Radioactive Iodine in Differentiated Thyroid Carcinoma: A Systematic AGREE II Clinical Practice Guideline Appraisal.

OBJECTIVE: Identify and appraise clinical practice guidelines (CPGs) for radioactive iodine (RAI) indications in differentiated thyroid carcinoma (DTC), and the treatment for radioactive iodine refractory (RAI-R) DTC using the Appraisal of Guidelines for Research and Evaluation II tool. DATA SOURCES: MEDLINE (Pubmed), Ovid (EMBASE), and Scopus. REVIEW METHODS: A systematic literature search was conducted to identify CPGs addressing RAI in DTC. CPGs were appraised by 4 independent reviewers in 6 distinct areas of quality. Scaled domain scores were subsequently calculated for each domain. Intraclass correlation coefficients were calculated for each domain to assess interrater reliability. RESULTS: Sixteen guidelines were found addressing RAI indications for DTC. Of these 16, 9 also addressed the treatment of RAI-R DTC. A further 6 unique guidelines were identified that exclusively address RAI-R DTC, bringing the total number of guidelines to 22. The American Thyroid Association (ATA) guidelines for adult thyroid cancer were the highest scoring with a mean score of 83.5%. Two guidelines scored >60% in 5 or more domains, qualifying as "high" quality: ATA and British Thyroid Association. The highest scoring domain was domain 4: clarity of presentation (80.4%) while the lowest scoring domain was domain 5: applicability (38.6%). CONCLUSION: Of the 22 guidelines identified, only two were "high quality." CPGs exclusively addressing the treatment of RAI-R DTC were weak with most guidelines scoring in the "low" quality range. This report reveals an unmet need for rigorously developed guidelines addressing indications for RAI in DTC, as well as the treatment for RAI-R DTC.

Insulin reciprocally regulates glucagon secretion in humans.

OBJECTIVE: We tested the hypothesis that an increase in insulin per se, i.e., in the absence of zinc, suppresses glucagon secretion during euglycemia and that a decrease in insulin per se stimulates glucagon secretion during hypoglycemia in humans. RESEARCH DESIGN AND METHODS: We measured plasma glucagon concentrations in patients with type 1 diabetes infused with the zinc-free insulin glulisine on three occasions. Glulisine was infused with clamped euglycemia (∼95 mg/dl [5.3 mmol/l]) from 0 to 60 min on all three occasions. Then, glulisine was discontinued with clamped euglycemia or with clamped hypoglycemia (∼55 mg/dl [3.0 mmol/l]) or continued with clamped hypoglycemia from 60 to 180 min. RESULTS: Plasma glucagon concentrations were suppressed by -13 ± 3, -9 ± 3, and -12 ± 2 pg/ml (-3.7 ± 0.9, -2.6 ± 0.9, and -3.4 ± 0.6 pmol/l), respectively, (all P < 0.01) during zinc-free hyperinsulinemic euglycemia over the first 60 min. Glucagon levels remained suppressed following a decrease in zinc-free insulin with euglycemia (-14 ± 3 pg/ml [-4.0 ± 0.9 pmol/l]) and during sustained hyperinsulinemia with hypoglycemia (-14 ± 2 pg/ml [-4.0 ± 0.6 pmol/l]) but increased to -3 ± 3 pg/ml (-0.9 ± 0.9 pmol/l) (P < 0.01) following a decrease in zinc-free insulin with hypoglycemia over the next 120 min. CONCLUSIONS: These data indicate that an increase in insulin per se suppresses glucagon secretion and a decrease in insulin per se, in concert with a low glucose concentration, stimulates glucagon secretion. Thus, they document that insulin is a ß-cell secretory product that, in concert with glucose and among other signals, reciprocally regulates α-cell glucagon secretion in humans.

Glucagon supports postabsorptive plasma glucose concentrations in humans with biologically optimal insulin levels.

OBJECTIVE: Based on the premise that postabsorptive patients with type 1 diabetes receiving intravenous insulin in a dose that maintains stable euglycemia are receiving biologically optimal insulin replacement, we tested the hypothesis that glucagon supports postabsorptive plasma glucose concentrations in humans. RESEARCH DESIGN AND METHODS: Fourteen patients with type 1 diabetes were studied after an overnight fast on up to five occasions. Insulin was infused intravenously to hold plasma glucose concentrations at ∼100 mg/dl (5.6 mmol/l) overnight and fixed from -60 to 240 min the following morning. From 0 through 180 min the patients also received 1) saline, 2) octreotide 30 ng · kg(-1) · min(-1) with growth hormone replacement or octreotide with growth hormone, plus 3) glucagon in doses of 0.5 ng · kg(-1) · min(-1), 4) 1.0 ng · kg(-1) · min(-1), and 5) 2.0 ng · kg(-1) · min(-1). RESULTS: Compared with a mean ± SE of 98 ± 5 mg/dl (5.4 ± 0.3 mmol/l) at 180 min during saline, mean plasma glucose concentrations declined to 58 ± 1 mg/dl (3.2 ± 0.1 mmol/l) (P < 0.001) at 180 min during octreotide plus saline and were 104 ± 16 mg/dl (5.8 ± 0.9 mmol/l) (NS), 143 ± 13 mg/dl (7.9 ± 0.7 mmol/l) (P = 0.004), and 160 ± 15 mg/dl (8.9 ± 0.8 mmol/l) (P < 0.001) at 180 min during octreotide plus glucagon in doses of 0.5, 1.0, and 2.0 ng · kg(-1) · min(-1), respectively. CONCLUSIONS: In the setting of biologically optimal insulin replacement, suppression of glucagon secretion with octreotide caused a progressive fall in plasma glucose concentrations that was prevented by glucagon replacement. These data document that glucagon supports postabsorptive glucose concentrations in humans.

Beta-cell-mediated signaling predominates over direct alpha-cell signaling in the regulation of glucagon secretion in humans.

OBJECTIVE: Given evidence of both indirect and direct signaling, we tested the hypothesis that increased beta-cell-mediated signaling of alpha-cells negates direct alpha-cell signaling in the regulation of glucagon secretion in humans. RESEARCH DESIGN AND METHODS: We measured plasma glucagon concentrations before and after ingestion of a formula mixed meal and, on a separate occasion, ingestion of the sulfonylurea glimepiride in 24 basal insulin-infused, demonstrably beta-cell-deficient patients with type 1 diabetes and 20 nondiabetic, demonstrably beta-cell-sufficient individuals; the latter were infused with glucose to prevent hypoglycemia after glimepiride. RESULTS: After the mixed meal, plasma glucagon concentrations increased from 22 +/- 1 pmol/l (78 +/- 4 pg/ml) to 30 +/- 2 pmol/l (103 +/- 7 pg/ml) in the patients with type 1 diabetes but were unchanged from 27 +/- 1 pmol/l (93 +/- 3 pg/ml) to 26 +/- 1 pmol/l (89 +/- 3 pg/ml) in the nondiabetic individuals (P < 0.0001). After glimepiride, plasma glucagon concentrations increased from 24 +/- 1 pmol/l (83 +/- 4 pg/ml) to 26 +/- 1 pmol/l (91 +/- 4 pg/ml) in the patients with type 1 diabetes and decreased from 28 +/- 1 pmol/l (97 +/- 5 pg/ml) to 24 +/- 1 pmol/l (82 +/- 4 pg/ml) in the nondiabetic individuals (P < 0.0001). Thus, in the presence of both beta-cell and alpha-cell secretory stimuli (increased amino acid and glucose levels, a sulfonylurea) glucagon secretion was prevented when beta-cell secretion was sufficient but not when beta-cell secretion was deficient. CONCLUSIONS: These data indicate that, among the array of signals, indirect reciprocal beta-cell-mediated signaling predominates over direct alpha-cell signaling in the regulation of glucagon secretion in humans.

Terbutaline and the prevention of nocturnal hypoglycemia in type 1 diabetes.

OBJECTIVE: Bedtime administration of 5.0 mg of the beta(2)-adrenergic agonist terbutaline prevents nocturnal hypoglycemia but causes morning hyperglycemia in type 1 diabetes. We tested the hypothesis that 2.5 mg terbutaline prevents nocturnal hypoglycemia without causing morning hyperglycemia. RESEARCH DESIGN AND METHODS: This was a randomized double-blind crossover pilot study (placebo, 2.5 mg terbutaline, and 5.0 mg terbutaline) in 15 patients with type 1 diabetes. RESULTS: Mean +/- SE nadir nocturnal plasma glucose concentrations were 87 +/- 14 mg/dl following placebo, 100 +/- 14 mg/dl following 2.5 mg terbutaline, and 122 +/- 13 mg/dl following 5.0 mg terbutaline (P < 0.05 vs. placebo). Nadir levels were <50 mg/dl in 5, 2, and 0 patients (P < 0.05 vs. placebo), respectively. Morning levels were 113 +/- 18, 127 +/- 17, and 183 +/- 19 mg/dl (P < 0.02 vs. placebo), respectively. CONCLUSIONS: Terbutaline may be shown to be effective and safe in the prevention of nocturnal hypoglycemia in type 1 diabetes in a suitably powered randomized controlled trial.

Glucagon, in concert with insulin, supports the postabsorptive plasma glucose concentration in humans.

OBJECTIVE: Given the interest in glucagon antagonism as a potential treatment of diabetes, we tested the hypothesis that glucagon, in concert with insulin, supports the postabsorptive plasma glucose concentration in humans. RESEARCH DESIGN AND METHODS: Following preliminary studies that indicated that a peripheral intravenous insulin dose of 0.1 mU x kg(-1) x min(-1) (lower than those used previously) provides basal insulin replacement and that a glucagon dose of 1.0 ng x kg(-1) x min(-1) underreplaces basal glucagon, we infused the somatostatin analog octreotide (30 ng x kg(-1) x min(-1)) (with growth hormone replacement) over 4 h in 14 healthy adults on four separate occasions to produce endogenous insulin and glucagon deficiency with 1) saline (combined insulin and glucagon deficiency), 2) insulin replacement (isolated glucagon deficiency), 3) partial glucagon replacement (insulin and partial glucagon deficiency), and 4) insulin and partial glucagon replacement (partial glucagon deficiency). RESULTS: During combined insulin and glucagon deficiency, glucose production decreased and then increased, and mean (+/-SE) plasma glucose decreased from 83 +/- 1 to 63 +/- 2 mg/dl at 60 min and then increased to 89 +/- 3 mg/dl at 240 min. During isolated glucagon deficiency, plasma glucose decreased to hypoglycemic levels and was 55 +/- 2 mg/dl at 240 min (P < 0.0001 vs. combined insulin and glucagon deficiency). Partial glucagon replacement raised plasma glucose to higher levels (P = 0.0469) during insulin deficiency and to higher levels (P = 0.0090) during insulin replacement. CONCLUSIONS: These three findings provide direct evidence that glucagon, in concert with insulin, supports the postabsorptive plasma glucose concentration in humans.

Basal insulin, glucagon, and growth hormone replacement.

Conclusions drawn from the pancreatic (or islet) clamp technique (suppression of endogenous insulin, glucagon, and growth hormone secretion with somatostatin and replacement of basal hormone levels by intravenous infusion) are critically dependent on the biological appropriateness of the selected doses of the replaced hormones. To assess the appropriateness of representative doses we infused saline alone, insulin (initially 0.20 mU.kg(-1).min(-1)) alone, glucagon (1.0 ng.kg(-1).min(-1)) alone, and growth hormone (3.0 ng.kg(-1).min(-1)) alone intravenously for 4 h in 13 healthy individuals. That dose of insulin raised plasma insulin concentrations approximately threefold, suppressed glucose production, and drove plasma glucose concentrations down to subphysiological levels (65 +/- 3 mg/dl, P < 0.0001 vs. saline), resulting in nearly complete suppression of insulin secretion (P < 0.0001) and stimulation of glucagon (P = 0.0059) and epinephrine (P = 0.0009) secretion. An insulin dose of 0.15 mU.kg(-1).min(-1) caused similar effects, but a dose of 0.10 mU.kg(-1).min(-1) did not. The glucagon and growth hormone infusions did not alter plasma glucose levels or those of glucoregulatory factors. Thus, insulin "replacement" doses of 0.20 and even 0.15 mU.kg(-1).min(-1) are excessive, and conclusions drawn from the pancreatic clamp technique using such doses may need to be reassessed.