Biomedical subjects
Publications and source records attributed to H E Lebovitz.
The sulfonylureas may prevent progression from impaired glucose tolerance to diabetes as well as control hyperglycemia. Patient response depends on the physiologic status of insulin secretion and effectiveness, however.
Explore the source record for details and available documents.
PURPOSE: Non-insulin-dependent diabetes mellitus (NIDDM) in black Americans consists of two variants: one with insulin resistance and one with normal insulin sensitivity. This study examined whether cardiovascular disease risk factors are significantly different between the two variants. PATIENTS AND METHODS: Twenty-two black patients with NIDDM in near-normoglycemic remission who were receiving no pharmacologic therapy for NIDDM were evaluated for insulin sensitivity by the euglycemic insulin clamp, plasma insulin levels, degree of obesity, glucose metabolism, serum total, high-density lipoprotein (HDL), and low-density lipoprotein (LDL) cholesterol levels, and fasting plasma triglyceride levels. RESULTS: Fifty-nine percent of these patients had normal insulin sensitivity (glucose disposal rate in response to a 1 mU.kg-1.minute-1 insulin infusion greater than 6.0 mg.kg-1.minute-1). The insulin-sensitive patients were less obese (body mass index [BMI] 26.5 +/- 0.6 versus 30.8 +/- 0.9 kg/m2) and had lower fasting plasma insulin levels (56.9 +/- 7.8 versus 88.0 +/- 6.0 pmol/L), lower serum cholesterol (4.47 +/- 0.30 versus 6.39 +/- 0.26 mmol/L), lower serum LDL cholesterol (2.77 +/- 0.31 versus 4.51 +/- 0.27 mmol/L), and lower fasting plasma triglyceride levels (0.83 +/- 0.08 versus 1.45 +/- 0.16 mmol/L) than the insulin-resistant patients. Serum HDL cholesterol was not different between the two groups and was in the high-normal range (1.31 +/- 0.08 and 1.19 +/- 0.07 mmol/L). Univariate analysis demonstrated that serum total cholesterol, LDL cholesterol, and fasting plasma triglycerides were highly correlated with insulin-mediated glucose disposal and fasting plasma insulin. The differences in insulin sensitivity and lipid profiles were independent of obesity, as they were present in six insulin-resistant and six insulin-sensitive patients matched for BMI. CONCLUSIONS: Black patients with the insulin-sensitive variant of NIDDM have a low risk factor profile for cardiovascular disease as compared with those with the insulin-resistant variant, who have a high risk factor profile. A high prevalence of the insulin-sensitive variant of NIDDM in the black population might explain the lower prevalence of angina and myocardial infarction in black patients with NIDDM as compared with white patients with NIDDM.
OBJECTIVE: We had previously shown two variants among black non-insulin-dependent diabetic (NIDDM) subjects in a normoglycemic remission: one with insulin resistance and the other with normal insulin sensitivity. This study examined whether these two variants exist in the ordinary hyperglycemic black NIDDM population. RESEARCH DESIGN AND METHODS: Fifty-two black NIDDM subjects were assessed for insulin-stimulated glucose disposal (euglycemic clamp), glycemic control (fasting plasma glucose and HbA1c), and fasting lipid profiles. RESULTS: The distribution of glucose disposal in 30 black NIDDM subjects (body mass index; BMI less than 30 kg/m2) was bimodal, which indicated two populations. Eighteen of 30 subjects (BMI 26.4 +/- 0.5 kg/m2) had insulin resistance (glucose disposal 3.21 +/- 0.24 mg.kg-1.min-1). Twelve of 30 subjects (BMI 24.83 +/- 1.1 kg/m2) had normal insulin sensitivity (glucose disposal 7.19 +/- 0.46 mg.kg-1.min-1). Twenty-one of the remaining 22 subjects (BMI 33.4 +/- 0.7 kg/m2) were insulin resistant (glucose disposal 2.88 +/- 0.21 mg.kg-1.min-1). Fasting serum triglyceride levels were lowest in the insulin-sensitive population (0.91 +/- 0.07 mM) and different from the insulin-resistant population, BMI less than 30 and greater than 30 kg/m2, (1.20 +/- 0.10 mM, P less than 0.05 and 1.42 +/- 0.17 mM, P less than 0.025, respectively). Fasting serum low-density lipoprotein cholesterol levels were not significantly different among the groups, although it did increase with insulin resistance and increasing obesity. Total serum cholesterol levels and glycemic control were similar for all three groups. Serum high-density lipoprotein cholesterol levels were higher in women compared with men. CONCLUSIONS: In the hyperglycemic black NIDDM population, two variants exist: one with insulin resistance and one with normal insulin sensitivity. This insulin-sensitive variant represents 40% of subjects with a BMI less than 30 kg/m2. Moreover, the insulin-sensitive group has a lower risk profile for cardiovascular disease.
Normoglycemic remission has been observed in black non-insulin-dependent diabetic individuals. Thirty-three patients presented with severe hyperglycemia (mean glucose 682 mg/dl) and were hospitalized for initial treatment. Following intensive outpatient therapy including insulin or sulfonylurea for 0.25 to 96 weeks, they became normoglycemic without pharmacologic treatment. This state was characterized by normal glycosylated hemoglobin levels in 29 of 30 patients and fasting plasma glucose levels of less than or equal to 115 mg/dl in 25 of 33 patients. During clinical remission these individuals were characterized as being lean to moderately obese (body mass index less than 30.5 kg/m), relatively young (45 years of age), and largely male (male:female ratio was 2:1). Thirty percent of the patients underwent normoglycemic remission after 3 months of treatment, 64% within 6 months, and 85% within 12 months. Normoglycemic remission was not related to weight loss or amelioration of stress and lasted from several months to as long 97 months. The results of the oral glucose tolerance test during remission showed that 9 had normal, 7 had impaired, and 17 had diabetic glucose tolerance. Thirteen of the 33 patients relapsed and developed hyperglycemia after a mean of 24.9 months. Relapse was not associated with weight gain or acute stress. Islet cell antibodies were uniformly absent, implying that these individuals did not have an autoimmune form of diabetes. It is not known if remission in non-insulin-dependent diabetes is unique to the black population. Neither the prevalence nor the mechanism of the development of remission is known at this time.
The effects of 4 weeks of streptozotocin-induced diabetes in the rat on sciatic nerve homogenate protein kinase activities were studied. There was a 47 +/- 7% inhibition of Ca+2-dependent protein kinase activity in nerves from the diabetic rats compared to that in their paired normal controls. This Ca+2-dependent activity did not require the addition of phospholipid and was only minimally affected by Sephadex G-50 gel filtration, suggesting that endogenous phospholipid activation was not responsible for this activity. The addition of phospholipid in the presence of Ca+2 revealed an additional activity in these homogenates which probably represents the Ca+2-phospholipid-dependent protein kinase (protein kinase-C). The diabetic state did not appear to alter that activity. The Ca+2-dependent protein kinase was sensitive to agents known to inhibit calmodulin-dependent protein kinase or protein kinase-C. The IC50 values of the inhibitors for the Ca+2-dependent protein kinase, however, differed from those reported for the other two kinases.
Our objective was to define glomerular filtration rate (GFR) and renal plasma flow (RPF) in Black Americans with non-insulin-dependent diabetes mellitus (NIDDM). This was a cross-sectional study of 71 Black NIDDM patients with diagnosed diabetes duration from 1 mo to 21 yr. Hyperglycemia was regulated and stabilized before patients were entered into the study. GFR and RPF were determined by the clearance of [125I]iothalamate and 131I-labeled hippuran, respectively, with a constant-infusion technique and four urine collection periods. Hyperfiltration, as defined by a GFR of greater than 140 ml.min-1.1.73 m-2, was found in 7 of 20 patients (35%) with newly diagnosed (less than 2 yr duration) NIDDM. The percentage of patients with hyperfiltration decreased with increasing duration of diagnosed diabetes. Decreasing GFR and RPF occurred with increasing duration of diagnosed diabetes. In conclusion, renal hemodynamic changes in Black Americans with NIDDM are similar to those known to occur in White populations with IDDM.
Although controversies remain as to the usefulness of sulfonylureas, most evidence is in favor of their use in many if not patients with non-insulin-dependent diabetes mellitus. When used properly, sulfonylureas improve insulin secretion and action, and these effects may be maintained for years. If combined with hypocaloric dietary regulation, rapid- and short-acting sulfonylureas may help patients reach and maintain euglycemia without provoking chronic hyperinsulinemia or weight increase. There is no evidence that sulfonylurea treatment causes beta-cell exhaustion; instead, the antihyperglycemic effect helps improve beta-cell function. Sulfonylurea "failures" are often dietary failures or may be due to late introduction of these drugs, i.e., when beta-cell function is already attenuated. Desensitization of the insulinotropic effect of sulfonylureas may occur but might be avoided by discontinuous (less than 24 h/day) sulfonylurea exposure, i.e., once-daily administration of a short-acting sulfonylurea in a moderate dose. The most important adverse effect of sulfonylureas is long-lasting hypoglycemia, which may lead to permanent neurological damage and even death. This is mainly seen in elderly subjects who are exposed to some intercurrent event, e.g., acute energy deprivation or a drug interaction, i.e., aspirin. Long-acting sulfonylureas may be more likely to promote long-lasting hypoglycemia. The dose-response relationships of sulfonylureas have been poorly investigated, and sulfonylurea therapy should always be initiated and maintained at the lowest possible dose.
This study describes and characterizes a putative sulfonylurea receptor. The radioligand used was [3H]glipizide (9 Ci/mmol). The beta-cell plasma membranes were derived from a transplantable rat insulinoma generated by subcutaneous injection of RINm5F cells and purified by ultracentrifugation on a 15-55% sucrose gradient. Specific binding of [3H]glipizide to purified beta-cell plasma membranes was determined to be maximal at temperatures of 4-23 degrees C, pH 7.3, and an incubation of 2 h. Scatchard analysis indicated a single binding site with Kd = 7 nM and sulfonylurea binding of 0.93 pmol/mg membrane protein. Displacement of [3H]glipizide from the purified beta-cell plasma membranes by various sulfonylureas and their analogues correlated well with their known hypoglycemic and insulin-releasing activities. Various agents, including nutrients, agents affecting Ca2+ flux, gastrointestinal hormones, and pancreatic hormones, had no effect on [3H]glipizide binding to the beta-cell plasma membranes. Putative sulfonylurea receptors on beta-cell and brain cell plasma membranes have been reported by several groups of investigators. Sulfonylurea binding to the beta-cell is hypothesized to close an ATP-sensitive K+ channel, which leads to depolarization of the membrane and activation of a voltage-dependent Ca2+ channel.
The effects of 3 mo of treatment with a combination of glipizide and human proinsulin were studied in a small group of closely monitored patients. The patients had non-insulin-dependent diabetes mellitus (NIDDM) and poor glucose regulation, despite maximal sulfonylurea therapy. This was a randomized double-blind placebo-controlled trial in which there were three treatment groups who received either 20 mg glipizide given 30 min before breakfast and dinner and human proinsulin given subcutaneously at bedtime (n = 5), glipizide and human proinsulin placebo (n = 5), or glipizide placebo and human proinsulin (n = 5). Glycemic regulation was assessed by measurements of 24-h plasma glucose profiles and glycosylated hemoglobin. Our observations demonstrate that the combination of glipizide plus human proinsulin was more effective than either agent alone in controlling overall glycemia in patients with NIDDM. The data support the concept of use of an agent during the day that has its major effects postprandially and another agent at bedtime that is relatively hepatospecific.
Combination sulfonylurea-insulin therapy for patients with diabetes mellitus has been evaluated by numerous investigators with various experimental designs. Much of the data are conflicting, and clear conclusions do not seem justified. Insulin-sulfonylurea therapy is probably not clinically useful in most patients with insulin-dependent diabetes mellitus. Most non-insulin-dependent diabetic (NIDDM) patients are also unlikely to have meaningful improvement in glycemic regulation on insulin-sulfonylurea therapy. A subset of NIDDM patients who are mildly to moderately obese, have adequate endogenous insulin secretory reserve, and are in poor glycemic regulation (fasting plasma glucose greater than 11 mM and/or HbA1 greater than 10%), despite twice-daily insulin administration of greater than 70 U/day, may show significant improvement of glycemic regulation and/or decreases in insulin daily dose on insulin-sulfonylurea therapy. The mechanisms by which insulin-sulfonylurea therapy improves glycemic regulation and decreases insulin requirements involve an increase in endogenous insulin secretion and possibly some extrapancreatic actions of the sulfonylureas on muscle and liver.
To define the sequence of events that is involved in the pathogenesis of non-insulin-dependent diabetes mellitus (NIDDM), we studied 16 NIDDM individuals (15 of 16 Black patients) with a mean age of 44 yr who had been near normoglycemic for 2-91 mo while off of antidiabetic medicine. With the euglycemic insulin clamp at 100 microU/ml insulin, we defined two populations, one with normal peripheral insulin sensitivity (glucose disposal 7.51 +/- 0.97 mg.kg-1.min-1) and the other with insulin resistance (glucose disposal 3.35 +/- 0.58 mg.kg-1.min-1; P less than .001). The populations did not differ in age, degree of obesity, fasting plasma glucose, glycosylated hemoglobin, clinical presentation, or clinical course. Basal plasma insulin levels were normal in the sensitive group and significantly elevated in the resistant group. Islet cell cytoplasmic antibodies were absent in all patients. Insulin action on the liver was normal in both groups. Basal hepatic glucose production measured with D-[3-3H]glucose was lower in the insulin-resistant group (1.53 +/- 0.11 mg.kg-1.min-1) than in the insulin-sensitive group (1.88 +/- 0.06 mg.kg-1.min-1) or normal control subjects (1.93 +/- 0.05 mg.kg-1.min-1). The decreased basal hepatic glucose production appeared to be secondary to the twofold higher fasting plasma insulin level seen in the insulin-resistant group. The insulin concentration necessary to suppress basal hepatic glucose production by 50% was 29.6 microU/ml in the insulin-sensitive group and 30.5 microU/ml in the insulin-resistant group.(ABSTRACT TRUNCATED AT 250 WORDS)
Explore the source record for details and available documents.
Pancreatic polypeptide (PP) deficiency has been associated with impaired hepatic sensitivity to insulin and pancreatogenic diabetes in chronic pancreatitis. Since pancreatic resection might also result in PP deficiency, hepatic responses to insulin infusion (0.25 mU/kg/min) were determined by the euglycemic glucose clamp technique in 10 patients who had previously undergone pancreatic resection for trauma and in eight healthy control subjects. Six resection patients (RES-PP) demonstrated deficient PP levels, with a mean increase of plasma immunoreactive PP of 20 +/- 7 pg/ml above basal rate after a test meal compared with 232 +/- 82 pg/ml in control subjects (p less than 0.01) and 353 +/- 133 pg/ml in four other patients undergoing resection with normal levels of immunoreactive PP (RES + PP) (p less than 0.03). Three identical insulin infusion studies were performed in each subject, the second of which was performed during the final 2 hours of an 8-hour infusion of bovine PP (2.0 pmol/kg/min). Whereas hepatic glucose production (HGP) in control subjects fell 74% +/- 4% from a basal rate of 2.0 +/- 0.1 mg/kg/min to a 60- to 120-minute value of 0.5 +/- 0.1 mg/kg/min during insulin infusion, HGP was suppressed only 58% +/- 5% in RES-PP subjects, from 1.9 +/- 0.1 to 0.8 +/- 0.1 mg/kg/min (p less than 0.05 vs controls). Intravenous infusion of PP corrected the hepatic resistance to insulin seen in the PP-deficient group. During PP infusion, HGP was suppressed 74% +/- 5% in RES-PP subjects, from 2.1 +/- 0.2 to 0.5 +/- 0.1 mg/kg/min (p less than 0.04 compared with initial study). PP infusion produced no significant change in glucose metabolism in control and RES + PP subjects. Overall glucose disposal rates were not altered by PP infusion in any group. These findings support a role of PP as a glucoregulatory hormone and suggest that PP deficiency may serve as a reversible pathophysiologic factor in the abnormal glucose metabolism seen after pancreatic resection.
This article reviews the history of oral hypoglycemic agents in the treatment of patients with non-insulin-dependent diabetes mellitus. It chronicles the rise and fall of the use of these agents as the major treatment modality for NIDDM, from their initial success in the late 1950's, to their being abandoned after the controversial findings of the University Group Diabetes Program, to their eventual resurgence as important agents in the management of hyperglycemia in NIDDM patients.
Explore the source record for details and available documents.
Explore the source record for details and available documents.
Mongrel dogs were prepared by cholecystectomy, ligation of the lesser pancreatic duct, and insertion of modified Thomas cannulas into the stomach and duodenum. When the dogs had recovered from surgery, studies were performed on them, conscious and unanesthetized after an overnight fast. The common bile duct was catheterized through the opened duodenal cannula for collection of hepatic bile. Bile flow was stabilized by the intravenous infusion of sodium taurocholate. After 2 hr of taurocholate infusion, insulin was added to the infusion and continued for the duration of the experiment. Glucose was administered intravenously during the first 120 min of insulin administration to maintain euglycemia; then the glucose was discontinued. The intravenous infusion of insulin during euglycemia maintained by glucose infusion caused a significant increase in bile flow and a decrease in bile salt concentration, but no change in bile salt output. There was a decrease in cholesterol concentration and output and in phospholipid concentration, but no significant change in phospholipid output. When glucose infusion was discontinued and hypoglycemia occurred, there was a further significant increase in bile flow, but no other change. These studies demonstrate that the choleretic action of insulin is not dependent upon hypoglycemia and that intravenously administered insulin may cause increased bile secretion without increase in serum glucagon concentration. These experiments also confirm that insulin choleresis may be associated with a decline in cholesterol output.