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Aims To describe and compare the health system responses for type 1 diabetes in Kyrgyzstan, Mali, Peru and Tanzania. Methods The Rapid Assessment Protocol for Insulin Access, a multi-level assessment of the health system, was implemented in Kyrgyzstan, Mali, Peru and Tanzania using document reviews, site visits and interviews to assess the delivery of care and access to insulin. Results Despite the existence of noncommunicable or diabetes strategies and Universal Health Coverage policies including diabetes-related supplies, this has not necessarily translated into access to insulin or diabetes care for all. Insulin and related supplies were often unavailable and unaffordable. Across the four countries test strips and insulin, when paid for by the individual, represented respectively 48-82% and 25-36% of total costs. Care was mainly delivered at tertiary-level hospitals by specialists. Only Kyrgyzstan had data collection systems integrated into the Ministry of Health structure. In addition, issues with healthcare worker training and education and empowerment of people with diabetes were present in these health systems. Conclusions People with type 1 diabetes in these countries face different barriers, including the cost of insulin and care. Given the renewed attention to diabetes on the global health agenda tailored health system responses for type 1 diabetes are needed. Insulin should be prioritized as it is the foundation of type 1 diabetes care, but other elements of care and support need to be fostered by different actors.

Objective Rates of adolescents with severe obesity continue to rise worldwide, with concurrent increases in metabolic and bariatric surgery (MBS) uptake. The gap between support (lifestyle, pharmacotherapy) interventions and MBS as treatment options for adolescents has been understudied. This review, couched in a socio-ecological framework, investigates how support interventions for adolescents with severe obesity could be combined or sequenced with MBS to optimize health outcomes. Methods A comprehensive search revealed 36 published articles between 1995 and 2019 that included the combination of support interventions and MBS among adolescents. Results There were no studies that specifically reported outcomes or effect sizes for the combination of lifestyle intervention with MBS. Previous studies have reported individual results for either lifestyle intervention or MBS but not for their compound effect. Conclusions As rates of adolescents with severe obesity are on the rise globally, future research should focus on how partnering support interventions with MBS can amplify positive short- and long-term health outcomes and within a socio-ecological framework. Understanding the sequence of these approaches will be of particular importance. High-risk and vulnerable populations such as ethnic minorities who have suffered a disproportionate burden of the obesity epidemic must be included in rigorously tested future trials of combination interventions to maximize health outcomes worldwide.

Obesity is a global epidemic, accompanied by increased risk of type 2 diabetes and cardiovascular disease. Adipose tissue hypertrophy is associated with adipose tissue inflammation, which alters secretion of adipose tissue-derived bioactive products, known as adipokines. Adipokines determine vessel wall properties such as smooth muscle tone and vessel wall inflammation. Exercise is a mainstay of prevention of chronic, non-communicable diseases, type 2 diabetes and cardiovascular disease in particular. Aside from reducing adipose tissue mass, exercise has been shown to reduce inflammatory activity in this tissue. Mechanistically, contracting muscles release bioactive molecules known as myokines, which have been shown to alter adipose tissue metabolic phenotype. In adipose tissue, myokines induce browning, enhance fatty acid oxidation and improve insulin sensitivity. In the past years, so-called perivascular adipose tissue surrounding the vasculature (PVAT) has been shown to control vascular tone and inflammation through local release of adipokines. In obesity, an increase in mass and inflammation of PVAT culminate in dysregulation of adipokine secretion, which contributes to vascular dysfunction. This review describes our current understanding of the mechanisms by which active muscles interact with adipose tissue and improve vascular function. Aside from the exercise-dependent regulation of canonical adipose tissue function, we will focus on interaction between skeletal muscle and PVAT and the role of novel myokines, such as interleukin-15, fibroblast growth factor 21 and irisin, in this cross talk.

SummaryObjectives We postulated the mechanism for the association between angiotensin-converting enzyme (ACE) gene insertion/deletion (I/D) polymorphism and insulin sensitivity might relate to changes in blood flow regulation. We studied the association of this polymorphism with insulin action, and insulin-mediated changes in limb blood flow (LBF), under conditions of high and low salt intake. We also studied effects of genotype and salt loading on renin–angiotensin–aldosterone system (RAAS) activity. Materials/Methods Twenty people with (10 I/I; 10 D/D) and 23 without (10 I/I; 13 D/D), type 2 diabetes were studied during 6 days of 40 mmol/day and 220 mmol/day sodium diet in a randomized, double-blind cross-over fashion. On the sixth day of each condition, we measured 24-h blood pressure, plasma volume, LBF and insulin sensitivity during hyperinsulinaemic clamp at low (40 mU/m2/min) and high (600 mU/m2/min) dose insulin infusion. Results Salt intake variation produced greater effects on the renin–angiotensin–aldosterone system than ACE genotype. Diabetes status and insulin infusion were associated with differences in the metabolic clearance rate of glucose, (P

Objective The mechanisms underlying obesity-related hypertension are incompletely understood. Microvascular dysfunction might play a role by increasing peripheral vascular resistance (PVR). Metabolic and microvascular effects of insulin are impaired in obesity, but how these impairments contribute to disturbed blood pressure homeostasis is unclear. Specifically, it is unknown whether local microvascular vasoactive effects of insulin play a role in determining systemic vascular resistance. The aim of this study was to investigate the association between PVR and local microvascular effects of insulin. Design and Methods Thirty-seven healthy, overweight subjects (age 25-55 years, BMI 25-30 kg/m2) were cross-sectionally studied. Local insulin-mediated vasodilation was measured using skin laser Doppler fluxmetry combined with transcutaneous iontophoresis of insulin. For comparison, local vasodilatory effects of acetylcholine and sodium nitroprusside were measured. PVR was calculated from mean arterial pressure and cardiac output, assessed by pulse-dye densitometry. Results PVR was inversely correlated with insulin-mediated vasodilation (r = −0.50; P < 0.01). This finding was maintained after adjustment for age, sex, blood pressure, and smoking. PVR was not associated with local microvascular effects of acetylcholine. Conclusions Our study in overweight subjects suggests that insulin's role in the microvasculature may contribute to blood pressure control.

Health system reform in Kyrgyzstan is seen as a relative success story in central Asia. Initially, most attention focused on structural changes, and it is only since 2006 that the delivery of care and the experience of health service users have risen on the agenda. One exception from the earlier period was a rapid appraisal of the management of diabetes, undertaken in 2002. Using that study as a baseline, we describe the findings of a new evaluation of diabetes management, undertaken in 2009, using the Rapid Assessment Protocol for Insulin Access, now implemented in seven countries. Access to care has improved through the creation of the Family Medical Centres and the deployment of endocrinologists to them. Another improvement is the access to insulin and related medicines, although assessment of the procurement system reveals that the government is getting very poor value for money. Looking ahead, there are grounds for optimism that the passage of the law on diabetes may progressively have a greater impact. Although the law is not yet fully implemented, it has enabled the diabetes associations to defend the rights of their members. This increased capacity is credited with some improvements in diabetes care.

ObjectiveTo assess improvements in diabetes care in Mozambique between 2003 and 2009 following the implementation of the Diabetes UK Twinning Programme.MethodsAs in 2003, a Rapid Assessment Protocol was implemented from August to September 2009 in order to assess the improvements in diabetes

Aim To provide data on changes in illegal drug use in women following imprisonment. Design Prospective cohort study. Setting Recruitment took place in two prisons in the Midlands and South-East England and follow-up in 13 prisons across England. Participants A total of 505 women prisoners participated, a response rate of 82%. Measurements Questions about drug use were contained within a questionnaire which examined broad aspects of health. On entry into prison, women answered questions about daily drug use and injecting drug use prior to imprisonment. One month later the questionnaires examined drug use during this period of imprisonment. Findings Prior to imprisonment, 53% [95% confidence interval (CI): 49–58%] of women took at least one illegal drug daily and 38% (CI: 34–42%) said they had ever injected drugs. Following imprisonment, some women continued to use drugs; 14% (CI: 10–20%) of women reported using at least one illegal drug daily and 2% (CI: 0.7–5%) of women had injected drugs. There were important changes in the types of drugs used; there was a change in use from crack and heroin to benzodiazepines and opiate substitutes. Prior to imprisonment, women most commonly used crack and heroin, but in prison the two most commonly used illegal drugs were benzodiazepines and opiate substitutes. Conclusions The study provides quantitative evidence of the impact of imprisonment on drug use among women. It highlights the need for enhanced drug treatment services and stronger measures to reduce the availability of illegal drugs to women in prison.

Early in sporulation, the cell divides asymmetrically to give two sister compartments, a smaller prespore and a larger mother cell. Differential gene expression in these compartments depends on the regulation of the first sporulation-specific sigma factor, sigma(F), which is activated only in the prespore. Regulation relies on the interactions of four proteins -sigma(F), its antisigma SpoIIAB (which also has protein kinase activity), the anti-antisigma SpoIIAA and the protein phosphatase SpoIIE. Before asymmetric division, and in the mother cell after division, sigma(F) is held in an inactive complex with SpoIIAB and ATP; SpoIIAA is in its phosphorylated form. To disrupt the complex so as to liberate sigma(F) in the prespore, dephosphorylated SpoIIAA is needed, and this is made available by SpoIIE. Thereafter, SpoIIAB and SpoIIE are active simultaneously in the prespore, cycling SpoIIAA through phosphorylated and non-phosphorylated forms. This cycle detains SpoIIAB in a state in which it cannot inhibit sigma(F). Results from biophysical techniques, mathematical simulations and enzyme kinetics have now helped to elucidate the dynamics of the protein-protein interactions involved. An understanding of these dynamics largely accounts for the regulation of sigma(F). We show that the system is tuned to be highly efficient in its use of components and extremely economical in conserving ATP.

SigmaB, an alternative sigma-factor of Bacillus subtilis, mediates the response of the cell to a variety of physical insults. Within the environmental stress signalling pathway RsbU, a protein phosphatase, is stimulated by its interaction with the protein kinase RsbT. In the absence of stress RsbT is expected to be trapped by an alternative binding partner, RsbS. Here, we have demonstrated that RsbS alone cannot act as an alternative partner for RsbT, but instead requires the presence of RsbR to create a high molecular mass RsbR:RsbS complex (approximately 1 MDa) able to capture RsbT. In this complex the phosphorylation state of RsbS, and not that of RsbR, controlled the binding to RsbT, whose kinase activity towards RsbS could be counterbalanced by the activity of RsbX, the phosphatase for RsbS-P. The RsbR:RsbS complex recruited RsbT from a mixture of RsbT and RsbU. The phosphorylated form of RsbR in the complex enhanced the kinase activity of RsbT towards RsbS. This supramolecular complex thus has the functional properties of an alternative partner for RsbT. Electron micrographs of this complex are presented, and the purification of the RsbR:RsbS complex from cellular extracts provides evidence for the existence of such a complex in vivo.

Sigma-F, the first sporulation-specific transcription factor of Bacillus subtilis, is regulated by an anti-sigma factor SpoIIAB, which can also act as a protein kinase that phosphorylates the anti-anti-sigma factor SpoIIAA. The time course of phosphorylation reaction is biphasic, a fact that has been interpreted in terms of a mechanism for sequestering SpoIIAB away from sigmaF and thus allowing activation of sigmaF when needed. Site-directed mutagenesis of SpoIIAA has allowed us to isolate two mutants that cannot activate sigmaF and which are therefore Spo-. The two mutant SpoIIAA proteins, SpoIIAAL61A and SpoIIAAL90A, are phosphorylated with linear kinetics; in addition they are less able to form the stable non-covalent complex that wild-type SpoIIAA makes with SpoIIAB in the presence of ADP. The phosphorylated form of SpoIIAAL90A was hydrolysed by the specific phosphatase SpoIIE at the same rate as wild-type SpoIIAA-P, but the rate of hydrolysis of SpoIIAAL61A-P was much slower. The secondary structure and the global fold of the mutant proteins were unchanged from the wild type. The results are interpreted in terms of a model for the wild type in which SpoIIAB, after phosphorylating SpoIIAA, is released in a form that is tightly bound to ADP and which then makes a ternary complex with an unreacted SpoIIAA. We propose that it is the inability to make this ternary complex that deprives the mutant cells of a means of keeping SpoIIAB from inhibiting sigmaF.

The actin-like protein FtsA is present in many eubacteria, and genetic experiments have shown that it plays an important, sometimes essential, role in cell division. Here, we show that Bacillus subtilis FtsA is targeted to division sites in both vegetative and sporulating cells. As in other organisms FtsA is probably recruited immediately after FtsZ. In sporulating cells of B. subtilis FtsZ is recruited to potential division sites at both poles of the cell, but asymmetric division occurs at only one pole. We have now found that FtsA is recruited to only one cell pole, suggesting that it may play an important role in the generation of asymmetry in this system. FtsA is present in much higher quantities in B. subtilis than in Escherichia coli, with approximately one molecule of FtsA for five of FtsZ. This means that there is sufficient FtsA to form a complete circumferential ring at the division site. Therefore, FtsA may have a direct structural role in cell division. We have purified FtsA and shown that it behaves as a dimer and that it has both ATP-binding and ATP-hydrolysis activities. This suggests that ATP hydrolysis by FtsA is required, together with GTP hydrolysis by FtsZ, for cell division in B. subtilis (and possibly in most eubacteria).

Defects of both sodium–hydrogen exchange (NHE) and sodium–lithium countertransport (SLC) have been described in subjects at increased risk of coronary heart disease (CHD). Sodium transport is linked to the regulation of cell volume, intracellular pH and cell growth, which may explain aspects of this association. However, impaired growth in early life is also linked to adult CHD, and ‘programmed’ alterations of cell behaviour are postulated to be responsible for this. In this study, therefore, we examined whether NHE or SLC in adults are predicted by anthropometric measures at birth, as well as being associated with insulin resistance syndrome (IRS) variables in adulthood. Red cell SLC was measured in 26 adults, and NHE in dermal fibroblasts from another 15 subjects characterized anthropometrically at birth. SLC activity correlated with LDL cholesterol, triglycerides and urate (r=0·42 – 0·49; 0·05 > P>0·01), but not birth anthropometry. NHE Vmax correlated with plasma insulin (r=0·80; P

SpoIIE is a bifunctional protein with two critical roles in the establishment of cell fate in Bacillus subtilis. First, SpoIIE is needed for the normal formation of the asymmetrically positioned septum that forms early in sporulation and separates the mother cell from the prespore compartment. Secondly, SpoIIE is essential for the activation of the first compartment-specific transcription factor sigma(F) in the prespore. After initiation of sporulation, SpoIIE localizes to the potential asymmetric cell division sites near one or both cell poles. Localization of SpoIIE was shown to be dependent on the essential cell division protein FtsZ. To understand how SpoIIE is targeted to the asymmetric septum we have now analysed its interaction with FtsZ in vitro. Using the yeast two-hybrid system and purified FtsZ, and full-length and truncated SpoIIE proteins, we demonstrate that the two proteins interact directly and that domain II and possibly domain I of SpoIIE are required for the interaction. Moreover, we show that SpoIIE interacts with itself and suggest that this self-interaction plays a role in assembly of SpoIIE into the division machinery.

Objectives To describe duration of symptoms and patterns of diagnosis and referral in women with chronic pelvic pain. Design Retrospective cohort analysis of the MediPlus UK Primary Care Database. Setting One hundred and thirty-six general practices in the UK. Study group A cohort of 5051 incident cases of chronic pelvic pain. Methods The cohort was followed up from the start of their symptoms in 1992 until the end of the chronic pelvic pain episode or the end of 1995. Main outcome measures Duration of symptoms, frequency of diagnoses and referral rates. Results A third of women had symptoms persisting for more than two years. Duration of symptoms increased significantly with age (P < 0.001) from a median of 13.7 months in 13–20 year olds to 20.2 months in women over the age of 60. Irritable bowel syndrome and cystitis were the most common diagnoses at all ages. Twenty-eight percent of women never received a diagnosis during three to four years of follow up after first consultation, and 60% of women had no evidence of a specialist referral. Women aged 21–50 and women whose final diagnosis was endometriosis received the largest number of diagnoses and had the highest referral rates. Conclusions The numbers and types of diagnosis given to a woman with chronic pelvic pain and the likelihood of specialist referral depend on her age, as well as on the duration of symptoms. Women seen in secondary care for chronic pelvic pain are a highly selected group and are likely to represent only the tip of the iceberg.

AIMS: To provide estimates of the 10-year risk of coronary heart disease events for diabetic and nondiabetic men and women with different levels of risk factors and, for diabetic subjects, with and without microalbuminuria. METHODS: Use of risk coefficients derived from the Framingham Study and a meta-analysis of the influence of microalbuminuria on cardiovascular disease. The risk of a coronary heart disease event has been calculated for men and women with and without diabetes mellitus, and among diabetic subjects, with and without microalbuminuria, according to age, systolic blood pressure and the ratio of total to high density lipoprotein cholesterol. RESULTS: These risk estimates have been developed as a series of colour charts. The use of Framingham estimates of risk have been validated by comparing them with estimates derived from the Dundee Risk Disk and from the PROCAM Study, these estimates providing reasonable agreement despite the geographical and temporal differences in their development. CONCLUSIONS: These charts permit the overall level of risk to be derived, which can inform decision making about thresholds for therapeutic interventions, as well as assisting in patient education.

OBJECTIVE In order to examine the role of insulin-like growth factors in the pathogenesis of accelerated macrovascular disease in noninsulin-dependent diabetes mellitus (NIDDM), we investigated the relationship between the insulin resistance syndrome and the IGF axis. DESIGN Cross-sectional analysis of the relationship between insulin resistance syndrome variables and concentrations of IGF-1, IGF-2, IGFBP-1 and IGFBP-3 in 80 subjects with NIDDM. RESULTS After correcting for age, sex and body mass index, concentrations of IGFBP-1, correlated with those of HDL-cholesterol (r = 0.40; P

OBJECTIVE Previous in vitro studies have demonstrated significant 11-beta hydroxysteroid dehydrogenase (11 β-HSD) oxo-reductase activity in visceral, but not subcutaneous adipose stromal cells. We have conducted an in vivo study of the cortisol–cortisone shuttle in subcutaneous abdominal adipose tissue. DESIGN We measured arteriovenous (A-V) differences in serum cortisol and cortisone across subcutaneous abdominal adipose tissue and forearm muscle in a heterogeneous group of subjects. PATIENTS We studied 34 subjects (male:female = 12 : 22), age median (interquartile range) 45 (19–65) years, body mass index 32.7 (20.4–77.1) kg m−2, total body fat 34.4 (5.6–119.1) kg. MEASUREMENTS Serum cortisol and cortisone were measured in serum samples from a radial artery, superficial epigastric vein and deep forearm vein. Abdominal adipose and forearm blood flow rates were measured by 133Xenon washout and plethysmography, respectively. RESULTS For cortisone, there was significant (P

Diabetic retinopathy remains the most common cause of blindness in people of working age but the provision of high quality eye screening for diabetic patients is still erratic in many health districts in the UK. National consensus guidelines recommend comprehensive population coverage, high sensitivity (>80%), high specificity (>95%), agreed clinical criteria, referral procedures and centralized data collection to facilitate audit. This study looks at the effectiveness of implementing a prompted recall programme for retinal screening in an inner-city district of North London. The scheme uses trained, accredited optometrists to screen patients with diabetes who are looked after in the community by their general practitioner. During the first 17 months of the scheme, 63 optometrists attended training and gained accreditation. Of the 666 patients recruited, 645 were scheduled for screening and 536 (83%) attended. Fourteen per cent of patients screened were found to have background retinopathy and 2.3% sight-threatening eye disease. In two audits, carried out 15 months apart in a random sample of GP practices, the incidence of recorded dilated fundoscopy increased from 48% at baseline to 56%, an increase of 8% (95% CIs 2%-14%). For referable eye disease, the sensitivity of this screening technique was 100%, the specificity 94% (95% CIs 90%-98%), the positive predictive value 79% (95% CIs 72%-86%) and the negative predictive value 100%. The administrative cost per case screened was Pound Sterling 12.60 (excluding clinical costs and any additional optometry payment).

Objective To examine the prevalence of folic acid supplementation prior to conception and in the first trimester of pregnancy, and to identify sociodemographic variables associated with the use of supplements. Design Observational study. Setting District general hospital in the south in England. Population Nine hundred and sixty-three randomly selected pregnant nulliparous Caucasian women recruited from May 1994 to February 1996 inclusive. Methods Questionnaire administered at approximately 16 weeks gestation. Main outcome measures Intakes of supplemental folic acid before conception and during pregnancy. Results 31.5% (303/963) (95% CI 28.5–34.4) of pregnant women reported using supplements containing folic acid prior to conception. The proportion using pre-conceptional folic acid increased by approximately 1% per month during the 22 months of the study. 38.1% (367/962) (35.1 to 41.2) of women began taking folic acid only after the confirmation of pregnancy, and this proportion appeared constant over time. Young age, smoking and low educational attainment were statistically significant predictors of failure to use folic acid both before and during pregnancy. Conclusions Use of folic acid before conception in nulliparous women is much higher than the 2% to 3% reported in earlier studies of all pregnant women, and appears to be increasing. However, many women still only begin taking folic acid after conception, despite current health education strategies. New approaches, focusing on women who are currently least likely to take folic acid - those who are young, are of low educational backgrounds, and are smokers - may now be required. Given the inevitably of unplanned pregnancies, efforts must also be made to increase the currently static uptake of folic acid immediately after the confirmation of pregnancy.

The role of nutrient supply in the replicative capacity and secretory phenotype of cultured human diploid cells is unclear. We examined the relationship between amino acid privation, the secretion of vascular endothelial growth factor (VEGF) and growth phenotype of vascular smooth muscle cells (VSMC), and endothelial cells. Cultures of VSMCs, but not endothelial cells, were growth inhibited by exposure to medium that was 75% deficient in leucine, methionine, arginine, and cysteine over two passages. Exposed VSMC cultures exhibited an increased vulnerability to apoptosis. The maximal cumulative population doubling of the exposed cells was reduced significantly compared with the control cells (25.7 +/- 2.0 doublings vs. 27.9 +/- 2.1 doublings; P < 0.03). Constitutive VEGF production first became evident in the later passages of the exposed and nonexposed cell cultures. However, production of VEGF was 17-fold greater in the exposed cultures at the tenth passage (P < 0.001). The replicative capacity and constitutive production of VEGF in VSMCs in culture may be programmed by transient privation of amino acids. These observations are relevant to new concepts concerning the pathogenesis of vascular disease.

The outcome at age 2 years of preterm babies recruited into a three-arm randomised controlled trial of prophylactic volume expansion was ascertained in two ways: from a neurodevelopmental assessment performed by a paediatrician and from responses on a brief questionnaire completed by the child's personal health visitor. Of 776 babies recruited into the trial, 604 survived to the age of 2 years and the findings of a paediatric assessment were available for all survivors. Questionnaires were sent to the health visitors of 601 of the survivors; 513 (85.4%) were returned. There was sufficient information on the returned questionnaires to categorise 449 of the children as normal, impaired, moderately disabled or severely disabled. We were unable to detect a response bias by severity of disability. Agreement on individual questions ranged between 86.3% and 98.4%. There was some mismatch in the reporting of vision (weighted kappa = 0.71) and hearing (weighted kappa = 0.73), with differences in perception of level of severity of sensory loss. Health visitors tended to underestimate the child's functional level compared with the paediatrician. However, of 56 children classified as severely disabled by the paediatrician, 48 were classified similarly and eight as moderately disabled on the basis of the questionnaire. The end point of the trial was death or severe disability at 2 years of age. There was close similarity in the trial results whether based on the paediatric assessment or on the questionnaire. Further refinement of the questionnaire is needed, but this methodology may be useful in ascertaining the frequency of severe disability in large cohorts of babies.

The diabetic patient has a substantially increased in-hospital mortality after acute myocardial infarction, which is around twice that of non-diabetic subjects. A number of interventions can substantially improve this outcome. The use of thrombolytic therapy reduces case fatality proportionately to a similar degree to that in non-diabetic patients, but because of the higher background risk, absolute benefits are substantially greater. In the world literature, there is just one reported case of intraocular haemorrhage after thrombolysis in a diabetic patient, and that resolved in 3 weeks, meaning that anxieties around theoretical adverse effects of thrombolysis should not preclude its use. There is no evidence regarding the advantages of any one thrombolytic agent in these subjects. Aspirin treatment again has similar benefits to those in non-diabetic subjects, and should be administered at presentation. Some evidence suggests that a higher dose of aspirin should be used in diabetic, compared to non-diabetic, patients. Finally, the DIGAMI Study has shown that insulin and glucose infusion during the hospital admission, followed by multiple injection therapy thereafter, reduces mortality by around one-third, both at 12 months and at around 3 1/2 years. Whether these advantages are because of improved early or late glycaemic control, or because of withdrawal of sulphonylureas, is still unclear, but this uncertainty should not stand in the way of introducing policies for insulin infusion in all diabetic patients admitted with acute myocardial infarction.

In non-diabetic subjects, insulin concentrations and insulin resistance are clearly connected, and both correlate with leptin levels, making interpretations about mechanisms difficult. In non-insulin-dependent (Type 2) diabetes mellitus (NIDDM), however, insulin concentrations and insulin resistance are less closely associated. Therefore, we examined the relationship of plasma leptin concentrations within insulin resistance and insulin levels in 32 subjects with NIDDM, who underwent measurement of insulin resistance with an insulin sensitivity test. Plasma leptin was measured with an in-house monoclonal immunoradiometric assay. Fasting leptin level correlated with BMI (r = 0.78; p < 0.001), metabolic clearance rate of glucose (= -0.44; p = 0.015), and fasting specific insulin (r = 0.58; p = 0.001), but not with age, cholesterol, triglycerides or blood pressure (r = -0.26 to 0.21; p = NS). In linear regression analysis, after adjustment for BMI and gender, leptin concentrations correlated with those of insulin (partial r = 0.42; p = 0.025), but not insulin resistance (partial r = -0.10; p = NS). We conclude that in NIDDM, concentrations of plasma leptin are closely related to those of insulin per se and to obesity, but not to insulin resistance. Insulin may be an important regulator of leptin concentration in NIDDM.

We have investigated the effects of metformin treatment on concentrations of proinsulin-like molecules in subjects with Type 2 (non-insulin-dependent) diabetes mellitus. Metformin was given for 12 weeks in an increasing dose up to 850 mg three times daily in a double-blind placebo-controlled cross-over design to 27 subjects (age 53.0 +/- 9.9 years; 19 male, 8 female). Concentrations of insulin and proinsulin-like molecules were measured by highly specific enzymoimmunometric assays. The end of metformin treatment was compared with end of placebo treatment. Metformin lowered fasting plasma glucose concentrations (at 12 weeks, metformin: 8.0 +/- 2.5 vs placebo: 12.0 +/- 2.3 mmol l-1, p r2 0.001;). Concentrations of intact (median change -2.9 (range -28.4 to +2.5 pmol l-1), p = 0.02) and des 31,32 proinsulin (median change -1.6 (range -14.1 to +5.4 pmol l-1), p = 0.07) and percentage of proinsulin-like molecules were reduced by metformin treatment (median change -6% (range -16% to +6%), p = 0.02). Changes in the ratio of proinsulin-like molecules were significantly related with those in fasting plasma glucose (r1 = 0.69, p < 0.001). Changes in concentrations of intact and des 31,32 proinsulin on metformin were not related to changes in body mass index or fasting glucose concentration or changes in concentrations of total triglyceride, cholesterol, and plasminogen activator inhibitor-1. Therefore, metformin treatment in subjects with Type 2 diabetes mellitus significantly reduced concentrations of proinsulin-like molecules over a 12-week period. However, these changes were not related to changes in cardiovascular risk factors seen during metformin treatment. We conclude that short-term effects of metformin treatment on proinsulin-like molecules are similar to those previously observed with dietary treatment in subjects with Type 2 diabetes but opposite to those of sulphonylurea treatment. The effect of long-term treatment with metformin on proinsulin-like molecules needs to be assessed.

In order to study the plasminogen activator inhibitor activity (PAI-1) in subjects at different risk of non-insulin-dependent diabetes and ischaemic heart disease we examined 89 subjects with diet controlled NIDDM (49 Caucasian, 40 Asian), 29 with impaired glucose tolerance (IGT) (13 Caucasian, 16 Asian), and 149 with normal glucose tolerance (67 Caucasian, 82 Asian). Diabetes was diagnosed by WHO criteria and highly specific, monoclonal antibody-based assays were used to measure insulin, intact proinsulin, and des 31,32 proinsulin. Subjects with NIDDM were significantly more obese, had more central distribution of obesity, higher fasting plasma specific insulin concentrations (NIDDM median 74 pmol l-1 vs IGT 41 pmol l-1, p < 0.01 and vs normals 34 pmol l-1, p < 0.001) and higher PAI-1 activity than normals and those with IGT (NIDDM 23.0 +/- 6.9 vs IGT 16.8 +/- 5.0, p < 0.001 and vs normals 17.1 +/- 6.9 AU ml-1, p < 0.001). However, PAI-1 activity was not significantly different between Asian and Caucasian normals (17.5 +/- 7.3 vs 16.5 +/- 6.4 AU ml-1, p = ns) and diabetic (22.8 +/- 7.3 vs 23.1 +/- 6.6 AU ml-1, p = ns) subjects. In addition to relationships with obesity and plasma triglyceride, PAI-1 activity, after controlling for age, sex, body mass index, and waist-hip ratio, was related to fasting insulin (partial r = 0.22, p < 0.001), intact proinsulin (partial r = 0.36, p < 0.001), and des 31,32 proinsulin concentrations (partial r = 0.33, p < 0.001) as measured by highly specific assays. The association of PAI-1 with diabetes was weakened but remained statistically significant (p = 0.042) after controlling for age, sex, ethnicity, obesity, plasma triglyceride, and all insulin-like molecules. We conclude that, although PAI-1 activity is raised in subjects with diet-treated NIDDM, it is normal in subjects with IGT and non-diabetic Asians, populations at high risk of NIDDM and ischaemic heart disease. Raised PAI-1 activity may play an important role in the pathogenesis of macrovascular disease in subjects with NIDDM, but is unlikely to explain excess risk of ischaemic heart disease in Asians and those with impaired glucose tolerance.

A population-based cross-sectional survey was carried out to study potential environmental risk factors contributing to diabetes and cardiovascular risk in the same homogeneous group in the United Kingdom and in Dar es Salaam, Tanzania. In Dar es Salaam, 222 members of the Bhatia community aged 15 years and over were studied. In the UK, 180 randomly selected subjects aged 15 years and over participated. Age, sex, and body mass index adjusted mean levels of fasting glucose (5.5 mmol l-1 vs 5.1 mmol l-1 (p < 0.001)) and 2 h glucose (6.8 mmol l-1 vs 6.0 mmol l-1 (p < 0.001)) were significantly higher in Tanzanian subjects than in UK subjects. Mean levels of serum triglycerides (1.5 mmol l-1 vs. 1.3 mmol l-1 (p < 0.05)) and systolic blood pressure (135 mmHg vs 127 mmHG (p < 0.05) were significantly higher in subjects in the UK. The age and sex adjusted prevalence of impaired glucose tolerance (28.4% vs 11.4% (p < 0.001)), newly diagnosed diabetes (8.6 % vs 1.5% (p < 0.01)), hypercholesterolaemia (9.9% vs 1.5% (p < 0.001)), and smoking (12.1% vs 3.9% (p < 0.01)) were significantly higher in subjects in Tanzania compared to subjects in the UK. The prevalence of known diabetes, hypertriglyceridaemia, hypertension, and obesity did not show significant differences between subjects in Tanzania and those in the UK. Within the same homogeneous community with the same likely genetic predisposition, there are substantial geographical differences in cardiovascular risk factors, the causes of which remain to be determined.

The standard risk factors--dyslipidaemia, hypertension and smoking--provide little help in explaining the raised cardiovascular risk in diabetes. It can be calculated that intervening for disturbances of these risk factors could do little to rectify the loss of life expectancy of around 10 years for a middle-aged diabetic man. Three new risk factors are discussed, which together may contribute to some of the excess cardiovascular risk in diabetes. Plasminogen activator inhibitor is an inhibitor of fibrinolysis which is elevated in concentration in diabetic subjects, and may increase both the incidence of thrombotic events and the risk of reinfarction after the initial infarct. Recent work also suggests that high activity of this substance may impair pharmacological fibrinolysis. Proinsulin-like molecules are elevated in concentration in diabetic patients and correlate with levels of a number of other risk factors. Whilst these correlations may represent cause and effect for plasminogen activator inhibitor, there is no evidence that changes in levels of proinsulin-like molecules influence levels of other risk factors. Microalbuminuria provides a powerful indicator of cardiovascular risk in both diabetic and non-diabetic subjects, but whilst the mechanisms for this association are unclear, they are again unlikely to be mediated through changes in levels of standard risk factors. Recent observations of an association between short stature and microalbuminuria suggest that intrauterine or early infant nutrition may represent a common antecedent, these having also been shown to predict both components of the insulin resistance syndrome and cardiovascular disease in adult life.

Eleven Type 2 diabetic subjects (10 male 1 female: age 56.2 +/- 9.7 (SD) yr) were treated in random order either with insulin or with sulphonylureas for 8 weeks each, without attempting to alter glycaemic control between the two treatment periods. Insulin treatment was associated with suppression of endogenous insulin secretion (fasting C-peptide levels -35.0 +/- 24.2%; p = 0.006), and of intact proinsulin (-43.1 +/- 36.8%; p = 0.03) and 32,33 split proinsulin -20.1 +/- 27.0%; p = 0.03). Activity of plasminogen activator inhibitor (PAI-1), a fast acting inhibitor of fibrinolysis, decreased significantly (-14.3% +/- 27.5%; p = 0.02) but no changes occurred in concentration of lipoproteins or apoproteins between therapies. Changes in concentrations of 32,33 split and intact proinsulin were closely and significantly related (rs = 0.83; p < 0.001) to each other but not with changes in concentrations of C-peptide (intact proinsulin rs = -0.41; p = 0.11) and 32,33 split proinsulin rs = -0.27; (p = 0.21). Percentage changes in intact proinsulin concentrations were positively correlated with those in PAI-1 (rs = 0.51; p = 0.05). There was, however a paradoxical negative relationship between changes in C-peptide concentrations and those of PAI-1 (rs = -0.73; p = 0.006). These preliminary observations suggest that insulin treatment in Type 2 diabetic subjects without any changes in glycaemic control is associated with a reduced activity of PAI-1, but is without effect on any other cardiovascular risk factors. Concentrations of insulin precursor molecules may play a role in determining fibrinolytic activity.

In order to test the effect of stress on injection-site blood flow and blood glucose control, 16 C-peptide negative patients were studied on a stress day, when a 30-min Stroop Colour-Word Test was completed, and a control day, when a cartoon was shown. Unmodified insulin was injected subcutaneously into the thigh before the test, and injection-site blood flow measured throughout the experiment with a thermal clearance probe. Blood glucose and plasma free insulin, glucagon, growth hormone, cortisol, and catecholamines were measured at intervals before, during, and after stress. Patients showed a significant overall rise in injection-site blood flow with the Stroop test from 4.1 (SD 1.6) to 5.2 (1.8) ml 100-g-1 min-1 (increase 38.1 (37.8) %, p less than 0.001). There was no overall significant difference between stress and control days in blood glucose or plasma free insulin levels, with differences in mean blood glucose levels during stress between the 2 days varying from -4.2 mmol l-1 to +6.3 mmol l-1 in individual patients. The increase in injection-site blood flow with stress correlated significantly with the increase in plasma free insulin concentration both during (r = 0.55) and after stress (r = 0.71). Differences in blood glucose concentration between stress and control day for each patient showed strong correlation with differences in plasma free insulin both during (r = -0.73) and after stress (r = -0.79). Differences in counter-regulatory hormones occurred but correlated poorly with blood glucose difference. Thus, stress affects the blood flow at the injection site, and this in turn affects insulin absorption. Most of the blood glucose response to stress is explained by changes in free insulin concentration.

SUMMARY We have compared insulin concentrations measured by radioimmunoassay (RIA) in plasma from 50 fasting non-insulin-dependent diabetics (NIDDM) with those measured by a new monoclonal antibody-based two-site immunoradiometric assay (IRMA) of insulin (which has no significant cross-reaction with proinsulin-like molecules). We find that the RIA measures the sum of the insulin and proinsulin like molecules and that the IRMA insulin concentrations are 38% of those measured by the RIA in those diabetic subjects. We conclude that the importance of insulin deficiency in NIDDM may have been obscured by this error.

South Asian subjects in the United Kingdom have a substantially increased risk of both diabetes and cardiovascular disease. The excess risk of cardiovascular disease is not explained by risk factors such as smoking, blood pressure or dyslipidaemia. It has been proposed that the insulin resistance syndrome, perhaps consequent upon central obesity, may underlie the risk of both glucose intolerance and cardiovascular disease. In non-diabetic south Asian subjects we have found higher concentrations of insulin and of proinsulin-like molecules, higher blood pressure, and lower concentrations of high density lipoprotein cholesterol, but no elevation of activity of plasminogen activator inhibitor. Newly diagnosed diabetic subjects from the south Asian population are younger and thinner than newly diagnosed europid subjects, but are more centrally obese and hyperinsulinaemic. It is possible that the coexistence of diabetes and cardiovascular disease represents the consequence of a common antecedent.