Troglitazone,an insulin action enhancer,improves glycaemic control and insulin sensitivity in elderly Type 2 diabetic patients

The management of Type 2 diabetes mellitus with currently available oral agents may be complicated in the elderly by an increased frequency of side-effects. The effects of troglitazone, an insulin action enhancer, were studied in elderly patients with Type 2 diabetes in a double-blind, parallel-group, placebo-controlled trial. A total of 229 patients (41 % male), mean age 75 (range 69–85) years, with two fasting capillary blood glucose values ≥7 and ≤15 mmol l⁻¹ (and within 4.0 mmol l⁻¹ of each other) and previously treated with either diet alone (30 %) or oral hypoglycaemic agents, were randomized to placebo or troglitazone 400 mg once daily or 200 mg twice daily, or 800 mg once daily or 400 mg twice daily, for 12 weeks. After 12 weeks’ treatment, fasting serum glucose was significantly lower in troglitazone-treated patients (troglitazone, adjusted geometric mean 9.4–10.4 mmol l⁻¹ vs placebo 12.7 mmol l⁻¹, p<0.001). Adjusted geometric mean fructosamine was also lower in troglitazone-treated patients by 5 to 15 % compared to placebo (P <0.05 at all doses except 400 mg od). There was no significant difference between troglitazone doses for improvement in glycaemic control. Troglitazone lowered adjusted geometric mean fasting plasma insulin by 27–34 % compared to placebo (P<0.001) and insulin sensitivity (HOMA-S) improved by 9–15 % in all troglitazone dose groups (p<0.001). Troglitazone also lowered serum non-esterified fatty acids and triglyceride. Adverse event incidence in troglitazone-treated patients was similar to that in patients treated with placebo. No weight gain or symptomatic hypoglycaemia was recorded at any of the doses studied. Troglitazone is effective and well tolerated in elderly patients with Type 2 diabetes mellitus, providing improved glycaemic control in the absence of weight gain. © 1998 John Wiley & Sons, Ltd.     

Metabolic effects of darglitazone,an insulin sensitizer,in NIDDM subjects

Summary Insulin resistance is a significant pathogenetic factor in the development of non-insulin-dependent diabetes mellitus (NIDDM). A new class of drugs, the thiazolidinediones, have been shown to lower blood glucose levels without stimulating insulin secretion. We report the metabolic effect of the thiazolidinedione, darglitazone, in obese NIDDM subjects. Nineteen subjects were enrolled in a doubleblind placebo-controlled study in which 25 mg of darglitazone was given once a day for 14 days. Nine subjects received the active drug and ten subjects received placebo. Darglitazone-treated subjects showed; 1) a decrease in 24-h plasma glucose area under the curve from 292.8±31.2 to 235.2±21.6 mmol · h^–1 · l^–1 p=0.002; 2) a decrease in 24-h serum insulin area under the curve from 1027.2±254.4 to 765.6±170.4 U · h^–1 · l^–1 p=0.045; 3) a decrease in 24-h non-esterified fatty acid area under the curve from 1900±236 to 947±63 g · h^–1 · l^–1 p=0.002; 4) a decrease in mean 24-h serum triglyceride by 25.9±6.2% as compared to – 3.9±4.8% for the placebo-treated group, p=0.012. Placebo-treated subjects showed no change in their metabolic parameters after treatment. Thus, darglitazone is effective in increasing insulin effectiveness in obese NIDDM subjects. The potential for this and similar drugs to treat or prevent NIDDM as well as the insulin-resistance syndrome needs to be explored.Abbreviations NIDDM Non-insulin-dependent diabetes mellitus - NEFA non-esterified fatty acids - IVGTT intravenous glucose tolerance test - AUC area under the curve     

Tesaglitazar, a novel dual peroxisome proliferator-activated receptor α/γ agonist, dose-dependently improves the metabolic abnormalities associated with insulin resistance in a non-diabetic population

Aims/hypothesis Insulin resistance is associated with abnormalities in lipid and glucose metabolism, which are major components of metabolic syndrome and risk factors for vascular disease. This study examined the effect of tesaglitazar (Galida), a novel, dual-acting peroxisome proliferator-activated receptor / agonist, on lipid and glucose metabolism in patients with evidence of insulin resistance.Methods A 12-week, multicentre, randomised, double-blind, placebo-controlled, dose-finding study compared the efficacy and safety of oral tesaglitazar (0.1, 0.25, 0.5 and 1.0 mg/day) and placebo in 390 non-diabetic patients with hypertriglyceridaemia (plasma triglyceride concentration >1.7 mmol/l) and abdominal obesity (waist-to-hip ratio >0.90 for men and >0.85 for women).Results A 1.0-mg dose of tesaglitazar reduced fasting triglycerides (the primary endpoint) by 37% (95% CI: –43% to –30%; p<0.0001), non-HDL-cholesterol by 15% (95% CI: –20% to –10%; p<0.0001) and NEFA by 40% (95% CI: –51% to –27%; p<0.0001), and increased HDL-cholesterol by 16% (95% CI: 8 to –24%; p<0.0001). At the end of treatment there was a dose-dependent increase in patients with pattern A LDL particle diameter (40% at baseline vs 87% at 12 weeks for tesaglitazar 1.0 mg). Tesaglitazar produced significant reductions in fasting insulin concentration (–35%; p<0.0001) and plasma glucose concentration (–0.47 mmol/l; p<0.0001). Respiratory infection and gastrointestinal symptoms were the most common adverse events and were similarly frequent in all groups.Conclusions/interpretation Tesaglitazar was well tolerated and produced significant, dose-dependent improvements in lipid and glucose metabolism and insulin sensitivity. Tesaglitazar may have the potential to prevent vascular complications and delay progression to diabetes in these patients.     

Dutogliptin,a selective DPP4 inhibitor,improves glycaemic control in patients with type 2 diabetes: a 12‐week,double‐blind,randomized, placebo‐controlled,multicentre trial

Aim: To determine efficacy and tolerability of dutogliptin, a dipeptidyl peptidase 4 (DPP4) inhibitor, in patients with type 2 diabetes mellitus. Methods: This was a 12‐week, multicentre, randomized, double‐blind, placebo‐controlled trial in 423 patients with type 2 diabetes with suboptimal metabolic control. Following a 2‐week single‐blind placebo run‐in, patients aged 18–75 years with a body mass index of 25–48 kg/m² and baseline HbA1c of 7.3–11.0% were randomized 2:2:1 to receive once‐daily oral therapy with either dutogliptin (400 or 200 mg) or placebo on a background medication of either metformin alone, a thiazolidinedione (TZD) alone or a combination of metformin plus a TZD. Results: Average HbA1c at baseline was 8.4%. Administration of dutogliptin 400 and 200 mg for 12 weeks decreased HbA1c by ?0.52% (p < 0.001) and ?0.35% (p = 0.006), respectively (placebo‐corrected values), with absolute changes in HbA1c for the 400 mg, 200 mg and placebo groups of ?0.82, ?0.64 and ?0.3%, respectively. The proportion of patients achieving an HbA1c < 7% was 27, 21 and 12% at dutogliptin doses of 400 and 200 mg or placebo, respectively (p = 0.008 for comparison of 400 mg vs. placebo). Fasting plasma glucose (FPG) levels were significantly reduced in both active treatment groups compared to placebo: the placebo‐corrected difference was ?1.00 mmol/l (p < 0.001) for the 400 mg group and ?0.88 mmol/l (p = 0.003) for the 200 mg group. Dutogliptin caused significantly greater reductions in postprandial glucose AUC _0–2h in both the 400 and 200 mg groups (placebo corrected values ?2.58 mmol/l/h, p < 0.001 and ?1.63 mmol/l/h, p = 0.032, respectively). In general, patients tolerated the study drug well. There were minor, not clinically meaningful differences in adverse events (AEs) between dutogliptin‐treated patients and placebo controls, and 60% of all reported AEs were mild. Vital signs and body weight were stable, and routine safety laboratory parameters did not change compared with placebo. Trough ex vivo DPP4 inhibition at the end of the 12‐week treatment period was 80 and 70%, at the 400 and 200 mg doses of dutogliptin, respectively. Conclusions: Dutogliptin treatment for 12 weeks improved glycaemic control in patients with type 2 diabetes who were on a background medication of metformin, a TZD or metformin plus a TZD. Tolerability was favourable for both doses tested. The 400 mg dose of dutogliptin resulted in larger changes of HbA1c and FPG and more subjects reached an HbA1c target of < 7% than the 200 mg dose.     

The effect of a new specific α-amylase inhibitor on post-prandial glucose and insulin excursions in normal subjects and Type 2 (non-insulin-dependent) diabetic patients

Summary Trestatin (Ro 9-0154), a new specific -amylase inhibitor of microbial origin, was tested in six normal subjects and seven Type 2 (non-insulin-dependent) diabetic patients. In normal subjects the maximal increases in blood glucose following a 115-g starch meal were 2.19±0.57 mmol/l (mean±SEM) with placebo, but 1.32±0.39 mmol/l with 10 mg, 1.06±0.26 mmol/l with 20 mg, 0.43±0.07 mmol/l with 50 mg (p<0.05) and 0.26±0.14 mmol/l with 100 mg (p<0.05) Trestatin. The corresponding increases in plasma insulin were 116.5±19.6mU/l; 74.8±17.5 mU/l; 50.7±8.3 mU/l; 28.7±6.9 mU/l (p<0.05) and 16.5±3.2 mU/l (p<0.05). In the diabetic patients the maximal increases in blood glucose following a 50-g starch meal were 6.09±0.02 mmol/l with placebo, but 3.17±0.59 mmol/ (p<0.05) with 10 mg and 1.69±0.41 mmol/l (p<0.05) with 30 mg Trestatin. The corresponding insulin increases were: 58.8±12.7 mU/l, 31.5±9.7mU/l (p<0.05) and 23.4±4.8 mU/l (p<0.05). Trestatin fully retained this pharmacological activity during treatment for 4 weeks in the diabetic patients. Trestatin did not influence glucose and insulin profiles after oral glucose and sucrose. These results are consistent with a specific inhibition of -amylase in man.     

Short Term Effect of Atorvastatin and Vitamin E on Serum Levels of C3, a Sensitive Marker of the Risk of Myocardial Infarction in Men

C3 complement is produced in response to macrophage activation and is a reliable marker of the risk of myocardial infarction in men. This study was designed to ascertain whether the treatment with atorvastatin, a powerful cholesterol lowering drug, and/or vitamin E, a natural antioxidant, may induce a short term decrease in serum C3 in subjects with persistently elevated levels. From an initial random sample of 1100 men aged 55–64 years, 140 subjects with 3 consecutive C3 measurements in the high tertile (>1.19 g/l) were selected. Those with total cholesterol <5.56 mmol/l were double blindly randomized in groups 1 (placebo, N = 28, G1) and 2 (vitamin E 600 IU/day, N = 30, G2). The subjects with total cholesterol values 5.56 mmol/l were randomized in groups 3 (placebo, N = 30, G3), 4 (atorvastatin 10 mg/day, N = 27, G4) and 5 (atorvastatin 10 mg/day + vitamin E 600 IU/day, N = 25, G5). After 3 months C3 levels were substantially unchanged in the first 4 groups, while in G5 a very significant decrement occurred: –0.070 g/l (5.2%); 95% CI 0.043–0.098; p < 0.0001. Normal levels of C3 (1.19 g/l) were reached by 28% of G5 subjects. In G2 and G5 vitamin E levels increased by 60 and 36%, while in G4 they decreased by 23% (p < 0.0001), paralleling cholesterol and triglyceride fall. In all groups a progressive decrease in HDL cholesterol occurred (–17%, p < 0.0001). In conclusion, treatment with atorvastatin plus vitamin E for three months can lower persistently elevated C3 levels.     

Treatment of symptomatic diabetic peripheral neuropathy with the anti-oxidant α-lipoic acid

Summary Anti-oxidant treatment has been shown to prevent nerve dysfunction in experimental diabetes mellitus, thus providing a rationale of potential therapeutic value for diabetic patients. The effects of the anti-oxidant -lipoic acid (thioctic acid) were studied in a 3-week multicentre, randomized, double-blind placebo-controlled trial (Alpha-Lipoic Acid in Diabetic Neuropathy; ALADIN) in 328 non-insulin-dependent diabetic patients with symptomatic peripheral neuropathy who were randomly assigned to treatment with intravenous infusion of -lipoic acid using three doses (1200, 600, or 100 mg ALA) or placebo (PLAC). Neuropathic symptoms (pain, burning, paraesthesiae, and numbness) were scored at baseline and at each visit (days 2–5, 8–12, and 15–19) prior to infusion. In addition, the Hamburg Pain Adjective List, a multidimensional specific pain questionnaire, and the Neuropathy Symptom and Disability Scores were assessed at baseline and day 19. According to the protocol 260 (65/63/66/66) patients completed the study. The total symptom score in the feet decreased from baseline to day 19 by –4.5±3.7 (–58.6%) points (mean ± SD) in ALA 1200, –5.0±4.1 (–63.5%) points in ALA 600, –3.3±2.8 (–43.2%) points in ALA 100, and –2.6±3.2 (–38.4%) points in PLAC (ALA 1200 vs PLAC: p=0.003; ALA 600 vs PLAC: p<0.001). The response rates after 19 days, defined as an improvement in the total symptom score of at least 30%, were 70.8% in ALA 1200, 82.5% in ALA 600, 65.2% in ALA 100, and 57.6% in PLAC (ALA 600 vs PLAC; p=0.002). The total scale of the Pain Adjective List was significantly reduced in ALA 1200 and ALA 600 as compared with PLAC after 19 days (both p<0.01). The rates of adverse events were 32.6% in ALA 1200, 18.2% in ALA 600, 13.6% in ALA 100, and 20.7% in PLAC. These findings substantiate that intravenous treatment with -lipoic acid using a dose of 600 mg/day over 3 weeks is superior to placebo in reducing symptoms of diabetic peripheral neuropathy, without causing significant adverse reactions.Abbreviations ALA -lipoic acid - HPAL Hamburg Pain Adjective List - NCV nerve conduction velocity - NDS Neuropathy Disability Score - NSS Neuropathy Symptom Score - TSS total symptom score - VPT vibration perception threshold - NIDDM non-insulin-dependent diabetes mellitus - IDDM insulin-dependent diabetes mellitus     

Effect of Combination Therapy of Troglitazone and Sulphonylureas in Patients with Type 2 Diabetes Who Were Poorly Controlled by Sulphonylurea Therapy Alone

The clinical efficacy of troglitazone, a new oral hypoglycaemic agent was investigated in Type 2 diabetes in combination with sulphonylureas. Two hundred and ninety-one patients with Type 2 diabetes (age 21–81 years) whose previous glycaemic control by sulphonylureas was judged stable but unsatisfactory (fasting plasma glucose (FPG) > 8.3 mmol l⁻¹) were randomly allocated into the troglitazone treatment group (troglitazone group, n = 145) or the placebo treatment group (placebo group, n = 146). They were treated by test drugs for 12 weeks in combination with the same dose of sulphonylureas before the trial. One hundred and twenty-two patients who received troglitazone and 126 patients who received placebo were evaluated for efficacy. The baseline characteristics did not differ significantly between the two groups. In the troglitazone group, FPG and HbA_1C decreased significantly after the treatment (before vs after, FPG: 10.8 ± 2.0 mmol l⁻¹ vs 9.2 ± 2.5 mmol l⁻¹, p < 0.001; HbA_1C: 9.2 ± 1.4 % vs 8.5 ± 1.5 %, p < 0.001). FPG and HbA_1C did not change after the treatment in the placebo group (before vs after, FPG: 10.5 ± 1.7 mmol l⁻¹ vs 10.7 ± 2.2 mmol l⁻¹; HbA_1C: 9.0 ± 1.5 % vs 9.2 ± 1.6 %). Serum total cholesterol and HDL-cholesterol did not change in either group, however, serum triglyceride significantly decreased in the troglitazone group. No serious adverse events occurred in either group. In conclusion, troglitazone 400 mg day⁻¹ had a significant hypoglycaemic effect in combination with sulphonylureas without any serious adverse events. Troglitazone, developed as an insulin action enhancer, can be a useful hypoglycaemic agent in the treatment of patients with Type 2 diabetes who are not well controlled by sulphonylureas alone.     

The biochemical basis of increased hepatic glucose production in a mouse model of type 2 (non-insulin-dependent) diabetes mellitus

Summary The mechanism of increased hepatic glucose production in obese non-insulin-dependent diabetic (NIDDM) patients is unknown. The New Zealand Obese (NZO) mouse, a polygenic model of obesity and NIDDM shows increased hepatic glucose production. To determine the mechanism of this phenomenon, we measured gluconeogenesis from U-¹⁴C-glycerol and U-¹⁴C-alanine and relevant gluconeogenic enzymes. Gluconeogenesis from glycerol (0.07±0.01 vs 0.21±0.02 mol · min^–1 · body mass index (BMI)^–1, p<0.005) and alanine (0.57±0.07 vs 0.99±0.07 mol · min^–1 · BMI^–1, p<0.005) was elevated in control mice NZO vs as was glycerol turnover (0.25±0.02 vs 0.63±0.09 mol · min^–1 · BMI^–1, p<0.05). Fructose 1,6-bisphosphatase activity (44.2±1.9 vs 55.7±4.1 nmol · min^–1 · mg protein^–1, p<0.05) and protein levels (6.9±1.1 vs 16.7±2.3 arbitrary units, p<0.01) were increased in NZO mouse livers, as was the activity of pyruvate carboxylase (0.12±0.01 vs 0.17±0.02 nmol · min^–1 · mg protein^–1, p<0.05). To ascertain whether elevated lipid supply is responsible for these biochemical changes in NZO mice, we fed lean control mice a 60% fat diet for 2 weeks. Fat-fed mice were hyperinsulinaemic (76.37±4.06 vs 98.00±7.07 pmol/l, p=0.05) and had elevated plasma non-esterified fatty acid levels (0.44±0.05 vs 0.59±0.03 mmol/l, p=0.05). Fructose 1,6-bisphosphatase activity (43.86±2.54 vs 52.93±3.09 nmol · min^–1 · mg protein^–1, p=0.05) and protein levels (33.03±0.96 vs 40.04±1.26 arbitrary units, p=0.005) and pyruvate carboxylase activity (0.10±0.003 vs 0.14±0.01 nmol · min^–1 · mg protein^–1, p<0.05) were elevated in fat-fed mice. We conclude that in NZO mice increased hepatic glucose production is due to elevated lipolysis resulting from obesity.Abbreviations HGP Hepatic glucose production - NZO New Zealand Obese - FBPase fructose 1,6-bisphosphatase - PC pyruvate carboxylase - PEPCK phosphoenolpyruvate carboxykinase - BMI body mass index - NIDDM non-insulin-dependent diabetes mellitus - NZC lean control mice - NEFA non-esterified fatty acids     

Pioglitazone elicits long-term improvements in insulin sensitivity in patients with type 2 diabetes: comparisons with gliclazide-based regimens

Aims/hypothesis Recent studies have demonstrated that pioglitazone (PIO) has beneficial effects on insulin sensitivity compared with placebo in patients with type 2 diabetes. The effects of PIO and gliclazide (GLIC)-based therapy on insulin sensitivity have not previously been directly compared. This analysis aimed to compare the effects of 52 weeks of treatment with PIO (30–45 mg/day) and GLIC (80–320 mg/day), both titrated to maximum tolerable doses, as monotherapy or in combination with metformin (MET), on insulin sensitivity and lipid parameters known to be related to insulin sensitivity in patients with type 2 diabetes.Methods We performed an analysis of 1,880 patients with inadequately controlled type 2 diabetes (HbA₁c 7.5–11.0%) who were participants in two parallel-group, double-blind, double-dummy, randomised, multicentre, clinical trials. Measures of insulin sensitivity and lipids were assessed.Results The PIO- and GLIC-based regimens produced similar levels of glycaemic control (HbA₁c). In both trials, insulin sensitivity as assessed using the homeostasis model assessment was improved in patients receiving PIO, but decreased in those receiving GLIC (mean change, baseline to endpoint: PIO 15.5, GLIC –15.6; p<0.001 and PIO+MET 18.9, GLIC+MET –5.3; p<0.001). Improvements in the atherogenic index of plasma (mean change: PIO –0.17, GLIC –0.08; p<0.001 and PIO+MET –0.17, GLIC+MET –0.02; p<0.001), triglycerides (mean change, mmol/l: PIO+MET –0.62, GLIC+MET –0.22; p<0.001) and NEFA (mean change, mmol/l: PIO+MET –0.12, GLIC+MET–0.05; p<0.001) were greater in PIO-treated patients than in patients receiving GLIC.Conclusions/interpretation The PIO-based regimens resulted in improved insulin sensitivity and more favourable insulin sensitivity-related lipid profiles compared with the GLIC-based regimens. These benefits may be important in the management of cardiovascular risk in patients with type 2 diabetes.     

Glucose tolerance and plasma insulin response to intravenous glucose infusion and test meal in rats with microencapsulated islet allografts

Summary Albino Oxford rats made diabetic with 75 mg/kg streptozotocin were intraperitoneally transplanted with 2500–2900 alginate-polylysine microencapsulated Lewis islets (n=9, total islet tissue volume 8.0–11.0 l), or a similar volume of non-encapsulated Lewis islets (n=5). All rats with microencapsulated islets became normoglycaemic, and remained normoglycaemic for 5–16 weeks. In rats with non-encapsulated islet grafts, only a temporary decrease in blood glucose was observed, and all were again severely hyperglycaemic at 1 week after implantation. At 5–6 weeks after transplantation, glucose tolerance in rats with microencapsulated islets was tested by intravenous glucose infusion (10 mg/min over 20 min) and test meal administration (n=4). During glucose infusion, maximum glucose levels were 13.0±0.4 mmol/l in rats with microcapsules and 8.9±0.4 mmol/l in healthy control rats (p<0.01). Concomitant maximum plasma insulin levels were 215±17 pmol/l in rats with microcapsules and 715±85 pmol/l in controls (p<0.001). After the test meal, maximum blood glucose was 10.6±0.9 mmol/l in rats with microcapsules and 6.2±0.1 mmol/l in controls (p<0.001), with concomitant maximum plasma insulin levels of 247±11 pmol/l and 586±59 pmol/l, respectively (p<0.001). In conclusion, although the glucose tolerance is impaired and plasma insulin responses to intravenous glucose-load and test-meal are reduced, the alginate-polylysine membrane does provide adequate immunoisolation for the prolongation of allograft survival, resulting in prolonged normoglycaemia in streptozotocin diabetic rats.     

Effect of metformin on insulin-stimulated glucose transport in isolated skeletal muscle obtained from patients with NIDDM

Summary Metformin has been demonstrated to lower blood glucose in vivo by a mechanism which increases peripheral glucose uptake. Furthermore, the therapeutic concentration of metformin has been estimated to be in the order of 0.01 mmol/l. We investigated the effect of metformin on insulin-stimulated 3-0-methylglucose transport in isolated skeletal muscle obtained from seven patients with non-insulin-dependent diabetes mellitus (NIDDM) and from eight healthy subjects. Whole body insulin-mediated glucose utilization was decreased by 45% (p<0.05) in the diabetic subjects when studied at 8 mmol/l glucose, compared to the healthy subjects studied at 5 mmol/l glucose. Metformin, at concentrations of 0.1 and 0.01 mmol/l, had no effect on basal or insulin-stimulated (100 U/ml) glucose transport in muscle strips from either of the groups. However, the two control subjects and three patients with NIDDM which displayed a low rate of insulin-mediated glucose utilization (<20 mol·kg^–1·min^–1), as well as in vitro insulin resistance, demonstrated increased insulin-stimulated glucose transport in the presence of metformin at 0.1 mmol/l (p<0.05). In conclusion, the concentration of metformin resulting in a potentiating effect on insulin-stimulated glucose transport in insulin-resistant human skeletal muscle is 10-fold higher than the therapeutic concentrations administered to patients with NIDDM. Thus, it is conceivable that the hypoglycaemic effect of metformin in vivo may be due to an accumulation of the drug in the extracellular space of skeletal muscle, or to an effect of the drug distal to the glucose transport step.Abbreviations NIDDM Non-insulin-dependent diabetes mellitus - KHB Krebs-Henseleit's bicarbonate buffer - HEPES N-2, hydroxyethyl-piperazine-N'-2-ethanesulfonic acid - BSA bovine serum albumin - RIA radioimmunoassay - HbA_1c glycated haemoglobin A_1c - BMI body mass index (kg/m²) - GLUT 1 HepG2/erythrocyte - GLUT 4 insulin-regulatable glucose transporter     

Coronary heart disease in young Type 1 (insulin-dependent) diabetic patients with and without diabetic nephropathy: incidence and risk factors

Summary Fifty-nine Type 1 (insulin-dependent) diabetic patients with (group I) and 59 patients without nephropathy (group II) pair-matched according to sex (30 males and 29 females), age (33 years, range 15–48) and diabetes duration (19 years, range 6–42) were followed for a period of 10 years from about 5 years before to 5 years after onset of proteinuria. The cumulative incidence of coronary heart disease was estimated, and blood pressure and serum cholesterol were followed. Within six years after onset of proteinuria the cumulative incidence of coronary heart disease was increased eight-fold in group I (40%) compared with group II (5%), (p<0.001). Blood pressure was higher in group I compared with group II from before onset of proteinuria (135/86±17/9 mmHg vs 129/80±15/8 mmHg, p<0.001), and serum cholesterol elevated from onset of proteinuria in group I (6.3±1.2 mmol/l) vs. group II (5.5±1.0 mmol/l), (p<0.005). Patients in group I who developed coronary heart disease had similar age (36 years, range 21–51, vs 38 years, range 21–53), sex (50% males vs. 52% males), smoking frequency (50% vs 49%), diabetes duration (22 years, range 9–39, vs 24 years, range 10–42) and serum creatinine (110 mol/l, range 69–284, vs 108 mol, range 72–1024) compared with patients not developing coronary heart disease. However, the patients with coronary heart disease had higher blood pressure (135/87mmHg±16/9 vs 128/82±15/7, p<0.05) and serum cholesterol (7.3 mmol/l+ 1.2 vs 6.4 mmol/l±0.9, p<0.05) than patients without coronary heart disease. Thus, patients developing clinical nephropathy have a highly increased incidence of coronary heart disease compared with patients not developing nephropathy. Patients who developed coronary heart disease were characterized by higher blood pressure and serum cholesterol.     

Effects of natural free radical scavengers on peripheral nerve and neurovascular function in diabetic rats

Summary Increased generation of reactive oxygen species, coupled with impaired endogenous scavenging mechanisms, plays a prominent role in the aetiology of neurovascular abnormalities in experimental diabetes mellitus. We examined the efficacy of the natural anti-oxidants vitamins C, E and -carotene in preventing nerve conduction and nutritive blood flow deficits in streptozotocin-diabetic rats. One month of diabetes caused a 19.1% reduction in sciatic motor conduction velocity (p<0.001). This was approximately prevented 80–90% by high-dose (1000 mg · kg^–1 · day^–1) vitamin E and -carotene treatments (p<0.001). Vitamin C had lesser effects; the maximum protection found for motor conduction velocity was 36% using a dose of 150 mg · kg^–1 · day^–1 (p<0.001). High dose (500 mg · kg^–1 · day^–1) vitamin C had a lesser effect on conduction than intermediate doses. Joint vitamin C and lower dose (500 mg · kg^–1 · day^–1) vitamin E treatment had a predominantly additive preventive effect against nerve dysfunction. Resistance to hypoxic conduction failure for sciatic nerve in vitro was markedly increased by diabetes and this remained relatively unaffected by treatment. Sciatic nutritive endoneurial blood flow, measured using microelectrode polarography and hydrogen clearance, was reduced 46.1% by 1 month of diabetes (p<0.001). This was prevented to the extent of 87%, 36% and 98% by vitamins E, C and -carotene, respectively (p<0.01). These data emphasize the role of oxidative stress in the development of early neurovascular changes in experimental diabetes and show that naturally available scavengers have a neuroprotective action.Abbreviations NCV Nerve conduction velocity - NO nitric oxide - ROS reactive oxygen species     

Long-term efficacy and tolerability of add-on pioglitazone therapy to failing monotherapy compared with addition of gliclazide or metformin in patients with type 2 diabetes

Aims/hypothesis The aim of this analysis was to examine the long-term effects of pioglitazone or gliclazide addition to failing metformin monotherapy and pioglitazone or metformin addition to failing sulphonylurea monotherapy in patients with type 2 diabetes.Methods Two 2-year, randomised, multicentre trials were performed in patients with inadequately controlled type 2 diabetes (HbA₁c 7.5–11% inclusive), who were receiving either metformin or a sulphonylurea at 50% of the maximum recommended dose or at the maximum tolerated dose. In the first study, patients on metformin received add-on therapy with pioglitazone (15–45 mg/day, n=317) or gliclazide (80–320 mg/day, n=313). In the second study, patients on sulphonylurea therapy were randomised to receive add-on therapy with either pioglitazone (15–45 mg/day, n=319) or metformin (850–2,550 mg/day, n=320). HbA₁c, fasting plasma glucose, insulin and lipids were investigated.Results At week 104, the mean reduction from baseline in HbA₁c was 0.89% for pioglitazone and 0.77% for gliclazide addition to metformin (p=0.200). There was a statistically significant between-group difference for the change in mean fasting plasma glucose at week 104 (–1.8 mmol/l for pioglitazone vs –1.1 mmol/l for gliclazide, p<0.001). There were no significant differences in changes from baseline in glycaemic parameters for pioglitazone compared with metformin addition to sulphonylurea therapy. Whether added to metformin or sulphonylurea, pioglitazone caused significantly greater decreases in triglycerides and significantly greater increases in HDL cholesterol than the comparator regimens (p0.001). There were decreases in LDL cholesterol in the comparator groups and these were significantly different from the small changes observed with pioglitazone (p<0.001). All treatment regimens were well tolerated. There were weight increases of 2.5 kg and 3.7 kg in the pioglitazone and 1.2 kg in the gliclazide add-on groups, and there was a mean decrease of 1.7 kg in the metformin add-on group.Conclusions/interpretation As add-on therapy to existing sulphonylurea or metformin therapy, pioglitazone improved glycaemic control and this improvement was sustained over 2 years. Furthermore, there were potential benefits in terms of improvements in specific lipid abnormalities. This could offer an advantage over the addition of other oral agents in the long-term treatment of diabetes.     

Interactions between essential fatty acid,prostanoid, polyol pathway and nitric oxide mechanisms in the neurovascular deficit of diabetic rats

Summary Impaired -6 essential fatty acid metabolism and exaggerated polyol pathway flux contribute to the neurovascular abnormalities in streptozotocin-diabetic rats. The potential interactions between these mechanisms were examined by comparing the effects of threshold doses of aldose reductase inhibitors and evening primrose oil, alone and in combination, on neurovascular deficits. In addition, highdose aldose reductase inhibitor and evening primrose oil treatment effects were challenged by co-treatment with the cyclo-oxygenase inhibitor, flurbiprofen, or the nitric oxide synthase inhibitor, N^G-nitro-l-arginine. Eight weeks of diabetes caused an 18.9% reduction in sciatic motor conduction velocity (p<0.001). This was only modestly ameliorated by a 0.1% dietary supplement of evening primrose oil or the aldose reductase inhibitors ZD5522 (0.25 mg · kg^–1 · day^–1) and WAY121509 (0.2 mg · kg^–1· day^–1) for the final 2 weeks. However, joint treatment with primrose oil and ZD5522 or WAY121509 caused marked 71.5 and 82.4% corrections, respectively, of the conduction deficit. Sciatic nutritive blood flow was 43.1% reduced by diabetes (p<0.001) and this was corrected by 67.8% with joint ZD5522 and primrose oil treatment (p<0.001). High-dose WAY121509 (10 mg · kg^–1 · day^–1) and primrose oil (10% dietary supplement) prevented sciatic conduction velocity and nutritive blood flow deficits in 1-month diabetic rats (p<0.001). However, these effects were abolished by flurbiprofen (5 mg · kg^–1 · day^–1) and N^G-nitro-l-arginine (10 mg · kg^–1 · day^–1) co-treatment (p<0.001). Thus, the data provide evidence for synergistic interactions between polyol pathway/nitric oxide and essential fatty acid/cyclo-oxygenase systems in the control of neurovascular function in diabetic rats, from which a potential therapeutic advantage could be derived.Abbreviations ARI Aldose reductase inhibitor - EPO evening primrose oil - NCV nerve conduction velocity - NO nitric oxide - NOLA N^G-nitro-l-arginine     

Marine lipids normalize cholesteryl ester transfer in IDDM

Summary Patients with insulin-dependent diabetes mellitus (IDDM) have a pathological increase in cholesteryl ester transfer (CET) that enriches the apolipoprotein B-containing lipoproteins with cholesteryl ester and increases their atherogenicity. Since we have shown earlier that omega-3 (n-3) fatty acids present in marine lipids normalize both CET and lipoprotein composition in non-diabetic patients with hypercholesterolaemia, we sought to determine whether the same beneficial effects could be achieved in nine normolipidaemic (triglycerides 1.10; cholesterol 4.94, high density lipoprotein 1.10 mmol/l) IDDM patients (fructosamine 424±156; normal 174–286 mol/l) treated for 2 months with n-3 fatty acids (4.6 g/day). Before treatment, CET measured by both mass and isotopic assays was abnormally accelerated (p<0.001). While marine lipids modestly decreased triglyceride levels (–14%; p<0.05), CET fell dramatically in all subjects (mass assay: –97% at 1 h; isotopic assay: –58%; p<0.001) to below control levels with no change in glycaemic control (fructosamine 408±103 mol/l). The mass of cholesteryl ester transfer protein paradoxically increased significantly (pre-treatment: 2.04±0.86 vs post-treatment 2.48±0.97 g/ml; p<0.05). Since it is believed that accelerated CET promotes the formation of atherogenic cholesteryl ester-enriched apo B-containing lipoproteins, the capacity of marine lipids to reverse this functional abnormality without altering glycaemic control suggests that these agents may have an adjunctive role to play in the nutritional therapy of IDDM.Abbreviations IDDM Insulin-dependent diabetes mellitus - NIDDM non-insulin-dependent diabetes mellitus - CET cholesteryl ester transfer - CETP cholesteryl ester transfer protein - HDL high density lipoprotein - LpL lipoprotein lipase - apo B apolipoprotein B - n-3 fatty acids omega-3 fatty acids     

Liver and muscle insulin sensitivity,glycogen concentration and glycogen synthase activity in a rat model of non-insulin-dependent diabetes

Summary Mild diabetes was induced in adult rats with streptozotocin (45 mg/kg body weight), and insulin sensitivity, glycogen deposition and glycogen synthase activity assessed in liver and muscle 5 weeks later. Diabetic rats had significantly elevated fasting blood glucose concentrations (5.6±0.1 versus 3.6±0.1 mmol/l, p<0.001), and blood glucose concentrations 2 h after a 1 g/kg glucose load (12.0±0.6 versus 3.7±0.2 mmol/l, p<0.001). After a 20-h fast hepatic glucose output was significantly elevated (58±3 versus 47±3 mol·min^–1·kg^–1, p<0.05), and failed to suppress at high insulin concentrations during a euglycaemic clamp (hepatic glucose output 21±4 versus 2±4 mol·min^–1·kg^–1, p<0.02). Liver glycogen was lower in the diabetic rats by the end of the clamp (16±3 versus 38±6 mol/g wet wt, p<0.05). At the end of the clamp total glucose turnover was lower in the diabetic rats (107±4 versus 161±17 mol·min^–1· kg^–1, p<0.01), as was skeletal muscle glycogen synthase activity (0.46±0.04 versus 0.67±0.05 U/g wet wt, p<0.01) and glycogen concentration (22±2 versus 33±3 mol/g wet wt, p<0.05). Blood lactate and pyruvate responses suggested that glycolytic pathways were similarly affected. Thus, insulin insensitivity develops in both liver and skeletal muscle after 5 weeks of mild streptozotocin-induced diabetes.     

Decrease of Intragastric Acidity in Healthy Subjects Dosed with Ranitidine 75 mg, Cimetidine 200 mg, or Placebo

This study assessed the duration of action of single doses of ranitidine (75 mg), cimetidine (200 mg), or placebo on intragastric acidity in healthy subjects. When dosed with placebo, mean daytime intragastric acidity (0–10 hr after dose) was 37.62 mmol/liter, decreasing to 17.21 mmol/liter (mean decrease 59%; P < 0.001 vs placebo) and 25.06 mmol/liter (mean decrease 35%; P < 0.001 vs placebo) when treated with ranitidine and cimetidine, respectively. Ranitidine inhibited intragastric acidity to a greater degree than cimetidine (P < 0.001). Mean nighttime (10–20 hr after-dose) intragastric acidity when dosed with placebo was 34.37 mmol/liter, decreasing to 29.06 mmol/liter (mean decrease 18%; P = 0.027 vs placebo) when dosed with ranitidine and remaining virtually unchanged at 33.85 mmol/liter (mean decrease 2%; NS vs. placebo) when dosed with cimetidine. Ranitidine inhibited acidity to a greater degree than cimetidine (P = 0.043). The inhibitory effect of ranitidine, 75 mg, on intragastric acidity can be detected from 0–15 hr after an oral dose. Cimetidine 200 mg has little inhibitory effect beyond 10 hr.     

The effects of a specific growth hormone antagonist on overnight insulin requirements and insulin sensitivity in young adults with Type 1 diabetes mellitus

Aims/hypothesis Growth hormone hypersecretion in Type 1 diabetes could exacerbate insulin resistance and contribute to declining glycaemic control. Our aim was to determine the effects of specific growth hormone blockade on insulin sensitivity and lipolysis in young adults with Type 1 diabetes.Methods We studied the effects of two doses of a specific growth hormone antagonist (B2036-PEG; Somavert, Pharmacia Corporation, Milton Keynes, UK) on insulin sensitivity in seven young adults (17–22 yrs, 3M) with Type 1 diabetes. Subjects recieved 5 and 10 mg B2036-PEG, in random order for 3 weeks, with a 3-week washout. At baseline and following each treatment block, an overnight (03:00 to 08:00 h) insulin infusion for euglycaemia (5 mmol/l), followed by two-step hyperinsulinaemic euglycaemic clamp, using [6,6 ²H₂] glucose and ²H₅ glycerol to measure glucose and glycerol turnover was performed.Results Compared to baseline, overnight insulin requirements decreased with both doses: (means±SEM) 0.34±0.02 mU/Kg/min vs 0.25±0.01 (5 mg) (p=0.04), and 0.24±0.01 (10 mg) (p=0.004). IGF-I (ng/ml) decreased following 10 mg [223.5±23.9 vs 154.6±28.1 (p=0.005], but not 5 mg. Mean overnight non esterified fatty acid concentrations (mmol/l) decreased with 10 mg [0.51±0.04 vs 0.38±0.04 (p=0.03)], as did -hydroxybutyrate (mmol/l); [0.31±0.04 vs 0.15±0.02 (p=0.004)]. Glycerol production rate, an index of lipolysis, was lower following 10 mg (p=0.04), but insulin sensitivity during the clamp did not change with either dose.Conclusion/interpretation Treatment with both doses of B2036-PEG reduced overnight insulin requirements. The 10 mg dose suppressed lipolysis and reduced IGF-I. Failure to show enhanced insulin sensitivity during the clamp with the 10 mg dose could reflect opposing actions of growth hormone and IGF-I.Abbreviations T1DM Type 1 diabetes mellitus - GH growth hormone - IGF-I insulin-like growth factor 1 - IGFBP-1 IGF binding protein 1 - IGFBP-3 IGF binding protein 3 - NEFA non eosterified fatty acids - OHB -hydroxybutyrate