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Biomedical subjects

D M Nathan

Publications and source records attributed to D M Nathan.

At least 37 records · Page 2Linked to original sources
PubMed1997

Effects of fasting and glucose infusion on basal and overnight leptin concentrations in normal-weight women.

The plasma concentration of leptin is reduced in association with chronic energy restriction and weight loss in humans, but little is known about the acute effects of fasting and glucose infusion on leptin. In this study, plasma leptin, insulin, glucose, and fatty acid concentrations were measured daily in 14 healthy, normal-weight, female volunteers aged 24 +/- 4 y with a body mass index (kg/m2) of 24.2 +/- 3.6 during a 4-d fast. The mean plasma leptin concentration decreased by 54 +/- 8% with fasting (P = 0.0006, ANOVA). In a stepwise-regression model, the change in leptin concentration with fasting correlated most significantly with the change in insulin (R2 = 0.48, P = 0.0057) and to a lesser extent with the change in body fat by bioimpedance analysis (R2 = 0.19, P = 0.03). Plasma leptin concentrations measured every 20 min from 2000 to 0800 on the fourth night of the fast did not show a time-dependent rise. A continuous intravenous infusion of 5% glucose providing 1414 +/- 323 kJ/d (338 +/- 78 kcal/d) was begun after 4 d of fasting in seven subjects who continued to fast for an additional 6 d. Within 24 h of the glucose infusion, leptin concentrations increased significantly by 80 +/- 52% (P < 0.05). These data show the sensitivity of plasma leptin concentrations to small changes in energy supply and suggest a basic role of substrate metabolism in the short-term regulation of leptin.

Adult↗
PubMed1997

Long-term therapy of IDDM with an implantable insulin pump. The Implantable Insulin Pump Trial Study Group.

OBJECTIVE: To examine the long-term benefits and risks of treatment of IDDM with an implantable programmable insulin pump. RESEARCH DESIGN AND METHODS: Seventy-six patients with IDDM were studied at nine clinical centers. After 3-4 months of intensive subcutaneous therapy, the Infusaid Model 1000 pump was implanted, and insulin was delivered either intraperitoneally or intravenously for an average of 39.6 +/- 10 months (251 patient-years). Data was collected for glycemic control, lipid levels, weight gain, insulin requirements, adverse events, and quality of life. Sixty-three patients were also followed for 8.5 +/- 6.3 months (45 patient-years) after pump therapy was discontinued. RESULTS: Mean quarterly HbA1c fell with subcutaneous intensive therapy and remained stable on implantable pump therapy between 6.9 and 7.5%. Severe hypoglycemia was relatively rare, with only 4 episodes/100 patient-years of implantable pump therapy. This rate was significantly less than with subcutaneous intensive therapy before implantable pump initiation (33 episodes/100 patient-years) or after discontinuation of implantable pump therapy (36/100 patient-years) (P < 0.003). Weight did not increase significantly in the 1st year of therapy, but increased by 2.0 +/- 4.3 kg after 3 years of therapy. There were no significant differences in metabolic control or adverse events between intraperitoneal and intravenous insulin therapy except for minor differences in lipid levels and the more frequent development of catheter obstruction with intravenous delivery. Most pump slow-downs and catheter occlusions were corrected noninvasively. Quality of life, as measured by the Diabetes Control and Complications Trial instrument, showed high satisfaction and improved impact scores. CONCLUSIONS: Long-term implantable pump therapy maintained HbA1c in a range similar to intensive subcutaneous therapy, but with fewer episodes of severe hypoglycemia. Although pump and catheter occlusions remain a limitation, patient satisfaction with implantable pump therapy remains high.

Adult↗
PubMed1997

Risk variable clustering in the insulin resistance syndrome. The Framingham Offspring Study.

Insulin resistance has been hypothesized to unify the clustering of hypertension, glucose intolerance, hyperinsulinemia, increased levels of triglyceride and decreased HDL cholesterol, and central and overall obesity. We tested this hypothesis with factor analysis, a statistical technique that should identify one factor if a single process underlies the clustering of these risk variables. From 2,458 nondiabetic subjects of the Framingham Offspring Study, we collected clinical data, fasting and 2-h postchallenge glucose and insulin levels, and fasting lipid levels. We performed factor analyses separately for men and women in the entire population and among subgroups with features of the insulin resistance syndrome. Subjects ranged in age from 26 to 82 years (mean age 54); 53% were women, 13.4% had impaired glucose tolerance, 27.6% had hypertension, 40% were obese, and 11.6% were hyperinsulinemic, defined by elevated fasting insulin levels. Underlying the clustering of these risk variables were three factors. Fasting and 2-h postchallenge insulin levels, fasting triglyceride and HDL cholesterol levels, BMI, and waist-to-hip ratio were associated with one factor. Fasting and 2-h levels of glucose and insulin were associated with a second factor. Systolic blood pressure, diastolic blood pressure, and BMI were associated with a third factor. Results were similar for men and women and for all subgroups. These results were consistent with more than one independent physiological process underlying risk variable clustering: a central metabolic syndrome (characterized by hyperinsulinemia, dyslipidemia, and obesity), glucose intolerance, and hypertension. Glucose intolerance and hypertension were linked to the central syndrome through shared correlations with insulin levels and obesity. Insulin resistance (reflected by hyperinsulinemia) alone did not appear to underlie all features of the insulin resistance syndrome.

Adult↗
PubMed1996

The pathophysiology of diabetic complications: how much does the glucose hypothesis explain?

OBJECTIVE: To examine the putative pathogenetic mechanisms of the long-term, specific complications of diabetes mellitus. DATA SOURCES: Literature review relevant to long-term diabetic complications and their pathogenesis. STUDY SELECTION: Studies of animal models of diabetes, epidemiologic investigations of diabetes and its long-term complications, and interventional studies examining intensive treatment of diabetes and its effect on the development and progression of complications. DATA SYNTHESIS: Diabetic retinopathy, nephropathy, and neuropathy occur in all clinical forms of diabetes mellitus, regardless of the cause of the diabetes. Hyperglycemia appears to be the major variable shared among these different clinical forms; and epidemiologic data, studies in animal models of diabetes, and the results of recent interventional studies such as the Diabetes Control and Complications Trial, all support an important and perhaps dominant role of hyperglycemia in the pathogenesis of complications. However, the diverse complications may not share the same pathogenesis. Different pathogenetic mechanisms may operate in different types of diabetic complications or at different stages of specific complications, or both. CONCLUSIONS: The level of chronic glycemia is the best established concomitant factor associated with diabetic complications. The mechanism by which hyperglycemia might cause complications remains unknown, and evidence for a uniform pathogenetic mechanism is far from established.

Animals↗
PubMed1996

Tracking of glycated hemoglobin in the original cohort of the Framingham Heart Study.

Glycated hemoglobin measures average blood glucose over the preceding 2 to 3 months. The authors examined the tracking of the major glycated hemoglobin A1c (HbA1c), over a period of 4 to 6 years. Two HbA1c measurements were obtained between 1986 and 1993 from 639 elderly, presumptively nondiabetic members of the original cohort of the Framingham Heart Study, Framingham, Massachusetts. Mean +/- standard deviation (SD) baseline and follow-up HbA1c were 5.43% +/- 0.7 and 5.71% +/- 0.9, respectively. Intraclass correlation of 0.59 between baseline and follow-up measurements indicated good reliability of a single HbA1c measurement. Ninety-one percent of follow-up measurements were within +/- 20% of baseline value; HbA1c values tended to move 15% closer to the baseline mean over time. There was a modest tendency for HbA1c values to increase with time; the mean difference between measurements was 0.28% +/- 0.7 SD (p < 0.0001). Change in HbA1c was positively associated with age and body mass index at baseline examination, and negatively associated with cigarette smoking, even after controlling for age and body mass index. These effects were very small, however. We conclude that glycated hemoglobin reliably categorizes the glucose control of nondiabetic subjects over a period of 4 to 6 years, confirming its value as an epidemiological measure.

Aged↗
PubMed1996

Glycemic control in diabetes mellitus: have changes in therapy made a difference?

PURPOSE: New methods of measuring and controlling glycemia in diabetes mellitus have been developed and implemented in the past 10 years. We examined whether glycemia, as measured by glycosylated hemoglobin, changed in outpatient insulin-dependent diabetes mellitus (IDDM) and noninsulin-dependent diabetes mellitus (NIDDM) populations between 1985 and 1993 and whether contemporaneous changes in therapy could account for observed changes in glycemia. PATIENTS AND METHODS: Outpatients were selected based on having glycated hemoglobin (HbA1c) measured in the Massachusetts General Hospital laboratory during March 1985 (IDDM n = 94 and NIDDM n = 137) or during March 1993 (IDDM n = 89 and NIDDM n = 118). Chart reviews established demographic and clinical characteristics, including frequency of blood glucose self-monitoring, insulin injections, office visits, and HbA1c measurements during the year prior to the HbA1c result. RESULTS: Mean HbA1c level was significantly lower in the 1993 IDDM cohort compared with the 1985 cohort (8.77% +/- 1.7% versus 9.47% +/- 2.1%, P = 0.014). In the NIDDM cohorts, the difference in mean HbA1c did not achieve statistical significance (8.35% +/- 1.6% in 1993 versus 8.75% +/- 2.1% in 1985, P = 0.09); however, when adjusted for differences in NIDDM duration, HbA1c in the 1993 cohort was significantly lower than that in the 1985 cohort. The largest decrease in HbA1c in NIDDM was in patients treated with insulin (9.53% +/- 2.0% versus 8.54% +/- 1.5% in 1985 and 1993, respectively, P = 0.004). Multiple linear regression analyses demonstrated that increased frequency of self-monitoring and of insulin injections were associated with lower HbA1c in IDDM. CONCLUSIONS: The level of average glycemia has decreased in IDDM patients over the past 8 years, attributable, at least in part, to an increased frequency of monitoring and of insulin injections. Glycemia decreased in NIDDM, especially in the subset of patients treated with insulin. This temporal shift in glycemic control should have a salutary effect on the development of long-term microvascular and neurologic complications.

Adult↗
PubMed1996

Postprandial insulin profiles with implantable pump therapy may explain decreased frequency of severe hypoglycemia, compared with intensive subcutaneous regimens, in insulin-dependent diabetes mellitus patients.

PURPOSE: To examine the mechanism of the decreased frequency of severe hypoglycemia with implantable pump therapy compared with subcutaneous intensive therapy. PATIENTS AND METHODS: Eight subjects with insulin-dependent diabetes mellitus (IDDM), enrolled in an implantable insulin pump study, were admitted to the General Clinical Research Center and on 2 separate days were given either a dose of preprandial insulin chosen to maintain normoglycemia for a standard (450 kcal, 50% carbohydrate) breakfast or 1.75 times the dose. The two doses were administered subcutaneously (by syringe or with an external pump) during one inpatient admission and by implantable pump (intraperitoneally, n=6; or intravenously, n=2) during a separate admission. Blood glucose, plasma-free insulin, and neurocognitive function were measured for 4 hours after the meal. RESULTS: Subcutaneous administration resulted in 7 episodes of hypoglycemia (2 with the usual dose and 5 with the 1.75-fold dose), defined as blood glucose less than 50 mg/dL; implantable pump treatment resulted in only 2 episodes, both with the 1.75-fold dose (P <0.05, Fisher's two-tailed test for implantable versus subcutaneous). Compared with subcutaneous delivery, implantable pump therapy provided significantly lower insulin levels during the final 2 hours after administration of the usual dose and the 1.75-fold dose (P <0.005). In addition to the decreased frequency of hypoglycemia, implantable pump therapy resulted in significantly lower area under the glycemia curve during the first 120 minutes with the 1.75-fold dose compared with subcutaneous administration. CONCLUSIONS: The lower frequency of severe hypoglycemia with intensive therapy administered by implantable pump therapy is explained by the more rapid clearance of insulin delivered intraperitoneally or intravenously compared with intensive subcutaneous injection regimens. The lower frequency of severe hypoglycemia with implantable pump therapy compared with subcutaneous therapy demonstrated in clinical trials is confirmed by this study, in which we attempted to induce hypoglycemia.

Adult↗
PubMed1996

The effect of acarbose on insulin sensitivity in subjects with impaired glucose tolerance.

OBJECTIVE: To study the effect of acarbose, an alpha-glucosidase inhibitor, on postprandial plasma glucose and insulin and insulin sensitivity in subjects with impaired glucose tolerance (IGT). RESEARCH DESIGN AND METHODS: Subjects with IGT were randomly treated in a double-blind fashion with placebo (n = 10) or acarbose (n = 8) at 100 mg t.i.d. for 4 months. All subjects were submitted before randomization and at the end of the study to a standardized breakfast and a 12-h daytime plasma glucose and plasma insulin profile, and insulin sensitivity was measured as steady-state plasma glucose (SSPG) using the insulin suppression test. RESULTS: While placebo had no effect on postprandial plasma glucose and plasma insulin incremental area under the curve (AUC) (3.03 +/- 0.5 vs. 3.76 +/- 0.6 mmol.h-1.l-1, P = NS; 1,488 +/- 229 vs. 1,609 +/- 253 pmol.h-1.l-1, P = NS), acarbose resulted in a significant reduction for both glucose (1.44 +/- 0.3 vs. 4.45 +/- 0.9 mmol.h-1.l-1, P = 0.002) and insulin (626.7 +/- 104.3 vs. 1,338.3 +/- 220.5 pmol.h-1.l-1, P = 0.003). The reduction in 12-h plasma glucose and insulin AUC on acarbose (11.2 +/- 2.1 mmol.h-1.l-1 and 7.5 +/- 0.7 nmol.h-1.l-1) was significantly greater than that on placebo (4.0 +/- 1.6 mmol.h-1.l-1 and 0.8 +/- 0.4 nmol.h-1.l-1) (P = 0.014 and 0.041). While SSPG was not affected by placebo (13.9 +/- 0.4 vs. 13.8 +/- 0.3 mmol/l; P = NS), it was significantly improved by acarbose (10.9 +/- 1.4 vs. 13.1 +/- 1.5 mmol/l, P < 0.004) and was also significantly different from placebo at 4 months (P < 0.02). CONCLUSIONS: It is concluded that in subjects with IGT, acarbose treatment decreases postprandial plasma glucose and insulin and improves insulin sensitivity. Acarbose may therefore be potentially useful to prevent the progression of IGT to NIDDM.

Acarbose↗
PubMed1995

Prevention of long-term complications of non-insulin-dependent diabetes mellitus.

Non-insulin-dependent diabetes mellitus (NIDDM) may be the most rapidly-growing chronic disease in the world. Its long-term complications, including retinopathy, nephropathy, neuropathy, and accelerated macrovascular disease cause major morbidity and mortality. Although therapy that normalizes glycemia may prevent the development and delay the progression of long-term complications in NIDDM, as has been demonstrated in insulin-dependent diabetes mellitus (IDDM), no direct data exist to support the efficacy of "intensive therapy" in NIDDM. An alternative approach to preventing the development of long-term complications may be to intervene more distally, i.e., inhibit the mechanism(s) by which elevated glucose levels cause complications. Potential pathogenic mechanisms include the accumulation of sorbitol and other biochemical changes in tissues with aldose reductase, and the modification of proteins by glycation. Pharmacologic probes, including aldose reductase inhibitors and glycation inhibitors such as aminoguanidine, are currently under study and may provide an efficient means of preventing complications, independent of the ambient glycemic level.

Diabetes Mellitus, Type 2↗
PubMed1994

Utilization and cost analysis of bedside capillary glucose testing in a large teaching hospital: implications for managing point of care testing.

PURPOSE: To study the use and cost of bedside capillary glucose testing in a large teaching hospital. PATIENTS AND METHODS: In a prospective study of 40 inpatient units and 10 outpatient units at Massachusetts General Hospital, records were maintained by each unit of the date, time, operator, and results of patient and quality control tests. Cost analysis was performed using data from time studies, test tallies in logbooks, and hospital administration records. RESULTS: The number of glucose meters in the hospital increased from 10 to 54 over a 2-year period. In 1992, 67,596 tests were performed by the bedside method, representing 30.7% of all glucose measurements performed in the institution. The majority of tests (94.7%) were performed on inpatients, and 10.2% of all hospital admissions underwent bedside glucose testing. The impact on the number of glucose tests performed in the clinical laboratories was minimal, indicating that bedside glucose testing was added as an extra test rather than as a substitute for laboratory-based glucose measurements. The cost of bedside glucose testing was $4.19 per test compared with $3.84 in the clinical laboratory. The cost varied from one unit to another (median $5.52, range $3.08 to $48.16), an effect largely attributed to the difference in the volume of tests performed by different units. In seven high-volume units the cost per test was lower than the corresponding value in the laboratory. The cost of bedside glucose testing included labor (80.2%) and supplies (19.8%). The percent of costs attributed directly to patient testing was 57.7%, whereas the costs for all other related activities (training, quality control, and quality assurance) was 42.3%. CONCLUSIONS: Bedside capillary glucose testing is a rapidly expanding technology and is performed on a significant percentage of hospital admissions. Bedside glucose testing is not inherently more expensive than centralized laboratory measurements but implementation on inefficient care units with low utilization can add substantially to the cost. Much of the excess cost of the bedside method can be attributed to the high costs of quality control and quality assurance, training, and documentation.

Blood Glucose↗
PubMed1994

The uses of outcomes research for medical effectiveness, quality of care, and reimbursement in type II diabetes.

Randomized controlled trials (RCTs), such as the Diabetes Control and Complications Trial (DCCT), usually evaluate the efficacy of a single treatment strategy. The DCCT, for example, evaluates intensive diabetes management aimed at achieving glucose levels as close to normal as possible to modify specific pathophysiological outcomes--specifically, the development or worsening of microvascular disease. In contrast, longitudinal observational studies, such as the type II diabetes Patient Outcome Research Team (PORT) study, address medical effectiveness; that is, how well prevailing treatments work in clinical practice settings. The PORT relies heavily on patient-reported measures of general and diabetes-specific health status, in addition to using complications as major study outcomes. In the type II diabetes PORT, 4,000 patients with type II diabetes and a wide range of socioeconomic, demographic, and disease characteristics, from three widely dispersed geographic settings and varying systems of care, are being followed for a 2.5-year period. Data are collected from periodic self-administered patient questionnaires and from administrative data bases. In the PORT study, nonmutable confounders, such as case-mix, and potentially mutable features, such as patients' preferences for treatment, health habits, regimen adherence, family support, and physician's interpersonal style, are carefully measured. The PORT study will examine the effectiveness of preventive care and established disease treatment in relation to eye, cardiovascular, and extremity disease, measuring and relating use of health-care services to patient outcomes. The results have the potential for maximizing quality of care and minimizing use of services in type II diabetes by matching physician-level profiles of patient outcomes with medical-care-process data and making this information accessible to practicing physicians.

Clinical Trials as Topic↗
PubMed1993

The effect of intensive treatment of diabetes on the development and progression of long-term complications in insulin-dependent diabetes mellitus.

BACKGROUND: Long-term microvascular and neurologic complications cause major morbidity and mortality in patients with insulin-dependent diabetes mellitus (IDDM). We examined whether intensive treatment with the goal of maintaining blood glucose concentrations close to the normal range could decrease the frequency and severity of these complications. METHODS: A total of 1441 patients with IDDM--726 with no retinopathy at base line (the primary-prevention cohort) and 715 with mild retinopathy (the secondary-intervention cohort) were randomly assigned to intensive therapy administered either with an external insulin pump or by three or more daily insulin injections and guided by frequent blood glucose monitoring or to conventional therapy with one or two daily insulin injections. The patients were followed for a mean of 6.5 years, and the appearance and progression of retinopathy and other complications were assessed regularly. RESULTS: In the primary-prevention cohort, intensive therapy reduced the adjusted mean risk for the development of retinopathy by 76 percent (95 percent confidence interval, 62 to 85 percent), as compared with conventional therapy. In the secondary-intervention cohort, intensive therapy slowed the progression of retinopathy by 54 percent (95 percent confidence interval, 39 to 66 percent) and reduced the development of proliferative or severe nonproliferative retinopathy by 47 percent (95 percent confidence interval, 14 to 67 percent). In the two cohorts combined, intensive therapy reduced the occurrence of microalbuminuria (urinary albumin excretion of > or = 40 mg per 24 hours) by 39 percent (95 percent confidence interval, 21 to 52 percent), that of albuminuria (urinary albumin excretion of > or = 300 mg per 24 hours) by 54 percent (95 percent confidence interval 19 to 74 percent), and that of clinical neuropathy by 60 percent (95 percent confidence interval, 38 to 74 percent). The chief adverse event associated with intensive therapy was a two-to-threefold increase in severe hypoglycemia. CONCLUSIONS: Intensive therapy effectively delays the onset and slows the progression of diabetic retinopathy, nephropathy, and neuropathy in patients with IDDM.

Adolescent↗
PubMed1993

Baseline analysis of renal function in the Diabetes Control and Complications Trial. The Diabetes Control and Complications Trial Research Group [corrected].

To determine whether there are relationships between nephropathy, retinopathy and putative risk factors at points very early in the development of long-term complications of IDDM, we have analyzed baseline data pertinent to nephropathy in the 726 subjects in the primary prevention cohort and the 715 subjects in the secondary intervention cohort of the DCCT. AER correlated positively with CCr and HbA1c in both cohorts and with degree of retinopathy and duration of IDDM in the secondary cohort. Within the secondary cohort only mean BP and HbA1c levels were significantly increased (P < 0.005) in the 73 subjects with AER > or = 28 micrograms/24 hr compared to the 642 subjects with AER < 28 micrograms/24 hr. Stratification of all subjects in the secondary cohort showed significant associations (P < 0.001) between retinopathy level, AER, duration of diabetes at entry and entry HbA1c. Even very early in the development of retinopathy and nephropathy, there is a relationship between them and with level of metabolic control. The prospective studies of the DCCT are designed to answer the question of whether intensive diabetes treatment will affect the development and/or progression of retinopathy, and, possibly, of nephropathy.

Adolescent↗
PubMed1993

Defective major histocompatibility complex class I expression on lymphoid cells in autoimmunity.

Lymphocytes from patients with insulin-dependent diabetes mellitus (IDDM), a chronic autoimmune disease, have recently been shown to have decreased surface expression of MHC class I antigens. Since IDDM and other autoimmune diseases share a strong genetic association with MHC class II genes, which may in turn be linked to genes that affect MHC class I expression, we studied other autoimmune diseases to determine whether MHC class I expression is abnormal. Fresh PBLs were isolated from patients with IDDM, Hashimoto's thyroiditis, Graves' disease, systemic lupus erythematosis, rheumatoid arthritis, and Sjogren's syndrome. Nondiabetic and non-insulin-dependent diabetes mellitus patients served as controls. MHC class I expression was measured with a conformationally dependent monoclonal antibody, W6/32. Freshly prepared PBLs from the autoimmune diseases studied and the corresponding fresh EBV-transformed B cell lines had decreased MHC class I expression compared with PBLs from normal volunteers and non-insulin-dependent (nonautoimmune) diabetic patients. Only 3 of more than 180 donors without IDDM or other clinically recognized autoimmune disease had persistently decreased MHC class I expression; one patient was treated with immunosuppressive drugs, and subsequent screening of the other two patients revealed high titers of autoantibodies, revealing clinically occult autoimmunity. Patients with nonautoimmune inflammation (osteomyelitis or tuberculosis) had normal MHC class I expression. Autoimmune diseases are characterized by decreased expression of MHC class I on lymphocytes. MHC class I expression may be necessary for self-tolerance, and abnormalities in such expression may lead to autoimmunity.

Adult↗