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Biomedical subjects

O Kolterman

Publications and source records attributed to O Kolterman.

10 recordsLinked to original sources
PubMed1992

Recovery and hypersecretion of insulin and reversal of insulin resistance after withdrawal of short-term cyclosporine treatment.

We have previously demonstrated decreased insulin release and insulin resistance in dogs treated with cyclosporine (20 mg/kg/day). In this study we examine the changes caused by a lower CsA dose and evaluate the reversal of these changes. Six animals were treated for 2 weeks with oral CsA (15 mg/kg/day), after which CsA was discontinued. Glucagon stimulation tests (GST) and euglycemic clamp studies (ECS) were used to evaluate changes in insulin release and insulin resistance. GST were performed before CsA, after 2 weeks of CsA, and 3, 9, and 15 days after discontinuing CsA. ECS were performed before CsA, after 2 weeks of CsA, and 2, 4, 8, and 14 days after discontinuing CsA. The mean serum CsA level after 2 weeks of treatment was 188 +/- 28 ng/ml. GST demonstrated decreased insulin release during CsA with recovery and hypersecretion after CsA withdrawal. ECS showed peripheral insulin resistance during CsA with a rapid recovery and a temporary increase in insulin sensitivity after CsA withdrawal. Comparisons were made with our previous study group given 20 mg/kg/day of CsA. In summary, CsA induces a dose-dependent impairment of glucose homeostasis due to inhibition of insulin release and development of peripheral insulin resistance. Withdrawal of short-term CsA at commonly used therapeutic doses results in reversal of and temporary overcompensation for these changes. CsA withdrawal after long-term treatment results in a slower normalization of the insulin response as compared with after short-term treatment. The hypersecretory reaction of the beta cell may be of help in further investigations of mechanisms of CsA- and FK506-induced inhibition of insulin release.

Animals↗
PubMed1991

Insulin resistance and diabetes due to different mutations in the tyrosine kinase domain of both insulin receptor gene alleles.

Mutations in the insulin receptor gene can lead to in vivo and in vitro insulin resistance and can be the cause of diabetes mellitus in selected patients. We have studied a 22-year-old diabetic woman with Type A insulin resistance and acanthosis nigricans. Insulin binding to the patient's erythrocytes, monocytes, adipocytes, fibroblasts, and transformed lymphocytes was decreased. Receptor autophosphorylation and tyrosine kinase activity toward an exogenous substrate were reduced in partially purified insulin receptors from the proband's transformed lymphocytes. Determination of the nucleotide sequence of the patient's insulin receptor cDNA revealed that the subject was a compound heterozygote who inherited two different mutant insulin receptor gene alleles. The paternal allele contains a missense mutation encoding the substitution of glutamine for arginine at position 981 in the tyrosine kinase domain of the receptor. The maternal allele contains a nonsense mutation causing premature termination after amino acid 988 in the beta-subunit, thereby deleting most of the kinase domain. The mRNA encoded by the allele with the premature stop codon is likely to be unstable, since mRNA transcripts from this allele were decreased markedly compared with the other allele. The mother, who is heterozygous for the nonsense mutation, exhibited only mild insulin resistance, whereas the proband was severely insulin-resistant; this indicates that the missense mutation is biologically significant. In summary, (1) we have identified a patient and her family with a genetic form of insulin resistance and diabetes due to a defect at the level of the insulin receptor; (2) the proband is a compound heterozygote displaying a missense mutation (position 981) in one allele and a nonsense mutation (position 988) in the other insulin receptor gene allele; (3) the missense mutation is in the kinase domain and encodes a receptor with impaired in vitro kinase activity; and (4) based on the in vitro and in vivo phenotype, the kinase domain mutation at position 981 is biologically significant leading to insulin resistance.

Adult↗
PubMed1990

Inhibition of insulin release by cyclosporine and production of peripheral insulin resistance in the dog.

Cyclosporine has been shown to cause glucose intolerance in both humans and animals. This can result from alterations in insulin release, insulin metabolism, the sensitivity of peripheral or hepatic tissues to insulin, or a combination of these factors. The present study was designed to simultaneously evaluate the effect of CsA on these variables. A group of chronically catheterized dogs were administered oral CsA (20 mg/kg/day) for a period of 10 weeks. The glucagon stimulation test (GST) and the euglycemic glucose clamp technique, using a primed continuous infusion of 3H-3-glucose and a continuous insulin infusion (0.8 mU/kg/min), were employed to evaluate pancreatic insulin release, peripheral glucose disposal rate (Rd), hepatic glucose output (HGO), and metabolic clearance rate (MCR) of insulin. The dogs were tested before and after 2, 6, and 10 weeks of CsA administration. Serum CsA levels were 358 +/- 85, 244 +/- 48, and 355 +/- 81 ng/ml at 2, 6, and 10 weeks, respectively (P = NS). Elevated fasting glucose and an abnormal glucose response to an i.v. bolus of glucagon (0.25 U) were noted after 2, 6, and 10 weeks of CsA administration. The areas under the glucose curve (AUCG) for 0-60 min were 9605 +/- 773, 11634 +/- 1226, 12380 +/- 719, and 12626 +/- 1560 mg/min/dl at 0, 2, 6, and 10 weeks, P(F3, 15 = 5.1) = 0.012, demonstrating a CsA-induced disturbance of glucose homeostasis. The areas under the insulin curve (AUCI) for 0-20 min of the insulin response curve were 2033 +/- 203, 1089 +/- 187, 1038 +/- 179, and 972 +/- 161 uU/min/dl at 0, 2, 6, and 10 weeks, P(F3, 15 = 13.1) less than 0.001, indicating a 50% reduction during CsA treatment. CsA did not affect basal Rd, but peripheral insulin resistance was noted in the insulin-stimulated state. Rd during the third hour of the insulin infusion decreased from 6.72 +/- 0.69 to 4.42 +/- 0.44, 5.02 +/- 0.64, 4.47 +/- 0.52 mg/kg/min at 0, 2, 6, and 10 weeks, respectively, P(F3, 15 = 6.94) less than 0.004. HGO suppression by insulin and MCR of insulin were not altered by CsA. Similarly, glucagon secretion did not appear to be influenced by CsA. In conclusion, this study has simultaneously evaluated the effect of CsA on several aspects of glucose and insulin metabolism in the dog. CsA administration produces abnormal glucose homeostasis by reducing pancreatic insulin release, in addition to inducing peripheral insulin resistance.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗
PubMed1990

Computerized ambulatory-care pharmacy information system for direct order entry by prescribers.

A computer system that links prescribers in a diabetes center to an ambulatory-care satellite pharmacy is described. In 1988 an ambulatory-care center serving the diabetic patients of a 437-bed university teaching hospital moved to a new location. To maintain efficient communication of prescription information from the diabetes center to a designated ambulatory-care satellite pharmacy, a program that enables diabetes center prescribers to enter their orders directly into the satellite pharmacy computer system was implemented. The pharmacy department's prescription-entry screen was reprogrammed so that it could be more easily used by prescribers, and a "default" list of the most frequently prescribed drugs was generated to simplify direct order entry. Prescription information entered at the diabetes center is transmitted to the satellite pharmacy; the filled prescriptions are usually ready by the time patients arrive. The average number of prescriptions entered into the computer per week remained steady during the first 14 weeks that the system was in use but increased substantially after diabetes center personnel were given a summary of use data and other information pertaining to the new system. However, because of the availability of only one terminal for order entry and the inherent ease and speed of writing prescriptions on paper, use of the system has not met expectations despite the benefits it offers. Prescribers in a diabetes center did not frequently enter prescription information into a computer system linked to the hospital's ambulatory-care pharmacy because the traditional method of writing prescriptions remained available and convenient.

California↗
PubMed1987

Selective suppression of hepatic glucose output by human proinsulin in the dog.

By using the euglycemic glucose-clamp technique we have observed the effects of comparable low dose proinsulin and insulin infusions on isotopically determined glucose turnover in 20 anesthetized dogs. In each animal somatostatin (SRIF) infusion was used to suppress endogenous pancreatic hormone secretion and basal glucagon was replaced. Peripheral proinsulin (0.083 micrograms X kg-1 X min-1) and insulin (350 microU X kg-1 X min-1) levels 15- to 20-fold higher than insulin on a molar basis, based on previous observations that proinsulin has only 5-10% the biologic potency of insulin. Three groups of infusion studies were performed: SRIF and glucagon (n = 5); SRIF, glucagon, and proinsulin (n = 10); and SRIF, glucagon, and insulin (n = 5). The mean serum proinsulin level of 2.43 +/- 0.36 pmol/ml achieved represented a 17-fold excess compared with the mean serum insulin level of 0.14 +/- 0.03 pmol (20 +/- 4 microU/ml). At these concentrations, both hormones reduced hepatic glucose production rates by approximately 50% to 2.0 +/- 0.2 mg X kg-1 X min-1 and 1.8 +/- 0.5 mg X kg-1 X min-1, respectively. In contrast, proinsulin failed to stimulate peripheral glucose utilization, whereas insulin led to a 2.0 +/- 0.3 mg X kg-1 X min-1 increment (approximately 50% increase) in glucose uptake (P less than 0.05). Thus at low infusion rates proinsulin exerts its effect predominantly by suppressing hepatic glucose production without measurable stimulation of peripheral glucose disposal. In contrast, for a comparable degree of hepatic glucose output suppression, insulin also significantly stimulates glucose disposal.

Animals↗
PubMed1987

Non-insulin-mediated glucose uptake predominates in postabsorptive dogs.

Overall glucose uptake represents the sum of insulin-mediated glucose uptake (IMGU) and non-insulin-mediated glucose uptake (NIMGU). In this study, we compared the rate of NIMGU in conscious and anesthetized dogs. Rates of glucose disposal were compared in the basal state and during severe insulinopenia after endogenous insulin suppression by high-dose somatostatin (SRIF) infusion. Steady-state NIMGU rates were calculated 2 h after commencing SRIF infusion. Three groups of studies were performed: 1) SRIF in conscious dogs; 2) SRIF in anesthetized dogs; and 3) SRIF plus glucagon, also in anesthetized dogs. In all three groups, serum insulin levels were reduced to below assay sensitivity after SRIF infusion. The basal metabolic clearance rate of glucose (MCRg) for each group was 3.8 +/- 0.4, 3.6 +/- 0.3, and 3.6 +/- 0.3 ml X kg-1 X min-1, respectively (P = NS, all groups). Steady-state NIMGU rates were 2.4 +/- 0.2 (conscious), 2.5 +/- 0.1 (anesthetized, SRIF only), and 2.4 +/- 0.1 ml/kg/min (anesthetized, SRIF plus glucagon). Thus, absolute rates of NIMGU expressed as MCRg in conscious and anesthetized animals do not differ and in the three groups studied comprise approximately the same proportion of the basal glucose uptake (approximately 64, approximately 69, and approximately 66%, respectively). We conclude that approximately 66% of basal postabsorptive glucose uptake occurs via NIMGU mechanisms and that this pathway is unaffected by anesthesia and surgery.

Absorption↗
PubMed1987

Continuous subcutaneous insulin infusion in an obese insulin-resistant pregnant woman with type II diabetes: accelerated fetal growth and neonatal complications.

This is the first report to describe prolonged continuous subcutaneous insulin infusion in a massively obese insulin-resistant pregnant woman with type II diabetes. Maternal 24-hour plasma glucose levels became normal by 48 hours, and normoglycemia was maintained with high daily doses of insulin (530 U-333 U/24 hours) from 29 weeks' gestation until delivery at 38.5 weeks. Excellent diabetic control was associated with euglycemia, normal glycosylated hemoglobin concentration, and a significant decrease in mean 24-hour plasma C-peptide (P less than .004) and glucagon (P less than .003) levels. Unexpectedly, fetal growth accelerated during constant insulin infusion despite normal maternal plasma glucose levels. The newborn infant was large (4530 g), with a striking truncal accumulation of fat, hypoglycemia (30-minute plasma glucose 11 mg/dL), and polycythemia (central venous hematocrit 71%). Normalization of maternal plasma glucose levels failed to ameliorate established macrosomia, and did not prevent the neonatal complications that are common in infants of diabetic mothers.

Adult↗
PubMed1979

A structurally abnormal insulin causing human diabetes.

Insulin isolated from the pancreas of a diabetic patient with fasting hyperinsulinaemia showed decreased activity in binding to cell membrane insulin receptors and in stimulating cellular 2-deoxyglucose transport and glucose oxidation. Chemical studies suggest that the isolated hormone is a mixture of normal insulin and an abnormal variant which contains a leucine for phenylalanine substitution at position 24 or 25 of the insulin B-chain.

Amino Acid Sequence↗
PubMed1978

The effect of ten days of fasting on various aspects of carbohydrate metabolism in obese diabetic subjects with significant fasting hyperglycemia.

Patients with nonketotic diabetes mellitus, who were both obese and had significant fasting hyperglycemia (mean plasma glucose = 310 mg/100 ml), were fasted for 10 days. There was a prompt drop of plasma glucose levels as the result of the caloric deprivation with a mean fall of approximately 200 mg/dl at the end of the fast. The drop in plasma glucose level that occurred during the fast was associated with a drop in plasma insulin level. Fasting plasma glucose concentration rose immediately after food intake was resumed and stabilized within 3--4 days at levels halfway between the initial and the lowest value. At this time, the patients also seemed capable of disposing of an oral glucose load more efficiently. The apparent improvement in carbohydrate homeostasis observed after the fast could not be attributed to an increase in insulin response, but was associated with some amelioration of the insulin resistance that characterizes these patients. Unfortunately, the beneficial effects of the 10-day period of caloric deprivation were transitory and fasting plasma glucose values had returned to prefast levels in most patients within a few months.

Adult↗