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Biomedical subjects

J H Karam

Publications and source records attributed to J H Karam.

At least 19 recordsLinked to original sources
PubMed1992

Human GLUT4/muscle-fat glucose-transporter gene. Characterization and genetic variation.

Four overlapping DNA fragments spanning 32 kb containing the human GLUT4 facilitative glucose-transporter gene were isolated and characterized. The sequence of the GLUT4 gene (approximately 6.3 kb) and 2.0 kb of the promoter region was determined. The sequence of the promoter revealed potential binding sites for transcription factors known to regulate gene expression in muscle cells and adipocytes. However, transfection of constructs including 2 kb of the GLUT4 promoter fused to the bacterial CAT gene into 3T3-L1 adipocytes displayed only weak promoter activity. Because insulin resistance plays a prominent role in the development of NIDDM, genetic variation in the sequence of GLUT4 also was evaluated. Oligonucleotide primer pairs were selected that allowed the protein-coding region of the human GLUT4 gene to be amplified by PCR. The sequence of the protein-coding region of the GLUT4 gene and all intron-exon junctions was determined for a single diabetic Pima Indian and was identical to that of the cloned gene and cDNA. SSCP analysis was used to screen patients with diabetes mellitus and normal, healthy nondiabetic individuals for mutations at the GLUT4 locus. In addition to the silent substitution in the codon for Asn130 (AAC or AAT) and a Val383 (GTC)-->Ile(ATC) replacement described previously, two new variants were identified. One was a T-->A substitution in intron 1 that was found in 1 of 36 NIDDM patients who were typed for this variant. The second was a Ile385(ATT)-->Thr(ACT) replacement that occurred in 1 normal individual and was not found in any of 676 other normal and diabetic subjects. A large and racially diverse group of normal and diabetic individuals also was screened for the Ile383 polymorphism. It occurred in both diabetic and nondiabetic subjects. There is no indication from our data that these polymorphisms are associated with NIDDM.

3T3 Cells↗
PubMed1992

The aggregation of the 5' insulin gene polymorphism in insulin dependent (type I) diabetes mellitus families.

Population studies have suggested an increased frequency of small DNA insertions (class I alleles) 5' to the insulin gene in insulin dependent (type I) diabetes mellitus (IDDM). The present study examined this relationship within families. Forty-one families with at least one diabetic offspring were studied. Analysis of the insulin gene polymorphism was performed by digestion of DNA with Bg1I, SstI, RsaI, or PvuII and hybridisation with an insulin gene probe or polymorphic region specific probes. An increased frequency of class I alleles was found among the parents of diabetics (p = 0.02), as well as a trend towards increased frequency of parents homozygous for class I alleles and matings of two homozygous subjects. This increased homozygosity for class I alleles was present in non-diabetic sibs as well (p = 0.01). These results show that ascertainment through an offspring with IDDM selects for families with high frequencies of homozygosity for the class I allele and thus suggests that the insulin gene polymorphism is indeed providing part of the genetic predisposition to IDDM. When the major portion of genetic predisposition is provided by other genes (estimates are that HLA accounts for 30 to 70% in IDDM), identification of additional susceptibility genes becomes difficult. Even when formal linkage analysis is uninformative, our studies indicate that analysis for aggregation of specific alleles within families is a useful approach to this problem.

Diabetes Mellitus, Type 1↗
PubMed1979

Feedback-controlled dextrose infusion during surgical management of insulinomas.

Through the use of a feedback-controlled dextrose infusion system, we obtained continuous monitoring of the blood glucose level in a patient undergoing surgery for multiple pancreatic beta-cell tumors. In addition, this device infused dextrose at variable rates to maintain a predetermined euglycemic level of 90 mg/dl. Before locating the source of excessive insulin production, the maximum dextrose infusion rate of 400 mg/min was required; but after extirpation of multiple insulinomas, the dextrose-infusion rate declined whereas the blood glucose level rose above the preselected level. These results emphasize the usefulness of a monitoring and infusion system not only in protecting the patient from the hazard of hypoglycemia under anesthesia but also as an aid in determining whether all insulin-secreting tumors have been removed.

Adenoma, Islet Cell↗
PubMed1979

Dopamine during alpha- or beta-adrenergic blockade in man. Hormonal, metabolic, and cardiovascular effects.

We studied the contribution of alpha- and beta-adrenergic receptor activation to the cardiovascular, metabolic, and hormonal effects of dopamine. At a concentration of 1.5 mug/kg.min, the infusion of dopamine in 12 normal volunteers was associated with a transient but significant rise in pulse rate, which was prevented by propranolol. Venous plasma glucose did not change throughout the experiments, and a mild increase in plasma free fatty acid levels observed during the administration of dopamine alone was antagonized by propranolol. In contrast, neither the beta-adrenergic blocker, propranolol, nor the alpha-adrenergic blocker, phentolamine, was effective in inhibiting the dopamine-induced rise in plasma glucagon (from 82+/-9 to 128+/-14 pg/ml; P < 0.005) and serum insulin (from 7.5+/-1 to 13+/-1.5 muU/ml; P < 0.005) or its suppression of plasma prolactin (from 8.5+/-1 to 5.2+/-0.8 ng/ml; P < 0.001). Although serum growth hormone levels did not change during the infusion of dopamine alone, an obvious rise occurred in three subjects during the combined infusion of propranolol and dopamine. Whereas some metabolic and cardiovascular effects of dopamine are mediated through adrenergic mechanisms, these observations indicate that this is not the case for the effects of this catecholamine on glucagon, insulin, and prolactin secretion, and thus provide further support for the theory of a specific dopaminergic sensitivity of these hormonal systems in man.

Adrenergic alpha-Antagonists↗
PubMed1979

Phentolamine and the action of somatostatin in man.

The inhibition by somatostatin (SRIF) of basal and arginine-stimulated glucagon, insulin, and glucose levels was compared with that obtained when SRIF was preceded by alpha-adrenergic blockade with phentolamine. No noteworthy differences were observed, except that the characteristic rebound of insulin upon discontinuation of SRIF was significantly lower with phentolamine (P less than 0.01). These results indicate that inhibition of basal and arginine-stimulated glucagon and insulin secretion by SRIF in man is not mediated through activation by alpha-adrenergic receptors.

Adult↗
PubMed1979

Prolactin-secreting pituitary adenomas in multiple endocrine adenomatosis, type I.

In three unrelated families, four patients with multiple endocrine adenomatosis, type I, had confirmed or highly probable prolactin-secreting pituitary adenomas. In one patient, selective transsphenoidal tumor resection resulted in normal prolactin levels and resumption of menses. Heretofore, the majority of pituitary tumors in such patients had been thought to be nonsecreting chromophobe adenomas, but recent studies have shown that, in sporadic cases, as many as three fourths of "nonsecreting" pituitary tumors in fact secrete prolactin. Thus, based on our experience and reports of others, we believe that prolactin-secreting tumors may be common in patients with pituitary tumors as part of the syndrome of multiple endocrine adenomatosis, type I, and we recommend that serum prolactin be measured when evaluating these patients and their families.

Adult↗
PubMed1978

Diabetes mellitus following rodenticide ingestion in man.

Ketotic, insulin-requiring diabetes mellitus and a severe peripheral neuropathy developed in a previously healthy 25-year-old man several days after he attempted suicide with rat poison containing N-3-pyridylmethyl N'-p-nitrophenyl urea. Study of islet-cell function ten months after ingestion showed a reduced disappearance rate of intravenous glucose and depressed C-peptide response to intravenous glucose when compared with a normal control but no impairment of glucagon release after intravenous arginine stimulation. Nerve conduction studies demonstrated severe sensory and mild motor neuropathy. Quadriceps capillary basement membrane thickness was in the diabetic range. Because at least 15 similar occurrences have been reported to the manufacturer, this agent appears to be diabetogenic in man, probably causing beta-cell destruction. Niacinamide, which can prevent glucose intolerance in both streptozocin- and alloxan-treated animals and prevents death in rats given this rodenticide, may be a useful antidote.

Adult↗
PubMed1977

Plasma glucagon suppression by phenformin in man.

In an attempt to elucidate the mechanism of action of phenformin, eleven juvenile-onset, insulin-requiring diabetic subjects underwent four different treatment regimens during standard breakfast tests. These four treatments were: control (no insulin or phenformin); insulin alone (15 U regular insulin administered subcutaneously one-half hour before breakfast); phenformin alone (50 mg of the timed-release capsule given twice daily for three days before the study and two and one-half hours before breakfast on the day of study); and phenformin plus insulin (in the amounts and at the times stated above). Phenformin was found to decrease postprandial hyperglycaemia significantly when compared with control values, and its addition to insulin further decreased the postprandial glucose rise below that found with insulin alone (p less than 0.005). These effects were associated with a reduction in early (30-min) postprandial hyperglucagonaemia (p less than 0.05). Triglyceride levels, gastrin secretion, growth hormone levels, and increments of alpha-amino nitrogen were not affected by phenformin. Thls, suppression of postprandial hyperglucagonaemia may be an additional mechanism in the reduction of postprandial hyperglycaemia after phenformin.

Adult↗
PubMed1977

Clinical evaluation of somatostatin as a potential ajunct to insulin in the management of diabetes mellitus.

To determine whether somatostatin, an inhibitor of glucagon and growth hormone secretion, might be useful as an adjunct to insulin the management of diabetic hyperglycaemia, seven insulin-requiring diabetic men were given somatostatin (100 microgram/h, IV) continuously for 3 days after their diabetes had been treated intensively by diet and insulin on a metabolic ward. During infusion of somatostatin and despite reduction in average insulin dose exceeding 50%, there was improvement in diabetic control as assessed by postprandial hyperglycaemia, 24-h glycosuria and the average daily serum glucose level and its fluctuation; when somatostatin was discontinued, but insulin doses held constant, diabetic control rapidly worsened. No adverse effects were observed. These results indicate that somatostatin plus insulin can be a more effective regimen than insulin alone in controlling diabetic hyperglycaemia. A longer acting and more selective somatostatin preparation may prove useful as an adjunct to insulin in the management of diabetes.

Adult↗
PubMed1977

Differential effects of L-dopa and apomorphine on glucagon secretion in man: evidence against central dopaminergic stimulation of glucagon.

In 6 normal subjects, L-dopa (500 mg PO) and apomorphine (0.6 mg sc) increased circulating growth hormone and suppressed prolactin levels in a parallel and quantitatively similar fashion, but only L-dopa induced a rise in plasma glucagon, glucose, and insulin levels. The failure of apomorphine to affect glucagon secretion, despite a substantial effect on growth hormone and prolactin, was also observed in insulin-dependent diabetics known to exhibit A-cell hyperresponsiveness to various stimuli. In view of the highly dissimilar molecular and pharmacologic characteristics of L-dopa and apomorphine, these data do not exclude a local dopaminergic effect of L-dopa at the pancreatic level, but strongly militate against a central dopaminergic pathway for glucagon stimulation.

Adult↗
PubMed1977

The effect of chronic oral antidiabetic therapy on insulin and glucagon responses to a meal.

Nineteen maturity-onset diabetic patients receiving oral hypoglycemic therapy in a university diabetes clinic completed a study to assess the efficacy of the oral agents and to determine their effects on pancreatic islet hormone secretion. All patients were receiving sulfonylureas, and seven were also receiving phenformin. The subjects were studied as outpatients in the clinic setting on four different occasions with collections of a baseline blood sample before a standard breakfast and a second sampling two hours postprandially, twice while on their prescribed medication and twice after having been withdrawn from the medication. The values obtained during the two studies on the two studies off medications were reproducible for each subject. Analysis of the results by paired differences revealed that mean 24-hour urine glucose values deteriorated significantly (p less than 0.005) after oral antidiabetic therapy was withdrawn; similarly, mean plasma glucose values, both at baseline and two hours postprandially, rose significantly (p less than 0.001) when subjects were off medication. Baseline serum insulin values were not changed, but postprandial levels were significantly higher on oral agents (p less than 0.005). Plasma immunoreactive glucagon was significantly lower both at baseline (p less than 0.02) and postprandially (p less than 0.005) when the subjects were on their antidiabetic medications. During the trial off medication, 16 patients became symptomatic, with three of these developing symptoms severe enough to require hospitalization. It is apparent from this study that oral hypoglycemic medications can play a role in controlling symptoms in maturity-onset diabetic patients and that the beneficial effect of these agents on hyperglycemia may, in part, be explained by their stimulation of endogenous insulin secretion and partial suppression of endogenous glucagon.

Acetohexamide↗
PubMed1977

Serum phenformin concentrations in patients with phenformin-associated lactic acidosis.

Phenformin concentrations were measured in serum from seven patients with phenformin-associated lactic acidosis, and initial values ranging from 20 to 625 ng./ml. were obtained. Five of the seven patients had serum concentrations within the usual therapeutic range of up to 241 ng./ml. Serum phenformin concentrations were measured serially, and apparent half-lives of 5, 25, and 30 hours were obtained in three patients with serum creatinine concentrations of 1.7, 7.6, and 6.0 mg./dl., respectively. Although the half-life of phenformin was prolonged in azotemic patients, no correlation between serum creatinine concentration and serum phenformin could be demonstrated; furthermore, the severity of lactic acidosis as measured by arterial pH and lactate concentration did not correlate with the serum creatinine concentration.

Aged↗
PubMed1977

Jejunoileal bypass as a treatment of morbid obesity.

Seventy-five morbidly obese patients underwent jejunoileal bypass between December 1968 and October 1975. The average weight of 45 patients who had had the bypasses for over two years stabilized at 62.4% of the maximum preoperative value. Postoperative complications included recurrent diarrhea in 11% (8/74) and serum electrolyte deficits in 64% (48/75), most of which were transient. Potassium and calcium deficiencies were usually correctable by oral supplementation, but hypomagnesemia persisted in 23% (16/71) despite supplementation. Nine percent (4/43) had biopsy-proved hepatic cirrhosis after one year. Other complications were polyarthralgia, bone demineralization, renal stones, and vasculitis. Three patients required reanastomosis to original bowel continuity; all rapidly regained weight. One died of vasculitis and hepatic failure attributable to the bypass. Jejunoileal bypass is suitable only in morbidly obese patients with particularly high motivation, whose risk factors outweigh those risks incurred through bypass.

Arteritis↗