Meera Shah

Contribution of Endogenous Glucagon-Like Peptide 1 to Glucose Metabolism After Roux-en-Y Gastric Bypass

The contribution of elevated glucagon-like peptide 1 (GLP-1) to postprandial glucose metabolism after Roux-en-Y gastric bypass (RYGB) has been the subject of uncertainty. We used exendin-9,39, a competitive antagonist of GLP-1, to examine glucose metabolism, islet hormone secretion, and gastrointestinal transit in subjects after RYGB and in matched control subjects. Subjects were studied in the presence or absence of exendin-9,39 infused at 300 pmol/kg/min. Exendin-9,39 resulted in an increase in integrated postprandial glucose concentrations post-RYGB (3.6 ± 0.5 vs. 2.0 ± 0.4 mol/6 h, P = 0.001). Exendin-9,39 decreased insulin concentrations (12.3 ± 2.2 vs. 18.1 ± 3.1 nmol/6 h, P = 0.002) and the β-cell response to glucose (ϕTotal, 13 ± 1 vs. 11 ± 1 × 10−9 min−1, P = 0.01) but did not alter the disposition index (DI). In control subjects, exendin-9,39 also increased glucose (2.2 ± 0.4 vs. 1.7 ± 0.3 mol/6 h, P = 0.03) without accompanying changes in insulin concentrations, resulting in an impaired DI. Post-RYGB, acceleration of stomach emptying during the first 30 min by exendin-9,39 did not alter meal appearance, and similarly, suppression of glucose production and stimulation of glucose disappearance were unaltered in RYGB subjects. These data indicate that endogenous GLP-1 has effects on glucose metabolism and on gastrointestinal motility years after RYGB. However, it remains uncertain whether this explains all of the changes after RYGB.

Effects of GLP-1 on appetite and weight.

Glucagon-like peptide 1 (GLP-1) is a cleavage product of the pre-proglucagon gene which is expressed in the α-cells of the pancreas, the L-cells of the intestine, and neurons located in the caudal brainstem and hypothalamus. GLP-1 is of relevance to appetite and weight maintenance because it has actions on the gastrointestinal tract as well as the direct regulation of appetite. It delays gastric emptying and gut motility in humans. In addition, interventricular injections of GLP-1 inhibit food intake, independent of the presence of food in the stomach or gastric emptying. Peripherally administered GLP-1 also affects the central regulation of feeding. It is therefore the synergistic actions of GLP-1 in the gut and brain, acting on both central and peripheral receptors that seem responsible for the effects of the hormone on satiety.

TCF7L2 Genotype and α-Cell Function in Humans Without Diabetes.

The diabetes-associated allele in TCF7L2 increases the rate of conversion to diabetes; however, the mechanism by which this occurs remains elusive. We hypothesized that the diabetes-associated allele in this locus (rs7903146) impairs insulin secretion and that this defect would be exacerbated by acute free fatty acid (FFA)–induced insulin resistance. We studied 120 individuals of whom one-half were homozygous for the diabetes-associated allele TT at rs7903146 and one-half were homozygous for the protective allele CC. After a screening examination during which glucose tolerance status was determined, subjects were studied on two occasions in random order while undergoing an oral challenge. During one study day, FFA was elevated by infusion of Intralipid plus heparin. On the other study day, subjects received the same amount of glycerol as present in the Intralipid infusion. β-Cell responsivity indices were estimated with the oral C-peptide minimal model. We report that β-cell responsivity was slightly impaired in the TT genotype group. Moreover, the hyperbolic relationship between insulin secretion and β-cell responsivity differed significantly between genotypes. Subjects also exhibited impaired suppression of glucagon after an oral challenge. These data imply that a genetic variant harbored within the TCF7L2 locus impairs glucose tolerance through effects on glucagon as well as on insulin secretion.

Six and 12 Weeks of Caloric Restriction Increases β Cell Function and Lowers Fasting and Postprandial Glucose Concentrations in People with Type 2 Diabetes

BACKGROUND Caloric restriction alone has been shown to improve insulin action and fasting glucose metabolism; however, the mechanism by which this occurs remains uncertain. OBJECTIVE We sought to quantify the effect of caloric restriction on β cell function and glucose metabolism in people with type 2 diabetes. METHODS Nine subjects (2 men, 7 women) with type 2 diabetes [BMI (in kg/m(2)): 40.6 ± 1.4; age: 58 ± 3 y; glycated hemoglobin: 6.9% ± 0.2%] were studied using a triple-tracer mixed meal after withdrawal of oral diabetes therapy. The oral minimal model was used to measure β cell function. Caloric restriction limited subjects to a pureed diet (<900 kcal/d) for the 12 wk of study. The studies were repeated after 6 and 12 wk of caloric restriction. RESULTS Fasting glucose concentrations decreased significantly from baseline after 6 wk of caloric restriction with no further reduction after a further 6 wk of caloric restriction (9.8 ± 1.3, 5.9 ± 0.2, and 6.2 ± 0.3 mmol/L at baseline and after 6 and 12 wk of caloric restriction, respectively; P = 0.01) because of decreased fasting endogenous glucose production (EGP: 20.4 ± 1.1, 16.2 ± 0.8, and 17.4 ± 1.1 μmol · kg(-1) · min(-1) at baseline and after 6 and 12 wk of caloric restriction, respectively; P = 0.03). These changes were accompanied by an improvement in β cell function measured by the disposition index (189 ± 51, 436 ± 68, and 449 ± 67 10(-14) dL · kg(-1) · min(-2) · pmol(-1) at baseline and after 6 and 12 wk of caloric restriction, respectively; P = 0.01). CONCLUSIONS Six weeks of caloric restriction lowers fasting glucose and EGP with accompanying improvements in β cell function in people with type 2 diabetes. An additional 6 wk of caloric restriction maintained the improvement in glucose metabolism. This trial was registered at clinicaltrials.gov as NCT01094054.

Teriparatide Therapy and Reduced Postoperative Hospitalization for Postsurgical Hypoparathyroidism

IMPORTANCE Up to 20% of patients undergoing thyroidectomy develop hypocalcemia after surgery. Although usually transient, severe symptomatic hypocalcemia may occur. Teriparatide acetate (recombinant human parathyroid hormone 1-34) therapy can rapidly raise calcium levels. OBJECTIVE To test the hypothesis that teriparatide therapy in patients with postthyroidectomy hypoparathyroidism would expedite relief of symptomatic hypocalcemia and reduce the duration of hospitalization compared with standard treatment. DESIGN, SETTING, AND PARTICIPANTS Case series of all hospitalized patients 18 years or older treated with teriparatide for symptomatic postthyroidectomy hypocalcemia occurring immediately after thyroidectomy at Mayo Clinic, Rochester, Minnesota, between January 1, 2008, and June 30, 2014. A secondary analysis was performed with matched control and cohort groups having postthyroidectomy hypocalcemia of similar degree who received standard treatment only. Participants included 8 hospitalized patients who received teriparatide therapy after 24 hours of standard treatment (cases) and eight control patients selected from a cohort of 1193 thyroidectomies were matched for age, sex, body mass index, and nadir calcium levels. INTERVENTION Teriparatide acetate therapy (20 µg twice daily) subcutaneously for 1 week, with the option of continuing at 20 µg/d for up to 3 weeks. MAIN OUTCOMES AND MEASURES Safety, symptom resolution, calcium supplementation, and duration of hospitalization. RESULTS Among the 16 case and control patients the median nadir calcium level was 7.1 mg/dL in both groups. Most patients underwent thyroidectomy for thyroid cancer. Teriparatide therapy was safe, with no adverse events noted, and completely eliminated symptomatic hypocalcemia in all treated patients within 24 hours of initiation. Hospital discharge occurred at a median of 1.0 day (interquartile range, 1.0-1.0 day) after teriparatide therapy initiation among cases vs 2.5 days (interquartile range, 1.8-3.0 days) after the equivalent clinical point was reached in controls (P = .01). This value was 2.0 days in the source cohort (P = .02). On hospital discharge, patients had similar calcium levels. Six months after surgery, all patients treated with teriparatide showed partial or complete parathyroid recovery. Calcium supplementation and calcium levels were comparable between the groups. CONCLUSIONS AND RELEVANCE In this pilot study, teriparatide therapy in patients with postthyroidectomy hypoparathyroidism was safe, rapidly eliminated hypocalcemic symptoms, and likely reduced the duration of hospitalization. Given the limitations of this small study, a large-scale randomized trial is needed to verify these results and to assess the long-term effect of teriparatide therapy on clinical outcomes.

The effect of vagal nerve blockade using electrical impulses on glucose metabolism in nondiabetic subjects.

Purpose Vagal interruption causes weight loss in humans and decreases endogenous glucose production in animals. However, it is unknown if this is due to a direct effect on glucose metabolism. We sought to determine if vagal blockade using electrical impulses alters glucose metabolism in humans. Patients and methods We utilized a randomized, cross-over study design where participants were studied after 2 weeks of activation or inactivation of vagal nerve blockade (VNB). Seven obese subjects with impaired fasting glucose previously enrolled in a long-term study to examine the effect of VNB on weight took part. We used a standardized triple-tracer mixed meal to enable measurement of the rate of meal appearance, endogenous glucose production, and glucose disappearance. The 550 kcal meal was also labeled with 111In-diethylene triamine pentaacetic acid (DTPA) to measure gastrointestinal transit. Insulin action and β-cell responsivity indices were estimated using the minimal model. Results Integrated glucose, insulin, and glucagon concentrations did not differ between study days. This was also reflected in a lack of effect on β-cell responsivity and insulin action. Furthermore, fasting and postprandial endogenous glucose production, integrated meal appearance, and glucose disposal did not differ in the presence or absence of VNB. Similarly, gastric emptying and colonic transit were unchanged by VNB. Conclusion In this pilot study in nondiabetic humans, electrical vagal blockade had no acute effects on glucose metabolism, insulin secretion and action, or gastric emptying. It remains to be determined if more pronounced effects would be observed in diabetic subjects.

Diabetes-Associated Variation in TCF7L2 Is Not Associated With Hepatic or Extrahepatic Insulin Resistance

A common genetic variation in TCF7L2 is associated with type 2 diabetes. However, the mechanism by which this occurs remains elusive. In addition to affecting insulin secretion, genetic variation at the TCF7L2 locus may alter insulin action or directly modify hepatic glucose metabolism. We sought to determine whether the diabetes-associated variant in this locus (the T allele of rs7903146) increases fasting endogenous glucose production (EGP), and impairs insulin-induced suppression of EGP and insulin-stimulated glucose disappearance. To address this, we studied individuals who were either homozygous for the diabetes-associated allele (TT) at rs7903146 or were homozygous for the protective allele (CC). Subjects were matched for other anthropometric characteristics and were studied using a euglycemic clamp. EGP and glucose uptake were measured using the tracer dilution technique, and the relative contribution of gluconeogenesis to EGP was quantitated using deuterated water corrected for transaldolase exchange. We report that the diabetes-associated variation in TCF7L2 did not associate with fasting EGP, insulin-induced suppression of EGP, and insulin-induced stimulation of glucose uptake. There was no association with the contribution of gluconeogenesis and glycogenolysis to EGP. These data indicate that genetic variation at TCF7L2 does not predispose an individual to type 2 diabetes by altering either hepatic or extrahepatic insulin action.

De-novo Inflammatory Bowel Disease After Bariatric Surgery: A Large Case Series

Background Case reports of inflammatory bowel diseases [IBD] have been reported in patients with a history of bariatric surgery. Our aim was to characterize patients who were diagnosed with IBD after having undergone bariatric surgery. Methods Electronic medical records were reviewed at two institutions to identify patients who developed de-novo Crohns disease or ulcerative colitis [UC] after bariatric surgery. Data on demographics, type of bariatric surgical procedure, IBD subtype, phenotype and medication usage were obtained. The incidence rate of de-novo IBD after bariatric surgery [per 100000 person-years] and standardized incidence ratio [SIR] were estimated from a prospective bariatric surgery database. Results A total of 44 patients with de-novo IBD after bariatric surgery were identified [31 Crohns disease, 12 UC, one IBD unclassified]. Most patients were female [88.6%], with median age at IBD onset of 44 years [IQR, 37-52] and median time to IBD diagnosis after bariatric surgery of 7 years [IQR, 3-10]. Sixty-eight per cent underwent Roux-en-Y gastric bypass. In the prospective database, the incidence of IBD in patients who underwent bariatric surgery was 26.7 per 100000 person-years [4.5 for UC and 22.3 for Crohns disease]. The age-adjusted SIR ranged from 3.56 in the 40-49 year age group to 4.73 in the 30-39 year age group. Conclusion We described a case series of patients developing de-novo IBD after bariatric surgery. There appears to be a numerically higher incidence of Crohns disease in this population. Confirmation of causality is required in larger patient cohorts.

When Is It Appropriate to Use Glutamine in Critical Illness

Glutamine is a nonessential amino acid, which under trauma or critical illness can become essential. A number of historic small single-center randomized controlled trials (RCTs) have demonstrated positive treatment effects on clinical outcomes with glutamine supplementation. Meta-analyses based on these trials demonstrated a significant reduction in hospital mortality, intensive care unit (ICU) length of stay (LOS), and hospital LOS with intravenous (IV) glutamine. Similar results were not noted in 2 large multicenter RCTs (REDOXS and MetaPlus) assessing the efficacy of glutamine supplementation in ventilated ICU patients. The REDOXS trial of 40 ICUs randomized 1223 ventilated ICU patients to glutamine (IV and enteral), antioxidants, both glutamine and antioxidants, or placebo. The main conclusions were a trend toward increased 28-day mortality and significant increased hospital and 6-month mortality in those who received glutamine. The MetaPlus trial of 14 ICUs, which randomized 301 ventilated ICU patients to glutamine-enriched enteral vs an isocaloric diet, noted increased 6-month mortality in the glutamine-supplemented group. Newer RCTs have focused on specific populations and have demonstrated benefits in burn and elective surgery patients with glutamine supplementation. Whether larger studies will confirm these findings is yet to be determined. Recent American Society for Parenteral and Enteral Nutrition guidelines recommend that IV and enteral glutamine should not be used in the critical care setting based on the moderate quality of evidence available. We agree with these recommendations and would encourage larger multicenter studies to evaluate the risks and benefits of glutamine in burn and elective surgery patients.

Impaired insulin action is associated with increased glucagon concentrations in nondiabetic humans

Context Abnormal glucagon concentrations contribute to hyperglycemia, but the mechanisms of α-cell dysfunction in prediabetes are unclear. Objective We sought to determine the relative contributions of insulin secretion and action to α-cell dysfunction in nondiabetic participants across the spectrum of glucose tolerance. Design This was a cross-sectional study. A subset of participants (n = 120) was studied in the presence and absence of free fatty acid (FFA) elevation, achieved by infusion of Intralipid (Baxter Healthcare, Deerfield, IL) plus heparin, to cause insulin resistance. Setting An inpatient clinical research unit at an academic medical center. Participants A total of 310 nondiabetic persons participated in this study. Interventions Participants underwent a seven-sample oral glucose tolerance test. Subsequently, 120 participants were studied on two occasions. On one day, infusion of Intralipid plus heparin raised FFA. On the other day, participants received glycerol as a control. Main Outcome Measure(s) We examined the relationship of glucagon concentration with indices of insulin action after adjusting for the effects of age, sex, and weight. Subsequently, we sought to determine whether an acute decrease in insulin action, produced by FFA elevation, altered glucagon concentrations in nondiabetic participants. Results Fasting glucagon concentrations correlated positively with fasting insulin and C-peptide concentrations and inversely with insulin action. Fasting glucagon was not associated with any index of β-cell function in response to an oral challenge. As expected, FFA elevation decreased insulin action and also raised glucagon concentrations. Conclusions In nondiabetic participants, glucagon secretion was altered by changes in insulin action.