Hyperinsulinemia and central adiposity: influence of chronic insulin therapy in type 1 diabetes.
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Adipose Tissue↗
Biomedical subjects
U M Kabadi
Publications and source records attributed to U M Kabadi.
Normal thyroxine and elevated thyrotropin concentrations: evolving hypothyroidism or persistent euthyroidism with reset thyrostat.
BACKGROUND: The natural course in subjects manifesting normal serum thyroxine (T4), and triiodothyronine (T3), with an elevated thyrotropin (TSH) level demonstrated two distinct outcomes, one progressing to well defined hypothyroidism as expressed by onset of subnormal T4, T3 and a further rise in TSH and the other remaining in the same state. However, thyroid hormone concentrations at the time of diagnosis fail to distinguish between the two groups. Therefore, we examined the influence of alteration in circulating TSH levels on thyroid gland function at the time of diagnosis in subjects with this syndrome to assess the role of pituitary thyroid axis in these different outcomes. METHODS: 24 hour 131I thyroidal uptake was determined in 14 men and 3 women manifesting normal T4, T3 and elevated TSH prior to and again after 1) subcutaneous administration of bovine TSH, 10 units daily for 3 days and 2) daily oral administration of L-triiodothyronine 75 micrograms for 7 days in a randomized sequence at interval of 4 weeks. Subjects were then followed for up to 16 years to assess the natural course. RESULTS: Basal 24 hour 131I uptake values were within the normal range (10-35%) in all subjects and increased on TSH administration and declined following LT3 administration. However, in eight subjects, these responses were markedly lower (< 20%) when compared with the minimum change (50%) noted in normal volunteers. These subjects progressed to manifest hypothyroidism requiring LT4 therapy within two years as reflected by a progressive decrease to subnormal T4 levels with a further rise in serum TSH. The remaining nine subjects, demonstrated normal responses (> 50%) and only one of these became hypothyroid during the follow-up period of 16 years. CONCLUSION: All subjects with normal T4 and T3 with elevated TSH do not manifest "subclinical or evolving hypothyroidism". Two distinct populations seem to exist, one with inhibited pituitary thyroid axis progressing to hypothyroidism or true "subclinical hypothyroidism" at the time of diagnosis and the other with normal pituitary thyroid axis, a state of euthyroidism with "reset thyrostat" at a higher TSH concentration, a state probably persisting for their remaining life span.
Adult↗
Pancreatic alpha-cell function in idiopathic reactive hypoglycemia.
Idiopathic reactive hypoglycemia (IRH) is a well-documented but overdiagnosed syndrome. The presence of transient hypoglycemia and enhanced insulin secretion and/or increased insulin sensitivity before the onset of IRH is well documented. However, the data regarding glucagon secretion are sparse. Therefore, this study assessed glucagon and insulin responses to (1) oral ingestion of 100 g glucose oral glucose tolerance test (OGTT) and (2) a 100-g protein meal after an overnight fast in a randomized sequence at intervals of 7 to 10 days in five subjects with previously well-documented IRH and six normal subjects. Basal plasma glucose and insulin levels were not significantly different in both groups. However, basal glucagon was significantly higher (P < .025) in IRH subjects (347 +/- 83 ng/L) compared with normals (135 +/- 20 ng/L). In IRH subjects during the OGTT, hypoglycemia (2.7 +/- 0.11 mmol/L) occurred at 150 +/- 16 minutes and was preceded by a markedly higher (P < .01) peak glucose concentration (11.7 +/- 0.6 mmol/L) at 36 +/- 6 minutes in comparison to normals (8.8 +/- 0.4 mmol/L), indicating the presence of impaired glucose tolerance in these subjects. Similarly, the plasma insulin increase was significantly higher (P < .01) but delayed in IRH subjects compared with normals. In contrast, glucagon suppression was not significantly different in both groups, although glucagon failed to increase following hypoglycemia in IRH. During a protein meal, plasma glucose declined in both groups, with a significantly (P < .05) greater decrease in IRH subjects (-0.8 +/- 0.2 mmol/L) compared with normals (0.5 +/- 0.1 mmol/L). However, the glucagon increase was significantly (P < .01) blunted in IRH subjects (61% +/- 15%) in comparison to normals (152% +/- 39%). Thus, basal hyperglucagonemia with normal glucose concentration may suggest the presence of a hyposensitivity of the glucagon receptor in IRH. Moreover, the lack of appropriate suppression during the OGTT despite marked hyperglycemia, the lack of an increase at the onset of hypoglycemia, and the inhibited response to a protein meal in IRH subjects compared with normals denote altered glucagon secretion in IRH. Therefore, it is likely that glucagon receptor downregulation and impaired glucagon sensitivity and secretion may contribute to postprandial hypoglycemia in IRH.
Adult↗
Influence of age on optimal daily levothyroxine dosage in patients with primary hypothyroidism grouped according to etiology.
BACKGROUND: Optimal daily levothyroxine (LT4) dosage is reported to be significantly smaller in the elderly with primary hypothyroidism when compared with their younger counterparts. However, this finding has not been studied in different etiologic groups. METHODS: This study assessed the influence of age on optimal daily LT. dosage in 337 patients with primary hypothyroidism grouped according to etiology. RESULTS: Daily LT. dosage declined with increasing age in 99 patients with Hashimoto's thyroiditis, in 73 patients with idiopathic variety, and in 47 patients with hypothyroidism due to radical neck surgery and/or neck radiation for non-thyroidal malignancies. In contrast, daily LT. dosage rose with age in 85 patients who had radioiodine (131I) therapy and/or subtotal thyroidectomy for hyperthyroidism. Finally, daily LT. dosage was not significantly altered in 22 patients with subclinical hypothyroidism or in 11 patients with drug-induced hypothyroidism. CONCLUSION: Optimal daily LT4 dosage does not decline universally in all elderly with primary hypothyroidism: it appears to depend also on the etiology of the disorder.
Adult↗
Efficacy of insulin and sulfonylurea combination therapy in type II diabetes. A meta-analysis of the randomized placebo-controlled trials.
BACKGROUND: Numerous studies demonstrate the efficacy of the combination therapy of insulin and sulfonylurea in subjects with type II diabetes mellitus. However, two recent meta-analyses of randomized trials during the last decade provided inconsistent conclusions and failed to resolve the controversy. OBJECTIVE: To assess the efficacy of insulin and sulfonylurea combination therapy in type II diabetes mellitus by performing meta-analysis of only the controlled studies selected according to specific strict criteria. METHODS: A computerized literature survey was conducted using the MEDLINE database from January 1980 through March 1992 with the search headings of "sulfonylurea" and "insulin" and "combination therapy in diabetes mellitus. "A manual search was also performed using references from each retrieved report. Case reports, review articles, editorials, and citations reported in non-English-language journals without English translations were excluded. Forty-three citations were obtained. Four strict inclusion criteria were used to select studies: randomized, placebo-controlled trials (oral agent plus insulin vs placebo plus insulin); homogeneous target population (subjects with type II diabetes); intervention using the same sulfonylurea agent in a combination therapy; and uniform outcome measures to evaluate efficacy such as body weight; values for serum glucose, glycohemoglobin, and C peptide; daily insulin dosage; and lipid concentrations. More stringent qualitative subcriteria were then used to eliminate bias in the final unanimous selection by two blinded reviewers. Data were pooled and analyzed using Student's t test and Winer's combined test. RESULTS: Sixteen studies satisfied the inclusion criteria. Metabolic control improved with the combination therapy as reflected by a significant lowering of fasting serum glucose values (P < .01) and glycohemoglobin concentrations (P < .025). Moreover, improved metabolic control was achieved with a significantly smaller daily insulin dose (P < .01) and without a significant change in body weight. Finally, the combination therapy enhanced the endogenous insulin secretion as expressed by an increase in fasting serum C peptide concentration (P < .05). CONCLUSIONS: Combination therapy with insulin and sulfonylurea may be a more appropriate and a suitable option to insulin monotherapy in subjects with non-insulin-dependent diabetes in whom primary or secondary failure to sulfonylurea developed. It may also be a more cost-effective way of long-term management in this group of subjects, especially in the elderly.
Blood Glucose↗
The effect on metabolic control of second-generation sulfonylurea drugs in patients with NIDDM after secondary failure to first-generation agents.
BACKGROUND: The literature contains few data examining the results of therapy with second-generation sulfonylurea drugs in subjects with non-insulin-dependent diabetes mellitus (NIDDM) after the onset of secondary failure to first-generation agents. The present study was undertaken to assess the efficacy of therapy with second-generation sulfonylurea in subjects with NIDDM following secondary failure to first-generation agents. METHODS: The study included 55 subjects with NIDDM who manifested secondary failure to first-generation sulfonylurea therapy. Of these, 29 subjects underwent therapy with the second-generation sulfonylurea glipizide, and 26 subjects were treated with glyburide, both drugs administered in the maximum daily dosage. Before initiation of the second-generation sulfonylurea agents and again at the end of 6 months, metabolic control was assessed by determination of fasting plasma glucose, glycosylated hemoglobin (HbA1c), and the lipid profile. RESULTS: Fasting plasma glucose and HbA1c levels were 209 +/- 31 mg/dL and 12.3 +/- 2.1%, respectively, before initiation of glipizide, and did not significantly change following therapy (fasting plasma glucose, 211 +/- 34 mg/dL; HbA1c, 11.7 +/- 1.8%). Similarly, no significant alteration was noted in these metabolic values in the glyburide group (before glyburide therapy, fasting plasma glucose, 180 +/- 16 mg/dL; HbA1c, 11.2 +/- 1.6%; after glyburide therapy, fasting plasma glucose, 184 +/- 20 mg/dL; HbA1c, 11.0 +/- 1.5%). Lipids also were not significantly altered following therapy with either glipizide or glyburide. Finally, for all subjects, fasting plasma glucose and HbA1c were 200 +/- 27 mg/dL and 11.9 +/- 2.0%, respectively, during treatment with first-generation drugs and did not change significantly following therapy with the second-generation agents (fasting plasma glucose, 205 +/- 20 mg/dL; HbA1c, 11.2 +/- 1.2%). P values were > .60 for all comparisons. CONCLUSIONS: Treatment with second-generation sulfonylurea agents for patients with NIDDM following onset of secondary failure to first-generation sulfonylurea drugs achieves no better metabolic control than treatment with first-generation agents.
Adult↗
Serum thyrotropin in primary hypothyroidism. A possible predictor of optimal daily levothyroxine dose in primary hypothyroidism.
BACKGROUND: Pretreatment thyrotropin levels may be a reliable predictor of the optimal daily dose of levothyroxine sodium in patients with primary hypothyroidism. However, the older method of serum thyrotropin determination, with the reference range of less than 1 to 8 mU/L, has given way to a newer, supersensitive thyrotropin assay, with a reference range of 0.5 to 5.0 mU/L. Thus, at present, the previously established relationship between the levothyroxine dose and the pretreatment serum thyrotropin concentration may not be reliable in predicting the optimal daily dose of levothyroxine. METHODS: We reassessed the relationship between the optimal daily levothyroxine dose and the pretreatment serum thyrotropin concentration as determined by the newer assay in 192 consecutive patients with primary hypothyroidism referred to an endocrinology clinic over a period of 4 years. RESULTS: The optimal daily dose of levothyroxine sodium ranged from 25 to 225 micrograms, with most patients (65%) requiring 100 to 150 micrograms/d and a median dose of 125 micrograms. Multiple regression analysis documented a significant curvilinear correlation between the mean pretreatment serum thryrotropin concentration and the optimal daily levothyroxine dose for individual groups divided according to available tablet strengths (r = .994, P < .001). A simple linear regression was also significant (r = .92, P < .001), although with an intercept much higher than the minimum levothyroxine sodium dose of 25 micrograms/d. However, the relationships markedly improved when the linear regressions were determined separately for two further subgroups at the median daily dose of 125 micrograms, providing equations to predict even the smallest optimal daily dose of levothyroxine. CONCLUSION: Pretreatment thyrotropin levels determined by new assays may also provide a useful guideline in determining the optimal daily maintenance dose of levothyroxine in patients with primary hypothyroidism.
Adult↗
More uniform diurnal blood glucose control and a reduction in daily insulin dosage on addition of glibenclamide to insulin in type 1 diabetes mellitus: role of enhanced insulin sensitivity.
Combination therapy with insulin and sulphonylurea has gained acceptance in management of subjects with Type 2 (non-insulin-dependent) diabetes mellitus. However, its role in management of Type 1 (insulin-dependent) diabetes mellitus remains controversial. In this study, the effect of combination therapy with insulin and glibenclamide on metabolic control, daily insulin dosage, and insulin sensitivity was assessed in subjects with Type 1 diabetes mellitus. Ten men with Type 1 diabetes mellitus participated in a randomized, double-blind, crossover, clinical trial with three treatment regimens, namely (1) insulin alone, (2) insulin and placebo, (3) insulin and glibenclamide, each lasting 3 months. Combination therapy induced: (1) reduction in daily insulin dosage; (2) more uniform blood glucose control as reflected by a lower average 24 h blood glucose level, a smaller difference between mean preprandial and 2 h postprandial blood glucose concentrations, decreased 24 h urine glucose excretion, and a decline in number of hypoglycaemic events; (3) improved insulin sensitivity as expressed by more rapid plasma glucose disappearance rate, without a significant alteration in fasting plasma glucagon and 1h postprandial serum C-peptide levels; when compared with treatment with either insulin alone or with insulin and placebo. Therefore, it is apparent that the addition of glibenclamide to insulin reduces daily insulin dosage and renders a greater uniformity to diurnal blood glucose control, most probably secondary to enhancement of insulin sensitivity.
Adult↗
Pancreatic ketoacidosis: ketonemia associated with acute pancreatitis.
Ketonaemia is well documented as a consequence of prolonged starvation, acute alcoholism, and uncontrolled diabetes mellitus. However, its occurrence in acute pancreatitis has not been described. In this report, three patients who manifested ketoacidosis at the time of presentation of acute pancreatitis are described. In none of these patients could ketoacidosis be attributed to any of the well known pathogenetic factors such as ethanol, diabetes mellitus or prolonged starvation. In one patient, both the serum ketone titres and increased anion gap persisted for several days during the recovery period, despite appropriate therapy (including restriction of oral intake or nasogastric suction, intravenous fluids, and analgesic administration), before declining in parallel with a decrease in serum lipase levels, and became undetectable following near normalisation of serum lipase. Therefore, we believe that pancreatic ketosis or ketoacidosis may be a distinct syndrome with ketogenesis being promoted and maintained by extremely high circulating pancreatic lipase concentrations.
Acid-Base Equilibrium↗
Renal calculi in primary hyperaldosteronism.
Increased urinary calcium (Ca++) excretion and the presence of negative Ca++ balance is well documented in primary hyperaldosteronism. However, renal calculi as a major manifestation of this disorder has not previously been described. This report describes a patient who presented with renal calculi in association with primary hyperaldosteronism. We believe that primary hyperaldosteronism was a major pathogenetic factor in the formation of renal calculi since the increased urinary excretion of Ca++ and uric acid noted at onset declined following a short-term spironolactone administration and remission from renal calculi has persisted following initial nephrolithotomy and continued spironolactone therapy, which also corrected hypertension and hypokalemia, a hallmark of this disorder.
Humans↗
Combinations sulfonylurea and insulin therapy in diabetes mellitus.
Management of diabetes mellitus (DM) continues to undergo evolutionary changes with further refinements as a result of enhanced understanding of the pathophysiology, technologic advances in glucose monitoring techniques and equipment, and an abundance of new drugs and insulin administration devices. Clearly, the maintenance of near normal blood glucose levels remains the prime goal of therapy in both noninsulin-dependent diabetes mellitus (NIDDM) and insulin-dependent diabetes mellitus (IDDM) especially in the light of the recent diabetes control and complications trial. In addition, the data has always supported the role of sustained hyperglycemia in precipitating diabetic ketosis and hyperglycemic nonketotic state, as well as recurrent infections and changes in lipid levels leading to atherosclerosis in large-sized and medium-sized arteries. Basic therapeutic modalities to achieve euglycemia in NIDDM patients remain the diet, exercise, oral agents, and insulin. Optimal management of associated medical disorders, such as hypertension and obesity, also is important to prevent the onset or progress of angiopathic complications. Combination therapy with insulin and oral agents is a frequently used treatment strategy in the last decade to achieve optimal metabolic control in this population if the therapy with oral agents alone fails to achieve this objective. Furthermore, in patients with IDDM manifesting extreme excursion of diurnal glycemia, this approach deserves trial as suggested in recent studies. However, it is imperative to assess this modality in light of the knowledge of pathophysiology of DM.
Diabetes Mellitus↗
The effect of recurrent practice at home on the acceptability of capillary blood glucose readings. Accuracy of self blood glucose testing.
OBJECTIVE: To judge how reliably patients perform capillary blood glucose testing over time with recurrent practice at home and to assess if a clinic glucose meter is an acceptable alternative to the clinical laboratory for monitoring patient performance. RESEARCH DESIGN AND METHODS: We compared capillary blood glucose readings obtained by patients with their own equipment and the venous blood glucose determinations by the clinical laboratory at three biweekly visits during the initial phase in 40 subjects attending the diabetes clinic at the Veterans' Affairs Medical Center in Phoenix, Arizona. We also compared patient-generated readings using their own equipment and the readings obtained by the clinic glucose meter and strips at five weekly visits during the second phase in 11 subjects who continued further participation. Error grid analysis was used for both comparisons. Capillary blood glucose readings obtained with clinic glucose meter and strips on one hand were correlated with venous blood glucose levels determined by the clinical laboratory. RESULTS: During the initial phase, 30 subjects consistently obtained clinically acceptable comparisons (zone A on the error grid, i.e., within 20% of the laboratory value) or improved over time, 9 subjects showed deterioration, and 1 subject failed to obtain zone A results on any of the visits. Three subjects who had consistently obtained zone A results during the initial phase maintained their performance, whereas eight subjects who had failed to achieve zone A values by the end of the initial phase gradually improved and ultimately achieved zone A values by the end of the study. A highly significant correlation was noted between clinic meter readings and laboratory values (r = 0.93, P < 0.00001). CONCLUSIONS: Clinically acceptable user proficiency in capillary blood glucose testing can be maintained in most subjects, with recurrent intensive education during follow-up clinic visits. Therefore, we recommend that these comparisons be performed and patient's technique be observed at each visit to monitor their performance. The clinic glucose meter is a suitable alternative to a clinical laboratory for user proficiency checks.
Adult↗
Acceptability of capillary blood glucose testing with Companion 2 after intensive individual patient training.
This study determined the accuracy and precision of the MediSense Companion 2 Blood Glucose Monitoring System in the hands of newly trained patients, after individual training. 101 subjects attending a diabetes clinic at a Veterans Affairs Medical Center participated in the study. Subjects were individually trained in the use of the Companion 2 system. They performed 10 practice control solution tests prior to two capillary blood glucose tests. Venous blood was collected within 15 minutes for comparative laboratory analysis. The comparisons were performed by both the linear regression and the total Grid analysis. The correlation between the first capillary blood glucose test results and the laboratory values was highly significant (r = 0.94, p = 0.0001). Total Error Analysis also revealed that the Systematic Error (SE), Random Error (RE) and Total Error (TE) were all well within the acceptable norms at two glucose levels of 5.5 mmol/(100 mg/dL) and 11.1 mmol/L (200 mg/dL); (SE < 15%, RE < 10% and TE < 15%). Therefore, this study demonstrates that Companion 2 provides precise and accurate values during capillary blood glucose testing by newly trained subjects following intensive individual training.
Adult↗
Falsely low serum thyroxine concentration measured with the Abbott TDx.
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Chemistry, Clinical↗
'Subclinical hypothyroidism'. Natural course of the syndrome during a prolonged follow-up study.
OBJECTIVE: To determine the natural course of the syndrome "subclinical hypothyroidism." DESIGN: Prospective study of 30 subjects with "subclinical hypothyroidism," as documented precisely by normal serum thyroxine and triiodothyronine concentrations and high serum thyrotropin levels on three occasions at intervals of 2 to 3 weeks. The subjects were followed up for 4 to 15 years (mean, 8.2 +/- 2.3 years), with repeated determinations of thyroid hormone indices at intervals of 3 to 6 months. SETTING: Endocrinology Clinic at the Veterans Affairs Medical Center. RESULTS: 16 subjects developed definitive primary hypothyroidism within 3 months to 2 years, as reflected by a progressive rise in serum thyrotropin level with a gradual decline in serum thyroxine and triiodothyronine concentrations, with serum thyroxine levels falling to subnormal concentrations. In 14 of these subjects, primary hypothyroidism could be attributed to known etiologic factors, whereas in the remaining two the cause was not apparent. Persistently elevated serum thyrotropin with normal serum thyroxine and triiodothyronine concentrations following a cyclic pattern was observed in 14 subjects during the follow-up period. In 11 of these subjects, there was a history of non-radical surgery or conventional radiation therapy to the neck area, whereas in the remaining three subjects, no apparent cause could be identified. CONCLUSIONS: "Subclinical hypothyroidism" is not always a forerunner of primary hypothyroidism. Two distinct populations evolve: (1) those with true preclinical or subclinical hypothyroidism, which may be predicted by the presence of one of the well-known etiologic factors responsible for onset of primary hypothyroidism, and (2) euthyroidism with reset thyrostat--a permanent state without a definitive progression to hypothyroidism, most probably secondary to a previous subtle insult to the thyroid gland.
Adult↗
Hepatic regulation of pancreatic alpha-cell function.
The direct feedback regulation between the endocrine gland and its target organ is an expected biological relationship. However, such a phenomenon is far from being well established in the case of the endocrine pancreas and its major target organ, the liver, especially since plasma glucose has been established as the prime regulator. In this perspective, I have reexamined the feedback regulation between plasma glucose and glucagon secretion by the pancreatic alpha cell. Surprisingly, available data in the literature appear to document a frequent breakdown of this well-established interdependence between plasma glucose and pancreatic alpha cells, as reflected by a sustained elevation of plasma glucagon levels in several physiologic and pathologic states with concurrent euglycemia or hyperglycemia. Moreover, normal or low glucagon concentrations in the presence of fasting hypoglycemia in patients with insulinoma or non-islet cell tumors secreting insulin-like peptides and in patients with hepatic glycogen storage disorders may enhance our hypothesis that plasma glucose level may not be the major regulator of glucagon secretion. Extensive data in the literature show that hyperglucagonemic states are characterized by a unique metabolic environment, namely hepatic glycogen depletion. Similarly, hepatic glycogen stores are abundant in the presence of normal or low glucagon concentrations. These findings imply a distinct relationship between hepatic glycogen content and plasma glucagon level.(ABSTRACT TRUNCATED AT 250 WORDS)
Animals↗
Combination sulfonylurea and insulin therapy in non-insulin-dependent diabetes mellitus.
Clinicians are frequently faced with treating non-insulin-dependent diabetics (NIDDM) who do not exhibit optimal glycemic control on maximal dosages of oral sulfonylurea agents or large dosages of insulin. Sustained hyperglycemia is implicated in the onset and progression of retinopathy, nephropathy, and neuropathy. Recent studies also suggest that hyperinsulinemia contributes to hypertension and altered lipid levels. Hence, the maintenance of euglycemia with minimal circulating insulin concentrations is the prime goal of therapy. Most studies document that the efficacy of combination therapy requires smaller insulin doses, enhances glycemic control without adverse effects on body weight or lipids, and decreases hypoglycemic episodes compared with insulin monotherapy. Therefore, combination therapy may be the optimal therapeutic option in NIDDM clients manifesting secondary failure to oral agents or insulin resistance.
Diabetes Mellitus, Type 2↗
Severe sensory motor polyneuropathy at the onset of diabetes mellitus. Total remission with testosterone therapy following recognition of associated hypogonadism.
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Diabetic Neuropathies↗