Cardiovascular events after a dramatic reduction of HbA1c in hospitalized subjects with type 2 diabetes and high long-term glucose exposure.

OBJECTIVE: In long-lasting diabetes, a dramatic reduction of HbA1c can precede adverse events such as worsening retinopathies or painful neuropathies. We have now analyzed its possible link with later cardiovascular events in subjects with type 2 diabetes, according to their long-term glucose exposure evaluated by skin autofluorescence (SAF) measured with an AGE-READER (Diagnoptics, Groningen, The Netherland). RESEARCH DESIGN AND METHODS: We studied retrospectively a cohort of patients hospitalized for uncontrolled and/or complicated type 2 diabetes from 2009 to 2017. A previous dramatic reduction of HbA1c was defined by more than -1.5 %/4 months, and later cardiovascular events as myocardial infarction, stroke, revascularization procedures, and cardiovascular-related death. Survival analyses were performed before and after categorizing the subjects for their SAF. RESULTS: The 386 subjects were 57.5 % men, 62 ± 9 years old, with a 14 ± 9 years duration of diabetes, most were treated by insulin (63.7 %). The dramatic HbA1c reducers (-3.0 ± 1.5 %) represented 16.5 % of the population. During the 51 months (IQR: 30-71) of follow-up, 53 cardiovascular events occurred and were related to the SAF (2.70 ± 0.64 AUs). Linkage was established between the SAF, the reduction of HbA1c and the cardiovascular events (p = 0.017). With a SAF higher than the median (2.65 AUs), the dramatic reduction of HbA1c was related to later cardiovascular events (HR: 3.84, 95%CI: 1.68-8.76). CONCLUSIONS: A dramatic decline of HbA1c leads to a higher risk of cardiovascular events in hospitalized subjects with type 2 diabetes and a high long-term glucose exposure.

Skin autofluorescence predicts cancer in subjects with type 2 diabetes.

INTRODUCTION: Subjects with type 2 diabetes have an excess risk of cancer. The potential role of advanced glycation end products (AGEs) accumulated during long-term hyperglycemia in cancer development has been suggested by biological studies but clinical data are missing. AGEs can be estimated by measuring the skin autofluorescence. We searched whether the skin autofluorescence could predict new cancers in persons with type 2 diabetes. RESEARCH DESIGN AND METHODS: From 2009 to 2015, we measured the skin autofluorescence of 413 subjects hospitalized for uncontrolled or complicated type 2 diabetes, without any history of cancer. The participants were followed for at least 1 year and the occurrences of new cancers were compared according to their initial skin autofluorescences. RESULTS: The participants were mainly men (57.9%), with poorly controlled (HbA1c 72±14 mmol/mol or 8.7%±1.8%) and/or complicated type 2 diabetes. Their median skin autofluorescence was 2.6 (2.2-3.0) arbitrary units. Forty-five new cancer cases (10.9%) were registered during 4.8±2.3 years of follow-up: 75.6% of these subjects had skin autofluorescence higher than the median (χ2: p=0.001). By Cox regression analysis adjusted for age, gender, body mass index, history of smoking and renal parameters, skin autofluorescence >2.6 predicted a 2.57-fold higher risk of cancer (95% CI 1.28 to 5.19, p=0.008). This association remained significant after excluding the eight cancers that occurred in the 4 years after inclusion (OR 2.95, 95% CI 1.36 to 6.38, p=0.006). As a continuous variable, skin autofluorescence was also related to new cancers (OR 1.05, 95% CI 1.01 to 1.10, p=0.045). CONCLUSIONS: Skin autofluorescence, a potential marker of glycemic memory, predicts the occurrence of cancer in subjects with type 2 diabetes. This relation provides a new clinical argument for the role of AGEs in cancer. Their estimation by measuring the skin autofluorescence may help select subjects with diabetes in cancer screening programs.

Plasma concentrations of lipoproteins and risk of lower-limb peripheral artery disease in people with type 2 diabetes: the SURDIAGENE study.

AIMS/HYPOTHESIS: The lipid profile has not been fully investigated in individuals with peripheral artery disease (PAD). We aimed to evaluate the relationship between plasma concentrations of lipoproteins and the prevalence of lower-limb PAD at baseline and its incidence during follow-up in people with type 2 diabetes. METHODS: Plasma concentrations of total cholesterol, HDL-cholesterol, triacylglycerol and apolipoprotein (Apo) A-I, ApoA-II, ApoB-100 and Apo(a) were measured at baseline using colorimetric or MS methods in the SURDIAGENE cohort. Total cholesterol/HDL-cholesterol ratio, non-HDL-cholesterol and LDL-cholesterol were estimated using computation formulas. Logistic and Cox proportional hazard regression models were fitted to estimate OR or HR, with related 95% CI, for baseline prevalence or incidence of major PAD (lower-limb amputation or requirement of revascularisation) during follow-up by increasing lipoprotein tertiles, after adjustment for key confounders. RESULTS: Among 1468 participants (women 42%, mean ± SD age 65 ± 11 years, duration of diabetes 14 ± 10 years at baseline), 129 (8.8%) had a baseline history of major PAD. Major PAD was less prevalent at baseline in the highest (vs lowest) tertile of HDL-cholesterol (OR 0.42 [95% CI 0.26, 0.71], p = 0.001) and ApoA-I (OR 0.39 [95% CI 0.23, 0.67], p = 0.0007), and more frequent in the highest tertile of total cholesterol/HDL-cholesterol ratio (OR 1.95 [95% CI 1.18, 3.24], p = 0.01). Among 1339 participants without a history of PAD at baseline, incident PAD occurred in 97 (7.2%) during a median (25th-75th percentile) duration of follow-up of 7.1 (4.4-10.7) years, corresponding to 9685 person-years and an incidence rate of 9.8 (95% CI 8.0, 12.0) per 1000 person-years. The risk of incident PAD was lower in the top (vs bottom) tertile of HDL-cholesterol (HR 0.54 [95% CI 0.30, 0.95], p = 0.03) or ApoA-I (HR 0.50 [95% CI 0.28, 0.86], p = 0.01) and higher in the top tertile of total cholesterol/HDL-cholesterol ratio (HR 2.81 [95% CI 1.61, 5.04], p = 0.0002) and non-HDL-cholesterol (HR 1.80 [95% CI 1.06, 3.12], p = 0.03). CONCLUSIONS/INTERPRETATION: We reported independent associations between HDL-cholesterol, ApoA-I, total cholesterol/HDL-cholesterol ratio or non-HDL-cholesterol and the prevalence or the incidence of major PAD in people with type 2 diabetes. Our findings provide a picture of lipoprotein profile in people with type 2 diabetes. Graphical abstract.

Relationship Between Diabetic Retinopathy Stages and Risk of Major Lower-Extremity Arterial Disease in Patients With Type 2 Diabetes.

OBJECTIVE: We evaluated the association between diabetic retinopathy stages and lower-extremity arterial disease (LEAD), its prognostic value, and the influence of potential contributors to this relationship in a prospective cohort of patients with type 2 diabetes. RESEARCH DESIGN AND METHODS: Diabetic retinopathy was staged at baseline as absent, nonproliferative, or proliferative. A Cox regression model was fitted in order to compute the hazard ratio (HR) (95% CI) for major LEAD (lower-limb amputation or revascularization) during follow-up by baseline retinopathy stages. The retinopathy-LEAD association was assessed in subgroups by age, sex, diabetes duration, HbA1c, systolic blood pressure, diabetic kidney disease, smoking, and macrovascular disease at baseline. The performance of retinopathy in stratifying LEAD risk was assessed by using the C statistic, integrated discrimination improvement (IDI), and net reclassification improvement (NRI). RESULTS: Among 1,320 participants without a history of LEAD at baseline, 94 (7.1%) developed a major LEAD during a 7.1-year median follow-up (incidence rate 9.6 per 1,000 person-years [95% CI 7.8-11.7]). The LEAD incidence rate (per 1,000 person-years) increased as retinopathy worsened: it was 5.5 (95% CI 3.9-7.8) in participants in whom retinopathy was absent, 14.6 (11.1-19.3) in those with nonproliferative retinopathy, and 20.1 (11.1-36.3) in those with proliferative retinopathy. Nonproliferative retinopathy (adjusted HR 2.31 [95% CI 1.43-3.81], P = 0.0006) and proliferative retinopathy (3.14 [1.40-6.15], P = 0.007) remained associated with major LEAD. No heterogeneity was observed across subgroups. Retinopathy enhanced the C statistic (+0.023 [95% CI 0.003-0.044], P = 0.02), IDI (0.209 [0.130-0.321], P < 0.001), and NRI (0.562 [0.382-0.799], P < 0.001) values for risk of LEAD, beyond traditional risk factors. CONCLUSIONS: An independent dose-response relationship was identified between diabetic retinopathy stages and major LEAD. Retinopathy yielded incremental prognostic information for stratifying risk of LEAD, suggesting its usefulness as a predictor of LEAD.

Comparison of a new versus standard removable offloading device in patients with neuropathic diabetic foot ulcers: a French national, multicentre, open-label randomized, controlled trial.

INTRODUCTION: The offloading is crucial to heal neuropathic diabetic foot ulcer (DFU). Removable offloading are the most used devices. Orthèse diabète is a new customized removable knee-high offloading device immobilizing foot and ankle joints, with some specific and innovative features that may improve offloading. We aimed to evaluate the efficiency of this device in DFU healing. RESEARCH, DESIGN AND METHODS: The evaluation of Offloading using a new removable ORTHOsis in DIABetic foot study is a French multicenter (13 centers) randomized controlled trial with blinded end points evaluation. Adults with neuropathic DFU were randomly assigned to either Orthèse Diabète (experimental device), or any type of conventional (usually used in France) removable offloading devices (control group). The primary outcome was the 3-month proportion of patients with fully healed DFU. RESULTS: Among 112 randomized patients (men 78%, age 62±10 years), the primary outcome occurred in 19 (33%) participants using conventional device vs 19 (35%) Orthèse Diabète users (p=0.79). Study groups were also comparable in terms of prespecified secondary end points including occurrence of new DFU (25% vs 27% in conventional and experimental groups), ipsilateral lower-limb amputation (4% vs 10%) or infectious complications (14% vs 13%) (p>0.05 for all). Adverse events were comparable between groups, including 4 deaths unrelated to study allocation (1 sudden death, 2 ventricular arrhythmias and 1 pancreatic cancer). Adverse events believed to be related to the device were higher in the Orthèse Diabète group than in the control group (15% vs 4%). Orthèse Diabète was less frequently worn than conventional devices (46% vs 66%, p=0.04). CONCLUSIONS: Orthèse Diabète, a new removable offloading orthosis immobilizing foot and ankle joints did not show superiority compared with conventional removable devices in neuropathic DFU healing and cannot be recommended to heal DFU. TRIAL REGISTRATION NUMBER: NCT01956162.

Euglycemic ketoacidosis induced by therapeutic fasting in a non-diabetic patient.

BACKGROUND: Ketoacidosis is a severe metabolic complication mainly reported in diabetic patients. Therapeutic fasting is a millennial worldwide practice, believed to improve a large panel of health conditions, but its efficiency and safety profile have not yet been established. We report here a case of euglycemic ketoacidosis in a non-diabetic woman. CASE DESCRIPTION: A 51-year-old woman without a history of excessive alcohol use or medical history, except for a depressive disorder, was admitted in the emergency room for altered general status, deep asthenia, muscular weakness, articular pain, nausea, vomiting, and consciousness disorders. She was practicing during the previous 48 h a therapeutic fasting following a progressive restrictive diet for 4 d. She was diagnosed with ketoacidosis and hospitalized in the intensive care unit. Her laboratory test results indicated pH 7.28, bicarbonate 7 mmol/L, significant ketone bodies, glycemia 8.9 mmol/L without glycosuria, and negative blood alcohol assessment. Glycated hemoglobin was 5.5%, and blood glucose never went above 9 mmol/L. Serum concentrations of free fatty acids were high at 1.13 mmol/L (normal range: 0.13-0.45). Plasma insulin and peptide C were in the normal ranges. Comprehensive plasma and urinary biochemistry panels, including energetic substrates, and chromatography of amino acids and organic acids did not indicate any energetic or metabolic deficiency. The ketoacidosis regressed, and the overall outcome was favorable after intravenous glucose infusion for 48 h, without insulin requirement. CONCLUSIONS: This report is the first case, to our knowledge, of euglycemic ketoacidosis thought to be induced by therapeutic fasting in a non-diabetic patient. Practitioners should be aware of this complication of fasting.

Lower extremity arterial disease in patients with diabetes: a contemporary narrative review.

Lower-extremity arterial disease (LEAD) is a major endemic disease with an alarming increased prevalence worldwide. It is a common and severe condition with excess risk of major cardiovascular events and death. It also leads to a high rate of lower-limb adverse events and non-traumatic amputation. The American Diabetes Association recommends a widespread medical history and clinical examination to screen for LEAD. The ankle brachial index (ABI) is the first non-invasive tool recommended to diagnose LEAD although its variable performance in patients with diabetes. The performance of ABI is particularly affected by the presence of peripheral neuropathy, medial arterial calcification, and incompressible arteries. There is no strong evidence today to support an alternative test for LEAD diagnosis in these conditions. The management of LEAD requires a strict control of cardiovascular risk factors including diabetes, hypertension, and dyslipidaemia. The benefit of intensive versus standard glucose control on the risk of LEAD has not been clearly established. Antihypertensive, lipid-lowering, and antiplatelet agents are obviously worthfull to reduce major cardiovascular adverse events, but few randomised controlled trials (RCTs) have evaluated the benefits of these treatments in terms of LEAD and its related adverse events. Smoking cessation, physical activity, supervised walking rehabilitation and healthy diet are also crucial in LEAD management. Several advances have been achieved in endovascular and surgical revascularization procedures, with obvious improvement in LEAD management. The revascularization strategy should take into account several factors including anatomical localizations of lesions, medical history of each patients and operator experience. Further studies, especially RCTs, are needed to evaluate the interest of different therapeutic strategies on the occurrence and progression of LEAD and its related adverse events in patients with diabetes.

The evaluation of off-loading using a new removable oRTHOsis in DIABetic foot (ORTHODIAB) randomized controlled trial: study design and rational.

BACKGROUND: Off-loading is essential for diabetic foot management, but remains understudied. The evaluation of Off-loading using a new removable oRTHOsis in DIABetic foot (ORTHODIAB) trial aims to evaluate the efficacy of a new removable device "Orthèse Diabète" in the healing of diabetic foot. METHODS/DESIGN: ORTHODIAB is a French multi-centre randomized, open label trial, with a blinded end points evaluation by an adjudication committee according to the Prospective Randomized Open Blinded End-point. Main endpoints are adjudicated based on the analysis of diabetic foot photographs. Orthèse Diabète is a new removable off-loading orthosis (PROTEOR, France) allowing innovative functions including real-time evaluation of off-loading and estimation of patients' adherence. Diabetic patients with neuropathic plantar ulcer or amputation wounds (toes or transmetatarsal) are assigned to one of 2 parallel-groups: Orthèse Diabète or control group (any removable device) according to a central computer-based randomization. Study visits are scheduled for 6 months (days D7 and D14, and months M1, M2, M3, and M6). The primary endpoint is the proportion of patients whose principal ulcer is healed at M3. Secondary endpoints are: the proportion of patients whose principal ulcer is healed at M1, M2 and M6; the proportion of patients whose initial ulcers are all healed at M1, M2, M3, and M6; principal ulcer area reduction; time-related ulcer-free survival; development of new ulcers; new lower-extremity amputation; infectious complications; off-loading adherence; and patient satisfaction. The study protocol was approved by the French National Agency for Medicines and Health Products Safety, and by the ethics committee of Saint-Louis Hospital (Paris). Comprehensive study information including a Patient Information Sheet has been provided to each patient who must give written informed consent before enrolment. Monitoring, data management, and statistical analyses are providing by UMANIS Life Science (Paris), independently to the sponsor. Since 27/10/2013, 13 centres have agreed to participate in this study, 117 participants were included, and 70 have achieved the study schedules. The study completion is expected for the end of 2016, and the main results will be published in 2017. CONCLUSION: ORTHODIAB trial evaluates an innovating removable off-loading device, seeking to improve diabetic foot healing (ClinicalTrials.gov identifier: NCT01956162).

Insulin induces a positive relationship between the rates of ATP and glycogen changes in isolated rat liver in presence of glucose; a 31P and 13C NMR study.

BACKGROUND: There is an emerging theory suggesting that insulin, which is known to be the predominant postprandial anabolic hormone, is also a major regulator of mitochondrial oxidative phosphorylation in human skeletal muscle. However, little is known about its effects in the liver. Since there is a theoretical relationship between glycogen metabolism and energy status, a simultaneous and continuous investigation of hepatic ATP and glycogen content was performed in intact and isolated perfused liver by 31P and 13C nuclear magnetic resonance (NMR) The hepatic rates of ATP and glycogen changes were evaluated with different concentrations of insulin and glucose during continuous and short-term supply. RESULTS: Liver from rats fed ad libitum were perfused with Krebs-Henseleit Buffer (KHB)(controls) or KHB containing 6 mM glucose, 30 mM glucose, insulin alone, insulin + 6 mM glucose, insulin + 30 mM glucose. In the control, glycogenolysis occurred at a rate of -0.53 +/- 0.021 % x min(-1) and ATP content decreased at a rate of -0.28 +/- 0.029 % x min(-1). In the absence of insulin, there was a close proportional relationship between the glycogen flux and the glucose concentration, whereas ATP rates never varied. With insulin + glucose, both glycogen and ATP rates were strongly related to the glucose concentration; the magnitude of net glycogen flux was linearly correlated to the magnitude of net ATP flux: flux(glycogen) = 72.543(fluxATP) + 172.08, R2 = 0.98. CONCLUSION: Only the co-infusion of 30 mM glucose and insulin led to (i) a net glycogen synthesis, (ii) the maintenance of the hepatic ATP content, and a strong positive correlation between their net fluxes. This has never previously been reported. The specific effect of insulin on ATP change is likely related to a rapid stimulation of the hepatic mitochondrial oxidative phosphorylation. We propose that variations in the correlation between rates of ATP and glycogen changes could be a probe for insulin resistance due to the action of substrates, drugs or pathologic situations. Consequently, any work evaluating insulin resistance on isolated organs or in vivo should determine both ATP and glycogen fluxes.

Estimation of glomerular filtration rate in diabetic subjects: Cockcroft formula or modification of Diet in Renal Disease study equation?

OBJECTIVE: The Cockcroft-Gault formula is recommended for the evaluation of renal function in diabetic patients. The more recent Modification of Diet in Renal Disease (MDRD) study equation seems more accurate, but it has not been validated in diabetic patients. This study compares the two methods. RESEARCH DESIGN AND METHODS: In 160 diabetic patients, we compared the Cockcroft-Gault formula and MDRD equation estimations to glomerular filtration rates (GFRs) measured by an isotopic method ((51)Cr-EDTA) by correlation studies and a Bland-Altman procedure. Their accuracy for the diagnosis of moderately (GFR <60 ml . min(-1) . 1.73 m(-2)) or severely (GFR <30 ml . min(-1) . 1.73 m(-2)) impaired renal function were compared with receiver operating characteristic (ROC) curves. RESULTS: Both the Cockcroft-Gault formula (r = 0.74; P < 0.0001) and MDRD equation (r = 0.81; P < 0.0001) were well correlated with isotopic GFR. The Bland-Altman procedure revealed a bias for the MDRD equation, which was not the case for the Cockcroft-Gault formula. Analysis of ROC curves showed that the MDRD equation had a better maximal accuracy for the diagnosis of moderate (areas under the curve [AUCs] 0.868 for the Cockcroft-Gault formula and 0.927 for the MDRD equation; P = 0.012) and severe renal failure (AUC 0.883 for the Cockcroft-Gault formula and 0.962 for the MDRD equation; P = 0.0001). In the 87 patients with renal insufficiency, the MDRD equation estimation was better correlated with isotopic GFR (Cockcroft-Gault formula r = 0.57; the MDRD equation r = 0.78; P < 0.01), and it was not biased as evaluated by the Bland-Altman procedure. CONCLUSIONS: Although both equations have imperfections, the MDRD equation is more accurate for the diagnosis and stratification of renal failure in diabetic patients.