Liraglutide, a once-daily human GLP-1 analogue, improves pancreatic B-cell function and arginine-stimulated insulin secretion during hyperglycaemia in patients with Type 2 diabetes mellitus.

AIMS: To assess the effect of liraglutide, a once-daily human glucagon-like peptide-1 analogue on pancreatic B-cell function. methods: Patients with Type 2 diabetes (n = 39) were randomized to treatment with 0.65, 1.25 or 1.9 mg/day liraglutide or placebo for 14 weeks. First- and second-phase insulin release were measured by means of the insulin-modified frequently sampled intravenous glucose tolerance test. Arginine-stimulated insulin secretion was measured during a hyperglycaemic clamp (20 mmol/l). Glucose effectiveness and insulin sensitivity were estimated by means of the insulin-modified frequently sampled intravenous glucose tolerance test. RESULTS: The two highest doses of liraglutide (1.25 and 1.9 mg/day) significantly increased first-phase insulin secretion by 118 and 103%, respectively (P < 0.05). Second-phase insulin secretion was significantly increased only in the 1.25 mg/day group vs. placebo. Arginine-stimulated insulin secretion increased significantly at the two highest dose levels vs. placebo by 114 and 94%, respectively (P < 0.05). There was no significant treatment effect on glucose effectiveness or insulin sensitivity. CONCLUSIONS: Fourteen weeks of treatment with liraglutide showed improvements in first- and second-phase insulin secretion, together with improvements in arginine-stimulated insulin secretion during hyperglycaemia.

The North Jutland County Diabetic Retinopathy Study (NCDRS) 2. Non-ophthalmic parameters and clinically significant macular oedema.

BACKGROUND: The influence of non-ophthalmic parameters on the prevalence of clinically significant macular oedema has not been unambiguously established. The present study was initiated with the aim of clarification. METHODS: This cross-sectional study comprised 656 type 1 and 328 type 2 diabetic subjects undergoing retinopathy screening in the county of North Jutland. The association between the presence of clinically significant macular oedema and blood pressure, HbA1c, BMI, age, onset of diabetes, duration of diabetes, blood-pressure-reducing medication, lipid-lowering medication, neuropathy and urinary albumin excretion was explored using multiple logistic regression analysis. RESULTS: We found no significant association between the presence of clinically significant macular oedema and any of the examined parameters in type 1 diabetic subjects. In type 2 diabetic subjects, the duration of diabetes, HbA1c, neuropathy and increased urinary albumin excretion was significantly associated with the presence of clinically significant macular oedema. CONCLUSIONS: The risk factors for clinically significant macular oedema differ in type 1 and type 2 diabetic subjects and can account only in part for this manifestation.

The North Jutland County Diabetic Retinopathy Study: population characteristics.

BACKGROUND: Several population-based studies have reported blood glucose levels and blood pressure to be risk factors for the development of diabetic retinopathy. These studies were initiated more than two decades ago and may therefore reflect the treatment and population composition of a previous era, suggesting new studies of the present population with diabetes. AIM AND METHODS: This cross-section study included 656 people with type 1 diabetes and 328 with type 2 diabetes. Crude prevalence rates of proliferative diabetic retinopathy, clinically significant macular oedema and several specific retinal lesions were assessed, together with their association to a simplified and internationally approved retinal grading. RESULTS: The point prevalence of proliferative retinopathy was found to be 0.8% and 0.3% for type 1 and type 2 diabetes. Equivalent prevalence rates of clinically significant macular oedema were 7.9% and 12.8%, respectively. The most frequently occurring retinal manifestations increased in number until retinopathy level 3, and then decreased. CONCLUSION: The point prevalence of proliferative retinopathy is lower than that found in previous studies, whereas it is increased for clinically significant macular oedema. These data suggest different risk factors for these clinical entities.

Risk and short-term prognosis of myocardial infarction among users of antidiabetic drugs.

Old sulphonylureas have been linked with adverse cardiovascular effects; however, data on the clinical implications are sparse. We examined the association between use of sulphonylureas and other antidiabetic drugs and the risk and case fatality rate (CFR) of myocardial infarction (MI) in a population-based case-control and follow-up study, respectively. A total of 6738 cases of first-time MI and 67,374 age- and gender-matched population controls were identified from the Hospital Discharge Registry and the Civil Registration System of North Jutland County, Denmark, in the period 1994 through 2002. Prescriptions for antidiabetic drugs before the index date were retrieved from a prescription database. We estimated odds ratios (ORs) of MI (case-control study) and 30-day CFR (follow-up study) associated with antidiabetic drug use adjusted for possible confounding factors and using nondiabetic subjects as the reference group. The risk of MI appeared higher among users of old sulphonylureas (adjusted OR, 2.07; 95% confidence interval (CI), 1.81-2.37) than among users of new sulphonylureas (adjusted OR, 1.36; 95% CI, 1.01-1.84). The adjusted ORs among users of nonsulphonylurea oral antidiabetic drugs, insulin, and patients with diabetes not receiving pharmacotherapy were 1.38 (95% CI, 0.90-2.11), 2.56 (95% CI, 2.16-3.03), and 3.51 (95% CI, 2.92-4.22), respectively. The overall 30-day CFR was 24.6%, but varied between 9.5% and 37.0% among the different categories. New sulphonylureas may be associated with a lower risk of MI than old sulphonylureas. Furthermore, the 30-day CFR may vary according to type of antidiabetic drug. These differences indicate the need for further examination of the cardiovascular safety of antidiabetic drugs.

Can a cilio-retinal artery influence diabetic maculopathy?

AIM: To explore the influence of a cilio-retinal artery on diabetic maculopathy. METHODS: In the county of North Jutland 481 diabetic subjects underwent examination for diabetic retinopathy during the period 1 June 2000 to 30 June 2001. A unilateral cilio-retinal artery was observed in 104 patients among which 29 revealed variation in right and left eye maculopathy. A bilateral cilio-retinal artery was observed in 15 diabetic subjects. The influence of a cilio-retinal artery on diabetic maculopathy was explored in a paired study. RESULTS: Diabetic maculopathy was found to be more severe in 26 of 29 eyes with a cilio-retinal artery (p<0.01) compared to eyes without it. The number of red dots (p<0.0001) and hard exudates (p=0.0002) were found to be significantly increased in eyes with a cilio-retinal artery, as also the number of eyes with central photocoagulation (p<0.05). In addition, clinically significant macular oedema was found to be significantly increased in eyes with a cilio-retinal artery compared to eyes without it (0.01

The effect of n-3 fatty acids on neutrophil chemiluminescence.

The effect of dietary supplementation with n-3 polyunsaturated fatty acids (PUFAs) on the production of free oxygen radicals from activated neutrophils was investigated in healthy subjects, using chemiluminescence. In the first study 22 persons were give 4 g n-3 PUFAs daily for 6 weeks. There was a median reduction of chemiluminescence from neutrophils stimulated with opsonized zymosan of 37% (p < 0.001). The median content of eicosapentaenoic acid in platelets, used as an indicator for cellular fatty acid profile, increased from 0.70 to 2.80% (p < 0.001), and there was a significant negative correlation between the chemiluminescence signal and the content of eicosapentaenoic acid in platelets (p < 0.001). In a second, low-dose study 24 persons were allocated to daily supplementation with either 0.65 g n-3 PUFAs or with a control oil for 6 weeks. Compared to the control group there was a median reduction of 38 and 44% in chemiluminescence from neutrophils stimulated with opsonized zymosan and phorbol,12-myristate,13-acetate (PMA), respectively. Neither of these differences, however, was statistically significant. These findings lend support for a possible role of n-3 PUFAs in the management of inflammatory disorders.

[Fish oils and rheumatoid arthritis. A randomized and double-blind study]. / Fiskeolie og reumatoid artrit. En randomiseret og dobbeltblind undersøgelse.

The effect of dietary supplementation with n-3 polyunsaturated fatty acids (n-3 PUFA) on disease variables in patients with active rheumatoid arthritis was evaluated in a multicentre, randomized and double blind study. Fifty-one patients with active rheumatoid arthritis were included from three Danish hospital Departments of Rheumatology. The patients were allocated to 12 weeks of treatment with either six n-3 PUFA capsules (3.6 g) or six capsules with a fat composition averaging the Danish diet. Small but significant improvements in morning stiffness, joint tenderness and C-reactive protein were observed. There were no serious side-effects. Dietary supplementation with n-3 PUFA in patients with active rheumatoid arthritis has a modest effect on three out of eight disease variables, without effect on other traditional parameters for monitoring disease activity.

The acute effects of a single very high dose of n-3 fatty acids on plasma lipids and lipoproteins in healthy subjects.

Forty healthy volunteers were allocated in a double blind, randomized study to receive either 20 g of n-3 polyunsaturated fatty acids (PUFA) or 20 g of n-6 PUFA at their evening meal. The effect on plasma lipids and lipoproteins of this single dose of fish oil vs. corn oil was studied the next morning, 14 h after ingestion. Plasma triglycerides and very low density lipoprotein-cholesterol significantly decreased (33%) after n-3 PUFA (P < 0.001), and significantly (P < 0.01) more than after intake of n-6 PUFA. The decrease in plasma triglycerides after n-3 PUFA ingestion was more pronounced in subjects with higher baseline levels of triglycerides (P < 0.001). Total cholesterol decreased after both supplements, but did not differ between the supplements. Low density lipoprotein-cholesterol did not change, and high density lipoprotein-cholesterol significantly decreased in subjects given n-3 PUFA compared to baseline, but not when compared to subjects receiving n-6 PUFA. In conclusion, we have shown that a single very high dose of n-3 PUFA has a pronounced hypotriglyceridemic effect, which is directly related to the initial plasma level.

[Short-term and long-term effects on glycosylated hemoglobin after transition from conventional insulin treatment to multiple insulin injection regime in a diabetic outpatient clinic]. / Kort- og langtidseffekten på glykosyleret haemoglobin ved overgang fra konventionel insulinbehandling til multipel insulininjektionsregi i et diabetesambulatorium.

In order to examine the short- and long term effects of basal/bolus insulin therapy on the metabolic regulation assessed by glycosylated haemoglobin (HbA1c) the first 201 patients in the diabetes out-patient clinic of the Section of Endocrinology, Department of Medicine, Aalborg Hospital, assigned for this treatment were prospectively studied. In all 201 patients a significant decrease in mean HbA1c value was observed after 21 months on multiple injection therapy (8.5% vs 8.1%; p < 0.001). The higher the HbA1c value on conventional therapy, the greater was the observed decrease in HbA1c following six months on basal/bolus therapy (r = 0.57, p < 0.001). According to an anonymous questionnaire completed by the first 140 patients six months after the start of multiple injection therapy, 97% of the patients preferred to continue with basal/bolus therapy with NovoPen, and 87% felt that they had achieved a better general condition and that the basal/bolus regime made their daily life easier. It is concluded that basal/bolus therapy with NovoPen may combine the attainment of improved metabolic control assessed by a decrease in mean HbA1c in many poorly regulated patients and the subjective experience of an improved quality of life.

The effect of low-dose supplementation with n-3 polyunsaturated fatty acids on some risk markers of coronary heart disease.

Epidemiological data have suggested that a low dose of dietary n-3 polyunsaturated fatty acids from seafood may protect against coronary heart disease. We studied the effect of supplementation with a low dose of very long-chain n-3 fatty acids (0.65 g day-1) on plasma lipids, haemostasis, and neutrophil aggregation. Twenty-four healthy subjects were randomized to supplementation with very long-chain n-3 fatty acids or a control oil for 8 weeks. Laboratory analyses were done twice before and twice at the end of the supplementation period. The supplement with n-3 polyunsaturated fatty acid did not significantly affect plasma lipids or plasma levels of fibrinogen, factor VII, plasminogen activator inhibitor, whole blood aggregation or aggregability of neutrophil leukocytes. Therefore, the potential beneficial effect of very long-chain n-3 fatty acids in coronary heart disease is likely to be mediated through other mechanisms.

The effects of dietary supplementation with n-3 polyunsaturated fatty acids in patients with rheumatoid arthritis: a randomized, double blind trial.

STUDY OBJECTIVE: To determine the effect of dietary supplementation with n-3 polyunsaturated fatty acids (n-3 PUFA) on disease variables in patients with rheumatoid arthritis. DESIGN: Multicenter, randomized, placebo controlled, double blind. SETTING: Three Danish hospital Departments of Rheumatology. PATIENTS: Fifty-one patients with active rheumatoid arthritis. INTERVENTION: Random allocation to 12 weeks of treatment with either six n-3 PUFA capsules (3.6 g) or six capsules with fat composition as the average Danish diet. MAIN RESULTS: Significant improvement of morning stiffness and joint tenderness. No significant effect on the four other assessed clinical parameters. No serious side effects. CONCLUSIONS: Dietary supplementation with n-3 PUFA in patients with rheumatoid arthritis improved two out of six patient reported disease parameters. Further studies are needed to clarify the more precise role of n-3 PUFA in the treatment of rheumatoid arthritis.

Decreased interleukin-1 beta levels in plasma from rheumatoid arthritis patients after dietary supplementation with n-3 polyunsaturated fatty acids.

The effects of dietary supplementation with n-3 fatty acids on the level of cytokines and complement activation in plasma from patients with rheumatoid arthritis were examined. Thirty-two patients with active rheumatoid arthritis were included in a 12-week double-blind, randomized study of dietary supplementation with n-3 fatty acids (3.6 g per day) or placebo. The cytokines were measured in plasma before and after treatment with fish oil or placebo. In general, cytokine values at the upper limits of the calculated normal areas were found. The Interleukin-1 beta concentration in plasma was reduced significantly after 12 weeks of dietary supplementation with fish oil (p < 0.03). No significant difference was observed in the placebo group. The tumour necrosis factor alpha activity in plasma did not change significantly (p = 0.167). No significant changes were observed in the degree of complement activation. The clinical status of the patients was improved in the fish oil group, but not in the placebo group, judged by Ritchie's articular index (p < 0.02). We conclude that dietary supplementation with n-3 fatty acids results in significantly reduced plasma IL-1 beta levels in patients with rheumatoid arthritis. Even though the cytokine levels were low, the anti-inflammatory effect of n-3 fatty acids could in part be explained by their ability to decrease cytokine production.

The acute effect of a single very high dose of N-3 fatty acids on coagulation and fibrinolysis.

The objective of the study was to investigate the acute effect of a single very high dose of n-3 PUFA on coagulation and fibrinolysis. Forty healthy volunteers were randomized into two groups to receive either 20 grams of n-3 PUFA or 20 grams of n-6 PUFA as a single dose at 6 p.m. with their evening meal. Coagulation and fibrinolysis were evaluated in the fasting state at 8 a.m. the next morning and compared to values obtained at 8 a.m. the day before, when the participants were on their habitual diets. PAI-1 activity in plasma increased by a mean of 62% in subjects randomized to receive n-3 PUFA despite that no changes could be demonstrated in t-PA antigen levels. PAI-1 activity was unaltered in the 20 controls receiving n-6 PUFA. Plasma fibrinogen, coagulation factor VII, thrombin-antithrombin complexes and D-dimer did not significantly change after either supplement. The substantial increase in levels of PAI-1 activity in plasma after a single very high dose of n-3 PUFA may limit the usefulness of single very high doses of n-3 PUFA in acute clinical conditions.

Normal lipoprotein(a) concentrations and apolipoprotein(a) isoforms in patients with insulin-dependent diabetes mellitus.

Lipoprotein(a) [Lp(a)] is an LDL particle in which apoliporotein B-100 is attached to a large plasminogen-like protein called apolipoprotein(a) [apo(a)]. Apo(a) has several genetically determined phenotypes differing in molecular weight, to which Lp(a) concentrations in plasma are inversely correlated, and plasma Lp(a) concentrations above 20-30 mg dl-1 are an independant risk factor for ischaemic heart disease (IHD). To investigate whether Lp(a) could be important for the high cardiovascular mortality rate in patients with insulin dependent diabetes mellitus (IDDM), we determined Lp(a) concentrations and phenotypes in a group of 108 men (median age 32 years) with IDDM without nephropathy. A group of 40-year-old men (n = 466) served as controls. The median Lp(a) concentration was 7.4 mg dl-1 [95% CI 4.9 to 11.7] in the diabetic patients and 6.3 mg dl-1 [95% CI 5.2 to 7.0] in controls. The Lp(a) concentration exceeded 30 mg dl-1 in 22% of IDDM patients and in 20% of controls (P = 0.13). Moreover, the distribution of apo(a) phenotypes did not differ between patients and control. Lp(a) levels and apo(a) phenotypes are thus apparently the same in IDDM patients without nephropathy and controls. These findings do not exclude the possibility that Lp(a) may be increased in patients with nephropathy in whom coronary artery disease frequently co-exist or that Lp(a) in a given concentration is more atherogenic in IDDM patients than in persons without IDDM.

Does increased glomerular filtration rate or disturbed tubular function early in the course of childhood type 1 diabetes predict the development of nephropathy?

To clarify whether glomerular hyperfiltration or disturbances in renal tubular function may be early markers of the later development of nephropathy a follow-up study was performed in 34 young Type 1 diabetic patients, who had originally been investigated 12 years previously. The initial median age was 14 (range 7-18) years and median diabetes duration 7 (2-14) years. At initial examination only one of the 34 diabetic patients exhibited increased urinary albumin excretion rate. The median glomerular filtration rate was increased (136 vs 107 ml min-1 1.73 m-2; p less than 0.0001) and median threshold concentration of phosphate per litre of glomerular filtrate was decreased (1.27 vs 1.76 mmol l-1; p less than 0.0001) in the diabetic group as compared to that of 28 healthy children. At follow-up 17 patients showed increased urinary albumin excretion rate and the median glomerular filtration rate in this group was significantly lower than that of 17 patients with normal urinary albumin excretion rate (108 vs 125 ml min-1 1.73 m-2; p less than 0.05). However, no relationships were found between the increased urinary albumin excretion (incipient and/or overt diabetic nephropathy) at follow-up to either the initial glomerular filtration rate (134 vs 137 ml min-1 1.73 m-2; p greater than 0.05) or to renal tubular function assessed from urinary excretion rate of beta 2-microglobulin (0.059 vs 0.069 microgram min-1; p greater than 0.05) and the renal threshold concentration of phosphate per litre of glomerular filtrate (1.29 vs 1.22 mmol l-1; p greater than 0.05).

Long-term supplementation with n-3 fatty acids, I: Effect on blood lipids, haemostasis and blood pressure.

The effect of dietary supplementation with 4 g of n-3 polyunsaturated fatty acids (PUFA) daily for 9 months on blood pressure, plasma lipids and lipoproteins, platelet function, coagulation and fibrinolysis was studied in 24 healthy volunteers. Each variable was determined before, after 6 weeks and 9 months of supplementation with n-3 PUFA, and 3 months after the supplementation period had ended. Systolic and diastolic blood pressure declined after intake of n-3 PUFAs. Plasma triglycerides were reduced, and there was a trend towards an increase in HDL-cholesterol after 9 months of supplementation, while total cholesterol, LDL-cholesterol and apolipoproteins A1 and B were unaltered. The bleeding time was increased, and plasma levels of von Willebrand factor decreased after 9 months supplementation with n-3 PUFA. Fibrinogen levels increased, while fibrinolysis was reduced after 9 months supplementation with n-3 PUFA. Overall, no clear benefit on lipid pattern and haemostasis was achieved with respect to development of coronary heart disease.

Long-term supplementation with n-3 fatty acids, II: Effect on neutrophil and monocyte chemotaxis.

The effect of a daily supplement with 4 g of n-3 polyunsaturated fatty acids (PUFA) for 9 months to 24 healthy volunteers on neutrophil and monocyte chemotaxis was studied using the under-agarose technique. Autologous serum and n-formyl-methionyl-leucyl-phenylalanine were used as chemoattractants. The effect after 9 months of supplementation with n-3 PUFA was also compared to results after short-term supplementation with n-3 PUFA for 6 weeks. Monocyte chemotaxis was reduced after 9 months of supplementation with n-3 PUFA to the same extent as after 6 weeks supplement. Neutrophil-directed migration towards chemoattractants was reduced after 9 months on fish oil, and this decrease was significantly greater than the decrease obtained after 6 weeks of supplementation. The spontaneous migration of neutrophils was significantly attenuated after 9 months compared to baseline and to 6 weeks. These findings lend support to a role for n-3 PUFA in the management of chronic inflammatory and atherosclerotic vascular diseases.