Skin autofluorescence and peripheral neuropathy four years later in type 1 diabetes.

OBJECTIVE: Advanced glycation end products (AGEs) are involved in diabetes complications. We aimed to investigate whether the accumulation of AGEs measured by skin autofluorescence (sAF) was associated with signs of diabetic peripheral neuropathy and to sensitivity, pain, motor and autonomic function 4 years later in patients with type 1 diabetes. METHODS: At baseline, 188 patients (age 51 years, diabetes duration 22 years) underwent skin autofluorescence measurement using the AGE Reader. Four years later, signs of diabetic peripheral neuropathy were defined as the presence of neuropathic pain and/or feet sensory loss or foot ulceration. Neurological tests were systematically performed: vibration perception threshold by neuroesthesiometry, neuropathic pain by the Douleur Neuropathique en 4 Questions score, muscle strength by dynamometry and electrochemical skin conductance. Multivariate analyses were adjusted by age, sex, height, body mass index, tobacco, HbA1c , diabetes duration, estimated glomerular filtration rate and albumin excretion rate. RESULTS: At the 4-year follow-up, 13.8% of patients had signs of diabetic peripheral neuropathy. The baseline sAF was higher in those with signs of diabetic peripheral neuropathy (2.5 ± 0.7 vs 2.1 ± 0.5 arbitrary units (AU), p < 0.0005). In the multivariate analysis, a 1 SD higher skin autofluorescence at baseline was associated with an increased risk of signs of neuropathy (OR = 2.68, p = 0.01). All of the neurological tests were significantly altered in the highest quartile of the baseline sAF (>2.4 AU) compared with the lowest quartiles after multivariate adjustment. CONCLUSION: This non-invasive measurement of skin autofluorescence may have a value for diabetic peripheral neuropathy in type 1 diabetes and a potential clinical utility for detection of diabetic peripheral neuropathy. Copyright © 2016 John Wiley & Sons, Ltd.

Treatment by a moisturizer of xerosis and cracks of the feet in men and women with diabetes: a randomized, double-blind, placebo-controlled study.

AIM: To evaluate a moisturizer containing urea, glycerine and petrolatum for healing deep open fissures on the feet of people with diabetes. If left untreated, open fissures, an entry point for bacteria, can lead to infection, ulceration and further complications. METHODS: This randomized, double-blind, multicentre study at 19 hospitals, general practices and diabetologists in France and Belgium included participants with diabetes and a deep open target fissure on their heel. Participants were randomized to test cream or placebo (1 : 1) for 4 weeks. Complete target fissure healing after 4 weeks (primary criterion) and 2 weeks, target fissure closure, overall fissure healing and xerosis were assessed. RESULTS: Some 167 participants were randomized (80 to test cream; 87 to placebo); all were included in the efficacy analyses. The percentage of participants with complete target fissure healing after 4 weeks was higher with test cream than placebo (46.3% vs. 33.3%): the difference did not reach statistical significance (P = 0.088). Fewer participants still had a deep open target fissure with test cream than placebo, the difference was statistically significant and clinically relevant after 2 (24.7% vs. 42.7%, P = 0.027) and 4 weeks (6.4% vs. 24.1%, P = 0.002). The difference in overall fissure healing between test cream and placebo was significant (P < 0.001) and test cream resulted in greater xerosis improvement (P < 0.001 and P = 0.002 at 2 and 4 weeks, respectively). CONCLUSION: The activity of the test cream for treating feet fissures of people with diabetes was confirmed by an improvement in open fissure healing and xerosis. The cream was well tolerated.

Is skin autofluorescence a marker of metabolic memory in pregnant women with diabetes?

AIM: To determine whether skin autofluorescence can help to detect those who have previously had abnormal glucose levels among women referred for diabetes during pregnancy. METHODS: Using an advanced glycation end product reader (AGE Reader(tm) (;) DiagnOptics BV, Groningen, the Netherlands), we measured forearm skin autofluorescence at 24-30 weeks of gestation in all women who were referred to our Nutrition Diabetology unit for diabetes during pregnancy. RESULTS: The study included 230 women (200 with gestational diabetes and 30 with pre-gestational diabetes, of whom 21 had Type 1 and nine had Type 2 diabetes) and a reference group of 22 normoglycaemic non-pregnant women. Skin autofluorescence was significantly higher in women with pre-gestational diabetes (1.97 ± 0.44 arbitary units) compared with gestational diabetes (1.77 ± 0.32 arbitary units; P = 0.003) and lower in the reference group (1.60 ± 0.32 arbitary units; P = 0.009 vs all pregnant women). Among women with gestational diabetes, 71 had a history of hyperglycaemia (i.e. gestational diabetes or macrosomia in a previous pregnancy or discovery of diabetes before 24th gestational week in the present pregnancy). These women had higher levels of skin autofluorescence (1.83 ± 0.35 arbitary units) than women with gestational diabetes without previous history of hyperglycaemia (1.73 ± 0.30 arbitary units; P = 0.04, non-significant, adjusted for age). Skin autofluorescence increased with the number of criteria present for previous hyperglycaemia (P for trend = 0.008) and was significantly associated with having two or three criteria for hyperglycaemia after adjusting for age (P = 0.02). CONCLUSIONS: Skin autofluorescence could reflect previous long-term hyperglycaemia in pregnant women, and could therefore be a marker of metabolic memory.

Insulin glargine and risk of cancer: a cohort study in the French National Healthcare Insurance Database.

AIMS/HYPOTHESIS: Using the Echantillon Généraliste de Bénéficiaires: random 1/97 permanent sample of the French national healthcare insurance system database (EGB), we investigated whether, as previously suspected, the risk of cancer in insulin glargine (A21Gly,B31Arg,B32Arg human insulin) users is higher than in human insulin users. The investigation period was from 1 January 2003 to 30 June 2010. METHODS: We used Cox proportional hazards time-dependent models that were stratified on propensity score quartiles for use of insulin glargine vs human insulin, and adjusted for insulin, biguanide and sulfonylurea possession rates to assess the risk of cancer or death in all or incident exclusive or predominant (≥ 80% use time) users of insulin glargine compared with equivalent human insulin users. RESULTS: Only type 2 diabetic patients were studied. Exposure rates varied from 2,273 and 614 patient-years for incident exclusive users of insulin glargine or human insulin, respectively, to 3125 and 2341 patient-years for all patients predominantly using insulin glargine or human insulin, respectively. All-type cancer HRs with insulin glargine vs human insulin ranged from 0.59 (95% CI 0.28, 1.25) in incident exclusive users to 0.58 (95% CI 0.34, 1.01) in all predominant users. Cancer risk increased with exposure to insulin or sulfonylureas in these patients. Adjusted HRs for death or cancer associated with insulin glargine compared with human insulin ranged from 0.58 (95% CI 0.32, 1.06) to 0.56 (95% CI 0.36, 0.87). CONCLUSIONS/INTERPRETATION: There was no excess risk of cancer in type 2 diabetic patients on insulin glargine alone compared with those on human insulin alone. The overall risk of death or cancer in patients on insulin glargine was about half that of patients on human insulin, thereby excluding a competitive risk bias.

RARgamma and TRbeta expressions are decreased in PBMC and SWAT of obese subjects in weight gain.

In order to evaluate the expression of nuclear receptors at the peripheral level in obese subjects, messenger RNA (mRNA) levels of different isoforms of retinoic acid receptor (RAR), triiodothyronine (TR), and peroxisome proliferator-activated receptor (PPAR) were determined and compared in peripheral mononuclear blood cells (PBMC) and subcutaneous white adipose tissue (SWAT). Twelve lean subjects and 68 obese subjects divided into weight gain (WG), weight-stable (WS), and weight loss (WL) groups were studied. Nuclear receptor mRNA levels were assessed in PBMC and SWAT using a quantitative real-time reverse transcription polymerase chain reaction method. mRNA levels of RARgamma were significantly lower in PBMC of obese subjects (WG -19%, WS -30%, and WL -24.7%) as in SWAT of WG (-50%). Lower mRNA levels of TRbeta were observed in PBMC and SWAT of WG (-50.7% and -28%, respectively) just as for TRalpha in PBMC of WG (-19%). In contrast, retinoid X receptors alpha (RXRalpha) and RARalpha mRNA levels were higher in PBMC of obese subjects (+53% and +54.5% in WG, +56% and +67% in WS, and +68% and +49.7% in WL, respectively), while expression of RXRalpha was lower in SWAT of WG (-24.5%). As for PPARgamma, its mRNA level was significantly higher in PBMC of WG subjects (+34%) while its expression was not modified in SWAT, contrary to the PPARgamma2 isoform which was significantly higher. These data show that in both adipose tissue and blood compartment of obese subjects, expressions of RARgamma and TRbeta were downregulated. Thus, we suggest that the expression in PBMC of obese subjects may constitute new cellular indicators of nuclear receptor retinoid and thyroid status.

Cystatin C improves the diagnosis and stratification of chronic kidney disease, and the estimation of glomerular filtration rate in diabetes.

AIMS: Estimation of glomerular filtration rate (GFR) is recommended to diagnose and stratify chronic kidney disease (CKD). Can cystatin-C (cysC) assay improve the results in diabetic patients? METHODS: In 124 diabetic patients with a wide range of GFR, as determined by 51Cr-EDTA clearance (i-GFR), we estimated 'e-GFR' by: the recommended Cockcroft-Gault (CG) formula and Modification of Diet in Renal Disease (MDRD) study equation; the new Mayo Clinic quadratic (MCQ) equation; the recently proposed composite estimation including both serum creatinine and cysC; and a simplified approach dividing the MDRD by cysC if less than 1.10mg/L. RESULTS: The highest diagnostic accuracy (receiver operating characteristic [ROC] curves) and the highest proportions of well-stratified patients were obtained by cysC and the MDRD which, however, underestimated i-GFR for patients without CKD (-17%, P<0.001). The CG overestimated GFR in KDOQI stages 1 and 2, ignored stage 5 and was the least accurate. The MCQ equation overrepresented stage 2, overestimating GFR at this stage (+23%, P<0.005). The composite estimation (54.7+/-27.0mL per minute 1.73m(2)) correlated best with i-GFR (56.1+/-35.3; r=0.90, P<0.001), and did not significantly differ from it across the entire population and within each Kidney Disease Outcome Quality Initiative (KDOQI) stage but was also biased (Bland-Altman procedure). Simply dividing the MDRD by cysC ifless than1.10mg/L produced a comparable performance and eliminated the bias. CONCLUSION: The recommended creatinine-based estimations of GFR need to be improved. CysC assay helps in the diagnosis and stratification of CKD and leads to better estimates of GFR in diabetic patients without any substantial increase in complexity.

[Microalbuminuria and urinary albumin excretion: French guidelines]. / Microalbuminurie et excrétion urinaire d'albumine: recommandations pour la pratique clinique.

UNLABELLED: Measurement of urinary albumin excretion (UAE) may be done on a morning urinary sample or on a 24 hour-urine sample. Values defining microalbuminuria are: - 24-hour urine sample: 30-300 mg/24 hours - Morning urine sample: 20-200 mg/mL or 30-300 mg/g creatinine or 2.5-25 mg/mmol creatinine (men) or 3.5-35 mg/mol (women). - Timed urine sample: 20-200 mug/min. The optimal use of semi-quantitative urine test-strip is not clearly defined. It is generally believed that microalbuminuria reflects a generalized impairment of the endothelium; however, no definite proof has been shown in humans. In diabetic subjects, microalbuminuria is a marker of increased risk of cardiovascular (CV) and renal morbidity and mortality in type 1 and type 2 diabetic subjects. The increase in UAE during follow-up is also a marker of CV and renal risk in type 1 and type 2 diabetic subjects; its decrease during follow-up is associated with lower risks. In non-diabetic subjects, microalbuminuria is a marker of increased risk for diabetes mellitus, deterioration of the renal function, CV morbidity and all-cause mortality. It is a marker of increased risk for the development of hypertension in normotensive subjects, and is associated with unfavorable outcome in patients with cancer and lymphoma. Persistence or elevation of UAE overtime is associated with deleterious outcome in some hypertensive subjects. Measurement of UAE may be recommended in hypertensive subjects with 1 or 2 CV risk factors in whom CV risk remains difficult to assess, and in those with refractory hypertension: microalbuminuria indicates a high CV risk and must lead to strict control of arterial pressure. Studies focused on microalbuminuria in non-diabetic, non-hypertensive subjects are limited; most of them suggest that microalbuminuria predicts CV complications and deleterious outcome as it is in diabetic or hypertensive subjects. Subjects with a history of CV or cerebrovascular disease have an even greater CV risk if microalbuminuria is present than if it is not; however, in all cases, therapeutic intervention must be aggressive regardless of whether microalbuminuria is present or not. It is not recommended to measure UAE in non-diabetic non-hypertensive subjects in the absence of history of renal disease. Monitoring of renal function (UAE, serum creatinine and estimation of GFR) is annually recommended in all subjects with microalbuminuria. MANAGEMENT: in patients with microalbuminuria, weight reduction, sodium restriction (< 6 g/day), smoking cessation, strict glucose control in diabetic subjects, strict arterial pressure control are necessary; in diabetic subjects: use of maximal doses of ACEI or ARB are recommended; ACEI/ARB and thiazides have synergistic actions on arterial pressure and reduction of UAE; in non-diabetic subjects, any of the five classes of anti-hypertensive medications (ACEI, ARB, thiazides, calcium channel blockers or beta-blockers) can be used.

Microalbuminuria and urinary albumin excretion: French clinical practice guidelines.

Urinary albumin excretion (UAE) may be assayed on a morning urinary sample or a 24 h-urine sample. Values defining microalbuminuria are: 1) 24-h urine sample: 30-300 mg/24 h; 2) morning urine sample: 20-200 mg/ml or 30-300 mg/g creatinine or 2.5-25 mg/mmol creatinine (men) or 3.5-35 mg/mmol (women); 3) timed urine sample: 20-200 mug/min. The optimal use of semi-quantitative urine test-strip is not clearly defined. It is generally believed that microalbuminuria reflects a generalized impairment of the endothelium; however, no definite proof has been obtained in humans. IN DIABETIC SUBJECTS: Microalbuminuria is a marker of increased risk of cardiovascular (CV) and renal morbidity and mortality in type 1 and type 2 diabetic subjects. The increase in UAE during follow-up is associated with greater CV and renal risks in type 1 and type 2 diabetic subjects; its decrease during follow-up is associated with lower risks. IN NON-DIABETIC SUBJECTS: Microalbuminuria is a marker of increased risk for diabetes mellitus, deterioration of renal function, CV morbidity and all-cause mortality. It is a marker of increased risk for the development of hypertension in normotensive subjects, and is associated with unfavorable outcome in patients with cancer and lymphoma. Persistence of elevated UAE during follow-up is associated with poor outcome in some hypertensive subjects. Measurement of UAE may be recommended in hypertensive medium-risk subjects with 1 or 2 CV risk factors in whom CV risk remains difficult to assess, and in those with refractory hypertension: microalbuminuria indicates a high CV risk and must lead to strict control of arterial pressure. Studies focused on microalbuminuria in non-diabetic non-hypertensive subjects are limited; most of them suggest that microalbuminuria predicts CV complications and deleterious outcome. Subjects with a history of CV or cerebrovascular disease have an even greater CV risk if microalbuminuria is present than if it is not; however, in all cases, therapeutic intervention must be aggressive regardless of whether microalbuminuria is present or not. It is not recommended to measure UAE in non-diabetic non-hypertensive subjects in the absence of history of renal disease. Monitoring of renal function (UAE, serum creatinine and estimation of GFR) is recommended annually in all subjects with microalbuminuria. MANAGEMENT: In patients with microalbuminuria, weight reduction, sodium restriction (<6 g per day), smoking cessation, strict glucose control in diabetic subjects, strict arterial pressure control are necessary; in diabetic subjects: use of maximal doses of angiotensin-converting enzyme inhibitors (ACEI) or angiotensin receptor blockers (ARB) are recommended; ACEI/ARB and thiazides have synergistic actions on arterial pressure and reduction of UAE; in non-diabetic subjects, any of the five classes of anti-hypertensive medications (ACEI, ARB, thiazides, calcium channel blockers or beta-blockers) can be used.

Air displacement plethysmography can detect moderate changes in body composition.

OBJECTIVES: To determine the sensitivity of air displacement plethysmography (APD) for evaluation of changes in body composition in normal subjects. DESIGN: Comparison of measurements with and without oil or water loads. SUBJECTS AND METHODS: Ten healthy volunteers were analyzed, without and with 1 l and 2 l of oil or water. The measured and true changes in fat mass and fat-free mass were compared by paired t-tests. A correlation study and a Bland & Altman procedure was performed on the 60 measurements of adiposity changes in 30 subjects carrying 0.5 l (n=8 x 2), 1 l (n=10 x 2) and 2 l (n=12 x 2) oil and water loads. RESULTS: Fat-free mass increased when the 10 subjects were carrying water. When they carried oil, fat mass increased, however, a approximately 0.5 kg increase of fat-free mass was also detected. Two liters loads led to distinct changes: +1.49+/-0.59 kg fat and +0.50+/-0.60 kg fat-free with oil and +0.37+/-0.57 kg fat and +1.70+/-0.56 kg fat-free with water (both P<0.001). Mixed loads (+1 l oil and 1 l water) led to detect +0.85+/-0.48 kg fat and +1.09+/-0.45 kg fat-free (both P<0.005 vs without load). For the 30 subjects analyzed thrice, measured changes in fat and fat-free mass were slightly underestimated (-15%, NS) but correlated with the true changes. Measured changes in adiposity were correlated with the true changes, with no bias as indicated by the Bland & Altman procedure. CONCLUSION: APD detects approximately 2 kg changes in fat or fat-free mass in small populations.

How to better systematize the diagnosis of neuropathy?

Two attitudes can be proposed, one consisting of making a diagnosis of neuropathy, the other seeking to grade the stage that it has reached in order to give a prognosis and above all determine the right way in which to educate the patient. In order to do this, it is important for the diagnosis to be thorough. It should be based both on listening to what the patient has to say and examining him/her. It is vital to listen to the patient because the warning signs are discreet, yet very evocative, and they will be a great help in making a positive diagnosis. They should not be confused with signs of arterial damage. They should then be interpreted by means of clinical examination and the tools that are available, i.e. essentially monitoring the osteo-tendinous reflexes and sensory signs. The sensory signs can only be studied with high-quality instruments, i.e. either a monofilament of proven technical quality and that should be used with care in line with good clinical practice recommendations, or by using a graduated tuning fork, or a neuroesthesiometer which will make it possible to obtained graduated responses, not simply binary responses of the "yes/no" variety. A whole series of scores have been put forward combining both functional and physical signs, making it possible to try to quantify the stage reached and the extent of the neuropathy. It is only by using a thorough and regularly applied routine that we can progress to establishing a better prognosis and providing a better educational service for the patient.

Blood ketone monitoring: a comparison between gestational diabetes and non-diabetic pregnant women.

AIM: To measure ketonemia in a control population of pregnant women and in a population of women with gestational diabetes (GDM). To define a normal ketonemia threshold for the controls and to determine whether or not this value could play a role in the clinical management of women with GDM. METHOD: Fifty-six women with a normal OGTT and 49 women with GDM were included and monitored from the 25th to the 37th week of pregnancy. Control subjects agreed to perform glycaemia and ketonemia self-monitoring 3 times a day. In addition, women with GDM were asked to measure their postprandial glycaemia. Glycaemia and ketonemia measurements were performed using Optium meters. Subjects kept a 24-hour food record twice a week. RESULTS: The mean ketonemia was lower in the control group than in the GDM group (0.01+/-0.10 vs. 0.04+/-0.009 mmol/l; P<0.001). Ketonemia values measured before the midday meal and prior to the evening meal were lower for control subjects than for GDM patients (P=0.002 and P=0.005). Fasting ketonemia was unrelated to ketonuria in the GDM group, whereas there was a correlation in the control group (P=0.006). At least one chronic increase in ketonemia levels was observed in 47% of the women with GDM, compared with only 12% of controls. The lowest levels of evening glycaemia correlated with the highest levels of ketonemia; women with GDM reported lower food and carbohydrate intakes than controls (P<0.001). CONCLUSION: This work has enabled the establishment of ketonemia reference standards in non-diabetic pregnant women. If ketonemia does indeed indicate overly restrictive dietary behavior, this parameter could be employed for monitoring adherence to the nutritional recommendations for GDM.

A simplified Cockcroft-Gault formula to improve the prediction of the glomerular filtration rate in diabetic patients.

AIM: The National Kidney Foundation recommends stratification of renal failure into moderate (Glomerular Filtration Rate: GFR = 30-60 mL/min/1.73 m2), severe (15-30) or terminal (<15) using the Cockcroft-Gault (CG) or the Modification of Diet in Renal Disease (MDRD) equations. We studied the biases in these methods in an attempt to improve the standard CG (MCG) and devise a strategy for stratification. METHODS: GFR was measured by 51Cr-EDTA clearance in 200 diabetic patients: 100 (Group 1: study of concordance) before 2003 and 100 thereafter (Group 2: validation of MCG). The CG was modified by replacing body weight by its mean value: 76. RESULTS: In group 1, the recommended equations only correctly stratified 50 patients. The CG, not the MDRD, underestimated GFR if BMI was normal, and overestimated it in obese patients. In group 2, the MCG was well correlated with GFR and not biased by weight. Over the whole population, the MCG and MDRD were more accurate for the diagnosis of moderate and severe renal failure. The MDRD showed the lowest differences with GFR, except if GFR > 60, where the MCG performed better. All formulae overestimated low GFR, the MDRD also underestimated high GFR. The best stratification (147/200) was obtained using the MCG if creatininemia < 120 micromol/l and the MDRD if creatininemia > or =120 micromol/l. CONCLUSION: The CG is biased by weight, the MCG corrects this. The more accurate MDRD cannot be used in all patients as it underestimates high GFR. The best stratification was obtained using the MCG at low and the MDRD at high creatininemia.

Continuous intraperitoneal insulin infusion does not increase the risk of organ-specific autoimmune disease in type 1 diabetic patients: results of a multicentric, comparative study.

AIM: The purpose of this national multicenter prospective study by the French EVADIAC group was to investigate the possibility that continuous intraperitoneal insulin infusion using an implanted pump (CIpii) increases the risk of autoimmune disease in type 1 diabetic patients as it increased anti-insulin immunogenicity. METHODS: Prevalence of clinical (Hashimoto's disease, hyperthyroidism, gastric atrophic disease and vitiligo) and subclinical (presence of anti-thyroperoxidase antibodies, anti-intrinsic factor antibodies, abnormal TSH levels) autoimmune diseases was estimated by comparing two groups of patients already treated by either CIpii (n=154) or external pump (CSII) (n=121) for an average of 6 years. Incidence of autoimmune disease was determined by comparing the same measurements one year after inclusion. RESULTS: No significant difference was observed for the total prevalence of clinical and subclinical auto-immune thyroid and gastric di-seases (35.6% and 3.2% respectively in the CIpii group versus 40.4% and 2.6% in the CSII group). No significant difference for the incidence of clinical and subclinical auto-immune diseases was observed: 7.2% and 0% in CIpii and 7.3% and 1.7% in CSII. CONCLUSION: As previously shown AIA (anti-insulin antibodies) levels were higher in CIpii than in CSII (32.9% vs 20.2%, P<0.0001) but no correlation was observed with either clinical or subclinical autoimmune disease. This large-scale study eliminates the possibility that CIpii increases the risk of autoimmune disease.

13C nuclear magnetic resonance study of glycogen resynthesis in muscle after glycogen-depleting exercise in healthy men receiving an infusion of lipid emulsion.

In healthy individuals, glycogen recovery after a strong depletion is known to be rapid and insulin independent during the initial phase, and subsequently, slow and insulin dependent. Free fatty acids (FFAs) as a putative source of insulin resistance (IR) could thus impair glycogen recovery during the second period. Using in vivo 13C nuclear magnetic resonance (NMR), we studied the effect of long-chain triglyceride emulsion on gastrocnemius glycogen resynthesis during a 3-h recovery period after 90 min of moderate exercise consisting of plantar flexion on overnight-fasted healthy men (n = 8). In separate experiments, each subject was infused with 10% Ivelip (0.015 ml x kg(-1) x min(-1)) or 10% glycerol (0.13 mg x kg(-1) x min(-1)). NMR spectra were acquired before and at the end of the exercise and during the recovery period. Whole-body glucose and lipid oxidation rates (indirect calorimetry), plasma insulin, C-peptide, glucose, lactate, beta-hydroxybutyrate, triglycerides, and FFAs were determined. Glycogen consumption was 47.6 +/- 4.5% (glycerol) and 49.7 +/- 4.8% (Ivelip) of the initial glycogen. An acquired IR in the Ivelip group was significant at the onset of the recovery period by homeostasis model assessment (P = 0.002). Glycogen resynthesis in the glycerol group appeared faster during the 1st h than during the subsequent 2nd h of the postexercise period. The glycogen resynthesis level was significantly lower in the Ivelip group than in the glycerol group during the recovery period (P = 0.04 during the 1st h and P = 0.001 during the next 2 h). During the recovery, plasma lactate and whole-body oxidation rates were similar in the two groups, whereas glycemia was significantly higher in the Ivelip group. A decreased cellular uptake of glucose as a substrate for glycogenosynthesis, rather than a competition between oxidation of carbohydrate and FFA, is discussed.

Reproducibility and variability in the action of injected insulin.

Insulin-treated patients are generally taught to adapt their doses of insulin according to the glycemic level obtained during self-tests. They usually adhere to medical recommendations, but are often confused by the results, which may not correspond to expectations. Patients have to contend with variability and a certain degree of unpredictability in the results. Our knowledge of the factors involved in this variability is often imprecise. We review here the factors depending on the preparation of insulin itself, not only with regard to its crystallization but also the speed at which the hexamers dissociate into dimers. The development of fast and slow-acting analogues is discussed along with their value in improving glycemic predictability. In addition to these factors, we mention those stemming from the injection technique itself, which are directly related to the instructions given to the patients. For crystallized insulin preparations, shaking the bottle is an important element that the development of slow-acting analogues should eliminate, but the time lapse before withdrawing the needle, the anatomical site of the insulin injection, and the depth of the injection are also factors for variability. Greater predictability in the action of insulin will be obtained from a combination of progress in manufacturing procedures and better patient education.

Use of the glucose clamp technique for confirmation of insulinoma autonomous hyperinsulinism.

The diagnosis of insulinoma on the basis of persistent hypoglycemia requires further confirmation. The insulin suppression test has been used to support this diagnosis prior to surgical intervention. In this study the euglycemic clamp technique was used to compare five control volunteers with four hypoglycemic patients with suspected insulinoma. Insulin was infused over successive two-hour periods at 2, 4, and 8 mU/kg/min. Plasma glucose levels were clamped at 80 mg/dL (4.4 mmol/L) using an artificial pancreas. High insulin levels were measured in all subjects, ranging from 225 +/- 30 microU/mL (1614 +/- 215 pmol/L) to 1018 +/- 239 microU/mL (7304 +/- 1714 pmol/L). Levels of C peptide fell to 0.1 ng/mL (0.028 nmol/L) in control subjects but remained at high levels in the patients. Insulinoma was confirmed on laparotomy in all four patients. In two patients tested after removal of the tumor the results were found to have returned to normal.

Short-term effect of red wine (consumed during meals) on insulin requirement and glucose tolerance in diabetic patients.

OBJECTIVE: To determine the effect of wine on insulin requirement or glucose tolerance. RESEARCH DESIGN AND METHODS: Five men with insulin-treated diabetes and 10 men with non-insulin-treated diabetes ate the same lunch with the same volume of either water or red wine (2 glasses). Insulin requirement was determined with an artificial pancreas (Biostator). Glucose tolerance was evaluated from the postprandial glycemic level. RESULTS: There was no significant difference in insulin requirement determined with an artificial pancreas in the insulin-treated patients after the two meals (31.5 +/- 4.21 U with water and 31.8 +/- 4.3 U with wine). Glucose tolerance in the non-insulin-treated patients was lower after the meal with wine. CONCLUSIONS: Moderate prandial wine consumption has no adverse effect on the glycemic control of diabetic patients. Thus, it appears unnecessary to proscribe the consumption of red wine in moderation with meals to diabetic patients. Wine contains tannins and phytates that can explain its action.

Extra-pancreatic manifestations in diabetes secondary to mitochondrial DNA point mutation within the tRNALeu(UUR) gene.

OBJECTIVE: A point mutation in the mitochondrial genome has been identified as a cause of diabetes and deafness. We report two pedigrees with and A-to-G transition at nucleotide 3243 of mtDNA within the tRNALeu(UUR) gene and focus our investigations on other localizations of the anomaly, particularly muscle and retina. RESEARCH DESIGN AND METHODS: Muscular localization has been studied in probands by invasive and noninvasive methods, including muscle biopsy (evaluation of the proportion of mutated mtDNA in comparison to blood cells, measurement of respiratory chain complex activities and histological and histochemical aspects) and 31P-nuclear magnetic resonance (NMR) spectroscopy. Ophthalmic and angiographic examination of retina, electroretinography, and visual evoked potentials were performed in five subjects. RESULTS: This mutation, previously described in patients with mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes (MELAS), was expressed more abundantly in muscle than in nucleated blood cells. This low expression in blood cells could hamper the diagnosis for some patients. In addition, despite poor clinical expression, muscle was found to be highly affected. Ragged red fibers and dystrophic mitochondria were observed in muscle biopsy. Histochemical assays showed decreased activity of respiratory chain complexes, and 31P-NMR in vivo data further confirmed the defect of muscle oxidative processes. Exercise-induced lactate production was increased. Finally, in both families, an atypical "salt and pepper" pigmentary retinopathy was observed without consequences on visual acuity. CONCLUSIONS: In diabetes secondary to 3243 mtDNA mutation, infraclinical muscular and ocular lesions are frequent. These two locations of the disease, which are easily investigated by simple methods, can help in the diagnosis of this new type of diabetes.

Short-term insulin therapy and normoglycemia. Effects on erythrocyte lipid peroxidation in NIDDM patients.

OBJECTIVE: To evaluate erythrocyte lipid peroxidation (LPO) before and after an adaptive short-term insulin therapy in NIDDM patients who were chronically hyperglycemic. RESEARCH DESIGN AND METHODS: Twenty-six patients with NIDDM (mean HbA1c, 11.28%) aged 53.04 +/- 2.03 years were submitted for 3 days to constant intravenous glucose and continuous insulin perfusion at an adaptable rate to maintain glycemia within the normal range. An evaluation of LPO at baseline and after euglycemic insulin therapy was determined by erythrocyte free and total malondialdehyde (MDA) levels, polyunsaturated fatty acid (PUFA) percentage, vitamin E and glutathione content, and the following antioxidant enzymatic activity determinations: glutathione peroxidase (GPX), superoxide dismutase (SOD) and catalase (CAT). Fasting serum glucose, HbA1c, triglycerides, cholesterol, and HDL cholesterol levels were also determined at these time points. RESULTS: At baseline, erythrocyte free and total MDA were significantly higher in NIDDM patients than in control subjects (11.14 +/- 0.80 vs. 1.74 +/- 0.11 nmol/g Hb [P < 0.0001] for free MDA; 18.04 +/- 1.79 vs. 7.85 +/- 0.55 nmol/g Hb [P < 0.0001] for total MDA). PUFAs, particularly C20:4 and C22:5, were increased (14.69 +/- 0.34 vs. 12.03 +/- 0.31 and 2.31 +/- 0.04 vs. 1.71 +/- 0.03% of total fatty acids, respectively). Vitamin E and glutathione were reduced significantly (6.16 +/- 0.61 vs. 14.84 +/- 0.64 nmol/g Hb and 0.42 +/- 0.04 vs. 0.97 +/- 0.06 mmol/l, respectively). No difference was observed for the enzymatic activities. After euglycemic insulin therapy, triglycerides significantly decreased compared with baseline concentrations (1.55 +/- 0.13 vs. 2.42 +/- 0.22 mmol/l; P < 0.001), whereas other lipidic parameters were unchanged. Free MDA significantly decreased (8.60 +/- 0.76 vs. 11.14 +/- 0.80 nmol/g Hb [P < 0.01]), while vitamin E increased (7.93 +/- 0.73 vs. 6.16 +/- 0.61 nmol/g Hb [P < 0.05]). No difference was observed for PUFAs, glutathione, or total MDA. CONCLUSIONS: The observed erythrocyte LPO in NIDDM decreased after a short-term adaptive insulin therapy. This decrease could be principally attributed to the normalized glycemia that reduces reactive oxygen species (ROS) production, which in turn may explain the increase in erythrocyte membrane vitamin E and the decrease in MDA. This study shows the value of a euglycemic environment in NIDDM to reduce LPO and, at long range, to minimize clinical diabetes complications.

Self, Voices and Embodiment: A Phenomenological Analysis.

OBJECTIVE: The primary aim of this study was to examine first-person phenomenological descriptions of the relationship between the self and Auditory Verbal Hallucinations (AVHs). Complex AVHs are frequently described as entities with clear interpersonal characteristics. Strikingly, investigations of first-person (subjective) descriptions of the phenomenology of the relationship are virtually absent from the literature. METHOD: Twenty participants with psychosis and actively experiencing AVHs were recruited from the University of Illinois at Chicago. A mixed-methods design involving qualitative and quantitative components was utilized. Following a priority-sequence model of complementarity, quantitative analyses were used to test elements of emergent qualitative themes. RESULTS: The qualitative analysis identified three foundational constructs in the relationship between self and voices: 'understanding of origin,' 'distinct interpersonal identities,' and 'locus of control.' Quantitative analyses further supported identified links of these constructs. Subjects experienced their AVHs as having identities distinct from self and actively engaged with their AVHs experienced a greater sense of autonomy and control over AVHs. DISCUSSION: Given the clinical importance of AVHs and emerging strategies targeting the relationship between the hearer and voices, our findings highlight the importance of these relational constructs in improvement and innovation of clinical interventions. Our analyses also underscore the value of detailed voice assessments such as those provided by the Maastricht Interview are needed in the evaluation process. Subjects narratives shows that the relational phenomena between hearer and AVH(s) is dynamic, and can be influenced and changed through the hearers' engagement, conversation, and negotiation with their voices.