RESUMEN
BACKGROUND: In addition to its glucose-lowering effect, metformin treatment has been suggested to improve lipidaemia in patients with type 2 diabetes. In contrast, in patients with type 1 diabetes (T1DM), information about the effect of metformin treatment on lipidaemia is limited. In this study, we report the effect of a 1-year treatment with metformin vs. placebo on plasma lipids in T1DM patients and persistent poor glycaemic control. METHODS: One hundred T1DM patients with haemoglobinA(1c) (HbA(1c)) > or =8.5% during the year before enrolment entered a 1-month run-in period on placebo treatment. Thereafter, patients were randomized (baseline) to treatment with either metformin (1000 mg twice daily) or placebo for 12 months (double masked). Patients continued ongoing insulin therapy and their usual outpatient clinical care. Outcomes were assessed at baseline and after 1 year. RESULTS: After 1 year, in those patients who did not start or stop statin therapy during the trial, metformin treatment significantly reduced total and LDL cholesterol by approximately 0.3 mmol/l compared with placebo (p = 0.021 and p = 0.018 respectively). Adjustment for statin use or known cardiovascular disease did not change conclusions. In statin users (metformin: n = 22, placebo: n = 13), metformin significantly lowered levels of LDL and non-HDL cholesterol by approximately 0.5 mmol/l compared with placebo (adjusted for changes in statin dose or agent: p = 0.048 and p = 0.033 respectively). HbA(1c) (previously reported) was not significant different between treatments. CONCLUSION: In patients with poorly controlled T1DM, at similar glycaemic levels, adjunct metformin therapy during 1 year significantly lowered levels of proatherogenic cholesterolaemia independent of statin therapy.
Asunto(s)
Colesterol/sangre , Diabetes Mellitus Tipo 1/sangre , Diabetes Mellitus Tipo 1/tratamiento farmacológico , Hipoglucemiantes/uso terapéutico , Metformina/uso terapéutico , Adulto , Femenino , Hemoglobina Glucada/análisis , Humanos , Masculino , Persona de Mediana EdadRESUMEN
OBJECTIVE: Low density lipoprotein cholesterol (LDL-C) is an independent and modifiable risk factor for development of cardiovascular disease (CVD). Postprandial lipid metabolism has been linked to CVD, but little is known about the postprandial LDL-C profile in patients with type-2 diabetes (T2DM). We aimed to study the postprandial levels of LDL-C in T2DM patients. MATERIAL AND METHODS: After an overnight fast, 74 T2DM patients, mean age approximately 60 years, were served a standard fat-rich meal of 3515 kJ containing 54% fat, 13 % protein and 33 % carbohydrates. Only drinking water was allowed postprandially. Blood samples were drawn at times 0 (fasting), 1.5, 3.0, 4.5 and 6.0 h (postprandial). In all samples, LDL-C was measured with modified beta quantification (separation by ultracentrifugation followed by measurement of infranate high density lipoprotein cholesterol (HLD-C) using a homogeneous assay). RESULTS: At all postprandial times, levels of LDL-C showed highly significant (p < 0.005) decreases compared to time 0 (mean [95% CI] maximum change in LDL-C levels at 3.0 h: -0.16 mmol/L [-0.12; -0.20]; p < 0.001). Independently of fasting LDL-C levels and ongoing statin therapy, LDL-C decreased significantly more in female compared to male patients postprandially (mean [95% CI] maximum unadjusted change versus time 0 in LDL-C for men [n=56] at 3.0 h: -0.14 mmol/L [-0.19; -0.10], p < 0.001; for women [n=18] at 4.5 h: -0.26 mmol/L [-0.35; -0.18], p < 0.001; -0.14 mmol/L [-0.24; -0.05], p = 0.005 between genders for the mean [95% CI] fasting adjusted difference at 4.5 h in the change versus time 0 in LDL-C; gender by time interaction: p = 0.007 (repeated measures mixed model)). CONCLUSIONS: In T2DM patients served a fat-rich meal, levels of LDL-C decreased significantly more in women compared to men postprandially, irrespective of fasting levels or ongoing statin therapy. This might have implications in the atherosclerotic process and on any difference in the risk of CVD between genders.
Asunto(s)
LDL-Colesterol/sangre , Diabetes Mellitus Tipo 2/sangre , Periodo Posprandial/fisiología , Complicaciones de la Diabetes/sangre , Grasas de la Dieta , Ayuno/sangre , Femenino , Humanos , Inhibidores de Hidroximetilglutaril-CoA Reductasas/uso terapéutico , Lípidos/sangre , MasculinoRESUMEN
AIM: Metformin is the 'drug-of-first-choice' in obese patients with type 2 diabetes mellitus (T2DM) due to its antihyperglycaemic and cardiovascular protective potentials. In non-obese patients with T2DM, insulin secretagogues are empirically used as first choice. In this investigator-initiated trial, we evaluated the effect of metformin vs. an insulin secretagogue, repaglinide on glycaemic regulation and markers of inflammation and insulin sensitivity in non-obese patients with T2DM. METHODS: A single-centre, double-masked, double-dummy, crossover study during 2 x 4 months involved 96 non-obese (body mass index < or = 27 kg/m(2)) insulin-naïve patients with T2DM. At enrolment, previous oral hypoglycaemic agents (OHA) were stopped and patients entered a 1-month run-in on diet-only treatment. Hereafter, patients were randomized to either repaglinide 2 mg thrice daily followed by metformin 1 g twice daily or vice versa each during 4 months with 1-month washout between interventions. RESULTS: End-of-treatment levels of haemoglobin A(1c) (HbA(1c)), fasting plasma glucose, mean of seven-point home-monitored plasma glucose and fasting levels of high-sensitivity C-reactive protein and adiponectin were not significantly different between treatments. However, body weight, waist circumference, fasting serum levels of insulin and C-peptide were lower and less number of patients experienced hypoglycaemia during treatment with metformin vs. repaglinide. Both drugs were well tolerated. CONCLUSIONS: In non-obese patients with T2DM, overall glycaemic regulation was equivalent with less hypoglycaemia during metformin vs. repaglinide treatment for 2 x 4 months. Metformin was more effective targeting non-glycaemic cardiovascular risk markers related to total and abdominal body fat stores as well as fasting insulinaemia. These findings may suggest the use of metformin as the preferred OHA also in non-obese patients with T2DM.
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Carbamatos/uso terapéutico , Diabetes Mellitus Tipo 2/complicaciones , Hiperglucemia/tratamiento farmacológico , Hipoglucemiantes/uso terapéutico , Metformina/uso terapéutico , Piperidinas/uso terapéutico , Adiponectina/sangre , Biomarcadores/análisis , Glucemia/análisis , Peso Corporal/efectos de los fármacos , Péptido C/sangre , Proteína C-Reactiva/análisis , Carbamatos/efectos adversos , Estudios Cruzados , Método Doble Ciego , Femenino , Hemoglobina Glucada/análisis , Humanos , Hiperglucemia/complicaciones , Hipoglucemiantes/efectos adversos , Insulina/sangre , Masculino , Metformina/efectos adversos , Persona de Mediana Edad , Cooperación del Paciente , Piperidinas/efectos adversos , Estudios Prospectivos , Relación Cintura-CaderaRESUMEN
BACKGROUND: Although genotyping studies suggest that hereditary haemochromatosis is one of the most common genetic disorders in white people, it is still thought of as an uncommon disease. Our aim was to test the hypothesis that hereditary haemochromatosis is a disease often overlooked in patients with late-onset type 1 diabetes mellitus, a late manifestation of untreated iron overload. METHODS: We did a retrospective study in which we genotyped for the C282Y and H63D mutations in the haemochromatosis gene in 716 unselected Danish patients who developed type 1 diabetes mellitus after age 30 years and 9174 controls from the general Danish population. We also screened for hereditary haemochromatosis by assessment of transferrin saturation. FINDINGS: More patients with diabetes (n=9, relative frequency 1.26%, 95% CI 0.58-2.37) than controls (23, 0.25%, 0.16-0.38) were homozygous for C282Y (odds ratio 4.6, 2.0-10.1, p=0.0001). These patients had unrecognised signs of haemochromatosis. Transferrin saturation and ferritin concentrations ranged from 57% to 102% and 17 microg/L to 8125 microg/L, respectively. Frequency of compound heterozygosity (C282Y/H63D) did not differ between patients with diabetes (eight) and controls (131) (odds ratio 0.8, 95% CI 0.4-1.7). Positive and negative predictive values of transferrin saturation greater than 50%, in identification of C282Y homozygosity, were 0.26 and 1.00, respectively. A saturation of less than 50% therefore excluded C282Y homozygosity, whereas a saturation of more than 50% suggested C282Y homozygosity. INTERPRETATION: Measurement of transferrin saturation followed by genetic testing could prevent liver and heart problems and improve life expectancy in patients with diabetes. Population screening before the onset of diabetes might improve the outlook of patients even further, but will be less cost effective.
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Diabetes Mellitus Tipo 1/genética , Hemocromatosis/genética , Transferrina/metabolismo , Adulto , Análisis de Varianza , Dinamarca/epidemiología , Diabetes Mellitus Tipo 1/complicaciones , Diabetes Mellitus Tipo 1/epidemiología , Femenino , Genotipo , Hemocromatosis/complicaciones , Hemocromatosis/epidemiología , Humanos , Hepatopatías/enzimología , Masculino , Persona de Mediana Edad , Prevalencia , Estudios RetrospectivosRESUMEN
Kidney function and size were studied in seven well-controlled male Type 1 (insulin-dependent) diabetic patients before and after administration of highly purified human growth hormone for one week. Glomerular filtration rate, renal plasma flow (steady state infusion technique with urinary collections using 125I-iothalamate and 131I-hippuran), kidney size (ultrasonic scanning) and urinary excretion rates of albumin and beta-2-microglobulin were measured. Highly purified growth hormone was injected subcutaneously, 2 IU in the morning and 4 IU in the evening. The growth hormone dosage applied induced an elevation in plasma growth hormone concentration from the normal level seen in these very well controlled diabetics to levels within the range previously demonstrated in normally controlled Type 1 diabetic patients. During the week of growth hormone administration, glycaemic control was maintained unchanged by increasing the insulin dose by 79 +/- 9% (mean +/- SEM). Glomerular filtration rate increased from 122 +/- 3 to 131 +/- 3 ml/min X 1.73 m2 (p less than 0.05) and renal plasma flow increased from 535 +/- 10 to 569 +/- 22 ml/min x 1.73 m2 (p less than 0.05). Kidney size changed from 128 +/- 5 to 133 +/- 5 ml/1.73 m2 (NS). Urinary excretion rates of albumin and beta-2-microglobulin were unchanged. The present findings suggest that the growth hormone elevation typically found in Type 1 diabetic patients with reasonable clinical control, contributes to the enhanced glomerular filtration rate and renal plasma flow present in that disease.
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Diabetes Mellitus/fisiopatología , Hormona del Crecimiento , Riñón/fisiopatología , Adulto , Diabetes Mellitus/patología , Tasa de Filtración Glomerular , Hormona del Crecimiento/sangre , Humanos , Riñón/patología , Masculino , Circulación RenalRESUMEN
The glucose analyser and insulin infusion modules of the Biostator were tested. The infusion system was reliable since more than 99% of the computed volume of insulin solution was delivered by the infusion pump at infusion rates above 1/100 of maximum, and no insulin was adsorbed onto infusion bags or tubing. Blood glucose results from the Biostator were compared with routine laboratory methods during long-term feedback control. Both slope (0.73) and scatter (r=0.87) around the regression line were unsatisfactory when the recommended calibration procedure was used. Tests in fasting non-diabetic subjects showed a significant correlation between the variation in Biostator glucose read-out and the plasma protein concentration in the detector outflow. In diabetics the ratio between Biostator glucose read-out and laboratory glucose determinations declined significantly with time. These observations led to the introduction of a standardization procedure based on externally determined blood glucose concentrations. During long-term feedback experiments in diabetics this procedure resulted in a significant increase in slope (0.84) but no improvement in scatter around the regression line. Repeated OGTTs revealed a set of constants for the algorithms, which enabled normal glucose tolerance to be achieved with smaller amounts of insulin.
Asunto(s)
Glucemia/análisis , Sistemas de Infusión de Insulina , Adolescente , Adulto , Diabetes Mellitus/sangre , Estudios de Evaluación como Asunto , Prueba de Tolerancia a la Glucosa , Humanos , Insulina/sangre , Matemática , Persona de Mediana Edad , Análisis de Regresión , Factores de TiempoRESUMEN
The effect of intravenous glucose infusion on glomerular filtration rate and renal plasma flow (constant infusion technique using 125I-iothalamate and 131I-hippuran) and on urinary excretion of albumin and beta-2-microglobulin were studied in ten normal subjects and seven metabolically well-controlled insulin-dependent diabetics. Following glucose infusion in normal subjects (n = 10) blood glucose increased from 4.7 +/- 0.1 to 10.9 +/- 0.4 mmol/l (SEM) (p less than or equal to 0.01). Glomerular filtration rate increased from 116 +/- 2 to 123 +/- 3 ml/mi x 1.73 m2 (p less than or equal to 0.01), while no change in renal plasma flow was seen - 552 +/- 11 versus 553 +/- 18 ml/min x 1.73 m2. Volume expansion with intravenous saline infusion in six of the normal subjects induced no changes in blood glucose or kidney function. In seven strictly controlled insulin-dependent diabetics, blood glucose values were raised from 4.6 +/- 0.4 to 16.0 +/- 0.6 mmol/l and clamped by means of an 'artificial beta cell'. Glomerular filtration rate increased in all patients, from 133 +/- 5 to 140 +/- 6 ml/min x 1.73 m2 (p less than or equal to 0.02), as did renal plasma flow from 576 +/- 26 to 623 +/- 38 ml/min x 1.73 m2 (p less than or equal to 0.02). Urinary albumin excretion remained unchanged in both normal subjects and diabetics. beta-2-microglobulin excretion rate increased significantly in the diabetics following glucose infusion, while no significant change was seen in the normal subjects. Our results show that hyperglycaemia per se contributes to the increased glomerular filtration rate and renal plasma flow in insulin-dependent diabetes.
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Diabetes Mellitus/fisiopatología , Glucosa/farmacología , Riñón/efectos de los fármacos , Adulto , Glucemia/metabolismo , Proteínas Sanguíneas/metabolismo , Tasa de Filtración Glomerular/efectos de los fármacos , Humanos , Riñón/fisiopatología , Masculino , Circulación Renal/efectos de los fármacosRESUMEN
Glomerular filtration rate (GFR), renal plasma flow (RPF) and kidney volume were measured in thirteen male subjects (mean age 30 years) with short-term insulin-dependent diabetes (mean duration of disease 2.4 years) and fourteen normal male subjects (mean age 29 years). GFR and RPF were measured by constant infusion technique using I125-iothalamate and 131I-hippuran. Kidney size was determined by means of ultrasound. GFR, RPF and kidney volume were increased in the diabetic patients compared to the normal controls, 144 versus 113 ml/min X 1.73 m2 (p less than 0.0005), 627 versus 523 ml/min X 1.73 m2 (p less than 0.0025) and 278 versus 224 ml/1.73 m2 (p less than 0.0005) respectively. Combining results from diabetic patients and controls revealed a positive correlation between kidney size and GFR (r = 0.70, p less than 0.001) and between kidney size and RPF (r = 0.61, p less than 0.001). Within the groups kidney size and RPF correlated significantly in the diabetics (p less than 0.01) and the same was found for kidney size and GFR (0.025 less than p less than 0.05), while no correlations were found in the normal group. GFR and RPF correlated in the diabetics when evaluated separately (r = 0.81, p less than 0.001) and in the controls (r = 0.73, p less than 0.001). The previous and present data suggest that the mechanisms of the elevated GFR in insulin-dependent diabetics are enhanced RPF, increased transglomerular hydrostatic pressure gradient and increased glomerular ultrafiltration coefficient. The increased kidney size is probably the main cause of the above alterations in the GFR determinants.