Effect of empagliflozin on ectopic fat stores and myocardial energetics in type 2 diabetes: the EMPACEF study.

BACKGROUND: Empagliflozin is a sodium-glucose cotransporter 2 (SGLT2) inhibitor that has demonstrated cardiovascular and renal protection in patients with type 2 diabetes (T2D). We hypothesized that empaglifozin (EMPA) could modulate ectopic fat stores and myocardial energetics in high-fat-high-sucrose (HFHS) diet mice and in type 2 diabetics (T2D). METHODS: C57BL/6 HFHS mice (n = 24) and T2D subjects (n = 56) were randomly assigned to 12 weeks of treatment with EMPA (30 mg/kg in mice, 10 mg/day in humans) or with placebo. A 4.7 T or 3 T MRI with 1H-MRS evaluation-myocardial fat (primary endpoint) and liver fat content (LFC)-were performed at baseline and at 12 weeks. In humans, standard cardiac MRI was coupled with myocardial energetics (PCr/ATP) measured with 31P-MRS. Subcutaneous (SAT) abdominal, visceral (VAT), epicardial and pancreatic fat were also evaluated. The primary efficacy endpoint was the change in epicardial fat volume between EMPA and placebo from baseline to 12 weeks. Secondary endpoints were the differences in PCr/ATP ratio, myocardial, liver and pancreatic fat content, SAT and VAT between groups at 12 weeks. RESULTS: In mice fed HFHS, EMPA significantly improved glucose tolerance and increased blood ketone bodies (KB) and ß-hydroxybutyrate levels (p < 0.05) compared to placebo. Mice fed HFHS had increased myocardial and liver fat content compared to standard diet mice. EMPA significantly attenuated liver fat content by 55%, (p < 0.001) but had no effect on myocardial fat. In the human study, all the 56 patients had normal LV function with mean LVEF = 63.4 ± 7.9%. Compared to placebo, T2D patients treated with EMPA significantly lost weight (- 2.6 kg [- 1.2; - 3.7]) and improved their HbA1c by 0.88 ± 0.74%. Hematocrit and EPO levels were significantly increased in the EMPA group compared to placebo (p < 0.0001, p = 0.041). EMPA significantly increased glycosuria and plasma KB levels compared to placebo (p < 0.0001, p = 0.012, respectively), and significantly reduced liver fat content (- 27 ± 23 vs. - 2 ± 24%, p = 0.0005) and visceral fat (- 7.8% [- 15.3; - 5.6] vs. - 0.1% [- 1.1;6.5], p = 0.043), but had no effect on myocardial or epicardial fat. At 12 weeks, no significant change was observed in the myocardial PCr/ATP (p = 0.57 between groups). CONCLUSIONS: EMPA effectively reduced liver fat in mice and humans without changing epicardial, myocardial fat or myocardial energetics, rebutting the thrifty substrate hypothesis for cardiovascular protection of SGLT2 inhibitors. Trial registration NCT, NCT03118336. Registered 18 April 2017, https://clinicaltrials.gov/ct2/show/NCT03118336.

Exenatide decreases liver fat content and epicardial adipose tissue in patients with obesity and type 2 diabetes: a prospective randomized clinical trial using magnetic resonance imaging and spectroscopy.

AIM: To conduct a prospective randomized trial to investigate the effect of glucagon-like peptide-1 (GLP-1) analogues on ectopic fat stores. METHODS: A total of 44 obese subjects with type 2 diabetes uncontrolled on oral antidiabetic drugs were randomly assigned to receive exenatide or reference treatment according to French guidelines. Epicardial adipose tissue (EAT), myocardial triglyceride content (MTGC), hepatic triglyceride content (HTGC) and pancreatic triglyceride content (PTGC) were assessed 45 min after a standardized meal with 3T magnetic resonance imaging and proton magnetic resonance spectroscopy before and after 26 weeks of treatment. RESULTS: The study population had a mean glycated haemoglobin (HbA1c) level of 7.5 ± 0.2% and a mean body mass index of 36.1 ± 1.1 kg/m(2) . Ninety five percent had hepatic steatosis at baseline (HTGC ≥ 5.6%). Exenatide and reference treatment led to a similar improvement in HbA1c (-0.7 ± 0.3% vs. -0.7 ± 0.4%; p = 0.29), whereas significant weight loss was observed only in the exenatide group (-5.5 ± 1.2 kg vs. -0.2 ± 0.8 kg; p = 0.001 for the difference between groups). Exenatide induced a significant reduction in EAT (-8.8 ± 2.1%) and HTGC (-23.8 ± 9.5%), compared with the reference treatment (EAT: -1.2 ± 1.6%, p = 0.003; HTGC: +12.5 ± 9.6%, p = 0.007). No significant difference was observed in other ectopic fat stores, PTGC or MTGC. In the group treated with exenatide, reductions in liver fat and EAT were not associated with homeostatic model assessment of insulin resistance index, adiponectin, HbA1c or fructosamin change, but were significantly related to weight loss (r = 0.47, p = 0.03, and r = 0.50, p = 0.018, respectively). CONCLUSION: Our data indicate that exenatide is an effective treatment to reduce liver fat content and epicardial fat in obese patients with type 2 diabetes, and these effects are mainly weight loss dependent.

Independent positive association of plasma ß-carotene concentrations with adiponectin among non-diabetic obese subjects.

PURPOSE: Many epidemiological studies find an inverse correlation between carotenoids intake or carotenoids plasma concentrations and body mass index (BMI), insulin resistance or metabolic syndrome in the general population. However, it is not clear whether these relationships occur in obese population. METHODS: We conducted a cross-sectional study in 108 obese non-diabetic patients. RESULTS: There was an inverse correlation between plasma levels of pro-vitamin A carotenoids (α-carotene, ß-carotene and ß-cryptoxanthin) and both BMI and insulin resistance (estimated by the HOMA-IR). No correlation between plasma concentrations of lycopene or lutein/zeaxanthin and BMI or insulin resistance was found. The inverse association between the three pro-vitamin A carotenoids and HOMA-IR disappeared after adjustment for BMI and waist circumference. Interestingly, we identified a positive association between concentrations of ß-carotene and adiponectin in plasma that was independent of sex, age, smoking status, BMI and waist circumference. To our knowledge, such association has never been described in obese patients. CONCLUSION: These results suggest the existence of a favourable effect of ß-carotene on insulin sensitivity in obese individuals that could involve a positive regulation of adiponectin, either directly or via its pro-vitamin A activity. The demonstration of the potential benefits of ß-carotene towards insulin sensitivity would open the way to dietary strategies to prevent metabolic syndrome.

Obstructive sleep apnoea syndrome in patients living with diabetes: Which patients should be screened?

AIM: Because type 2 diabetes (T2D) is related to obesity, it is often associated with obstructive sleep apnoea syndrome (OSAS), although OSAS is also frequently diagnosed in patients with type 1 diabetes (T1D) and may promote gestational diabetes. Thus, this systematic review of the scientific evidence aimed to evaluate the epidemiological association between OSAS and all forms of diabetes, the current understanding of the pathophysiological mechanisms behind these associations, the expected benefits and limitations of OSAS treatment in patients with diabetes and, finally, to propose which patients require screening for OSAS. METHODS: A panel comprising French expert endocrinologists and pneumologists was convened. Two of these experts made a search of the relevant literature for each subpart of the present report; all panel experts then critically reviewed the entire report separately as well as collectively. RESULTS: There is little evidence to support the notion that OSAS treatment improves glycated haemoglobin, although it may improve nighttime blood glucose control and insulin sensitivity. However, there is robust evidence that OSAS treatment lowers 24-h blood pressure. CONCLUSION: The high prevalence of OSAS in patients with T1D and T2D justifies screening for the syndrome, which should be based on clinical symptoms, as the benefits of OSAS treatment are mainly improvement of symptoms related to sleep apnoea. There are also several clinical situations wherein screening for OSAS seems justified in patients with diabetes even when they have no symptoms, particularly to optimalize control of blood pressure in cases of resistant hypertension and microvascular complications.

A pilot study of gestational diabetes mellitus not controlled by diet alone: First-line medical treatment with myoinositol may limit the need for insulin.

AIM: This study assessed whether myoinositol might be a first-line medical treatment for gestational diabetes mellitus (GDM). METHODS: For 12 months, women with GDM not controlled by diet (n=32) were prospectively treated with myoinositol 1200mg and folic acid 400µg/day, while consecutive women (n=28) with insulin-requiring GDM treated during the previous year at our centre constituted the control group. Baseline characteristics and care were similar in both groups. RESULTS: Insulin was required in eight women (25%) in the myoinositol group who, compared with the 24 who did not need insulin, were older (37±5 vs. 32±5 years, respectively; P=0.018) and had a larger percentage of high self-monitored glucose values (45±8% vs. 32±14%; P<0.0001) during the week prior to the introduction of myoinositol treatment. All of the women had similar pregnancy outcomes regardless of their GDM management, although less labour induction was required in the myoinositol group (OR: 0.22 [0.07-0.65]), which had no side effects. CONCLUSION: This pilot study suggests that myoinositol may be a safe first-line medical treatment for uncontrolled GDM.

Systemic allergy to human insulin and its rapid and long acting analogs: successful treatment by continuous subcutaneous insulin lispro infusion.

Since the introduction of highly purified human recombinant insulin, allergy to insulin has become a very rare clinical situation, encountered in less than 1% of patients. It results in potentially life-threatening immediate or delayed, local and general manifestations. Different treatments of unequal efficiency have been proposed, the use of insulin analogs showing benefits in certain situations. We report the case of a type 2 diabetic patient who presented local reactions and then an anaphylactic shock after the introduction of insulin analog premixes. Intra-dermal reactions performed with porcine, human and insulin analogs preparations (aspart, lispro, glargine) were all positive, as well as the specific anti-insulin IgE measurement. Because we could not achieve normoglycaemia with maximal oral treatment and low caloric diet, we decided to attempt a desensitisation by continuous subcutaneous infusion of insulin lispro, since the lowest skin reaction was obtained with this insulin. We were able to induce a tolerance, by means of very low basal rate, very slowly increased, without any boluses, and maintaining antihistamine therapy. Six months later, the patient remains free of any symptom and has achieved a quite good glycaemic control. We describe for the first time a case of allergy to human insulin and to all available rapid and long acting analogs. We show the interest of a treatment with CSII of analogs in order to induce tolerance.

[Gelatinous bone marrow transformation in anorexia nervosa]. / Transformation gélatineuse de la moelle osseuse au cours de l'anorexie mentale.

Moderate hematologic abnormalities, like anemia or leukopenia, are frequently seen in anorexia nervosa, whereas pancytopenia and bone marrow abnormalities are uncommon. We report a case of tricytopenia with gelatinous bone marrow transformation in anorexia nervosa. Marrow gelatinous transformation (also called serous fat atrophy or starvation marrow) is characterized by the association of marrow hypoplasia and interstitial infiltration of a ground gelatinous substance (acidic mucopolysaccharides). Changes in peripheral blood cell counts are various and moderate, and do not always reflect the severity of bone marrow damage. The pathogenesis is not yet well elucidated but is certainly related to the nutritional status because gelatinous bone marrow transformation is found in anorexia nervosa and in other clinical situations with cachexia. Gelatinous transformation of the marrow is reversible with feeding.

Options for intensification of basal insulin in type 2 diabetes: Premeal insulin or short-acting GLP-1 receptor agonists?

Type 2 diabetes is an evolutive disease with a progressive defect of beta-cell insulin secretion. This characteristic points to a need for treatment that takes into account such a natural history. When oral antidiabetic drugs fail to achieve the patient's target HbA1c level, basal insulin treatment is usually initiated and titrated in association with oral drugs to manage fasting hyperglycaemia. Over a period of time, it is enough to simply achieve the HbA1c target. However, when even a good fasting blood glucose level is no longer sufficient to control overall glycaemia, then prandial treatment must be combined with the titrated basal insulin to deal with the postprandial hyperglycaemia responsible for the elevation of HbA1c. Of the different therapeutic options now available for this, rapid-acting insulins and GLP-1 receptor agonists (RAs) can be used. Rapid-acting insulins can be added either at each meal, achieving full insulin supplementation with a basal-bolus regimen, or at the main meal only as a "basal-plus" regimen. Compared with the full basal-bolus, the basal-plus strategy is associated with fewer injections, yet provides similar efficacy in terms of HbA1c improvement, but with less weight gain and lower hypoglycaemic risk. As for GLP-1 RAs, numerous studies, and especially those using short-acting GLP-1 RAs, have demonstrated more pronounced effects on postprandial hyperglycaemia, good complementary effects with basal insulin, and significant improvement of HbA1c with no weight gain and a low risk of hypoglycaemia. Similarly, direct and indirect comparisons of the use of rapid-acting insulins and GLP-1 RAs to intensify basal insulin have shown comparable efficacy in terms of HbA1c control, but with less weight gain and fewer hypoglycaemic episodes with GLP-1 RAs.

On the meaning of low-dose ACTH(1-24) tests to assess functionality of the hypothalamic-pituitary-adrenal axis.

To analyse further the ACTH(1-24) low-dose test, which is of clinical interest, we have examined the dose-response relationship between plasma ACTH(1-24) and cortisol concentrations after i.v. administration of increasing doses (1, 5 or 250 microg) of ACTH(1-24) as a bolus. In addition, we have measured plasma ACTH(1-39) and cortisol levels after an insulin tolerance test (ITT). Although there was a dose response relationship between plasma ACTH(1-24) immunoreactivity and the dose injected, cortisol peaks were comparable, but lower than those reached after an ITT. Under these experimental conditions, an increase in plasma ACTH as low as 13 pmol/l (i.e. the increase obtained with the 1 microg dose) induced a near maximal cortisol response. Following injection of 1 microg ACTH(1-24), peak ACTH values were short lasting, similar to physiological daily bursts. After injection of 5 microg ACTH(1-24), plasma ACTH concentrations were higher than those reached during an ITT, but clearly shorter lasting. Injection of 250 microg ACTH(1-24) induced strikingly supraphysiological levels of plasma ACTH. We conclude that neither regular nor low-dose ACTH tests can fully reproduce the ITT. Our observations strongly suggest that the low-dose ACTH(1-24) test (1 microg) can be useful to estimate the adrenal sensitivity under basal, physiological conditions.

A study of the human aortic valve orifice by transesophageal echocardiography.

The transverse short-axis plane of the aortic valve was imaged by transesophageal echocardiography at a relatively high frame rate in 25 anesthetized patients undergoing heart surgery. The effective, time-averaged aortic valve area (a-AVA) was compared with areas obtained with triangular and circular valve orifice models (t-AVA and c-AVA, respectively). The aortic valve orifice was circular during 33.6% +/- 17.5% of systole. The relations between the triangular or circular aortic valve areas and a-AVA were as follows: t-AVA = 1.04 x a-AVA - 0.14 (r = 0.90; standard error of the estimate = 0.24 cm2) and c-AVA = 1.37 x a-AVA + 0.00 (r = 0.90; SEE = 0.30 cm2). Bias analysis showed no significant difference between a-AVA and t-AVA (bias = -0.04 +/- 0.23 cm2; difference not significant) but a significant overestimation of the average valve area by c-AVA (bias = +0.88 +/- 0.30 cm2; p < 0.001). Thus the aortic valve orifice was not circular for the entire duration of systole and valve area calculations based on a triangular model approximated a-AVA more closely than did those based on a circular model. These findings suggest that, for echocardiographic measurements that incorporate the aortic valve orifice area (e.g., stroke volume determinations), the use of a triangular valve area model, rather than a circular model, may produce more accurate results in anesthetized patients with heart disease.

Diabetic mastopathy, complication of type 1 diabetes mellitus: report of two cases and a review of the literature.

The breast is not classically included among the organs damaged by diabetic complications. The first cases of breast lesions associated with Type 1 diabetes mellitus were only described in 1984. The disease, designated as diabetic or fibrous mastopathy, is benign but may clinically simulate breast carcinoma. Its frequency is difficult to evaluate, and its pathogenesis is not yet clearly understood. We report two cases of diabetic mastopathy, together with a review of the medical literature on this subject and a description of the main characteristics of the disease. Diagnosis is based on the clinical context (premenopausal women with longstanding Type 1 diabetes mellitus who develop a hard, painless, mobile lump on one or both breasts), radiology (dense glandular tissue on mammography and marked acoustical shadowing of sound waves on sonography), and histopathology (fibrosis and perivascular and periductal lymphocytic infiltration).

Erosive polyarthritis and Crohn's disease. A case with HLA DRB1 determination.

The authors report the case of a 49-year-old woman with an asymmetrical, seronegative and peripheral polyarthritis with erosions, who subsequently developed Crohn's disease. She was diagnosed as having an erosive Crohn polyarthritis as no evidence of rheumatoid arthritis was found. However, the patient was homozygote for DR4 and the HLA DRB1 oligotyping was 0401/0404. This corresponds to two susceptibility alleles for rheumatoid arthritis responsible for the severity of this disease. Erosive polyarthritis is rarely encountered in inflammatory bowel diseases. The underlying mechanism of the erosions in these conditions is unknown but granulomatous synovitis with contiguous erosive bone changes has been reported. HLA DR has not been previously reported in erosive Crohn polyarthritis. The homozygosity for DR4 with DRB1*0401/0404 subtypes suggests that DR4 could contribute to the erosive course in this patient. This question is of interest, and HLA DR must be further studied in inflammatory bowel diseases with erosive arthritic manifestations.

Characterization of the specific response to serotonin of mouse tumour-feeding arterioles.

PURPOSE: To investigate the role of tumour versus non-tumour factors in the specific response to serotonin (5-HT) of tumour-feeding arterioles (TFA). MATERIALS AND METHODS: Using mouse models of intra-vital microscopy, the response to topical administration of 5-HT was studied in arterioles feeding tumours: fibrosarcoma (Meth A), murine mammary adenocarcinoma (EMT6) and human colo-rectal carcinoma (HRT18) intra-cutaneously implanted. RESULTS: For all types of tumour, 5-HT induced a far more pronounced constriction of TFA than of control arterioles. The presence of a tumour implanted in the connective tissue between the skin and the cremaster muscle also affected the reactivity of muscle arterioles. Conversely, the response to serotonin by neovessels grown after implantation of an exogenous element under the skin did not differ from that of control arterioles. CONCLUSIONS: Changes in reactivity to serotonin were not dependent on the type of tumour implanted in the skin and were not present for a non-tumour implant. The presence of the tumour can alter the reactivity of vessels from tissue in contact with the tumour even if these vessels did not feed the tumour. This phenomenon is local and was not found in the vessels at a distance from the tumour.

Hemodynamic effects of epinephrine associated to an epidural clonidine-bupivacaïne mixture during combined lumbar epidural and general anesthesia.

Clonidine or epinephrine are frequently combined to epidural local anesthetics to strengthen sensory block and prolong analgesia. Both drugs impair the hemodynamic profile of central neural blockade but the effects of their combination on arterial pressure and heart rate are not known and were examined in this double-blind prospective randomised study. Forty four patients scheduled for lumbar disc surgery were allocated to two groups. Epidural anesthesia was obtained by administration of 150 micrograms clonidine in 15 ml bupivacaine 0.25% solution without (group C) or with (group C + E) 37.5 micrograms epinephrine. Systolic, mean, diastolic arterial pressure and heart rate were measured throughout the study. Combined epidural and general anesthesia induced a significant decrease in arterial pressure and heart rate in both groups. SAP and MAP decreased significantly less in the patients receiving epinephrine. Low dose epidural epinephrine decreases arterial pressure instability during combined epidural and general anesthesia.

[Interviews with families of organ donors: analysis of motivation for acceptance or refusal of donation]. / Entretiens avec les familles de donneurs d'organes: analyse des motivations d'acceptation ou de refus du don.

OBJECTIVE: The reasons for organ donation acceptance or refusal are still unclear. This study analysed the influence of the circumstances of the conversations with the relatives of brain dead patients on their consent for organ donation. STUDY DESIGN: Prospective study. MATERIAL: The analysis included 41 questionnaires collected over nine months in one organ harvesting centre and focusing on the circumstances of death, the conditions of the conversations and the reasons for acceptance or refusal. METHODS: Questionnaire filled in by the physicians after the interviews of the relatives of brain dead patients. RESULTS: The refusal rate was higher (54 vs 21%) when only one physician participated in the conversation, when more than two relatives had to decide (42 vs 24%), when conversations took place during night or when the request for organ donation followed immediately the announcement of death (43 vs 20%). Most often the relatives gave their decision within minutes following the request. CONCLUSION: The circumstances of conversation with families play an essential role in their decision-making. A written guideline implementation for these conversations would probably be beneficial for the decisions of families in favour of organ donation.

[The beginnings of vaccine diffusion in France (1800-1850)]. / Les débuts de la diffusion de la vaccine en France (1800-1850).

First factor of mortality at the eighteenth century, smallpox killed each year about 50.000 to 80.000 people in France and 25.000 to 30.000 in England. In 1796, Edward Jenner discovered the fabulous properties of the cowpox which, transplanted from cow to human, immunized against the disease. In France, between 1800 and 1850, a few hundreds of vaccinators took part in a significant crusade against smallpox. They went in the villages and the thatched cottages, fought against the routine, and, sometimes, against the hostility of the mayors or the priests. Moreover, the cow-pox often missed or lost its strength. Despite everything, their efforts were crowned success: during the nineteenth century, small-pox mortality drops by 90%.

[Effect of weight loss on adipose tissue distribution and insulin sensitivity].

OBJECTIVE: To discuss the effect of weight reduction on fat distribution and parameters of insulin sensitivity. METHODS: 12 Caucasian women with simple obesity, aged 21 to 65 years, were treated by low caloric and high protein diet for four weeks. A series of examinations were taken before and after the treat, using computerized tomography for visceral and subcutaneous fat, using euglycemic insulin clamp for parameters of insulin sensitivity. RESULTS: Weight loss was (6 +/- 2) kg (2-11 kg). body mass index (BMI), waist, total fat, visceral fat, and subcutaneous fat reduced significantly. However waist-hip rate, visceral-total fat rate, and subcutaneous-total fat rate did not change significantly. Fasting serum insulin, and fasting insulin-glucose rate decreased significantly. Insulin metabolic clearance rate and, insulin sensitive index increased significantly. Fasting peptide C did not change significantly. CONCLUSIONS: The low caloric and high protein diet can reduce visceral and subcutaneous fat. Weight loss can improve insulin sensitivity and increase insulin metabolic clearance rate.

Ramadan fasting with diabetes: an interview study of inpatients' and general practitioners' attitudes in the South of France.

AIM: The aim of this study was to evaluate attitudes in hospital inpatients and physicians towards Ramadan fasting and diabetes in Marseille. METHODOLOGY: This cross-sectional study was conducted during the three months prior to the month of Ramadan. A total of 101 patients (age: 57±17 years) and 101 general practitioners (GPs) were recruited into the study. RESULTS: The patients had low levels of education (52% illiteracy). Of the 101 patients, 52 continued to fast during Ramadan, and only 65 patients had discussed the matter with their GP. Of these, 36 were told that fasting was forbidden, but more than half (n=19) fasted despite the medical advice. Six patients thus experienced daily hypoglycaemia because they had continued to take their hypoglycaemic agent or insulin analogue at noon. Both inadequate education and religious attitudes were found to endanger patients during the fast: 15 patients skipped the meal scheduled before dawn, five of whom persisted in taking their sulphonylurea. Also, 27% of patients refused, in spite of daytime hypoglycaemia, to ingest anything orally to avoid breaking their fast. Among the GP population, medical knowledge of Ramadan fasting with diabetes was low, leading to medically unjustified negative advice for fasting and a lack of patient education on adjusting treatments. This particular situation weakened the patient-physician relationship. CONCLUSION: This study confirms the importance of Ramadan fasting for Muslim patients, and reveals a wide cross-cultural gap between GPs and their patients. Systematic advice on treatment adjustment needs to be given. For this reason, we encourage more sensitive care of these patients and more medical training for physicians.