Type 2 diabetes mellitus in people with severe mental illness: inequalities by ethnicity and age. Cross-sectional analysis of 588 408 records from the UK.

AIMS: To investigate whether the association of severe mental illness with Type 2 diabetes varies by ethnicity and age. METHODS: We conducted a cross-sectional analysis of data from an ethnically diverse sample of 588 408 individuals aged ≥18 years, registered to 98% of general practices (primary care) in London, UK. The outcome of interest was prevalent Type 2 diabetes. RESULTS: Relative to people without severe mental illness, the relative risk of Type 2 diabetes in people with severe mental illness was greatest in the youngest age groups. In the white British group the relative risks were 9.99 (95% CI 5.34, 18.69) in those aged 18-34 years, 2.89 (95% CI 2.43, 3.45) in those aged 35-54 years and 1.16 (95% CI 1.04, 1.30) in those aged ≥55 years, with similar trends across all ethnic minority groups. Additional adjustment for anti-psychotic prescriptions only marginally attenuated the associations. Assessment of estimated prevalence of Type 2 diabetes in severe mental illness by ethnicity (absolute measures of effect) indicated that the association between severe mental illness and Type 2 diabetes was more marked in ethnic minorities than in the white British group with severe mental illness, especially for Indian, Pakistani and Bangladeshi individuals with severe mental illness. CONCLUSIONS: The relative risk of Type 2 diabetes is elevated in younger populations. Most associations persisted despite adjustment for anti-psychotic prescriptions. Ethnic minority groups had a higher prevalence of Type 2 diabetes in the presence of severe mental illness. Future research and policy, particularly with respect to screening and clinical care for Type 2 diabetes in populations with severe mental illness, should take these findings into account.

Basal insulin peglispro: Overview of a novel long-acting insulin with reduced peripheral effect resulting in a hepato-preferential action.

Basal insulin peglispro (BIL) is a novel basal insulin with a flat, prolonged activity profile. BIL has been demonstrated in a dog model, in healthy men and in patients with type 1 diabetes (T1D) to have significant hepato-preferential action resulting from reduced peripheral activity. In the IMAGINE-Phase 3 clinical trial program, more than 6000 patients were included, of whom ~3900 received BIL. Of the 7 pivotal IMAGINE trials, 3 studies were double-blinded and 3 were in T1D patients. BIL consistently demonstrated a greater HbA1c reduction, less glycaemic variability and a clinically relevant reduction in the rates of nocturnal hypoglycaemia across comparator [glargine and isophane insulin (NPH)] studies. Trials using basal/bolus regimens had higher rates of total hypoglycaemia with BIL due to higher rates of daytime hypoglycaemia. Severe hypoglycaemia rates were similar to comparator among both patients with T1D or type 2 diabetes (T2D). T1D patients lost weight compared with glargine (GL). Patients with T2D tended to gain less weight with BIL than with glargine. Compared to glargine, BIL was associated with higher liver fat, triglycerides and alanine aminotransferase (ALT) levels, including a higher frequency of elevation of ALT ≥3 times the upper limit of normal, but without severe, acute drug-induced liver injury. Injection site reactions, primarily lipohypertrophy, were more frequent with BIL. In conclusion, BIL demonstrated better glycaemic control with reduced glucose variability and nocturnal hypoglycaemia but higher triglycerides, ALT and liver fat relative to conventional comparator insulin. The hepato-preferential action of BIL with reduced peripheral activity may account for these findings.

Evaluation of immunogenicity of LY2963016 insulin glargine compared with Lantus® insulin glargine in patients with type 1 or type 2 diabetes mellitus.

AIMS: To compare the immunogenicity profiles and the potential effects on clinical outcomes of LY2963016 insulin glargine (LY IGlar) and Lantus® insulin glargine (IGlar), products with identical primary amino acid sequences, in patients with type 1 or type 2 diabetes mellitus (T1DM or T2DM). METHODS: To assess immunogenicity, anti-insulin glargine antibodies (measured as percent binding) were compared between treatments in 52-week (open-label) and 24-week (double-blind) randomized studies in total study populations of patients with T1DM (N = 535) and T2DM (N = 756), respectively, and two subgroups of patients with T2DM: insulin-naïve patients and those reporting prestudy IGlar treatment (prior IGlar). Relationships between insulin antibody levels and clinical outcomes were assessed using analysis of covariance and partial correlations. Insulin antibody levels were assessed using Wilcoxon rank sum. Treatment comparisons for treatment-emergent antibody response (TEAR) and incidence of detectable antibodies were analysed using Fisher's exact test. RESULTS: No significant treatment differences were observed for insulin antibody levels, incidence of detectable anti-insulin glargine antibodies, or incidence of TEAR [overall and endpoint, by last-observation-carried-forward (LOCF)] in patients with T1DM or patients with T2DM, including the insulin-naïve subgroup. A statistically significant difference was noted in the overall incidence of detectable antibodies but not at endpoint (LOCF) nor in TEAR for the prior IGlar subgroup of patients with T2DM. Insulin antibody levels were low (<5%) in both treatment groups. Insulin antibody levels or developing TEAR was not associated with clinical outcomes. CONCLUSIONS: LY IGlar and IGlar have similar immunogenicity profiles; anti-insulin glargine antibody levels were low for both treatments, with no observed effect on efficacy and safety outcomes.

Reduced peripheral activity leading to hepato-preferential action of basal insulin peglispro compared with insulin glargine in patients with type 1 diabetes.

AIMS: Basal insulin peglispro (BIL), a novel PEGylated basal insulin with a large hydrodynamic size, has a delayed absorption and reduced clearance that prolongs the duration of action. The current study compared the effects of BIL and insulin glargine (GL) on endogenous glucose production (EGP), glucose disposal rate (GDR) and lipolysis in patients with type 1 diabetes. MATERIALS AND METHODS: This was a randomized, open-label, four-period, crossover study. Patients received intravenous infusions of BIL and GL, each at two dose levels selected for partial and maximal suppression of EGP, during an 8 to 10 h euglycemic clamp procedure with d-[3-3 H] glucose. RESULTS: Following correction for equivalent human insulin concentrations (EHIC), low-dose GL infusion resulted in similar EGP at the end of the clamp compared to low-dose BIL infusion (GL/BIL ratio of 1.03) but a higher GDR (GL/BIL ratio of 2.42), indicating similar hepatic activity but attenuated peripheral activity of BIL. Consistent with this, the EHIC-corrected GDR/EGP at the end of the clamp was 1.72-fold greater for GL than BIL following low-dose administration. At the lower dose of BIL and GL (concentrations in the therapeutic range), BIL produced less suppression of lipolysis compared with GL as indicated by free fatty acid and glycerol levels at the end of the clamp. CONCLUSIONS: Compared with GL, BIL restored the hepato-peripheral insulin action gradient seen in normal physiology via its peripherally restricted action on target tissues related to carbohydrate and lipid metabolism.

Ethnicity and cardiovascular health inequalities in people with severe mental illnesses: protocol for the E-CHASM study.

PURPOSE: People with severe mental illnesses (SMI) experience a 17- to 20-year reduction in life expectancy. One-third of deaths are due to cardiovascular disease. This study will establish the relationship of SMI with cardiovascular disease in ethnic minority groups (Indian, Pakistani, Bangladeshi, black Caribbean, black African and Irish), in the UK. METHODS: E-CHASM is a mixed methods study utilising data from 1.25 million electronic patient records. Secondary analysis of routine patient records will establish if differences in cause-specific mortality, cardiovascular disease prevalence and disparities in accessing healthcare for ethnic minority people living with SMI exist. A nested qualitative study will be used to assess barriers to accessing healthcare, both from the perspectives of service users and providers. RESULTS: In primary care, 993,116 individuals, aged 18+, provided data from 186/189 (98 %) practices in four inner-city boroughs (local government areas) in London. Prevalence of SMI according to primary care records, ranged from 1.3-1.7 %, across boroughs. The primary care sample included Bangladeshi [n = 94,643 (10 %)], Indian [n = 6086 (6 %)], Pakistani [n = 35,596 (4 %)], black Caribbean [n = 45,013 (5 %)], black African [n = 75,454 (8 %)] and Irish people [n = 13,745 (1 %)]. In the secondary care database, 12,432 individuals with SMI over 2007-2013 contributed information; prevalent diagnoses were schizophrenia [n = 6805 (55 %)], schizoaffective disorders [n = 1438 (12 %)] and bipolar affective disorder [n = 4112 (33 %)]. Largest ethnic minority groups in this sample were black Caribbean [1432 (12 %)] and black African (1393 (11 %)). CONCLUSIONS: There is a dearth of research examining cardiovascular disease in minority ethnic groups with severe mental illnesses. The E-CHASM study will address this knowledge gap.

Short-term administration of the glucagon receptor antagonist LY2409021 lowers blood glucose in healthy people and in those with type 2 diabetes.

AIM: To describe the clinical effects of single and multiple doses of a potent, selective, orally administered, small-molecule antagonist of the human glucagon receptor, LY2409021, in healthy subjects and in patients with type 2 diabetes. METHODS: LY2409021 was administered in dose-escalation studies to healthy subjects (n = 23) and patients with type 2 diabetes (n = 9) as single doses (Study 1) and daily to patients with type 2 diabetes (n = 47) for 28 days (Study 2). Safety, tolerability, pharmacokinetic (PK) and pharmacodynamic (PD) assessments were made after single doses and in patients receiving once-daily doses of LY2409021 (5, 30, 60 or 90 mg) for 28 days. RESULTS: LY2409021 was well tolerated at all dose levels in both studies. Fasting and postprandial glucose were reduced and glucagon levels increased after single and multiple dosing, with reductions in fasting serum glucose of up to ∼1.25 mmol/l on day 28. Serum aminotransferases increased in a dose-dependent manner with multiple dosing and reversed after cessation of dosing. Significant glucose-lowering was observed with LY2409021 at dose levels associated with only minor aminotransferase increases. CONCLUSION: Blockade of glucagon signalling in patients with type 2 diabetes is well tolerated and results in substantial reduction of fasting and postprandial glucose with minimal hypoglycaemia, but with reversible increases in aminotransferases. Inhibition of glucagon signalling by LY2409021 is a promising potential treatment for patients with type 2 diabetes and should be evaluated in longer clinical trials to better evaluate benefits and risks.

Efficacy and safety of LY2963016 insulin glargine compared with insulin glargine (Lantus®) in patients with type 1 diabetes in a randomized controlled trial: the ELEMENT 1 study.

AIMS: To compare the efficacy and safety of LY2963016 insulin glargine (LY IGlar) and the reference product (Lantus®) insulin glargine (IGlar) in patients with type 1 diabetes (T1D). METHODS: This phase III, randomized, open-label, 52-week study enrolled patients with T1D [glycated haemoglobin (HbA1c) ≤11%] being treated with basal (once-daily) and bolus insulin. Patients were randomized to receive once-daily LY IGlar (n = 268) or IGlar (n = 267) in combination with mealtime insulin lispro for 52 weeks. The primary efficacy outcome was to test the non-inferiority (0.4% and then 0.3% margin) of LY IGlar to IGlar as measured by change in HbA1c from baseline to 24 weeks. RESULTS: Both treatment groups had similar and significant (p < 0.001) within-group decreases in mean HbA1c values from baseline. LY IGlar met the non-inferiority criteria compared with IGlar for change in HbA1c from baseline to 24 weeks [-0.35 vs -0.46%, least-squares mean difference 0.108% (95% confidence interval -0.002 to 0.219), p > 0.05]. There were no significant (p > 0.05) treatment differences in other efficacy measures, including proportion of patients reaching HbA1c <7%, daily mean blood glucose, and insulin dose at 24 and 52 weeks. At 52 weeks, similar findings were observed between LY IGlar and IGlar for safety outcomes, including adverse events, allergic reactions, hypoglycaemia, weight change and insulin antibodies. CONCLUSIONS: Both LY IGlar and IGlar, when used in combination with mealtime insulin lispro, provided effective and similar glucose control and similar safety profiles.

Similar efficacy and safety of LY2963016 insulin glargine and insulin glargine (Lantus®) in patients with type 2 diabetes who were insulin-naïve or previously treated with insulin glargine: a randomized, double-blind controlled trial (the ELEMENT 2 study).

AIMS: To compare the efficacy and safety of LY2963016 insulin glargine (LY IGlar) and the reference product (Lantus(®)) insulin glargine (IGlar) in combination with oral antihyperglycaemic medications in patients with type 2 diabetes (T2D). METHODS: This phase III, randomized, double-blind, 24-week study enrolled patients with T2D who were insulin-naïve [glycated haemoglobin (HbA1c) ≥7 and ≤11.0%] or previously on IGlar (HbA1c ≤11%) and treated with ≥2 oral antihyperglycaemic medications. Patients were randomized to receive once-daily LY IGlar (n = 376) or IGlar (n = 380) for 24 weeks. The primary efficacy outcome was to test the non-inferiority (0.4% and then 0.3% margin) of LY IGlar to IGlar, as measured by change in HbA1c from baseline to 24 weeks. RESULTS: Both treatment groups had similar and significant (p < 0.001) within-group decreases in mean HbA1c values from baseline. LY IGlar met non-inferiority criteria compared with IGlar for change in HbA1c from baseline [-1.29 vs -1.34%; respectively, least-squares mean difference 0.052% (95% confidence interval -0.070 to 0.175); p > 0.05]. There were no treatment differences (p > 0.05) in fasting plasma glucose, proportion of patients reaching HbA1c <7% or insulin dose at 24 weeks. Adverse events, allergic reactions, weight change, hypoglycaemia and insulin antibodies were similar between treatment groups. Similar findings were observed in patients who were insulin-naïve or previously treated with IGlar at baseline. CONCLUSIONS: Both LY IGlar and IGlar, when used in combination with oral antihyperglycaemic medications, provided effective and similar glucose control with similar safety profiles in patients with T2D.

Antipsychotic exposure prior to acute myocardial infarction in patients with serious mental illness.

OBJECTIVE: To investigate the association between acute myocardial infarction (AMI) and recent exposure to antipsychotic agents in people with serious mental illness (SMI), and modifying influences. METHOD: A case-crossover design was applied using the Taiwan National Health Insurance Research Database (NHIRD) to compare the exposure frequency of antipsychotic agents within individuals of schizophrenia or bipolar disorder between 60-day case and control periods prior to their first AMI episode during 1996-2007. RESULTS: A sample of 834 patients with incident AMI was analysed. AMI was significantly associated with more recent antipsychotic exposure in schizophrenia after adjustment (OR 1.87, 95% confidence interval 1.15-3.03) bipolar disorder (OR 1.06, 0.51-2.21). This association in schizophrenia was significantly stronger in men and in patients without previous diagnoses of cardiovascular risk factors. CONCLUSION: These findings are consistent with a short-term risk effect of antipsychotic exposure on risk of AMI and identify potentially vulnerable groups. Further research is required to clarify underlying biological mechanisms.

Contrasting weight changes with LY2605541, a novel long-acting insulin, and insulin glargine despite similar improved glycaemic control in T1DM and T2DM.

AIMS: The basal insulin analogue LY2605541, a PEGylated insulin lispro with prolonged duration of action, was previously shown to be associated with modest weight loss in Phase 2, randomized, open-label trials in type 2 (N=288) and type 1 (N=137) diabetes mellitus (T2DM and T1DM), compared with modest weight gain with insulin glargine. Exploratory analyses were conducted to further characterize these findings. METHODS: Pearson correlations between change in body weight and other variables were calculated. Continuous variables were analysed using a mixed linear model with repeated measurements. Proportions of subjects with weight loss were analysed using Fisher's exact test for T2DM and Nagelkerke's method for T1DM. RESULTS: Weight loss was more common in LY2605541-treated patients than in patients treated with insulin glargine (T2DM: 56.9 vs. 40.2%, p=0.011; T1DM: 66.1 vs. 40.3%, p<0.001). More LY2605541-treated patients experienced ≥5% weight loss compared to patients treated with glargine (T2DM: 4.8 vs. 0%, p=0.033; T1DM: 11.9 vs. 0.8%, p<0.001). In both the T1DM and T2DM studies, weight change did not correlate with baseline body mass index (BMI), or change in HDL-cholesterol in either treatment group. No consistent correlations were found across both studies between weight change and any of the variables assessed; however, weight change was significantly correlated with hypoglycaemia rate in glargine-treated T2DM patients. CONCLUSION: In two Phase 2 trials, improved glycaemic control with long-acting basal insulin analogue LY2605541 is associated with weight loss in previously insulin-treated patients. This weight change is independent of baseline BMI or hypoglycaemia.

Born into adversity: psychological distress in two birth cohorts of second-generation Irish children growing up in Britain.

BACKGROUND: Worldwide, the Irish diaspora experience health inequalities persisting across generations. The present study sought to establish the prevalence of psychological morbidity in the children of migrant parents from Ireland, and reasons for differences. METHODS: Data from two British birth cohorts were used for analysis. Each surveyed 17 000 babies born in one week in 1958 and 1970 and followed up through childhood. Validated scales assessed psychological health. RESULTS: Relative to the rest of the cohort, second-generation Irish children grew up in material hardship and showed greater psychological problems at ages 7, 11 (1958 cohort) and 16 (both cohorts). Adjusting for material adversity and maternal psychological distress markedly reduced differences. Relative to non-Irish parents, Irish-born parents were more likely to report chronic health problems (odds ratio [OR]: 1.29; 95% confidence interval [CI]: 1.08-1.54), and Irish-born mothers were more likely to be psychologically distressed (OR: 1.44; 95% CI: 1.13-1.84, when child was 10). Effect sizes diminished once material adversity was taken into account. CONCLUSIONS: Second-generation Irish children experienced high levels of psychological morbidity, but this was accounted for through adverse material circumstances in childhood and psychological distress in parents. Public health initiatives focusing on settlement experiences may reduce health inequalities in migrant children.

Migration, social mobility and common mental disorders: critical review of the literature and meta-analysis.

OBJECTIVE: Changes in socio-economic position in people who migrate may have adverse associations with mental health. The main objective of this review was to assess the association of social mobility with common mental disorders in migrant and second-generation groups, to inform future research. DESIGN: Systematic review and meta-analysis of English-language studies assessing the association of social mobility in migrant or second-generation groups with common mental disorders. Approaches to operationalise 'social mobility' were reviewed. RESULTS: Twelve studies (n=18,548) met criteria for retrieval. Very few included second-generation groups, and most studies were cross-sectional in design. Approaches to operationalise 'social mobility' varied between studies. Downward intragenerational social mobility was associated with migration in the majority of studies. Random effects meta-analysis (n=5179) suggested that migrants to higher income countries who experienced downward mobility or underemployment were more likely to screen positive for common mental disorders, relative to migrants who were upwardly mobile or experienced no changes to socio-economic position. Conclusions on second-generation groups were limited by the lack of research highlighted for these groups. Downward intragenerational mobility associated with migration may be associated with vulnerability to common mental disorders in some migrant groups. CONCLUSION: Given the increasing scale of global migration, further research is needed to clarify how changes to socio-economic position associated with international migration may impact on the mental health of migrants, and in their children.

The prevalence, correlates and impact of dementia in Cuba. A 10/66 group population-based survey.

BACKGROUND: We aimed to estimate the prevalence, correlates and impact of dementia in Havana and Matanzas, Cuba. METHODS: A 1-phase catchment area survey of all over 65-year-old residents of 7 catchment areas in Havana and 1 in Matanzas was conducted. Dementia diagnosis was established according to DSM-IV and our own, pre-validated 10/66 criteria. The impact of dementia was assessed through associations with needs for care, cutting back on work to care and caregiver psychological morbidity. RESULTS: We interviewed 2,944 older people, a response proportion of 96.4%. The prevalence of DSM-IV dementia was 6.4% and that of 10/66 dementia 10.8%. Both dementia outcomes were associated with older age, less education, a family history of dementia, shorter leg length and smaller skull circumference. Dementia, rather than physical health problems or depression, was the main contributor to needs for care (population-attributable prevalence fraction = 64.6%) and caregiver cutting back on work (population-attributable prevalence fraction = 57.3%). CONCLUSION: The prevalence of dementia in Cuba is similar to Europe. Among health conditions, dementia is the major contributor to dependency and caregiver economic and psychological strain. More attention needs to be given to it and other chronic diseases associated more with disability than premature mortality.

Direct in vitro effect of a sulfonylurea to increase human fibroblast insulin receptors.

We have studied the effects of the oral sulfonylurea agent glyburide to modulate insulin receptors on nontransformed human fibroblasts in tissue culture. When glyburide was added to monolayers of human fibroblasts, a dose-dependent increase in the number of cell surface receptors was observed with a maximum effect (19% increase) seen at 1 microgram/ml glyburide. Insulin can induce a loss of insulin receptors in these cells, and when fibroblasts are exposed to 100 ng/ml insulin for 6 h, approximately 60% of the initial complement of cell surface receptors are lost. When the process of insulin-induced receptor loss (or down regulation) was studied in the presence of glyburide, the drug exerted a marked inhibitory effect on this regulatory process. Thus, glyburide inhibited insulin-induced receptor loss in a dose-dependent fashion, and the maximally effective drug concentration (1 microgram/ml) inhibited 34% of the receptor loss. These studies demonstrate a direct in vitro effect of this oral hypoglycemic agent to increase the number of cell surface insulin receptors or prevent their loss, presumably by slowing the rate of receptor internalization. These findings may explain the well known extrapancreatic effect of sulfonylurea agents to improve insulin-mediated tissue glucose metabolism.

Insulin binding, internalization, and insulin receptor regulation in fibroblasts from type II, non-insulin-dependent diabetic subjects.

The ability of insulin to bind, internalize, and regulate its own receptor was investigated in cultured human fibroblasts obtained from 8 normal subjects and 8 patients with type II, non-insulin-dependent diabetes mellitus (NIDDM). The ability of the cells from the two groups to bind insulin was the same, and Scatchard analysis demonstrated identical curvilinear plots. When cells were incubated at 37 degrees C with the lysosomotropic agent, chloroquine, and 125I-insulin, the drug led to a marked, but comparable, increase in cell-associated radioactivity in both control and diabetic fibroblasts (236 and 245% increase, respectively). Insulin pretreatment leads to a loss of insulin receptors in cultured human fibroblasts and preincubation with insulin led to a comparable dose-dependent decrease in subsequent insulin binding in both normal and diabetic fibroblasts. Scatchard analysis demonstrated that this decrease in binding was entirely due to a decrease in receptor number with no change in receptor affinity. These data demonstrate normal insulin binding, insulin internalization, and insulin-mediated receptor loss in fibroblasts from patients with with NIDDM, and these cells are several generations removed form the in vivo milieu. Thus, these results provide direct evidence that the well-known decrease in insulin binding in freshly isolated cells from patients with NIDDM, and these cells are several generations removed from the in vivo milieu. Thus, these results provide direct evidence that the well-known decrease in insulin binding in freshly isolated cells form patients with NIDDM is a reflection of environmental factors rather than an intrinsic (genetic) cellular abnormality.

Functional characteristics of decreased insulin receptors on fibroblasts obtained from a subject with severe insulin resistance and acanthosis nigricans.

In a patient with severe insulin resistance and acanthosis nigricans, a decrease in the number of insulin receptors has been found on freshly isolated monocytes and cultured fibroblasts compatible with a primary or genetic decrease in cell-surface insulin receptors. To determine the functional characteristics of the remaining receptors on these cells, insulin-stimulated glucose uptake, insulin internalization, and insulin-induced receptor loss were evaluated in monolayer fibroblasts obtained from this subject. Maximal insulin stimulation of 2-deoxyglucose was markedly blunted, compatible with abnormal insulin responsiveness due to a functional impairment of the remaining receptors. In the presence of chloroquine, the acanthotic subject's fibroblasts internalized more insulin per available receptor compared with the normal cell line, suggesting an accelerated rate of insulin internalization. When the rate of insulin internalization was more directly determined by assessing the rate of appearance of acid-resistant, cell-associated radioactivity at 37 degrees C, a similar increase in insulin internalization rate was evident. When downregulation was assessed, insulin's ability to induce receptor loss in the acanthotic subject's cell line was augmented. Thus, a primary or genetic decrease in insulin receptors on cultured fibroblasts from a patient with acanthosis nigricans and insulin resistance is associated with functional impairment of the remaining receptors leading to significant alterations in ligand processing and subsequent insulin action.

Autophosphorylation of cultured skin fibroblast insulin receptors from patients with severe insulin resistance and acanthosis nigricans.

The severe insulin resistance with acanthosis nigricans seen in young women without insulin-receptor autoantibodies is characterized by hyperinsulinemia and decreased in vivo responsiveness to insulin. We evaluated the potential cellular defects in insulin-receptor binding and autophosphorylation in 12 subjects with this syndrome. When evaluated as a group, insulin binding to freshly isolated monocytes was 55% that of controls. Specific binding of insulin to skin fibroblasts in monolayer culture was 49% that of controls. Maximal insulin-stimulated receptor autophosphorylation was only 27% that of controls. Individual data demonstrated that the diminished autophosphorylation activity was out of proportion to the diminished fibroblast insulin binding in cell lines from most subjects and was less than 50% of the predicted activity in 6 of the 12 studied cell lines. These data are consistent with genetically determined defects leading to diminished numbers of cell surface insulin receptors with intact tyrosine kinase autophosphorylation in many of our cell lines. However, in at least half, there appeared to be an additional defect beyond insulin binding, resulting in a disproportionate decrease in insulin-sensitive phosphorylation of the insulin-receptor beta-subunit.

Metabolic effects of hydrochlorothiazide and enalapril during treatment of the hypertensive diabetic patient. Enalapril for hypertensive diabetics.

To determine the effect of enalapril maleate and low-dose hydrochlorothiazide therapy on blood pressure and glucose and lipid homeostasis in hypertensive type II diabetic patients, we treated nine of these patients sequentially with placebo, hydrochlorothiazide (25 mg/d with supplemental potassium chloride), and enalapril (10 to 20 mg/d). Sitting blood pressure fell significantly and to comparable levels with both hydrochlorothiazide and enalapril monotherapy. Enalapril monotherapy was associated with a slight, but not significant, fall in fasting blood glucose levels and with a significant fall in hemoglobin A1c levels. This improved glucose homeostasis could not be explained satisfactorily by changes in peripheral insulin sensitivity or hepatic glucose output, determined with the euglycemic clamp technique, or by changes in fasting serum insulin levels or monocyte insulin binding. In these low doses, hydrochlorothiazide did not worsen glucose homeostasis. Serum total cholesterol levels were significantly lower with enalapril therapy than with hydrochlorothiazide therapy or with placebo, and serum high-density lipoprotein cholesterol and triglyceride levels did not change significantly with either treatment. Thus, by providing effective blood pressure control and beneficial metabolic effects, enalapril therapy appears ideal for treatment of hypertension in diabetic patients. Similarly, low-dose hydrochlorothiazide therapy appears to have fewer metabolic complications in these patients and is, therefore, a logical alternative to substitute for, or add to, enalapril therapy.

Molecular variations in Vibrio alginolyticus and V. harveyi in shrimp-farming systems upon stress.

A study was performed to investigate the genomic variations in the shrimp farm isolates of Vibrio alginolyticus and V. harveyi when the isolates were subjected to environmental stress. Samples of shrimps, water and sediment were collected from Southern Indian coastal shrimp farms. Vibrio isolates were biochemically identified and confirmed using 16S rDNA and gyrB gene specific PCR. The bacterial strains were genotyped by PCR fingerprinting using GTG(5) and IS (Insertion Sequence) primers. Seven strains each of V. alginolyticus and V. harveyi were subjected to 10 passages through trypticase soya broth (TSB), which contained different NaCl concentrations (3, 6 and 8%) and trypticase soya agar (TSA). V. alginolyticus was also passaged through TSB with a 12% NaCl concentration. PCR fingerprinting, which was performed on the strains that were passaged through different salt concentrations, confirmed that V. alginolyticus and V. harveyi could affect the genomic variations, depending on the environmental conditions of the culture. The study highlights the complex genotypic variations that occur in Vibrio strains of tropical aquatic environment because of varied environmental conditions, which result in genetic divergence and/or probable convergence. Such genetic divergence and/or convergence can lead to the organismal adaptive variation, which results in their ability to cause a productive infection in aquatic organisms or generation of new strains.

Regulation of insulin receptors in cultured human fibroblasts.

The ability of insulin to regulate its own receptor was investigated in cultured human fibroblasts. Physiological insulin concentrations led to a loss of insulin receptors, and this process was dependent on cellular energy and ongoing protein synthesis. The insulin concentration primarily affected the rate of receptor loss rather than the eventual cellular receptor concentration. Studies of receptor regeneration revealed that the absolute rate of insertion of new or recycled receptors into the plasma membrane was constant and independent of the amount of proceeding receptor loss or the time over which receptor loss occurred. These results are compatible with the concept that insulin-induced receptor loss in cultured human fibroblasts is a self-limited process mediated by an endocytotic internalization pathway which is dependent on new protein synthesis. Receptor regeneration is a distinct cellular process dependent on ongoing protein synthesis and does not imply represent the absence of ongoing receptor loss.