alpha-Glucosidase inhibition improves postprandial hyperglycemia and decreases insulin requirements in insulin-dependent diabetes mellitus

In patients with diabetes mellitus, delayed increases in circulating insulin levels followed by prolonged hyperinsulinemia due to slow absorption of subcutaneously administered insulin hinders maintenance of euglycemia. To determine whether a delay in carbohydrate absorption would increase the effectiveness of subcutaneous insulin in controlling postprandial hyperglycemia in patients with insulin-dependent diabetes mellitus and whether it could allow insulin to be taken immediately prior to meals, the effects of an alpha-glucosidase inhibitor (Acarbose Boyer AG, Wuppertal, Germany) on postprandial plasma glucose profiles were determined in six subjects with insulin-dependent diabetes when a subcutaneous insulin infusion was started immediately or 30 minutes prior to meal ingestion. When 25% less insulin (9 v 12 units) was given along with Acarbose 30 minutes prior to meal ingestion, postprandial hyperglycemia decreased by 45% (areas under the curve, AUC, 8193 +/- 1960 v 14783 +/- 2260 mg/dL X min, P less than 0.02). When similar amounts of insulin (12 units) were given immediately prior to meal ingestion, postprandial hyperglycemia decreased 55% (AUC 6187 +/- 2240 v 13642 +/- 1579 mg/dL X min, P less than 0.001). These results indicate that delay in carbohydrate absorption improves the effectiveness of subcutaneous insulin in controlling postprandial hyperglycemia in patients with insulin-dependent diabetes mellitus and may permit satisfactory postprandial glycemic control when insulin is administered immediately prior to meal ingestion. Thus, an agent like Acarbose, which delays carbohydrate absorption, may be useful as an adjunct to insulin in the treatment of diabetes mellitus.     

Sequence of events during development of the dawn phenomenon in insulin-dependent diabetes mellitus

During constant insulin infusion (0.15 mU X kg-1 X min-1) from 12 PM to 8 AM in 10 IDDM patients previously rendered euglycemic (Biostator), plasma glucose (5.4 +/- 0.2 mmol/L at 12 PM) increased by 3:30 AM and reached 12.1 +/- 1.6 mmol/L at 8 AM (P less than 0.001). Glucose production also increased at 3:30 AM; hyperglycemia, glucose utilization did not increase until after 5 AM. Plasma growth hormone (12 PM to 4 AM), cortisol (after 3:30 AM), noradrenaline (after 1:30 AM), and adrenaline (after 3:30 AM) but not glucagon increased significantly overnight, although plasma adrenaline and noradrenaline remained at subthreshold levels. Insulin clearance increased (approximately 25%, P less than 0.05) but only after 7 AM, resulting in a 4 mU/L decrease in plasma insulin. A significant correlation was found between increases in plasma glucose and increases in glucose production (r = 0.74, P less than 0.05) which in turn were significantly correlated with nocturnal peaks in plasma growth hormone (r = 0.66, P less than 0.05). From the sequence of events observed, we conclude that the Dawn Phenomenon in IDDM begins earlier than is currently thought (approximately 3:30 AM), that it is due to both accelerated glucose production and impaired glucose utilization, and that nocturnal increases in sympathetic nervous system activity and/or growth hormone secretion, but not changes in secretion of cortisol, adrenaline and glucagon or changes in insulin clearance, may be of pathogenetic importance.     

Effects of the disaccharidase inhibitor acarbose on meal and intravenous glucose tolerance in normal man

To determine whether the effects of the disaccharidase inhibitor Acarbose on glucose tolerance could be solely explained via an action on intestinal nutrient absorption, the effects of this agent and placebo (100 mg p.o.) on intravenous and postprandial glucose tolerance were compared in six normal subjects. Acarbose significantly diminished plasma glucose, insulin, and gastrointestinal inhibitory polypeptide responses following meal ingestion without affecting plasma glucagon and pancreatic polypeptide responses, but had no effect on plasma glucose and insulin responses following intravenous injection of glucose. These results suggest that the acute effects of Acarbose on glucose tolerance can be explained on the basis of its ability to alter intestinal nutrient absorption.     

Effects of a long-acting somatostatin analogue on postprandial hyperglycemia in insulin-dependent diabetes mellitus

To determine whether an agent such as WY-41,747, a long-acting somatostatin analogue, could be useful as an adjunct to insulin in the treatment of diabetes mellitus, postprandial plasma glucose concentrations were determined in subjects with insulin-dependent diabetes rendered euglycemic with the Biostator insulin infusion device under four conditions: (1) subcutaneous minipump infusion of insulin alone (13 +/- 1 units) over 30 minutes beginning 30 minutes before ingestion of a meal using insulin doses determined by the Biostator; (2) the same conditions as 1 but beginning immediately before meal ingestion; (3) the same conditions as 1 but with less insulin (7 +/- 1 units) accompanied by the analogue (0.01-0.05 mg/kg); (4) the same conditions as 2 but with the analogue and less insulin (11 +/- 1 units). Administration of the somatostatin analogue increased the effectiveness of insulin in controlling postprandial hyperglycemia and permitted satisfactory postprandial glycemic control when the insulin infusion was initiated immediately before meal ingestion. Administration of the analogue suppressed postprandial plasma glucagon and triglyceride concentrations and delayed xylose absorption. These results suggest that subcutaneous administration of a long-acting somatostatin analogue such as WY-41,747 along with insulin may be clinically useful in the treatment of diabetes mellitus.     

Adrenergic modulation of pancreatic somatostatin,insulin, and glucagon secretion: Evidence for differential sensitivity of islet A,B, and D cells

To characterize the adrenergic effects of epinephrine on somatostatin, insulin and glucagon release and to assess the potential interactions of islet A, B, and D cell function, isolated rat islets were incubated in vitro with epinephrine (0.05–20 μM) in the presence and absence of the alpha adrenergic antagonist, phentolamine (2 or 4 μM), and/or the beta adrenergic antagonist, propranolol (2 μM). At concentrations of epinephrine at or less than 1 μM, somatostatin and insulin release were inhibited while glucagon release was unaffected. At greater epinephrine concentrations, somatostatin and glucagon release were increased while insulin release was further suppressed. The threshold as well as the half-maximal effect of epinephrine occurred at lower concentrations for somatostatin release than for insulin and glucagon release. The inhibitory effect of 0.5 μM epinephrine on somatostatin and insulin release was completely reversed by phentolamine and was unaffected by propranolol. The stimulatory effect of 2 and 20 μM epinephrine on somatostatin and glucagon release was not observed when propranolol was included in the incubation medium along with epinephrine. These results demonstrate that rat islet A, B, and D cells differ in their sensitivity to alpha and beta adrenergic effects. At low concentrations of epinephrine, alpha adrenergic effects on D cells predominate over beta adrenergic effects whereas at greater concentrations of epinephrine alpha and beta effects appear to be equal; alpha adrenergic effects of epinephrine predominate over those of beta on the B cell at least up to 20 μM epinephrine; exclusively beta adrenergic effects of epinephrine are observed on the A cell at least up to 20 μM epinephrine.     

Effect of intermittent physiologic hyperglucagonemia on postprandial plasma glucose levels in normal man

The ability of glucagon to impair glucose tolerance has been questioned by studies involving infusion of exogenous glucagon during a glucose load. Since such hormone administration may not reflect the physiologic pattern of glucagon secretion and may result in hepatic downregulation to glucagon, the present experiments have examined the effects of intermittent andogenous hyperglucagonemia (induced by episodic infusion of arginine) on plasma glucose profiles of normal man following ingestion of mixed meals. In control studies following meal ingestion, plasma glucose, insulin and glucagon increased respectively 15–30 mg/dl, 30–60 uU/ml and 25–50 pg/ml. When meals were accompanied by arginine infusions, plasma glucagon responses were augmented three to fourfold (p < 0.05). Amplitudes of glycemic excursions during infusion of arginine (345 ± 40 mg/dl) were significantly augmented compared to those observed in control studies (286 ± 34 mg/dl, p < 0.02). These results indicate that intermittent increases in plasma glucagon within the physiologic range can adversely affect postprandial glucose profiles in normal man despite concomitant hyperinsulinemia and suggest that such hyperglucagonemia may contribute to impaired postprandial glucose tolerance in diabetic individuals in whom insulin secretion is deficient.     

Theophylline potentiates glucagon-induced hepatic glucose production in man but does not prevent hepatic downregulation to glucagon

Prolonged hyperglucagonemia causes only a transient increase in hepatic glucose production. To determine whether activation of hepatic phosphodiesterase by glucagon is responsible for the transient nature of this response, the effect of infusion of the phosphodiestrase inhibitor theophylline alone, glucagon alone, and glucagon plus theophylline on isotopically determined glucose production was examined in normal human subjects. Infusion of theophylline alone did not alter rates of glucose production or utilization. Infusion of glucagon alone increased glucose production transiently from a basal rate of 1.9 ± 0.1 mg/kg/min to a maximum at min 30 of 2.8 ± 0.3 mg/kg/min followed by a return to rates no different from basal by min 60; plasma glucose increased from 89 ± 3 mg/dl to a maximum of 114 ± 5 mg/dl. Infusion of glucagon in the presence of theophylline resulted in greater increases in both plasma glucose (maximum at min 60 of 134 ± 9 mg/dl) and glucose production (maximum at min 30 of 3.5 ± 0.3 mg/kg/min) than had occurred during infusion of glucagon alone; the increase in glucose production, however, was not sustained. Thus theophylline potentiated glucagon-induced stimulation of hepatic glucose production, but it did not prevent the evanescent hepatic response to sustained hyperglucagonemia. Therefore, the present studies indicate that glucagon activation of hepatic phosphodiesterase does not appear to be responsible for the transient nature of the increase in hepatic glucose production observed during prolonged hyperglucagonemia.     

Stereospecific determination and in vivo monodeiodination of thyroxine enantiomers in euthyroid man

To compare in man the absorption, serum disappearance, and peripheral monodeiodination of the thyroxine enantiomers, we studied six euthyroid subjects who, on separate occasions, orally ingested 3 mg of either dextrothyroxine (DT₄) or levothyroxine (LT₄). We measured the serum concentrations of total T₄ (TT₄), total T₃, and reverse T₃ (rT₃) by nonstereospecific radioimmunoassay and we determined serum DT₄ by stereospecific chromatography. Mean serum TT₄ levels from 4 hours were significantly greater after LT₄ administration. After DT₄ administration, stereospecific analysis of serum revealed two T₄ peaks that persisted from 2 to 48 hours. The mean serum LT₄ leved did not significantly change during the 48 hours after DT₄ administration. Increases in serum T₃ and rT₃ were seen from 2 hours after administration of either enantiomer. From 12 hours the levels of both triiodothyronines after LT₄ were significantly higher than after DT₄. In this short term study we found no evidence that in man DT₄ is converted to LT₄, nor is it preferentially deiodinated to rT₃. The greater and more persistent increases in serum T₄ and T₃ observed after LT₄ probably contribute to the known higher bioactivity of that enantiomer.     

Osteoid osteoma: 95 cases and a review of the literature

Osteoid osteoma is a benign bone tumor occurring primarily in patients under the age of 30 yr. Bone pain at night and relief by aspirin or other nonsteroidal antiinflammatory agents is a common symptom complex. The proximal femur and spine are frequent sites of involvement, but almost any bone can be involved. If plain roentgenograms do not demonstrate the lesion, tomography or a bone scan may be helpful. Complete surgical excision is the therapy of choice with a low recurrence rate. Osteoid osteoma may present initially with symptoms suggestive of inflammatory arthritis, degenerative joint disease, neoplasm, or infection. This lesion can therefore be a difficult diagnostic problem, especially if routine roentgenograms are normal. A high index of suspicion is necessary to make the diagnosis.     

The clinical aspects of biclonal gammopathies. Review of 57 cases

Between 1966 and 1979, biclonal gammopathy was recognized in 57 patients. Clinical and laboratory features differentiated three groups: biclonal gammopathy of undetermined significance, 37 cases (65 percent); multiple myeloma, nine cases (16 percent); and lymphoproliferative disease--including lymphoma, macroglobulinemia, chronic lymphocytic leukemia and unclassified lymphoproliferative disorders--11 cases (19 percent). With biclonal gammopathy of undetermined significance, symptomatic multiple myeloma developed after two years in one patient; the others remained stable. One patient with multiple myeloma had osteosclerotic myeloma and a severe sensorimotor peripheral neuropathy, and another presented with plasma cell leukemia. In the remainder response to therapy and survival were much the same as in patients with multiple myeloma with a monoclonal protein. Patients with lymphoproliferative disease responded to chemotherapy like that for monoclonal gammopathy. Of the 57 patients, 30 (53 percent) had IgG and IgA components, 15 (26 percent) had IgG and IgM, six had two IgG components, three had IgA and IgM, one had IgA proteins, one had IgA and IgE and 1 had triclonal gammopathy. Of the 115 light chains, 70 percent were kappa; the chains were both kappa and lambda in 63 percent of biclonal pairs. In many cases, serum electrophoresis produced only a single band on the acetate strip, and the biclonal gammopathy was not recognized until immunoelectrophoresis was done. Although the clinical features of biclonal gammopathy and its response to therapy are similar to those of monoclonal gammopathy, this subject is of importance because of the lack of clinical data in the literature.     

Clinical features and long-term natural history of the postpericardiotomy syndrome

We followed 34 consecutive patients with the postpericardiotomy syndrome for a median of 7 years. In each patient, the syndrome was documented by the occurrence of: (1) a pericardial type of pain or pericardial rub (or both); and (2) fever or an elevated erythrocyte sedimentation rate. The postpericardiotomy syndrome occurred at a median postoperative time of 4 weeks (range, 2 to 52 weeks). The duration of the syndrome was highly variable (range, 2 to 100 days; median, 22 days) and depended primarily on treatment; the median duration of symptoms in 21 patients treated with salicylates alone was only 4 days. Of the 9 patients receiving anticoagulants alone and in whom this treatment was continued, none had clinical evidence of hemopericardium. On follow-up, 7 patients (21%) had an initial recurrence at an interval of 1 to 3 months; 5 of these patients had further recurrences at an interval of 3 to 30 months.This long-term study indicates that the postpericardiotomy syndrome is a benign but often recurrent clinical entity, presumably related to viral and/or immunologic factors.     

Anaplastic plasma cell myeloma and immunoblastic lymphoma. Clinical, pathologic, and immunologic comparison

To test whether highly anaplastic myeloma and immunoblastic lymphoma are truly identical disease processes, simultaneous series were compared in respect to cytomorphologic features, immunoglobulin content or secretion, clinical and laboratory findings, and patient survival. Although the series partially overlapped in each studied feature, different trends served to distinguish them. Of the 14 patients with myeloma, all were dead at two years, whereas six of the 22 patients with lymphoma were disease-free at 35 to 78 months. Only 50 percent of patients with myeloma received intensive chemotherapy, whereas all 19 patients with stage III or IV lymphoma received such therapy. Myelomas secreted predominantly IgA heavy chain rather than IgG and lambda light chain rather than kappa. Lymphomas contained predominantly IgM rather than IgG and kappa rather than lambda. There were no IgM myelomas and no IgA lymphomas. The shorter survival of patients with the extremely anaplastic form of myeloma, as compared with patients who had immunoblastic lymphoma, may relate, in part, to prior therapy for previous lower grade myeloma; however, intrinsic differences in the nature of these two disease processes are reflected in their disparate immunologic characteristics.     

Employment and recreation patterns in patients treated by percutaneous transluminal coronary angioplasty: a multicenter study

Employment and recreational patterns were analyzed in 279 patients who underwent percutaneous transluminal coronary angioplasty (PTCA) for treatment of symptomatic coronary artery disease. PTCA was successful in 180 patients (65%). When it was unsuccessful, coronary artery bypass graft surgery was usually performed (80%). Return-to-work rates were high irrespective of the outcome of PTCA. Of patients employed full-time or part-time before treatment, 98.5% of those who had successful PTCA alone and 97% of those whose PTCA was unsuccessful but who underwent uncomplicated coronary artery bypass surgery maintained or improved their work status. In a subgroup of men who had been employed in occupations requiring physical labor, 85% of the men whose PTCA was successful returned to work, compared with 68% of those whose PTCA was unsuccessful. The interval from attempted PTCA to return to work was significantly shorter in the successfully treated group; in patients with successful PTCA, the median time to return to work was 14 days, compared with 60 days in patients in whom PTCA was unsuccessful (p less than 0.001). During follow-up, patients with successful PTCA had less angina and were more active in recreational activities than patients who required alternative treatments.     

Return to work after coronary angioplasty: A report from the national heart, lung, and blood institute percutaneous transluminal coronary angioplasty registry

Employment status was analyzed in 2,250 patients enrolled at 65 clinical centers in the NHLBI PTCA Registry. Patients were classified into 3 groups depending on the outcome of PTCA. In 63.6%, PTCA was successful without MI or CABG (Group A); in 25.3%, PTCA was unsuccessful and was followed by CABG (Group B); and in 11.1%, PTCA was unsuccessful and was followed by medical therapy alone (Group C). At entry, 68.3% of all patients were employed full- or part-time. The clinical characteristics of the 3 groups were different. Patients in Group C had a higher incidence of previous MI and previous CABG. In addition, patients in Group C had a significantly decreased baseline employment rate compared with those in Group A. At a mean follow-up of 1.5 years, there was a small but similar decrease in the percentage employed fullor part-time in all groups.

Employment status also was analyzed in a subset of 1,150 patients working full- or part-time at baseline and aged 60 years or younger, who would be expected to have the highest return to work rates. At a mean follow-up of 1.4 years, 81 to 86% of patients remained working irrespective of the outcome of PTCA. However, patients with successful PTCA returned to work significantly sooner. The occurrence of chest pain during follow-up in these patients was an important predictor of return to work, irrespective of the outcome of dilatation. In patients with chest pain during follow-up, only 77% were working, compared with 90% of patients who had not had chest pain.     

Lipid metabolism in pregnancy. VIII. Effects of dietary fat versus carbohydrate on lipoprotein and hepatic lipids and tissue triglyceride lipases

We have asked, is hypertriglyceridemia in the fed state in pregnancy due to intolerance to exogenous fat, accumulation of endogenous triglycerides, or accumulation of remnants of d < 1.006 lipoprotein metabolism? To answer these questions, we fed rat-free diets high in starch or sucrose, or diets containing fat or fat plus cholesterol to pregnant and nonpregnant rats for 12 days until gestational day 21 (term = 22 days). Blood was obtained 0, 4, or 8 hr after removal of food from the cages. Lipid concentrations were determined in chylomicrons and very low, low, and high density lipoproteins. Hypertriglyceridemia in pregnancy exists on both starch and sucrose containing fat-free diets and is exaggerated 4 and 8 hr after food is removed from the cage. The triglyceride rise occurs in d < 1.006 lipoproteins. With fat feeding, chylomicron triglyceride concentrations are not significantly elevated in pregnant rats, 0 or 8 hr postabsorptively despite greater food intake in pregnancy. In contrast, very low density lipoprotein (VLDL) triglyceride concentrations are elevated at all times following fat feeding in pregnant compared to nonpregnant animals. A significant contribution of lipoprotein remnants to the triglyceride rise in d < 1.006 lipoproteins seems unlikely since an isolated increase in VLDL cholesterol is not observed. No statistically significant accumulation of hepatic triglycerides occurs on any diet in pregnancy. Diet induced shifts in adipose tissue and muscle lipoprotein lipase activity are exaggerated in pregnancy while hepase in unaffected. Fetal weight is similar on all diets except sucrose where weight is reduced. Conclusions: Hypertriglyceridemia in fed pregnant rats is due to an increase in endogenous triglycerides. Remnant lipid accumulation does not appear to contribute to the endogenous hypertriglyceridemia. There is no intolerance to exogenous (dietary) fat. The results are compatible with an unimpaired delivery of exogenous fat to fat oxidizing tissues thereby maximizing glucose availability for fetal growth.     

Amelioration of streptozotocin-induced diabetes in rats: effect of islet isografts on plasma lipids and other metabolic abnormalities.

Administration of streptozotocin in rats results in many metabolic abnormalities, including hyperlipidemia. Plasma triglycerides, cholesterol, insulin, and glucose levels were compared in normal rats, in rats with streptozotocin-induced diabetes, and in streptozotocin-injected rats ameliorated of diabetes 1 mo later by transplantation of adult or neonatal islets to the liver or the lung. Mean plasma glucose levels were 98 ± 4 mg/dl in normal rats, 504 ± 36 mg/dl in untreated diabetic rats, and 139 ± 18, 146 ± 9, and 117 ± 19 mg/dl in recipients of intraportal adult islets, intraportal neonatal islets, and i.v. neonatal islets, respectively; the glucose levels in the recipients of intraportal islets were significantly higher than in normal rats. Mean plasma insulin levels were 23 ± 4 μU/ml in normal rats, 12 ± 5 μU/ml in diabetic rats, and 46 ± 14, 84 ± 25, and 30 ± 5 μU/ml in recipients of intraportal adult islets, intraportal neonatal islets, and i.v. neonatal islets, respectively; the insulin levels in the recipients of intraportal islets were also significantly higher than those in normal rats. Mean plasma triglyceride levels were 35 ± 3 mg/dl in normal rats, 280 ± 72 mg/dl in diabetic rats, and 49 ± 9, 58 ± 8, and 70 ± 4 mg/dl in recipients of intraportal adult islets, intraportal neonatal islets, and i.v. neonatal islets, respectively; the levels in recipients of neonatal islets were significantly higher than those in normal rats. Mean plasma cholesterol levels were 122 ± 10 mg/dl in normal rats, 88 ± 13 mg/dl in diabetic rats, and 105 ± 10, 166 ± 19, and 114 ± 18 mg/dl in recipients of intraportal adult islets, intraportal neonatal islets, and i.v. neonatal islets, respectively; the levels were significantly higher than normal only for the group receiving neonatal islet tissue via the portal vein. Islet transplantation ameliorated diabetes, but mild hyperglycemia persisted even though plasma insulin levels were elevated above normal in recipients of intraportal islets. In addition, plasma triglyceride levels remained slightly elevated after transplantation of neonatal islets, and cholesterol levels were elevated in the group with the highest insulin levels. Possible mechanisms to explain the abnormalities after islet transplantation are discussed. The results indicate the difficulty in restoring completely normal metabolism by ectopic islet transplantation in diabetic recipients.     

Neurocrest and colonic tumors: new clinical syndrome. Report of three cases

This report describes three patients with both multiple intestinal polyps and tumors of neural crest origin. This combination of findings may represent a new clinical syndrome. The embryologic relationships between tumors derived from endoderm and tumors derived from neurocrest are described. An inherent defect in tissue proliferation or repair is postulated to explain the abnormal growth in these two different cell lines.     

Normal serum thyroxine values in patients with acute psychiatric illness

The medical records of 278 consecutive patients with acute psychiatric illness admitted to a closed psychiatric unit after admission from the emergency room were reviewed. Serum thyroxine levels had been determined within 72 hours of admission in 106 patients (38 percent); in 74 of these patients (70 percent), the determination had been made within 24 hours. Ten patients (9 percent) were hypothyroxinemic, but further thyroid testing revealed that they were functionally euthyroid. Only one patient had hyperthyroxinemia, which was considered secondary to her postpartum state. The prevalence of hypothyroxinemia in the population studied is consistent with that in previous reports. However, the striking absence of hyperthyroxinemia in these patients is contrary to findings in several recent reports. Further prospective studies should clarify this issue.