Effects of Pioglitazone on Glucose-Dependent Insulinotropic Polypeptide-Mediated Insulin Secretion and Adipocyte Receptor Expression in Patients With Type 2 Diabetes.

Incretin hormone dysregulation contributes to reduced insulin secretion and hyperglycemia in patients with type 2 diabetes mellitus (T2DM). Resistance to glucose-dependent insulinotropic polypeptide (GIP) action may occur through desensitization or downregulation of ß-cell GIP receptors (GIP-R). Studies in rodents and cell lines show GIP-R expression can be regulated through peroxisome proliferator-activated receptor γ (PPARγ) response elements (PPREs). Whether this occurs in humans is unknown. To test this, we conducted a randomized, double-blind, placebo-controlled trial of pioglitazone therapy on GIP-mediated insulin secretion and adipocyte GIP-R expression in subjects with well-controlled T2DM. Insulin sensitivity improved, but the insulinotropic effect of infused GIP was unchanged following 12 weeks of pioglitazone treatment. In parallel, we observed increased GIP-R mRNA expression in subcutaneous abdominal adipocytes from subjects treated with pioglitazone. Treatment of cultured human adipocytes with troglitazone increased PPARγ binding to GIP-R PPREs. These results show PPARγ agonists regulate GIP-R expression through PPREs in human adipocytes, but suggest this mechanism is not important for regulation of the insulinotropic effect of GIP in subjects with T2DM. Because GIP has antilipolytic and lipogenic effects in adipocytes, the increased GIP-R expression may mediate accretion of fat in patients with T2DM treated with PPARγ agonists.

Does GLP-1 suppress its own basal secretion?

PURPOSE/AIM: Negative feedback controls in endocrine regulatory systems are well recognized. The incretins and their role in glucose regulation have been of major interest recently. Whether the same negative control system applies to the regulation of incretin secretion is not clear. We sought to examine the hypothesis that exogenous administration of glucagon like peptide-1, GLP-1(7-36) amide or its metabolite GLP-1(9-36) amide, reduces the endogenous basal release of this incretin. MATERIALS AND METHODS: We evaluated the endogenous basal release of GLP-1 using two separate study designs. In protocol A we examined the GLP-1(7-36) amide levels during the infusion of GLP-1(9-36) amide. In protocol B, we used PYY and GLP-2 as biomarkers for the endogenous basal release of GLP-1(7-36) amide and assessed the endogenous basal release of these two hormones during the GLP-1(7-36) infusion. Twelve lean and 12 obese subjects were enrolled in protocol A and 10 obese volunteers in protocol B. RESULTS: The plasma levels of GLP-1(7-36) amide in protocol A and PYY and GLP-2 in protocol B remained unchanged during the exogenous infusion of GLP-1(9-36) and GLP-1(7-36) amide, respectively. CONCLUSIONS: The negative feedback control system as described by inhibition of the release of endogenous hormone while infusing it exogenously was not observed for the basal secretion of GLP-1(7-36) amide.

Mechanisms of type 2 diabetes resolution after Roux-en-Y gastric bypass.

BACKGROUND: Bariatric surgery is the most effective treatment for the reduction of weight and resolution of type 2 diabetes mellitus (T2 DM). The objective of this study was to longitudinally assess hormonal and tissue responses after RYGB. METHODS: Eight patients (5 with T2 DM) were studied before and after RYGB. A standardized test meal (STM) was administered before and at 1, 3, 6, 9, 12, and 15 months. Separately, a 2-hour hyperinsulinemic-euglycemic clamp (E-clamp) and a 2-hour hyperglycemic clamp (H-clamp) were performed before and at 1, 3, 6, and 12 months. Glucagon-like peptide-1 (GLP-1) was infused during the last hour of the H-clamp. Body composition was assessed with DXA methodology. RESULTS: Enrollment body mass index was 49±3 kg/m(2) (X±SE). STM glucose and insulin responses were normalized by 3 and 6 months. GLP-1 level increased dramatically at 1, 3, and 6 months, normalizing by 12 and 15 months. Insulin sensitivity (M of E-clamp) increased progressively at 3-12 months as fat mass decreased. The insulin response to glucose alone fell progressively over 12 months but the glucose clearance/metabolism (M of H-clamp) did not change significantly until 12 months. In response to GLP-1 infusion, insulin levels fell progressively throughout the 12 months. CONCLUSION: The early hypersecretion of GLP-1 leads to hyperinsulinemia and early normalization of glucose levels. The GLP-1 response normalizes within 1 year after surgery. Enhanced peripheral tissue sensitivity to insulin starts at 3 months and is associated with fat mass loss. ß-cell sensitivity improves at 12 months and after the loss of ≈33% of excess weight. There is a tightly controlled feedback loop between peripheral tissue sensitivity and ß-cell and L-cell (GLP-1) responses.

GLP-1(32-36)amide, a novel pentapeptide cleavage product of GLP-1, modulates whole body glucose metabolism in dogs.

We have previously demonstrated in human subjects who under euglycemic clamp conditions GLP-1(9-36)amide infusions inhibit endogenous glucose production without substantial insulinotropic effects. An earlier report indicates that GLP-1(9-36)amide is cleaved to a nonapeptide, GLP-1(28-36)amide and a pentapeptide GLP-1(32-36)amide (LVKGR amide). Here we study the effects of the pentapeptide on whole body glucose disposal during hyperglycemic clamp studies. Five dogs underwent indwelling catheterizations. Following recovery, the dogs underwent a 180 min hyperglycemic clamp (basal glucose +98 mg/dl) in a cross-over design. Saline or pentapeptide (30 pmol kg(-1) min(-1)) was infused during the last 120 min after commencement of the hyperglycemic clamp in a primed continuous manner. During the last 30 min of the pentapeptide infusion, glucose utilization (M) significantly increased to 21.4±2.9 mg kg(-1) min(-1)compared to M of 14.3±1.1 mg kg(-1)min(-1) during the saline infusion (P=0.026, paired t-test; P=0.062, Mann-Whitney U test). During this interval, no significant differences in insulin (26.6±3.2 vs. 23.7±2.5 µU/ml, P=NS) or glucagon secretion (34.0±2.1 vs. 31.7±1.8 pg/ml, P=NS) were observed. These findings demonstrate that under hyperglycemic clamp studies the pentapeptide modulates glucose metabolism by a stimulation of whole-body glucose disposal. Further, the findings suggest that the metabolic benefits previously observed during GLP-1(9-36)amide infusions in humans might be due, at least in part, to the metabolic effects of the pentapeptide that is cleaved from the pro-peptide, GLP-1(9-36)amide in the circulation.

The glucoregulatory benefits of glucagon-like peptide-1 (7-36) amide infusion during intensive insulin therapy in critically ill surgical patients: a pilot study.

OBJECTIVES: Intensive insulin therapy for tight glycemic control in critically ill surgical patients has been shown to reduce mortality; however, intensive insulin therapy is associated with iatrogenic hypoglycemia and increased variability of blood glucose levels. The incretin glucagon-like peptide-1 (7-36) amide is both insulinotropic and insulinomimetic and has been suggested as an adjunct to improve glycemic control in critically ill patients. We hypothesized that the addition of continuous infusion of glucagon-like peptide-1 to intensive insulin therapy would result in better glucose control, reduced requirement of exogenous insulin administration, and fewer hypoglycemic events. DESIGN: Prospective, randomized, double-blind, placebo-controlled clinical trial. SETTING: Surgical or burn ICU. PATIENTS: Eighteen patients who required intensive insulin therapy. INTERVENTIONS: A 72-hour continuous infusion of either glucagon-like peptide-1 (1.5 pmol/kg/min) or normal saline plus intensive insulin therapy. MEASUREMENTS AND MAIN RESULTS: The glucagon-like peptide-1 cohort (n = 9) and saline cohort (n = 9) were similar in age, Acute Physiology and Chronic Health Evaluation score, and history of diabetes. Blood glucose levels in the glucagon-like peptide-1 group were better controlled with much less variability. The coefficient of variation of blood glucose ranged from 7.2% to 30.4% in the glucagon-like peptide-1 group and from 19.8% to 56.8% in saline group. The mean blood glucose coefficient of variation for the glucagon-like peptide-1 and saline groups was 18.0% ± 2.7% and 30.3% ± 4.0% (p = 0.010), respectively. The 72-hour average insulin infusion rates were 3.37 ± 0.61 and 4.57 ± 1.18 U/hr (p = not significant). The incidents of hypoglycemia (≤ 2.78 mmol/L) in both groups were low (one in the glucagon-like peptide-1 group, three in the saline group). CONCLUSIONS: Glucagon-like peptide-1 (7-36) amide is a safe and efficacious form of adjunct therapy in patients with hyperglycemia in the surgical ICU setting. Improved stability of blood glucose is a favorable outcome, which enhances the safety of intensive insulin therapy. Larger studies of this potentially valuable therapy for glycemic control in the ICU are justified.

Hormonal response to a mixed-meal challenge after reversal of gastric bypass for hypoglycemia.

CONTEXT: Severe hypoglycemia is a rare and challenging complication of Roux-en-Y gastric bypass (RYGB), which is characterized by hypersecretion of insulin and incretin hormones in the postprandial state. OBJECTIVE: The objective of the study was to determine the clinical and hormonal responses to a mixed-meal challenge after the reversal of RYGB in 2 patients with post-RYGB hypoglycemia. We hypothesized that the reversal of RYGB would lead to clinical improvement in hypoglycemia through the attenuation of incretin hormone secretion. DESIGN/SETTING/SUBJECTS/OUTCOME MEASURES: Two patients with post-RYGB hypoglycemia underwent a standardized meal tolerance test prior to and 8 and 18 months after RYGB reversal, respectively, with the measurement of glucagon-like peptide-1 (GLP-1), glucose-dependent insulinotropic polypeptide (GIP), insulin, and glucose levels. Gastric bypass was reversed by reattaching the small gastric pouch to the bypassed distal stomach and resecting the Roux limb to restore the normal flow of food bolus. RESULTS: Both subjects showed persistent evidence of hypoglycemia with marked hyperinsulinemia after the RYGB reversal. GLP-1 levels after the RYGB reversal decreased by 76% and 70%, respectively, from their prereversal levels and to the level of nonhypoglycemic post-RYGB controls. In contrast, GIP levels after the RYGB reversal increased by 3-10 times the level before the reversal and 8-26 times that of the nonhypoglycemic post-RYGB controls. CONCLUSIONS: Reversal of RYGB did not alleviate hyperinsulinemic hypoglycemia upon a mixed-meal challenge in our patients, thus suggesting its limited clinical benefit as treatment of post-RYGB hypoglycemia. The marked increase in GIP levels and concurrent decrease in GLP-1 levels in our patients suggest a possible role of GIP in persistent hyperinsulinemic hypoglycemia after the reversal of RYGB.

Advances in the etiology and management of hyperinsulinemic hypoglycemia after Roux-en-Y gastric bypass.

INTRODUCTION: Hyperinsulinemic hypoglycemia with severe neuroglycopenia has been identified as a late complication of Roux-en-Y gastric bypass (RYGB) in a small number of patients. DISCUSSION: The rapid resolution of type 2 diabetes mellitus after RYGB is probably related to increased secretion of the incretin hormones glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1), and patients with post-RYGB hypoglycemia demonstrate prolonged elevations of GIP and GLP-1 compared to non-hypoglycemic post-RYGB patients. Nesidioblastosis has been identified in some patients with post-RYGB hypoglycemia and is likely due to the trophic effects of GIP and GLP-1 on pancreatic islets. CONCLUSIONS: Treatment of hypoglycemia after RYGB should begin with strict dietary (low carbohydrate) alteration and may require a trial of diazoxide, octreotide, or calcium-channel antagonists, among other drugs. Surgical therapy should include consideration of a restrictive form of bariatric procedure, with or without reconstitution of gastrointestinal continuity. Partial or total pancreatic resection should be avoided.

Hyperinsulinemic hypoglycemia after Roux-en-Y gastric bypass: unraveling the role of gut hormonal and pancreatic endocrine dysfunction.

BACKGROUND: Profound hypoglycemia occurs rarely as a late complication after Roux-en-Y gastric bypass (RYGB). We investigated the role of glucagon-like-peptide-1 (GLP-1) in four subjects who developed recurrent neuro-glycopenia 2 to 3 y after RYGB. METHODS: A standardized test meal (STM) was administered to all four subjects. A 2 h hyperglycemic clamp with GLP-1 infusion during the second hour was performed in one subject, before, during a 4 wk trial of octreotide (Oc), and after 85% distal pancreatectomy. After cessation of both glucose and GLP-1 infusion at the end of the 2 h clamp, blood glucose levels were monitored for 30 min. Responses were compared with a control group (five subjects 12 mo status post-RYGB without hypoglycemic symptoms). RESULTS: During STM, both GLP-1 and insulin levels were elevated 3- to 4-fold in all subjects, and plasma glucose-dependent insulinotropic peptide (GIP) levels were elevated 2-fold. Insulin responses to hyperglycemia ± GLP-1 infusion in one subject were comparable to controls, but after cessation of glucose infusion, glucose levels fell to 40 mg/dL. During Oc, the GLP-1 and insulin responses to STM were reduced (>50%). During the clamp, insulin response to hyperglycemia alone was reduced, but remained unchanged during GLP-1. Glucagon levels during hyperglycemia alone were suppressed and further suppressed after the addition of GLP-1. With the substantial drop in glucose during the 30 min follow-up, glucagon levels failed to rise. Due to persistent symptoms, one subject underwent 85% distal pancreatectomy; postoperatively, the subject remained asymptomatic (blood glucose: 119-220 mg/dL), but a repeat STM showed persistence of elevated levels of GLP-1. Histologically enlarged islets, and ß-cell clusters scattered throughout the acinar parenchyma were seen, as well as ß-cells present within pancreatic duct epithelium. An increase in pancreatic and duodenal homeobox-1 protein (PDX-1) expression was observed in the subject compared with control pancreatic tissue. CONCLUSIONS: A persistent exaggerated hypersecretion of GLP-1, which has been shown to be insulinotropic, insulinomimetic, and glucagonostatic, is the likely cause of post-RYGB hypoglycemia. The hypertrophy and ectopic location of ß-cells is likely due to overexpression of the islet cell transcription factor, PDX-1, caused by prolonged hypersecretion of GLP-1.

Diabetes and pancreatic cancer: chicken or egg?

OBJECTIVES: Although half of all patients with pancreatic cancer are diabetic at the time of diagnosis, it remains unclear whether the diabetes associated with pancreatic cancer is a cause or an effect of the malignancy. METHODS: Epidemiologic studies were reviewed, the geographic prevalence of diabetes and the incidence of pancreatic cancer were examined, and clinical and laboratory studies were reviewed. RESULTS: Long-standing diabetes increases the risk of pancreatic cancer by 40% to 100%, and recent-onset diabetes is associated with a 4- to 7-fold increase in risk, such that 1% to 2% of patients with recent-onset diabetes will develop pancreatic cancer within 3 years. Treatment of diabetes or morbid obesity decreases the risk of pancreatic cancer, and metformin therapy decreases the risk due to both its antidiabetic and antineoplastic effects. Recent-onset diabetes associated with pancreatic cancer likely represents secondary or type 3 diabetes. The discrimination of type 3 diabetes from the more prevalent type 2 diabetes may identify the high-risk subgroup of diabetic patients in whom potentially curable pancreatic cancer may be found. CONCLUSIONS: Type 2 and type 1 diabetes mellitus increase the risk of pancreatic cancer with a latency period of more than 5 years. Type 3 diabetes mellitus is an effect, and therefore a harbinger, of pancreatic cancer in at least 30% of patients.

Pancreatic polypeptide administration enhances insulin sensitivity and reduces the insulin requirement of patients on insulin pump therapy.

INTRODUCTION: The effects of pancreatic polypeptide (PP) infusion were examined in patients on insulin pump therapy to determine whether PP administration can reduce insulin requirements in patients with type 1 diabetes mellitus (T1DM) or type 3c diabetes mellitus (T3cDM; pancreatogenic). METHODS: Ten subjects with long-standing T1DM (n = 7) or T3cDM (n = 3) on insulin pump treatment received a 72 h subcutaneous infusion of 2 pmol/kg/min bovine PP or saline by portable infusion pump in a single-blinded, randomized, crossover design. RESULTS: Pancreatic polypeptide infusion raised plasma PP levels to 450-700 pmol/liter. Daily insulin infusion requirements (I) fell from 48 ± 6.9 to 40 ± 7.5 U on day 2 (p < .05) and from 46 ± 7.7 to 37 ± 6.6 U on day 3 (p < .05) of PP infusion compared with saline. Corrected for average blood glucose concentration (G), I/G fell in 10/10 subjects during the second 24 h period and in 7/10 subjects during the third 24 h period; sensitivity to insulin, calculated as 1/(I/G), increased 45% ± 12% on day 2 (p < .01) and 34% ± 14% on day 3 (p < .05) of PP infusion. Pancreatic polypeptide responses to a test meal were compared with the change in insulin infusion requirements in 5 subjects; the reduction in insulin requirements seen during PP infusion correlated with the degree of baseline PP deficiency (p < .002). CONCLUSIONS: A concurrent subcutaneous infusion of PP enhances insulin sensitivity and reduces insulin requirements in patients with long-standing T1DM and T3cDM on insulin pump therapy. The benefit of PP infusion correlated with the degree of PP deficiency.

Accuracy and reliability of the Nova StatStrip® glucose meter for real-time blood glucose determinations during glucose clamp studies.

AIMS/HYPOTHESIS: The Andres clamp technique, which requires accurate and timely determination of glucose, utilizes the Beckman or Yellow Springs Instruments (YSI) glucose analyzers. Both instruments require maintenance, a dedicated operator, preparation of a plasma sample, and a duplicate measurement that takes ≥2 minutes. The Nova StatStrip glucose meter was evaluated for accuracy, reliability, and near-real-time availability of glucose. METHODS: Blood samples from 24 patients who underwent 6-hour clamp studies and 12 patients who had a standardized meal tolerance test (SMT) were measured. Specimens were analyzed simultaneously and immediately upon collection by Beckman, YSI, and Nova. RESULTS: Of 1004 data pairs for the Nova device versus Beckman, the Nova data points ranged from 32 to 444, while Beckman ranged from 42 to 412. The coefficient for the slope of Beckman versus Nova was 1.009 (r = 0.978). Using error grid analysis, the number and percentage of values for Nova were 976 (97.2%) in the A zone and 28 (2.8%) in the B zone. Of 399 data pairs for the Nova device versus YSI, the Nova data points ranged from 46 to 255, whereas YSI ranged from 47 to 231. The coefficient for the slope of YSI versus Nova was 1.023 (r = 0.989). All Nova readings fell in the A zone. Time required for final reading, in duplicate, was 15 seconds for Nova and 120-180 seconds for Beckman and YSI. CONCLUSIONS: The simplicity of Nova and its reliability, accuracy, and speed make it an acceptable replacement device for Beckman and YSI in the conduct of clamps, especially when perturbations require rapid glucose determination.

Impact of acute biochemical castration on insulin sensitivity in healthy adult men.

INTRODUCTION: Evidence supports an inverse relationship between serum testosterone (T) and insulin resistance in men. However, data with respect to causality are limited. The aim of this study was to explore the impact of acute biochemical castration on insulin sensitivity in healthy adult men. METHODS: Ten healthy, adult males (mean age 41.0 +/- 3.9 yr) were studied. Subjects were studied at baseline and after 2 and 4 weeks of biochemical castration. Outpatient hospital research setting. Body composition (dual-energy x-ray absorptiometry), energy expenditure (indirect calorimetry), abdominal and visceral adiposity (MRI), skeletal muscle intramyocellular lipid content ([IMCL] (1)H-MR spectroscopy), and insulin sensitivity (hyperinsulinemic-euglycemic clamp) were assessed before and after 2 and 4 weeks of biochemical castration induced by a GnRH antagonist (acyline 300 mug/kg subcutaneous every 10-14 days). Serum T, insulin and glucose levels, body composition, abdominal visceral fat, IMCL, and glucose disposal rate (M) were measured. RESULTS AND CONCLUSION: Acyline administration suppressed serum T to frankly hypogonadal levels in all subjects for the duration of the study (P <0.009). No significant changes in body composition, energy expenditure, or M were observed at either 2 or 4 weeks of castration. Acyline is an effective GnRH antagonist inducing acute castration in all subjects. ii) Four weeks of biochemical castration has no impact on insulin sensitivity in healthy men likely due to unchanged body composition variables. iii) Insulin resistance associated with chronic low T levels may be largely driven by decreased fat free mass, increased percent body fat, and/or other metabolic regulatory factors.

Glucose metabolism in burn patients: the role of insulin and other endocrine hormones.

Severe burn causes a catabolic response with profound effects on glucose and muscle protein metabolism. This response is characterized by hyperglycemia and loss of muscle mass, both of which have been associated with significantly increased morbidity and mortality. In critically ill surgical patients, obtaining tight glycemic control with intensive insulin therapy was shown to reduce morbidity and mortality and has increasingly become the standard of care. In addition to its well-known anti-hyperglycemic action and reduction in infections, insulin promotes muscle anabolism and regulates the systemic inflammatory response. Despite a demonstrated benefit of insulin administration on the maintenance of skeletal muscle mass, it is unknown if this effect translates to improved clinical outcomes in the thermally injured. Further, insulin therapy has the potential to cause hypoglycemia and requires frequent monitoring of blood glucose levels. A better understanding of the clinical benefit associated with tight glycemic control in the burned patient, as well as newer strategies to achieve and maintain that control, may provide improved methods to reduce the clinical morbidity and mortality in the thermally injured patient.

Intensive insulin therapy confers a similar survival benefit in the burn intensive care unit to the surgical intensive care unit.

BACKGROUND: In contrast to the benefits of intensive insulin therapy (IIT) in the surgical intensive care unit (SICU), its benefits in the burn ICU (BICU) remain unclear. Furthermore, IIT and tight glycemic control has received little attention in elderly ICU patients. METHODS: We evaluated the normalization of blood glucose level with IIT in BICU and SICU patients. From October 2006 to July 2007, 970 patients were admitted to our BICU and our SICU. A total of 79 of these patients met criteria for initiation of IIT, 37 of who required IIT for at least 72 hours. Data were analyzed to determine if tight glycemic control (blood glucose < or =150 mg/dL by day 3) is associated with reduced morbidity and mortality. RESULTS: Tight control was better achieved in SICU patients (45%) than in BICU patients (33%). Daily insulin requirements were approximately 2-fold greater in SICU patients compared with BICU patients (P < .05). Tight control in both SICU and BICU patients was associated with a decreased incidence of sepsis compared with poor glycemic control (10% vs 58% and 60% vs 70%, respectively) and a decreased mortality rate (0 vs 58% and 20% vs 50%; SICU vs BICU, respectively). The percentage of total body surface area burned in BICU patients was 10% and 45% in the < or =150 and >150 mg/dL groups. Mortality rate in the poor control group was >10-fold greater than that of the tight control group; for patients > or =65 years of age, mortality was nearly double than that of patients <65 years of age. The greatest mortality rate (62%) was seen in patients >65 years of age with poor control. CONCLUSION: Tight control with IIT is associated with an increased survival rate in both BICU and SICU patients. Age is associated with survival, with patients older than 65 years of age having the greatest mortality rate.

Clinical review: The extrapancreatic effects of glucagon-like peptide-1 and related peptides.

CONTEXT: Glucagon-like peptide-1 (GLP-1) 7-36 amide, an insulinotropic hormone released from the intestinal L cells in response to nutrient ingestion, has been extensively reviewed with respect to beta-cell function. However GLP-1 receptors are abundant in many other tissues. Thus, the function of GLP-1 is not limited to the islet cells, and it has regulatory actions on many other organs. EVIDENCE ACQUISITION: A review of published, peer-reviewed medical literature (1987 to September 2008) on the extrapancreatic actions of GLP-1 was performed. EVIDENCE SYNTHESIS: The extrapancreatic actions of GLP-1 include inhibition of gastric emptying and gastric acid secretion, thereby fulfilling the definition of GLP-1 as an enterogastrone. Other important extrapancreatic actions of GLP-1 include a regulatory role in hepatic glucose production, the inhibition of pancreatic exocrine secretion, cardioprotective and cardiotropic effects, the regulation of appetite and satiety, and stimulation of afferent sensory nerves. The primary metabolite of GLP-1, GLP-1 (9-36) amide, or GLP-1m, is the truncated product of degradation by dipeptidyl peptidase-4. GLP-1m has insulinomimetic effects on hepatic glucose production and cardiac function. Exendin-4 present in the salivary gland of the reptile, Gila monster (Heloderma suspectum), is a high-affinity agonist for the mammalian GLP-1 receptor. It is resistant to degradation by dipeptidyl peptidase-4, and therefore has a prolonged half-life. CONCLUSION: GLP-1 and its metabolite have important extrapancreatic effects particularly with regard to the cardiovascular system and insulinomimetic effects with respect to glucose homeostasis. These effects may be particularly important in the obese state. GLP-1, GLP-1m, and exendin-4 therefore have potential therapeutic roles because of their diffuse extrapancreatic actions.

Numerical and clinical accuracy of a continuous glucose monitoring system during intravenous insulin therapy in the surgical and burn intensive care units.

BACKGROUND: Intensive insulin therapy (IIT) for glycemic control in critically ill patients has been shown to be beneficial. Continuous glucose monitoring systems (CGMSs) have been approved as an adjunct to complement standard glucose monitoring in type 2 diabetes mellitus. This study was designed to evaluate the accuracy of a real-time CGMS (DexCom STS) in the intensive care unit (ICU). We also evaluated its reliability and accuracy using a hyperinsulinemic-euglycemic and a hyperglycemic clamp study. METHODS: Nineteen patients were enrolled in this 7-day study [13 = surgical intensive care unit (SICU), 6 = burn intensive care unit (BICU)]. The patients were on IIT for at least 2 h prior the subcutaneous sensor insertion. Mean age and body mass index for SICU and BICU patients were 60.3 +/- 3.7 and 64.5 +/- 6.2 years and 36.6 +/- 5.0 and 33.85 +/- 3.4 kg/m2, respectively. DexCom accuracy was analyzed separately for the Johnson & Johnson (J&J) calibration finger sticks, Roche Accucheck finger sticks, and the Hitachi 917 analyzer measurements on serum using Clarke error grid analysis and Bland-Altman analysis. In the clamp studies, 20 patients were enrolled, and the data were analyzed similarly. RESULTS: There were 1065 pairs of DexCom-Accucheck, 232 pairs of DexCom-J&J, and 84 pairs of DexCom-Hitachi in ICU patients. For DexCom-Accucheck, 68.26% of the pairs fell into zone A, 31.83% into zone B, and 0.75% into zone C. There were no values in zones D or E. From the 1102 matching DexCom-Beckman pairs in clamp studies, 42.29% were in zone A, 55.90% were in zone B, and 4.08% were in zone C. CONCLUSIONS: Despite the high percentage of measurements in zones A and B, underestimation of hypoglycemia by DexCom measurements makes it an unreliable device in the ICU setting.

GLP-1 (9-36) amide, cleavage product of GLP-1 (7-36) amide, is a glucoregulatory peptide.

OBJECTIVE: Glucagon-like peptide-1 (GLP-1) (7-36) amide is a glucoregulatory hormone with insulinotropic and insulinomimetic actions. We determined whether the insulinomimetic effects of GLP-1 are mediated through its principal metabolite, GLP-1 (9-36) amide (GLP-1m). METHODS AND PROCEDURES: Glucose turnover during two, 2-h, euglycemic clamps was measured in 12 lean and 12 obese (BMI <25 or >30 kg/m(2)) male and female subject volunteers with normal oral glucose tolerance test. Saline or GLP-1m were infused from 0 to 60 min in each study. Additionally, seven lean and six obese subjects underwent a third clamp in which the GLP-1 receptor (GLP-1R) antagonist, exendin (9-39) amide was infused from -60 to 60 min with GLP-1m from 0 to 60 min. RESULTS: No glucose infusion was required in lean subjects to sustain euglycemia (glucose clamp) during saline or GLP-1m infusions. However, in obese subjects glucose infusion was necessary during GLP-1m infusion alone in order to compensate for a marked (>50%) inhibition of hepatic glucose production (HGP). Plasma insulin levels remained constant in lean subjects but rose significantly in obese subjects after termination of the peptide infusions. During GLP-1R blockade, infusion of glucose was immediately required upon starting GLP-1m infusions in all subjects due to a more dramatic reduction in HGP, as well as a delayed and modest insulinotropic response. DISCUSSION: We conclude that GLP-1m potently inhibits HGP and is a weak insulinotropic agent. These properties are particularly apparent and pronounced in obese but only become apparent in lean subjects during GLP-1 (7-36) receptor blockade. These previously unrecognized antidiabetogenic actions of GLP-1m may have therapeutic usefulness.