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Background: Exenatide therapy is effective in combination with metformin or sulfonylureas for treating type 2 diabetes. Thiazolidinediones (TZDs) also are commonly used, but the efficacy of exenatide with a TZD has not been reported.Objective: To compare the effects of exenatide versus placebo on glycemic control.Design: Placebo run-in, randomized, double-blind, placebo-controlled trial conducted from May 2004 to August 2005.Setting: 49 sites in Canada, Spain, and the United States.Patients: 233 (exenatide group, n = 121; placebo group, n = 112) patients with type 2 diabetes that was suboptimally controlled with TZD treatment (with or without metformin). Mean (+/-SE) baseline glycated hemoglobin A1c level was 7.9% +/- 0.1%.Interventions: Subcutaneous abdominal injections of 10 microg of exenatide or placebo twice daily, added to a TZD (with or without metformin) for 16 weeks.Measurements: The primary outcome was change from baseline in hemoglobin A1c level. Other outcomes were fasting serum glucose level, body weight, self-monitored blood glucose level, and any adverse events.Results: Exenatide treatment reduced hemoglobin A(1c) level (mean difference, -0.98% [95% CI, -1.21% to -0.74%]), serum fasting glucose level (mean difference, -1.69 mmol/L [-30.5 mg/dL] [CI, -2.22 to -1.17 mmol/L {-40.0 to -21.1 mg/dL}]), and body weight (mean difference, -1.51 kg [CI, -2.15 to -0.88 kg]). Sixteen percent of patients in the exenatide group and 2% of patients in the placebo group discontinued treatment because of adverse events. In the exenatide group, 40% (n = 48) of patients experienced nausea (mostly mild [n = 21] or moderate [n = 19]), 13% experienced vomiting, and 11% experienced hypoglycemia. In the placebo group, 15% of patients experienced nausea, 1% experienced vomiting, and 7% experienced hypoglycemia.Limitations: Combinations with TZDs and sulfonylureas were not tested. Trial duration was relatively short. Only 71% and 86% of patients in the exenatide and placebo groups, respectively, completed the study.Conclusions: Exenatide therapy improved glycemic control, reduced body weight, and caused gastrointestinal symptoms more than placebo in patients with type 2 diabetes that was suboptimally controlled with TZD therapy. ClinicalTrials.gov registration number: NCT00099320. For more information on exenatide click here. [ABSTRACT FROM AUTHOR]

Background: Physicians may use either insulin or exenatide injections for patients with type 2 diabetes mellitus who have poor glycemic control despite taking oral blood glucose-lowering drugs.Objective: To compare effects of exenatide and insulin glargine on glycemic control in patients with type 2 diabetes mellitus that is suboptimally controlled with metformin and a sulfonylurea.Design: 26-week multicenter, open-label, randomized, controlled trial.Setting: 82 outpatient study centers in 13 countries.Patients: 551 patients with type 2 diabetes and inadequate glycemic control (defined as hemoglobin A1c level ranging from 7.0% to 10.0%) despite combination metformin and sulfonylurea therapy.Intervention: Exenatide, 10 microg twice daily, or insulin glargine, 1 daily dose titrated to maintain fasting blood glucose levels of less than 5.6 mmol/L (<100 mg/dL).Measurements: Hemoglobin A1c level, fasting plasma glucose level, body weight, 7-point self-monitored blood glucose, standardized test-meal challenge, safety, and tolerability.Results: Baseline mean hemoglobin A1c level was 8.2% for patients receiving exenatide and 8.3% for those receiving insulin glargine. At week 26, both exenatide and insulin glargine reduced hemoglobin A1c levels by 1.11% (difference, 0.017 percentage point [95% CI, -0.123 to 0.157 percentage point]). Exenatide reduced postprandial glucose excursions more than insulin glargine, while insulin glargine reduced fasting glucose concentrations more than exenatide. Body weight decreased 2.3 kg with exenatide and increased 1.8 kg with insulin glargine (difference, -4.1 kg [CI, -4.6 to -3.5 kg]). Rates of symptomatic hypoglycemia were similar, but nocturnal hypoglycemia occurred less frequently with exenatide (0.9 event/patient-year versus 2.4 events/patient-year; difference, -1.6 events/patient-year [CI, -2.3 to -0.9 event/patient year]). Gastrointestinal symptoms were more common in the exenatide group than in the insulin glargine group, including nausea (57.1% vs. 8.6%), vomiting (17.4% vs. 3.7%) and diarrhea (8.5% vs. 3.0%).Limitations: The trial was open-label and did not assess clinical complications related to diabetes. Of the 551 participants, 19.4% of those receiving exenatide and 9.7% of those receiving insulin glargine withdrew from the study. Only 21.6% of the insulin glargine group and 8.6% of the exenatide group achieved the target level for fasting plasma glucose of less than 5.6 mmol/L (<100 mg/dL).Conclusions: Exenatide and insulin glargine achieved similar improvements in overall glycemic control in patients with type 2 diabetes that was suboptimally controlled with oral combination therapy. Exenatide was associated with weight reduction and had a higher incidence of gastrointestinal adverse effects than insulin glargine. [ABSTRACT FROM AUTHOR]

Background: Evaluation of exenatide monotherapy in patients with type 2 diabetes may be of clinical interest based on improvements in glycemic control and weight that have been reported with the use of exenatide in combination with oral antidiabetic agents.Objective: The aim of this study was to evaluate the efficacy and tolerability of exenatide monotherapy in patients with type 2 diabetes naive to antidiabetic agents and whose disease was inadequately controlled with diet and exercise alone.Methods: This 24-week, double-blind, placebo-controlled, parallel-group study was conducted at 23 centers across the United States, Puerto Rico, Romania, Russia, and India. Patients aged >/=18 years with type 2 diabetes were randomly assigned to receive exenatide 5 microg, exenatide 10 [micro]g, or placebo administered SC BID. Patients were instructed by investigators to maintain their individualized prestudy diet and exercise regimens throughout the study. Efficacy measures included: glycosylated hemoglobin (HbA[1c]); fasting serum glucose (FSG); 6-point self-monitored blood glucose; percentages of patients achieving HbA[1c] values /=1 treatment-emergent adverse event. Nausea was reported with the greatest incidence (5 [micro]g, 3%; 10 [micro]g, 13%; placebo, 0%; P = 0.010 for the combined exenatide group vs placebo). Most (88%) treatment-emergent adverse events were mild or moderate in intensity. Hypoglycemia was reported in 5%, 4%, and 1% of patients in the exenatide 5- and 10-[micro]g and placebo groups, respectively (P = NS), with no incidents of severe hypoglycemia reported.Conclusions: In these patients with type 2 diabetes naive to treatment with antidiabetic agents, exenatide monotherapy was associated with improved HbA[1c], improved fasting and postprandial glucose control, reduced weight, improved beta-cell function (HOMA-B), and improved blood pressure, and was well tolerated. These results suggest that exenatide monotherapy may provide a viable treatment option beyond diet and exercise and support further study of exenatide monotherapy in antidiabetic drug-naive patients with type 2 diabetes. [ABSTRACT FROM AUTHOR]

Objective: To determine the effect of chronic daily exenatide treatment on β-cell function in type 2 diabetes (T2DM)., Background: Glucagon-like peptide receptor agonists, such as exenatide, are commonly used to treat patients with T2DM. Drugs in this class are insulinotropic but lower blood glucose by multiple mechanisms such that effects on β-cell function can be difficult to discern by conventional measures., Design: Seventy-nine subjects with previously untreated T2DM were studied before and after 24 weeks of treatment with one of the two doses of exenatide, 5- or 10-μg twice daily, or placebo. All subjects had oral glucose tolerance tests (OGTT) before and after randomization with measurement of plasma glucose, insulin and C-peptide concentrations. Insulin secretion rates (ISR), peripheral insulin sensitivity (OGIS) and hepatic insulin resistance index (Hep-IR) were calculated., Results: During the trial, all three groups lost similar, small but significant, amounts of weight. Compared to placebo, 24 weeks of daily high- or low-dose exenatide treatment reduced HbA1c and improved fasting and postprandial hyperglycaemia. Exenatide was associated with improved OGIS and Hep-IR independent of changes in weight. Plasma insulin levels and ISR during the OGTT did not differ before or after treatment with exenatide or placebo. However, when considered as a function of plasma glucose and insulin sensitivity, both doses of exenatide improved ISR proportionately to the improvement in plasma glucose. The higher dose of exenatide was associated with a significant improvement in β-cell sensitivity to glucose., Conclusions: These findings demonstrate that in persons with early T2DM, chronic treatment with exenatide enhanced ISR and increased β-cell sensitivity to glucose. These improvements in β-cell function were not clearly reflected in plasma insulin and C-peptide levels, but became apparent when glycemia and insulin sensitivity were accounted for., (© 2013 John Wiley & Sons Ltd.)

This study assessed the dose-dependent efficacy and safety of exenatide over 12 weeks in Japanese patients with type 2 diabetes suboptimally controlled despite therapeutic doses of sulfonylurea (SU), SU plus biguanide, or SU plus thiazolidinedione. Patients were randomly assigned to placebo (N = 40), 2.5 microg (N = 38), 5 microg (N = 37), or 10 microg (N = 38) exenatide administered subcutaneously twice daily (BID). Patients randomly assigned to 10 microg exenatide received 5 microg BID for the first 4 weeks, with the dose escalated to 10 microg BID for the final 8 weeks. Patients were 60.3 +/- 9.7 years old, with body mass index 25.3 +/- 4.3 kg/m(2) and hemoglobin A1c (HbA1c) 8.0 +/- 0.8%. Baseline-to-endpoint HbA1c changes (%) were +0.02 +/- 0.1 (placebo), -0.9 +/- 0.1 (2.5 microg), -1.2 +/- 0.1 (5 microg), and -1.4 +/- 0.1 (10 microg) (all p < 0.001 vs. placebo). Of patients with baseline HbA1c -7%, 5.1% (placebo), 50.0% (2.5 microg), 71.4% (5 microg), and 79.4% (10 microg) achieved HbA1c <7% at endpoint (p < 0.001, trend test). Baseline-to-endpoint fasting plasma glucose changes (mg/dL) were +6.0 +/- 4.8 (placebo), -18.6 +/- 5.7 (2.5 microg), -25.0 +/- 7.0 (5 microg), and -28.9 +/- 5.9 (10 microg) (all p < or = 0.001 vs. placebo). Treatment-emergent adverse events were mostly mild; dose-dependent increases in incidence were observed for hypoglycemia, nausea, anorexia, decreased appetite, and diarrhea (all p < or = 0.044, trend test). Over 12 weeks, exenatide dose-dependently improved glycemic control in Japanese patients with type 2 diabetes.

Objective: To evaluate whether exenatide administered before breakfast and dinner (BD) or before lunch and dinner (LD) provided similar glycemic control in Latin American patients with type 2 diabetes mellitus (T2DM) who consume a small breakfast., Methods: In this open-label, 2-arm study, patients taking metformin, sulfonylureas, and/or thiazolidinediones were randomized to exenatide before BD or before LD (5-mug exenatide for 4 weeks, then 10-microg exenatide for 8 weeks). Treatment assignment was determined by a computer-generated random sequence using an interactive response system. Patients were eligible for study inclusion if they consumed <15% of their total caloric intake at breakfast. The primary endpoint was HbA(1c) change from baseline to endpoint. Secondary endpoints included fasting serum glucose (FSG) level, 7-point SMBG profile, and safety. Clinicaltrials.gov Identifier: NCT00359879., Results: 377 participants (55% female, age 54 +/- 10 years, weight 82 +/- 15 kg, BMI 31 +/- 4 kg/m(2), HbA(1c) 8.4 +/- 0.9%; mean +/- SD) from Brazil and Mexico were randomized to study treatment. HbA(1c) reduction with exenatide administration before BD was non-inferior to administration before LD (mean difference between (LD-BD) treatments: 0.14%; 95% CI -0.04 to 0.32%, p=0.120). Both treatments resulted in statistically significant HbA(1c) reductions at endpoint (BD -1.2% and LD -1.1%, respectively, p<0.001). In Brazil, the non-inferiority criteria were met for HbA(1c) reduction between treatment arms (-0.12%; CI -0.37 to 0.13%, p=0.344), whereas in Mexico, there was a difference favoring exenatide administration before BD (0.41%; CI 0.16 to 0.66%, p=0.002). At endpoint, there were no statistical significant differences between the BD and LD arms in mean change in FSG (0.50 mmol/L; CI -0.02 to 1.02 mmol/L, p=0.058) and daily mean change in SMBG (0.19 mmol/L; CI -0.17 to 0.54 mmol/L, p=0.295). The rates of symptomatic hypoglycemia (5.2 events/patient-year vs. 6.1 events/patient-year) and nausea (23% vs. 25%), were similar between the BD and LD arms, respectively. A limitation of the study design was that caloric intake of patients and meal times were not monitored., Conclusions: In T2DM patients who consume a small breakfast, exenatide administration before breakfast or lunch resulted in significant improvement in glycemic control.

Objective: This 16-week study explored the safety of substituting exenatide for insulin in patients with type 2 diabetes using insulin in combination with oral antidiabetes agents., Research Design and Methods: Successful maintenance of glycemic control was predefined as an A1C increase of < 0.5%. A total of 49 patients (aged 53 +/- 8 years, with BMI 34 +/- 4 kg/m2, A1C 8.1 +/- 1.1%, and duration of diabetes 11 +/- 7 years) were randomized to either substitute exenatide for insulin or remain on their current insulin regimen. Patients who either completed > or = 8 weeks of study or discontinued because of loss of glycemic control were included in primary efficacy analysis., Results: A total of 62% (18 of 29) of the exenatide-treated patients maintained glycemic control compared with 81% (13 of 16) of the insulin-treated patients. Of the 11 exenatide-treated patients who did not maintain control, 5 discontinued before week 16 because of loss of glucose control. The overall safety profile was generally consistent with previous exenatide trials. The mean overall hypoglycemia rates were 1.72 and 0.97 events/patient-year for the exenatide and insulin reference groups, respectively., Conclusions: This pilot study suggests that it is feasible to sustain glycemic control when substituting exenatide for insulin. Although it is not possible to characterize clear predictors of outcome given the size and exploratory nature of the study, the data suggest that patients with longer disease duration, who are taking higher doses of insulin and have less endogenous beta-cell function, may experience deterioration in glucose control if exenatide is substituted for insulin therapy.

Aim: The ability of the incretin mimetic exenatide to improve glycaemic control and reduce body weight was assessed over 82 weeks in patients with type 2 diabetes failing to achieve glycaemic control with maximally effective doses of metformin., Methods: In this interim 82-week analysis, 150 (total cohort) of an eligible population of 183 patients opted to continue exenatide treatment in an uncontrolled open-label extension of a 30-week double-blind, placebo-controlled trial. Of these, 92 patients (completer cohort) achieved 82 weeks of exenatide therapy. Patients continued metformin throughout the study., Results: At the end of the placebo-controlled trial, exenatide resulted in an haemoglobin A1c (HbA1c) reduction from baseline of -1.0 +/- 0.1% (mean +/- SE) (exenatide treatment arms), with durable HbA1c reductions after 82 weeks of -1.3 +/- 0.1%. The percent of patients who achieved HbA1c < or = 7% at weeks 30 and 82 was 46 and 59% respectively. After 30 weeks, exenatide caused a reduction in weight from baseline of -3.0 +/- 0.6 kg, with a progressive reduction in weight of -5.3 +/- 0.8 kg after 82 weeks. In addition, exenatide treatment produced clinically significant improvements in cardiovascular risk factors after 82 weeks. The most frequent adverse event after 30 and 82 weeks of exenatide was nausea, which was generally of mild-or-moderate intensity. It decreased in incidence after initiation in the controlled trial and the uncontrolled open-label extension. Hypoglycaemia was rare, with no severe events., Conclusion: Exenatide was generally well tolerated, producing a durable reduction in HbA1c and a progressive reduction in weight over 82 weeks in patients with type 2 diabetes failing to achieve glycaemic control with metformin.

Objective: To compare the overall efficacy of combination therapies focused on fasting or postprandial blood glucose in patients with type 2 diabetes not adequately controlled with oral sulfonylurea agents alone., Research Design and Methods: A total of 135 patients were randomly assigned for 3 months to 1 of 3 combination regimens with glyburide (G) that addressed postprandial blood glucose with insulin lispro (L+G), premeal blood glucose with metformin (M+G), or fasting blood glucose (FBG) with bedtime NPH insulin (NPH+G)., Results: At end point, HbA1c was significantly lower with all therapies (P = 0.001) and was significantly lower for L+G (7.68+/-0.88%) compared with either NPH+G (8.51+/-1.38%, P = 0.003) or M+G (8.31+/-1.31%, P = 0.025). FBG at end point was significantly lower for NPH+G (8.49+/-2.36 mmol/l) compared with either L+G (10.57+/-1.97 mmol/l, P = 0.001) or M+G (9.69+/-2.89 mmol/l, P = 0.029). The mean 2-h postprandial glucose after a test meal was significantly lower for L+G (10.87+/-2.88 mmol/l) versus NPH+G (12.21+/-3.12 mmol/, P = 0.052) or versus M+G (12.72+/-3.26 mmol/l, P = 0.009). The overall rate of hypoglycemia (episodes per 30 days) was low and not statistically significant between groups (P = 0.156)., Conclusions: Adding a second antihyperglycemic agent, regardless of its timing of action, lowers HbA1c and glucose values. However, when insulin lispro was used to focus on postprandial blood glucose, there was a greater impact on overall metabolic control. These data support the importance of lowering postprandial blood glucose to optimize overall glycemic control and thus improve long-term outcomes.

Objective: The objective of the study was to assess the efficacy and safety of repaglinide compared with placebo in the treatment of patients with type 2 diabetes., Research Design and Methods: This was a phase II multicenter, double-blind, placebo-controlled, randomized, dose-adjustment and maintenance trial. After screening and a 2-week washout period, 99 patients were randomized to receive either repaglinide (n = 66) or placebo (n = 33). Patients underwent 6 weeks of dose adjustment followed by 12 weeks of dose maintenance. Fasting and stimulated glycosylated hemoglobin (HbA1c), plasma glucose, insulin, and C-peptide were measured at predetermined intervals. Adverse events and hypoglycemic episodes were recorded., Results: From baseline to last visit, mean HbA1c decreased from 8.5 to 7.8% in patients treated with repaglinide and increased from 8.1 to 9.3% in patients receiving placebo, with a statistically significant difference of - 1.7% (P < 0.0001) between treatment groups at the last visit. Mean fasting plasma glucose and postprandial glucose increased in patients receiving placebo and decreased in patients treated with repaglinide, with statistically significant (P < 0.01) differences between groups at the last visit. Concentrations of fasting and postprandial insulin and C-peptide were lower at the last visit compared with baseline for patients treated with placebo and higher for patients treated with repaglinide, and the differences between groups were statistically significant (P < 0.05). Overall, repaglinide was well tolerated., Conclusions: This study demonstrated that repaglinide was safe and efficacious in lowering blood glucose concentrations. In addition to overall improvement in glycemic control noted with repaglinide in both sulfonylurea-treated patients and oral hypoglycemic agent-naive patients, repaglinide had a potent glucose-lowering effect in the postprandial period.

Objective: To compare the efficacy, benefits, and risks of glyburide and glipizide in elderly patients with non-insulin-dependent diabetes mellitus (NIDDM)., Research Design and Methods: Twenty-one elderly outpatients (mean age 70 yr) were treated for 8 wk, after being dose-titrated to achieve a fasting plasma glucose (FPG) concentration of less than 7.8 mM with glyburide or glipizide in a randomized crossover trial. FPG and postprandial plasma glucose, serum C-peptide, and HbA1c levels were measured. In 13 patients, self-monitoring of blood glucose (SMBG) with a memory meter was performed seven times per week., Results: Glipizide (11.9 mg) and glyburide (8.4 mg) produced similar fasting and postprandial plasma glucose and HbA1c concentrations. No significant differences in basal or stimulated C-peptide levels were detected. Despite a few patient reports of hypoglycemia, a high incidence of SMBG readings less than 4.5 mM was attributed to the use of both drugs., Conclusions: Both treatments proved effective for glycemic control; however, both second-generation sulfonylureas are associated with a significant risk of hypoglycemia in elderly NIDDM patients. The proper use of sulfonylureas in this population should include close surveillance of ambulatory glucose monitoring and intensive and repeated patient education about the risks of hypoglycemia.

To define whether rapid rate of fall in blood glucose stimulates counterregulatory hormonal responses in diabetic man, blood glucose in eight hyperglycemic diabetic subjects was rapidly lowered by intravenous insulin administration. Despite precipitous declines in blood glucose, plasma epinephrine and growth hormone remained virtually unchanged. In contrast, norepinephrine and cortisol increased significantly (P less than 0.025) in the face of hyperglycemia or euglycemia, while glucagon was suppressed (P less than 0.025). A transient modest fall in mean arterial pressure and a rise in pulse rate were noted. No correlation was observed between glucose disappearance rate or decrement in glucose concentration and the hormonal responses. After sham insulin administration, no change was observed in plasma epinephrine, norepinephrine, and cortisol levels. These findings suggest that rate of fall in blood glucose per se is not a primary signal for counterregulatory hormonal response. Cortisol but not growth hormone release during falling blood glucose in diabetic subjects can occur despite elevated blood glucose levels. The etiology of norepinephrine and cortisol change is unclear.

To investigate whether prostaglandins (PGs) play a role in the regulation of insulin secretion during starvation, we have studied the effects of two inhibitors of PG synthesis, indomethacin (INDO) and acetylsalicylic acid (ASA), on plasma insulin during a 72-h fast. Five lean males and six obese females were given 200 mg INDO daily throughout a 72-h fast during which plasma glucose was maintained at normal postabsorptive levels by a continuous infusion of glucose. In addition, four obese females were treated with 3 g ASA in a similar protocol. Another six lean males and six obese females served as a control group, receiving only iv glucose during the fast. In both the lean and obese control subjects, a significant decrease in plasma insulin was noted by 72 h (lean, 53 +/- 8% of basal insulin; obese, 69 +/- 6%; P less than 0.02). By contrast, aspirin and INDO administration prevented the decline in plasma insulin in both lean (INDO, 92 +/- 5%) and obese (INDO, 109 +/- 11%; ASA, 111 +/- 17%) subjects. These data suggest that endogenous PG production may be a controlling factor in insulin secretion during starvation.

To examine whether decreased insulin secretion during starvation is related to a change in the ability of insulin to inhibit its own secretion, plasma C-peptide was measured after plasma insulin levels were acutely raised by intravenous (IV) insulin infusion in a dose of 40 and 80 mU/M2/min in obese subjects before and after a 72 hour fast. Plasma glucose concentration was maintained +/- 4% of basal levels by a variable glucose infusion. During the 80 mU infusion, at plasma insulin levels of 200 microU/mL, plasma C-peptide fell by 0.17 pmol/mL in the fed state. In the fasted state, despite basal levels that were 36% lower, C-peptide decreased by 0.21 pmol/mL. Highly significant increases in percent suppression after fasting were noted during both 40 mU and 80 mU studies. The plasma C-peptide response was related to the insulin infusion dose in both the fed and fasted state. In contrast, alpha cell suppression by insulin, as determined by plasma glucagon levels, was not altered by fasting. It is concluded that enhanced inhibitory influences of insulin on the beta cell during starvation may be a physiologically important mechanism for diminished insulin secretion during the transition from the fed to the fasting state.

The effect of aspirin on glucose and insulin metabolism was examined with the hyperglycemic clamp technique in 8 normal volunteers. When the plasma glucose concentration was acutely raised and maintained at 125 mg/dl above the basal level after treatment with aspirin (3 g daily for 3 days), acute (0-10 min) and sustained (20-120 min) insulin release were 70% and 45% greater than before treatment. Despite the increased plasma insulin level, the glucose infusion rate remained unchanged (8 +/- 0.9 to 9.1 +/- 1.2 mg/kg X min). Consequently, the ratio of the glucose infusion rate to the plasma insulin level, an index of tissue sensitivity to endogenous insulin, decreased by 30%, indicative of impaired insulin action. Aspirin did not alter fasting levels of FFA. When ibuprofen, another prostaglandin synthesis inhibitor, was given to 10 normal volunteers, only an effect on acute insulin release could be demonstrated. These results demonstrate that aspirin not only enhances beta-cell sensitivity to glucose, but also impairs glucose metabolism in insulin-sensitive tissues. It is not clear whether these effects are related to aspirin's ability to inhibit prostaglandin synthesis.

We have evaluated a commercially available, direct, solid-phase radioimmunoassay kit for progesterone determination in serum or plasma. The assay is precise, within-run precision (CV) in the clinically significant ranges being 2.5 to 5.2%, between-run 5.5 to 5.8%. Mean analytical recovery of different concentrations of progesterone added to serum was 99.7% (range 95.3 to 102.7%). Fourteen closely related steroids showed no cross reactivity. The minimum detection limit was 0.5 microgram/L. Luteal-phase progesterone concentrations in serum were increased (greater than 3 micrograms/L) in 19 normal ovulatory menstrual cycles and decreased (less than 1.5 micrograms/L) in two nonovulatory cycles. We found this direct assay for progesterone to be analytically and clinically sound, and useful for assessing luteal-phase function.

Prostaglandin (PG) E2 stimulates glucose-induced insulin release from isolated rat pancreatic islets but inhibits acute insulin release to intravenous (i.v.) glucose in man. Since PGs act as intracellular messengers, we have studied the effect of endogenous PG inhibition with indomethacin (a potent PG synthesis inhibitor) to clarify these differences. The acute insulin response (AIR) to 5 g and 20 g i.v. glucose, 5 i.v. arginine, and 1 mg i.v. glucagon before and one hour after ingestion of 50 mg indomethacin (INDO) or placebo was studied in healthy lean subjects. INDO significantly lowered basal insulin levels (pre, 9.5 +/- 1.6; post, 6.4 +/- 1.8 muU/ml, X +/- SE, p less than 0.02, paired t-test) while placebo failed to alter basal insulin (pre, 8 +/- 2.7; post, 6.9 +/- 0.6 muU/ml). INDO substantially blunted the AIR to 5 g glucose (delta3-5' IRI pre,20.3 +/- 3; post, 8.4 +/- 2.4 muU/ml, p less than 0.005), 20 g glucose (delta3-5' IRI pre, 38.1 +/- 9.7; post, 18.9 +/- 8 muU/ml, p less than 0.005), and 1 mg glucagon (0-10' IRI area pre, 375 +/- 73; post, 149 +/- 30 muU . min/ml, p less than 0.05), but it failed to influence agrinine-stimulated AIR (0-10' IRI area pre, 161 +/- 34; post, 186 +/- 31). Thus, PG inhibition with INDO lowers basal, glucose-, and glucagon-stimulated AIR. Our data suggest that endogenous PGs enhance insulin secretion.

To study the effect of physiological increments in plasma secretin concentrations on basal and glucose-stimulated insulin release, bolus iv glucose injections (5 g) were given to normal weight volunteers (less than 108% ideal BW) before, during, and 30 min after a secretin infusion at a rate of 0.125 U/kg.h, raising mean plasma immunoreactive secretin to 35.5 +/- 8.3 pg/ml. Acute insulin responses to glucose were unaffected during or after the secretin infusion. Furthermore, when plasma glucose was elevated to postprandial levels (128--165 mg/dl), a similar secretin infusion also failed to alter acute insulin responses. In addition, no changes in basal glucose or insulin levels were found when endogenous secretin concentrations were increased by intraduodenal acid infusion. Thus, increases in plasma secretin to concentrations seen in the postprandial state fail to alter acute insulin secretion. It is unlikely that secretin plays any role in the intestinal stimulation of insulin secretion.

Liver glycogen stores may be mobilized during hypoglycemia by release of adrenomedullary catecholamines, by release of norepinephrine from sympathetic nerve endings and by release of glucagon. To clarify the nature of peripheral sympathetic control of hepatic glycogenolysis during glucopenia in man, 2-deoxy-d-glucose (2 DG), a competitive inhibitor of glucose metabolism, was infused intravenously (50 mg/kg) to nine normal volunteers and four adrenalectomized patients for 20 min. In normal volunteers, the initial elevation of free fatty acids (FFA) and growth hormone (HGH) correspond with the rise in total catecholamines, with maximal levels attained at 60 min; lactate and cortisol rose at a slower rate, no change in IRI was noted. Plasma glucose levels were 148 percent of preinfusion values by 120 min and remained elevated. In adrenalectomized subjects, despite no change in plasma FFA, lactate, catecholamines and glucagon, glucose rose 20 percent by 150 min; the growth hormone and insulin responses were similar to normals; A significant increase in glucose response from 60 min onward was found in the 2 DG infusion studies when compared to cortisone administration, alone. Thus, during glucopenia, plasma glucose rose in spite of unchanged adrenomedullary catecholamine and glucagon levels. The findings indicate that the sympathetic neurotransmitter, norepinephrine, contributes to counter-regulatory events during 2 DG-induced glucopenia presumably via its release from hepatic sympathetic nerve endings,

The usefulness of measurements of urinary C-peptide excretion in indirectly assessing integrated insulin secretion during starvation was studied in eight obese subjects during a 72-h fast. Blood and urine samples were collected at 12-h intervals for measurement of insulin and C-peptide immunoreactivity. After 60 h, serum insulin and plasma C-peptide levels declined 47% and 37%, respectively, and the values were highly correlated (r = 0.8; P less than 0.001). By 72 h, urinary C-peptide excretion had declined to 70% of the level in the first 12-h period. The urinary clearance of C-peptide was not altered by starvation. A highly significant correlation was found between urinary C-peptide and C-peptide secretory rate (P less than 0.001). The molar ratio of plasma C-peptide to insulin remained constant during the fasting period. These data indicate that basal insulin secretion can be added to the list of physiological conditions in which beta-cell secretion can be effectively evaluated by urinary C-peptide measurement.

Using a modification of the glucose clamp technique, we have studied the efficacy of commonly used foods to correct hypoglycemia in insulin-dependent diabetics. After lowering the plasma glucose level to 55 mg/dL at a steady-state plasma free insulin concentration of about 50 microU/mL, patients were fed 20 g of carbohydrate as milk, orange juice, or D-glucose or 40 g of carbohydrate as orange juice. The data indicate that 20 g of carbohydrate as D-glucose corrects hypoglycemia without rebound hyperglycemia. In an outpatient setting, this treatment also proved effective in spontaneous episodes of hypoglycemia. We conclude that (1) the D-glucose content of the ingested carbohydrate is an important determinant of the glycemic response, and (2) at times of moderately severe hypoglycemia, ingestion of 20 g of D-glucose provides an effective glycemic response for periods of at least 40 minutes. In view of these data, a table is provided listing some common sources of 20 g of D-glucose.

We present here the first performance evaluation of a new direct method for free thyroxin (T4) in serum by radioimmunoassay, with use of coated tubes and a radiolabeled T4 analog (Diagnostic Products Corp.). The assay is precise and robust: within-run imprecision (CV), 3.1-6.6%; between-run imprecision, 4.0-7.9%; no demonstrable variation between technologists irrespective of experience with the method. No outliers were observed when we compared the free T4 results with serum total T4. Reference values are reported for a total of 1243 euthyroid subjects; there was no significant age effect on serum free T4 in women 26 to 72 years old. The biological variation was about +/- 35% of the mean (2 SD). Free T4 results are the same for serum and plasma. The assay performs well in hypothyroidism and hyperthyroidism, and distinguishes individuals with thyroid disease from normal individuals. Free T4 values in women taking oral contraceptives are normal. Depressed results were often observed in acute nonthyroidal illness and continuing pregnancy. These results were directly comparable with those of another commercial direct radiolabeled-T4 analog kit for free T4.

We have evaluated a new commercially available radioimmunoassay kit for albumin determination in urine. The assay is precise; within-run precision (CV) in the clinically significant ranges is 1.8-3.5%, between-run, 1.2-8.5%. The minimum detection limit was 0.6 micrograms/ml. Analytic recovery of different concentrations of albumin added to urine ranged from 98% to 103%. Samples, stored in plastic containers, were stable at room temperature for periods up to 7 days. Mean albumin excretion rates, measured in 20 normal volunteers for 3-h and 24-h periods during the same day were similar (7.1 +/- 4.6 [SD] versus 6.5 +/- 5.0 micrograms/min). In 8 normal subjects, 3-h excretion rates measured daily for 5 days showed no significant variability. In eight insulin-dependent diabetic subjects, albumin excretion measured in short periods of urine collection (3 h) were also in close agreement with 24-h collections (24.7 +/- 28.9 versus 17.6 +/- 18 micrograms/min). From these results it appears that this commercially available kit is suitable for conveniently monitoring microalbuminuria in large numbers of patients in research studies as well as for office practice. Such widespread use should make it possible to better determine the clinical usefulness of this test in the management of diabetic patients.

Recent evidence suggests that prostaglandins may exert a tonic inhibitory tone in the pancreatic beta cell during starvation. The effects of starvation on rat pancreatic prostaglandin E (PGE) content were studied. After 72 hrs of starvation, pancreatic PGE increased 250% above that of fed controls. Administration of streptozotocin, a selective beta-cell toxin, decreased pancreatic PGE significantly (p less than 0.005), but starvation partially reversed this trend. Thus, PGE may have a physiological role in modulating insulin secretion during starvation. It appears that both beta-cell and nonbeta-cell sources of PGE are involved in this phenomenon.

In order to examine the possibility that epinephrine is involved in either the mediation or modulation of the enhanced glucagon release during glucopenia, glucagon responses to insulin-induced hypoglycemia were evaluated in four men with bilateral adrenalectomy in comparison with ten normal men. In the adrenalectomized patients, the mean nadir of plasma glucose and the rate of ascent to baseline levels were indistinguishable from those observed in normal subjects. Similarly, glucagon responses in the adrenalectomized group were not different from those encountered in the normal volunteers. We conclude that epinephrine does not contribute significantly to the augmented glucagon release during abrupt glucopenia in normal man and is not necessary for normal recovery from hypoglycemia.

To determine whether centrally mediated adrenergic tone modulates lipolysis, ketogenesis, or insulinopenia during starvation, four lean male subjects with complete cervical cord transection and six lean healthy male volunteers were fasted for 48 hr. Plasma glucose and insulin levels decreased to comparable levels in both groups. Plasma free fatty acid (FFA) and beta-hydroxybutyrate concentrations rose to peak levels 1.23 +/- 0.08 mmoles/liter and 4.2 +/- 1.0 mmoles/liter at 36 and 48 hr in normals, respectively. Cord-sectioned subjects had similar peak FFA (1.2 "/- 0.12) and beta-hydroxybutyrate (5.6 +/- 0.3) concentrations. Urinary catecholamine excretion in four normal subjects failed to increase during the fast. Since normal glucose, free fatty acid, beta-hydroxybutyrate, and insulin relationships were maintained in sympathectomized subjects, it appears that central adrenergic mechanisms are not essential for initiation of lipolysis, ketonemia, or the hypoinsulinemia of early starvation. These results provide additional evidence that these metabolic events are primarily related to insulinopenia.

To investigate the adrenergic role in glucocounterregulatory mechanisms, single-blind randomised studies were performed in 7 normal males during severe insulin-induced hypoglycaemia with or without adrenergic blockade. Intravenous phentolamine administration (5 mg stat and 0.5 mg/min) did not interfere with the restoration of euglycaemia from hypoglycaemia. However, recovery of blood glucose in the presence of propranolol (3 mg/3 min and 0.8 mg/min) was retarded when compared with control studies (mean plasma glucose levels +/- SEM , 50 +/- 6 mg/dl versus 66 +/- 4 mg/dl at 120 min after insulin administration) despite appropriate glucagon, epinephrine, cortisol, and growth hormone responses. Plasma norepinephrine response was unaffected by propranolol but augmented threefold by phentolamine. Increases in plasma lactate, pyruvate and non-esterified fatty acids were blunted with propranolol while rebound non-esterified fatty acid was observed with phentolamine infusion. These data suggest that complete recovery of blood glucose from sever hypoglycaemia requires full sympathetic nervous system activity despite the integrity of other counterregulatory mechanisms.

The effect of insulin-induced hypoglycemia on plasma cyclic AMP levels was studied in normal volunteers, adrenalectomized, and sympathectomized subjects. Significant increases in plasma glucagon were observed in all groups. Normal subjects all had two- to threefold rises in plasma cAMP while no response was seen in any adrenalectomized or sympathectomized subject. These findings suggest that the mechanism for enhanced plasma cAMP release during insulin-induced hypoglycemia is catecholamine dependent. Glucagon does not contribute significantly to this response.

We evaluated the safety and efficacy of a highly supplemented controlled low-energy (1764 kJ [420 kcal]) diet in the treatment of non-insulin-dependent diabetes and obesity. Six obese, diabetic women ranging from 143% to 297% of ideal body weight were studied in a metabolic ward for 48 days. The subjects ingested a weight-maintenance diet during an eight-day control period followed by 40 days of an experimental diet containing 1764 kJ (420 kcal) of a mixture of protein (43% of energy intake), carbohydrates (51%), and fat (6%), supplemented with minerals, trace elements, and vitamins. The subjects were monitored for balances of nitrogen and minerals, as well as for the appearance of cardiac arrhythmias by 24-hour electrocardiographic recordings. Weight loss was rapid and sustained and averaged 10.1% +/- 0.8% over 40 days. Fasting plasma glucose levels declined from 16.2 +/- 1.9 mmol/L (293 +/- 36 mg/dL) to 6.9 +/- 0.8 mmol/L (126 +/- 16 mg/dL) by day 35. Similarly, hemoglobin A1c levels fell from 0.11 +/- 0.009 (11.2% +/- 0.9%) to 0.8 +/- 0.001 (8.2% +/- 1.1%). Urinary C-peptide levels declined from 62.2 +/- 15.6 nmol/48 h to 20.0 +/- 5.9 nmol/48 h by days 39 to 40 and paralleled the decline in plasma glucose values, the majority of which occurred in the first seven days. Concentrations of serum cholesterol and triglycerides decreased. Balances for nitrogen, potassium, and magnesium were negative at -1.7 g/24 h, -2.2 mEq/24 h, and -2.9 mg/dL, respectively. Blood pressure decreased without orthostasis. Resting metabolic rate fell a mean of 18% but remained within normal limits. Triiodothyronine levels also declined. Twenty-four-hour ambulatory electrocardiographic readings disclosed no significant bradyarrhythmia or tachyarrhythmia for any patient. These studies, based on a limited number of subjects, demonstrate that a highly supplemented controlled low-energy diet is a safe and efficacious treatment for diabetes and obesity, leading to significant decreases in weight, blood pressure, and levels of plasma glucose and plasma lipids. Such diets may be the optimal initial treatment of moderate to markedly obese patients with non-insulin-dependent diabetes.

Infusion of prostaglandin E2 (PGE2) has been previously shown to inhibit acute insulin release and cause glucose intolerance. The present studies were undertaken to assess the effects of PGE2 on 1) pancreatic beta-cell sensitivity to glucose, 2) glucose tolerance, 3) tissue sensitivity to insulin, 4) glucose production and clearance, and 5) plasma catecholamine, glucagon, and FFA levels. Six healthy adult subjects were studied with the hyperglycemic clamp technique (plasma glucose 125 mg/dl above basal for 2 h) before and 30 min after the start of a PGE2 infusion (10 micrograms/min). Plasma epinephrine, norepinephrine, and FFA were measured during the PGE2 infusion. In additional experiments, glucose production and utilization were measured isotopically ([3-3H]glucose) during PGE2 infusion. PG infusion diminished, but not significantly, acute insulin release (0-10 min preinfusion, 172 +/- 36; postinfusion, 148 +/- 45 microunits/ml . 10 min). Late insulin release (20-120 min) was unchanged. A significant decline occurred in the amount of glucose metabolized from 9 +/- 1.1 to 7.2 +/- 1 mg/kg . min. During the initial 30 min of PGE2 infusion, plasma FFA increased by 26 +/- 6% (P less than 0.025). Plasma epinephrine and norepinephrine rose from 40 +/- 6 to 104 +/- 24 pg/ml (P less than 0.05) and 204 +/- 17 to 440 +/- 30 pg/ml (P less than 0.01), respectively. PGE2 produced a prompt 30% rise in glucose output, which declined to basal levels by 60 min. Glucose clearance decreased transiently at 45 min by 23%. We conclude that the effects on glucose homeostasis noted during PGE2 infusion occur in the face of heightened adrenergic activity. These metabolic responses closely resemble adrenergically induced changes in glucose homeostasis. As such, before any metabolic effects can be attributed directly to infused PGE2, any metabolic effects can be attributed directly to infused PGE2, the role of concomitant catecholamine release must be considered.

The effects of insulin on glucose utilization, lipolysis, and potassium and phosphate metabolism were studied during short-term fasting in six lean subjects using a sequential euglycemic glucose clamp technique (two additional subjects were used in 70 mU/m2/min clamp studies). The subjects were infused with insulin for four hours at four rates ranging from 6 to 442 mU/m2/min before and after a 48-hour fast. Insulin was infused for one hour at each rate in all experiments. Fasting markedly reduced glucose utilization at all insulin infusion rates. On the other hand, the decline in levels of free fatty acids that occurred at insulin concentrations of 30 microU/ml was virtually identical before and after fasting. After insulin was infused for four hours, serum phosphate had decreased in all subjects (P less than 0.001) and strongly correlated with glucose disposal rates (r = 0.76, P less than 0.005). The plasma potassium level also declined in all subjects but did not relate to fasting or glucose disposal. These studies demonstrate that starvation produces selective insulin resistance. The biologic effect of insulin on glucose utilization and plasma phosphate shifts is clearly diminished. Free fatty acid and potassium metabolism are unaffected by starvation.

The effect of autonomic denervation on the metabolic and hormonal responses during intracellular glucopenia in man was investigated. 2-Deoxy-d-glucose (2 DG), a competitive inhibitor of glucose metabolism, was administered intravenously to nine normal volunteers and to five patients, three with complete cervical cord transection (C-6) and two with idiopathic orthostatic hypotension. Before, during, and after a 20 min infusion of 2 DG (50 mg/kg) plasma concentrations of glucose, lactate, FFA, total catecholamines, immunoreactive insulin (IRI), human growth hormone (HGH), and cortisol were determined for periods up to 150 min. In control subjects, the initial elevation of FFA, glucose. HGH, and cortisol corresponded with the rise in total catecholamines, with maximal levels attained at 60 min, lactate rose at a slower rate, reaching peak levels at 150 min: although no change in IRI was noted. In contrast, 2 DG-induced glucopenic stress in the autonomic denervated subjects was characterized by no detectable catecholamine release or significant rise in glucose, FFA, lactate, or IRI. However, HGH and cortisol responses in four of the five patients were of a similar or greater magnitude than controls.These studies demonstrate that the integrity of the sympathoadrenomedullary axis is essential for the counter-regulatory response to intracellular glucopenia in man. Cortisol and HGH have no apparent role in these events.