who had had diabetes for 14 +/- 1 yr. A completely matched group of 23 Type 1 diabetics with the same disease duration, but without residual beta cells, were also studied together with a healthy control group. Lymphocytes were marked with monoclonal OKT antibodies and examined by flow cytometry (FACS). There was no difference between the three groups in the absolute number of lymphocytes and helper T-cells (CD4+:40.2 +/- 1.3 vs. 40.4 +/- 1.3 vs. 41.1 +/- 1.8%). In respect of CD8+ (suppressor/cytotoxic) T-cells, the diabetics without beta cells showed 25.9 +/- 1.0%, significantly less than both the patients with preserved beta cell function (29.0 +/- 0.9%, p less than 0.02) and the controls (29.5 +/- 1.3%, p less than 0.02). CD3+ (pan) T-cells showed parallel changes (67.8 +/- 1.5 vs. 71.0 +/- 1.4 vs. 72.2 +/- 1.4%, p less than 0.05). The metabolic state was similar in the two patient groups, and there was no correlation between metabolic and immunological parameters. It is unknown whether the normalization of the T-cell subpopulation, especially the CD8+ lymphocytes, in patients with residual beta cell function at a point when the disease process is apparently at rest, is of causal significance, or of only marker significance.