Glycaemic control and hypoglycaemia benefits with insulin glargine 300 U/mL extend to people with type 2 diabetes and mild-to-moderate renal impairment.

AIM: To investigate the impact of renal function on the safety and efficacy of insulin glargine 300 U/mL (Gla-300) and insulin glargine 100 U/mL (Gla-100). MATERIALS AND METHODS: A meta-analysis was performed using pooled 6-month data from the EDITION 1, 2 and 3 trials (N = 2496). Eligible participants, aged ≥18 years with a diagnosis of type 2 diabetes (T2DM), were randomized to receive once-daily evening injections of Gla-300 or Gla-100. Pooled results were assessed by two renal function subgroups: estimated glomerular filtration rate (eGFR) <60 and ≥60 mL/min/1.73 m2 . RESULTS: The decrease in glycated haemoglobin (HbA1c) after 6 months and the proportion of individuals with T2DM achieving HbA1c targets were similar in the Gla-300 and Gla-100 groups, for both renal function subgroups. There was a reduced risk of nocturnal (12:00-5:59 am) confirmed (≤3.9 mmol/L [≤70 mg/dL]) or severe hypoglycaemia with Gla-300 in both renal function subgroups (eGFR <60 mL/min/1.73 m2 : relative risk [RR] 0.76 [95% confidence interval {CI} 0.62-0.94] and eGFR ≥60 mL/min/1.73 m2 : RR 0.75 [95% CI 0.67-0.85]). For confirmed (≤70 mg/dL [≤3.9 mmol/L]) or severe hypoglycaemia at any time of day (24 hours) the hypoglycaemia risk was lower with Gla-300 vs Gla-100 in both the lower (RR 0.94 [95% CI 0.86-1.03]) and higher (RR 0.90 [95% CI 0.85-0.95]) eGFR subgroups. CONCLUSIONS: Gla-300 provided similar glycaemic control to Gla-100, while indicating a reduced overall risk of confirmed (≤3.9 and <3.0 mmol/L [≤70 and <54 mg/dL]) or severe hypoglycaemia, with no significant difference between renal function subgroups.

Cardiovascular Complications Over 5 Years and Their Association With Survival in the GERODIAB Cohort of Elderly French Patients With Type 2 Diabetes.

OBJECTIVE: The GERODIAB study is a multicenter prospective observational study performed over 5 years in French patients aged 70 years or above with type 2 diabetes. This report deals with their cardiovascular complications and their relationship with survival. RESEARCH DESIGN AND METHODS: Consecutive patients (n = 987, median age = 77 years) were included from 56 diabetes centers over 1 year. Individual characteristics, history and complications of diabetes, geriatric factors, and clinical and biological parameters were recorded. Survival was analyzed using the Kaplan-Meier method and proportional hazards regression models. RESULTS: The frequency of cardiovascular complications increased from 47% at inclusion to 67% at 5 years. The most frequent complications were coronary heart disease (increasing from 30% to 41%) and vascular disease of the lower limbs (25% to 35%) and of the cerebral vessels (15% to 26%). Heart failure was less common, but its frequency doubled during the follow-up (9% to 20%). It was strongly associated with poor survival (P < 0.0001), as was vascular disease of the lower limbs (P = 0.0004), whereas coronary heart disease (P = 0.0056) and vascular disease of cerebral vessels (P = 0.026) had mild associations. Amputation (P < 0.0001) and foot wounds (P < 0.0001) were strongly associated with survival. In multivariate models, heart failure was the strongest predictor of poor survival (hazard ratio [HR] 1.96 [95% CI 1.45-2.64]; P < 0.0001). It remained significant when other factors were considered simultaneously (HR 1.92 [95% CI 1.43-2.58]; P < 0.0001). CONCLUSIONS: Cardiovascular complications are associated with poor survival in elderly patients with type 2 diabetes, especially heart failure.

New Insulin Delivery Recommendations.

Many primary care professionals manage injection or infusion therapies in patients with diabetes. Few published guidelines have been available to help such professionals and their patients manage these therapies. Herein, we present new, practical, and comprehensive recommendations for diabetes injections and infusions. These recommendations were informed by a large international survey of current practice and were written and vetted by 183 diabetes experts from 54 countries at the Forum for Injection Technique and Therapy: Expert Recommendations (FITTER) workshop held in Rome, Italy, in 2015. Recommendations are organized around the themes of anatomy, physiology, pathology, psychology, and technology. Key among the recommendations are that the shortest needles (currently the 4-mm pen and 6-mm syringe needles) are safe, effective, and less painful and should be the first-line choice in all patient categories; intramuscular injections should be avoided, especially with long-acting insulins, because severe hypoglycemia may result; lipohypertrophy is a frequent complication of therapy that distorts insulin absorption, and, therefore, injections and infusions should not be given into these lesions and correct site rotation will help prevent them; effective long-term therapy with insulin is critically dependent on addressing psychological hurdles upstream, even before insulin has been started; inappropriate disposal of used sharps poses a risk of infection with blood-borne pathogens; and mitigation is possible with proper training, effective disposal strategies, and the use of safety devices. Adherence to these new recommendations should lead to more effective therapies, improved outcomes, and lower costs for patients with diabetes.

Reasons for non-intensification of treatment in people with type 2 diabetes receiving oral monotherapy: Outcomes from the prospective DIAttitude study.

OBJECTIVES: To describe the management of glucose-lowering agents in people with type 2 diabetes initially on oral monotherapy, cared for by French general practitioners, and to identify reasons underlying treatment non-intensification. METHODS: People with type 2 diabetes on oral monotherapy were recruited by general practitioners and followed-up over 12 months. Patient characteristics, HbA1c, and glucose-lowering treatments were recorded electronically. Management objectives and reasons for treatment non-intensification were solicited from the general practitioners. RESULTS: A total of 1212 patients were enrolled by 198 general practitioners; 937 patients (mean age 68 years) were treated with oral monotherapy, and 916 patients had at least two successive HbA1c values recorded. Of these, 390 patients (43%) had HbA1c≥6.5% on both occasions, and 164/390 (42%) had their treatment intensified. The 226 patients whose treatment was not intensified were older (69±11 years vs. 66±12 years, P=0.02) and had better glycaemic control at study inclusion (6.9%±0.6 vs. 7.3%±0.8, P<0.0001) than treatment intensified patients. Among uncontrolled patients, there were no differences in general practitioner treatment objectives at inclusion for treatment intensified and non-intensified patients; the main reason given by general practitioners for non-intensification was that the patient had an adequate HbA1c (66%). HbA1c did exceed the 6.5% target, but was less than 7.0% in 69% of cases. CONCLUSIONS: General practitioners showed a patient-centred approach to treatment, but clinical inertia was apparent for 31% of the uncontrolled patients.

Simple calculator to estimate the medical cost of diabetes in sub-Saharan Africa.

AIM: To design a medical cost calculator and show that diabetes care is beyond reach of the majority particularly patients with complications. METHODS: Out-of-pocket expenditures of patients for medical treatment of type-2 diabetes were estimated based on price data collected in Benin, Burkina Faso, Guinea and Mali. A detailed protocol for realistic medical care of diabetes and its complications in the African context was defined. Care components were based on existing guidelines, published data and clinical experience. Prices were obtained in public and private health facilities. The cost calculator used Excel. The cost for basic management of uncomplicated diabetes was calculated per person and per year. Incremental costs were also computed per annum for chronic complications and per episode for acute complications. RESULTS: Wide variations of estimated care costs were observed among countries and between the public and private healthcare system. The minimum estimated cost for the treatment of uncomplicated diabetes (in the public sector) would amount to 21%-34% of the country's gross national income per capita, 26%-47% in the presence of retinopathy, and above 70% for nephropathy, the most expensive complication. CONCLUSION: The study provided objective evidence for the exorbitant medical cost of diabetes considering that no medical insurance is available in the study countries. Although the calculator only estimates the cost of inaction, it is innovative and of interest for several stakeholders.

Hypoglycemia hospitalization frequency in patients with type 2 diabetes mellitus: a comparison of dipeptidyl peptidase 4 inhibitors and insulin secretagogues using the French health insurance database.

AIM: We aimed to compare the frequency of severe hypoglycemia leading to hospitalization (HH) and emergency visits (EV) for any cause in patients with type 2 diabetes mellitus exposed to dipeptidyl peptidase 4 (DPP4) inhibitors (DPP4-i) versus those exposed to insulin secretagogues (IS; sulfonylureas or glinides). METHODS: Data were extracted from the EGB (Echantillon Généraliste des Bénéficiaires) database, comprising a representative sample of ~1% of patients registered in the French National Health Insurance System (~600,000 patients). Type 2 diabetes mellitus patients exposed to regimens containing either a DPP4-i (excluding treatment with IS, insulin, or glucagon-like peptide 1 analog) or IS (excluding treatment with insulin and any incretin therapy) between 2009 and 2012 were selected. HH and EV during the exposure periods were identified in both cohorts. A similar analysis was conducted considering vildagliptin alone versus IS. Comparative analyses adjusting for covariates within the model (subjects matched for key characteristics) and using multinomial regression models were performed. RESULTS: Overall, 7,152 patients exposed to any DPP4-i and 1,440 patients exposed to vildagliptin were compared to 10,019 patients exposed to IS. Eight patients (0.11%) from the DPP4-i cohort and none from the vildagliptin cohort (0.0%) were hospitalized for hypoglycemia versus 130 patients (1.30%) from the IS cohort (138 hospitalizations) (P=0.02 and P<0.0001, respectively). Crude rates of HH/1,000 patient-years were 1.4 (95% CI: 0.7; 2.4) in the DPP4-i cohort, 0.0 in the vildagliptin cohort (95% CI: 0.0; 4.0), versus 5.6 (95% CI, 4.7; 6.6) in the IS cohort (P<0.0001). After adjustments, rates per 1,000 patient-years of HH were 1.4 (95% CI: 0.7; 2.4) with DPP4-i versus 7.5 (95% CI: 6.0; 9.2) with IS (P<0.0001), and 0.0 (95% CI: 0.0; 4.0) with vildagliptin versus 13.6 (95% CI: 10.4; 17.5) with IS (P<0.0001). Adjusted EV rates were also significantly lower with all DPP4-i or with vildagliptin, as compared to IS (P<0.0001). Consistent results were found when considering only treatment initiations for all compared cohorts. CONCLUSION: HH and EV were significantly less frequent in patients exposed to any DPP4-i or to vildagliptin versus IS. These real-life data should be considered in the benefit/risk evaluation of the drugs.

The multinational second Diabetes, Attitudes, Wishes and Needs study: results of the French survey.

AIM: The second Diabetes, Attitudes, Wishes and Needs (DAWN2™) multinational cross-sectional study was aimed at generating insights to facilitate innovative efforts by people with diabetes (PWD), family members (FMs), and health care professionals (HCPs) to improve self-management and psychosocial support in diabetes. Here, the French data from the DAWN2™ study are described. METHODS: In France, 500 PWD (80 with type 1 diabetes [T1] and 420 with type 2 diabetes [T2]), 120 FMs, and 288 HCPs were recruited. The questionnaires assessed the impact of diabetes on quality of life and mood, self-management, attitudes/beliefs, and care/support. RESULTS: Diabetes negatively impacted the emotional well-being of 59% of people with T1 versus 45% of people with T2 (P<0.05) and about half of FMs. A high level of distress was felt by about half of PWD and FMs. About half of HCPs reported assessing depression in their patients. Sixty-two percent of FMs considered managing diabetes to be a burden. Hypoglycemia was a source of concern for 64% of people with T1 and 73% of FMs of insulin users. About two-thirds of non-insulin-medicated people with T2 agreed to start insulin if prescribed, while half of HCPs preferred to delay insulin initiation. A discrepancy between HCPs' perceptions of their interactions with their patients and PWD's recollection of these interactions with regard to patients' personal needs and distress was also observed. CONCLUSION: While distress remains under-assessed by HCPs, the negative impact of diabetes on the lives of PWD and FMs clearly induces distress on both groups. These findings provide new understanding of barriers precluding optimal management of diabetes. Developing strategies to overcome these barriers is now warranted.

Experience with DPP-4 inhibitors in the management of patients with type 2 diabetes fasting during Ramadan.

A large proportion of Muslim patients with type 2 diabetes mellitus (T2DM) elect to fast during the holy month of Ramadan. For these patients hypo- and hyperglycemia constitute two major complications associated with the profound changes in food pattern during the Ramadan fast, and efficacious treatment options with a low risk of hypoglycemia are therefore needed to manage their T2DM as effectively and safely as possible. Dipeptidyl peptidase-4 (DPP-4) inhibitors modulate insulin and glucagon secretion in a glucose-dependent manner, and consequently a low propensity of hypoglycemia has consistently been reported across different patient populations with these agents. Promising data with DPP-4 inhibitors have now also started to emerge in patients with T2DM fasting during Ramadan. The objective of this review is to provide a comprehensive overview of the currently available evidence and potential role of DPP-4 inhibitors in the management of patients with T2DM fasting during Ramadan whose diabetes is treated with oral antidiabetic drugs, and to discuss the mechanistic basis for their beneficial effects in this setting.

Experience with Vildagliptin in Type 2 Diabetic Patients Fasting During Ramadan in France: Insights from the VERDI Study.

AIM: To assess in real life the rate of hypoglycemia during Ramadan in patients with type 2 diabetes (T2DM) in France, according to their ongoing dual therapy of metformin-vildagliptin or metformin-sulfonylurea/glinide (IS). METHODS: Prospective, non-interventional study with 2 visits (within 8 weeks before and 6 weeks after the end of Ramadan 2012). Study diaries were not used to collect events or record values of glucose monitoring. One hundred and ninety-eight patients on stable oral dual therapy for ≥2 months and with glycosylated hemoglobin (HbA1c) ≤8.0% were recruited by 62 centers: 83 in the IS cohort and 115 in the vildagliptin cohort. RESULTS: Approximately 90% of patients were from Maghreb. The two cohorts were well balanced: 60% men, mean age 59 years, BMI 28 kg/m(2), metformin dose ~2,000 mg/day, and HbA1c 7.2%. Distinct therapeutic management was planned in view of Ramadan with drug-adaptation intended in 61.4% of IS and 18.3% of vildagliptin patients. Hypoglycemia was reported in 37% of IS and 34% of vildagliptin patients; episodes declared as confirmed in 30.8% and 23.5%, respectively, and episodes documented as adverse event (AE) in 17.9% (22 episodes) and 7.5% (13 episodes), respectively (P = 0.025). Severe episodes were reported in 3.9% of IS and 1.7% of vildagliptin patients. 10.4% of IS and 2.6% of vildagliptin patients reported severe episodes and/or unscheduled medical visits due to hypoglycemia (P = 0.029). Glycemic control remained stable in both cohorts. Compliance with fasting was high, as well as adherence to drug with ≥5 missed-dose for 15.4% of IS and 8.5% of vildagliptin patients. CONCLUSION: Although the overall frequency of malaise suggestive of hypoglycemia was high, which would be expected with prolonged fasting in a well-controlled T2DM population during hot summer days, the incidence of more severe and better-documented episodes (AE, severe event, event leading to unscheduled medical visit) were much lower, with consistently less events with vildagliptin therapy.

The severity of nocturnal hypoxia but not abdominal adiposity is associated with insulin resistance in non-obese men with sleep apnea.

BACKGROUND: Beyond obesity, sleep apnea syndrome is frequently associated with excess abdominal adiposity that could contribute to the deteriorated cardiometabolic risk profile of apneic patients. METHODS: The present study addressed the respective contribution of the severity of sleep apnea syndrome and excess abdominal adiposity to the cardiometabolic risk profile of 38 non obese men with polysomnography-diagnosed sleep apnea syndrome (apnea-hypopnea index >15 events/hour). These otherwise healthy men performed a 75g-oral glucose tolerance test (OGTT) with plasma lipid/inflammatory and redox profiles. Twenty-one apneic men with high-waist circumference (>94 cm) were compared to 17 apneic men with low-waist circumference. RESULTS: Apneic men with high-waist circumference had higher AUC glucose and AUC insulin than apneic men with low-waist circumference. Accordingly, apneic men with high-waist circumference had higher hepatic insulin resistance as reflected by higher HOMA-resistance index, and lower global insulin sensitivity as reflected by lower insulin sensitivity index of Matsuda (derived from OGTT). The sleep structure and the apnea-hypopnea index were not different between the two groups. However, apneic men with high-waist circumference presented with lower mean nocturnal oxyhemoglobin (SpO2). In the 38 men, waist circumference and mean nocturnal SpO2 were inversely correlated (r = -0.43, p = 0.011) and were both associated with plasma glucose/insulin homeostasis indices: the higher the waist circumference, the lower the mean nocturnal SpO2, the lower the insulin-sensitivity. Finally, in multivariable regression model, mean nocturnal SpO2 and not waist circumference was associated with insulin-resistance. CONCLUSION: Thus, excess abdominal adiposity in non obese apneic men was associated with a deteriorated insulin-sensitivity that could be driven by a more severe nocturnal hypoxemia.

[Management of type 2 diabetes: new or previous agents, how to choose?]. / Prise en charge du diabète de type 2 : anciens ou nouveaux médicaments, comment choisir ?

Once lifestyle measures implemented, if hyperglycemia persists, above individual HbA1c targets, a medication should be started in type 2 diabetic patients (T2DM). First, unless exception, an oral antidiabetic drug. Except in case of intolerance, the initial monotherapy, metformin remains the strengthening treatment. Latter, combination of two oral drugs, now offers several options, mainly the choice to associate a "conventional insulin-secretor", sulfonylureas, glinide, or a "new one" belonging the class of "incretin", more readily a gliptine (DPP-4 inhibitors) rather than injectable GLP-1 analogue which can also be sometimes chosen at this stage. These options are mostly new and have the advantage a neutral or favourable (for GLP-1) effect on body weight in obese type 2 DM patient and the absence of any hypoglycaemic risk in both classes of incretins. But this risk varies depending on the patient profile, much higher if the target HbA1c is low (6 to 6.5 or 7%), or in the elderly, fragile and/or in case of renal insufficiency. These two different situations with a high risk of hypoglycaemia, define best indications of this new class. If dual oral therapy does not achieve the goals we are faced with three options: triple oral therapy: metformin-sulfonylurea-gliptine or one of two approaches with injections, insulin or GLP-1 analogues. The use of GLP-1 analogues is often delayed today and put wrongly in balance with the transition to insulin, a use already delayed in France and insufficient. The use of incretins is new and needs to be validated by studies of sustainability on glycemic control, prevention of microvascular and macrovascular complications and after years on the market security of use, primarily on the exocrine pancreas. In short, individualization of strategies and HbA1c targets are required, the new molecules can help us in this process. This individualization can easily be done through the handy guide proposed by the experts ADA EASD statement, endorsed by the SFD, abandoning the complex algorithm recently again proposed by HAS and ANSM in 2013. A recommendation that prioritizes the costs of the strategies. An absolutely critical issue, while admitting not to have the tools to measure them in all their dimensions. Finally, we must reconsider every treatment after a maximum of 6 months of use, if the results are deemed inadequate substitute rather than adding drugs.

Economic evaluation of Vacuum Assisted Closure® Therapy for the treatment of diabetic foot ulcers in France.

The objective of the study was to assess the cost-effectiveness of Vacuum Assisted Closure® (V.A.C.®) Therapy compared with advanced wound care (AWC) for the treatment of diabetic foot ulcers (DFUs) in France. A cost-effectiveness model intended to reflect the management of DFUs was updated for the French setting. The Markov model follows the progression of 1000 hypothetical patients over a 1-year period. The model was populated with French-specific data, obtained from published sources and clinical experts. The analysis evaluated costs and health outcomes, in terms of quality-adjusted life-years (QALYs), wounds healed and amputations, from the perspective of the payer. The patients treated with V.A.C.® Therapy experienced more QALYs (0.787 versus 0.784) and improved healing rates (50.2% versus 48.5%) at a lower total cost of care (€24,881 versus €28,855 per patient per year) when compared with AWC. Sensitivity analyses conducted around key model parameters indicated that the results were affected by hospital resource use and costs. DFU treatment using V.A.C.® Therapy in France was associated with lower costs, additional QALYs, more healed ulcers and fewer amputations than treatment with AWC. V.A.C.® Therapy was therefore found to be the dominant treatment option.

[Towards new recommendations for the treatment of type 2 diabetes? An expert's point of view]. / Vers de nouvelles recommandations de traitement du diabète de type 2? Point de vue d'un expert.

Type 2 diabetes is growing rapidly, as its cost and the daily concern of general practitioners. Many treatment advances are now available and many more are in development. Currently the drugs based on the "incretin" phenomenon are the more recent and innovative (tree different DPP-inhibitors and two GLP1 analogues) with a specific benefit, no hypoglycemic attacks and a better body weight control. Thus the recommendations for the management of hyperglycaemia are becoming increasingly complex and difficult to write. The first recommendation is to not drift HbAlc, the second, is to use metformin as first line treatment for most patients in the absence of intolerance. The delay in passing to combination (two 0ADs) remains excessive; it must be done without delay at 6.5 or 7% HbA1c. There are four possible combinations today (acarbose, sulfonylureas, gliptins, glitazones). Then, one can choose between triple oral therapy, insulin and GLP1 analogues. Deciding who needs what becomes more difficult regarding the different phenotypes and specificities of each patient, the economic considerations and the benefit/risk of the different classes or strategies. Thereby, recommendations cannot enter so many details and strategies. The need for continuing medical education and the referral to diabetologist more often is becoming essential.

Combination treatment in the management of type 2 diabetes: focus on vildagliptin and metformin as a single tablet.

Vildagliptin is a potent and selective inhibitor of dipeptidyl peptidase-IV (DPP-4), orally active, that improves glycemic control in patients with type 2 diabetes (T2DM) primarily by enhancing pancreatic (alpha and beta) islet function. Thus vildagliptin has been shown both to improve insulin secretion and to suppress the inappropriate glucagon secretion seen in patients with T2DM. Vildagliptin reduces HbA(1c) when given as monotherapy, without weight gain and with minimal hypoglycemia, or in combination with the most commonly prescribed classes of oral hypoglycemic drugs: metformin, a sulfonylurea, a thiazolidinedione, or insulin. Metformin, with a different mode of action not addressing beta-cell dysfunction, has been used for about 50 years and still represents the universal first line therapy of all guidelines. However, given the multiple pathophysiological abnormalities in T2DM and the progressive nature of the disease, intensification of therapy with combinations is typically required over time. Recent guidelines imply that patients will require pharmacologic combinations much earlier to attain and sustain the increasingly stringent glycemic targets, with careful drug selection to avoid unwanted adverse events, especially hypoglycemia. The combination of metformin and vildagliptin offers advantages when compared to currently used combinations with additive efficacy and complimentary mechanisms of action, since it does not increase the risk of hypoglycemia and does not promote weight gain. Therefore, by specifically combining these agents in a single tablet, there is considerable potential to achieve better blood glucose control and to improve compliance to therapy.

Impairment of the antioxidant properties of serum albumin in patients with diabetes: protective effects of metformin.

Free radical production is increased during diabetes. Serum albumin is a major antioxidant agent, and structural modification of albumin induced by glucose or free radicals impairs its antioxidant properties. Therefore the aim of the present study was to compare the antioxidant capacities and structural changes in albumin in patients with T2DM (Type 2 diabetes mellitus) treated with MET (metformin) or SU (sulfonylureas) and in healthy control subjects. Structural changes in albumin were studied by fluorescence quenching in the presence of acrylamide. Albumin thiols and fructosamines, reflecting oxidized and glycation-induced changes in serum albumin respectively, were assessed. Structural changes in albumin were demonstrated by a significant decrease in fluorescence quenching in patients with T2DM, with patients treated with MET exhibiting a significant difference in the conformation of albumin compared with patients treated with SU. Oxidation, resulting in a significant decrease in thiol groups and plasma total antioxidant capacity, and glycation, associated with a significant increase in fructosamines, were both found when comparing healthy control subjects with patients with T2DM. When patients treated with MET were compared with those treated with SU, oxidative stress and glycation were found to be significantly lower in MET-treated patients. In conclusion, patients with T2DM have a decrease in the antioxidant properties of serum albumin which may aggravate oxidative stress and, thus, contribute to vascular and metabolic morbidities. Moreover, a significant protection of albumin was found in patients with T2DM treated with MET.

Comparison of the effects of zinc alone and zinc associated with selenium and vitamin E on insulin sensitivity and oxidative stress in high-fructose-fed rats.

PURPOSE: In the present study, we investigated the effect of an association of micronutrients (zinc (Zn), selenium (Se) and vitamin E (vit E)) on insulin activity and antioxidant status in an animal model of insulin resistance, the high-fructose-fed rat. PROCEDURES: Five experimental groups were compared: a control group (C) receiving a standard diet, a high-fructose-fed group (F) where 58% of the diet carbohydrate was fructose, a high-fructose-fed group supplemented with Zn alone (FZn group), a high-fructose-fed group supplemented micronutrients (Zn, Se and vit E) (FMicro group). A fifth group consumed a high-fructose diet and received metformin in the drinking water (200mg/day/rat) (FMet group). Insulin sensitivity was measured using the euglycemic hyperinsulinic glucose clamp technique. Metabolic parameters, trace elements and antioxidant parameters were measured in blood samples from all groups. RESULTS: High-fructose-fed rats were resistant to insulin as indicated by the lower glucose infusion rate. The insulin sensitivity of FZn, FMicro and FMet groups was higher than that of F group, with the highest insulin sensitivity for the FMicro group. No statistically significant difference in glycemia between the groups was observed. The ratio of reduced to oxidized glutathione was higher in FZn and FMicro groups than in all other groups, as a consequence of decreased oxidized glutathione. CONCLUSION: Our results provide direct evidence that micronutrients have a beneficial effect on insulin sensitivity and some components of the antioxidant defense system in an animal model of insulin resistance.

In vivo assessment of cardiac insulin resistance by nuclear probes using an iodinated tracer of glucose transport.

PURPOSE: Insulin resistance, implying depressed cellular sensitivity to insulin, is a risk factor for type 2 diabetes and cardiovascular disease. This study is the first step towards the development of a technique of insulin resistance measurement in humans with a new tracer of glucose transport, [(123)I]6-deoxy-6-iodo-D-glucose (6DIG). METHODS: We investigated 6DIG kinetics in anaesthetised control rats and in three models of insulin-resistant rats: fructose fed, Zucker and ZDF. The study of myocardial 6DIG activity was performed under two conditions: first, 6DIG was injected under the baseline condition and then it was injected after a bolus injection of insulin. After each injection, radioactivity was measured over 45 min by external detection via NaI probes, in the heart and blood. A tri-compartment model was developed to obtain fractional transfer coefficients of 6DIG from the blood to the heart. RESULTS: These coefficients were significantly increased with insulin in control rats and did not change significantly in insulin-resistant rats. The ratio of the coefficient obtained under insulin to that obtained under basal conditions gave an index of cardiac insulin resistance for each animal. The mean values of these ratios were significantly lower in insulin-resistant than in control rats: 1.16 +/- 0.06 vs 2.28 +/- 0.18 (p < 0.001) for the fructose-fed group, 0.92 +/- 0.05 vs 1.62 +/- 0.25 (p < 0.01) for the Zucker group and 1.34 +/- 0.06 vs 2.01 +/- 0.26 (p < 0.05) for the ZDF group. CONCLUSION: These results show that 6DIG could be a useful tracer to image cardiac insulin resistance.

Assessment of insulin resistance in fructose-fed rats with 125I-6-deoxy-6-iodo-D-glucose, a new tracer of glucose transport.

PURPOSE: Insulin resistance, characterised by an insulin-stimulated glucose transport defect, is an important feature of the pre-diabetic state that has been observed in numerous pathological disorders. The purpose of this study was to assess variations in glucose transport in rats using (125)I-6-deoxy-6-iodo-D-glucose (6DIG), a new tracer of glucose transport proposed as an imaging tool to assess insulin resistance in vivo. METHODS: Two protocols were performed, a hyperinsulinaemic-euglycaemic clamp and a normoinsulinaemic-normoglycaemic protocol, in awake control and insulin-resistant fructose-fed rats. The tracer was injected at steady state, and activity in 11 tissues and the blood was assessed ex vivo at several time points. A multicompartmental mathematical model was developed to obtain fractional transfer coefficients of 6DIG from the blood to the organs. RESULTS: Insulin sensitivity of fructose-fed rats, estimated by the glucose infusion rate, was reduced by 40% compared with control rats. At steady state, 6DIG uptake was significantly stimulated by insulin in insulin-sensitive tissues of control rats (basal versus insulin: diaphragm, p < 0.01; muscle, p<0.05; heart, p<0.001), whereas insulin did not stimulate 6DIG uptake in insulin-resistant fructose-fed rats. Moreover, in these tissues, the fractional transfer coefficients of entrance were significantly increased with insulin in control rats (basal vs insulin: diaphragm, p<0.001; muscle, p<0.001; heart, p<0.01) whereas no significant changes were observed in fructose-fed rats. CONCLUSION: This study sets the stage for the future use of 6DIG as a non-invasive means for the evaluation of insulin resistance by nuclear imaging.