Responsiveness of different dynamic contrast-enhanced magnetic resonance imaging approaches: a post-hoc analysis of a randomized controlled trial of certolizumab pegol in rheumatoid arthritis.

Objective: The aim was to explore dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) as an early marker of therapeutic response in patients with rheumatoid arthritis (RA) starting treatment with certolizumab pegol (CZP).Method: In 40 RA patients initiating CZP (27 patients) or 2 weeks of placebo (PCB) followed by CZP (13 patients), DCE-MRI of the metacarpophalangeal (MCP) and proximal interphalangeal (PIP) joints was performed at weeks 0, 1, 2, 4, 8, and 16. Using semi-automated software, three methods for drawing volume regions of interest (ROIs) in MCP2-5 and PIP2-5 were applied: 'Standard' (slices: all; joints: MCP2-5 together and PIP2-5 together), 'Detailed' (slices: slices with high-quality visualization; joints: as Standard), and 'Single-joint' (slices: as Detailed; joints: each joint separately). The number of enhancing voxels (Nvoxel), initial rate of enhancement (IRE), and maximum enhancement (ME) were extracted and analysed for each method.Results: Nvoxel in MCP2-5, and IRE and ME in PIP2-5 decreased statistically significantly (Wilcoxon rank-sum test, p < 0.02-0.03) after 16 weeks of treatment for the Standard method. Nvoxel and ME decreased significantly more in the CZP group than in the PCB group after 1 week of treatment, but not at later time-points. There were no significant changes for DCE-MRI parameters for the Detailed and Single-joint methods.Conclusions: Certain DCE-MRI parameters detected decreased inflammation during CZP treatment in RA patients. Using specific criteria for ROIs, as in the Detailed and Single-joint methods, decreased the statistical power and could not show any changes over time.

Monitoring total-body inflammation and damage in joints and entheses: the first follow-up study of whole-body magnetic resonance imaging in rheumatoid arthritis.

OBJECTIVE: To investigate changes in whole-body magnetic resonance imaging (WBMRI) inflammatory and structural lesions in most joints and entheses in patients with rheumatoid arthritis (RA) treated with adalimumab. METHODS: WBMRI was obtained at weeks 0, 6, 16, and 52 in a 52 week follow-up study of 37 RA patients starting treatment with adalimumab. Readability and reliability of WBMRI were investigated for 76 peripheral joints, 23 discovertebral units, the sacroiliac joints, and 33 entheses. Changes in WBMRI joint and entheses counts were investigated. RESULTS: The readability of peripheral and axial joints was 82-100%, being less for elbows and small joints of the feet. For entheses, 72-100% were readable, except for entheses at the anterior chest wall, elbow, knee, and plantar fascia. The intrareader agreement was high for bone marrow oedema (BMO), bone erosion (80-100%), and enthesitis (77-100%), and slightly lower for synovitis and soft tissue inflammation (50-100%). All synovitis, BMO, and soft tissue inflammation counts decreased numerically during treatment. The 26-joint synovitis WBMRI count decreased significantly during the first 16 weeks for patients with a good European League Against Rheumatism (EULAR) response (from median 6 to 4, p < 0.05), but not for patients with a moderate or no EULAR response. There were no overall changes in structural lesions. CONCLUSIONS: WBMRI allows simultaneous monitoring of most axial and peripheral joints and entheses in RA patients and can visualize a decrease in inflammatory counts during treatment. This first WBMRI follow-up study of patients with RA encourages further investigation of the usefulness of WBMRI in RA.

Differentiation between early rheumatoid arthritis patients and healthy persons by conventional and dynamic contrast-enhanced magnetic resonance imaging.

OBJECTIVES: To identify the magnetic resonance imaging (MRI) parameter that best differentiates healthy persons and patients with early rheumatoid arthritis (RA), and to investigated responsiveness to treatment of various MRI parameters. METHOD: Conventional MRI and dynamic contrast-enhanced (DCE)-MRI of the hand were performed once for 26 healthy persons, and before and after 6 and 12 months of disease-modifying anti-rheumatic drug (DMARD) treatment for 14 early RA patients, using a 1.0-T MRI unit. One-slice DCE-MRI was analysed using Dynamika version 4.2. The number of enhancing voxels (Nvoxel), the initial rate of enhancement (IRE), the maximum enhancement (ME), ME×Nvoxel, and IRE×Nvoxel were calculated for wrist and 2nd-5th metacarpophalangeal (MCP) joints. Conventional MR images were evaluated using the RA MRI scoring system (RAMRIS) synovitis score. RESULTS: Using DCE-MRI, enhancement was demonstrated in 61.5% of healthy persons and in 91.7% of RA patients at baseline, with a median Nvoxel of 3 and 362, respectively. At baseline, all parameters were higher for patients than for healthy persons (all p ≤ 0.003). Only one patient had a baseline RAMRIS synovitis score below the 95th percentile of the healthy persons. The corresponding number of patients was 3 for Nvoxel, ME×Nvoxel and IRE×Nvoxel, and 10 for IRE and ME. The RAMRIS synovitis score and IRE showed the highest responsiveness, with a standardized response mean (SRM) of -1.00 and -0.88, respectively. CONCLUSIONS: The RAMRIS synovitis scoring of conventional MRI, and to a lesser extent the one-slice DCE-MRI parameters of synovial volume, differentiated early RA patients and healthy persons. The decrease in RAMRIS synovitis score, Nvoxel, and IRE showed sensitivity to change during treatment.

Children under the age of seven with diabetes are increasing their cardiovascular risk by their food choices.

AIM: Early-onset diabetes increases the risk of cardiovascular disease. This study examined the eating habits of children under 7 years of age with diabetes to see whether their diet increased that risk even further. METHODS: A total of 24 children with type 1 diabetes (mean age 4.5 years) and 27 healthy controls (mean age 4.6 years) participated in this cross-sectional study. Food intake was assessed by two 4-day food records. RESULTS: Children with type 1 diabetes had a higher energy intake from protein (18 vs 15%, p < 0.05) and fat (35 vs 31%, p < 0.05) but lower intake from carbohydrates (47 vs 54%, p < 0.05), than the healthy control group. Intake of saturated fat was higher than recommended in both groups, and consumption of fruit and vegetables was lower than recommended, but similar, in both the diabetes and control groups (191 vs 207 g per day). Total intake of fat was negatively correlated with intake of fruit and vegetables (r = -0.74 p < 0.05) in children with type 1 diabetes. CONCLUSION: Children under 7 years of age with type 1 diabetes eat too much saturated fat and not enough fruit and vegetables. Their diet should be improved to reduce their cardiovascular risk.

Reliability and responsiveness of dynamic contrast-enhanced magnetic resonance imaging in rheumatoid arthritis.

OBJECTIVES: To investigate the responsiveness to treatment and the reliability of dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) in rheumatoid arthritis (RA) knee joints. METHODS: DCE-MRI was performed in 12 clinically active RA knee joints before and 1, 7, 30, and 180 days after intra-articular injection with 80 mg methylprednisolone. Using semi-automated image processing software, DCE-MRI parameters, including the initial rate of enhancement (IRE) and maximal enhancement (ME), were generated for three regions of interest (ROIs): 'Whole slice', 'Quick ROI', and 'Precise ROI'. The smallest detectable difference (SDD), the smallest detectable change (SDC), and intra- and inter-reader intraclass correlation coefficients (ICCs) were used to assess the reliability of DCE-MRI. Responsiveness to treatment was assessed by the standardized response mean (SRM). RESULTS: In all patients clinical remission of the knee was achieved at day 7. All DCE-MRI parameters decreased from day 0 to day 7. Using the Quick and Precise ROI methods, respectively, IRE decreased by 63% and 69%, ME decreased by 11% and 11%, N decreased by 55% and 57%, and IRE × N decreased by 84% and 85%. The intra- and inter-reader ICCs were very high (0.96-1.00). The decrease in DCE-MRI parameters was larger than the SDC for all patients. SRM was large for all parameters, ranging from -1.04 to -2.40. When the Whole slice ROI method was used, no parameters were responsive to treatment. CONCLUSIONS: DCE-MRI analysed using semi-automatic software is a reliable and responsive tool for assessing treatment in RA knees joints. Rough manual delineation of the joint to omit enhancement artefacts is necessary.

Dynamic gadolinium-enhanced magnetic resonance imaging allows accurate assessment of the synovial inflammatory activity in rheumatoid arthritis knee joints: a comparison with synovial histology.

OBJECTIVE: To determine whether dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) evaluated using semi-automatic image processing software can accurately assess synovial inflammation in rheumatoid arthritis (RA) knee joints. METHODS: In 17 RA patients undergoing knee surgery, the average grade of histological synovial inflammation was determined from four biopsies obtained during surgery. A preoperative series of T(1)-weighted dynamic fast low-angle shot (FLASH) MR images was obtained. Parameters characterizing contrast uptake dynamics, including the initial rate of enhancement (IRE), were generated by the software in three different areas: (I) the entire slice (Whole slice); (II) a manually outlined region of interest (ROI) drawn quickly around the joint, omitting large artefacts such as blood vessels (Quick ROI); and (III) a manually outlined ROI following the synovial capsule of the knee joint (Precise ROI). Intra- and inter-reader agreement was assessed using the intra-class correlation coefficient (ICC). RESULTS: The IRE from the Quick ROI and the Precise ROI revealed high correlations to the grade of histological inflammation (Spearman's correlation coefficient (rho) = 0.70, p = 0.001 and rho = 0.74, p = 0.001, respectively). Intra- and inter-reader ICCs were very high (0.93-1.00). No Whole slice parameters were correlated to histology. CONCLUSION: DCE-MRI provides fast and accurate assessment of synovial inflammation in RA patients. Manual outlining of the joint to omit large artefacts is necessary.

Low mannose-binding lectin concentration is associated with severe infection in patients with hematological cancer who are undergoing chemotherapy.

BACKGROUND: Mannose-binding lectin (MBL) is a serum lectin involved in innate immune response. Low serum MBL concentration may constitute a risk factor for infection in patients receiving myelosuppressive chemotherapy. METHODS: We conducted a prospective, observational study that assessed MBL concentration as a risk factor for infection in patients with hematological malignancy who were hospitalized to undergo at least 1 chemotherapy cycle. MBL deficiency was defined using an algorithm that considered the serum MBL concentration and the MBL genotype. The primary end point was the ratio of duration of febrile neutropenia to the duration of neutropenia. Secondary end points included the incidence of severe infection (e.g., sepsis, pneumonia, bacteremia, and invasive fungal infection). Logistic regression analysis was conducted, and Fisher's exact test was used to analyze binary outcomes, and Kaplan-Meier estimates and log rank tests were used for time-to-event variables. RESULTS: We analyzed 255 patients who received 569 cycles of chemotherapy. The median duration of neutropenia per cycle was 7 days (interquartile range, 0-13 days). Sixty-two patients (24%) were found to have MBL deficiency. Febrile neutropenia occurred at least once in 200 patients. No difference in the primary outcome was seen. The incidence of severe infection was higher among MBL-deficient patients than among non-MBL-deficient patients (1.96 vs. 1.34 cases per 100 days for analysis of all patients [P=.008] and 1.85 vs. 0.94 cases per 100 days excluding patients with acute leukemia [P<.001]). CONCLUSIONS: MBL deficiency does not predispose adults with hematological cancer to more-frequent or more-prolonged febrile episodes during myelosuppressive chemotherapy, but MBL-deficient patients have a greater number of severe infections and experience their first severe infection earlier, compared with nondeficient patients.

Postprandial interstitial insulin concentrations in type 2 diabetes relatives.

BACKGROUND: An endothelial barrier for the insulin transport from the circulation to the target tissues of insulin has previously been suggested to contribute to insulin resistance. The interstitial insulin concentration (I-insulin) and insulin kinetics following a mixed meal have, however, previously not been characterized in human adipose tissue. SUBJECTS AND METHODS: Eight nondiabetic first-degree relatives (FDR) of type 2 diabetes patients were recruited. Their I-insulin was measured by microdialysis after a test meal with or without oral administration of the insulin secretagogue nateglinide (120 mg). In parallel, adipose tissue blood flow and lipolysis were measured by xenon-clearance and microdialysis, respectively. RESULTS: The I-insulin increased after the test meal, and this response was more prominent on the day the subjects received the nateglinide tablet when compared with the day the subjects received the placebo tablet [I-insulin incremental area under the curve (IAUC) nateglinide 7612 +/- 3032 vs. Plac 4682 +/- 2613 pmol L(-1) min; P < 0.05, mean +/- SE]. However, the postprandial I-insulin(max)/P-insulin(max) ratio was similar on the two test days (nateglinide: 213 +/- 62 vs. 501 +/- 92 pmol L(-1), I/P-ratio: 0.38 +/- 0.06 and placebo: 159 +/- 39 vs. 410 +/- 74 pmol L(-1), I/P-ratio: 0.36 +/- 0.05). There was no difference in time of onset of insulin action in situ, or responsiveness, when comparing placebo and nateglinide. CONCLUSIONS: Microdialysis can now be used to measure the I-insulin in human adipose tissue following a mixed meal. The data also showed that the transendothelial delivery of insulin occurs rapidly, supporting the concept that transcapillary insulin transfer is a nonsaturable process in nondiabetic first-degree relatives of type 2 diabetes patients.

No acute effect of nateglinide on postprandial lipid and lipoprotein responses in subjects at risk for type 2 diabetes.

BACKGROUND: To study the acute effect of nateglinide, an insulinotropic agent, on the postprandial triglyceride and lipoprotein responses in subjects at risk for type 2 diabetes. METHODS: Six women and 10 men, with at least one first-degree relative with type 2 diabetes were included (Age: 48 +/- 7 years, BMI: 27.5 +/- 2.8 kg m(-2), P-triglycerides: 1.3 +/- 0.4 mmol L(-1), P-cholesterol: 5.4 +/- 0.6 mmol L(-1), B-glucose: 4.6 +/- 0.3 mmol L(-1)). They each had two 8-h meal tolerance tests with either nateglinide or placebo given 10 min prior to the meals in randomized order. Lipoprotein fractions were separated by density gradient ultracentrifugation. First-phase insulin secretion was assessed by an intravenous glucose tolerance test (300 mg kg(-1) body weight) and insulin sensitivity by a hyperinsulinaemic euglycaemic clamp (40 mU m(-2) min(-1)). RESULTS: The 1-h insulin levels during the meal tolerance test were significantly higher with nateglinide (577 +/- 81 vs 376 +/- 58 pmol L(-1), p < 0.001), as well as the response during the first two hours (IAUC: 41 243 +/- 5844 vs 29 956 +/- 4662 pmol L(-1) min, p < 0.01). Accordingly, nateglinide lowered the 8-h postprandial glucose response by around 60% compared to placebo (p < 0.001). In contrast, no significant lowering was seen in the excursion of postprandial triglycerides in total plasma or lipoprotein fractions. Consistently, the concentration of exogenous (apoB-48) and endogenous (apoB-100) lipoproteins was not reduced by nateglinide. CONCLUSIONS: Acute administration of nateglinide reduces, as expected, the postprandial glucose concentration, but no reduction in triglyceride or lipoprotein responses are seen in subjects at risk for type 2 diabetes.

Attitudes and barriers to dietary advice aimed at reducing risk of type 2 diabetes in first-degree relatives of patients with type 2 diabetes.

OBJECTIVE: To evaluate the attitudes to and adoption of dietary advice in nondiabetic first-degree relatives of patients with type 2 diabetes and to examine barriers to adherence. DESIGN: One-year controlled intervention study, where treatment group (n=73) received lifestyle education. Attitudes towards dietary advice, change in dietary habits and importance of potential barriers to adherence were evaluated by questionnaires. Nondiabetic relatives (25-55 years; males and females) of individuals with type 2 diabetes were recruited. Education was based on current nutrition recommendations and aimed at improving dietary fat quality, increasing intake of fruit and vegetables, with additional advice to reduce dietary glycaemic index (GI). MAIN OUTCOME MEASURES: Attitudes and importance of barriers were classified by the intervened subjects into four categories ranging from 'No problem' to 'Yes, definitely a problem'. Dietary adherence was monitored by food frequency questionnaire at baseline and after 1 year. RESULTS: Participants were generally in favour of advice aimed at improving dietary fat quality. Attitudes towards advice to reduce GI varied widely. Food selection changed in accordance with predefined dietary goals. 'Forgetfulness', 'low availability in lunch restaurant' and 'lack of ideas for cooking' were barriers to adherence. CONCLUSIONS: Dietary advice aimed at reducing risk of type 2 diabetes was generally positively received and adopted in subjects with heredity for the disease. The most prevalent barriers reported are potentially modifiable.

Early alterations in the postprandial VLDL1 apoB-100 and apoB-48 metabolism in men with strong heredity for type 2 diabetes.

OBJECTIVES: To study the postprandial triglyceride-rich lipoprotein (TRL) metabolism, specifically the concentrations of very low-density lipoproteins (VLDL); from intestine (apoB-48) and liver (apoB-100), in men with normal fasting triglycerides but at increased risk of developing type 2 diabetes. DESIGN: Cross-sectional study. SUBJECTS AND SETTINGS: Sixteen healthy men with at least two first-degree relatives with type 2 diabetes were individually matched with 16 control subjects without known diabetes heredity for: age, body mass index, and fasting triglyceride level. They underwent an 8-h meal tolerance test (919 kcal, 51 g fat) during which lipoproteins were separated by density gradient ultracentrifugation. They were characterized by euglycaemic hyperinsulinaemic clamp, peak VO2, 7-day diet registration and computed tomography. RESULTS: The relatives were, as expected, more insulin resistant than the controls and had increased concentration of postprandial VLDL1 particles (49% higher for VLDL1 apoB-48, P = 0.04 and 21% higher for VLDL1 apoB-100, P = 0.048). The elevation was related to insulin sensitivity, but not to lifestyle and body composition. Moreover, the concentration of postprandial triglycerides in VLDL1 fraction was inversely related to low-density lipoprotein (LDL) size in both relatives (rs = -0.60, P = 0.03) and controls (rs = -0.72, P = 0.004). There were no differences in the concentration of triglycerides or apoB-48 and apoB-100 particles in the other fractions (plasma, chylomicron or VLDL2). CONCLUSION: Increased postprandial concentration of TRLs in the VLDL1 fraction seems to be present at an early stage in the development of diabetes and probably contributes to the excess risk of future coronary events in insulin-resistant men.

Comparison of the soluble basal insulin analog insulin detemir with NPH insulin: a randomized open crossover trial in type 1 diabetic subjects on basal-bolus therapy.

OBJECTIVE: Insulin detemir (NN304) is a soluble basal insulin analog developed to cover basal insulin requirements. This trial aimed to compare the blood glucose-lowering effect of insulin detemir with that of NPH insulin (NPH) and to evaluate the two treatments with regard to intrasubject variation of fasting blood glucose, incidence of hypoglycemia, dose requirements, and safety. RESEARCH DESIGN AND METHODS: This multicenter open randomized crossover trial in 59 type 1 diabetic subjects comprised a 2-week run-in period on a basal-bolus regimen with NPH insulin once daily, followed by two 6-week periods of optimized basal-bolus therapy with either once-daily insulin detemir or NPH insulin. RESULTS: The area under the curve, in the time interval 23:00-8:00, derived from 24-h serum glucose profiles, was not statistically significantly different for the two treatment periods (insulin detemir:NPH ratio 89.2:83.5, P = 0.59). The intrasubject variation in fasting blood glucose during the last 4 days of treatment was lower for insulin detemir compared with NPH (P < 0.001). Mean dose requirements of insulin detemir were 2.35 times higher (95% CI 2.22-2.48) compared with NPH. During the last week of treatment, fewer subjects experienced hypoglycemic episodes on insulin detemir (60%) compared with NPH treatment (77%) (P = 0.049). CONCLUSIONS: Insulin detemir was as effective as NPH in maintaining glycemic control when administered at a higher molar dose. The results indicate that insulin detemir may provide more predictable fasting blood glucose with lower intrasubject variation and reduced risk of hypoglycemia compared with NPH.

Dietary fibre, lente carbohydrates and the insulin-resistant diseases.

Several epidemiological studies link consumption of fibre-rich foods to a reduced risk of type 2 diabetes and CHD. The 'fibre hypothesis' suggested that this was a direct effect of fibre. However, fibre-rich foods contain different types of fibre as well as other potentially beneficial compounds, and many foods naturally high in fibre have low glycaemic and insulinaemic indices, possibly due to food form. The question therefore emerges as to the effect of isolated fibre per se on insulin sensitivity, lipids and other risk factors associated with the metabolic syndrome. Many beneficial effects are seen with pharmacological doses of isolated viscous soluble fibre, including improved insulin sensitivity, decreased LDL-cholesterol levels and decreased clotting factors. Similar effects are seen with low glycaemic-index foods. In contrast, insoluble non-viscous cereal fibre is not seen to act directly on risk factors when taken in refined foods such as in milled flour. Since cereal fibre, the major type of fibre in western diets, does not directly act on the risk factors for the metabolic syndrome, the question remains as to possible mechanisms. Until now, fibre and the nature and processing of the starch and particle size have been seen as the main determinants of the metabolic response to starchy foods. However, fibre-rich foods also have an increased protein-to-carbohydrate ratio. Hence we suggest that the protective effect of fibre may also be due to increased vegetable protein content, which may act directly to reduce clotting factors and oxidized LDL-cholesterol levels.

Suppression of nocturnal fatty acid concentrations by bedtime carbohydrate supplement in type 2 diabetes: effects on insulin sensitivity, lipids, and glycemic control.

BACKGROUND: Bedtime ingestion of slow-release carbohydrates leads to sustained nocturnal fatty acid suppression and improved glucose tolerance in type 2 diabetic patients. OBJECTIVE: This study assessed the effects of 2 different doses of bedtime carbohydrate supplement (BCS) on morning glycemic control and glycated hemoglobin (Hb A(1c)) in type 2 diabetic patients. In addition, the effects of the high-dose BCS on insulin sensitivity and postprandial glucose and triacylglycerol concentrations were assessed. DESIGN: Two BCS doses were studied separately in 7-wk randomized, placebo-controlled, double-blind studies with either a parallel (low-dose BCS; n = 24 patients) or crossover (high-dose BCS; n = 14 patients) design. The effects of the low and high doses (0.30 and 0.55 g uncooked cornstarch/kg body wt, respectively) were compared with those of a starch-free placebo. RESULTS: Compared with the starch-free placebo, the high-dose BCS ( approximately 45 g) produced enhanced nocturnal glucose (P < 0.01) and insulin (P < 0.01) concentrations as well as a 32% suppression of fatty acid concentrations (P < 0.01). Moreover, glucose tolerance (P < 0.05) and C-peptide response (P < 0.05) improved after breakfast the next morning. The low-dose BCS ( approximately 25 g) improved fasting blood glucose concentrations (P < 0.05). However, there were no improvements in insulin sensitivity, postprandial triacylglycerol concentrations, or Hb A(1c) after 7 wk. CONCLUSION: Nocturnal fatty acid suppression by BCS improved fasting and postprandial blood glucose concentrations in type 2 diabetic patients the next morning. In contrast, no improvements in insulin sensitivity, postprandial triacylglycerol concentrations, or long-term glycemic control assessed by Hb A(1c) were seen after BCS supplementation.

Viscous and nonviscous fibres, nonabsorbable and low glycaemic index carbohydrates, blood lipids and coronary heart disease.

Viscous fibres such as guar, glucomannans, pectins, oat betaglucan and psyllium continue to be seen as hypocholesterolaemic. Nevertheless, in large cohort studies, ironically it is the insoluble cereal fibre that has been demonstrated to relate negatively to cardiovascular disease and diabetes, despite an absence of effect on fasting lipids or postprandial glycaemia. In general, resistant or nonabsorbable starch is lipid neutral, whereas some nonabsorbable sugars or oligosaccharides may raise serum cholesterol, possibly through providing more acetate after colonic fermentation by colonic microflora. On the other hand, fructo-oligosaccharides appear to reduce serum triglycerides for reasons that are not entirely clear. Of possibly greater recent interest have been the carbohydrates that are not so much resistant to absorption, but rather are slowly absorbed. They possess some of the features of dietary fibre in providing a substrate for colonic bacterial fermentation. In the small intestine, however, they form lente or sustained release carbohydrate. In the form of low glycaemic index foods, lente carbohydrate consumption has been shown to relate to improved blood lipid profiles in hyperlipidaemic individuals and improved glycaemic control in diabetes. In larger cohort studies, low glycaemic index foods or low glycaemic load diets have been associated with higher HDL-cholesterol levels and reduced incidence of diabetes and cardiovascular disease.

Low cellular IRS 1 gene and protein expression predict insulin resistance and NIDDM.

We examined the gene and protein expression of IRS 1 (insulin receptor substrate 1) in adipocytes from two groups of healthy individuals with an increased propensity for non-insulin-dependent diabetes mellitus (NIDDM): those with two first-degree relatives with diabetes and another group with massive obesity. A low expression of IRS 1 (

Breakfast glycaemic response in patients with type 2 diabetes: effects of bedtime dietary carbohydrates.

OBJECTIVES: Bedtime carbohydrate (CHO) intake in patients with type-2 diabetes may improve glucose tolerance at breakfast the next morning. We examined the 'overnight second-meal effect' of bedtime supplements containing 'rapid' or 'slow' CHOs. DESIGN: Randomized cross-over study with three test-periods, each consisting of two days on a standardized diet, followed by a breakfast tolerance test on the third morning. SETTING: The Lundberg Laboratory for Diabetes Research, Sahlgrenska University Hospital, Göteborg, Sweden. SUBJECTS: Sixteen patients with type 2 diabetes on oral agents and/or diet. INTERVENTIONS: Two different bedtime (22.00 h) CHO supplements (0.46 g available CHO/kg body weight) were compared to a starch-free placebo ('normal' food regimen). The CHOs were provided as uncooked cornstarch (slow-release CHOs) or white bread (rapid CHOs). RESULTS: On the mornings after different bedtime meals we found similar fasting glucose, insulin, free fatty acid and lactate levels. However, the glycaemic response after breakfast was 21% less after uncooked cornstarch compared to placebo ingestion at bedtime (406 +/- 46 vs 511 +/- 61 mmol min l(-1), P < 0.01). In contrast, it did not differ when the evening meal consisted of white bread (451 +/- 57 mmol min l(-1)) compared to placebo. According to an in vitro analysis, uncooked cornstarch contained approximately 4 times more slowly digestible starch as compared to white bread. CONCLUSIONS: A bedtime meal providing uncooked cornstarch improved breakfast tolerance the next morning while, in contrast, this was not found following a bedtime meal of white bread. The results are consistent, therefore, with the concept that an increased intake of slowly digestible carbohydrates exert an overnight second-meal effect in patients with type 2 diabetes.

Postprandial hypertriglyceridemia and insulin resistance in normoglycemic first-degree relatives of patients with type 2 diabetes.

BACKGROUND: Impaired ability to eliminate lipids in the postprandial state is an atherogenic trait associated with insulin resistance. OBJECTIVE: To assess insulin sensitivity and postprandial triglyceride metabolism in prediabetic persons. DESIGN: Cross-sectional study. SETTING: Sahlgrenska University Hospital, Göteborg, Sweden. PARTICIPANTS: 13 healthy, normotriglyceridemic men with two first-degree relatives with type 2 diabetes and 13 carefully matched controls without known diabetes heredity. MEASUREMENTS: Oral glucose tolerance test, insulin sensitivity (euglycemic clamp technique), and fasting and postprandial triglyceride levels after a mixed meal. RESULTS: Relatives of persons with type 2 diabetes were insulin resistant but had normal glucose tolerance. They exhibited postprandial hypertriglyceridemia; the 6-hour triglyceride incremental area under the curve was 50% higher than that of the control group (P = 0.037). CONCLUSIONS: These healthy male first-degree relatives of patients with type 2 diabetes are insulin resistant and exhibit postprandial lipid intolerance despite having normal fasting triglyceride levels. These characteristics, which occur in the absence of glucose intolerance, are associated with an increased risk for macroangiopathy.

Bedtime uncooked cornstarch supplement prevents nocturnal hypoglycaemia in intensively treated type 1 diabetes subjects.

OBJECTIVES: The present study tests two interrelated hypotheses: (1) that bedtime ingestion of uncooked cornstarch exerts a lower and delayed nocturnal blood glucose peak compared with a conventional snack; (2) that bedtime carbohydrate supplement, administered as uncooked cornstarch, prevents nocturnal hypoglycaemia without altering metabolic control in intensively treated type 1 diabetes (IDDM) patients. DESIGN AND SUBJECTS: The above hypotheses were tested separately (1) by pooling and analysing data from two overnight studies of comparable groups of patients with non-insulin dependent diabetes mellitus (NIDDM) (14 and 10 patients, respectively), and (2) by a double-blind, randomized 4-week cross-over study in 12 intensively treated IDDM patients. SETTING: Sahlgrenska University Hospital, Göteborg. Sweden. INTERVENTIONS: (1) Ingestion of uncooked cornstarch and wholemeal bread (0.6 g of carbohydrates kg-1 body weight) and carbohydrate-free placebo at 22.00 h. (2) Intake of uncooked cornstarch (0.3 g kg-1 body weight) and carbohydrate-free placebo at 23.00 h. MAIN OUTCOME MEASURES: (1) Nocturnal glucose and insulin levels; (2) frequency of self-estimated hypoglycaemia (blood glucose [BG] levels < 3.0 mmol L-1) at 03.00 h, HbA1c and fasting lipids. RESULTS: Bedtime uncooked cornstarch ingestion led to a lower (2.9 +/- 0.5 vs. 5.2 +/- 0.6 mM, P = 0.01) and delayed (4.3 +/- 0.6 vs. 2.0 +/- 0.0 h, P < 0.01) BG peak, compared with a conventional snack, in NIDDM patients. Four weeks of bedtime uncooked cornstarch supplement, as compared with placebo, led to a 70% reduction in the frequency of self-estimated hypoglycaemia at 03.00 h (P < 0.05), without affecting HbA1c or fasting lipids in IDDM patients. CONCLUSIONS: Uncooked cornstarch, ingested at bedtime, mimicked the nocturnal glucose utilization profile following insulin replacement, with a peak in blood glucose after 4 h. In IDDM patients, bedtime uncooked cornstarch supplement diminished the number of self-estimated hypoglycaemic episodes, without adversely affecting HbA1c and lipid levels. Hence, bedtime uncooked cornstarch ingestion may be feasible to prevent a mid-nocturnal glycaemic decline following insulin replacement in IDDM and, based on the nocturnal blood glucose profile, may also be preferable compared with conventional snacks.

Insulin signaling and action in fat cells: associations with insulin resistance and type 2 diabetes.

Adipose tissue only accounts for a relatively small proportion (< 10%) of the peripheral glucose utilization in response to insulin. However, the fat cells may still play an important role in insulin resistance and Syndrome X through, for instance, its endocrine functions (production of leptin, TNF alpha, PAI-1, etc.) and involvement in lipid metabolism (FFA release and hydrolysis of triglycerides). The fat cells are also highly sensitive to insulin and may thus be used to elucidate molecular mechanisms for insulin resistance in man. Examinations of the intracellular signaling mechanisms for insulin in fat cells from individuals with Type 2 diabetes revealed markedly lower insulin-stimulated PI3-kinase activity. This was due to a pronounced reduction in the cellular expression of the docking protein, IRS 1, whereas expression of IRS 2 was normal. However, IRS 2-associated PI3-kinase activity was only approximately one-third of that found to be associated with IRS 1 in normal cells. Downstream activation and serine phosphorylation of PKB/Akt by insulin were also markedly reduced in Type 2 diabetes. Furthermore, the dose-response curve for this effect of insulin was similar to that for glucose transport in both normal and Type 2 diabetic cells. Thus, these data show that both PI3-kinase and PKB activation by insulin are markedly reduced in Type 2 diabetes. We also examined whether an attenuated activation of PI3-kinase by insulin can be seen in non-diabetic insulin-resistant states. Approximately 30% of healthy subjects with at least two first-degree relatives with Type 2 diabetes exhibited perturbations in IRS-1 expression and signaling. These individuals were characterized by insulin resistance as well as other markers of Syndrome X. Thus, impaired IRS-1 expression and downstream signaling events in fat cells in response to insulin are associated with insulin resistance and Syndrome X.