Correlates of fractures in elderly, diabetic outpatients.

It is widely recognized that patients presenting diabetes are at increased risk for fractures. In a retrospective case-control study, 101 cases were selected from medical charts of outpatients older than 70 with diabetes mellitus and a fracture within the past 5 years. Glycosylated hemoglobin (HbA1c) had been measured within 4 months around the assessment. Each case was matched for sex and age with one control, diabetic patient with no fracture. HbA1c level was similar in both groups. Patients with fractures presented significantly lower BMIs than controls, and had a higher rate of declared osteoporosis and comorbidity. A small number of cases were using vitamin D supplements while more were treated with benzodiazepine, opiates and Selective serotonin reuptake inhibitors (SSRI). This study suggests that, rather than the tight control of blood glucose, other factors such as medication and comorbidity could be associated with fracture risk in elderly diabetics.

[New oral antidiabetic drugs]. / Les nouveaux anti-diabétiques oraux.

The therapeutic options for type 2 diabetes have grown considerably in recent years with the successive emergence on the market of glitazones, incretin mimetics, gliptins and very soon gliflozins. Meanwhile, physicians have been advised to take into account individual patient characteristics and preferences when setting glycemic targets and choosing the most appropriate molecule. Faced with an abundance of options, clinicians, even those specialized in diabetology, are left confused and are divided in their choices. To guide them in their practice, the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD) jointly published a position statement in 2012. The guidelines posit that the main criteria to be considered are glucose-lowering efficacy, risk of hypoglycemia, effect on body weight, side effects and costs. Not surprisingly, they propose metformin as first line treatment but do not formulate a precise indication regarding the molecule to be introduced in case of metformin contra-indication, intolerance or monotherapy failure. In addition, there is no mention of gliflozins, which were still under evaluation at the time but are now approved and already marketed in some countries. Here we review the mechanisms of action, efficacy and side effects of the two most recent drug classes, namely incretin-based therapies and gliflozins, and try to position them in the therapeutic algorithm of type 2 diabetes.

[Screening strategy and diagnostic criteria for gestational diabetes. Proposals of the GGOLFB]. / Stratégie de dépistage et critères diagnostiques du diabète gestationnel. Propositions du GGOLFB.

For nearly 50 years, the strategy of screening and the diagnostic criteria for gestational diabetes have been the subject of endless controversies. They differ between countries and from one center to another, mainly because of the lack of hard data allowing to define glycemic thresholds at which a therapeutic management is needed. Recently, a large observational study has demonstrated the existence of a robust relationship between maternal blood sugar and several fetomaternal perinatal complications. This relationship is linear, with no clear threshold that would define gestational diabetes unambiguously. Meanwhile, two randomized intervention trials have shown that the therapeutic management of mild gestational diabetes was associated with improved perinatal outcomes. Based on these data, the " International Association of Diabetes and Pregnancy Study Group "(IADPSG) released new recommendations on screening methods and diagnostic criteria for gestational diabetes. Although already endorsed by several international associations and implemented in some countries, these recommendations still raise questions and criticisms. This is why the "Groupement des Gynécologues Obstétriciens de Langue Française de Belgique " (GGOLFB) organized a meeting between diabetologists and gynecologists which allowed to reach a consensus on the strategy that we intend to implement in our respective centers. The purpose of this paper is to briefly overview the recent advances in gestational diabetes and more particularly to make our key conclusions known to the medical community. This will enable the standardization of the management of gestational diabetes in the French-speaking part of Belgium.

[Screening strategy and diagnostic criteria for gestational diabetes. Proposals of the GGOLFB]. / Stratégie de dépistage et critères diagnostiques du diabète gestationnel. Propositions du GGOLFB.

For nearly 50 years, the strategy of screening and the diagnostic criteria for gestational diabetes have been the subject of endless controversies. They differ between countries and from one center to another, mainly because of the lack of hard data allowing to define glycemic thresholds at which a therapeutic management is needed. Recently, a large observational study has demonstrated the existence of a robust relationship between maternal blood sugar and several fetomaternal perinatal complications. This relationship is linear, with no clear threshold that would define gestational diabetes unambiguously. Meanwhile, two randomized intervention trials have shown that the therapeutic management of mild gestational diabetes was associated with improved perinatal outcomes. Based on these data, the "International Association of Diabetes and Pregnancy Study Group" (IADPSG) released new recommendations on screening methods and diagnostic criteria for gestational diabetes. Although already endorsed by several international associations and implemented in some countries, these recommendations still raise questions and criticisms. This is why the "Groupement des Gynécologues Obstétriciens de Langue Française de Belgique" (GGOLFB) organized a meeting between diabetologists and gynecologists which allowed to reach a consensus on the strategy that we intend to implement in our respective centers. The purpose of this paper is to briefly overview the recent advances in gestational diabetes and more particularly to make our key conclusions known to the medical community. This will enable the standardization of the management of gestational diabetes in the French-speaking part of Belgium.

Comparative pharmacoscintigraphic and pharmacokinetic evaluation of two new formulations of inhaled insulin in type 1 diabetic patients.

In this open, single-dose study, we compared the lung deposition and bioavailability of two newly developed insulin formulations for pulmonary delivery. Twelve type 1 diabetic patients were administered the two insulin products (2 U/kg b.w.), which had been radiolabelled with (99m)Tc. The formulations were either microparticles of insulin without excipients (F1) or lipid-coated insulin microparticles (F2). Lung deposition was assessed by γ-scintigraphy imaging performed immediately after administration. Bioavailability was evaluated by quantifying serum insulin levels over a period of 6 h. Lung deposition was found to be 50 ± 9% and 24 ± 8% for the F1 and F2 formulations, respectively. The insulin AUC0₋360 ratio of F1/F2 was 188%, which was consistent with scintigraphic imaging. The concordance between imaging and biological results suggests that the lower bioavailability of F2 is due to its lower lung deposition and not to a reduced absorption into the blood stream. Additional in vitro experiments indicated that the lower performance of F2 was most probably related to a lower disaggregation efficiency of the powder when administered at a sub-optimal flow rate. The two formulations showed interesting pharmacokinetic profiles (T(max) of 26 and 16 min for F1 and F2, respectively) that mimic the physiological insulin secretion pattern. The bioavailability of the developed formulations was within the range of other DPI insulin formulations that have reached the final stages of clinical development.

Hyperglycaemic clamp test for diabetes risk assessment in IA-2-antibody-positive relatives of type 1 diabetic patients.

AIMS/HYPOTHESIS: The aim of the study was to investigate the use of hyperglycaemic clamp tests to identify individuals who will develop diabetes among insulinoma-associated protein-2 antibody (IA-2A)-positive first-degree relatives (IA-2A(+) FDRs) of type 1 diabetic patients. METHODS: Hyperglycaemic clamps were performed in 17 non-diabetic IA-2A(+) FDRs aged 14 to 33 years and in 21 matched healthy volunteers (HVs). Insulin and C-peptide responses were measured during the first (5-10 min) and second (120-150 min) release phase, and after glucagon injection (150-160 min). Clamp-induced C-peptide release was compared with C-peptide release during OGTT. RESULTS: Seven (41%) FDRs developed diabetes 3-63 months after their initial clamp test. In all phases they had lower C-peptide responses than non-progressors (p < 0.05) and HVs (p < 0.002). All five FDRs with low first-phase release also had low second-phase release and developed diabetes 3-21 months later. Two of seven FDRs with normal first-phase but low second-phase release developed diabetes after 34 and 63 months, respectively. None of the five FDRs with normal C-peptide responses in all test phases has developed diabetes so far (follow-up 56 to 99 months). OGTT-induced C-peptide release also tended to be lower in progressors than in non-progressors or HVs, but there was less overlap in results between progressors and the other groups using the clamp. CONCLUSIONS/INTERPRETATION: Clamp-derived functional variables stratify risk of diabetes in IA-2A(+) FDRs and may more consistently identify progressors than OGTT-derived variables. A low first-phase C-peptide response specifically predicts impending diabetes while a low second-phase response may reflect an earlier disease stage. TRIAL REGISTRATION: ClinicalTrials.gov NCT00654121 FUNDING: The insulin trial was financially supported by Novo Nordisk Pharma nv.

[The incretin effect: a new therapeutic target in type 2 diabetes]. / L'effet incrétine: une nouvelle cible thérapeutique dans le diabète de type 2.

The two incretin hormones GLP-1 (Glucagon-Like Peptide-1) and GIP (Glucose-dependent Insulinotropic Peptide) are released by the gut in response to nutrient ingestion. Both of them potentiate glucose-induced insulin response, enhance insulin biosynthesis and, at least in rodents, preserve beta-cell mass through reduction of apoptosis and stimulation of beta-cell proliferation. In addition to its insulinotropic action, GLP-1 (but not GIP) suppresses glucagon secretion, delays gastric emptying and promotes satiety. Since in type 2 diabetes, the secretion of GLP-1 is dramatically reduced whereas its effects are retained, a number of pharmacological strategies aiming at restoring the incretin activity of this peptide have been explored. Because GLP-1 is rapidly degraded by the ubiquitous enzyme, dipeptidyl peptidase-IV (DPP-IV) and has a very short-lived action, DPP-IV resistant mimetics have been designed. Several randomized placebo-controlled studies with DPP-IV resistant GLP-1 analogues confirmed their efficacy to improve glycemic control in type 2 diabetic patients. The first one, exenatide, has been approved by the Food and Drug Administration (FDA) in 2005 for the treatment of type 2 diabetes. Longer-acting mimetics requiring only one injection per day or even per week are currently assessed in phase 3 trials. Another successful approach has been the development of orally active DPP-IV inhibitors which reversibly and selectively block the enzymatic activity. Many small-molecule DPP-IV inhibitors, called gliptins, have been shown to be effective as antihyperglycemic agents and, up to now, devoid of major adverse events. The first drug of this new therapeutic class having received FDA approval, sitagliptin, is now available for the treatment of type 2 diabetes in U.S. However, the efficacy/safety profile of these compounds and their positioning in the therapeutic algorithm of type 2 diabetes remains to be defined.

[Etiopathogenesis and pathophysiology of type 2 diabetes]. / Etiopathogénie et physiopathologie du diabète de type 2.

Etiopathogenesis of type 2 diabetes is complex and still partially unknown. Its etiology is determined by the interaction of genetic and environmental factors. The genetic contribution is important, but has a polygenic origin. Obesity, especially when fat mass is preferably located in the abdomen, is the main predisposing factor for type 2 diabetes, and almost 80% of diabetic patients are overweight or obese. The diabetogenic effect of obesity is due to the capacity of excessive fat mass to induce or aggravate insulin resistance. Increasing lack of physical activity is also a contributing factor as it increases insulin resistance. As far as pathophysiology is concerned, the development of type 2 diabetes results from the coexistence of abnormalities of insulin secretion and insulin action. Insulin secretory dysfunction, whose underlying mechanism remains poorly understood, is characterized by a relative defect in circulating insulin levels of variable severity. Resistance to insulin action is located in the liver (increased hepatic glucose production), in the skeletal muscle (decreased muscular glucose uptake) and in the adipose tissue (exaggerated lipolysis with elevated plasma free fatty acids). Changes in life-style habits (weight reduction, regular physical activity) are able to prevent or delay the development of type 2 diabetes.

Comparison of intraduodenal and intravenous glucose metabolism under clamp conditions in humans.

To determine whether the uptake and metabolic partition of glucose are influenced by its delivery route, 12 normal volunteers underwent two 3-h euglycemic (approximately 93 mg/dl) hyperinsulinemic (approximately 43 mU/l) clamps at a 3- to 5-wk interval, one with intravenous (i.v.) and the other with intraduodenal (i.d.) glucose labeled with [3-3H]- and [U-14C]glucose. Systemic glucose was traced with [6,6-2H2]glucose in eight subjects. During the last hour of the clamps, the average glucose infusion rate (5.85 +/- 0.37 vs. 5.43 +/- 0.43 mg.kg(-1).min(-1); P = 0.02) and exogenous glucose uptake (5.66 +/- 0.37 vs. 5.26 +/- 0.41 mg.kg(-1).min(-1); P = 0.04) were borderline higher in the i.d. than in the i.v. studies. The increased uptake was entirely accounted for by increased glycolysis (3H2O production), which was attributed to the stimulation of gut metabolism by the absorptive process. No difference was observed in glucose storage whether it was calculated as glucose uptake minus glycolysis (i.d. vs. i.v.: 2.44 +/- 0.28 vs. 2.40 +/- 0.31 mg.kg(-1).min(-1)) or as glucose uptake minus net glucose oxidation (2.86 +/- 0.33 vs. 2.81 +/- 0.35 mg.kg(-1).min(-1)). Because peripheral tissues were exposed to identical glucose, insulin, and free fatty acid levels under the two experimental conditions, we assumed that their glucose uptake and storage were similar during the two tests. We therefore suggest that hepatic glycogen storage (estimated as whole body minus peripheral storage) was also unaffected by the route of glucose delivery. On the other hand, in the i.d. tests, the glucose splanchnic extraction ratio calculated by the dual-isotope technique averaged 4.9 +/- 2.3%, which is close to the figures published for i.v. glucose. Despite the limitations related to whole body measurements, these two sets of data do not support the idea that enteral glucose stimulates hepatic uptake more efficiently than i.v. glucose.

Level of glycogen stores and amount of ingested glucose regulate net carbohydrate storage by different mechanisms.

The respective effects of the level of glycogen stores and the size of the glucose load on the pathways of carbohydrate (CHO) metabolism were compared over the 5-hour period following glucose ingestion in normal human subjects. For this purpose, labeling of the oral glucose load with [3-(3)H]- and [U(14)C] glucose was combined with indirect calorimetry. In group I, 75 g glucose was given to subjects who had either been "fed" with intravenous (IV) glucose or fasted for 13, 24, or 36 hours, or 4 days. In fed versus 4-day-fasted subjects, net CHO storage averaged approximately 15 versus 63 g/5 h (P <.001). About 83% of the increase in fasted subjects was due to suppression of glycogen breakdown, with only minimal stimulation of glycogen synthesis from oral glucose. Over the whole range of nutritional conditions tested, a strong positive correlation existed between basal CHO oxidation and glycogen breakdown occurring during the oral glucose tolerance test (OGTT), suggesting that the initial degree of repletion of hepatic glycogen stores is a major determinant of postprandial glycogen turnover. In group II, OGTTs with 33 and 100 g glucose were compared in 13-hour-fasted subjects. Net storage rose from approximately -6 to approximately 37 g/5 h (P <.001) solely because of an increase in glycogen synthesis with no inhibition of glycogen turnover. Overall, these results show that the initial dietary state and the size of the glucose load modulate postprandial net CHO accumulation by different mechanisms.

[The endocrinology department]. / Le Service d'Endocrinologie.

The clinical activities of the department of endocrinology encompass the care and treatment of diabetes, thyroid diseases, hypothalamo-pituitary, adrenal, gonadic and parathyroid diseases, obesity, hypercholesterolemia and paraneoplastic endocrine syndromes. These domains are briefly described. The research activities of the department have investigated the regulation of thyroid metabolism in vitro, the intrathyroid H2O2 generating system, the physiopathology of toxic thyroid nodules and the effects of ageing on the thyreotropic function of the normal ageing male. Studies of "jet lag" conditions have shed a new light on hormonal chronophysiology. Other investigations have considered the regulation of ketone body metabolism, the relationship between nutritional status and glucose metabolism, and some aspects of immunodiabetology.

Metabolic handling of intraduodenal vs. intravenous glucose in humans.

To determine whether the route of glucose administration affects whole body glucose metabolism, 14 healthy volunteers were randomly infused with intraduodenal (id) or intravenous (iv) glucose at 6 mg x kg(-1) x min(-1) for 180 min. Infused glucose was labeled with [2-(3)H]glucose in a first series of paired experiments designed to characterize kinetic parameters to be used in a second series of experiments in which [3-(3)H]- and [U-(14)C]glucose labeling was used to characterize the metabolic fate of infused glucose. Experiments with [2-(3)H]glucose showed that, after a lag period of only 20 min, id absorption averaged 105 +/- 3% of infusion. During the final hour of id and iv infusion of [3-(3)H]glucose, tissue uptake averaged 98 +/- 3 and 107 +/- 4% of infusion, respectively, and was equally divided between glycolysis ((3)H(2)O production) and storage (uptake-glycolysis). Glucose oxidation ((14)CO(2)), total carbohydrate oxidation (indirect calorimetry), and net carbohydrate balance were also similar, but the thermic effect of glucose was significantly greater after id infusion. Because insulin and estimated portal vein glucose levels were similar during the final 80 min of both infusions, our results suggest that hepatic glucose storage (and therefore muscle storage estimated as whole body minus liver storage) is not affected by the route of glucose administration.

[Role of diet in the treatment of diabetes]. / Rôle du régime alimentaire dans le traitement du diabète.

Although diet has always been recognized as the cornerstone in the management of diabetes, dietary recommendations are evolving continuously. There is now some consensus that the goals of medical nutrition therapy should be to attain and/or maintain a reasonable body weight, to ensure the best possible glycemic control and to reduce cardiovascular risk factors but the means to achieve these goals are still under discussion. Apart from caloric restriction which is, without any doubt, highly efficient but hardly applied in obese diabetic patients, the clinical benefits of the traditional measures to alleviate postprandial hyperglycemia (increasing meal frequency, consumption of carbohydrates with a low glycemic index and/or rich in fibers) are not unanimously acknowledged. The hotly debated issue regarding the ideal proportions of carbohydrates and fat advisable for diabetic individuals has lapsed progressively into disuse, all the arguments having run out. At the present time, there remain many unanswered important questions related to nutrition and diabetes because of the lack of long-term randomized studies evaluating the impact of a diet modification on morbidity and mortality. Considering the difficulties of changing our usual feeding patterns on a long term basis, these uncertainties will not readily be solved.

Ambulatory blood pressure and neuroendocrine control after diet-assisted gastric restrictive surgery.

BACKGROUND: Long-term weight control after conventional diet is disappointing but may be improved when diet is assisted by gastric restrictive surgery (GRS). OBJECTIVE: To determine the effects of GRS on ambulatory blood pressure (ABP) and neuroendocrine BP control in 28 morbidly obese subjects. METHODS: A BP and heart rate were recorded every 10 min for 25 h before and 4 months after GRS. Effects of marked reductions in body weight on the renin-angiotensinaldosterone system, on plasma insulin and on sympathetic activity were also determined. RESULTS: Body mass index decreased from 43 +/- 1 to 34 +/- 1 kg/m2 and systolic (S) BP decreased by 7 +/- 2 mmHg during daytime (P=0.01) and by 8 +/- 3 mmHg during the night (P=0.02). Pulse pressure, a marker of reduced arterial compliance, decreased by 5 +/- 1 mmHg throughout the 24 h period (P < 0.001). Diastolic BP remained unchanged. Heart rate decreased more during the night (-13 +/- 2 bpm, P<0.0001) than during daytime (-5 +/- 2 bpm, P=0.03). Reductions in SBP were largest in subjects with highest initial BP values (r = -0.63, P<0.001) but were unrelated to weight loss. GRS decreased fasting glycaemia, plasma insulin, plasma C peptide and 24 h urine sodium (n=20) and noradrenaline (n=19) excretion (P<0.01). CONCLUSIONS: Diet-assisted GRS favourably affects neuroendocrine BP control in obese patients. Reductions in sodium intake, insulin levels and sympathetic tone combined with possible improvements in arterial compliance induce persistent 24 h reductions in SBP and pulse BP. Reductions in BP are largest in subjects with highest initial BP values and are unrelated to the amount of weight loss, thereby emphasizing the importance of even moderate reductions in weight on BP control.

Effect of fasting on the intracellular metabolic partition of intravenously infused glucose in humans.

The effects of fasting on the pathways of insulin-stimulated glucose disposal were explored in three groups of seven normal subjects. Group 1 was submitted to a euglycemic hyperinsulinemic clamp ( approximately 100 microU/ml) after both a 12-h and a 4-day fast. The combined use of [3-(3)H]- and [U-(14)C]glucose allowed us to demonstrate that fasting inhibits, by approximately 50%, glucose disposal, glycolysis, glucose oxidation, and glycogen synthesis via the direct pathway. In group 2, in which the clamp glucose disposal during fasting was restored by hyperglycemia (155 +/- 15 mg/dl), fasting stimulated glycogen synthesis (+29 +/- 2%) and inhibited glycolysis (-32 +/- 3%) but only in its oxidative component (-40 +/- 3%). Results were similar in group 3 in which the clamp glucose disposal was restored by a pharmacological elevation of insulin ( approximately 2,800 microU/ml), but in this case, both glycogen synthesis and nonoxidative glycolysis participated in the rise in nonoxidative glucose disposal. In all groups, the reduction in total carbohydrate oxidation (indirect calorimetry) induced by fasting markedly exceeded the reduction in circulating glucose oxidation, suggesting that fasting also inhibits intracellular glycogen oxidation. Thus prior fasting favors glycogen retention by three mechanisms: 1) stimulation of glycogen synthesis via the direct pathway; 2) preferential inhibition of oxidative rather than nonoxidative glycolysis, thus allowing carbon conservation for glycogen synthesis via the indirect pathway; and 3) suppression of intracellular glycogen oxidation.

[New treatments for obesity]. / Les nouveaux traitements de l'obésité.

The aim of this short review is to summarize our knowledge on the pharmacological treatment of obesity. We consider first the old molecules, mostly amphetamine derivatives, which tend to be abandoned and second, the more recent ones which just appeared or are just about to become available. We also envision some therapeutical perspectives derived from recent advances in molecular biology. Although, it is "scientifically correct" to deliver an optimistic message regarding the possibility of finding an effective and safe treatment of obesity in the near future, we think that this is, on the contrary, an unrealistic goal.

Metabolic effects of short-term elevations of plasma cortisol are more pronounced in the evening than in the morning.

To determine whether elevations of cortisol levels have more pronounced effects on glucose levels and insulin secretion in the evening (at the trough of the daily rhythm) or in the morning (at the peak of the rhythm), nine normal men each participated in four studies performed in random order. In all studies, endogenous cortisol levels were suppressed by metyrapone administration, and caloric intake was exclusively under the form of a constant glucose infusion. The daily cortisol elevation was restored by administration of hydrocortisone (or placebo) either at 0500 h or at 1700 h. In each study, plasma levels of glucose, insulin, C-peptide, and cortisol were measured at 20-min intervals for 32 h. The initial effect of the hydrocortisone-induced cortisol pulse was a short-term inhibition of insulin secretion without concomitant glucose changes and was similar in the evening and in the morning. At both times of day, starting 4-6 h after hydrocortisone ingestion, glucose levels increased and remained higher than under placebo for at least 12 h. This delayed hyperglycemic effect was minimal in the morning but much more pronounced in the evening, when it was associated with robust increases in serum insulin and insulin secretion and with a 30% decrease in insulin clearance. Thus, elevations of evening cortisol levels could contribute to alterations in glucose tolerance, insulin sensitivity, and insulin secretion.

Mechanisms of whole-body glycogen deposition after oral glucose in normal subjects. Influence of the nutritional status.

It is known that prior fasting enhances whole-body glycogen retention after glucose ingestion. To identify the involved mechanisms, 33 normal volunteers underwent a total fast, varying between 14 h and 4 days, and ingested thereafter 75 g glucose labeled with [14C]glucose. Measurements of oral glucose oxidation (expired 14CO2, corrected for incomplete recovery) and total carbohydrate (CHO) oxidation (indirect calorimetry) were performed over the following 5 h. These data allowed us to calculate oral glucose storage (uptake oxidation), glycogen oxidation (CHO oxidation - oral glucose oxidation), and net CHO balance (oral glucose uptake - CHO oxidation). As compared with an overnight fast, prolonged fasting (4 days) inhibited the uptake (64.8 vs. 70.3 g/5 h; P < 0.01) and the oxidation (10.9 vs. 20.0 g/5 h; P < 0.001) of oral glucose and stimulated slightly its conversion to glycogen (53.9 vs. 50.3 g/5 h; P < 0.05). The latter effect played only a minor role in the marked increase in net CHO balance (52.3 vs. 25.2 g/5 h; P < 0.001), which was almost entirely related to a decrease in glycogen oxidation (1.6 vs. 25.1 g/5 h; P < 0.001). Considering the whole series of data, including intermediate durations of fast, it was observed that the modifications in postprandial CHO metabolism, induced by fasting, correlated strongly with basal CHO oxidation, suggesting that the degree of initial glycogen depletion is a major determinant of glycogen oxidation and net CHO storage. Thus, prior fasting stimulates postprandial glycogen retention, mainly through an inhibition of the glycogen turnover that exists in overnight-fasted subjects, during the absorptive period.