Optimization of evening insulin dose in patients using the short-acting insulin analog lispro

OBJECTIVE: A three-way, crossover, open-label, randomized study was designed to compare the evening and night (1800-0800) glycemic control when the evening premeal lispro dose was reduced by 20% and the bedtime basal NPH dose increased by 25%, or when the basal NPH dose was moved to before dinner at 1800, compared with the control arm on standard premeal human regular insulin and pre-bedtime NPH insulin. RESEARCH DESIGN AND METHODS: A total of 13 type 1 diabetic patients who use a premeal plus basal insulin regimen were studied on three separate days, with identical meals and snacks at the same times on each study day. On the control study day, patients received human regular insulin before dinner and NPH at bedtime in their usual doses. On another day, lispro was given before dinner with a dose reduction of 20%, and NPH at bedtime at 125% of usual dose. In the third regimen, the lispro and NPH were administered together in their usual dose before the evening meal by separate injections. The three regimens were tested in random order. RESULTS: Postprandial (1800-2200) blood glucose concentrations were lower after reduced-dose lispro compared with human regular insulin (6.0 +/- 0.3 [SEM] vs. 7.4 +/- 0.3 mmol/l, P < 0.05). Nighttime (2400-0400) blood glucose concentrations were not different (8.6 +/- 0.3 vs. 9.2 +/- 0.3 mmol/l, NS), and prebreakfast concentrations were also unchanged (7.7 +/- 0.9 vs. 8.7 +/- 0.8 mmol/l) after lispro with increased-dose NPH compared with standard insulin. By contrast, both nighttime (10.0 +/- 0.3 mmol/l, P < 0.05) and fasting glucose concentrations (10.8 +/- 0.6 mmol/l, P < 0.05) were significantly higher with dinnertime usual-dose lispro plus dinnertime usual-dose NPH compared with standard human insulin. Hypoglycemia at night (blood glucose < 3.0 mmol/l) did not differ between study days, but it was more frequent postprandially after dinner usual-dose lispro plus early NPH (2 vs. 7 patients, P = 0.062). CONCLUSIONS: With lower mealtime and higher basal bedtime insulin doses, patients using insulin lispro may be able to gain an overall improvement in evening blood glucose control without deteriorated nighttime glucose levels. Earlier basal NPH dosage alone does not ameliorate the nighttime hyperglycemia of short-acting insulin analog regimens.     

The 75-g glucose tolerance test in pregnancy: a reference range determined on a low-risk population and related to selected pregnancy outcomes

OBJECTIVE: To determine a reference range for the 75-g glucose tolerance test (GTT) in pregnancy using a group of women at low risk for gestational diabetes mellitus (GDM) and to determine the validity of this reference range by examining selected pregnancy outcomes for glucose-tolerant women with a 2-h result on the GTT up to 1.0 mmol/l below the diagnostic level for GDM compared with treated women with GDM. RESEARCH DESIGN AND METHODS: The reference range for the GTT was determined in 573 Caucasian women with an age <25 years and a BMI of <25 kg/m2. Selected pregnancy outcomes were compared between 272 treated women with GDM (diagnosed on the basis of a 2-h glucose level > or =8.0 mmol/l) and 308 women with a 2-h glucose level of 7.0-7.9 mmol/l. RESULTS: There was 95% confidence that at least 95% of all the fasting glucose levels are < or =5.1 mmol/l(92 mg/dl) and 95% confidence that at least 95% of all the 2-h glucose levels were < or =7.8 mmol/l (140 mg/dl). Treated women with GDM had a significantly reduced rate of large-for-gestational-age infants compared with glucose-tolerant women, without any increase in the rate of small-for-gestational-age infants or obstetric interventions. CONCLUSIONS: The reference range for the GTT in pregnancy should be determined on a low-risk population rather than on a total population. Consideration should be given to lowering the fasting glucose level to 5.0 mmol/l (90 mg/dl) and the 2-h level to 7.8 mmol/ (140 mg/dl). Glucose-tolerant women below this relatively low reference range have an increased rate of large-for-gestational-age infants and may benefit from treatment.     

Evaluation of a new semiautomatic electrode system for simultaneous measurement of ionized calcium and pH

The instrument (ICA 1 Radiometer, Copenhagen) measures the activity of calcium ion and hydrogen ion and displays the estimated concentration of free calcium ion (cCa2+) and pH at 37 degrees C in 110 microliter of whole blood or serum. The cCa2+ at pH 7.40 is calculated by means of a fixed relationship between cCa2+ and pH. The results are indicated on a display approximately 1 min after sample introduction. The measuring cycle plus automatic rinsing takes 3 min. The apparatus is equipped with a number of control functions. The sensitivity of the calcium electrode showed a fall from 100% to 92% over 20 weeks. The cell potential of the calcium cell showed a slow drift of--0.02 mV per day over a 20-week period while the pH cell which employs the same reference electrode showed no drift. Interference of Na+, K+, Li+, Mg2+ and H+ on the calcium measurement in whole blood is estimated to be at most +0.1%. The effect of erythrocytes on the static liquid junction potential is minimized by a special extrapolation procedure. The analytical standard deviation for cCa2+ in serum was 0.008 mmol/l within series, 0.017 mmol/l between days. The mean value for cCa2+ (at pH 7.4) in serum for 53 healthy adults was 1.249 mmol/l with a standard deviation of 0.036 mmol/l. cCa2+ in capillary blood at the actual pH from 20 healthy volunteers gave a mean value of 1.215 +/- 0.047 mmol/l (+/- 2SD) with pH 7.428 +/- 0.031 (+/- 2 SD). The slopes delta lgcCa2+/delta pH measured after equilibration at two different PCO2 values in venous blood (n = 20) and in serum (n = 104) gave a mean value of -0.221 +/- 0.040 (+/- 2 SD). The semi-automatic combined Ca2+ - pH electrode system makes the measurement of ionized calcium for clinical use a reliable and accurate analysis.     

Possible respect of patient quality of life--without reducing survival expectancy--in breast cancer treatment

The significance of sodium metabolism with respect to preeclampsia is discussed in the literature with a wide range of diverging opinions. The presented work analyses the influence of a low salt diet on the symptoms of preeclampsia and the consequences for the newborn. MATERIAL AND METHODS: 160 patients with preeclampsia between 1989 and 1993 were retrospectively studied. Serum sodium values (at hospital admission, lowest prepartal level, immediate and 3-8 days postpartum) were compared with the corresponding gestosis symptoms. RESULTS: The mean sodium serum concentration at admission was 135.6 mmol/l (lower norm: 136 mmol/l). This was significantly different from the mean lowest prepartal value of 134.9 mmol/l (p < 0.0001). Postpartum the mean fell again significantly to 134.0 mmol/l (p < 0.0001). None of the parameters for gestosis symptoms, which were investigated (diastolic blood pressure, edema, proteinuria, serum protein levels and hyperreflexia) showed any statistically significant association with the serum sodium concentration. Five patients had very low serum natrium values, 130 mmol/l, either at admission or during hospitalisation. Three of the five infants of these patients had hyponatremia; two needed sodium supplementation. CONCLUSION: There seems to be no reason supporting a low salt diet as therapy for preeclampsia, since it does not affect the symptoms and might lead to hyponatremia in the newborn.     

Dysrhythmia update: The effect of intermittent heart block on the central venous pressure trace

A prospective study of 71 patients with hyponatraemia was undertaken over an 18-month period in one surgical unit at King Edward VIII Hospital, Durban, to study the incidence and pattern of hyponatraemia. Electrolytes and urea values were measured serially in all patients. Hyponatraemia was defined as a serum sodium level of < 130 mmol/l. The incidence of hyponatraemia was 2.2%, the most common type being normovolaemic hypotonic hyponatraemia. Hyponatraemia was either mild (sodium level 120-130 mmol/l) or moderate (111-120 mmol/l). No patient had severe hyponatraemia (< 110 mmol/l). Hyponatraemia was corrected within 1-6 days using normal saline; in 73% of patients it was corrected within 24 hours. No patient developed neurological symptoms. A mortality rate of 28% was attributed to underlying illness, and hyponatraemia per se was asymptomatic in this study. Aggressive sodium correction was therefore not indicated.     

Spontaneous pregnancy toxaemia (ketosis) in sheep and the role of insulin

214 ewes suffering from pregnancy toxaemia (ketosis) were examined. Clinical signs during onset and course of disease and laboratory findings were compared between animals that survived and those which died. In the latter the onset of ketosis was earlier in pregnancy (day 143 +/- 7 vs. day 146 +/- 8) and duration of the disease was shorter (10 +/- 13 vs. 14 +/- 9 days). The animals that died showed more severe clinical signs and higher values of 3-hydroxy-butyrate (4.3 +/- 3.6 vs. 3.5 +/- 2.6 mmol/l) and cortisol (72 +/- 98 vs. 52 +/- 80 mmol/l) as well as lower values of insulin (37 + 12 vs. 3.5 + 2.6 mmol/l) and potassium (4.1 + 1.0 vs. 4.4 + 1.0 mmol/1) at onset of the disease than those which survived (all of differences with P < 0.05). Glucose levels did not differ between groups. Treated animals with glucose plus fructose infusions (n = 56) or with oral application of glucose precursors plus electrolytes (n = 126) had survival rates of 53.6% and 62.7%, respectively. Oral treatment with glucose precursors plus electrolytes and an additional subcutaneous insulin treatment (n = 15) led to an enhanced survival rate of 86.7% (P < 0.05). Low insulin levels in ketotic pregnant sheep and the therapeutic effect of insulin treatment support the hypothesis that insulin plays a causative role in the pathogenesis of ovine ketosis.     

Hormonal and reproductive influences and risk of melanoma in women

Ratiometric images of cytoplasmic Ca2+ concentration ([Ca2+]c) in individual cells were recorded simultaneously with a confocal ultraviolet-laser microscope in the Indo-1-loaded islets isolated from mice. After changes in [Ca2+]c in response to glucose or amino acids were recorded, the islet was fixed, permeabilized, and stained by the indirect immunofluorescence method against insulin or glucagon in situ; the individual cells were then identified in the focal plain identical to that used for the [Ca2+]c imaging. Almost all cells identified as insulin-positive (beta-cells) by their distinct immunofluorescence responded to the increase in glucose concentration from 3 to 11 mmol/l with an increase in [Ca2+]c. Major populations of cells (approximately 65%) identified as glucagon-positive (alpha-cells) responded to the addition of arginine (5-10 mmol/l) to 3 mmol/l glucose solution with an increase in [Ca2+]c. About half of the alpha-cells (47.6%) responded to the addition of alanine (5-10 mmol/l) to 3 mmol/l glucose solution with an increase in [Ca2+]c. In contrast, <13% of beta-cells responded to the addition of alanine (5-10 mmol/l) or arginine (5-10 mmol/l) to 3 mol/l glucose with an increase in [Ca2+]c. More than one-fourth of alpha-cells responded with an increase in [Ca2+]c when glucose concentration in perifusion solution was reduced from 11 to 0 mmol/l. These results indicate that [Ca2+]c changes in islet cells stimulated by glucose or amino acid were characteristic of the cell species, at least in the alpha- and beta-cell. This technique provides a useful tool to investigate not only the intracellular signal transduction but also the intercellular signal transmission in the intact islet.     

A fully enzymatic triglyceride determination in a continuous flow 12-channel analyzer (author's transl)

A fully enzymatic triglyceride determination utilizing enzymatic hydrolysis with a lipase-esterase mixture and subsequent enzymatic glycerol determination, has been adapted for use in a continuous flow 12-channel-analyzer. The method is linear up to 7.9 mmol/l (700 mg/100 ml). The analytical precision in the concentration range of 1.5 to 5.4 mmol/l (133 to 478 mg/100 ml) is characterized by relative standard deviations of 0.8 to 4.8%. In the lower measuring range at concentrations around 0.7 mmol/l (62 mg/100 ml) a mean relative standard deviation of 7.2% is found for 1140 measurements under routine conditions. For triglyceride concentrations of 0.9 to 7.7 mmol/80 to 680 mg/100 ml) a mean relative coefficient of verspill Q = 2.0 is determined. Bilirubin caused no observable interference in the determination. In comparison with the manual method by Eggstein & Kreutz (1966) Klin. Wochenschr. 44, 262-267) the results from the fully enzymatic method on the 12-channel-analyzer were lower by approximately 16%, corrected by an additive factor of 0.029 mmol/l (2.59 mg/100 ml). The accuracy controls with controls sera showed a difference of 10%.     

Medical, morphological and functional aspects of Greek football referees

Though the pig appears to be the islet donor of choice for grafts in diabetic patients, there may be a risk of transmission of infectious agents. In this context, we adopted a strategy of islet isolation from pigs raised and killed in specific pathogen-free (SPF) conditions as a minimum with regard to the concept of quality assurance. Accordingly, the present study investigated the function of SPF pig islets to determine whether they react qualitatively and quantitatively to nutriments, hormones and neuromediators with which they would be confronted in man and could therefore provide effective regulation during physiologic or physiopathologic situations. beta cells from 18 Large-White SPF pigs were functionally intact after 7 days in culture. Insulin stimulation indexes (SI) of 3.1 +/- 0.2, 2.2 +/- 0.1, and 4.4 +/- 0.3 were found respectively for 30 mmol/l K+, 100 mumol/l tolbutamide and 10 mmol/l theophylline. Basal insulin secretion (72.2 +/- 7.6 muU/min) had already increased significantly (p < 0.001) with 5.5 mmol/l glucose (184.2 +/- 25.5 muU/min, SI: 2.5 +/- 0.6), indicating that the threshold stimulatory concentration was comparable to that of human islets. Insulin secretion increased in a glucose dose-dependent manner (p < 0.001): SI: 3.1 +/- 0.3 and 3.6 +/- 0.2 with 11.0 mmol/l and 22.0 mmol/l glucose, which showed a satisfactory magnitude with reference to human islets. Even the subtle phenomenon of "glucose memory" was apparent in these pig islets. Arginine stimulated (p < 0.001) insulin secretion dose-dependently (SI: 2.2 +/- 0.3 with 5 mmol/l and 2.9 +/- 0.2 with 10 mmol/l). The ketone body beta-hydroxybutyrate (10 mmol/l) also induced insulin secretion (SI: 4.3 +/- 0.3). Insulin release was stimulated by 4 mumol/l gastric inhibitory peptide, revealing sensitivity to the hormonal enteroinsular axis, and by 2 mumol/l glucagon. Parasympathetic cholinergic influence was studied using 500 mumol/l carbamylcholine, which increased insulin secretion. The influence of orthosympathetic control and of stress situations was also studied. As in human islet response, epinephrine and the alpha 2-agonist clonidine (50 mumol/l) inhibited insulin secretion. Finally pre-culture of islets may be beneficial for graft outcome, provided that no deterioration in islet function occurs. A prolonged 21-day culture of SPF pig islets showed no decrease in insulin response to glucose, arginine and potassium, even with an unaltered threshold stimulatory glucose concentration. Thus, Large-White SPF pigs and the application of our isolation procedure provided islets with functional characteristics reproducibly compatible with potential utilisation for effective regulation of glycaemia under physiologic and physiopathologic situations in humans.     

Rabbit lens and retina phosphorylate glucose through a glucokinase-like enzyme: study in normal and spontaneously hyperglycemic animals

After having previously shown that some noninsulin-sensitive tissues (capillaries and optic nerve) phosphorylate glucose in a concentration-dependent manner through a glucokinase-like enzyme, here, we report data on glucose phosphorylation in rabbit lens and retina at various glucose concentrations (1, 5, 10, 25, 50, and 100 mmol/L). In the 3000 g supernatant of lens and retina homogenates from two separate groups of female albino rabbits ten animals in each group; 1.8-2.0 kg body weight; mean +/- SEM morning glycemia: 8.19 +/- 0.28 and 8.12 +/- 0.24 mmol/L, respectively) was assayed glucose phosphorylating activity (NADP reduction measured as change in optical density at 366 nm at pH 7.5). The enzyme activity did not reach the maximum at low glucose concentration (1 mmol/L), as it occurs in several tissues, but increased progressively in both tissues with the increase in glucose concentration. Values (mean +/- SEM) for lens were 0.197 +/- 0.031 nmol/min/mg protein at 1 mmol/L and 0.327 +/- 0.051 (the highest value) at 50 mmol/L glucose (+65.99%, p < 0.01; r = 0.31, p < 0.05). Values for retina were 36.02 +/- 2.12 at 1 mmol/L glucose and 42.48 +/- 2.79 (the highest value) at 25 mmol/L glucose (+17.93%, p < 0.001; r = 0.32, p < 0.05). These kinetic characteristics, somewhat reminiscent of those shown by hepatic glucokinase, are still more pronounced when we calculated the "glucokinase component," obtained by subtracting the activity at 1 mmol/L glucose (hexokinase component) from that at the highest glucose concentration (total glucose phosphorylating activity). In five rabbits of similar age and weight, with spontaneous hyperglycemia (mean +/- SEM morning glycemia: 11.71 +/- 0.60) glucose phosphorylation in the retina was lower than normal, value at pH 7.5 and 1 mmol/L glucose being 24.52 +/- 2.20 versus 36.02 +/- 2.12 of normal animals (-31.93%, p < 0.01). This, if occurs also in other tissues, could contribute to the hyperglycemia by reducing glucose utilization. In these animals, however, the glucose phosphorylating activity retained the responsivity to increasing glucose concentrations, with value at 100 mmol/L of 28.65 +/- 2.10, corresponding to + 16.84% over the value at 1 mmol/L (p < 0.01). Therefore, the actual glucose phosphorylation in the retina of these animals would depend both upon the enzyme level (which is reduced) and glucose concentration (which is increased). Due to the in vivo inhibition of the hexokinase component by glucose 6-phosphate, the glucokinase component in retina and lens may be predominant in vivo, making the stimulating effect of hyperglycemia much more important than it would appear from our in vitro data. This might play a role in the chronic diabetic complications.     

Comparative studies on the substrate specificity of lecithin:cholesterol acyltransferase towards the molecular species of phosphatidylcholine in the plasma of 14 vertebrates

We have studied, in a prospective blinded fashion, the effects of regular and extended-release gemfibrozil on plasma lipoprotein and apolipoprotein (apo) levels in hypercholesterolemic subjects with decreased high density lipoprotein (HDL) cholesterol (C) levels. Study participants were men and women 19 to 80 years of age with baseline plasma low density lipoprotein (LDL) C levels > or = 4.5 mmol/l (175 mg/dl), HDL-C levels < or = 1.2 mmol/l (45 mg/dl), and triglyceride levels < or = 3.4 mmol/L (300 mg/dl). All subjects were stabilized on a diet for eight weeks prior to entry into two different protocols. In the first protocol 229 subjects were randomized to placebo or extended-release gemfibrozil (1200 mg/day) for 3 months (placebo trial). In the second protocol 655 subjects were randomized to regular or extended-release gemfibrozil (1200 mg/day) for 6 months (equivalency trial). Changes in lipids and apos were stratified by baseline HDL-C levels (< 0.9 mmol/l, and 0.9-12.2 mmol/l). In both studies, treatment with gemfibrozil, either regular or extended-release, was associated with significant (P < 0.05) decreases in plasma very low density lipoprotein (VLDL) C and triglyceride levels of 42-45% and 33-37%, respectively, in subjects with HDL-C level < 0.9 mmol/l, and of 38-47% and 32-39%, respectively, in patients with HDL-C levels of 0.9-1.2 mmol/l. Modest reductions from baseline in directly measured LDL-C levels were observed in both groups (3-6% and 8-9%, respectively). These reductions were less than those observed for calculated LDL-C (7-10% and 11%, respectively). For apo B, reductions were 11-14% and 16-17% in the two groups. HDL-C, apo A-I, and apo A-II levels increased by 15-16%, 5-6%, and 21-25%, respectively, in patients with HDL-C < 0.9 mmol/l, and by 6-7%, 2-3%, and 19-22%, respectively, in patients with HDL-C of 0.9-1.2 mmol/l. These differences in HDL-C levels reached statistical significance in the equivalency trial (P < 0.0001) and were independent of baseline triglyceride levels. Our data indicate that gemfibrozil, either regular or extended-release, is highly effective in lowering plasma triglyceride levels and increases HDL-C levels by approximately 15% in hypercholesterolemic patients with low HDL-C levels (< 0.9 mmol/l). Moreover, this agent lowers VLDL-C somewhat more than triglyceride, resulting in an underestimation of calculated VLDL-C reductions and in an overestimation of calculated LDL-C reductions. This agent also raises apo A-II levels much more than apo A-I levels.     

Hyperkalemia in hospitalized patients treated with trimethoprim-sulfamethoxazole

OBJECTIVE: To determine the effect of standard-dose trimethoprim-sulfamethoxazole on serum potassium concentration in hospitalized patients. DESIGN: Prospective chart review. SETTING: Community-based teaching hospital. PATIENTS: 105 patients with various infections were hospitalized and treated. Eighty patients treated with standard-dose trimethoprim-sulfamethoxazole (trimethoprim, < or = 320 mg/d; sulfamethoxazole, < or = 1600 mg/d) composed the treatment group; 25 patients treated with other antibiotic agents served as the control group. MEASUREMENTS: Serum sodium, potassium, and chloride concentrations; serum carbon dioxide content; anion gap; blood urea nitrogen level; and serum creatinine level. RESULTS: The serum potassium concentration in the treatment group (mean +/- SD) was 3.89 +/- 0.46 mmol/L (95% CI, 3.79 to 3.99 mmol/L), and it increased by 1.21 mmol/L (CI, 1.09 to 1.32 mmol/L) 4.6 +/- 2.2 days after trimethoprim-sulfamethoxazole therapy was initiated. Blood urea nitrogen levels increased from 7.92 +/- 5.7 mmol/L (CI, 6.67 to 9.16 mmol/L) to 9.2 +/- 5.8 mmol/L (CI, 7.9 to 10.5 mmol/L), and serum creatinine levels increased from 102.5 +/- 49.5 mumol/L (CI, 91.4 to 113.6 mumol/L) to 126.1 +/- 70.7 mumol/L (CI, 110.3 to 141.9 mumol/L). Patients with a serum creatinine level of 106 mumol/L (1.2 mg/dL) or more developed a higher peak potassium concentration (5.37 +/- 0.59 mmol/L [CI, 5.15 to 5.59 mmol/L]) than patients with a serum creatinine level of less than 106 mumol/L (4.95 +/- 0.48 mmol/L [CI, 4.80 to 5.08 mmol/L]). Patients with diabetes had a slightly higher peak potassium concentration (5.14 +/- 0.45 mmol/L [CI, 4.93 to 5.39 mmol/L]) than did patients without diabetes (5.08 +/- 0.59 mmol/L [CI, 4.93 to 5.23 mmol/L]), but the difference was not statistically significant. The serum potassium concentration in the control group was 4.33 +/- 0.45 mmol/L (CI, 4.15 to 4.51 mmol/L), and it decreased nonsignificantly over 5 days of therapy. CONCLUSIONS: Standard-dose trimethoprim-sulfamethoxazole therapy used to treat various infections leads to an increase in serum potassium concentration. A peak serum potassium concentration greater than 5.0 mmol/L developed in 62.5% of patients; severe hyperkalemia (peak serum potassium concentration > or = 5.5 mmol/L) occurred in 21.2% of patients. Patients treated with standard-dose trimethoprim-sulfamethoxazole should be monitored closely for the development of hyperkalemia, especially if they have concurrent renal insufficiency (serum creatinine level > or = 106 mumol/L).     

Serum cholesterol concentration and death from suicide in men: Paris prospective study I

OBJECTIVE: To investigate whether low serum cholesterol concentration or changing serum cholesterol concentration is associated with risk of suicide in men. DESIGN: Cohort study with annual repeat measurements of serum cholesterol concentration (for up to four years). SETTING: Paris, France. SUBJECTS: 6393 working men, aged 43-52 in 1967-72, who had at least three measurements of serum cholesterol concentration. MAIN OUTCOME MEASURES: Individual change over time in serum cholesterol concentration (estimated using within person linear regression method); death from suicide during average of 17 years' follow up after last examination. RESULTS: 32 men committed suicide during follow up. After adjustment for age and other factors, relative risk of suicide for men with low average serum cholesterol concentration (< 4.78 mmol/l) compared with those with average serum cholesterol concentration of 4.78-6.21 mmol/l was 3.16 (95% confidence interval 1.38 to 7.22, P = 0.007). Men whose serum cholesterol concentration decreased by more than 0.13 mmol/l a year had multivariate adjusted relative risk of 2.17 (0.97 to 4.84, P = 0.056) compared with those whose cholesterol remained stable (change of < or = 0.13 mmol/l a year). CONCLUSION: Both low serum cholesterol concentration and declining cholesterol concentration were associated with increased risk of death from suicide in men. Although there is some evidence in favour of a concomitant rather than a causal effect for interpreting these associations, long term surveillance of subjects included in trials of lipid lowering treatments seems warranted.     

Reduced beta-adrenergic sensitivity in patients with type 1 diabetes and hypoglycemia unawareness

OBJECTIVE: We tested the hypothesis that impaired tissue sensitivity to catecholamines contributes to hypoglycemia unawareness in subjects with type 1 diabetes. RESEARCH DESIGN AND METHODS: A total of 21 subjects with type 1 diabetes underwent a standardized insulin infusion protocol to produce a stepwise decrease in plasma glucose to 45-min plateaus of 4.3, 3.6, 3.0, and 2.3 mmol/l. Glycemic thresholds, maximum responses for adrenergic and neuroglycopenic symptoms, and counterregulatory hormones were determined. Patients were classified as hypoglycemia unaware if the initiation of adrenergic symptoms occurred at a plasma glucose level 2 SD below that of nondiabetic volunteers. beta-Adrenergic sensitivity was measured as the dose of isoproterenol required to produce an increment in heart rate of 25 beats per minute above baseline (I25) in resting subjects. RESULTS: Subjects with type 1 diabetes and hypoglycemia unawareness experienced the onset of adrenergic symptoms at a lower plasma glucose level than did those with awareness (2.5+/-0.1 vs. 3.7+/-0.1 mmol/l, P < 0.001), whereas neuroglycopenic symptoms occurred at similar glucose levels (2.7+/-0.2 vs. 2.8+/- 0.1 mmol/l). The plasma glucose levels for counterregulatory hormone secretion (epinephrine 2.9+/-0.2 vs. 4.1+/-0.2 mmol/l; norepinephrine 2.7+/-0.1 vs. 3.2+/-0.2 mmol/l; cortisol 2.5+/-0.2 vs. 3.3+/-0.2 mmol/l, P < 0.01) were also lower in subjects with unawareness. The maximal epinephrine (1,954+/-486 vs. 5,332+/- 1,059 pmol/l, P < 0.01), norepinephrine (0.73 +/- 0.14 vs. 1.47+/-0.21 nmol/l, P = 0.04), and cortisol (276+/-110 vs. 579+/-83 nmol/l, P < 0.01) responses were reduced in the unaware group. I25 was greater in unaware subjects than in subjects without unawareness (1.5+/-0.3 vs. 0.8+/-0.2 microg), where I25 was not different from that of controls (0.8 +/-0.2 microg). CONCLUSIONS: We conclude that subjects with type 1 diabetes and hypoglycemia unawareness have reduced beta-adrenergic sensitivity, which may contribute to their impaired adrenergic warning symptoms during hypoglycemia.     

Effect of sodium in a rehydration beverage when consumed as a fluid or meal

To investigate the impact of fluid composition on rehydration effectiveness, 30 subjects (15 men and 15 women) were studied during 2 h of rehydration after a 2.5% body weight loss. In a randomized crossover design, subjects rehydrated with water (H2O), chicken broth (CB: 109.5 mmol/l Na, 25.3 mmol/l K), a carbohydrate-electrolyte drink (CE: 16.0 mmol/l Na, 3.3 mmol/l K), and chicken noodle soup (Soup: 333.8 mmol/l Na, 13.7 mmol/l K). Subjects ingested 175 ml at the start of rehydration and 20 min later; H2O was given every 20 min thereafter for a total volume equal to body weight loss during dehydration. At the end of the rehydration period, plasma volume was not significantly different from predehydration values in the CB (-1.6 +/- 1.1%) and Soup (-1.4 +/- 0.9%) trials. In contrast, plasma volume remained significantly (P < 0.01) below predehydration values in the H2O (-5.6 +/- 1.1%) and CE (-4.2 +/- 1.0%) trials after the rehydration period. Urine volume was greater in the CE (310 +/- 30 ml) than in the CB (188 +/- 20 ml) trial. Urine osmolality was higher in the CB and Soup trials than in the CE trial. Urinary sodium concentration was higher in the Soup and CB trials than in the CE and H2O trials. These results provide evidence that the inclusion of sodium in rehydration beverages, as well as consumption of a sodium-containing liquid meal, increases fluid retention and improves plasma volume restoration.     

Muscle glycogen accumulation after endurance exercise in trained and untrained individuals

Muscle glycogen accumulation was determined in six trained cyclists (Trn) and six untrained subjects (UT) at 6 and either 48 or 72 h after 2 h of cycling exercise at approximately 75% peak O2 uptake (VO2 peak), which terminated with five 1-min sprints. Subjects ate 10 g carbohydrate . kg-1 . day-1 for 48-72 h postexercise. Muscle glycogen accumulation averaged 71 +/- 9 (SE) mmol/kg (Trn) and 31 +/- 9 mmol/kg (UT) during the first 6 h postexercise (P < 0.01) and 79 +/- 22 mmol/kg (Trn) and 60 +/- 9 mmol/kg (UT) between 6 and 48 or 72 h postexercise (not significant). Muscle glycogen concentration was 164 +/- 21 mmol/kg (Trn) and 99 +/- 16 mmol/kg (UT) 48-72 h postexercise (P < 0.05). Muscle GLUT-4 content immediately postexercise was threefold higher in Trn than in UT (P < 0.05) and correlated with glycogen accumulation rates (r = 0.66, P < 0.05). Glycogen synthase in the active I form was 2.5 +/- 0.5, 3.3 +/- 0.5, and 1.0 +/- 0.3 micromol . g-1 . min-1 in Trn at 0, 6, and 48 or 72 h postexercise, respectively; corresponding values were 1.2 +/- 0.3, 2.7 +/- 0.5, and 1.6 +/- 0.3 micromol . g-1 . min-1 in UT (P < 0.05 at 0 h). Plasma insulin and plasma C-peptide area under the curve were lower in Trn than in UT over the first 6 h postexercise (P < 0.05). Plasma creatine kinase concentrations were 125 +/- 25 IU/l (Trn) and 91 +/- 9 IU/l (UT) preexercise and 112 +/- 14 IU/l (Trn) and 144 +/- 22 IU/l (UT; P < 0.05 vs. preexercise) at 48-72 h postexercise (normal: 30-200 IU/l). We conclude that endurance exercise training results in an increased ability to accumulate muscle glycogen after exercise.     

Effect of duodenal glucose infusion on blood glucose concentration in endotoxin-treated calves

The effect of endotoxemia on the intestinal absorption of glucose was evaluated in nine experiments performed on seven 3- to 5-week-old calves fitted with a duodenal cannula. An intraduodenal glucose load trial (infusion of 2 g glucose/kg b.w. as a 10% aqueous solution through the cannula over 60 min) was conducted in a group of 5 calves three times during the 4-day period: 48 h before and at 2 and 24 h after i.v. injection of E. coli 0111:B4 endotoxin (LPS) at a dose of 0.1 microgram/kg b.w. Control calves were treated similarly but instead of glucose they were infused intraduodenally with deionised water at a volume of 20 ml/kg b.w. In trial with glucose load performed 48 h before LPS administration, blood glucose concentration increased during the absorptive phase from 4.32 +/- 0.32 mmol/l to 11.45 +/- 0.87 mmol/l at 60 min and then decreased to a minimum value of 3.16 +/- 0.51 mmol/l at 240 min. During the initial phase of endotoxemia, blood glucose concentration did not change from baseline values in both groups of calves. Glucose concentration in control calves started to decrease at 165 min reaching a minimum value of 1.39 +/- 0.17 mmol/l at 210 min and then increased to 2.44 +/- 0.11 mmol/l at 480 min after LPS administration. The intraduodenal infusion of glucose at 2 h after LPS administration resulted in an increase in blood glucose concentration during the absorptive phase only in one calf. Blood glucose concentration in this calf increased between 30 and 90 min reaching a maximum value of 7.19 mmol/l at 60 min, and then decreased to a minimal value of 0.94 mmol/l at 180 min after glucose load. In the remaining four calves in this group, blood glucose concentration ranged from 3.89 +/- 0.37 mmol/l to 4.48 +/- 0.45 mmol/l up to 120 min, and then steadily decreased to a minimal value of 2.41 +/- 0.41 mmol/l at 300 min. In trial with glucose load performed 24 h after LPS administration, the rate of entry of glucose into the circulation during the absorptive phase was similar to that observed in the trial performed 48 h before LPS administration. In conclusion, these results indicate that endotoxemia impairs the intestinal absorption of glucose in calves. The magnitude of the absorption disturbance may vary in individual calves, and the inhibitory effect of LPS on the intestinal glucose absorption lasts less than 24 h.     

Optimal provision of daytime NPH insulin in patients using the insulin analog lispro

OBJECTIVE: Insulin lispro improves early postprandial blood glucose control but can result in late interprandial hyperglycemia. As an approach to resolving this problem, we performed a randomized, crossover study with four treatment arms, comparing the daytime metabolic profile after either premeal lispro alone or premeal lispro with optimal daytime NPH insulin and with standard human regular insulin. RESEARCH DESIGN AND METHODS: Twelve C-peptide negative type 1 diabetic patients were studied on four separate study days, at least 7 days apart. On each study day, patients received one of the four study insulin treatments, in random order, with identical meals and snacks. The four treatments were 1) premeal human regular insulin before lunch and supper at unchanged dose; 2) premeal lispro (unchanged dose) at lunchtime and dinner; 3) pre-lunch reduced-dose lispro (70%) before lunch and supper with supplemental lunchtime NPH and with a 6-h interval until dinner; and 4) pre-lunch reduced-dose lispro (70%) before lunch and supper with supplemental lunchtime NPH and with a 8-h interval until dinner. All patients were using their usual premeal plus basal insulin regimen during the period of the study, with human regular insulin before meals and NPH insulin at bedtime. RESULTS: Postprandial blood glucose concentrations (1230-1500) were lower after reduced or usual lispro dose compared with human regular insulin (5.5+/-0.2 and 5.6+/-0.2 vs. 8.2+/-0.5 mmol/l, P < 0.001), with no difference between the lispro doses. However, prepran-Dial (1800) blood glucose levels deteriorated to higher levels after usual-dose lispro alone compared with either human regular insulin (P < 0.05) or reduced-dose lispro plus NPH (P < 0.05) (8.9+/-0.3 vs. 7.1+/-0.8 and 6.4+/-0.4 mmol/l), with no difference between human regular insulin and reduced-dose lispro plus NPH. During the 2 h between the usual and delayed mealtime, blood glucose concentrations remained controlled on lispro plus NPH (2000: 6.5+/-0.4 mmol/l). CONCLUSIONS: Reduced-dose lunchtime lispro plus NPH maintained the improvement in postprandial blood glucose control with no deterioration in interprandial blood glucose control, even up to a late meal.     

Effects of changing diagnostic criteria on the risk of developing diabetes

OBJECTIVE: The American Diabetes Association (ADA) has recommended that the fasting plasma glucose (FPG) level used to diagnose diabetes be changed from 7.8 mmol/l (the level recommended by the National Diabetes Data Group [NDDG] in 1979) to 7.0 mmol/l. We examined the impact of this change on rates of progression to overt diabetes from different levels of FPG. RESEARCH DESIGN AND METHODS: Using the laboratory database of Mayo Clinic, we assembled a cohort of 8,098 nondiabetic Olmsted County residents 40 years of age or older on 1 July 1983. Subjects were followed for a median of 9 years. RESULTS: Among 7,567 individuals with follow-up FPG data, 778 (10.3%) progressed to ADA diabetes and 513 (6.8%; P < 0.0001) progressed to NDDG diabetes. The risk of developing ADA diabetes was 7, 19, and 39% for individuals with initial FPG values in the ranges of <5.6, 5.6-6.0, and 6.1-6.9 mmol/l, respectively. For progression to NDDG diabetes, the respective risks were 3, 11, and 25%. A clear gradient of risk was observed within the "normal" range of FPG (<5.6 mmol/l). Among the 793 individuals who developed ADA diabetes, 222 (29%) developed NDDG diabetes simultaneously and 291 (37%) developed NDDG diabetes later. In all FPG subgroups, progression to ADA diabetes occurred approximately 7 years sooner than progression to NDDG diabetes. CONCLUSIONS: The baseline level of FPG is a major predictor of an individual's risk of developing diabetes. The proposed change in the diagnostic criteria for diabetes will lead to earlier diagnosis among individuals who are destined to develop the disease.     

Sulphide impairment of substrate oxidation in rat colonocytes: a biochemical basis for ulcerative colitis?

1. Isolated colonic epithelial cells of the rat were incubated for 40 min with [6-14C]glucose and n-[1-14C]butyrate in the presence of 0.1-2.0 mmol/l NaHS, a concentration range found in the human colon. Metabolic products, 14CO2, acetoacetate, beta-hydroxybutyrate and lactate, were measured and injury to cells was judged by diminished production of metabolites. 2. Oxidation of n-butyrate to CO2 and acetoacetate was reduced at 0.1 and 0.5 mmol/l NaHS, whereas glucose oxidation remained unimpaired. At 1.0-2.0 mmol/l NaHS, n-butyrate and glucose oxidation were dose-dependently reduced at the same rate. 3. To bypass short-chain acyl-CoA dehydrogenase activity necessary for butyrate oxidation, ketogenesis from crotonate was measured in the presence of 1.0 mmol/l NaHS. Suppression by sulphide of ketogenesis from crotonate (-10.5 +/- 6.1%) compared with control conditions was not significant, whereas suppression of ketogenesis from n-butyrate (-36.00 +/- 5.14%) was significant (P = < 0.01). Inhibition of FAD-linked oxidation was more affected by NaHS than was NAD-linked oxidation. 4. L-Methionine (5.0 mmol/l) significantly redressed the impaired beta-oxidation induced by NaHS. Methionine equally improved CO2 and ketone body production, suggesting a global reversal of the action of sulphide. 5. Sulphide-induced oxidative changes closely mirror the impairment of beta-oxidation observed in colonocytes of patients with ulcerative colitis. A hypothesis for the disease process of ulcerative colitis is that sulphides may form persulphides with butyryl-CoA, which would inhibit cellular short-chain acyl-CoA deHydrogenase and beta-oxidation to induce an energy-deficiency state in colonocytes and mucosal inflammation.