Biomedical subjects

K Perlman

Publications and source records attributed to K Perlman.

10 recordsLinked to original sources

PubMed1991

Induction of calbindin-D 9k mRNA but not calcium transport in rat intestine by 1,25-dihydroxyvitamin D3 24-homologs.

The function and precise mechanism of regulation of calbindin-D 9k in intestine is largely unknown. It is suggested that this calcium binding protein is involved in active intestinal calcium transport and that its expression is mainly mediated by 1,25-dihydroxyvitamin D3. We examined the effect of two side chain modified analogs of 1,25-dihydroxyvitamin D3 as compared to 1,25-dihydroxyvitamin D3 itself on the regulation of the calbindin-D 9k at the mRNA level and on intestinal calcium transport in the rat. delta 22-24,24-dihomo-1,25-dihydroxyvitamin D3 at a single dose of 500, 1,000, and 2,000 pmol caused greater than 7.0-fold increase in calbindin-D 9k mRNA without stimulating intestinal calcium transport. A 10,000-pmol dose of delta 22-24,24,24-trihomo-1,25-dihydroxyvitamin D3 caused a 7.6-fold increase in calbindin-D 9k mRNA without significantly increasing intestinal absorption of calcium. In contrast, 1,25-dihydroxyvitamin D3 caused a parallel increase in calbindin-D 9k mRNA and intestinal absorption of calcium. Thus, calbindin 9k is not by itself responsible for 1,25-dihydroxyvitamin D3-mediated increase in intestinal absorption of calcium.

Animals↗

PubMed1990

24-homologated 1,25-dihydroxyvitamin D3 compounds: separation of calcium and cell differentiation activities.

A series of 24-homologated 1,25-dihydroxyvitamin D3 compounds have been chemically synthesized and studied with regard to their activity in inducing differentiation of human promyelocyte HL-60 cells to monocytes and in calcium mobilizing activity in vitamin D deficient rats. Homologation of 1,25-dihydroxyvitamin D3 or its delta 22 analogue by one or two carbons increases by 10-fold and three-carbon homologation reduces by half the activity in causing differentiation of HL-60. On the other hand, homologation causes a substantial decrease in in vivo calcium mobilization activity. The addition of each carbon at the 24-position decreases binding to the HL-60 receptor or rat intestinal receptor by 5-10-fold so that binding affinity of the trihomo compound for the receptors is 130 times less that of 1,25-dihydroxyvitamin D3. Thus, binding affinity for the receptor cannot account for the preferential activity of the 24-homologated compounds in inducing cell differentiation.

Animals↗

PubMed1990

24- and 26-homo-1,25-dihydroxyvitamin D3 analogs: potencies on in vitro bone resorption differ from those reported for cell differentiation.

It has been proposed that the stimulatory effects of 1,25-dihydroxyvitamin D on bone resorption may be mediated through actions on differentiation of marrow cells into monocytic osteoclast precursors. In human promyelocytic leukemia cells (HL-60), 24- and 26-homo-1,25-dihydroxyvitamin D3 and their delta 22 analogs and 24,24-dihomo-1,25-dihydroxyvitamin D3 are 10-fold more potent than 1,25-dihydroxyvitamin D3, and delta 22-24,24,24-trihomo-1,25-dihydroxyvitamin D3 is equipotent with 1,25-dihydroxyvitamin D3 in inducing differentiation into the monocytic phenotype. The effect of these 1,25-dihydroxyvitamin D3 analogous on resorption of fetal rat limb bones in vitro was determined in the present study. 1,25-Dihydroxyvitamin D3 was equipotent with 24-homo-1,25-dihydroxyvitamin D3, delta 22-24-homo-1,25-dihydroxyvitamin D3, 26-homo-1,25-dihydroxyvitamin D3, and delta 22-26-homo-1,25-dihydroxyvitamin D3 for in vitro bone resorption, whereas 24,24-dihomo-1,25-dihydroxyvitamin D3 and delta 22-24,24,24-trihomo-1,25-dihydroxyvitamin D3 were inactive. The failure of these analogs to show a higher bone-resorbing activity than 1,25-dihydroxyvitamin D3 were inactive. The failure of these analogs to show a higher bone-resorbing activity than 1,25-dihydroxyvitamin D3 provides evidence to suggest that the mechanism of 1,25-dihydroxyvitamin D3-induced bone resorption may not involve stimulation of monocytic cell differentiation.

Animals↗

PubMed1990

Angiotensin converting enzyme inhibitor therapy to decrease microalbuminuria in normotensive children with insulin-dependent diabetes mellitus.

It has been proposed that lowering glomerular pressure in children with insulin-dependent diabetes mellitus will reduce microalbuminuria and that this reduction may preserve renal function. We therefore conducted a double-blind, placebo-controlled, crossover trial to compare 3 months of treatment with the angiotensin converting enzyme inhibitor captopril (0.9 mg/kg/day), and 3 months of placebo administration to 12 normotensive adolescents with insulin-dependent diabetes mellitus, 11 with microalbuminuria (albumin excretion rate of 15 to 200 micrograms/min) and one with early overt nephropathy. Mean age (+/- SD) was 14.4 +/- 1.7 years, and disease duration was 5.1 +/- 2.5 years. Albumin excretion rate decreased significantly during captopril therapy (baseline 78 +/- 114 micrograms/min; mean of monthly measurements 38 +/- 55 micrograms/min vs placebo 78 +/- 140 micrograms/min; p less than 0.001). During captopril therapy, albumin excretion was reduced by 41 +/- 44% and decreased in 10 of 12 subjects, but was unchanged in two, one with a borderline albumin excretion rate (16.3 micrograms/min) and one with diabetes of short duration (2.9 years). Plasma renin activity rose significantly during captopril therapy, and mean arterial pressure decreased slightly (placebo 81 +/- 7 mm Hg; captopril 76 +/- 5 mm Hg; p = 0.004). After 3 months of captopril treatment, glomerular filtration rate and renal plasma flow did not change significantly. Hemoglobin Alc values remained stable during the study. The only side effect of captopril was diarrhea in one patient. We conclude that, in the short term, captopril is effective in decreasing albumin excretion rate in normotensive children with insulin-dependent diabetes mellitus and microalbuminuria, without significant side effects. Longer trials are indicated in an attempt to delay or prevent overt nephropathy.

Adolescent↗

PubMed1989

Severe hypoglycemia in children with insulin-dependent diabetes mellitus: frequency and predisposing factors.

We surveyed 311 children with insulin-dependent diabetes mellitus to evaluate the frequency and characteristics of those children experiencing severe hypoglycemia (defined by an episode of coma, convulsion, or both). The children and their parents completed a questionnaire, and we reviewed the hospital records to confirm reported episodes. Ninety-seven (31%) reported severe hypoglycemia, and a further 50 (16%) reported moderate hypoglycemia requiring the assistance of another person but not resulting in coma or convulsion. In 164 children (53%) there was no history of either moderate or severe hypoglycemia. Sixty-nine (22%) reported the occurrence of more than one severe hypoglycemic episode (range 2 to 20); 52 (16%) reported such an event in a single year. A total of 285 episodes were reported, 39% during sleep and 61% while awake. Children reporting such events tended to have diabetes of longer duration and be younger at the time of the first episode. Hemoglobin A1c concentration at the time closest to the severe episode was significantly lower than in children reporting no hypoglycemia. All families had been taught to use glucagon to reverse severe hypoglycemia at home, but it was available in only 80 of the 97 homes and used in only 30. These data suggest that severe hypoglycemia is common in children with insulin-dependent diabetes mellitus who are treated conventionally. Greater vigilance and education are required both to prevent and to treat severe hypoglycemia in children with insulin-dependent diabetes mellitus.

Adolescent↗

PubMed1988

Counterregulatory hormone responses preserved after long-term intravenous insulin infusion compared to continuous subcutaneous insulin infusion.

The counterregulatory hormone responses of cortisol, growth hormone, glucagon, epinephrine, norepinephrine, and dopamine to a fixed hypoglycemic stimulus (50 mg/dl for 1 h) were studied in five type I (insulin-dependent) diabetic subjects during conventional insulin therapy (CT), after 3 mo of continuous subcutaneous insulin infusion (SC), and after 3 mo of continuous intravenous insulin infusion (IV). During the two infusion periods, the overall mean levels of preprandial blood glucose (116 +/- 6 SC vs. 114 +/- 5 mg/dl IV) and glycosylated hemoglobin (6.1 +/- 2 SC vs. 5.9 +/- 2% IV) were virtually identical, but there were more hypoglycemic episodes and greater variability of preprandial blood glucose levels during SC than with IV. During the last 30 min of the hypoglycemic clamps, the mean levels of epinephrine and cortisol were significantly lower after 3 mo of SC (epinephrine, 268 +/- 80 pg/ml; cortisol, 14 +/- 1 microgram/dl) than with both CT (epinephrine 485 +/- 80 pg/ml; cortisol, 20 +/- 2 micrograms/dl) and IV (epinephrine, 443 +/- 62 pg/ml; cortisol, 19 +/- 2 micrograms/dl)(P less than .05). The mean growth hormone level was significantly (P less than .05) lower after SC (37 +/- 9 ng/ml) than after IV (79 +/- 12 ng/ml), but it did not reach statistical significance compared with CT (66 +/- 12 ng/ml). The mean glucagon, dopamine, and norepinephrine levels during the same period of hypoglycemia were not different when all treatment regimens were compared. We conclude that intensified insulin therapy with SC leads to significant blunting of the counterregulatory hormone response to hypoglycemia, whereas IV does not.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗

PubMed1987

Induction of monocytic differentiation of HL-60 cells by 1,25-dihydroxyvitamin D analogs.

1,25-Dihydroxyvitamin D3, the hormonal form of vitamin D, induces differentiation of HL-60 human promyelocytes into monocyte-like cells in vitro. We assessed the relative activity of 30 analogs of 1,25-dihydroxyvitamin D3 in inducing development of monocytic markers in HL-60 cells. The three differentiation markers assayed were nonspecific acid esterase activity, nitro blue tetrazolium reducing activity, and phagocytic capacity. Of the known metabolites of vitamin D, 1,25-dihydroxyvitamin D3 is the most active; 50% of the cells exhibit the mature phenotype following a 4-day treatment with 10(-8) M 1,25-dihydroxyvitamin D3. Removal of either the C-1 or C-25-hydroxyl group reduces activity by 2 orders of magnitude, while epimerization of the 1 alpha- to 1 beta-hydroxyl group virtually abolishes activity. Elongation of the steroidal side chain of 1,25-dihydroxyvitamin D3 by addition of one carbon at C-24 or C-26 improves the potency by an order of magnitude. Truncation of the steroidal side chain leads to a 10-fold reduction in activity for each carbon removed. Elimination of the C-26 and C-27 methyl groups reduces activity 100-fold. Analogs with short aliphatic side chains as 1 alpha-hydroxyhomo- and bishomopregnacholecalciferol have surprisingly high activity, being only 20-fold less potent than the natural hormone. The activity of most analogs in the HL-60 system parallels their known relative affinities for the well characterized 1,25-dihydroxyvitamin D3 receptor in chick intestine, providing further evidence that this function of 1,25-dihydroxyvitamin D3 is receptor mediated.

Calcitriol↗

PubMed1978

Circulating alanine production and disposal in healthy subjects.

UNLABELLED: Circulating-alanine production and disposal rates were estimated in eight healthy postabsorptive subjects by means of U-14C alanine and U-14C glucose infusions. The mean circulating-alanine production rate was 368 +/- S.E.M. 28 mumol/min. -1.8(2). Approximately 50 percent of circulating-alanine carbon exchanged rapidly with that of circulating lactate. Approximately 30 per cent of circulating alanine exchanged with protein stores. Other disposal was 29 +/- 2 per cent to circulating glucose and 40 +/- 4 per cent to oxidation. CONCLUSIONS: (1) The carbon moieties of circulating alanine and lactate are freely exchangeable. (2) Assessment of the contribution of alanine to gluconeogenesis will depend on establishing the extent to which the precursor pyruvate carbon is derived from glycolysis or from proteolysis. (3) If the principal pyruvate precursor is glycolysis, then the principal specific function of the glucose-alanine cycle appears to be ammonia transport.

Aged↗

PubMedDate not supplied

Controlled crossover study of subcutaneous and intravenous insulin infusion in type I diabetes.

Various routes of insulin infusion have been utilized to improve metabolic control in type I (insulin-dependent) diabetes. To determine the relative effectiveness of subcutaneous (SC) and intravenous (IV) systems of insulin-pump therapy, we studied five type I diabetic subjects aged 20-39 yr who were randomly assigned to a 3-mo period of either SC or IV insulin infusion and then crossed over to the alternate route for a similar period. After an initial 7- to 14-day period of in-hospital insulin-dose adjustment, all subjects were similarly followed as outpatients during both infusion periods, with a minimum of four daily preprandial self-measurements of blood glucose. Although the overall mean levels of blood glucose and HbA1c (116 +/- 6 vs. 114 +/- 5 mg/dl and 6.1 +/- 0.2 vs. 5.9 +/- 0.1% for the SC and IV systems, respectively) were similar, there was a greater incidence of low (less than 50 mg/dl) and high (greater than 180 mg/dl) preprandial blood glucose readings during SC- than during IV-pump therapy (P less than .05). Furthermore, the frequency of nocturnal and preprandial hypoglycemia was greater during SC-pump therapy (P less than .05 and P less than .02, respectively). Eight documented technical problems related to the pump and catheter occurred with the SC system, whereas 17 episodes occurred with the IV system. The number of episodes of ketosis (4 vs. 5 for SC and IV, respectively) was similar with both systems.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗

PubMedDate not supplied

Preprogrammed intravenous insulin infusion in diabetic humans: metabolic consequences of altering meal size.

New implantable, variable-rate, intravenous insulin infusion systems offer the possibility of increased dietary flexibility in the treatment of diabetes mellitus. However, the development of insulin infusion algorithms required to maintain near-normal glycemia in the presence of a nonconstant diet first requires information concerning the metabolic response to meals of varying size when the insulin dose is fixed. With this goal in mind, we studied five type I diabetics aged 16-40 yr who were treated for 3 wk with a portable intravenous insulin infusion system. Initially, the patient's usual prescribed diabetic diet was provided, and an individual waveform of insulin infusion resulting in diurnal normoglycemia was defined for each meal. Subsequently, small (12% of total daily calories) and large (36% of total daily calories) versions of the regular breakfast (24% of total daily calories) were provided without change in the insulin infusion waveforms, and the resulting metabolic profiles were studied. The overall mean fasting plasma glucose levels before the meals of varying size were not significantly different, but the incremental rises in plasma glucose with the small (31 +/- 5 mg/dl), regular (48 +/- 7 mg/dl), and large (64 +/- 5 mg/dl) breakfasts varied directly with the meal size. The subsequent mean plasma glucose levels before the regular lunch were significantly different (P less than .05) after the small (50 +/- 4 mg/dl) and large breakfasts (131 +/- 9 mg/dl), compared with the regular breakfast (81 +/- 7 mg/dl). Despite these differences, the plasma glucose levels before dinner were virtually identical. We conclude that large variations in meal size produce glycemic changes in keeping with the caloric content of the meal.(ABSTRACT TRUNCATED AT 250 WORDS)

Adolescent↗