Bilateral testicular enlargement due to adrenal remnant in a patient with C11 hydroxylase deficiency congenital adrenal hyperplasia.

The case of a 15-yr-old boy with C11 hydroxylase deficiency congenital adrenal hyperplasia is reported who was diagnosed and treated as true precocious puberty at the age of 2 yr because of virilization and bilateral testicular enlargement. He later developed hyperpigmentation, hypertension and short stature and because of an increase in testes size he underwent testicular biopsy with the assumption of Leydig cell tumor. With the intake of glucocorticoids his testes size, hypertension and hyperpigmentation improved markedly. We could find only 6 such cases in the literature and have reviewed their clinical and laboratory data. All patients showed the picture of virilization with hypertension. Leydig cell tumor was proposed as the differential diagnosis in all cases except ours. Ultrasonography was able to show testicular adrenal-like tissue in all those in whom the procedure was undertaken. In the 5 patients of whom we could find enough data, 1 responded partially and 4 responded markedly to corticosteroid therapy with shrinkage of testicular tumors. We conclude that clinical findings and US are very important in the early diagnosis of these patients and with adequate treatment most cases show shrinkage in testicular tumors.

Families with autosomal dominant brachydactyly type E, short stature, and severe hypertension.

BACKGROUND: Rare, monogenic forms of hypertension may give insight into novel mechanisms relevant to essential hypertension. Autosomal dominant hypertension with brachydactyly has been documented in a single Turkish kindred; the gene was mapped to chromosome 12p. OBJECTIVE: To describe the molecular genetics of additional families with autosomal dominant hypertension and brachydactyly. DESIGN: Case series. SETTING: Tertiary care medical centers. PATIENTS: An 11-member Canadian family and a 7-member U.S. family, neither of Turkish background, with autosomal dominant hypertension and type E brachydactyly. MEASUREMENTS: Clinical evaluation, genotyping, and haplotype analyses. RESULTS: The mode of inheritance, the type E brachydactyly, and the propensity for stroke were consistent with autosomal dominant hypertension with brachydactyly. The same markers on chromosome 12p cosegregated with the phenotype in the families. A haplotype analysis strongly supported the conclusion that these families have a molecular defect in the same gene. CONCLUSIONS: The syndrome of autosomal dominant hypertension and brachydactyly is not confined to patients of Turkish origin. All persons with brachydactyly should have their blood pressure measured, and the syndrome should be considered if hypertension is found.

Primary hyperaldosteronism causing posttransplantation hypertension: localization by adrenal vein sampling.

A 58 year-old man with end-stage renal disease who had received a cadaveric renal transplant presented with persistent hypertension and hypokalemia. Allograft renal artery stenosis, rejection, and cyclosporine effects were excluded. Hypokalemia persisted despite potassium supplementation and antihypertensive medications with hyperkalemic effects. The biochemical findings of primary hyperaldosteronism with a normal adrenal anatomy imaged by magnetic resonance imaging (MRI) necessitated adrenal vein sampling to lateralize a left adrenal adenoma. His hypokalemia was cured by the removal of the adenoma, and his blood pressure (BP) control was easily achieved with a less complex regimen of antihypertensives. We suggest that the concomitant existence of resistant hypokalemia and posttransplantation hypertension, especially in the cyclosporine era, should stimulate a search for hyperaldosteronism; once transplant renal artery stenosis has been excluded, the patient should be investigated for primary hyperaldosteronism. When imaging studies fail to show adrenal pathology, adrenal vein sampling will likely do so.

Idiopathic hyperplasia of the adrenal gland behaving like an aldosterone producing adenoma.

Primary hyperaldosteronism (adrenal adenoma and idiopathic hyperplasia) is a disorder with hypertension, hypokalemia, elevated serum aldosterone and suppressed plasma renin activity. Hyperplasia is managed medically whereas adenomas are treated surgically. Selective adrenal venous catheterization and aldosterone measurement is a useful tool in making the distinction in 95% of cases. We report a case of bilateral idiopathic hyperplasia of the adrenal glands adequately treated with medications for 6 years followed by worsening. Selective catheterization was consistent with a right sided adenoma. Surgical removal of the right adrenal gland alleviated her symptoms. Pathological examination showed focal nodular hyperplasia. We propose that in the course of the disease the focal hyperplastic nodule became autonomous and behaved like an adenoma. Monitoring of patients with adrenal hyperplasia for recurrence of symptoms is prudent as surgery is beneficial in patients who develop an autonomous nodule.

Changes in human blood pressure with season, age and solar cycles: a 26 year record.

The record was studied of a 71-year-old, diurnally active (0700-2200 hours) male psychiatrist (G.N.) who self-measured systolic and diastolic blood pressure (BPS and BPD) mostly but not exclusively on Sunday mornings, from 1969 to 1994. A large about-yearly change was revealed which increased with age and was accompanied by a decreasing trend in the yearly rhythm-adjusted mean (MESOR; P < 0.01). According to conventional criteria that specify only upper limits of acceptability, G.N. was hypertensive in summer and normotensive in other seasons. Since changes in both MESOR and circannual amplitude occurred, a systematic surveillance of BP is the chronobiological recommendation.

Factors influencing outcome of surgery for primary aldosteronism.

OBJECTIVE: To identify factors that influence the outcome of surgery for primary aldosteronism. DESIGN: A retrospective clinical series, with a mean follow-up of 106 months (range, 12-280 months), of 42 patients who underwent adrenalectomy for primary aldosteronism between the years 1970 and 1993. SETTING: All patients were operated on at the Boston University Medical Center Hospital. PATIENTS AND INTERVENTION: We reviewed the records of 22 women and 20 men, ranging in age from 25 to 68 years, who underwent adrenalectomy for primary aldosteronism. Tests performed for preoperative classification of the adrenal pathological abnormalities included adrenal venous sampling, postural stimulation test, iodocholesterol I 131 scintigraphy, and computed tomography. MAIN OUTCOME MEASURES: The surgical outcome was classified as follows: response, normal blood pressure measurement (< 160/95 mm Hg) without medication; incomplete response, normal blood pressure measurement with medication or blood pressure measurement greater than 160/95 mm Hg despite antihypertensive treatment. RESULTS: Twenty-five patients (60%) became normotensive following surgery. The following factors were associated with a complete response to adrenalectomy by univariate analysis: adenoma classification (odds ratio [OR] = 9.6, P = .002); preoperative response to spironolactone (OR = 8.3, P = .007); age younger than 44 years (OR = 6.2, P = .009); and duration of hypertension less than 5 years (OR = 5.1, P = .03). Response to spironolactone was predictive only in cases classified as adenoma (P = .004). Duration of hypertension showed a strong correlation with age (r = 0.62). Using stepwise logistic regression, adenoma pathological classification, response to spironolactone, and duration of hypertension less than 5 years contributed independently to a predictive model. Micronodular hyperplasia alone was associated with incomplete response. The presence of coexisting micronodular hyperplasia in patients with adenoma did not affect the odds for a complete response. Computed tomography for preoperative diagnosis of adenoma showed the same level of accuracy (75%) as that for postural stimulation test and iodocholesterol scintigraphy, but less than that for adrenal venous sampling (91%). CONCLUSIONS: The study showed that the main determinants of a surgical cure of hypertension in primary aldosteronism were presence of adenoma and preoperative response to spironolactone. We favor computed tomography as the initial test to establish preoperative diagnosis of adenoma because of its reproducibility and high specifity.

Prohormones in adrenal venous effluent in patients with primary hyperaldosteronism.

Aldosterone-producing adenoma (APA) and idiopathic hyperplasia (IHA) are two main causes of primary hyperaldosteronism, which differ in the modes of treatment. Some of the prohormones, such as 18-hydroxycorticosterone, are elevated in adenomas. 19-Nor-deoxycorticosterone (19-nor-DOC), produced in the kidney, has been shown to be excreted in excess in patients with APA. Deoxycorticosterone is a known precursor of aldosterone and 19-nor-DOC. This study is designed to evaluate the levels of prohormones in adrenal venous effluent in eight patients, three with APA, of which two were confirmed by surgical pathology and four with IHA, and one patient with primary adrenal hyperplasia. 19-OH-DOC, a precursor of 19-nor-DOC, was found to be the main prohormone in adrenal venous effluent in patients with both APA and IHA. 19-Oic-deoxycorticosterone and 19-nor-DOC were also detected, but in smaller quantities. 19-OH-DOC appears to be the main prohormone in adrenal venous effluent for the biosynthesis of 19-nor-DOC.

19-Acetylenic-deoxycorticosterone inhibits 19-hydroxylase and 11 beta-hydroxylase activities in dispersed bovine zona fasciculata cells.

19-Acetylenic-deoxycorticosterone (19-A-DOC) is believed to be a competitive irreversible inhibitor of the synthesis of 19-nor-deoxycorticosterone (19-nor-DOC), a potent mineralocorticoid implicated in some forms of human and animal hypertension. It has been shown to inactivate 11 beta/19-hydroxylase in hamster adrenal mitochondria. Dispersed bovine zona fasciculata cells were incubated for one hour with 1.5 x 10(-8) M ACTH and 0, 1, 10, or 100 microM 19-A-DOC and tritiated deoxycorticosterone (DOC) substrate. Steroids were separated using two sequential thin-layer chromatography systems and their tritium content was counted and corrected for recovery. The 19-A-DOC decreased synthesis of 19-hydroxydeoxycorticosterone, the precursor of 19-nor-DOC. The inhibitor also impaired 11-hydroxylation of DOC to form corticosterone. The data suggest that 19-A-DOC is an effective inhibitor of 11 beta/19-hydroxylase activity in dispersed bovine adrenal cells.

Hypothalamic-pituitary-adrenal function in non-AIDS patients with advanced HIV infection.

Patients with acquired immune deficiency syndrome (AIDS) are reported to have increased basal cortisol and reduced stimulated cortisol release, but the dysfunction in the hypothalamic-pituitary-adrenal (HPA) axis is not yet understood in patients with human immunodeficiency virus (HIV) infection during the advanced stage of disease that precedes the development of AIDS. To understand the status of the HPA axis during this phase of HIV infection, 25 non-AIDS ambulatory patients with advanced HIV infection and without evidence of adrenal or pituitary insufficiency were studied. Ovine corticotropin-releasing hormone was administered (1 microgram/kg BW) intravenously and plasma cortisol and adrenocorticotropin (ACTH) were measured over the following 120 minutes. Based on a standard response curve, obtained from CRH testing of 10 HIV negative volunteers with no HPA abnormalities, 13 patients were found to have normal response (group 1), 6 patients had reduced ACTH and cortisol response (group 2) and 6 patients had normal ACTH with reduced cortisol response (group 3). Basal cortisol and basal ACTH were comparable for control subjects and groups 1, 2, and 3. This suggests that, in advanced non-AIDS HIV patients with no clinical evidence of pituitary or adrenal disease, about 25% (group 2) have reduced pituitary reserve with high basal ACTH and cortisol, and about 25% (group 3) have reduced adrenal reserve with high basal cortisol and inappropriately normal basal ACTH, whereas about 50% (group 1) maintain normal HPA axis activity with increased basal cortisol secretion. The exact physiopathologic mechanism is not yet known, but an enhanced CRH production by the hypothalamus may explain the alterations in the HPA axis in advanced HIV disease.

19-Nor-corticosteroids in genetic hypertension. Effects of inhibitors of 11 beta, 18, 19-hydroxylase activity.

The long-term objective is to understand the role of the adrenal in altering systemic arterial blood pressure. This paper summarizes research on genetic hypertension in the rat and bears a relationship to several forms of human hypertension in which defects of steroid hydroxylases lead to increased secretion of mineralocorticoids other than aldosterone in genetic and experimental hypertension in rats. We demonstrated that 19-nor-corticosteroids are produced in excess in genetic and experimental hypertension in rats and man. We studied the enzymatic alteration responsible for excessive production of 19-nor-deoxycorticosterone (19-nor-DOC) in the salt-sensitive hypertensive rat S/JR. Biosynthesis of 19-nor-steroids involves hydroxylation of the C-19 methyl group. We characterized the adrenal 11 beta, 18,19-hydroxylase enzyme system in inbred salt-sensitive and resistant rats (R/JR). This system is capable of all three hydroxylations. The Km for 19-hydroxylation was different from S/JR and R/JR but was much greater for 11 beta- and 18-hydroxylation in both. This suggested that the catalytic site for 19-hydroxylation is different from that for 11 beta and 18. The S/JR adrenal enzyme binds the substrate with higher affinity than does the R/JR adrenal enzyme. We were unable to distinguish the cDNAs of the S/JR from the R/JR adrenal enzyme from bovine 11 beta-hydroxylase cDNA by restriction mapping. We were unable to demonstrate restriction length polymorphism. 19-Acetylenic DOC is an inhibitor which preferentially inhibits the 19-hydroxylation of DOC, and does not interfere with the 18- and 11 beta-hydroxylation. This inhibition leads to a reduction in blood pressure in the S/JR Dahl rat. We suggest that an S/JR 19-nor-DOC is involved in the development of salt-sensitivity and hypertension and that inhibition of its formation by acetylenic DOC and other aromatase and non-aromatase inhibitors is associated with reversal of these phenomena.

Antihypertensive effect of 19-acetylenic-deoxycorticosterone in inbred salt-sensitive rats.

Rats susceptible to the hypertensive effect of dietary salt (SS/Jr) have excess 19-nor-deoxycorticosterone (19-nor-DOC) compared with salt-resistant control rats (SR/Jr). 19-Nor-deoxycorticosterone is a hypertensinogenic mineralocorticoid believed to contribute to the salt sensitivity of SS/Jr. 19-Acetylenic-deoxycorticosterone (19-Ac-DOC), an inhibitor of 19-nor-DOC biosynthesis, was evaluated for its antihypertensive effect in 20 hypertensive female SS/Jr rats. At 60 days of age, the rats were started on a high-salt diet (8% NaCl); then, at 120 days, the 10 surviving rats were divided into two groups. Group 1 included five animals with blood pressure +/- standard error (BP +/- SE) of 208 +/- 2 mm Hg that had 19-Ac-DOC implants (1 mg released over 10 days). Group 2 consisted of five animals with a BP of 204 +/- 2 mm Hg that had placebo implants (vehicle only). At 130 days, when another set of pellets was implanted, four rats were still alive in group 1 (BP 165 +/- 5 mm Hg) and none in group 2. At 140 days, the four surviving rats had a BP of 157 +/- 2 mm Hg. Finally, at 150 days, after 10 days off any 19-Ac-DOC, only two rats remained alive (BP 200 +/- 0 mm Hg). Urinary corticosterone +/- SE, DOC +/- SE, and 19-nor-DOC +/- SE before the first implant were 10 +/- 3, 16 +/- 5, and 42 +/- 14 micrograms/week, respectively, and 7 +/- 2, 13 +/- 5, 23 +/- 13 micrograms/week, respectively, after the second implant.(ABSTRACT TRUNCATED AT 250 WORDS)

Angiotensin-converting enzyme in cardiovascular and adrenal tissues and implications for successful blood pressure management.

Components of the renin-angiotensin system, and the ability to synthesize these components locally, have been demonstrated in cardiovascular tissues. Locally generated angiotensin II may affect vascular tone, regional blood flow, cardiac contractility, and vascular and cardiac growth. Local renin-angiotensin systems may exert autocrine and paracrine functions, whereas the circulating system serves an endocrine function. Use of angiotensin-converting enzyme (ACE) inhibitors has provided further clarification of the activities of local renin-angiotensin systems. Tissue and systemic effects of these agents may prove equally important in determining their clinical efficacy. Experiments with quinapril demonstrated that inhibition of vascular ACE was a significant component of the antihypertensive effect of the drug. Differences at the tissue level may have implications for the efficacy and tolerability of a particular agent. Improved individualization of therapy may be accomplished by the use of newer ACE inhibitors with very favorable side effects profiles and tissue specificity. The newest agent, quinapril, appears to exert an important effect on vascular converting enzyme.

19-Nor-deoxycorticosterone production from aldosterone-producing adenomas.

19-Nor-deoxycorticosterone (19-nor-DOC), a hypertensinogenic mineralocorticoid, equipotent with aldosterone and independent of the renin-angiotensin system, is synthesized in the kidney and excreted in excess in the urine of patients with aldosterone-producing adenomas. This current study evaluated the adrenal and renal venous levels of aldosterone and 19-nor-DOC after adrenal and renal venous catheterization and blood sampling in five patients with aldosterone-producing adenomas. Aldosterone (mean +/- SEM) in the adrenal vein ipsilateral to the tumor (469 +/- 293 ng/dl) was higher than in the contralateral vein (70 +/- 59 ng/dl). 19-Nor-DOC (mean +/- SEM) was also higher in the ipsilateral (548 +/- 286 ng/dl) than in the contralateral (51 +/- 14 ng/dl) adrenal vein. In the renal veins, ipsilateral aldosterone (2.2 +/- 0.8 ng/dl) and 19-nor-DOC (12.2 +/- 2.4 ng/dl) were respectively similar to contralateral aldosterone (1.5 +/- 0.5 ng/dl) and 19-nor-DOC (14.6 +/- 1.3 ng/dl), whereas 19-nor-DOC was higher than aldosterone in each renal vein. The present study demonstrates that 19-nor-DOC is produced, not only from the kidneys, but also from the ipsilateral adrenal of patients with aldosterone-producing adenomas. The ipsilateral adrenal 19-nor-DOC production is comparable to that of aldosterone, suggesting that 19-nor-DOC may be contributing to the hypertension and hypokalemia in this disease. In the contralateral adrenal, aldosterone is suppressed to a greater extent than 19-nor-DOC, suggesting that these two steroids are under the influence of two different regulatory mechanisms.

Corticotropin-independent effect of ovine corticotropin-releasing hormone on cortisol release in man.

The effect of corticotropin-releasing hormone (CRH), independent of adrenocorticotropin hormone (ACTH), was evaluated in nine healthy individuals. Cortisol release and corresponding ACTH production were determined after separate intravenous administration of ovine-CRH (1 micrograms/kg BW) and insulin inducing hypoglycemia (0.1 u/kg BW). Adrenocorticotropin hormone (1-24; 250 micrograms intravenous bolus) revealed an adequate adrenal reserve capacity in all subjects. At the time of peak cortisol response following CRH and insulin administration, IR-cortisol increments were 14 +/- 1 micrograms/dl and 9 +/- 1 micrograms/dl (mean +/- SE), respectively (p less than .05); whereas ACTH (IR-ACTH) increments were 40 +/- 10 ng/l and 53 +/- 14 ng/l, respectively. The cortisol increment/ACTH increment ratios were 0.53 +/- 0.09 and 0/36 +/- 0.09, respectively (p less than 0.05), suggesting an ACTH-independent effect of CRH on cortisol production. The authors speculate that CRH may have a direct effect on the human adrenal gland or it may release ACTH-like factors that stimulate the human adrenal cortex.

Adrenocorticosteroid excretion in salt-sensitive and salt-resistant spontaneously hypertensive rats.

Two strains of spontaneously hypertensive rats (SHRs) differ in their susceptibility to the hypertensive effects of dietary NaCl. One strain exhibits a significant elevation of blood pressure after dietary NaCl loading (SHR-S), whereas the other does not (SHR-R). Since differences in adrenocortical steroid production may contribute to NaCl sensitivity, we compared 19-nordeoxycorticosterone (DOC), 18-OH-DOC, aldosterone, and corticosterone excretion in 6-week-old male rats from the SHR-S (n = 24) and SHR-R (n = 24) strains. The rats were housed in metabolic cages (two rats per cage) and given either basal (1%) or high (8%) NaCl diet. Urinary steroids were analyzed using thin-layer chromatography and radioimmunoassay methods. The high NaCl diet elevated the urinary excretion of the four corticosteroids in both rat strains. 19-nor-DOC decreased with time in both the SHR-S and SHR-R strains, and was not different between strains on either diet. Aldosterone was increased in the SHR-S strain compared with the SHR-R strain on the low NaCl diet, but aldosterone was not different between the two strains on the high NaCl diet. Corticosterone and 18-OH-DOC did not differ between strains. These data confirm that 19-nor-DOC is higher in young prehypertensive SHRs and decreases with age. Aldosterone excretion is higher in the SHR-S strain compared with the SHR-R strain on the low NaCl diet.(ABSTRACT TRUNCATED AT 250 WORDS)

19-Nordeoxycorticosterone synthesis by rat kidney inner medullary collecting duct cells.

19-Nordeoxycorticosterone (19-nor-Doc), a potent mineralocorticoid, was found to be synthesized by the isolated rat kidney perfused by an adrenal precursor (19-oxo-Doc). To determine if this bioconversion is a function of renal tubular cells, various adrenal precursors of 19-nor-Doc were added separately to rat kidney inner medullary collecting duct cells culture media at a concentration of 10 nM. While 4.6% +/- 1.0% of 19-oxo-Doc (n = 3) and 14.4% +/- 1.4% of 19-oic-Doc (n = 3) were converted to 19-nor-Doc after 24 hours of incubation, Doc, and 19-OH-Doc were not converted. This represents further evidence that Doc has to be metabolized to 19-oxo-Doc or 19-oic-Doc (19-carboxy-Doc) before it can be converted by the kidney inner medullary collecting duct cells to 19-nor-Doc.

19-nor-DOC biosynthesis in the isolated perfused rat kidney.

19-nor-deoxycorticosterone (19-nor-DOC) is a potent salt retaining and hypertensinogenic mineralocorticoid that is excreted in the urine. While the precursor of 19-nor-DOC, 19-oxo-DOC, is produced by the adrenal cortex, conversion to 19-nor-DOC does not occur in the adrenal gland. We have examined the hypothesis that 19-nor-DOC is synthesized from precursors in the kidney. 19-oxo-DOC was added to the perfusate of isolated rat kidney preparations (n = 5) at a concentration of 10 microM. During 1 h of perfusion following addition of 19-oxo-DOC, 71 +/- 6% of the precursor was converted to 19-oic-DOC, an immediate precursor of 19-nor-DOC, and 8.3 +/- 1.8% was converted to 19-nor-DOC. This represents the first definitive evidence that 19-nor-DOC is produced in the kidney from adrenal precursors.

Comparison of the mineralocorticoid activity of 19-oxygenated and 19-nor derivatives of deoxycorticosterone.

19-Nordeoxycorticosterone (19-nor-DOC) is a mineralocorticoid with several unresolved physiologic questions. First, is 19-nor-DOC synthesized in the kidney from a circulating adrenocortical precursor (19-oicdeoxycorticosterone [19-oic-DOC] or 19-oxodeoxycorticosterone [19-oxo-DOC])? Second, does 19-nor-DOC, synthesized in the kidney, have mineralocorticoid activity or is it excreted in the urine without biologic activity? To answer this question, we administered two of the putative 19-nor-DOC precursors (19-oxo-DOC and 19-oic-DOC) to adrenalectomized rats and measured the formation of 19-nor-DOC and bioactivity as the urinary Na+ to K+ ratio. Each of the 10-microgram steroid treatments produced an elevation of urinary-free 19-nor-DOC (0 to 2 hours), whereas at the 1-micrograms dose only 19-oic-DOCA produced an increased UF 19-nor-DOC. None of the treatments led to an increase of conjugated 19-nor-DOC except 10 microgram 19-oic-DOCA. Increased mineralocorticoid activity (decreased urinary Na+ to K+ ratio) was produced by aldosterone, 1 and 10 micrograms 19-nor-DOC, and 10 micrograms 19-oic-DOCA over the same time period. An anti-mineralocorticoid effect (increased urinary Na+ to K+ ratio) was produced by 1 microgram 19-oxo-DOC. Urinary-free 19-nor-DOC, but not conjugated 19-nor-DOC, correlated with the urinary mineralocorticoid effect (decreased Na+ to K+ ratio). These data support the contention that 19-oic-DOC is the circulating 19-nor-DOC precursor and that, at least at the higher dose, it has a mineralocorticoid action on the kidney.(ABSTRACT TRUNCATED AT 250 WORDS)

Could intranasal insulin be useful in the treatment of non-insulin-dependent diabetes mellitus?

To evaluate whether intranasal insulin might be useful as a meal-adjunct in the treatment of NIDDM we compared plasma glucose and insulin responses to a mixed breakfast (9 kcal/kg, 50% carbohydrate) following either intranasal insulin (INI) or placebo in eleven patients with NIDDM. Five patients treated with subcutaneous insulin and in good to moderate glycemic control and six patients who were 'failing' on oral agents and in poor glycemic control were studied. In the patients usually on sc insulin, INI inhibited postprandial hyperglycemia. Lower doses (1 U/kg vs 1.5 U/kg b.w.) were needed to accomplish this in 2 patients with low fasting glucose (less than or equal to 7.8 mmol/l) than in three patients with higher fasting glucose (10.5 +/- 0.5 mmol/l). In the patients on oral agents who had marked fasting hyperglycemia (14.8 +/- 0.8 mmol/l) an only transient reduction (for 90 to 120 min) of postprandial hyperglycemia was achieved when INI (1 U/kg) was given in addition to po glyburide (10 mg) prior to the meal. Following placebo in the group previously treated with sc insulin, plasma free insulin levels increased maximally by 23 mU/l, 75 min after the meal. The group on oral agents had a comparable but later peak increment (at 180 min) indicative of an even greater impairment of endogenous insulin secretion in response to hyperglycemia. Following INI, the peak increment in plasma insulin occurred earlier (30 min after the meal) and was greater in all patients (55 +/- 18, 139 +/- 68, 86 +/- 24 mU/l respectively for the prior sc insulin therapy group at doses of 1.0 and 1.5 U/kg and for the oral agent group at 1.0 U/kg).(ABSTRACT TRUNCATED AT 250 WORDS)