Stabilizing effect of exenatide in a patient with C‐peptide‐negative diabetes mellitus

Background Exenatide is an incretin mimetic licensed for treatment of Type 2 diabetes poorly controlled despite maximally tolerated doses of oral therapy. Similar in structure to the natural incretin hormone glucagon‐like peptide 1 (GLP‐1), it helps restore underlying pathophysiological abnormalities. Case report We report the successful use of exenatide, combined with insulin, in a 66‐year‐old woman initially diagnosed with Type 2 diabetes in 1989 but now exhibiting a Type 1 phenotype. Diet, lifestyle advice and oral glucose‐lowering agents were commenced but persisting poor control necessitated insulin therapy in 2005. She later presented twice in diabetic ketoacidosis, suggesting conversion to a Type 1 phenotype (postprandial C‐peptide < 94 pmol/l). Despite differing insulin regimens, control remained poor with frequent hyperglycaemic and hypoglycaemic excursions, severely impairing quality of life. Whilst an inpatient in 2007 [glycated haemoglobin (HbA_1c) 10.2%, body mass index (BMI) 31.5 kg/m²] exenatide was commenced in an attempt to stabilize glycaemic control. Dramatic improvements were seen and continued. Eight months later, HbA_1c had fallen by 2% with an 8‐kg weight loss and 10‐unit reduction in daily insulin dose. Quality of life dramatically improved. C‐peptide remains undetectable. Conclusions This patient with features of both Type 1 and Type 2 diabetes benefited greatly from exenatide with insulin therapy. The improvement seen in glycaemic control could not be attributable to enhanced insulin secretion but could be as a result of a combination of the other incretin effects (postprandial glucagon suppression, delayed gastric emptying and weight loss secondary to increased satiety) all improving insulin sensitivity, reducing insulin dose and smoothing control.     

Paraoxonase polymorphisms PON1 192 and 55 and longevity in Italian centenarians and Irish nonagenarians. A pooled analysis

BACKGROUND: PON1, an arylesterase, associated with high density lipoprotein (HDL), protects low density lipoprotein (LDL) against oxidative modification. Common polymorphisms PON1 55 (L/M) and 192 (Q/R) in the PON1 gene associate with atherosclerosis and heart disease. Because long-lived people seem protected from premature vascular death, we conducted a pooled statistical analysis to assess any association between these polymorphisms and longevity in a large combined group of Italian centenarians and octo/nonagenarians from Northern Ireland (NI). MATERIALS AND METHODS: Separated DNA was available from 1479 subjects from Italy and Northern Ireland (NI). In Italy 308 centenarians (males 67, females 241, mean age 100.8, SD2.1 years) and 579 young controls (males 347, females 232, mean age 40.7, SD 12.7 years) were included in the study. In NI, 296 octo/nonagenarians (males 92, females 204, mean age 89.8, SD 5.7 years) and 296 young sex-matched subjects (mean age 13.0, SD 1.4 years) had available DNA. PON1 55 (L/M) and 192 (Q/R) polymorphisms were studied using a PCR-RFLP approach. RESULTS: There was a significant difference in PON1 192 genotypes in Italian centenarians compared to younger controls (X(2)= 6.8, df = 2 p= 0.03) and a similar but non significant trend between octo/nonagenarian and young subjects in NI (X(2) = 4.0, df=2, p=0.14). Using logistic regression analysis on the combined Italian and Irish datasets, there was a small survival advantage for centenarian and octo/nonagenarian subjects who were heterozygous for PON1 192 R allele, (OR 1.3, CI 1-1.6; p=0.04 with a stepwise increase for RR homozygous subjects (OR 1.7, CI 1.1-2.6; p = 0.02) compared to QQ subjects. Comparing R and Q alleles there was a survival advantage for octo/nonagenarian/centenarian subjects who carried the R allele (OR 1.3, CI 1.1-1.5; p = 0.007) but there was no sex-specific effect p =0.77) LL, LM and MM genotypes of PON 55 polymorphisms showed similar frequencies in Italy (39.9, 47.0, 13.1%) and Ireland (39.5, 48.6, 11.9%) with no age or sex-related differences. The PON1 192R/Q and PON55L/M loci were in strong linkage disequilibrium with a Lewontin's D' coefficient -0.928 (elderly) and -0.965 (young). There was a significant difference in haplotype frequency of these linked loci in older compared to younger subjects (Likelihood Ratio X(2) = 9.60, df = 3, p= 0.02). CONCLUSION: These data suggest a modest association between the 192R allele and longevity in two very elderly populations in two European countries. Being homozygous for 192 RR further enhances survival advantage but this effect was not found to be sex specific. This finding is of interest because the 192R allele has previously been associated with increased risk of coronary heart disease. On the other hand, the 192R allele shows higher enzymatic activity, using paraoxon as substrate, and we postulate that its role in the metabolism of potentially toxic chemicals or other metabolic pathways may be important in survival to very old age.     

Aging reduces neural specialization in ventral visual cortex

The present study investigated whether neural structures become less functionally differentiated and specialized with age. We studied ventral visual cortex, an area of the brain that responds selectively to visual categories (faces, places, and words) in young adults, and that shows little atrophy with age. Functional MRI was used to estimate neural activity in this cortical area, while young and old adults viewed faces, houses, pseudowords, and chairs. The results demonstrated significantly less neural specialization for these stimulus categories in older adults across a range of analyses.     

Detection of ischemic wall dysfunction: Comparison between M-mode echocardiography and sonomicrometry

The quantification of regional ventricular function by M-mode echocardiography was compared to that by sonomicrometry in 10 closed-chest, sedated swine during temporary occlusions of the left circumflex coronary artery. Wall thickening during systole (%WT) was calculated to quantitate regional myocardial function, and percentage of fractional shortening (%FS) was calculated from both sonomicrometer tracings and M-mode echocardiograms. Ventricular dimensions at end diastole and end systole were also compared before and after 2 minutes of coronary artery occlusion. Both techniques detected significant changes in wall thickness, %WT, and %FS after occlusion. Changes in %WT during coronary artery occlusion detected by M-mode echocardiography and sonomicrometry had a significant linear relationship (p < 0.05). Discrepancy between the two techniques in the measurement of wall thickness at end diastole was attributed to the difficulty in measuring relatively small distances with M-mode echocardiograms. However, we conclude that the clinical M-mode echocardiogram is capable of detecting acute regional wall dysfunction associated with ischemia.     

The metabolic syndrome: peroxisome proliferator-activated receptor gamma and its therapeutic modulation

By the end of this decade, it has been estimated that between 200 million and 300 million people worldwide will meet World Health Organization diagnostic criteria for diabetes mellitus. This epidemic of predominantly type 2 diabetes has largely been mediated by our shift toward a more sedentary lifestyle predisposing to obesity and insulin resistance. Affected individuals can also exhibit an array of associated undesirable traits such as hypertension, dyslipidemia, and hypercoagulability, leading to morbidity and mortality from atherosclerotic vascular disease. The coexistence of several of these traits with insulin resistance constitutes the metabolic syndrome. Accordingly, improving insulin sensitivity in this group, and thereby potentially ameliorating the excess vascular risk, is a primary goal of treatment. Recent interest has focused on the thiazolidinediones, a novel class of antidiabetic agents, which act as insulin sensitizers and, therefore, potentially target the underlying metabolic disturbance. These agents are high-affinity ligands for the nuclear receptor peroxisome proliferator-activated receptor gamma, and a large body of in vitro and in vivo data has evolved to support their increasing clinical use. Importantly, clinical and laboratory findings in human subjects harboring natural mutations and polymorphisms within the receptor have provided additional insights. Here, we focus on the consequences of inherited variation in the human peroxisome proliferator-activated receptor gamma gene, linking this receptor to disordered glucose homeostasis, adipogenesis, lipid metabolism, and blood pressure regulation. These studies provide further support for the future development of more selective receptor modulators, targeting specific pathways to ameliorate facets of the metabolic syndrome.     

Intravenous gammaglobulin treatment of chronic idiopathic thrombocytopenic purpura

High-dose intravenous gammaglobulin (IVIgG) was given to 12 children and adults with chronic idiopathic thrombocytopenic purpura (ITP) to avoid splenectomy or because they either failed to respond to or required maintenance with high doses of steroids and/or immunosuppressives. The average platelet count increase to initial therapy was 239,500/microliters (range 23,000-790,000). A concomitant IgG Fc receptor blockade, measured by IgG-sensitized 51Cr-labeled autologous erythrocytes, was seen in 11 of 11 patients tested, both splenectomized and not splenectomized, lasting 3-4 wk. Six or more months after treatment, 2 children are in remission, 2 children and 2 adults are stable requiring no therapy with platelet counts of approximately 50,000 and 30,000, respectively, 3 children require maintenance IVIgG therapy at 2-10-wk intervals, and 1 child and 2 adults have become refractory to further IVIgG. Splenectomy was not performed in 4 children. Two adults were able to discontinue daily prednisone. The 3 patients who became unresponsive to Swiss Red Cross gamma-globulin (IgSRK) therapy did so in conjunction with a markedly elevated platelet-associated IgG and IgM. Serum IgM increased an average of 103 mg/dl after the IVIgG infusions. No significant side effects were seen.     

Low caloric expenditure in cardiac rehabilitation

BACKGROUND: Total physical activity energy expenditure is a determinant of weight loss and risk factor modification in adults. There has been very little study of physical activity energy expenditure in cardiac rehabilitation populations. METHODS: Exercise-related energy expenditure was calculated in 112 patients with coronary artery disease in an outpatient cardiac rehabilitation program. Gross energy expenditure was estimated with the heart rate/oxygen consumption relation as measured during metabolic exercise testing with expired gas analysis. RESULTS: The average exercise training energy expenditure (ETEE) per cardiac rehabilitation exercise session was quite low at 270 +/- 112 kcal. Baseline fitness level (peak oxygen consumption), body weight, total exercise duration per session, age, and body mass index were all significant determinants of ETEE (r = 0.56 to -0.37, all P <.01). Additionally, patients who had undergone coronary bypass surgery and patients with medical comorbidities expended significantly fewer calories during exercise. In women, there was a relation between ETEE and change in total and LDL cholesterol (r = -0.43 and -0.45, respectively), although no such relation was observed in men. CONCLUSION: Cardiac rehabilitation exercise training, as currently structured, burns surprisingly few calories and has little impact in the short term (3 months) on measures of obesity and lipid risk factors. Alternative training programs should be considered to maximize caloric expenditure and modify specific risk factors such as obesity and dyslipidemia.     

Evaluation of a QRS scoring system for estimating myocardial infarct size. II. Correlation with quantitative anatomic findings for anterior infarcts

The ability of an independently developed QRS point score to estimate the size of infarcts predominantly within the anterior third of the left ventricle was evaluated by quantitative pathologic-electrocardiographic correlation. The study was limited to 21 patients with a single infarct documented by postmortem examination, for whom an appropriately timed standard 12 lead electrocardiogram was available that did not exhibit signs of left or right ventricular hypertrophy, left or right bundle branch block or anterior or posterior fascicular block. At necropsy the heart was cut into five to seven slices. The location and size of the infarct was quantitated by computer-assisted planimetry of the slices.The electrocardiogram of 19 (90 percent) of the patients exhibited either a Q wave or an R wave of no more than 20 ms in lead V₂. The infarct in the two patients without this electrocardiographic finding was small, occupying 2 and 3 percent of the left ventricle, respectively. The percent infarction of the left ventricle correlated with the QRS point score (r = 0.80). Thus in patients without complicating factors in the electrocardiogram and with a single infarct, the electrocardiogram provides a marker for infarction in the anterior third of the left ventricle and permits estimation of infarct size.     

Immediate response of 5-methoxytryptophol in the circulation to hypoglycaemic stress induced by insulin.

Pineal indoles have been shown to affect the release of anterior pituitary hormones but details of the interrelationships are lacking. Using a new gas chromatography-mass spectrometry (g.c.-m.s.) assay the concentration of 5-methoxytryptophol (ML) was measured in plasma samples obtained from 16 children undergoing investigation of pituitary function for delayed growth. All the children received an insulin tolerance test (ITT) to study their endocrine response to stress. Some children received luteinizing hormone releasing hormone (LH-RH) and/or thyrotrophin releasing hormone (TRH). The change in concentration of ML during an ITT was similar to the change in concentration of blood sugar; a drop at 20 min followed by a rise at 30 min. This was not significantly altered by the administration of LH-RH or TRH, nor was there a different pattern of response in children who were deficient in growth hormone as opposed to those with idiopathic delayed growth. The fall in concentration of ML with stress may mediate the increased secretion of pituitary hormones. Alternatively, the pineal gland may respond directly to insulin.