Impaired Hyperglycemia-Induced Delay in Gastric Emptying in Patients With Type 1 Diabetes Deficient for Islet Amyloid Polypeptide

OBJECTIVE—Slowing of gastric emptying by hyperglycemia, a physiological response to minimize postprandial hyperglycemia, may be impaired in patients with type 1 diabetes. The causes and consequences on glucose homeostasis are unknown.RESEARCH DESIGN AND METHODS—Consequences of euglycemia- and hyperglycemia-induced changes in gastric emptying on postprandial glucose fluxes and excursions were studied in 10 healthy subjects and 15 type 1 diabetic subjects after ingestion of a mixed meal using the double isotope approach ([6,6-²H₂] and [1-¹³C]glucose) and scintigraphic measurements of gastric emptying.RESULTS—Gastric emptying was greater in type 1 diabetic subjects (90–120 min, P < 0.03), and 50% retention times were comparable in healthy subjects and type 1 diabetic subjects (167 ± 8 vs. 152 ± 10, P = 0.32). Hyperglycemia markedly delayed gastric emptying in healthy subjects but did not alter it in type 1 diabetic subjects (50% retention time 222 ± 18 vs. 167 ± 8 min, P = 0.003 and 148 ± 9 vs. 152 ± 10 min, P = 0.51). Plasma islet amyloid polypeptide (IAPP) increased approximately fourfold in healthy subjects (P < 0.001), whereas it was undetectable in type 1 diabetic subjects. IAPP replacement, using the analog pramlintide, in type 1 diabetic subjects slowed gastric emptying to a comparable extent, as did hyperglycemia in healthy subjects (P < 0.14), and greatly reduced postprandial hyperglycemia (P < 00.1). Meal-derived glucose appearance in plasma (10.7 ± 0.5 vs. 6.8 ± 0.7 μmol · kg⁻¹ · min⁻¹, P < 0.001) was reduced, and splanchnic glucose sequestration increased (14.0 ± 3.0 vs. 25.0 ± 6.0%, P = 0.04).CONCLUSIONS—In patients with type 1 diabetes the ability to delay gastric emptying in response to hyperglycemia is impaired. This impairment contributes to exaggerated rates of meal-derived glucose appearance and, ultimately, postprandial glucose excursions.The importance of insulin and glucagon in maintaining postprandial glycemic excursions within a narrow range is well established (1). However, alterations in gastric emptying, another potentially important factor (2), are not generally considered to be of clinical significance for postprandial hyperglycemia in diabetes unless diabetes late complications, such as gastroparesis, have emerged (3,4).Gastroparesis is a relatively rare diabetes late complication resulting from irreversible intestinal nerve damage (5) and has to be distinguished from the physiological inhibitory effects of acute hyperglycemia on gastric motility (6,7). The latter has been proposed as a defense mechanism to minimize postprandial hyperglycemia by reducing the rate of efflux of glucose into the circulation from the gut (8). This process may be of special importance for patients with type 1 diabetes because they have been reported to have a reduced ability to delay gastric emptying in response to hyperglycemia (9).The pancreatic β-cell hormone islet amyloid polypeptide (IAPP) is cosecreted with insulin in a fixed molar ratio (10) and reduces gastric emptying. Thus, patients with type 1 diabetes even without concomitant enteric neuropathy should have increased rather than delayed rates of gastric emptying, because they are IAPP deficient (11). Accordingly, the present studies were undertaken to test the hypothesis that impairment in hyperglycemia-induced delay in gastric emptying should result in greater meal-derived glucose appearance in the systemic circulation and thus should contribute to postprandial hyperglycemia in patients with type 1 diabetes.     

Transthorakale Echokardiographie bei thorakaler Messerstichverletzung

Penetrating chest trauma involving the heart is usually known with a high mortality rate. Neither the absence of hemodynamic depression nor ECG changes exclude a potential fatal injury to the heart. We report on the diagnosis and definitive treatment of a stab wound injury with transected coronary artery, concomittant ventricular penetration, and pulmonary injury.A 37-year-old female was admitted to our emergency room with multiple left-sided gashes (cheek, neck, upper extremity) and a single stab wound in the left thorax. At the scene of the accident the patient's hemodynamic condition was stable with no signs of shock or shortness of breath. Auscultation revealed regular respiratory sound on both lung sides. Hospital transfer by ground was uneventful. Chest X-ray showed left pleural effusion with no signs of pneumothorax. ECG demonstrated regular sinus rhythm without repolarization changes or low voltage. Transthoracic echocardiography revealed pericardial effusion with a swinging heart. The patient was electively intubated in the emergency room and transferred to the operating room for pericardial paracentesis. Median sternotomy was necessary due to extensive bleeding in the drain. Examination of the heart showed a laceration of the left coronary artery (LAD), left ventricle, and upper lobe of the left lung. Cardiopulmonary bypass was instituted and the LAD was ligated proximal to the penetration. The left internal thoracic artery was used for coronary revascularization of the LAD. Postoperative ECG and creatine kinase evaluations excluded myocardial ischemia. The patient was discharged from hospital at POD 10 fully recovered. Transthoracic echocardiography in the emergency room is the diagnostic tool of choice to exclude/confirm a potential cardiac injury. In the case of pericardial effusion, paracentesis sometimes followed by thoracotomy should be performed. The importance of rapid diagnosis and intervention should be emphasized to reduce mortality due to cardiac tamponade or acute myocardial infarction as illustrated by this case.     

Efficacy,safety and tolerability of green tea catechins in the treatment of external anogenital warts: a systematic review and meta‐analysis

Background External anogenital warts (EGWs) are non‐malignant skin tumours caused by human papillomavirus. They are one of the fastest growing sexually transmitted diseases. Current treatments are unsatisfactory. Green tea sinecatechin Polyphenon E ointment is a botanical extract from green tea leaves exhibiting anti‐oxidant, anti‐viral and anti‐tumour properties. Objective The aim of this study was to integrate valid information and provide basis for rational decision making regarding efficacy and safety of green tea extracts in the treatment of EGWs. Methods A systematic search in electronic databases was conducted using specific key terms. Main search was performed independently by two reviewers. The accumulated relevant literature was subsequently systematically reviewed and a meta‐analysis was conducted. Results Three randomized, double‐blind, placebo‐controlled studies evaluating efficacy and safety of Polyphenon E 15% and 10% in the treatment of warts were included in the systematic review and meta‐analysis. A total of 660 men and 587 women were enrolled. Regarding primary outcome, both Polyphenon E 15% and 10% demonstrated significantly higher likelihood of complete clearance of baseline and baseline and new warts compared with controls. No significant heterogeneity was detected. Recurrence rates were very low. Commonest local skin sign was erythema and local skin symptom was itching. Conclusions Efficacy of Polyphenon 15% and 10%, at least for the primary endpoint, is clearly indicated. Polyphenon E treatment exhibits very low recurrence rates and appears to have a rather favourable safety and tolerability profile. Recommendations for future studies should include evaluation of the efficacy of green tea catechins in the treatment of internal anogenital warts and direct comparison with its principal comparator, imiquimod.     

Paradoxical changes of muscle glutamine release during hyperinsulinemia euglycemia and hypoglycemia in humans: further evidence for the glucose-glutamine cycle

Insulin suppresses and counterregulatory hormones increase proteolysis. Therefore, if proteolysis were a major factor determining amino acid fluxes in plasma, one would expect release of glutamine into plasma to be suppressed by insulin under euglycemic conditions and to be stimulated under hypoglycemic conditions. However, release of glutamine into plasma remains unaltered or increases during euglycemic hyperinsulinemia and decreases during insulin-induced hypoglycemia. To investigate the mechanisms for these paradoxical observations and the role of skeletal muscle, we infused overnight fasted volunteers with [U-(14)C] glutamine and measured release of glutamine into plasma, its removal from plasma, and forearm glutamine net balance, fractional extraction, uptake and release during 4-hour euglycemic ( approximately 5.0 mmol/L, n = 7) and hypoglycemic ( approximately 3.1 mmol/L, n = 8) hyperinsulinemic ( approximately 230 pmol/L) clamp experiments. During the euglycemic clamps, plasma glutamine uptake and release (both P <.05) and forearm muscle glutamine fractional extraction (P <.05), uptake (P <.02) and release (P <.01) all increased, whereas forearm glutamine net balance remained unchanged. The increase in muscle glutamine release (from 1.85 +/- 0.26 to 2.18 +/- 0.30 micromol. kg(-1). min(-1)) accounted for approximately 60% of the increase in total glutamine release into plasma (from 5.54 +/- 0.47 to 6.10 +/- 0.64 micromol. kg(-1). min(-1)) and correlated positively with the increase in muscle glucose uptake (r = 0.80, P <.03). During the hypoglycemic clamps, plasma glutamine uptake and release and forearm glutamine release remained unaltered, but forearm glutamine fractional extraction and uptake decreased approximately 25% (both P <.01) so that forearm glutamine net release increased from 0.37 +/- 0.06 to 0.61 +/- 0.09 micromol. kg(-1). min(-1) (P <.03). We conclude that skeletal muscle is largely responsible for the increased release of glutamine into plasma during euglycemic hyperinsulinemia in humans, and that this may be due to increased conversion of glucose to glutamine as part of the glucose-glutamine cycle; during hypoglycemic hyperinsulinemia decreased glutamine uptake by skeletal muscle may be important for providing substrate for increased glutamine gluconeogenesis.     

Autoregulation of endogenous glucose production during hyperglucagonemia

Increased endogenous glucose production (EGP) contributes to fasting hyperglycemia in type II diabetes. In nondiabetic subjects, increased gluconeogenesis from lactate does not increase EGP. Type 2 diabetes is associated with hyperglucagonemia. The present study was undertaken to examine whether physiologic elevation of plasma glucagon overrides autoregulation of EGP. Eight healthy volunteers were studied on 2 occasions, once during a 3-hour infusion of 30 micromol/kg/min Na-lactate and once during a control infusion of Na-bicarbonate. Plasma glucagon, insulin, and growth hormone were clamped at identical levels in both experiments. Rates of appearance of glucose, lactate, and gluconeogenesis from lactate were measured by tracer techniques. Glucagon infusion rate was elevated when the lactate or bicarbonate infusions were started to induce physiologic hyperglucagonemia. Plasma glucagon increased from baseline levels (234 +/- 21 ng/L and 211 +/- 23 ng/L) to 313 +/- 47 ng/L (bicarbonate experiments) and 329 +/- 43 ng/L (lactate experiments, means +/- SE, P >.3). Lactate infusion increased plasma lactate concentrations from 1.1 +/- 0.9 to 4.6 +/- 0.5 mmol/L (P =.0003). Lactate conversion to glucose increased from 1.5+/-0.3 to 2.8+/-0.8 micromol/kg/min (P =.03) and from 1.7 +/- 0.3 to 8.1 +/- 0.8 micromol/kg/min (P =.0003) in the bicarbonate and lactate experiments, respectively. The increments in lactate conversion to glucose differed significantly (P =.0008). Nevertheless, plasma glucose and EGP were not different in the bicarbonate and lactate experiments: 5.4 +/- 0.5 versus 6.6 +/- 0.7 mmol/L (P =.21), and 10.5 +/- 0.6 versus 11.6 +/- 0.6 micromol/kg/min (P =.19). We conclude that in normal volunteers, neither hyperglucagonemia nor the combination of hyperglucagonemia and increased substrate availability alters the autoregulation of EGP.     

Circannual variation in lymphocyte subsets, revisited

BACKGROUND: Circadian and circannual variations in lymphocyte subsets, especially CD8+ T-lymphocytes, have been reported. This study focuses on CD4+ T-lymphocyte seasonal variation over a 6-year 8-month period. STUDY DESIGN AND METHODS: Lymphocyte subsets were quantitated monthly for four healthy individuals from 1986 through 1992 as part of a flow cytometry quality-control program. RESULTS: In general, there were no significant seasonal changes in the total number of white cells or in total lymphocyte counts. The absolute numbers of CD4+ T-lymphocytes were lowest in summer when the CD8+ T-lymphocytes were highest. Mean CD4+ T-lymphocyte counts were 846, 967, 618, and 695 per microL for Subjects 1 through 4, respectively, in winter and 432, 670, 355, and 766 per microL, respectively, in summer. Two healthy subjects had CD4+ T-lymphocyte counts lower than 300 per microL on one or more occasions during the study period. In three of the four subjects, the percentage of B-lymphocytes in winter was almost double that in summer. In one of the four subjects, no circannual rhythm was observed in these lymphocyte subpopulations. CONCLUSION: The seasonal variation in CD4+ T- lymphocyte counts demonstrated in three healthy individuals over almost 7 years is again of interest in light of renewed consideration of using surrogate tests, such as CD4+ T-lymphocyte counts, to screen for AIDS- like diseases that may be in the blood supply.     

Function of wild-type or mutant Rac2 and Rap1a GTPases in differentiated HL60 cell NADPH oxidase activation

Studies of neutrophil nicotinamide adenine dinucleotide phosphate (NADPH) oxidase activation in a cell-free system showed that the low molecular-weight guanosine triphosphatase (GTPase) Rac was required, and that Rap1a may participate in activation of the catalytic complex. Full-length posttranslationally modified Rac2 was active, whereas only the 1-166 truncated form of Rap1a was functional in the cell-free system, and thus, clarification of the function of Rap1a and Rac2 in intact human phagocytes is needed to provide further insight into their roles as signal transducers from plasma membrane receptors. In the present studies, oligonucleotide-directed mutagenesis was used to introduce a series of mutations into human rap1a or rac2 in the mammalian expression vector pSR alpha neo. HL60 cells transfected with wild-type or mutated rac2 or rap1a cDNA constructs and control HL60 cells transfected with the pSR alpha neo vector containing no inserted cDNA were selected in G418-containing media, then subclones were isolated. Compared with the parent HL60 cells, each of the stable transfected cell lines differentiated similarly into neutrophil-like cells and expressed comparable levels of NADPH oxidase components p47- phox, p67-phox and gp91-phox. The differentiated vector control cell line produced O2. in response to receptor stimulation at rates that were not significantly different from parent HL60 cells. O2-. production by differentiated cell lines expressing mutated N17 Rap1a or N17 Rac2 dominant-negative proteins was inhibited, whereas O2-. production by the subline overexpressing wild-type Rap1a was increased by fourfold. O2-. production by the differentiated cell line expressing GTPase-defective V12 Rap1a was also significantly inhibited, a finding that is consistent with a requirement for cycling between guanosine diphosphate- and GTP-bound forms of Rap1a for continuous NADPH oxidase activation in intact neutrophils. A model is proposed in which Rac2 mediates assembly of the p47 and p67 oxidase components on the cytosolic face of the plasma membrane via cytoskeletal reorganization, whereas Rap1a functions downstream as the final activation switch involving direct physical interaction with the transmembrane flavocytochrome component of the NADPH oxidase.     

The provision of renal replacement therapy for adults in England and Wales: recent trends and future directions

We assessed the level of provision of renal replacement therapy for adults in England and Wales. All autonomous main renal units in England (n = 52) and Wales (n = 5) were surveyed in 1996. Data for England were compared to the 1993 National Renal Review. The acceptance rate in England 1995 was 82 (80-85) per million population (p.m.p.) compared with 67 (65-70) p.m.p. in 1991-2. The rate in 1995 in Wales was 109 (98- 122) p.m.p. The prevalence rate in England was 476 p.m.p. at end-1995 compared to 393 p.m.p. in 1993, in Wales it was 487 p.m.p. The number of main renal units in England did not rise between 1993 and 1995; capacity was increased by use of more treatment shifts and temporary haemodialysis stations, and by opening more satellite units. The main growth was in hospital haemodialysis. There was an uneven geographical distribution of services. Patients accepted were older with more comorbidity. The use of better-quality processes of dialysis increased. The steady-state position for RRT will not be reached for over a decade. Health authorities will face continued pressure to fund increases in quantity and quality improvements. A stronger evidence base of the effectiveness of therapies, and a national registry to monitor the equity and cost-effectiveness of services are needed.      

Diagnostic and therapeutic implications of relationships between fasting, 2-hour postchallenge plasma glucose and hemoglobin a1c values

BACKGROUND: Increased fasting plasma glucose (FPG) and 2-hour postchallenge plasma glucose (PCPG) levels with normal hemoglobin A1c (HbA1c) levels are recognized as risk factors for cardiovascular disease. We undertook this study to determine the relationships between FPG and 2-hour PCPG levels over the normal HbA1c range and to assess the need to control FPG and 2-hour PCPG levels to achieve HbA1c targets recommended by the American Diabetes Association (ADA), International Diabetes Federation (IDF), and American College of Endocrinology (ACE). METHODS: The data of all healthy individuals with HbA1c values less than 7.0% (N = 457) who underwent oral glucose tolerance tests between 1986 and 2002 for either screening as potential research volunteers (93%) or diagnostic purposes (7%) were analyzed. RESULTS: Of 404 individuals with normal HbA1c levels (<6.0%), 60% had normal glucose tolerance, 33% had impaired glucose tolerance, 1% had isolated impaired FPG, and 6% had type 2 diabetes mellitus. Of 161 individuals without normal glucose tolerance, 80% had normal FPG levels. Both FPG and 2-hour PCPG levels increased as HbA1c increased and were significantly correlated (r = 0.63, P<.001), but the 2-hour PCPG level increased at a rate 4 times greater than FPG and accounted for a greater proportion of HbA1c. People who met the IDF and ACE HbA1c targets (<6.5%) had significantly lower 2-hour PCPG levels than those who met the ADA target (<7.0%) (P =.03), whereas FPG levels were similar. CONCLUSIONS: Most individuals with HbA1c values between 6.0% and 7.0% have normal FPG levels but abnormal 2-hour PCPG levels, suggesting that an upper limit of normal for FPG at 110 mg/dL (6.11 mmol/L) is too high and that attempts to lower HbA1c in these individuals will require treatment preferentially directed at lowering postprandial glucose levels.     

Efficacy and safety of the once-daily GLP-1 receptor agonist lixisenatide in monotherapy: a randomized, double-blind, placebo-controlled trial in patients with type 2 diabetes (GetGoal-Mono)

OBJECTIVE

To assess efficacy and safety of lixisenatide monotherapy in type 2 diabetes.

RESEARCH DESIGN AND METHODS

Randomized, double-blind, 12-week study of 361 patients not on glucose-lowering therapy (HbA_1c 7–10%) allocated to one of four once-daily subcutaneous dose increase regimens: lixisenatide 2-step (10 μg for 1 week, 15 μg for 1 week, and then 20 μg; n = 120), lixisenatide 1-step (10 μg for 2 weeks and then 20 μg; n = 119), placebo 2-step (n = 61), or placebo 1-step (n = 61) (placebo groups were combined for analyses). Primary end point was HbA_1c change from baseline to week 12.

RESULTS

Once-daily lixisenatide significantly improved HbA_1c (mean baseline 8.0%) in both groups (least squares mean change vs. placebo: −0.54% for 2-step, −0.66% for 1-step; P < 0.0001). Significantly more lixisenatide patients achieved HbA_1c <7.0% (52.2% 2-step, 46.5% 1-step) and ≤6.5% (31.9% 2-step, 25.4% 1-step) versus placebo (26.8% and 12.5%, respectively; P < 0.01). Lixisenatide led to marked significant improvements of 2-h postprandial glucose levels and blood glucose excursions measured during a standardized breakfast test. A significant decrease in fasting plasma glucose was observed in both lixisenatide groups versus placebo. Mean decreases in body weight (∼2 kg) were observed in all groups. The most common adverse events were gastrointestinal—nausea was the most frequent (lixisenatide 23% overall, placebo 4.1%). Symptomatic hypoglycemia occurred in 1.7% of lixisenatide and 1.6% of placebo patients, with no severe episodes. Safety/tolerability was similar for the two dose regimens.

CONCLUSIONS

Once-daily lixisenatide monotherapy significantly improved glycemic control with a pronounced postprandial effect (75% reduction in glucose excursion) and was safe and well tolerated in type 2 diabetes.In recent years, the use of glucagon-like peptide 1 (GLP-1) receptor agonists has become established as an important therapeutic option in the management of patients with type 2 diabetes (1,2). As a class, GLP-1 receptor agonists possess a number of favorable clinical characteristics in addition to their glucose-lowering effects, including a low propensity to cause hypoglycemia (as a result of their glucose-dependent action) and promotion of weight loss (3,4). Preclinical studies using in vitro and animal models also suggest that GLP-1 receptor agonists have the potential to preserve pancreatic islet β-cells, which may help to provide more stable metabolic control long term (5). As of today, three representatives of the GLP-1 receptor agonist class have been marketed: exenatide (twice-daily and once-weekly formulations) and liraglutide once daily.Lixisenatide (AVE0010) is a new selective once-daily GLP-1 receptor agonist in development for the treatment of type 2 diabetes mellitus (6–8). It is a 44-amino acid peptide that is amidated at the C-terminal end and shares some structural elements with exendin-4 (the main difference being the addition of 6 lysine residues at the C terminus) (9). Lixisenatide is highly selective for the GLP-1 receptor and exerts about fourfold higher affinity for the GLP-1 receptor than native human GLP-1 (9). The preclinical pharmacological profile of lixisenatide suggests that stimulation of insulin secretion by lixisenatide is strictly glucose dependent. In animal models, lixisenatide enhances insulin biosynthesis and stimulation of β-cell proliferation and delays gastric emptying and reduces food intake (9). In human islets, lixisenatide prevents lipotoxic islet insulin depletion and preserves insulin production, storage, and pancreatic β-cell function (9). Lixisenatide undergoes renal metabolism, but mild or moderate renal impairment does not appear to influence its pharmacokinetics or tolerability (10).In a 13-week, randomized, double-blind, placebo-controlled, parallel-group, phase II dose-ranging study, lixisenatide administered at doses of 5, 10, 20, or 30 μg once daily or twice daily in patients with type 2 diabetes inadequately controlled with metformin significantly improved HbA_1c compared with placebo (8). Dose-dependent improvements were also observed for fasting plasma glucose (FPG) and postprandial plasma glucose (PPG) associated with the morning meal and average self-monitored seven-point blood glucose levels (7). The dose of 20 μg administered once daily was found to provide the optimal balance of efficacy and tolerability (8).Accordingly, in this Phase III study, we assessed the safety and efficacy of 20 μg lixisenatide once daily in a 12-week, multicenter, randomized, double-blind, placebo-controlled, parallel-group monotherapy trial in patients with type 2 diabetes not currently receiving glucose-lowering therapy.