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Background: Insulin degludec is a new basal insulin that forms soluble multihexamer assemblies after subcutaneous injection, resulting in an ultra-long action profile. This study aimed to assess efficacy and safety of insulin degludec injected once a day or three times a week compared with insulin glargine once a day in insulin-naive people with type 2 diabetes, who were inadequately controlled with oral antidiabetic drugs., Methods: In this 16-week, randomised, open-label, parallel-group phase 2 trial, participants aged 18–75 years with type 2 diabetes and glycosylated haemoglobin (HbA(1C)) of 7·0–11·0% were enrolled and treated at 28 clinical sites in Canada, India, South Africa, and the USA. Participants were randomly allocated in a 1:1:1:1 ratio by computer-generated block randomisation to receive insulin degludec either once a day or three times a week or insulin glargine once a day, all in combination with metformin. Investigators were masked to data until database release. The primary outcome was HbA(1C) after 16 weeks of treatment. Analyses were done by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT00611884., Findings: Of 367 patients screened, 245 were eligible for inclusion. 62 participants were randomly allocated to receive insulin degludec three times a week (starting dose 20 U per injection [1 U=9 nmol]), 60 to receive insulin degludec once a day (starting dose 10 U [1 U=6 nmol]; group A), 61 to receive insulin degludec once a day (starting dose 10 U [1 U=9 nmol]; group B), and 62 to receive insulin glargine (starting dose 10 U [1 U=6 nmol]) once a day. At study end, mean HbA(1C) levels were much the same across treatment groups, at 7·3% (SD 1·1), 7·4% (1·0), 7·5% (1·1), and 7·2% (0·9), respectively. Estimated mean HbA(1C) treatment differences from insulin degludec by comparison with insulin glargine were 0·08% (95% CI –0·23 to 0·40) for the three dose per week schedule, 0·17% (–0·15 to 0·48) for group A, and 0·28% (–0·04 to 0·59) for group B. Few participants had hypoglycaemia and the number of adverse events was much the same across groups, with no apparent treatment-specific pattern., Interpretation: Insulin degludec provides comparable glycaemic control to insulin glargine without additional adverse events and might reduce dosing frequency due to its ultra-long action profile., Funding: Novo Nordisk.

Objective: Patient involvement into medical decisions as conceived in the shared decision making method (SDM) is essential in evidence based medicine. However, it is not conclusively evident how best to define, realize and evaluate involvement to enable patients making informed choices. We aimed at investigating the ability of four measures to indicate patient involvement. While use and reporting of these instruments might imply wide overlap regarding the addressed constructs this assumption seems questionable with respect to the diversity of the perspectives from which the assessments are administered., Methods: The study investigated a nested cohort (N = 79) of a randomized trial evaluating a patient decision aid on immunotherapy for multiple sclerosis. Convergent validities were calculated between observer ratings of videotaped physician-patient consultations (OPTION) and patients' perceptions of the communication (Shared Decision Making Questionnaire, Control Preference Scale & Decisional Conflict Scale)., Results: OPTION reliability was high to excellent. Communication performance was low according to OPTION and high according to the three patient administered measures. No correlations were found between observer and patient judges, neither for means nor for single items. Patient report measures showed some moderate correlations., Conclusion: Existing SDM measures do not refer to a single construct. A gold standard is missing to decide whether any of these measures has the potential to indicate patient involvement., Practice Implications: Pronounced heterogeneity of the underpinning constructs implies difficulties regarding the interpretation of existing evidence on the efficacy of SDM. Consideration of communication theory and basic definitions of SDM would recommend an inter-subjective focus of measurement., Trial Registration: Controlled-Trials.com ISRCTN25267500.

Background: Insulin is recommended as a second-line treatment after diet and metformin fail to reach and/or maintain glycemic targets considered to minimize the risk for long-term diabetic complications. Hypoglycemia and the fear of developing hypoglyce-mia, however, remain substantial barriers to the initiation and optimal use of insulin., Objective: The aim of this study was to compare biphasic insulin aspart 30 (BIAsp 30) with biphasic human insulin 30 (BHI 30) with respect to glycemic control and the risk for hypoglycemia using a meta-analysis of clinical trials comparing these insulins in patients with type 2 diabetes mellitus (T2DM)., Methods: We included all published and unpublished, randomized, controlled trials in adult patients with T2DM (treatment duration > or = 12 weeks) for which individual patient data were available. All clinical databases and local trial registries of Novo Nordisk A/S (Soeborg, Denmark) were searched to identify clinical trials comparing the 2 products. The predefined primary end point of the study was the overall rate of nocturnal hypoglyce-mia (major, minor, and symptoms-only hypoglycemia occurring from 12:00-6:00 AM). Hypoglycemia was analyzed using a negative binomial distribution model, accounting for exposure time. Glycemic end points were analyzed at 12 to 16 weeks of treatment using ANCOVA, adjusting for baseline. Secondary safety end points were the rates of major hypoglycemia (hypoglycemia requiring third-party assistance), minor hypoglycemia (symptoms confirmed by plasma glucose [PG] <3.1 mmol/L), daytime hypoglycemia (major, minor, and symptoms-only hypoglycemia occurring from 6:01 AM-11:59 PM), overall hypoglycemia (the sum of all major, minor, and symptoms-only episodes), and change in weight from baseline to 12 to 16 weeks of treatment. Secondary efficacy end points were changes in glycosylated hemoglobin (HbA(1c)), fasting PG (FPG), postprandial PG increment (averaged over breakfast, lunch, and dinner), and insulin dose., Results: Nine randomized, parallel or crossover trials were included (N = 1674; male sex, 57%; mean [SD] age, 61.0 [10.6] years; body mass index, 26.7 [4.6] kg/m(2); HbA(1c), 8.1% [1.4%]; duration of diabetes, 10.9 [7.9] years). Rates of overall hypoglycemia were not significantly different (rate ratio [RR] = 1.08; 95% CI, 0.94-1.24; P = NS) between treatments. BIAsp 30 had a 50% lower rate of nocturnal hypoglycemia than BHI 30 (RR = 0.50; 95% CI, 0.38-0.67; P < 0.01), whereas the rate of daytime hypoglycemia was 24% lower for BHI 30 (RR = 1.24; 95% CI, 1.08-1.43; P < 0.01). The likelihood of major hypo-glycemia was significantly lower with BIAsp 30 compared with BHI 30 (odds ratio = 0.45; 95% CI, 0.22-0.93; P < 0.05). BIAsp 30 was associated with reduced PPG increment (averaged over breakfast, lunch and dinner) compared with BHI 30 (treatment difference, -0.31; 95% CI, -0.49 to -0.07; P < 0.01). There was a significantly larger reduction in FPG associated with BHI 30 (treatment difference, 0.63; 95% CI, 0.31-0.95; P < 0.01). However, no significant treatment difference was found for HbA(1c) (treatment difference, 0.04; 95% CI, -0.02 to 0.10; P = NS)., Conclusion: This meta-analysis found BIAsp 30 to be associated with a significantly lower rate of nocturnal and major hypoglycemia, but a significantly increased risk for daytime hypoglycemia, compared with BHI 30 at a similar level of HbA(1c) in patients with T2DM.

Background: The treatment of skin ulcers frequently presents a management challenge. Nonhealing wounds with poor response to conventional wound management therapy represent a significant cause of disability, affecting approximately 1% of the global population. Activated protein C is a serine protease with anticoagulant, angiogenic, and anti-inflammatory properties that has shown efficacy in patients for the treatment of severe sepsis. We report 4 cases of nonhealing lower limb skin ulcers that were treated with activated protein C., Observations: The study included 4 patients whose wounds were not improving despite standard wound treatment for 4 months or more. Activated protein C was applied topically to their wounds once weekly for 4 weeks. All 4 patients showed a rapid positive response to treatment that was maintained during a 4-month follow-up period. The treatment was well tolerated, with no remarkable adverse effects or complications., Conclusions: Activated protein C can stimulate wound healing in patients with skin ulcers that are refractory to conventional wound-healing therapies. The likely mechanism of action is its recognized ability to stimulate angiogenesis and reepithelialization and to inhibit inflammation. Activated protein C has potential as a therapeutic option for patients with chronic skin ulcers.

We describe a 31-year-old woman who had ingested minocycline for 18 months prior to presenting with hyperthyroidism and a palpable thyroid nodule. There was no evidence of Graves' disease or autonomous nodule on thyroid scintigraphy, and a clinical diagnosis of thyroiditis was made. Fine-needle aspiration biopsy of the palpable lesion suggested papillary carcinoma, and the patient underwent a total thyroidectomy. Intraoperatively, the thyroid gland was found to have a striking black discoloration. Subsequent histological examination revealed the accumulation of pigment globules within the apical cytoplasm of the follicular cells, and associated findings of a drug-induced thyroiditis. The tumor nodule showed features of infarction and was felt to represent a necrotic papillary microcarcinoma. We postulate that in addition to causing black thyroid pigmentation, chronic minocycline use in our patient resulted in thyroiditis and subsequent hyperthyroidism. The papillary microcarcinoma was probably a coincidental finding.

Objective: This study aimed to determine the main themes and concerns for women with Multiple Sclerosis when considering motherhood., Method: Twenty women with multiple sclerosis from various stages in the decision-making process participated in focus-groups where information was gathered regarding their experiences of making this decision., Results: The themes emerging most frequently during the decision-making process were: a) concerns about the mother's own health and well-being; b) well-being of the child; c) coping with parenting; d) societal attitudes; e) experiencing parenting and f) timing and pressure of the decision., Conclusion: The results indicate that information regarding the effect of MS on pregnancy and child-rearing and the effect of pregnancy on MS and its progression need to be made more accessible to women. Information would be a valuable resource for women going through this decision-making process.

Degradation of extracellular matrix proteins by matrix metalloproteinases (MMPs) is integral to cell migration and tissue remodeling in diabetes mellitus and its complications. MMPs also regulate the function of leukocytes via proteolytic processing of cytokines/chemokines. In this study, we measured the production of MMP-9 and its natural tissue inhibitor (TIMP)-1 by leukocytes isolated from human type I diabetic patients. MMP-9 was also detected in serum and splenocytes from non-obese diabetic (NOD) and BALB/c mice. MMP-9 was markedly elevated in leukocytes from diabetics compared to non-diabetic controls. TIMP-1 production was also enhanced in leukocytes from diabetics, but substantially less than MMP-9, with the MMP-9/TIMP-1 ratio being 1.6-fold higher in neutrophils and 3-fold higher in monocytes than controls. Interleukin (IL)-2 or lipopolysaccharide (LPS) treatment increased MMP-9 production in leukocytes from both diabetics and normal controls, whereas insulin decreased MMP-9 expression. Recombinant MMP-9 stimulated the proliferation of mouse splenocytes from NOD or BALB/c and a MMP-9 inhibitor dose-dependently inhibited splenocyte proliferation. In conclusion, our results demonstrate firstly that MMP-9 expression is elevated in leukocytes from type I diabetic patients and NOD mice and secondly, that MMP-9 elevates proliferation of mouse splenocytes. These data suggest that elevated leukocyte MMP-9 may contribute to the pathogenesis of type I diabetes and its associated complications.

Background: It is estimated that 39% of people with diabetes worldwide who use insulin are prescribed premixes, largely because of the practical advantages of addressing both prandial and basal insulin needs with a single product. Rapid-acting premixed insulin analogues such as biphasic insulin aspart 30 (BIAsp 30 [30% soluble insulin aspart and 70% protamine-crystallized insulin aspart], NovoLog Mix 70/30, Novo Nordisk, Bagsvaerd, Denmark) have been developed recently to overcome the pharmacokinetic limitations of regular human insulin used in the most commonly prescribed premix, biphasic human insulin 30 (BHI 30, 30% human insulin and 70% neutral protamine Hagedorn [NPH] insulin). It would be expected that these pharmacokinetic improvements would enhance clinical performance. However, the efficacy of BIAsp 30 compared with other common treatment regimens has not yet been systematically reviewed., Objective: The aim of this paper is to review current data on the efficacy of BIAsp 30 in comparison with other treatment strategies in type 2 diabetes, including oral antidiabetic drugs (eg, metformin, sulfonylureas, meglitinides, thiazolidinediones), conventional insulins (eg, BHI 30, NPH insulin), and other analogue insulins (eg, insulin glargine, biphasic insulin lispro 25 [Mix 25, 25% biphasic insulin lispro and 75% protaminated lispro]). The focus will be on comparative efficacy (ie, postprandial glucose [PPG], blood glucose profiles, and glycosylated hemoglobin [HbA1c])., Methods: We identified human clinical studies published through February 2005 involving BIAsp 30 in patients with type 2 diabetes by performing a MEDLINE search (key words: biphasic insulin aspart, BIAsp 30, biphasic insulin, and premixed insulin). Additional papers were identified by assessing (1) the reference lists in these studies, (2) published conference proceedings, and (3) our reference files. A total of 21 relevant papers were retrieved: 13 were published as full manuscripts, 1 as a short communication, 5 as abstracts, and 1 as a poster. One paper is currently in press. Novo Nordisk supplied data from an unpublished trial (Study 1536, 2004), as well as data from a trial published in abstract form only (Study 1269, 2002)., Results: A regimen of BIAsp 30 BID, at breakfast and dinner, provides improved PPG control compared with BHI 30 BID, NPH BID, and insulin glargine OD for patients with type 2 diabetes. Fasting plasma glucose (FPG) with BIAsp 30 was not significantly different from FPG with insulin glargine; however, FPG was higher with BIAsp 30 than with NPH. BIAsp 30 prevented excessive PPG excursions whether it was injected at the beginning of a meal or < or =15 minutes after starting a meal. BIAsp 30 was not associated with an increased risk of major hypoglycemia compared with other insulin regimens used in the studies reviewed. The incidence of minor hypoglycemic events with BIAsp 30 varied across studies but occurred with frequency or risk similar to BHI 30, Mix 25, or NPH. Treat-to-target trials reported that BIAsp 30 can be used to intensify insulin therapy and to reach the glycemic target recommended by the American Diabetes Association (ie, HbA1c <7.0%). One study reported a greater lowering of postprandial triglyceride levels with BIAsp 30 than with BHI 30., Conclusions: BIAsp 30 BID can reduce PPG levels to a greater extent than other common treatment regimens, including basal insulin OD. Using BIAsp 30, even once daily, may allow some patients to reach glycemic targets with a degree of convenience and tolerability that may not be achievable with other treatment regimens.

The Diagnostic and Statistical Manual of Mental Disorders, fourth edition (DSM-IV) recognizes life-threatening illness as a potential stressor that can precipitate posttraumatic stress disorder (PTSD). This study represents the first study of PTSD in the context of having a diagnosis of multiple sclerosis (MS). Fifty-eight MS patients were administered the Clinician Administered PTSD Scale, the Geriatric Depression Scale, and Disease Steps Questionnaire. Nine participants (16%) met symptom criteria for PTSD. In terms of those who satisfied the reexperiencing criterion, 75% of participants reported intrusions related to future-oriented concerns about their prognosis. These findings suggest that a significant proportion of MS patients experience PTSD-type reactions. These results are discussed in terms of the suitability of the PTSD framework to account for the distinctive nature of stress reactions secondary to life-threatening illness.

Anemia is a common finding in diabetes, although most patients in these studies have type 2 disease. This study examines the prevalence and predictors of anemia in outpatients with type 1 diabetes. A full blood count was obtained in addition to routine testing in patients with type 1 diabetes at the Austin Medical Centre (n = 135), Melbourne, the Royal Prince Alfred Hospital (n = 42), and the Royal North Shore Hospital (n = 135), both in Sydney, Australia. One in seven patients had anemia (14%). Patients at greatest risk could be identified by the presence of diabetic kidney disease. More than half (52%) of patients with macroalbuminuria had anemia, compared with 24% of patients with microalbuminuria and less than 8% of normoalbuminuric patients. Patients with diabetes and renal impairment were more than six times more likely to have anemia than those with normal renal function. Patients with anemia were more likely to have retinopathy and macrovascular complications than were patients with a normal hemoglobin level, independent of comorbid renal disease. Anemia is a prevalent finding in patients with type 1 diabetes and represents a significant unrecognized burden. Patients at greatest risk can be identified by the presence of renal disease, in the form of albuminuria and/or renal impairment.

Postprandial hyperglycemia is implicated as a risk factor predisposing to vascular complications. This study was designed to assess recurrent short-term increases in glucose on markers of renal fibrogenesis. Human renal cortical fibroblasts were exposed to fluctuating short-term (2 h) increases to 15 mM d-glucose, three times a day over 72 h, on a background of 5 mM d-glucose. To determine whether observed changes were due to fluctuating osmolality, identical experiments were undertaken with cells exposed to l-glucose. Parallel experiments were performed in cells exposed to 5 mM d-glucose and constant exposure to either 15 or 7.5 mM d-glucose. Fluctuating d-glucose increased extracellular matrix, as measured by proline incorporation (P < 0.05), collagen IV (P < 0.005), and fibronectin production (P < 0.001), in association with increased tissue inhibitor of matrix metalloproteinase (MMP) (P < 0.05). Sustained exposure to 15 mM d-glucose increased fibronectin (P < 0.001), in association with increased MMP-2 (P = 0.01) and MMP-9 activity (P < 0.05), suggestive of a protective effect on collagen matrix accumulation. Transforming growth factor-beta(1) (TGF-beta(1)) mRNA was increased after short-term (90 min) exposure to 15 mM glucose (P < 0.05) and after 24-h exposure to 7.5 mM ? (P < 0.05). Normalization of TGF-beta(1) secretion occurred within 48 h of constant exposure to an elevated glucose. Fluctuating l-glucose also induced TGF-beta(1) mRNA and a profibrotic profile, however, to a lesser extent than observed with exposure to fluctuating d-glucose. The results suggest that exposure to fluctuating glucose concentrations increases renal interstitial fibrosis compared with stable elevations in d-glucose. The effects are, in part, due to the inherent osmotic changes.

Background: Anaemia is a common finding in patients with diabetes and constitutes an additional burden in patients with advancing age and comorbid vascular disease. This study examines the prevalence and predictors of anaemia in long-term outpatients with type 2 diabetes from three large clinical centres., Methods: A full blood count was obtained in addition to routine testing in a cross-sectional survey of all patients with type 2 diabetes in long-term follow-up at the Austin Medical Centre, Melbourne (n = 670) and the Royal Prince Alfred Hospital (n = 915) and the Royal North Shore Hospital (n = 540), Sydney, Australia. The prevalence and correlates of anaemia (haemoglobin < 130 g/l in men and < 120 g/l in women) were identified using multivariate logistic regression., Results: Roughly, one in five patients in each centre had anaemia. Patients at greatest risk could be readily identified by the presence of renal disease, manifested as impaired renal function and/or albuminuria in > 75% of patients with anaemia. Patients with diabetes and mild renal impairment [creatinine clearance (CCr) 60-90 ml/min/1.73 m(2)] were twice as likely to have anaemia as those with normal renal function (CCr > 90 ml/min/1.73 m(2)). Diabetics with moderate renal impairment (CCr < 60 ml/min/1.73 m(2)) were also twice as likely to have anaemia as those with mild renal impairment. Patients with anaemia were also more likely to have macrovascular disease, reflecting the high prevalence of nephropathy in these patients., Conclusions: Anaemia is a prevalent finding in patients with type 2 diabetes and represents a significant unrecognized burden. Patients at greatest risk can be identified by the presence of renal disease, either in the form of renal impairment and/or albuminuria.

Background: Potent oral bisphosphonates are the mainstay of therapy for osteoporosis. However, there are patients who cannot have oral bisphosphonates (e.g. because of gastrointestinal side-effects). Therefore, we wanted to examine the effects of intermittent i.v. pamidronate (APD) on bone mineral density (BMD) in patients who needed bisphosphonate therapy but could not have oral bisphosphonates., Aim: To assess BMD before and after intermittent i.v. APD in patients requiring a bisphosphonate either for the prevention of osteoporosis on concurrent steroid therapy or for the treatment of osteoporosis., Methods: This was a retrospective audit of 84 consecutive patients at risk of fractures commencing APD between October 1997 and May 2000. Patients were treated with intermittent i.v. APD. BMD as measured by dual-energy X-ray absorptiometry before and after APD was the main outcome., Results: The mean length of treatment and mean total APD dose were 16.8 +/- 7.0 months and 186.1 +/- 79.5 mg respectively. The reasons for using APD were failure to qualify for oral bisphosphonates on the pharmaceutical benefits scheme due to lack of documented minimal trauma fractures (58%), symptomatic gastro--oesophageal disease (20%), intolerance of oral bisphosphonates (18%) and lack of efficacy of calcitriol (4%). Mean baseline T-score at lumbar (L) 2-4 spine and femoral neck were -1.54 +/- 1.22 and - 2.87 +/- 1.19, respectively. From baseline to after APD treatment, there was a significant increase in L2-4 BMD (0.883 +/- 0.175 vs 0.912 +/- 0.176 g/cm(2), P < 0.001, mean increase +3.5%), in femoral neck BMD (0.667 +/- 0.137 vs 0.680 +/- 0.134 g/cm(2), P= 0.001, mean increase +2.1%) and in trochanteric BMD (0.549 +/- 0.129 vs 0.566 +/- 0.132 g/cm(2), P < 0.001, mean increase +3.1%). One-third of the patients were on oral glucocorticoids at the time of the present study and they had a similar increase in BMD compared to patients not on gluco-corticoids. Mild side-effects occurred in seven patients, none of whom discontinued treatment., Conclusion: Intermittent APD increases BMD and may be a suitable alternative for patients who cannot have oral bisphosphonates.

Whole-grain foods have always been considered a healthy part of the diet. Only recently have epidemiologic and other data shown that whole grains have a role in preventing cardiovascular disease, diabetes, some types of cancer, and even obesity. What nearly all consumers and most health professionals fail to realize is that whole grains deliver as many if not more phytochemicals and antioxidants than do fruits and vegetables. Healthy People 2010 (DHHS) recommends 3 servings of whole grains per day. Because the average intake in the United States is less than 1 serving per day, health professionals must mount an active campaign to help consumers better understand the important health benefits of whole grains and work to increase their intake in the diet.

The aim of this study was to determine the prevalence and extent of glycemic excursions (hypo- and hyperglycemic) in elderly patients with well-controlled type 2 diabetes using a Continuous Glucose Monitor System (CGMS) (Medtronic MiniMed). Elderly patients (>65 years old) with type 2 diabetes were recruited if their glycosylated hemoglobin (HbA1c) was <7.5% and if their oral hypoglycemic therapy included a sulfonylurea. Patients were asked to undergo two consecutive 72-h periods of continuous glucose monitoring at baseline and then again at 1 month (total 288 h). Patients were asked to record four self-monitored capillary blood glucose levels each day for calibration of the monitor and also to record meal times, exercise, and symptoms of hypoglycemia. The number of hyperglycemic (>144 mg/dL), hypoglycemic (<50 mg/dL), and borderline-hypoglycemic (50-65 mg/dL) events were determined (an event was defined as a glucose value that persisted for at least 15 min with or without symptoms). Twenty-five patients (21 men, four women) 73.9 +/- 4.4 years old with an HbA1c of 6.2 +/- 0.8% were each monitored for an average of 187.57 h. The mean glucose values were: fasting, 139 +/- 40 mg/dL; 2 h post-breakfast, 167 +/- 58 mg/dL; 2 h post-lunch, 157 +/- 53 mg/dL; and 2 h post-dinner, 149 +/- 49 mg/dL. Twenty patients (80%) experienced a total of 103 hypoglycemic events, and 14 of these patients experienced 54 events where the glucose levels were 144 mg/dL 2 h postprandial) were recorded after 57% of all meals (breakfast 60%, lunch 57.5%, dinner 55.2%). The CGMS was generally well tolerated, but 52% of patients could not be studied for the full 12 days of monitoring. Thus hypoglycemia and excessive postprandial glycemic excursions are common in well-controlled patients with type 2 diabetes treated with a sulfonylurea with or without metformin. The CGMS is a useful research and clinical tool to assess glycemia in patients with type 2 diabetes but is not tolerated by all subjects.

Despite mention in the Dietary Guidelines for Healthy Americans and in Healthy People 2010, the lack of a coordinated campaign promoting whole grain foods and their health benefits may be contributing to low consumption. Fiber consumption in the U.S. likewise falls below recommended levels, in part, as a result of suboptimal intake of whole grain foods. Research findings suggest that whole grain is related to reduced disease risk, and that whole grain foods have relevant biological activity in humans. This necessitates a call to action to help Americans increase whole grain consumption as a strategy for health. The establishment of a whole grain coalition could promote increased consumption by developing consumer messages: partnering with health professionals: advocating whole grains to government agencies; seeking funding for scientific research and market research; and educating consumers, as well as health professionals, food manufacturers and millers, about the value and benefit of whole grains.

Objective: Although it is accepted that elevated plasma homocysteine (tHcy) levels occur in end-stage renal disease and type 2 diabetes, the changes with milder renal dysfunction (e.g., microalbuminuria) are less clearly established. This study explores the relationship among tHcy, creatinine clearance (Ccr), and albumin excretion rate (AER) in a population with type 2 diabetes., Research Design and Methods: A total of 260 patients with type 2 diabetes were screened in our outpatient clinic during 10 months. Fasting blood samples were collected, and AER was calculated from an overnight timed urine sample. Ccr was calculated using the Cockroft-Gault formula., Results: A total of 198 subjects (76%) had normoalbuminuria (<20 microg/min), 50 subjects (19%) had microalbuminuria (20-200 microg/min), and 12 subjects (5%) had macroalbuminuria (>or=200 microg/min). Those with microalbuminuria had higher levels of tHcy than those with normoalbuminuria (13.2 +/- 7.8 vs. 11.3 +/- 4.6 micromol/l, P < 0.05). Patients were then subdivided based on low Ccr (<80 ml x min(-1) x 1.73 m(-2)) and normal Ccr (>or=80 x min(-1) x 1.73 m(-2)). None of the patients with macroalbuminuria had normal Ccr. In those with normoalbuminuria, tHcy levels were higher than in those with low Ccr than in those with normal Ccr (12.0 +/- 4.6 vs. 10.0 +/- 4.4 micromol/l, P < 0.01). The same was found for those with microalbuminuria (low Ccr versus normal Ccr: 14.6 +/- 9.0 vs. 10.2 +/- 2.8 micromol/l, P < 0.02). For normal Ccr, tHcy was similar irrespective of AER (normoalbuminuria versus microalbuminuria: 10.0 +/- 4.4 vs. 10.2 +/- 2.8 micromol/l, NS). For low Ccr, tHcy was higher in those with microalbuminuria versus normoalbuminuria (14.6 +/- 9.0 vs. 12.0 +/- 4.6 micromol/l, P = 0.01). Using multivariate regression, Ccr, but neither AER nor the presence of albuminuria, was an independent predictor of tHcy., Conclusions: These data strongly suggest that in patients with type 2 diabetes, the relationship between plasma tHcy and AER is largely due to associated changes in renal function, as defined by Ccr.

Objective: This study was undertaken to evaluate the effects of varying doses of phytoestrogens on lipid and bone metabolism in postmenopausal women., Design: A novel red clover isoflavone preparation (Rimostil) containing genistein, daidzein, formononetin, and biochanin was administered to 46 postmenopausal women in a double-blind protocol after a single-blind placebo phase and followed by a single-blind washout phase. Patients were randomized to receive either 28.5 mg, 57 mg, or 85.5 mg of phytoestrogens daily for a 6-month period., Results: At 6 months, the serum high-density lipoprotein cholesterol had risen significantly by 15.7-28.6% with different doses (p = 0.007, p = 0.002, p = 0.027), although the magnitude of the response was independent of the dose used. The serum apolipoprotein B fell significantly by 11.5-17.0% with different doses (p = 0.005, p = 0.043, p = 0.007) and the magnitude of the response was independent of the dose used. The bone mineral density of the proximal radius and ulna rose significantly by 4.1% over 6 months with 57 mg/day (p = 0.002) and by 3.0% with 85.5 mg/day (p = 0.023) of isoflavones. The response with 28.5 mg/day of isoflavones was not significant. There was no significant increase in endometrial thickness with any of the doses of isoflavone used., Conclusion: These results show that the administration of an isoflavone combination extracted from red clover was associated with a significant increase in high-density lipoprotein cholesterol, a significant fall in apolipoprotein B, and a significant increase in the predominantly cortical bone of the proximal radius and ulna after 6 months of treatment. Interpretation of the results is undertaken cautiously because of the absence of a simultaneously studied control group.

Pregestational diabetes mellitus (DM) is associated with adverse fetal and maternal outcomes. Studies suggest that optimal control of diabetes before and during pregnancy minimises these risks. There are few recent reviews of outcomes of pregnancies complicated by DM in Australia. Ninety-three pregnancies in women with DM at our hospital since 1989 were identified. We collected data for maternal age, type of diabetes, duration of therapy, complications of diabetes, maternal complications of pregnancy and fetal outcomes including malformations. The rate of pregnancy planning with optimal glycaemic control at conception was low in our population, particularly in patients with Type 1 diabetes. Women who smoked had worse glycaemic control, and a higher rate of miscarriage. There was a high rate of Caesarean section, particularly in those women with Type 1 diabetes (77.4%). The rate of Caesarean section was lower in planned pregnancies. There were no perinatal deaths. The number of neonates with major congenital anomalies was high (13%) in the Type 1 population. It is important to increase the rates of prepregnancy planning and to optimise glycaemic control before pregnancy. In many cases there has been a long interval between diagnosis and pregnancy, so all women with diabetes should receive counselling at frequent intervals about pregnancy and the importance of planning. Women who planned their pregnancies had improved outcomes, with decreased rate of Caesarean section, better glycaemic control and better neonatal Apgar scores. Women with diabetes should not smoke during pregnancy because of the increased risk of miscarriage and poorer glycaemic control.

Background: A 41-year-old premenopausal woman with newly diagnosed haemochromatosis was found to have osteopenia on screening bone mineral densitometry., Methods and Results: Liver biopsy showed grade 3 haemochromatosis with an hepatic iron index of 4. Investigation for secondary factors for osteopenia revealed no cause. The patient was clinically and biochemically eugonadal. Following venesection of 8 L blood (4 g iron) over 17 months and calcium supplementation, her bone density rose significantly. Neck of femur bone density increased by 6.0% over 13 months and lumbar vertebral bone density increased by 7.2%. There are no previous reports of response of bone density to venesection in eugonadal patients or in women with haemochromatosis.

We have performed a cross-sectional analysis of the relationship between prorenin values and the microvascular complications of diabetes in a well controlled population of insulin-dependent diabetes mellitus (IDDM) subjects. One hundred and thirty-nine subjects (75 men, 64 women, age 44 +/- 17 years; duration of diabetes 19 +/- 15 years), formed the study group. Sixty-seven subjects (48.2%) had no complications, 55 (39.6%) had retinopathy alone, and 17 (12.2%) had retinopathy and albuminuria. Patients with no complications had lower prorenin values than those with microvascular complications (p < 0.001), whilst patients with both albuminuria and retinopathy had higher values than those with retinopathy alone (p < 0.05). Retinopathy was associated with duration of diabetes (p < 0.0001), diastolic blood pressure (p < 0.02) and albuminuria (p < 0.0001) while albuminuria was associated with prorenin (p < 0.02), serum triglyceride (p < 0.01) and retinopathy (p < 0.001). Patients with albuminuria were 5.5 times more likely to have raised prorenin values (>80 ng/mL/h) than those with normal albumin excretion [95% confidence interval (CI): 1.48-20.12] and those with retinopathy alone were 2.5 times as likely (95% CI: 1.19-5.15). Eighty patients with IDDM (40 males, 40 females; age: 47 +/- 17 years; duration of diabetes: 20 +/- 15 years), had retinal photography performed to determine the association between the severity of retinopathy and prorenin values. Retinopathy was more severe in patients with retinopathy and albuminuria than in those with retinopathy alone (p < 0.002). When the prorenin values of patients with more marked retinopathy (eye grade greater than 3) were compared, prorenin values of those with retinopathy and albuminuria were greater than those of patients with retinopathy alone [269 (139-1406) versus 91 (41-273) ng/mL/h: geometric mean (range); p < 0.05]. Furthermore, when patients without albuminuria were considered, there was no significant difference between the prorenin levels of patients with more severe retinopathy (eye grade >3) when compared to patients with lesser degrees of retinopathy [91 (41-273) versus 69 (23-375). In patients with microvascular complications, prorenin values were independently predicted by albuminuria (p < 0.0001) and diastolic blood pressure (p < 0.02) but not the severity of retinopathy. In conclusion, prorenin values are significantly associated with the presence of microvascular complications in patients with IDDM. The association with albuminuria may be stronger than the association with retinopathy.

We report a case of polyglandular autoimmune deficiency presenting during pregnancy which was associated with a favourable outcome for both mother and fetus (apart from fetal growth retardation) with appropriate replacement therapy and adequate steroid cover at the time of delivery.

This study demonstrates that patients who have undergone coronary artery bypass graft (CABG) surgery have a high prevalence of abnormal glucose tolerance 3 months and 1 year later. Although only 6% were known to have diabetes mellitus (DM) preoperatively, a further 4% were classified DM at two oral glucose tolerance tests (OGTTs) over the subsequent year and a further 18% were classified as having impaired glucose tolerance (IGT) at 12 months. Reproducibility of the 120-minute plasma glucose level in the 75-g OGTT was estimated from a repeat test performed within 10 days. The coefficient of variation (CV) of 120-minute glucose was between 14% and 18%. The observed changes in class of glucose tolerance observed at OGTTs repeated 6 and 12 months after surgery differed from the predicted changes based purely on the estimated variability of 120-minute glucose measurement. There was evidence of regression to the mean for the IGT group. However, there was also evidence of deteriorating glucose tolerance in some subjects. Between 4% and 9% of those with IGT 3 months after CABG surgery developed DM by 12 months, and 26 (13%) of those with initially normal glucose tolerance (NGT) developed IGT. Insulin and glucose responses in the OGTT and estimates of insulin resistance and beta-cell function from fasting samples show that insulin resistance was the principal abnormality in IGT subjects, whereas in DM subjects, both insulin resistance and beta-cell dysfunction contributed. Analysis of preoperative patient characteristics showed that the presence of either a systolic blood pressure of 140 mm Hg or body mass index (BMI) of more than 25 kg/m2 identified 51% of the subjects who would at 1 year after surgery include all those who would be classified DM and 67% of those who would have IGT. Further analyses including insulin levels identified groups at particularly high risk of DM, but no combination of readily available preoperative measures identified all those destined to be classified IGT.

Complete temperature distributions are unavailable for many locations throughout the world. This distributional information is important for product design and operational planning. The problem of obtaining these temperature distributions is quite difficult and current techniques are limited in accuracy. This paper describes a new and effective approach to this problem that matches data-deficient locations to maximally similar locations with known distributions. A polynomial network is used to predict which of a set of sites with known distributions is most similar to a data-deficient site. Then an information theoretic criterion is optimized to find the unknown distribution that closely matches this maximally similar site. Tests with this approach demonstrate its effectiveness and its superiority to current methods.

The short-term administration of a nicotinic acid analogue (acipimox) increases insulin sensitivity and consequently glucose disposal, both in patients with non-insulin-dependent diabetes mellitus (NIDDM) and in patients with cirrhosis. This effect has been attributed to a decrease in plasma nonesterified fatty acid (NEFA) levels and fatty acid oxidation rates, and a corresponding increase in carbohydrate oxidation. The aim of the present study was to determine whether acipimox influenced glucose disposal independent of changes in lipid metabolism. Seven normal men (age, 31 +/- 4 years; body mass index, 23.2 +/- 1.8 kg.m-2; fat-free mass [FFM], 66.8 +/- 4.2 kg) were studied on two separate occasions with hyperinsulinemic (0.06 U.kg FFM-1.h-1) euglycemic clamps (duration, 150 minutes). A primed (150 U), continuous (0.4 U.kg-1.min-1) infusion of heparin together with 10% intralipid (25 mL.h-1) was infused in both studies from -90 to 150 minutes to maintain comparable levels of plasma NEFA and lipid oxidation rates. Acipimox (500-mg capsules) or placebo were administered orally in a double-blind random fashion at t = -90 and t = 0 minutes. Whole-body lipid and carbohydrate oxidation were measured in the last 30 minutes of both the basal (preclamp) period (-30 to 0 minutes) and the clamp period (120 to 150 minutes).(ABSTRACT TRUNCATED AT 250 WORDS)

Hyperlipidaemia, in particular raised concentrations of serum triglycerides, together with raised plasma non-esterified fatty acid concentrations, is common in patients with Type 2 (non-insulin-dependent) diabetes mellitus and may be associated with insulin insensitivity. Thirty non-obese Type 2 diabetic patients (15 controlled with diet alone and 15 with diet plus oral sulphonylurea therapy) were therefore recruited to take part in a double-blind, randomized, crossover comparison of acipimox (250 mg three times daily for 3 months) and placebo. Serum lipids, blood glucose control, insulin sensitivity, and glucose tolerance were measured before and after each treatment period. There was a significant decrease in serum triglycerides (2.05 +/- 1.08 vs 2.91 +/- 1.75: p < 0.005), cholesterol (5.66 +/- 1.02 vs 6.26 +/- 1.17: p = 0.0005), and apoprotein B (1.32 +/- 0.23 vs 1.44 +/- 0.25: p < 0.05) while HDL cholesterol and apoprotein A-1 concentrations were unchanged. There was no change in blood glucose control measured by fasting glucose, insulin, and HBA, concentrations, but there was a significant improvement in insulin action assessed by glucose-insulin infusion. Although plasma non-esterified fatty acid concentrations were lower during the oral glucose tolerance test after acipimox, there was no difference in either the peak or 2-h plasma glucose concentrations and the total area under the glucose curve did not change. Acipimox was well tolerated and no patients withdrew from the study for drug-related symptoms. Thus, acipimox effectively lowers serum cholesterol and triglycerides in patients with Type 2 diabetes without adversely altering blood glucose control, and appears to improve insulin sensitivity.

NEFAs characteristically are elevated in obese NIDDM patients in both the basal state and after insulin. This elevation might aggravate glycemic control both by decreasing peripheral glucose disposal (glucose-fatty acid cycle), and by increasing HGO. Thus, lowering plasma NEFA levels might improve carbohydrate metabolism. We therefore measured HGO and fuel use (by indirect calorimetry) both in the basal state and during the last 30 min of a hyperinsulinemic clamp (0.025U.kg-1.h-1) in 8 obese NIDDM patients (BMI 34.8 +/- 1.0 kg/m2) after complete overnight suppression of plasma NEFA levels with acipimox, a new nicotinic acid analogue. After acipimox, mean basal plasma NEFA and glycerol levels were lower than control values (0.11 +/- 0.02 vs. 0.65 +/- 0.04 mM, P < 0.001; and 16 +/- 3 vs. 68 +/- 7 microM, P = 0.004, respectively) and were accompanied by a fall in lipid oxidation (acipimox vs. placebo: 16.1 +/- 1.2 vs. 38.8 +/- 2.4 mg.m-2 x min-1; P < 0.001) and a rise in glucose oxidation (91.1 +/- 6.2 vs. 54.1 +/- 9.0 mg.m-2 x min-1; P = 0.002). Basal HGO and fasting plasma glucose levels were lower (94.1 +/- 9.2 vs. 118.5 +/- 9.5 mg.m-2 x min-1, P = 0.01; and 8.3 +/- 1.2 vs. 9.8 +/- 1.2 mM; P < 0.001), respectively.(ABSTRACT TRUNCATED AT 250 WORDS)

Hepatic cirrhosis is frequently associated with glucose intolerance and insulin resistance, but the mechanisms underlying the insulin insensitivity are unknown. Plasma concentrations of nonesterified fatty acids (NEFA) are typically elevated in cirrhosis, and the glucose-fatty acid cycle provides a mechanism by which fatty acids may play a role in regulating glucose metabolism. We have therefore investigated the effect of acute inhibition of lipolysis, using the nicotinic acid analogue, acipimox, in 10 male patients with cirrhosis. All subjects were studied in the postabsorptive state after a 10- to 12-hour fast and were given either acipimox 250 mg or a placebo orally 2 hours before a 75-g oral glucose tolerance test (OGTT) and an infusion of insulin (50 mU/kg/h) and glucose (6 mg/kg/min) (insulin sensitivity tests [IST]). The drug was taken in a double-blind crossover design for each test. During the 2 hours following acipimox, there were rapid decreases in plasma NEFA, glycerol, and 3-hydroxybutyrate, confirming inhibition of lipolysis, while there were significant decreases in glucose, insulin, and C-peptide (P less than .001) compared with patients receiving the placebo. Acipimox blunted the increase in glucose after oral glucose loading and decreased incremental glucose concentration (from 579 +/- 76 to 445 +/- 65 mmol/min/L, P less than .02) and incremental insulin concentration (from 13.4 +/- 2.5 to 9.0 +/- 1.4 U/min/L, P = .056) in the OGTT. Improvements in classification of glucose tolerance were seen in five subjects. During the IST, significant reductions occurred in steady-state blood glucose (to 8.8 +/- 1 mmol/L, P less than .02) and C-peptide (to 3.0 +/- 0.5 nmol/L, P less than .05).(ABSTRACT TRUNCATED AT 250 WORDS)

1. Increased rates of fatty acid oxidation are frequently observed in patients with non-insulin-dependent diabetes mellitus and may contribute to hyperglycaemia by both decreasing peripheral glucose disposal and, more importantly, by increasing the rate of gluconeogenesis and therefore hepatic glucose output. Despite this relationship between lipid and carbohydrate metabolism, fasting glucose concentrations do not fall acutely in patients with non-insulin-dependent diabetes mellitus when plasma non-esterified fatty acid concentrations and lipid oxidation rates are decreased, questioning the importance of this interaction to glycaemic control. We have therefore measured the acute changes that occur 120-150 min after administration of 500 mg of the antilipolytic agent acipimox in eight non-obese male patients with non-insulin-dependent diabetes mellitus. 2. After administration of acipimox, lipolysis was inhibited as reflected by lower plasma non-esterified fatty acid (0.05 +/- 0.02 versus 0.55 +/- 0.05 mmol/l, P less than 0.001) and blood glycerol (8 +/- 1 versus 56 +/- 8 mumol/l, P less than 0.001) concentrations. The lipid oxidation rate was decreased (0.63 +/- 0.05 versus 1.02 +/- 0.08 mg min-1 kg-1, P less than 0.001), whereas there was a significant increase in the carbohydrate oxidation rate (1.93 +/- 0.17 versus 1.22 +/- 0.18 mg min-1 kg-1, P = 0.02).(ABSTRACT TRUNCATED AT 250 WORDS)

1. Experimental elevation of plasma non-esterified fatty acid concentrations has been postulated to decrease insulin-stimulated glucose oxidation and storage rates. Possible mechanisms were examined by measuring skeletal muscle glycogen synthase activity and muscle glycogen content before and during hyperinsulinaemia while fasting plasma non-esterified fatty acid levels were maintained. 2. Fasting plasma non-esterified fatty acid levels were maintained in seven healthy male subjects by infusion of 20% (w/v) Intralipid (1 ml/min) for 120 min before and during a 240 min hyperinsulinaemic euglycaemic clamp (100 m-units h-1 kg-1) combined with indirect calorimetry. On the control day, 0.154 mol/l NaCl was infused. Vastus lateralis muscle biopsy was performed before and at the end of the insulin infusion. 3. On the Intralipid study day serum triacylglycerol (2.24 +/- 0.20 versus 0.67 +/- 0.10 mmol/l), plasma nonesterified fatty acid (395 +/- 13 versus 51 +/- 1 mumol/l), blood glycerol (152 +/- 2 versus 11 +/- 1 mumol/l) and blood 3-hydroxybutyrate clamp levels [mean (95% confidence interval)] [81 (64-104) versus 4 (3-5) mumol/l] were all significantly higher (all P less than 0.001) than on the control study day. Lipid oxidation rates were also elevated (1.07 +/- 0.07 versus 0.27 +/- 0.08 mg min-1 kg-1, P less than 0.001). During the clamp with Intralipid infusion, insulin-stimulated whole-body glucose disposal decreased by 28% (from 8.53 +/- 0.77 to 6.17 +/- 0.71 mg min-1 kg-1, P less than 0.005).(ABSTRACT TRUNCATED AT 250 WORDS)

A 23 year old man presented with classical hypothyroidism of 9 years duration. This was associated with pituitary enlargement, documented on magnetic resonance imaging (MRI), and abnormal half-field visual evoked responses (VERs). Following the initiation of thyroxine therapy the pituitary enlargement and the VER abnormalities resolved. The final diagnosis was of primary hypothyroidism with secondary pituitary hyperplasia.

Ketone bodies and non-esterified fatty acids (NEFA) inhibit insulin stimulated glucose uptake in muscle in-vitro. In man the infusion of ketone bodies lowers plasma NEFA levels thus confounding the interpretation of individual effects. The aim of this study was to examine the effect of ketone bodies on insulin mediated forearm glucose metabolism independent of the changes in the plasma NEFA levels. Seven healthy men received sodium 3-hydroxybutyrate (15 mumol kg-1 min-1) or sodium bicarbonate (control) for 240 min. Heparin (0.2 U kg-1 min-1) and insulin (0.01 U kg-1 h-1) were infused for 90 min (pre-clamp), followed by insulin alone (0.025 U kg-1 h-1) and euglycaemia was maintained (clamp). Plasma NEFA levels and rates of forearm NEFA uptake (+23 +/- 14 and +49 +/- 21 [mean +/- SEM] nmol 100 ml forearm [FA]-1 min-1) were comparable during the pre-clamp periods, and were suppressed equally during hyperinsulinaemia. Sodium 3-hydroxybutyrate infusion raised the blood ketone body levels from 70 +/- 4 mumol/l to a plateau of 450 +/- 30 mumol/l, while control levels declined from baseline (ketone body vs control; P less than 0.001).(ABSTRACT TRUNCATED AT 250 WORDS)

The purpose of this study was to examine the effect of physiological plasma nonesterified fatty acid (NEFA) levels on insulin-stimulated forearm and whole body glucose uptake and substrate oxidation during euglycemia and hyperglycemia. Seven healthy men received Intralipid and heparin for 210 min in two studies, with saline as control in two further studies. Insulin (0.05 U.kg-1.h-1) was infused from 60 min, and euglycemia was maintained during lipid (EL) and control (EC) studies, and hyperglycemia was maintained in the other studies (HL and HC). Forearm NEFA uptake was comparable in the lipid studies (+61 +/- 10 and +52 +/- 8 nmol.100 ml forearm-1.min-1, EL and HL) and was suppressed in the controls. With Intralipid, forearm glucose uptake decreased during euglycemia but not during hyperglycemia (+3.85 +/- 0.34 vs. +3.34 +/- 0.25 mumol.100 ml forearm-1.min-1, EC vs. EL, P less than 0.02), with comparable changes in whole body glucose uptake. Glucose oxidation and forearm alanine release decreased with Intralipid at both blood glucose levels, with no significant change in the rates of nonoxidative glucose disposal. These observations support the operation of the glucose-fatty acid cycle at physiological plasma NEFA levels at both blood glucose concentrations, but this was associated with a decrease in peripheral insulin sensitivity only during euglycemia.

The measurement of body composition is an important part of metabolic and epidemiological research, but most currently available methods are complex and expensive. We have, therefore, compared measurements of fat mass (FM) and lean body mass (LBM), obtained using a commercially available bioelectrical impedance monitor (The Holtain Body Composition Monitor) (IMP), and by measuring skinfold thickness (SFT), with values obtained by measuring total body potassium (TBK). Twenty subjects, 10 with a body mass index (BMI) less than 30 (kg m-2), (non-obese) and 10 with BMI greater than or equal to 30 (obese) took part in the study. There was a strongly significant linear relationship between LBM calculated from TBK and that calculated from impedance (IMP), in both non-obese and obese groups analysed separately (non-obese: r = 0.92; p less than 0.001 and obese: r = 0.92; p less than 0.001) and together (all: r = 0.89; p less than 0.001). LBM calculated from TBK was strongly linearly correlated with values derived from SFT for non-obese (r = 0.91; p less than 0.001) but not for obese subjects. Mean values of LBM of non-obese subjects derived by each method were not significantly different (TBK: 51.3 +/- 10.40 kg; IMP: 53.18 +/- 10.37 kg; SFT: 48.87 +/- 9.48 kg), but significant differences existed when the subjects were obese (TBK: 51.86 +/- 9.65 kg; IMP: 58.69 +/- 8.55 kg; SFT: 67.61 +/- 8.14 kg; p less than 0.01).(ABSTRACT TRUNCATED AT 250 WORDS)

The absorption of isophane (NPH) insulin from subcutaneous and intramuscular injection sites was measured in seven healthy volunteers using the euglycaemic clamp technique. Human Insulatard (Nordisk, Gentofte, Denmark) was administered in a dose of 0.25 U kg-body-weight-1 into the anterior compartment of the thigh. In random order injections were given either subcutaneously, via 12 mm needle at 45 degrees to the skin into a skinfold, or intramuscularly by 25 mm needle perpendicularly to the skin. Insulin concentrations rose more rapidly after intramuscular injection than after subcutaneous injection, being significantly higher as early as 60 min after injection (19.7 +/- 1.6 (+/- SE) vs 8.7 +/- 1.4 mU l-1; p less than 0.001). Thereafter insulin concentrations remained significantly higher for the remaining 360 min of study, reflected by a significantly greater area under the insulin concentration curve for the 420 min study (IM 8630 +/- 1256 vs SC 4908 +/- 465 mU l-1 min, p less than 0.05). A significantly greater quantity of infused glucose was required to maintain euglycaemia after intramuscular injection than after subcutaneous injection (923 +/- 256 vs 216 +/- 71 mg kg-1 min, p less than 0.05). These results demonstrate a striking difference in the pharmacokinetics of an isophane (NPH) insulin when injected into subcutaneous fat and muscle.

This outline is based on dietary advice, regular exercise, diabetes education (including glucose monitoring) and, if necessary, an oral hypoglycaemic agent or insulin. Precipitating factors such as dietary indiscretions, infections, drugs, thyrotoxicosis and haemochromatosis should be sought, and associated cardiovascular risk factors such as obesity, hyperlipidaemia, hypertension and a history of smoking should receive attention.

1. The purpose of the present study was to maintain physiological plasma non-esterified fatty acid levels and to (i) examine their effect on skeletal muscle insulin-stimulated glucose uptake and metabolite exchange using the forearm technique, and (ii) evaluate their effect on whole-body glucose uptake and fuel oxidation. 2. Intralipid (10%) and heparin (Lipid) or saline (Control) was administered to eight healthy male subjects on separate occasions for 210 min. Insulin, glucagon and somatostatin were administered from 60 to 210 min in each study and euglycaemia was maintained. 3. Plasma non-esterified fatty acid levels plateaued at 420 +/- 50 mumol/l with the Lipid infusion but were completely suppressed during the Control clamp. Forearm non-esterified fatty acid uptake increased with the Lipid infusion (+50 +/- 10 nmol min-1 100 ml-1 of forearm) and was accompanied by a significant decrease in forearm glucose uptake (+3.23 +/- 0.25 versus +3.65 +/- 0.35 mumol min-1 100 ml-1 of forearm, Lipid and Control, respectively; P less than 0.05) and alanine release (-84 +/- 12 versus -113 +/- 15 nmol min-1 100 ml-1 of forearm, Lipid and Control, respectively; P less than 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)

A number of reports on dialysis and transplantation for diabetic patients in the UK and USA are available. The aim of the present survey was to assess the prevalence, main characteristics and complications of diabetic patients treated by dialysis and transplantation in Italy. On 31 December 1987 in Italy, 1605 diabetic patients were being treated by dialysis or transplantation. The prevalence was 28 per million compared with the UK and the USA where the corresponding figures were 17 and 78 per million respectively. The annual incidence in 1987 was 9 per million (UK: 4 per million; USA: 33 per million). The mean age of the Italian diabetic patients was 59 years whereas that for British diabetic patients similarly evaluated was 48 years. Of the Italian diabetic patients 67% had NIDDM (UK: 22%; USA: 50%). Haemodialysis was used in 81% of the Italian patients, peritoneal dialysis in 14%, and only 5% were transplanted. This is in contrast to the UK where only 18% of the patients were treated by haemodialysis and 39% were transplanted. Amongst Italian patients who started RRT in 1987, 9% died within the year, and of the remainder 38% had severe bilateral visual impairment (UK 35%), 3% had had amputations (UK 6%), 7% had suffered from disabling strokes (UK 6%) and 7% had had a myocardial infarction (UK 17%). Before 31 December 1987 another 2.2% developed severe bilateral visual impairment, 0.6% underwent amputations, 1.0% had a disabling stroke and 0.6% suffered from a myocardial infarction. The proportion of diabetic patients treated by RRT in Italy is twice that of the UK but only half that of the USA.(ABSTRACT TRUNCATED AT 250 WORDS)

The spouses of 65 coronary artery bypass graft surgery (CAGS) patients were assessed to determine levels of psychological symptoms and social impairment both before and 12 months after surgery. There was substantial psychological morbidity in spouses pre-operatively, with from one-third to one-half having clinically significant levels of depression and/or anxiety symptoms. Pre-operatively there was also significant global psychosocial impairment in the spouse. Of the specific domains of psychosocial adjustment, recreational and psychological adjustment was most severely affected, vocational/domestic adjustment and sexual adjustment being less impaired, and extended family relationships showing minimal impairment. There was significant improvement in spouses' psychological and global psychosocial adjustment at 12 months, with recreational adjustment showing the greatest improvement. Significant improvements also occurred in vocational adjustment but not in domestic or sexual adjustment. Neither physical, psychological nor social adjustment variables preoperatively in either the patient or spouse were predictive of psychological morbidity in the spouse (anxiety or depression) at 12 months. Similarly there were no significant patient or spouse preoperative predictors of social adjustment in the spouse at 12 months. However, the patients post-operative psychological morbidity and the spouses social and psychological morbidity were related.

Factors contributing to resistance of maize to infestation by the corn weevilSitophilus zeamais were investigated in four populations of indigenous and improved maize from Belize. Resistance was related to the antifeedant properties of grain as well as sugar content and mechanical hardness. Grain extracts of all populations of maize significantly reduced insect feeding on treated artificial diets when compared to control diets. Consumption of treated diets was negatively correlated with phenolic content of the grain extract. An analysis by GC-MS indicated that ferulic acid andp-coumaric acid were the principal phenolics present in the extracts, and insect feeding was strongly deterred when pure substances were added to insect diets. Fluorescence associated with ferulic acid and related compounds in grain sections was located in the pericarp and aleurone layer and was especially intense in the most resistant grain variety.

Eighty-nine patients were prospectively studied to determine psychological and psychosocial impairment prior to and after coronary artery graft surgery (CAGS). Psychological morbidity prior to surgery was high, with one-third having clinically significant levels of depression and/or anxiety symptoms. Scores on the Psychosocial Adjustment to Illness Scale indicated a generally high level of psychosocial impairment pre-operatively, with vocational and domestic functioning being most severely affected, social and sexual functioning being less impaired, and extended family relationships being largely unaffected. In general, there was a significant reduction in psychological morbidity and an improvement in psychosocial functioning at 6 months, which remained at 12 months. Vocational and domestic functioning showed the greatest improvement. Sexual and social functioning showed modest improvements overall, with significant numbers reporting residual impairment due to their heart disease. These findings add to a growing body of evidence demonstrating generally favourable psychological and social outcome following CAGS.

The relation of the Type A behaviour pattern to coronary atherosclerosis was assessed in a sample of 519 coronary angiography patients. Type A measures were the Structured Interview and the Framingham questionnaire. Angiographic indices included a composite coronary occlusion index and number of coronary vessels significantly diseased. Univariate analysis involving the entire sample showed no significant relation between Type A and severity of coronary vessel disease. Analyses for two subsamples, namely males currently employed in white collar occupations and persons found to have significant disease at angiography, also failed to indicate a relationship between Type A and coronary disease. Multivariate analysis revealed sex, cholesterol and age to be risk factors for atherosclerosis; Type A behaviour was not. The implications of these findings are discussed.