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.

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.

In 23 morbidly obese patients we investigated the influence of a large weight loss (30.6 kg, range 17.5-90.8) on the plasma fibronectin concentrations. Further, changes in plasma fibronectin were related to serum insulin levels and to liver biochemistry. Between the measurements patients had been treated with an intermittent very-low-calorie formula diet sufficient in respect to protein, minerals and vitamins. They were investigated in weight-stable states. Before weight reduction, 14 patients (61%, 95% confidence limits 39-80%) had elevated plasma fibronectin levels. Plasma fibronectin decreased (medians 1.22 and 0.59 mumol/l before and after weight loss, p less than 0.01) and was after weight loss within the normal range in 14 patients. The change in plasma fibronectin was unassociated with the magnitude of the weight loss as well as with the reduction of overweight. The resulting plasma fibronectin levels were also uncorrelated with the body weight and with the final degree of overweight. Serum insulin decreased (p less than 0.01) during the weight reduction and the change correlated (p less than 0.05) with the change in plasma fibronectin. Serum lactate dehydrogenase, which is associated with the degree of hepatic fatty change, declined (p less than 0.01), but the individual change was unrelated with the change in plasma fibronectin. In conclusion, the elevated plasma fibronectin levels in morbidly obese subjects seem to normalize during weight loss. We suggest the normalization to be mediated--at least in part--by a reduction of the insulin levels.

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.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.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.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.

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.

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.

AIMS:To evaluate the long-term effectiveness and safety of repaglinide, a novel prandial glucose regulator, in comparison with glipizide in the treatment of patients with Type 2 diabetes.METHODS:Diet or tablet-treated patients with Type 2 diabetes (n = 256; age 40-75 years, body mass index (BMI) 20-35 kg/m2, HbA1c 4.2-12.8%), without signs of severe microvascular or macrovascular complications, were included in this double-blind, multicentre, parallel-group comparative trial. Patients were randomized at a 2:1 ratio to repaglinide, 1-4 mg at mealtimes, or glipizide, 5-15 mg daily.RESULTS:Changes in fasting blood glucose (FBG) and HbA1c during the 12 months of treatment showed a significant difference in favour of repaglinide. In oral hypoglycaemic agents (OHA)-naive patients, HbA1c decreased in the repaglinide and glipizide groups by 1.5% and 0.3%, respectively (P < 0.05 between groups). Fasting blood glucose decreased in the repaglinide group by 2.4 mmol/l and increased in the glipizide group by 1.0 mmol/l (P < 0.05 between groups). In the study population as a whole, repaglinide was able to maintain glycaemic control (HbA1c level) during the 1-year study period, whereas control deteriorated significantly with glipizide. Change in HbA1c from baseline was significantly better with repaglinide than with glipizide after 12 months (P < 0.05). In addition, FBG deteriorated significantly in the glipizide group compared with the repaglinide group (P < 0.05). No patients in either group experienced a major hypoglycaemic event; the number of patients experiencing minor hypoglycaemia was similar in the repaglinide and glipizide groups (15% and 19%, respectively).CONCLUSIONS:Repaglinide, given as a prandial glucose regulator, is shown to be an effective and safe treatment of patients with Type 2 diabetes, and is better than glipizide in controlling HbA1c and FBG levels, overall, and in OHA-naive patients.

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 before a test meal in insulin-treated type 2 diabetic patients with residual β-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 (Act-0) 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 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).

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.

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. © 1998 John Wiley & Sons, Ltd.

Objective: to evaluate the influence of the timing of the pre-meal administration of regular insulin on the metabolic control (HbA1c), post-prandial glycaemic excursions and hypoglycaemia in patients with insulin-dependent diabetes mellitus (IDDM). Design: A randomized cross-over design. Administration of regular insulin 30 min before meals (t(-30)) was compared with administration immediately before meals (t(0)) in two B-week treatment periods preceded by a 4-week run-in period. At the end of each treatment period a breakfast meal test was performed. Subjects: 17 IDDM patients (11 males, 6 females) aged 34.8+/-5.7(+/-SD) years with a diabetes duration of 8.5 +/-7.9 years and with a HbA1c of 8.7 +/-0.9% participated. Main outcome measures: metabolic control (HbA1c), post-prandial glycaemic excursions and the frequency of hypoglycaemia. Results: blood glucose profiles measured at the meal tests showed, that insulin injection at t(-30) in contrast to t(0) resulted in an initial non-significant decrease in blood glucose of 1.0 mmol/l, which resulted in significantly (P<0.05) lower post-prandial blood glucose values 20-70 minutes after meal start as compared to t(0). However, this difference in blood glucose was only seen after breakfast in the home monitored 7-point blood glucose profiles, whereas to resulted in the same or a lower blood glucose level compared with t(-30) during the rest of the day. The metabolic control, evaluated by HbA1c at the end of each treatment period, did not differ between the two regimens, t(0)=8.1% and t(-30) = 8.2%, respectively. No difference in the total number of hypoglycaemic events during the two periods was observed. Conclusion: Minor differences in post-prandial blood glucose excursions due to different timing of pre-meal insulin injection do not seem to influence the metabolic control as measured by ii-point blood glucose profiles, HbA1c and hypoglycaemic events. This study suggests that in IDDM patients on intensified insulin regimen, injection of regular human insulin immediately before meals does not result in deterioration of metabolic control.

Denervation hypersensitivity is a well-known phenomenon in patients with autonomic failure. In diabetic autonomic neuropathy hypersensitivity to beta-adrenergic stimulation has been demonstrated. We infused noradrenaline, mainly an alpha-adrenoceptor agonist, in three escalating doses (0.5, 2.5, and 5 mu g min(-1)) in three age and sex matched groups of eight subjects: healthy volunteers, diabetic patients with and without autonomic neuropathy. During steady state in each infusion period we measured heart rate, blood pressure, cardiac output, hepato-splanchnic blood flow, vascular resistance, glucose kinetics, metabolites (beta-hydroxybuturate, glycerol, and lactate), and glucoregulatory hormones (noradrenaline, adrenaline, growth hormone, pancreatic polypeptide, cortisol, and insulin). Systolic and mean blood pressure increased in all groups but diabetic patients with autonomic neuropathy showed a significantly higher increase (p < 0.01) than the other two groups, with a lower threshold for increase in blood pressure. Cardiac output, hepato-splanchnic blood flow, vascular resistance, and heart rate did not change in any of the groups. The incremental increase in glucose and beta-hydroxybuturate was higher in patients with autonomic neuropathy. Otherwise, only minor changes were seen in hormonal and metabolic parameters. The cardiovascular hypersensitivity seen in diabetic autonomic neuropathy was mainly explained by increased peripheral vascular resistance, which increased significantly (p < 0.05) more in these patients. In conclusion, diabetic patients with autonomic neuropathy show denervation hypersensitivity to alpha-adrenergic stimulation by noradrenaline, especially as regards cardiovascular effects.