Abdominal obesity and exaggerated postprandial lipemia are independent risk factors for cardiovas... more Abdominal obesity and exaggerated postprandial lipemia are independent risk factors for cardiovascular disease (CVD) and mortality, and both are affected by dietary behavior. We investigated whether dietary supplementation with whey protein and medium-chain saturated fatty acids (MC-SFAs) improved postprandial lipid metabolism in humans with abdominal obesity. We conducted a 12-wk, randomized, double-blinded, diet intervention study. Sixty-three adults were randomly allocated to one of 4 diets in a 2 × 2 factorial design. Participants consumed 60 g milk protein (whey or casein) and 63 g milk fat (with high or low MC-SFA content) daily. Before and after the intervention, a high-fat meal test was performed. We measured changes from baseline in fasting and postprandial triacylglycerol, apolipoprotein B-48 (apoB-48; reflecting chylomicrons of intestinal origin), free fatty acids (FFAs), insulin, glucose, glucagon, glucagon-like peptide 1 (GLP-1), and gastric inhibitory polypeptide (GIP)...
Endothelin-1 (ET-1), a potent endothelium-derived vasoconstrictor peptide, is secreted in respons... more Endothelin-1 (ET-1), a potent endothelium-derived vasoconstrictor peptide, is secreted in response to insulin. Elevated circulating ET-1 levels have been found in patients with diabetes mellitus and vascular dysfunction. The question arises whether ET-1 acts as a direct modulator of insulin secretion. To test this, we studied the effects of ET-1 on isolated mouse islets of Langerhans. ET-1 (1 nmol/l-1 Μmol/l) dose-dependently stimulated insulin secretion from islets incubated in the presence of 16.7 mmol/l glucose (p<0.05). The effect of ET-1 is glucose-dependent since no potentiation was found at 3.3 mmol/l glucose. Furthermore, ET-1 induced a large, transient increase in glucose-stimulated insulin secretion during islet perifusion in the presence (p<0.001), but not in the absence, of extracellular Ca2+. The rate of 45Ca2+-efflux from 45Ca2+-prelabelled islets was transiently stimulated by ET-1 during perifusion at 16.7 mmol/l glucose in the presence of extracellular Ca2+ (p<0.001). A short-lived increase in 45Ca2+-efflux was also observed in the absence of extracellular Ca2+ (p<0.05). It is suggested that the effects of ET-1 on insulin secretion are critically dependent on influx via Ca2+-channels. In addition, ET-1 transiently enhanced 86Rb+-efflux from 86Rb+-prelabelled islets both in the presence (p<0.001) and in the absence (p<0.001) of extracellular Ca2+ suggesting that ET-1 does not elicit insulin secretion by inhibition of the potassium permeability. Our study provides evidence that ET-1 stimulates insulin secretion via a direct effect on the islets of Langerhans.
Cardiac function was investigated by echocardiography in 24 short-term Type 1 diabetic patients w... more Cardiac function was investigated by echocardiography in 24 short-term Type 1 diabetic patients with a mean diabetes duration of 7 years (range 4–14 years) during conditions of ordinary metabolic control. Compared to 24 age and sex matched normal control subjects, measurements of myocardial contractility as left ventricular fractional shortening and mean circumferential shortening velocity were increased by 12% and 20% respectively. Another 8 Type 1 diabetic patients were examined during conditions of poor (hyperglycaemia and ketosis) and good metabolic control. Following improved glycaemic control, left ventricular fractional shortening and mean circumferential shortening velocity decreased by 16% and 24% respectively. Our findings show that short-term Type 1 diabetes is associated with increased myocardial contractility. Furthermore, this condition is related to the state of metabolic control.
Autonomic and somatosensory nerve function was studied in 24 insulin-dependent diabetic subjects ... more Autonomic and somatosensory nerve function was studied in 24 insulin-dependent diabetic subjects (aged 29 +/- 7 yrs, diabetes duration 8 +/- 4 yr) randomly allocated to either continuous subcutaneous insulin infusion (CSII; n = 12) or unchanged conventional insulin therapy (CIT; n = 12). Measures of glycemic control and somatosensory and autonomic nerve function were comparable in the two groups at the start. Glycemic control was significantly improved in the CSII group throughout study, whereas it remained unchanged in the CIT group. In the CIT group, vibratory perception threshold (VPT) of the great toe and the medial malleolus deteriorated, as did heart rate variation (HRV) at rest, at deep breathing (.05 less than P less than .06), and at standing. In contrast, CSII patients retained their VPT and HRV. Comparison of nerve function alterations during the 2-yr trial showed better preservation in CSII than in CIT patients of VPT in the great toe (0.8 +/- 1.7 vs. -1.4 +/- 1.9 V, P less than .01) and the medial malleolus (1.5 +/- 2.9 vs. -1.4 +/- 1.8 V, P less than .05) and of HRV at rest (10 +/- 24 vs. -13 +/- 22 ms, P less than .05) and at standing (-0.01 +/- 0.13 vs. -0.15 +/- 0.16 ms, P less than .05). We conclude that intensified glycemic control can favorably influence parasympathetic and somatosensory nerve function in insulin-dependent diabetes mellitus.
The appearance of microalbuminuria in diabetic patients predicts development of macroalbuminuria ... more The appearance of microalbuminuria in diabetic patients predicts development of macroalbuminuria and coronary heart disease. Autonomic dysfunction in ischaemic heart disease is related to an increased incidence of arrhythmic deaths. To assess sympathovagal balance in relation to microalbuminuria we performed 24-h spectral analysis of RR interval oscillations in 37 insulin-dependent diabetic patients. Patients were divided according to urinary albumin excretion as normo-(<20 Μg/min) (n=12), micro-(>20 and <200 Μg/min) (n=14) and macro-albuminuria (>200 Μg/min) (n=11). None had symptoms or signs of ischaemic heart disease at clinical examination or during stress testing. Fourteen matched healthy subjects served as controls. Overall RR interval variability was calculated as the 24-h standard deviation. The square root of power of the low-frequency (0.04–0.15 Hz) and high-frequency (0.15–0.40 Hz) component were considered indices of the sympathovagal interaction and vagal function, respectively. Patients with micro and macroalbuminuria had, compared to control subjects, significantly reduced 24-h standard deviation, a much smaller day/night difference in mean RR level and a significantly reduced amplitude of the low frequency and high frequency oscillations, which were even more reduced in macroalbuminuria. The differences in vagal function were also present after correction for mean RR level, and differences in physical training level and smoking. Insulin-dependent diabetic patients who develop microalbuminuria have significantly impaired vagal function and abnormal sympathovagal interaction, which is further deranged in macroalbuminuria. This early autonomic dysfunction may later contribute to a increased risk for sudden cardiac death.
Weight gain is often perceived as inevitable with insulin therapy, particularly as we strive for ... more Weight gain is often perceived as inevitable with insulin therapy, particularly as we strive for tight glycaemic control and are using increasingly proactive insulin titration regimes. The United Kingdom Prospective Diabetes Study documented that weight gain occurs most rapidly soon after insulin therapy is first initiated. The timing of this side effect is particularly undesirable, as weight gain may interfere with patients’ adjustment to insulin therapy and may undermine appropriate diabetes self-management behaviours. Until recently, many patients had little alternative other than to accept unwanted weight gain if they were to achieve sufficient glycaemic control to reduce risk of chronic complications of diabetes. Insulin detemir is a novel basal insulin analogue that has consistently been shown in randomized, controlled trials to have a weight-sparing effect (i.e. weight loss or reduced weight gain compared with other insulins) in both type 1 and type 2 diabetes. Indeed, unlike neutral protamine Hagedorn (NPH) insulin, the weight-sparing effect of insulin detemir appears to be most prominent in people who are the most obese. The mechanisms behind the weight-sparing effect of insulin detemir are still being clarified. Reduced risk of hypoglycaemia with insulin detemir, coupled with a more consistent and reliable delivery of the desired dose than is available with traditional basal insulin, such as NPH, has been proposed to minimize defensive snacking by patients, and help to limit weight gain. However, even if this was proven, it would be unlikely to fully explain the weight-sparing effect of insulin detemir. Two additional theories have been put forward. One suggests that due to its novel method of prolonging action via acylation and albumin binding, insulin detemir may differentially influence hepatocytes more than peripheral tissues, thus effectively suppressing hepatic glucose output without promoting lipogenesis in the periphery. The second theory suggests that insulin detemir may be more effective than human insulin in communicating satiety signals within the central nervous system. Further clarification of these hypotheses is required.
Abdominal obesity and exaggerated postprandial lipemia are independent risk factors for cardiovas... more Abdominal obesity and exaggerated postprandial lipemia are independent risk factors for cardiovascular disease (CVD) and mortality, and both are affected by dietary behavior. We investigated whether dietary supplementation with whey protein and medium-chain saturated fatty acids (MC-SFAs) improved postprandial lipid metabolism in humans with abdominal obesity. We conducted a 12-wk, randomized, double-blinded, diet intervention study. Sixty-three adults were randomly allocated to one of 4 diets in a 2 × 2 factorial design. Participants consumed 60 g milk protein (whey or casein) and 63 g milk fat (with high or low MC-SFA content) daily. Before and after the intervention, a high-fat meal test was performed. We measured changes from baseline in fasting and postprandial triacylglycerol, apolipoprotein B-48 (apoB-48; reflecting chylomicrons of intestinal origin), free fatty acids (FFAs), insulin, glucose, glucagon, glucagon-like peptide 1 (GLP-1), and gastric inhibitory polypeptide (GIP)...
Endothelin-1 (ET-1), a potent endothelium-derived vasoconstrictor peptide, is secreted in respons... more Endothelin-1 (ET-1), a potent endothelium-derived vasoconstrictor peptide, is secreted in response to insulin. Elevated circulating ET-1 levels have been found in patients with diabetes mellitus and vascular dysfunction. The question arises whether ET-1 acts as a direct modulator of insulin secretion. To test this, we studied the effects of ET-1 on isolated mouse islets of Langerhans. ET-1 (1 nmol/l-1 Μmol/l) dose-dependently stimulated insulin secretion from islets incubated in the presence of 16.7 mmol/l glucose (p<0.05). The effect of ET-1 is glucose-dependent since no potentiation was found at 3.3 mmol/l glucose. Furthermore, ET-1 induced a large, transient increase in glucose-stimulated insulin secretion during islet perifusion in the presence (p<0.001), but not in the absence, of extracellular Ca2+. The rate of 45Ca2+-efflux from 45Ca2+-prelabelled islets was transiently stimulated by ET-1 during perifusion at 16.7 mmol/l glucose in the presence of extracellular Ca2+ (p<0.001). A short-lived increase in 45Ca2+-efflux was also observed in the absence of extracellular Ca2+ (p<0.05). It is suggested that the effects of ET-1 on insulin secretion are critically dependent on influx via Ca2+-channels. In addition, ET-1 transiently enhanced 86Rb+-efflux from 86Rb+-prelabelled islets both in the presence (p<0.001) and in the absence (p<0.001) of extracellular Ca2+ suggesting that ET-1 does not elicit insulin secretion by inhibition of the potassium permeability. Our study provides evidence that ET-1 stimulates insulin secretion via a direct effect on the islets of Langerhans.
Cardiac function was investigated by echocardiography in 24 short-term Type 1 diabetic patients w... more Cardiac function was investigated by echocardiography in 24 short-term Type 1 diabetic patients with a mean diabetes duration of 7 years (range 4–14 years) during conditions of ordinary metabolic control. Compared to 24 age and sex matched normal control subjects, measurements of myocardial contractility as left ventricular fractional shortening and mean circumferential shortening velocity were increased by 12% and 20% respectively. Another 8 Type 1 diabetic patients were examined during conditions of poor (hyperglycaemia and ketosis) and good metabolic control. Following improved glycaemic control, left ventricular fractional shortening and mean circumferential shortening velocity decreased by 16% and 24% respectively. Our findings show that short-term Type 1 diabetes is associated with increased myocardial contractility. Furthermore, this condition is related to the state of metabolic control.
Autonomic and somatosensory nerve function was studied in 24 insulin-dependent diabetic subjects ... more Autonomic and somatosensory nerve function was studied in 24 insulin-dependent diabetic subjects (aged 29 +/- 7 yrs, diabetes duration 8 +/- 4 yr) randomly allocated to either continuous subcutaneous insulin infusion (CSII; n = 12) or unchanged conventional insulin therapy (CIT; n = 12). Measures of glycemic control and somatosensory and autonomic nerve function were comparable in the two groups at the start. Glycemic control was significantly improved in the CSII group throughout study, whereas it remained unchanged in the CIT group. In the CIT group, vibratory perception threshold (VPT) of the great toe and the medial malleolus deteriorated, as did heart rate variation (HRV) at rest, at deep breathing (.05 less than P less than .06), and at standing. In contrast, CSII patients retained their VPT and HRV. Comparison of nerve function alterations during the 2-yr trial showed better preservation in CSII than in CIT patients of VPT in the great toe (0.8 +/- 1.7 vs. -1.4 +/- 1.9 V, P less than .01) and the medial malleolus (1.5 +/- 2.9 vs. -1.4 +/- 1.8 V, P less than .05) and of HRV at rest (10 +/- 24 vs. -13 +/- 22 ms, P less than .05) and at standing (-0.01 +/- 0.13 vs. -0.15 +/- 0.16 ms, P less than .05). We conclude that intensified glycemic control can favorably influence parasympathetic and somatosensory nerve function in insulin-dependent diabetes mellitus.
The appearance of microalbuminuria in diabetic patients predicts development of macroalbuminuria ... more The appearance of microalbuminuria in diabetic patients predicts development of macroalbuminuria and coronary heart disease. Autonomic dysfunction in ischaemic heart disease is related to an increased incidence of arrhythmic deaths. To assess sympathovagal balance in relation to microalbuminuria we performed 24-h spectral analysis of RR interval oscillations in 37 insulin-dependent diabetic patients. Patients were divided according to urinary albumin excretion as normo-(<20 Μg/min) (n=12), micro-(>20 and <200 Μg/min) (n=14) and macro-albuminuria (>200 Μg/min) (n=11). None had symptoms or signs of ischaemic heart disease at clinical examination or during stress testing. Fourteen matched healthy subjects served as controls. Overall RR interval variability was calculated as the 24-h standard deviation. The square root of power of the low-frequency (0.04–0.15 Hz) and high-frequency (0.15–0.40 Hz) component were considered indices of the sympathovagal interaction and vagal function, respectively. Patients with micro and macroalbuminuria had, compared to control subjects, significantly reduced 24-h standard deviation, a much smaller day/night difference in mean RR level and a significantly reduced amplitude of the low frequency and high frequency oscillations, which were even more reduced in macroalbuminuria. The differences in vagal function were also present after correction for mean RR level, and differences in physical training level and smoking. Insulin-dependent diabetic patients who develop microalbuminuria have significantly impaired vagal function and abnormal sympathovagal interaction, which is further deranged in macroalbuminuria. This early autonomic dysfunction may later contribute to a increased risk for sudden cardiac death.
Weight gain is often perceived as inevitable with insulin therapy, particularly as we strive for ... more Weight gain is often perceived as inevitable with insulin therapy, particularly as we strive for tight glycaemic control and are using increasingly proactive insulin titration regimes. The United Kingdom Prospective Diabetes Study documented that weight gain occurs most rapidly soon after insulin therapy is first initiated. The timing of this side effect is particularly undesirable, as weight gain may interfere with patients’ adjustment to insulin therapy and may undermine appropriate diabetes self-management behaviours. Until recently, many patients had little alternative other than to accept unwanted weight gain if they were to achieve sufficient glycaemic control to reduce risk of chronic complications of diabetes. Insulin detemir is a novel basal insulin analogue that has consistently been shown in randomized, controlled trials to have a weight-sparing effect (i.e. weight loss or reduced weight gain compared with other insulins) in both type 1 and type 2 diabetes. Indeed, unlike neutral protamine Hagedorn (NPH) insulin, the weight-sparing effect of insulin detemir appears to be most prominent in people who are the most obese. The mechanisms behind the weight-sparing effect of insulin detemir are still being clarified. Reduced risk of hypoglycaemia with insulin detemir, coupled with a more consistent and reliable delivery of the desired dose than is available with traditional basal insulin, such as NPH, has been proposed to minimize defensive snacking by patients, and help to limit weight gain. However, even if this was proven, it would be unlikely to fully explain the weight-sparing effect of insulin detemir. Two additional theories have been put forward. One suggests that due to its novel method of prolonging action via acylation and albumin binding, insulin detemir may differentially influence hepatocytes more than peripheral tissues, thus effectively suppressing hepatic glucose output without promoting lipogenesis in the periphery. The second theory suggests that insulin detemir may be more effective than human insulin in communicating satiety signals within the central nervous system. Further clarification of these hypotheses is required.
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