[Insulin pump in the treatment of adult age diabetes].
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Biomedical subjects
Publications and source records attributed to Leo Niskanen.
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In men, hypoandrogenism is associated with features of the metabolic syndrome. It is not known whether men with the metabolic syndrome are at a higher risk of developing hypogonadism. We therefore assessed whether the metabolic syndrome predicts development of hypogonadism 11 yr later in 651 middle-aged Finnish men participating in a population-based cohort study. Men with the metabolic syndrome at baseline as defined by the World Health Organization (n = 114, 20%) had a 2.6-fold increased risk of developing hypogonadism as defined by total testosterone levels less than 11 nmol/liter at the 11-yr follow-up independent of age, smoking, and other potential confounders. Further adjustment for body mass index (OR, 2.0; 95% CI, 1.1-3.8) or baseline total testosterone levels (OR, 1.9; 95% CI, 1.0-3.4) attenuated the association. The association of the metabolic syndrome with hypogonadism as defined by calculated free testosterone levels less than 225 pmol/liter was similar, but weaker. The adjusted decrease in testosterone concentrations during the 11-yr follow-up was also greater in men with than without the metabolic syndrome. Smokers had a nonsignificantly lower risk of developing hypogonadism during follow-up, whereas a decrease in smoking increased the risk of hypogonadism. The metabolic syndrome predisposes to development of hypogonadism in middle-aged men. Prevention of abdominal obesity and the accompanying metabolic syndrome in middle age may decrease the risk of hypogonadism in men, especially in those who quit smoking.
Development of hypertension has been linked to chronic low-grade inflammation. However, it is not known whether this connection is mediated by features of the metabolic syndrome or smoking, or their changes, which themselves have been linked to inflammation. We studied the predictive value of highly sensitive C-reactive protein (hs-CRP), smoking, and abdominal obesity to the development of hypertension in an 11-year follow-up of a population-based study cohort comprising 379 middle-aged normotensive men. During the follow-up, 124 men (33%) developed hypertension. Men with hs-CRP > or =3.0 mg/L were 2.8x (95% confidence interval, 1.2 to 6.6) more likely to develop hypertension than with hs-CRP <1.0 mg/L even after adjustment for features of the metabolic syndrome, lifestyle factors, and their changes. Cigarette smoking was also associated with development of hypertension independently of inflammation and other confounders. Waist girth increased more in men who quit smoking than in other men. An increase in waist girth during follow-up strongly predicted incident hypertension. The decrease in smoking was not associated with a lower risk of hypertension in age-adjusted analyses. Hypertension is preceded by low-grade chronic inflammation in middle-aged white men independently of smoking or features of the metabolic syndrome. Furthermore, smoking may be a risk factor for hypertension. Although stopping smoking is beneficial with respect to health outcomes, the subsequent increase in weight and waist girth associated with smoking cessation may offset the decrease in the risk of hypertension that one may otherwise expect.
Dietary and serum fatty acid composition has been implicated in the pathogenesis of prostate and other cancers, but findings have been conflicting. Cohort studies reporting serum fatty acid composition are lacking. We assessed the association of fatty acid composition determined from dietary records and serum with incident cancer of the prostate and any site in a population-based cohort of 2,002 middle-aged Finnish men who were free of cancer at baseline and during the first 4 years of follow-up. During 12.6 years of follow-up, 46 men developed prostate cancer and 151 any cancer. Men with proportions of serum nonesterified [risk ratio (RR) 0.28; 95% confidence intervals (CI) 0.12-0.66] and esterified linoleic acid (RR 0.37; 95% CI = 0.16-0.86) and total polyunsaturated fatty acids (RR 0.30; 95% CI = 0.12-0.71) in the upper third were less than 1/3 as likely to develop prostate cancer during follow-up. Adjustment for possible confounders like socioeconomic status, physical activity, obesity and insulin concentrations did not attenuate the association. Similar but weaker associations with any cancer were found. Dietary linoleic acid intake also tended to be inversely associated with incident prostate cancer (age-adjusted RR for the upper vs. lower third 0.55; 95% CI = 0.26-1.14, p for the trend 0.097). Substitution of linoleic acid for saturated fat in middle-aged men consuming a high saturated-fat diet may decrease the risk of prostate and other cancers, although it is possible that some of the effect may be mediated by nutrients closely associated with vegetable fats.
In elderly subjects, heart rate responses to postural change are attenuated, whereas their vascular responses are augmented. Altered strategy in maintaining blood pressure homeostasis during upright position may result from various cardiovascular changes, including age-related cardiovascular autonomic dysfunction. This exploratory study was conducted to evaluate impact of age on cardiovascular autonomic responses to head-up tilt (HUT) in healthy subjects covering a wide age range. The study population consisted of 63 healthy, normal-weight, nonsmoking subjects aged 23-77 yr. Five-minute electrocardiogram and finger blood pressure recordings were performed in the supine position and in the upright position 5 min after 70 degrees HUT. Stroke volume was assessed from noninvasive blood pressure signals by the arterial pulse contour method. Heart rate variability (HRV) and systolic blood pressure variability (SBPV) were analyzed by using spectral analysis, and baroreflex sensitivity (BRS) was assessed by using sequence and cross-spectral methods. Cardiovascular autonomic activation during HUT consisted of decreases in HRV and BRS and an increase in SBPV. These changes became attenuated with aging. Age correlated significantly with amplitude of HUT-stimulated response of the high-frequency component (r = -0.61, P < 0.001) and the ratio of low-frequency to high-frequency power of HRV (r = -0.31, P < 0.05) and indexes of BRS (local BRS: r = -0.62, P < 0.001; cross-spectral baroreflex sensitivity in the low-frequency range: r = -0.38, P < 0.01). Blood pressure in the upright position was maintained well irrespective of age. However, the HUT-induced increase in heart rate was more pronounced in the younger subjects, whereas the increase in peripheral resistance was predominantly observed in the older subjects. Thus it is likely that whereas the dynamic capacity of cardiac autonomic regulation decreases, vascular responses related to vasoactive mechanisms and vascular sympathetic regulation become augmented with increasing age.
OBJECTIVE: The goal of this study was to compare the efficacy and safety profiles of biphasic insulin aspart 30 (30% soluble insulin aspart and 70% protaminated insulin aspart [BIAsp 30]) and biphasic insulin lispro 25 (25% soluble insulin lispro and 75% neutral protamine lispro [Mix25]) used in a BID injection regimen in patients with type 2 diabetes mellitus (DM). Also assessed was patients' preference for pen device--the NovoMix 30 FlexPen /NovoLog Mix 70/30 FlexPen (FlexPen) versus the Humalog Mix25 Pen/Humalog Mix75/25 Pen (Humalog Pen). METHODS: Patients with type 2 DM receiving current insulin treatment were randomized to a multinational, multicenter, open-label, 2-period, crossover comparison of BIAsp 30 and Mix25. Efficacy (by analyses of variance) and safety profiles were assessed after 12 weeks of treatment. Patients' preference for pen device was assessed by questionnaires. RESULTS: A total of 137 patients were randomized to treatment; 4 were withdrawn during the 2-week run-in treatment with biphasic human insulin 30. The mean (SD) characteristics of the remaining 133 patients (79 men, 54 women) were as follows: age, 62.3 (9.2) years; body mass index, 28.1 (3.9) kg/m(2); and glycosylated hemoglobin (HbA(1c)), 8.5% (1.1). Glycemic control was assessed by the measurement of HbA(1c) after 12 weeks of treatment. Treatment with BIAsp 30 was noninferior to treatment with Mix25 (upper limit of 90% CI for estimated difference [BIAsp 30 - Mix25] was <0.4%). Self-monitored blood glucose levels were comparable (P = NS). Adverse-event profiles were similar between treatments, as was the incidence of hypoglycemic episodes (0.69 episode/mo with BIAsp 30 and 0.62 episode/mo with Mix25, P = 0.292). For all device features assessed, the FlexPen consistently received higher scores (all P < 0.005). A total of 9.0% of patients experienced problems with the FlexPen, compared with 32.4% with the Humalog Pen (P < 0.001). Furthermore, 74.6% preferred to continue using the FlexPen, whereas 14.3% preferred the Humalog Pen (P < 0.001). CONCLUSIONS: In this study, glycemic control with BIAsp 30 and Mix25 was found to be comparable in these patients with type 2 DM. Safety profiles were similar for both regimens. Patients preferred and experienced fewer problems with the FlexPen than the Humalog Pen.
Recent definitions of the metabolic syndrome from the World Health Organization (WHO) and National Cholesterol Education Program (NCEP) have given us a clearer picture of the prevalence of the metabolic syndrome and the risks it poses for cardiovascular disease and type 2 diabetes. Solid epidemiological and trial evidence support lifestyle changes as the main modifiable risk factors, including abdominal obesity, sedentary lifestyle and a diet rich in saturated fat and low in fiber content, in the treatment of individual components of the metabolic syndrome. Physical activity may prevent the metabolic syndrome as defined by the WHO and NCEP, but the evidence for lifestyle changes using these definitions is still sparse. No trials on the treatment of the metabolic syndrome to prevent diabetes have been published. However, both the Finnish Diabetes Prevention Study and the Diabetes Prevention Program found that moderate lifestyle interventions in persons with impaired glucose tolerance, a condition related to the metabolic syndrome. decreased the incidence of type 2 diabetes by 58%. Some drugs may also prevent diabetes. Further research on lifestyle modifications in the prevention and treatment of the metabolic syndrome, and on how best to promote lifestyle changes, is needed. In the meantime, efforts to curb obesity and overweight, increase physical activity and improve compliance with current dietary recommendations should continue.
OBJECTIVE: The Captopril Prevention Project (CAPPP) was designed as a prospective intervention trial comparing the effect of a treatment based on the angiotensin-converting enzyme (ACE) inhibitor captopril with that of a conventional diuretic and/or beta-blocker-based therapy, in 10,985 hypertensive patients. There was no difference in the primary cardiovascular morbidity and mortality endpoint. A lower incidence of diabetes mellitus during captopril treatment was observed in the whole CAPPP cohort that was non-diabetic at baseline (n = 10,413) as well as in such CAPPP patients that were previously untreated (n = 5033). METHODS AND RESULTS: A multivariate analysis of variables associated with the risk of developing diabetes in CAPPP demonstrated that glucose, body mass index (BMI), haemoglobin (Hb), age, 'SBP x Untreated' (the interaction between systolic blood pressure at baseline and newly diagnosed hypertension), cholesterol and prior antihypertensive treatment came out as risk factors. Based on these factors, a risk score for development of diabetes was calculated for all non-diabetic patients, who were divided into tertiles. For each tertile of risk, captopril therapy was associated with a reduced risk of diabetes development compared with conventional diuretic and/or beta-blocker therapy. When the non-diabetic cohort was divided into two subcohorts; previously treated and previously untreated patients, it turned out that the risk factors for developing diabetes differed between these two subcohorts. Only glucose, BMI and Hb came out as risk factors in all analysed cohorts. CONCLUSION: A captopril-based antihypertensive treatment regimen is associated with a lower risk of diabetes development, compared with conventional therapy based on diuretics and/or beta-blockers.
OBJECTIVE: In men, hypoandrogenism is associated with features of the metabolic syndrome, but the role of sex hormones in the pathogenesis of the metabolic syndrome and diabetes is not well understood. We assessed the association of low levels of testosterone and sex hormone-binding globulin (SHBG) with the development of the metabolic syndrome and diabetes in men. RESEARCH DESIGN AND METHODS: Concentrations of SHBG and total and calculated free testosterone and factors related to insulin resistance were determined at baseline in 702 middle-aged Finnish men participating in a population-based cohort study. These men had neither diabetes nor the metabolic syndrome. RESULTS: After 11 years of follow-up, 147 men had developed the metabolic syndrome (National Cholesterol Education Program criteria) and 57 men diabetes. Men with total testosterone, calculated free testosterone, and SHBG levels in the lower fourth had a severalfold increased risk of developing the metabolic syndrome (odds ratio [OR] 2.3, 95% CI 1.5-3.4; 1.7, 1.2-2.5; and 2.8, 1.9-4.1, respectively) and diabetes (2.3, 1.3-4.1; 1.7, 0.9-3.0; and 4.3, 2.4-7.7, respectively) after adjustment for age. Adjustment for potential confounders such as cardiovascular disease, smoking, alcohol intake, and socioeconomic status did not alter the associations. Factors related to insulin resistance attenuated the associations, but they remained significant, except for free testosterone. CONCLUSIONS: Low total testosterone and SHBG levels independently predict development of the metabolic syndrome and diabetes in middle-aged men. Thus, hypoandrogenism is an early marker for disturbances in insulin and glucose metabolism that may progress to the metabolic syndrome or frank diabetes and may contribute to their pathogenesis.
OBJECTIVE: We screened the human aldose reductase (ALR) gene for DNA sequence variants in type 2 diabetic and nondiabetic subjects and investigated whether the previously reported and novel polymorphisms were associated with neurophysiologic deterioration and clinical peripheral neuropathy. RESEARCH DESIGN AND METHODS: The study population included 85 Finnish type 2 diabetic and 126 nondiabetic subjects. The genetic analyses were performed using the PCR, single-strand conformation polymorphism, restriction fragment-length polymorphism, and automated laser fluorescence scanning analyses. A detailed neurologic examination and neurophysiologic analyses were performed at the time of diagnosis and at the 10-year examination. RESULTS: The genetic screening identified four polymorphisms: C-106T, C-11G, A11370G, and C19739A. The C and Z-2 alleles of the C-106T polymorphism and the previously reported (CA)(n) repeat marker were more frequent in type 2 diabetic subjects than in nondiabetic subjects. At baseline, the diabetic subjects with the T allele of the C-106T polymorphism had lower sensory response amplitude values in the peroneal (P = 0.025), sural (P = 0.007), and radial (P = 0.057) nerves and, during follow-up, a greater decrease in the conduction velocity of the motor peroneal nerve than those with the C-106C genotype. No associations were found between the polymorphisms examined and clinical polyneuropathy. CONCLUSIONS: The C-106T polymorphism of the ALR gene may contribute to an early development of neurophysiologic deterioration in type 2 diabetic patients.
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OBJECTIVE: Individual components of metabolic syndrome have been linked to an increased risk for prostate cancers. We hypothesized that metabolic syndrome itself could confer an increased risk for incident prostate cancer. METHODS: The participants were a population-based sample of 1,880 men from eastern Finland without history of cancer or diabetes mellitus at baseline. RESULTS: The metabolic syndrome (WHO criteria) was present in 357 (19%) of subjects. During an average follow-up of 13 years, a total of 183 cancers occurred, of which 56 were due to prostate cancer. The metabolic syndrome at baseline was related to a 1.9-fold (95% confidence interval, 1.1-3.5) risk of prostate cancer after adjustment for age, alcohol consumption, physical fitness, and energy, fat, fiber, calcium, vitamin E, and alpha-linolenic acid intake. The association between metabolic syndrome and risk of prostate cancer was stronger among overweight and obese men with a body mass index > or = 27 kg/m2 (adjusted relative risk, 3.0; 95% confidence interval, 1.2-7.3) than in lighter men (relative risk, 1.8; 95% confidence interval, 0.7-4.7). CONCLUSIONS: Middle-aged men with the metabolic syndrome were more likely to develop prostate cancer in this prospective population-based study. This finding suggests that efforts to curb the epidemic of overweight and sedentary lifestyle and the accompanying metabolic syndrome may decrease the risk for prostate cancer.
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OBJECTIVE: To evaluate sex hormones in premenopausal white women with metabolic syndrome (MBS). DESIGN: Cross-sectional controlled community-based study. SETTING: Pieksämäki District Health Center, Pieksämäki, Finland. PATIENT(S): Five hundred forty-three women, aged 34 to 54 years, were screened according to National Cholesterol Education Program criteria: waist >88 cm, hypertension >/=130/>/=85 mm Hg, hypertriglyceridemia >/=1.7 mmol/L, high-density lipoprotein (HDL)-cholesterol <1.3 mmol/L, and fasting glucose >/=6.1 mmol/L. Sixty-three women fulfilled at least three of the above-mentioned criteria and were enrolled. Eighty-eight age-matched women without MBS served as controls. INTERVENTION(S): None. MAIN OUTCOME MEASURES: Sex steroid levels in relation to insulin sensitivity and body composition. RESULT(S): A markedly lower insulin sensitivity index and higher free androgen index were detected in the women with MBS than in the controls. Abdominal obesity and increased diastolic blood pressure were significantly associated with high free androgen index in multiple regression analysis. CONCLUSION(S): A hyperandrogenic hormone profile appeared to be a typical feature of premenopausal female MBS even without polycystic ovary syndrome (PCOS).
OBJECTIVE: We investigated the impact of a three-amino acid deletion (12Glu9) polymorphism in the alpha(2B)-adrenergic receptor gene on autonomic nervous function. The short form (Glu(9)/Glu(9)) of the polymorphism has previously been associated with a reduced basal metabolic rate in obese subjects. Because autonomic nervous function participates in the regulation of energy metabolism, there could be a link between this polymorphism and autonomic nervous function. RESEARCH METHODS AND PROCEDURES: Data of a 10-year follow-up study with 126 nondiabetic control subjects and 84 type 2 diabetic patients were used to determine the effects of the 12Glu9 polymorphism on autonomic nervous function. A deep breathing test and an orthostatic test were used to investigate parasympathetic and sympathetic autonomic nervous function. In addition, cardiovascular autonomic function was studied using power spectral analysis of heart rate variability. RESULTS: No significant differences were found in the frequency of the 12Glu9 deletion polymorphism between nondiabetic and diabetic subjects. The nondiabetic men with the Glu(9)/Glu(9) genotype, especially those with abdominal obesity, had significantly lower total and low-frequency power values in the power spectral analysis when compared with other men. Furthermore, in a longitudinal analysis of 10 years, the decrease in parasympathetic function was greater in nondiabetic men with the Glu(9)/Glu(9) genotype than in the men with the Glu(9)/Glu(12) or Glu(12)/Glu(12) genotypes. DISCUSSION: The results of the present study suggest that the 12Glu9 polymorphism of the alpha(2B)-adrenergic receptor gene modulates autonomic nervous function in Finnish nondiabetic men. In the nondiabetic men with the Glu(9)/Glu(9) genotype, the general autonomic tone is depressed, and vagal activity especially becomes impaired with time. Furthermore, this association is accentuated by central obesity.
The effects of hypoglycaemia during hyperinsulinaemia, occurring under various pathophysiological conditions, on the cardiovascular regulatory system and vasculature are largely unknown. The aim of the present study was to investigate regulatory and haemodynamic responses to acute hyperinsulinaemia and consequent hypoglycaemia in 18 healthy subjects. Blood sampling and 5 min ECG and blood pressure recordings were performed at baseline and during the euglycaemic and hypoglycaemic phases of a hyperinsulinaemic clamp. Heart rate variability (HRV) and blood pressure variability (BPV) were assessed by using power spectral analysis, and baroreflex sensitivity (BRS) was assessed using the cross-spectral method. Stroke volume was assessed from the non-invasive blood pressure signal by the arterial pulse contour method. Euglycaemic hyperinsulinaemia did not change plasma catecholamine concentrations, HRV, BPV, BRS, heart rate, blood pressure, stroke volume, cardiac output or peripheral resistance. However, hyperinsulinaemic hypoglycaemia resulted in an 11.7-fold increase in the plasma adrenaline concentration (from 0.19+/-0.03 to 1.68+/-0.32 nmol/l; P <0.001), and a modest 1.3-fold increase in the plasma noradrenaline concentration (from 1.74+/-0.22 to 2.02+/-0.19 nmol/l; P <0.05) compared with baseline. Furthermore, we observed significant decreases in diastolic blood pressure (from 68+/-3 to 60+/-3 mmHg; P <0.05) and peripheral resistance (from 24.1+/-1.2 to 18.5+/-1.1 mmHg.min(-1) x l(-1); P <0.01). Stroke volume and cardiac output increased markedly from the euglycaemic to the hypoglycaemic period only ( P <0.01 for both). Hypoglycaemia did not influence HRV, BPV or BRS. Our findings indicate that hyperinsulinaemic hypoglycaemia is characterized by a significant increase in the plasma adrenaline concentration and by decreases in peripheral resistance and blood pressure. Counter-regulation during hyperinsulinaemic hypoglycaemia involves selective adrenomedullary sympathetic activation, and does not influence cardiac parasympathetic regulation or baroreflex control of heart rate.
OBJECTIVE: Mild hypoandrogenism in men is associated with features of the metabolic syndrome, but the association with the metabolic syndrome itself using an accepted definition has not been described. DESIGN: Men with the metabolic syndrome were identified and testosterone and sex hormone-binding globulin (SHBG) levels were determined in a population-based cohort of 1896 non-diabetic middle-aged Finnish men. RESULTS: Calculated free testosterone and SHBG were 11% and 18% lower (P<0.001) in men with the metabolic syndrome (n=345, World Health Organisation definition). After categorisation by tertiles and adjusting for age and body mass index, total and free testosterone and SHBG were inversely associated with concentrations of insulin, glucose, triglycerides, C-reactive protein (CRP) and CRP-adjusted ferritin and positively associated with high-density lipoprotein cholesterol. Men with free testosterone levels in the lowest third were 2.7 (95% confidence interval (CI) 2.0-3.7) times more likely to have the metabolic syndrome in age-adjusted analyses, and 1.7 (95% CI 1.2-2.4) times more likely even after further adjusting for body mass index. Exclusion of men with cardiovascular disease did not alter the association. The inverse association of SHBG with the metabolic syndrome was somewhat stronger. CONCLUSIONS: Low testosterone and SHBG levels were strongly associated not only with components of the metabolic syndrome, but also with the metabolic syndrome itself, independently of body mass index. Furthermore, sex hormones were associated with inflammation and body iron stores. Even in the absence of late-stage consequences such as diabetes and cardiovascular disease, subtle derangements in sex hormones are present in the metabolic syndrome, and may contribute to its pathogenesis.
OBJECTIVE: Small size at birth has been associated with components of the metabolic syndrome, but little is known about the association with the metabolic syndrome itself or whether leisure-time physical activity (LTPA) and cardiorespiratory fitness modify that association. We studied the association of size at birth with the metabolic syndrome. RESEARCH DESIGN AND METHODS: Birth weight and length, the metabolic syndrome (World Health Organization criteria), LTPA over the previous 12 months, and VO(2max) were assessed in 462 nondiabetic middle-aged Finnish men who were part of a population-based cohort study. RESULTS: Men with a ponderal index (kg/m(3)) at birth in the lower third had higher fasting insulin and glucose levels than men in the upper third in age-adjusted analyses and were at least twofold more likely to have the metabolic syndrome, even in men without cardiovascular disease. Adjustment for childhood or adult socioeconomic status or adult BMI did not attenuate the association. Thinness at birth was even more clearly associated with hyperinsulinemia and the metabolic syndrome in men engaging in <25 min/wk of vigorous LTPA and in men with a VO(2max) <28.6 ml x kg(-1) x min(-1) or <2.44 l/min. In active and fit men, however, the association was absent. CONCLUSIONS: Small size at birth was associated with the metabolic syndrome in middle-aged men already before development of diabetes or cardiovascular disease. Thinness at birth may carry with it lifelong metabolic consequences, but regular strenuous physical activity and maintenance of cardiorespiratory fitness may alleviate or eliminate those consequences.