Proportional dose-response relationship and lower within-patient variability of insulin detemir and NPH insulin in subjects with type 1 diabetes mellitus.

AIMS: This study was conducted to evaluate the dose ratio of insulin detemir and neutral protamine Hagedorn (NPH) insulin over a range of therapeutically relevant subcutaneous doses. METHODS: The study was a randomized, double-blind, crossover 24-h-iso-glycemic clamp trial in 12 C-peptide-negative type 1 diabetic patients. Each subject received, by an incomplete block design selection, two of three possible doses of insulin detemir (0.15, 0.3, 0.6 U/kg) and NPH insulin (0.15, 0.3, 0.6 IU/kg), respectively. A detailed assessment of endogenous glucose production (EGP) and glucose uptake was performed, by use of stable isotopic labeled glucose tracer (D-[6,6- (2)H (2)] glucose). RESULTS: Dose proportionality was observed within the tested dose range. Regarding unit dose ratio, 0.68 U insulin detemir equals 1 IU NPH insulin (95% CI [0.35; 1.30]). There was no statistically significant difference in effect on the area under the curve (AUC) of glucose infusion rate (GIR) (AUC (GIR)) and the maximal GIR (GIR (max)) values, when comparing U (insulin detemir) to IU (NPH insulin). The pharmacodynamic within-subject profile was lower with insulin detemir in regard to AUC (GIR 0-24 h), GIR (max) and duration of action ( P<0.05). There was a tendency for a greater reduction of EGP with insulin detemir than with NPH insulin in regard to the area over the curve (AOC) of EGP in 24 hours (AOC (EGP 0-24 h)) ( P=0.07) and minimal EPG (EGP (min)) ( P=0.02). CONCLUSIONS: These data show that insulin detemir is dose-proportional to NPH insulin in type 1 diabetic patients at clinically relevant doses. The data indicate that insulin detemir has a lower degree of within-subject variability.

Effect of pre-slaughter physiological conditions on the oxidative stability of colour and lipid during chill storage of pork.

The physiological condition of the live animal was found to significantly affect colour, lipid oxidation and water holding capacity of chill stored pork chops (M. Longissimus dorsi) in a study, where various pre-slaughter conditions were achieved by the following four treatments: (A) control; (B) subjected to treadmill exercise immediately prior to stunning; (C) given epinephrine injection 15 h prior to slaughter; and (D) given epinephrine injection 15 h before slaughter and further subjected to treadmill exercise immediately before stunning. The treatments resulted in variations in energy metabolites (glycogen, lactate, creatine phosphate, ATP) and ultimate pH (pH(u)), with the lowest pH(u) in chops from treatments A and B, and in significantly different tristimulus colour L(∗)-, a(∗)- and b(∗)-parameters, although the effect of treatment on colour was not consistent during the chill storage period of 6 days. Overall, chops from treatments A and B had significantly higher L(∗)- and b(∗)-values (were paler and less blue) than chops from C and D during storage under conditions typical for retail trade. The initial a(∗)-values were higher (redder) in chops from treatments A and B, but the colour, as judged by the a(∗)-values, was less stable in meat from these treatments compared with treatments C and D. Lipid oxidation, evaluated by thiobarbituric acid reactive substances (TBARS) in the fresh meat, and drip loss, measured after 6 days of storage, were both significantly higher in chops from treatments A and B compared to chops obtained from treatments C and D. Statistical analysis relating the pH and the level of various energy metabolites post-mortem in the individual animals to the measured quality parameters, revealed that pH(u) was the most important factor affecting product quality. In conclusion, over all product quality depends on obtaining a pH(u) in the narrow range where both meat quality parameters such as colour, lipid oxidation and drip loss as well as microbiological aspects have to be considered.

Increase in serum prorenin precedes onset of microalbuminuria in patients with insulin-dependent diabetes mellitus.

AIMS/HYPOTHESIS: The renin-angiotensin system is possibly involved in the pathogenesis of diabetic nephropathy. The most striking change in renin-angiotensin system components in blood of patients with diabetic nephropathy is an increased prorenin concentration. We investigated prospectively serum concentrations of renin-angiotensin system components and the time course of prorenin increase in normoalbuminuric diabetic patients developing microalbuminuria. METHODS: Patients (n = 199) with Type I (insulin-dependent) diabetes mellitus and normoalbuminuria at baseline were prospectively followed for 10 years. The prorenin concentrations and other variables possibly associated with the occurrence of microalbuminuria, were investigated by Cox-regression analysis. RESULTS: Of the patients 29 developed microalbuminuria. Glycated haemoglobin values were higher at baseline in these patients. Serum prorenin was similar at baseline but rose in the 29 patients before the development of microalbuminuria and was stable in patients with stable albumin excretion. Renin, angiotensinogen and angiotensin converting enzyme serum concentrations were stable in both groups. Prorenin and glycated haemoglobin were independent prognostic factors for the development of microalbuminuria. A prognostic index, based on these variables, was constructed to estimate the relative risk of developing microalbuminuria. CONCLUSIONS/INTERPRETATION: Increase in serum prorenin precedes onset of microalbuminuria in normotensive patients with insulin-dependent diabetes mellitus. High concentrations of prorenin in combination with high values of glycated haemoglobin can be used as a predictor of development of microalbuminuria.

Randomized trial on protein vs carbohydrate in ad libitum fat reduced diet for the treatment of obesity.

OBJECTIVE: To study the effect on weight loss in obese subjects by replacement of carbohydrate by protein in ad libitum consumed fat-reduced diets. DESIGN: Randomized dietary intervention study over six months comparing two ad libitum fat reduced diets (30% of total energy) strictly controlled in composition: High-carbohydrate (HC, protein 12% of total energy) or high-protein (HP, protein 25% of total energy). SETTING AND PARTICIPANTS: Subjects were 65 healthy, overweight and obese subjects (50 women, 15 men, aged 18-55 y) randomly assigned to HC (n = 25), HP (n = 25) or a control group (C, n = 15). All food was provided by self-selection in a shop at the department, and compliance to the diet composition was evaluated by urinary nitrogen excretion. MAIN OUTCOME MEASURE: Change in body weight, body composition and blood lipids. RESULTS: More than 90% completed the trial. Weight loss after six months was 5.1 kg in the HC group and 8.9 kg in the HP group (difference 3.7 kg, 95% confidence interval (CI)(1.3-6.2 kg) P < 0.001), and fat loss was 4.3 kg and 7.6 kg, respectively (difference 3.3 kg (1.1-5.5 kg) P < 0.0001), whereas no changes occurred in the control group. More subjects lost > 10 kg in the HP group (35%) than in the HC group (9%). The HP diet only decreased fasting plasma triglycerides and free fatty acids significantly. CONCLUSIONS: Replacement of some dietary carbohydrate by protein in an ad libitum fat-reduced diet, improves weight loss and increases the proportion of subjects achieving a clinically relevant weight loss. More freedom to choose between protein-rich and complex carbohydrate-rich foods may allow obese subjects to choose more lean meat and dairy products, and hence improve adherence to low-fat diets in weight reduction programs.

[Microalbuminuria as predictor of atherosclerotic cardiovascular disease in IDDM]. / Mikroalbuminuri som praediktor af aterosklerotisk kardiovaskulaer sygdom ved IDDM.

The aim of this follow-up study was to assess whether slightly elevated urinary albumin excretion, i.e., microalbuminuria, precedes development of atherosclerotic vascular disease in IDDM. Out of 259 IDDM-patients 30 developed vascular disease during 2,457 person-years. Microalbuminuria was significantly predictive of vascular disease (hazard ratio (95% confidence interval) 1.06 (1.02-1.18) per 5 mg/24 hours increase in urinary albumin excretion; p = 0.002). The predictive effect was independent of age, sex, blood pressure, tobacco smoking, serum concentrations of total-cholesterol, HDL-cholesterol, sialic acid, and von Willebrand factor, and of haemoglobin A1c, insulin dose, diabetes duration, and diabetic nephropathy (hazard ratio (95% confidence interval) 1.04 (1.01-1.08) per 5 mg/24 hours increase in urinary albumin excretion; p = 0.03). It is concluded that slightly elevated urinary albumin excretion is an independent predictor of atherosclerotic vascular disease in insulin-dependent diabetes mellitus.

Twenty-four-hour energy expenditure: the role of body composition, thyroid status, sympathetic activity, and family membership.

The present study assessed the possible familial effect in 71 healthy Caucasian siblings on each of the variables determining the inter-individual variations in energy expenditure (EE) measured under standardized conditions. We found that the 24-h EE measured in respiration chambers of 71 siblings from 32 different families was positively correlated with fat-free mass, which explained 82% of the variation between subjects (P < 0.00001). An additional 10% of the total variation was explained by differences in spontaneous physical activity (P < 0.00001), fat mass (P < 0.00001), plasma concentration of free T3 (P < 0.003), and norepinephrine (P < 0.002), whereas plasma values of epinephrine and androgen hormones did not correlate with 24-h EE. After adjustment for gender, there was a familial aggregation of both 24-h and sleeping EE, as indicated by intraclass correlation coefficients (r) of 0.44 (P < 0.02) and 0.58 (P < 0.01), respectively. The familial effect on gender-adjusted 24-h EE was explained mainly by a familial resemblance of fat-free mass (ri = 0.48; P < 0.015) and fat mass (ri = 0.40; P < 0.03), whereas spontaneous physical activity and plasma concentrations of T2 and norepinephrine did not correlate in families. It is concluded that the familial aggregation of EE in Caucasians is mediated mainly through familial resemblance of body composition; even though plasma concentrations of free T3 and norepinephrine, independent of body composition, explain an additional proportion of the variation in EE, they do not contribute to the familial correlation.

Raised serum sialic acid concentration precedes onset of microalbuminuria in IDDM. A 10-year follow-up study.

OBJECTIVE: Elevated concentrations of serum sialic acid, a potent cardiovascular risk factor in the general population, have been found in patients with IDDM and microalbuminuria. We investigated whether a coincidence exists between the increase of sialic acid concentrations and albuminuria in the transition from normoalbuminuria to microalbuminuria. Furthermore, the predictability of increased sialic acid as well as von Willebrand factor (vWF) and total and HDL cholesterol concentrations in development of persistent microalbuminuria in IDDM was investigated. RESEARCH DESIGN AND METHODS: This 10-year prospective study was carried out in a cohort of 209 IDDM patients with normoalbuminuria at baseline. RESULTS: Of the cohort, 198 patients completed the follow-up period and 27 developed persistent microalbuminuria (urinary albumin excretion rate [UAER] > or = 30 mg/24 h). A coincident increase of UAER and serum sialic acid concentration was seen before persistent microalbuminuria was diagnosed. Elevation of serum sialic acid concentrations in those who later developed microalbuminuria occurred 3 years before the diagnosis of persistent microalbuminuria. Baseline serum sialic acid concentrations were significantly higher in the group of patients who later developed microalbuminuria than in the group who remained normoalbuminuric (2.02 +/- 0.41 vs. 1.85 +/- 0.31 mmol/l [means +/- SD], P < 0.05). Baseline serum sialic acid concentration correlated significantly with HbA1c, UAER, blood pressure, total cholesterol, HDL cholesterol, and vWF and was significantly predictive for development of microalbuminuria (hazards ratio [95% CI], 3.1 [1.2-8.1]; P = 0.02) after adjustments for sex, duration of diabetes, smoking, blood pressure, vWF, total cholesterol, and HDL cholesterol. Adjustment for the effects of HbA1c and UAER, however, canceled out the predictive effect of serum sialic acid. CONCLUSIONS: UAER and serum sialic acid concentration increase coincidentally before the onset of persistent microalbuminuria. An increased serum sialic acid concentration is predictive for the onset of microalbuminuria independent of age, sex, diabetes duration, smoking, blood pressure, vWF, and total HDL cholesterol.

Cohort study of predictive value of urinary albumin excretion for atherosclerotic vascular disease in patients with insulin dependent diabetes.

OBJECTIVE: To examine whether slightly elevated urinary albumin excretion precedes development of atherosclerotic vascular disease in patients with insulin dependent diabetes independently of conventional atherogenic risk factors and of diabetic nephropathy. DESIGN: Cohort study with 11 year follow up. SETTING: Diabetes centre in Denmark. SUBJECTS: 259 patients aged 19-51 with insulin dependent diabetes of 6-34 years' duration and without atherosclerotic vascular disease or diabetic nephropathy at baseline. MAIN OUTCOME MEASURES: Baseline variables: urinary albumin excretion, blood pressure, smoking habits, and serum concentrations of total cholesterol, high density lipoprotein cholesterol, sialic acid, and von Willebrand factor. END POINT: atherosclerotic vascular disease assessed by death certificates, mailed questionnaires, and hospital records. RESULTS: Thirty patients developed atherosclerotic vascular disease during follow up of 2457 person year. Elevated urinary albumin excretion was significantly predictive of atherosclerotic vascular disease (hazard ratio 1.06 (95% confidence interval 1.02 to 1.18) per 5 mg increase in 24 hour urinary albumin excretion, P = 0.002). Predictive effect was independent of age; sex; blood pressure; smoking; serum concentrations of total cholesterol, high density lipoprotein cholesterol, sialic acid, and von Willebrand factor; level of haemoglobin A(lc); insulin dose, duration of diabetes, and diabetic nephropathy (hazard ratio 1.04 (1.01 to 1.08) per 5 mg increase

The natural course of microalbuminuria in insulin-dependent diabetes: a 10-year prospective study.

The purpose of this study was to describe the clinical course in patients followed right from the onset of microalbuminuria to the development of diabetic nephropathy. A 10-year prospective follow-up of 209 consecutive normotensive insulin-dependent diabetic patients with normal urinary albumin excretion (UAE < 30 mg 24 h-1), age 34 (18-50) years and duration of diabetes 17 (10-30) years was performed. Twenty-four-hour urinary albumin excretion was measured every 4 months, glycated haemoglobin and supine blood pressure was measured annually. Two-hundred (96%) patients completed 10 (range 5-10) years follow-up. Twenty-nine (15%) patients developed persistent microalbuminuria (UAE 30-300 mg 24 h-1). Eight of these have progressed to nephropathy and one had died of diabetic nephropathy. Multiple stepwise logistic regression analysis demonstrated baseline urinary albumin excretion (p = 0.0016) and glycated haemoglobin (p = 0.0014) but not blood pressure as predictors of development of microalbuminuria within the following 10 years. The median annual increase in urinary albumin excretion was 27 (range 17-65) % in the 29 patients developing microalbuminuria. The median duration from onset of microalbuminuria to development of nephropathy was 7 years. The prevalence of patients receiving antihypertensive treatment (BP > 140/90 mmHg) increased from 10% at onset of microalbuminuria to 45% 4 years after onset of microalbuminuria. The prevalence of patients with proliferative retinopathy increased from 7% at onset of microalbuminuria to 28% 4 years after onset of microalbuminuria.(ABSTRACT TRUNCATED AT 250 WORDS)

A nonparametric test for comparing two samples where all observations are either left- or right-censored.

The situation is considered where the status of the individuals under study is assessed only once during their lifetime, and as a consequence the observed time to an event of interest is either left- or right-censored. Nonparametric estimation of the time to event distribution is reviewed and a nonparametric two-sample test is proposed. The performance of the test is illustrated by simulations and by a numerical example.

Endothelial function and serum lipids in the course of developing microalbuminuria in insulin-dependent diabetes mellitus.

Changed endothelial function and dyslipidemia are features of insulin-dependent diabetes mellitus complicated with clinical nephropathy. The time relationship between the appearance of these abnormalities is however not well known. We have therefore studied the coincidence of microalbuminuria, endothelial dysfunction and dyslipidemia during a 10 year prospective study of 209 insulin-dependent diabetic patients with normal urinary albumin excretion. Twenty-three patients developed progressing microalbuminuria defined as a median urinary albumin excretion > 30 mg/24-h in two consecutive years and a progression rate in albuminuria higher than 5% per year. Thirty patients who remained normoalbuminuric throughout the observation period were randomly selected to obtain a control group with comparable degree of glycaemic control. The mean level of von Willebrand factor before onset of microalbuminuria tended to be higher in patients developing microalbuminuria than in the control group (NS), but there was no increase in von Willebrand factor in the patients who developed microalbuminuria. Total cholesterol did not change, but a significant decrease in high density lipoprotein cholesterol was observed in patients who developed microalbuminuria. In conclusion, the study demonstrated coincidence of microalbuminuria and decreasing high density lipoprotein cholesterol, but no coincidence between onset of microalbuminuria and endothelial dysfunction assessed by von Willebrand factor.

Relationship between blood pressure and urinary albumin excretion in development of microalbuminuria.

Two hundred nine consecutive normotensive insulin-dependent diabetic (IDDM) patients were followed prospectively from November 1982 to January 1988. Patient urinary albumin excretion rate (UAE) had to be normal (less than 30 mg/24 h) on at least two occasions before inclusion in the study. Patients were aged 18-50 yr with a duration of diabetes of 10-30 yr. UAE was measured every 4 mo, and supine blood pressure was measured annually. Two hundred five patients completed the study. Five years later, 15 patients had developed persistent microalbuminuria with median UAE greater than 30 mg/24 h for at least 2 yr (group 2), and 190 patients stayed normoalbuminuric (group 1). Although within normal range, initial UAE was significantly elevated in group 2 compared with group 1 (mean 19 mg/24 h [range 15-23 mg/24 h] vs. 11 mg/24 h [10-12], 95% confidence interval [CI], P less than 0.001). Initially, there was no difference in blood pressure between group 2 (mean systolic 122 mmHg [117-127], diastolic 80 mmHg [76-84]) and group 1 (mean 126 mmHg [124-128], 79 mmHg [78-80], 95% CI), and a significant increase in diastolic blood pressure could first be detected during the 3rd yr of persistent microalbuminuria (mean systolic 132 mmHg [124-140], diastolic 85 mmHg [81-89] vs. 128 mmHg [126-130], 79 mmHg [78-80], P less than 0.05). Initial hemoglobin A1c was significantly elevated in group 2 compared with group 1 (9.6% [8.8-10.4] vs. 8.5% [8.3-8.7], P less than 0.01).(ABSTRACT TRUNCATED AT 250 WORDS)

Elemental diet: a therapeutic approach in chronic inflammatory bowel disease.

The therapeutic effect of an elemental diet (Pepti 2000) and blended normal diet (placebo) was investigated in 43 out-patients with chronic inflammatory bowel disease (IBD); 24 with ulcerative colitis (UC) and 19 with Crohn's disease (CD), in a mild to moderate state of disease activity. A pilot study on healthy volunteers was executed to investigate palatability of the two diets. The patients were randomized in a double-blind study to the two diet regimes for 14 d. A simultaneous determination of laboratory data including plasma C3c split product and urinary excretion of 51Cr-EDTA was carried out together with a careful registration of the clinical symptoms and signs. No significant effect on the stage of clinical activity was seen in CD. A significant effect on clinical activity was obtained in both UC groups. The clinical improvement was primarily due to a decrease in number of bowel movements both in the elemental diet group and in the group of patients on the blended normal diet. The gross appearance of rectal mucosa did not improve during the study period in the Pepti 2000 or in the placebo group. The concentration of complement split products in plasma remained unchanged. 51Cr-EDTA excretion, as an expression of a leaky bowel mucosa, also remained unchanged. It was concluded that an effect on inflammation could not be demonstrated even if both diets seem to have a beneficial effect on the stage of clinical activity, especially diarrhoea, in patients with UC.

Evaluation of insulin pump treatment under routine conditions.

Sixty-six patients with insulin-dependent diabetes mellitus (IDDM) initiated insulin pump treatment under routine conditions. Four patients (6%) discontinued treatment. One patient died. 61 patients were followed for a total period of 130 patient years. A sustained decrease in HbA1c was obtained during insulin pump treatment. The frequency of the following acute side effects was: ketoacidosis 0.06 episodes per patient per year, severe hypoglycaemia 0.09 episodes per patient per year and infection at the injection site 0.06 episodes per patient per year. Insulin pump treatment was well accepted by the patients; all but one wanted to continue insulin pump treatment. The major advantages were greater quality of life, greater flexibility as to meal times and better blood glucose regulation. The major disadvantages were technical problems: blockage of the infusion system, greater treatment expenses and the large pump size. We conclude that insulin pump treatment is well accepted as long-term treatment in selected IDDM patients. The improvement in metabolic control can be sustained through several years, and the frequency of severe hypoglycaemia during pump treatment is comparable to that of conventional insulin treatment. The risk of ketoacidosis requires more attention from the physician.

Nocturnal hypoglycaemia in patients receiving conventional treatment with insulin.

The prevalence of nocturnal biochemical hypoglycaemia--that is, blood glucose concentrations below 3 mmol/l (55 mg/100 ml)--was evaluated in a random sample of 58 insulin dependent diabetics receiving twice daily insulin. Seventeen patients had at least one blood glucose value below 3 mmol/l (55 mg/100 ml) and five a value below 2 mmol/l (36 mg/100 ml) during the night. Both bedtime (2300) and fasting morning (0700) blood glucose concentrations were significantly lower in the group with nocturnal hypoglycaemia compared with the group without (p less than 0.00001). If the bedtime blood glucose concentration was below 6 mmol/l (108 mg/100 ml) the risk of nocturnal hypoglycaemia was 80% (95% confidence limits 51-96%). If the bedtime blood glucose concentration was above 6 mmol/l the likelihood of hypoglycaemia not occurring during the night was 88% (74-96%). The mean glycosylated haemoglobin A1c (HbA1c) concentration in the group with nocturnal biochemical hypoglycaemia (8.2 (range 5.0-12.4)%) was significantly lower than that in the group without (9.4(7.0-14.2)%) (p less than 0.02). The prevalence of nocturnal hypoglycaemia in the patients receiving twice daily insulin (29%) was compared with that in 15 patients receiving thrice daily insulin (47%) and was not found to be significantly different. The likelihood of this risk being greater with thrice daily insulin was, however, 88%. No patient with nocturnal biochemical hypoglycaemia woke up during the night with symptomatic hypoglycaemia. Nocturnal biochemical hypoglycaemia is common during twice daily treatment with insulin, and low values of HbA1c might be associated with a higher risk of such hypoglycaemia. The blood glucose concentration at bedtime is a significant predictor of nocturnal biochemical hypoglycaemia, and HbA1c values might be of help in identifying patients at risk.

Low maternal but normal fetal prolactin levels in cigarette smoking pregnant women.

In the 36th week of pregnancy, levels of serum prolactin (PRL) (p less than 0.01) and estriol (p less than 0.05) were significantly lower in 101 consecutive women smoking 10 cigarettes or more per day, compared with a control group of 104 non-smoking pregnant women. Cord serum PRL was not related to maternal smoking habits, whereas estriol was significantly (p less than 0.05) lower in the infants of smokers, compared with the control group. The lower PRL levels in cigarette-smoking pregnant women may be due either to a direct effect of nicotine or secondary to lower estrogen levels, and the finding may be of clinical importance in relation to lactation.

PIP: In the 36th week of pregnancy, levels of serum prolactin (PRL. p 9.01) and estriol (p 0.05) were significantly lower in 101 consecutive women smoking 10 cigarettes or more/day, compared with a control group of 104 nonsmoking pregnant women. Cord serum PRL was not related to maternal smoking habits, whereas estriol was significantly (p 0.05) lower in the infants of smokers, compared with the control group. The lower PRL levels in cigarette-smoking pregnant women may be due to either a direct effect of nicotine or secondary to lower estrogen levels, and the finding may be of clinical inportance in relation to lactation.

Effect of guar gum on 24-hour insulin requirements of insulin-dependent diabetic subjects as assessed by an artificial pancreas.

The effect of guar gum on insulin requirements, mean blood glucose (MBG), and mean amplitude of glycemic excursions (MAGE) was investigated in seven insulin-dependent diabetic subjects without endogenous insulin secretion by means of an artificial pancreas (Biostator). Fifty-four hours after the withdrawal of long-acting insulin, the patients were controlled for two consecutive days by the artificial pancreas, under standardized identical conditions, except for the ingestion of guar gum before meals on the second day. The 24-h insulin requirements were significantly reduced by 12.4% on the day with guar gum (P < 0.05). No statistically significant effects were observed on MGG and MAGE.