One-year metreleptin improves insulin secretion in patients with diabetes linked to genetic lipodystrophic syndromes.

Recombinant methionyl human leptin (metreleptin) therapy was shown to improve hyperglycaemia, dyslipidaemia and insulin sensitivity in patients with lipodystrophic syndromes, but its effects on insulin secretion remain controversial. We used dynamic intravenous (i.v.) clamp procedures to measure insulin secretion, adjusted to insulin sensitivity, at baseline and after 1 year of metreleptin therapy, in 16 consecutive patients with lipodystrophy, diabetes and leptin deficiency. Patients, with a mean [± standard error of the mean (s.e.m.)] age of 39.2 (±4) years, presented with familial partial lipodystrophy (n = 11, 10 women) or congenital generalized lipodystrophy (n = 5, four women). Their mean (± s.e.m.) BMI (23.9 ± 0.7 kg/m(2) ), glycated haemoglobin levels (8.5 ± 0.4%) and serum triglycerides levels (4.6 ± 0.9 mmol/l) significantly decreased within 1 month of metreleptin therapy, then remained stable. Insulin sensitivity (from hyperglycaemic or euglycaemic-hyperinsulinaemic clamps, n = 4 and n = 12, respectively), insulin secretion during graded glucose infusion (n = 12), and acute insulin response to i.v. glucose adjusted to insulin sensitivity (disposition index, n = 12), significantly increased after 1 year of metreleptin therapy. The increase in disposition index was related to a decrease in percentage of total and trunk body fat. Metreleptin therapy improves not only insulin sensitivity, but also insulin secretion in patients with diabetes attributable to genetic lipodystrophies.

Regulation of hindbrain Pyy expression by acute food deprivation, prolonged caloric restriction, and weight loss surgery in mice.

PYY is a gut-derived putative satiety signal released in response to nutrient ingestion and is implicated in the regulation of energy homeostasis. Pyy-expressing neurons have been identified in the hindbrain of river lamprey, rodents, and primates. Despite this high evolutionary conservation, little is known about central PYY neurons. Using in situ hybridization, PYY-Cre;ROSA-EYFP mice, and immunohistochemistry, we identified PYY cell bodies in the gigantocellular reticular nucleus region of the hindbrain. PYY projections were present in the dorsal vagal complex and hypoglossal nucleus. In the hindbrain, Pyy mRNA was present at E9.5, and expression peaked at P2 and then decreased significantly by 70% at adulthood. We found that, in contrast to the circulation, PYY-(1-36) is the predominant isoform in mouse brainstem extracts in the ad libitum-fed state. However, following a 24-h fast, the relative amounts of PYY-(1-36) and PYY-(3-36) isoforms were similar. Interestingly, central Pyy expression showed nutritional regulation and decreased significantly by acute starvation, prolonged caloric restriction, and bariatric surgery (enterogastroanastomosis). Central Pyy expression correlated with body weight loss and circulating leptin and PYY concentrations. Central regulation of energy metabolism is not limited to the hypothalamus but also includes the midbrain and the brainstem. Our findings suggest a role for hindbrain PYY in the regulation of energy homeostasis and provide a starting point for further research on gigantocellular reticular nucleus PYY neurons, which will increase our understanding of the brain stem pathways in the integrated control of appetite and energy metabolism.

Pregnant type 1 diabetes women with rises in C-peptide display higher levels of regulatory T cells: A pilot study.

AIM: During pregnancy of type 1 diabetes (T1D) women, a C peptide rise has been described, which mechanism is unclear. In T1D, a defect of regulatory T cells (Tregs) and its major controlling cytokine, interleukin-2 (IL2), is observed. METHODS: Evolution of clinical, immunological (Treg (CD4+CD25hiCD127-/loFoxp3+ measured by flow cytometry and IL2 measured by luminex xMAP technology) and diabetes parameters (insulin dose per day, HbA1C, glycaemia, C peptide) was evaluated in 13 T1D women during the three trimesters of pregnancy and post-partum (PP, within 6 months) in a monocentric pilot study. Immunological parameters were compared with those of a healthy pregnant cohort (QuTe). RESULTS: An improvement of beta cell function (C peptide rise and/or a decrease of insulin dose-adjusted A1c index that estimate individual exogenous insulin need) was observed in seven women (group 1) whereas the six others (group 2) did not display any positive response to pregnancy. A higher level of Tregs and IL2 was observed in group 1 compared to group 2 during pregnancy and at PP for Tregs level. However, compared to the healthy cohort, T1D women displayed a Treg deficiency CONCLUSION: This pilot study highlights that higher level of Tregs and IL2 seem to allow improvement of endogenous insulin secretion of T1D women during pregnancy.

Intramyocellular lipid accumulation is associated with permanent relocation ex vivo and in vitro of fatty acid translocase (FAT)/CD36 in obese patients.

AIMS/HYPOTHESIS: Intramyocellular lipids (IMCL) accumulation is a classical feature of metabolic diseases. We hypothesised that IMCL accumulate mainly as a consequence of increased adiposity and independently of type 2 diabetes. To test this, we examined IMCL accumulation in two different models and four different populations of participants: muscle biopsies and primary human muscle cells derived from non-obese and obese participants with or without type 2 diabetes. The mechanism regulating IMCL accumulation was also studied. METHODS: Muscle biopsies were obtained from ten non-obese and seven obese participants without type 2 diabetes, and from eight non-obese and eight obese type 2 diabetic patients. Mitochondrial respiration, citrate synthase activity and both AMP-activated protein kinase and acetyl-CoA carboxylase phosphorylation were measured in muscle tissue. Lipid accumulation in muscle and primary myotubes was estimated by Oil Red O staining and fatty acid translocase (FAT)/CD36 localisation by immunofluorescence. RESULTS: Obesity and type 2 diabetes are independently characterised by skeletal muscle IMCL accumulation and permanent FAT/CD36 relocation. Mitochondrial function is not reduced in type 2 diabetes. IMCL accumulation was independent of type 2 diabetes in cultured myotubes and was correlated with obesity markers of the donor. In obese participants, membrane relocation of FAT/CD36 is a determinant of IMCL accumulation. CONCLUSIONS/INTERPRETATION: In skeletal muscle, mitochondrial function is normal in type 2 diabetes, while IMCL accumulation is dependent upon obesity or type 2 diabetes and is related to sarcolemmal FAT/CD36 relocation. In cultured myotubes, IMCL content and FAT/CD36 relocation are independent of type 2 diabetes, suggesting that distinct factors in obesity and type 2 diabetes contribute to permanent FAT/CD36 relocation ex vivo.

[Corticosteroid-induced diabetes: Novelties in pathophysiology and management]. / Diabète et corticoïdes : nouveautés et aspects pratiques.

Diabetes frequently occurs during corticosteroid treatment, sometimes necessitating urgent therapeutic management, with insulin for example. Corticosteroids induce insulin resistance in the liver, adipocytes and skeletal muscle, and have direct deleterious effects on insulin secretion. The development of insulin resistance during corticosteroid treatment, and the insufficient adaptation of insulin secretion, are key elements in the pathophysiology of corticosteroid-induced diabetes. The capacity of pancreatic ß-cells to increase insulin secretion in response to insulin resistance is partly genetically determined. A familial history of type 2 diabetes is, therefore, a major risk factor for diabetes development on corticosteroid treatment. Corticosteroid treatments are usually initiated at a fairly high dose, which is subsequently decreased to the lowest level sufficient to achieve disease control. Pharmacological management of diabetes is needed in patients with blood glucose levels exceeding 2.16 g/l (12 mmol/l) and insulin therapy can be started when blood glucose levels are higher than 3.6 g/l (20 mmol/l) with clinical symptoms of diabetes. Insulin can then be replaced with oral hypoglycemic compounds when both blood glucose levels and corticosteroid dose have decreased. Patient education is essential, particularly for the management of hypoglycemia when corticosteroids are withdrawn or their dose tapered.

The gut microbiota and diabetic cardiomyopathy in humans.

Type 2 diabetes (DT2) increases the risk of cardiovascular events and cardiac insufficiency. This insufficiency is mostly post-ischaemic in nature, but other aetiologies are possible in this high-risk population. In patients with DT2, diabetic cardiomyopathy is a recognized cause of cardiac insufficiency secondary to chronic hyperglycaemia and myocardial lipotoxicity, which promotes cardiomyocyte hypertrophy (and, frequently, apoptosis of these cells), interstitial fibrosis and a decrease in myocardial contractile performance. Several studies have shown that diabetic cardiomyopathy is associated with modifications to the intestinal microbiota, and changes in the synthesis of bacterial metabolites and their diffusion into the host, some of which appear to have direct deleterious effects on cardiac contractility. These findings open up new perspectives for pathophysiological studies by establishing the presence of a 'microbiota-myocardium' axis and raising the possibility of innovative new treatments. Correction of intestinal dysbiosis in patients with cardiac insufficiency could, therefore, constitute an innovative therapeutic approach to cases of this disease with a poor prognosis.

Bariatric surgery and the perioperative management of type 2 diabetes: Practical guidelines.

BACKGROUND: Metabolic surgery is now considered as a therapeutic option in type 2 diabetes (T2D). However, few data are available regarding perioperative management of T2D. OBJECTIVES: To assess current practice among bariatric teams regarding perioperative management of T2D in order to propose guidelines. METHODS: A two-round Delphi method using online surveys was employed among bariatric teams experts (surgeons, diabetologists, anesthetists, nutritionists): first round, 63 questions covering 6 topics (characteristics of experts/teams, characteristics of patients, operative technique, pre/postoperative management, diabetes remission); second round, 44 items needing clarification. They were discussed within national congress of corresponding learned societies. Consensus was defined as ≥66% agreement. RESULTS: A total of 170 experts participated. Experts favored gastric bypass to achieve remission (76.7%). Screening for retinopathy, cardiac ultrasound, and reaching an HbA1c<8% are required in the pre-operative period for 67%, 75.3% and 56.7% of experts, respectively. After surgery, insulin pump should not be stopped, basal insulin should be halved, and bolus insulin should be stopped except if severe hyperglycemia. DPP-IV inhibitors and metformin are preferred after surgery. Patients should be seen by a diabetologist within one month if on oral antidiabetic agents (71.8% of experts), 2 weeks if on injectable treatments (77.1% of experts), and immediately after surgery if on insulin pump (93.5% of experts). Long-term monitoring of HbA1c is necessary even if diabetes remission (100%). CONCLUSION: Rapid postoperative modifications of blood glucose require a close monitoring and a prompt adjustment of diabetes medications.

Impact of sex and glucose-lowering treatments on hypoglycaemic symptoms in people with type 2 diabetes and chronic kidney disease. The French Chronic Kidney Disease - Renal Epidemiology and Information Network (CKD-REIN) Study.

AIM: To describe current practices of glucose-lowering treatments in people with diabetes and chronic kidney disease (CKD), the associated glucose control and hypoglycaemic symptoms, with an emphasis on sex differences. METHODS: Among the 3033 patients with CKD stages 3-5 recruited into the French CKD-REIN study, 645 men and 288 women had type 2 diabetes and were treated by glucose-lowering drugs. RESULTS: Overall, 31% were treated only with insulin, 28% with combinations of insulin and another drug, 42% with non-insulin glucose-lowering drugs. In CKD stage 3, 40% of patients used metformin, 12% at stages 4&5, similar for men and women; in CKD stage 3, 53% used insulin, similar for men and women, but at stages 4&5, 59% of men and 77% of women used insulin. Patients were reasonably well controlled, with a median HbA1c of 7.1% (54mmol/mol) in men, 7.4% (57mmol/mol) in women (P=0.0003). Hypoglycaemic symptoms were reported by 40% of men and 59% of women; they were not associated with the estimated glomerular filtration rate, nor with albuminuria or with HbA1c in multivariable analyses, but they were more frequent in people treated with insulin, particularly with fast-acting and pre-mixed insulins. CONCLUSION: Glucose-lowering treatment, HbA1c and hypoglycaemic symptoms were sex dependent. Metformin use was similar in men and women, but unexpectedly low in CKD stage 3; its use could be encouraged rather than resorting to insulin. Hypoglycaemic symptoms were frequent and need to be more closely monitored, with appropriate patient-education, especially in women.

Increased uncoupling protein-2 and -3 mRNA expression during fasting in obese and lean humans.

Uncoupling protein-2 and -3 (UCP2 and UCP3) are mitochondrial proteins that show high sequence homology with the brown adipocyte-specific UCP1. UCP1 induces heat production by uncoupling respiration from ATP synthesis. UCP2 is widely expressed in human tissues, whereas UCP3 expression seems restricted to skeletal muscle, an important site of thermogenesis in humans. We have investigated the regulation of UCP2 and UCP3 gene expression in skeletal muscle and adipose tissue from lean and obese humans. UCP2 and -3 mRNA levels were not correlated with body mass index (BMI) in skeletal muscle, but a positive correlation (r = 0.55, P < 0.01, n = 22) was found between UCP2 mRNA level in adipose tissue and BMI. The effect of fasting was investigated in eight lean and six obese subjects maintained on a hypocaloric diet (1,045 kJ/d) for 5 d. Calorie restriction induced a similar 2-2.5-fold increase in UCP2 and -3 mRNA levels in lean and obese subjects. To study the effect of insulin on UCP gene expression, six lean and five obese subjects underwent a 3-h euglycemic hyperinsulinemic clamp. Insulin infusion did not modify UCP2 and -3 mRNA levels. In conclusion, the similar induction of gene expression observed during fasting in lean and obese subjects shows that there is no major alteration of UCP2 and -3 gene regulation in adipose tissue and skeletal muscle of obese subjects. The increase in UCP2 and -3 mRNA levels suggests a role for these proteins in the metabolic adaptation to fasting.

Targeting AMP-activated protein kinase as a novel therapeutic approach for the treatment of metabolic disorders.

In the light of recent studies in humans and rodents, AMP-activated protein kinase (AMPK), a phylogenetically conserved serine/threonine protein kinase, has been described as an integrator of regulatory signals monitoring systemic and cellular energy status. AMP-activated protein kinase (AMPK) has been proposed to function as a 'fuel gauge' to monitor cellular energy status in response to nutritional environmental variations. Recently, it has been proposed that AMPK could provide a link in metabolic defects underlying progression to the metabolic syndrome. AMPK is a heterotrimeric enzyme complex consisting of a catalytic subunit alpha and two regulatory subunits beta and gamma. AMPK is activated by rising AMP and falling ATP. AMP activates the system by binding to the gamma subunit that triggers phosphorylation of the catalytic alpha subunit by the upstream kinases LKB1 and CaMKKbeta (calmodulin-dependent protein kinase kinase). AMPK system is a regulator of energy balance that, once activated by low energy status, switches on ATP-producing catabolic pathways (such as fatty acid oxidation and glycolysis), and switches off ATP-consuming anabolic pathways (such as lipogenesis), both by short-term effect on phosphorylation of regulatory proteins and by long-term effect on gene expression. As well as acting at the level of the individual cell, the system also regulates food intake and energy expenditure at the whole body level, in particular by mediating the effects of insulin sensitizing adipokines leptin and adiponectin. AMPK is robustly activated during skeletal muscle contraction and myocardial ischaemia playing a role in glucose transport and fatty acid oxidation. In liver, activation of AMPK results in enhanced fatty acid oxidation as well as decreased glucose production. Moreover, the AMPK system is one of the probable targets for the anti-diabetic drugs biguanides and thiazolidinediones. Thus, the relationship between AMPK activation and beneficial metabolic effects provide the rationale for the development of new therapeutic strategies in metabolic disorders.

What is the evidence for metabolic surgery for type 2 diabetes? A critical perspective.

Bariatric surgery has emerged as a highly effective treatment not only for obesity, but also for type 2 diabetes (T2D). A meta-analysis has reported the complete resolution of T2D in 78.1% of cases of morbidly obese patients after bariatric surgery. Such extraordinary results obtained in diabetic patients with body mass index (BMI) scores>35kg/m2 have led investigators to question whether similar results might be achieved in patients with BMIs<35kg/m2. Preliminary studies suggest that metabolic surgery is safe and effective in patients with T2D and a BMI<35kg/m2, whereas other studies report that metabolic surgery is less effective for promoting T2D remission in these patients. Thus, the results are discordant. Long-term studies would be useful for determining the safety, efficacy and cost-effectiveness of metabolic surgery for this population with T2D. In 2015, it is probably premature to say that metabolic surgery is an accepted treatment option for T2D patients with BMIs<35kg/m2.

Regulation by insulin of gene expression in human skeletal muscle and adipose tissue. Evidence for specific defects in type 2 diabetes.

Defective regulation of gene expression may be involved in the pathogenesis of type 2 diabetes. We have characterized the concerted regulation by insulin (3-h hyperinsulinemic clamp) of the expression of 10 genes related to insulin action in skeletal muscle and in subcutaneous adipose tissue, and we have verified whether a defective regulation of some of them could be specifically encountered in tissues of type 2 diabetic patients. Basal mRNA levels (determined by reverse transcriptase-competitive polymerase chain reaction) of insulin receptor, insulin receptor substrate-1, p85alpha phosphatidylinositol 3-kinase (PI3K), p110alphaPI3K, p110betaPI3K, GLUT4, glycogen synthase, and sterol regulatory-element-binding protein-1c (SREBP-1c) were similar in muscle of control (n = 17), type 2 diabetic (n = 9), type 1 diabetic (n = 9), and nondiabetic obese (n = 9) subjects. In muscle, the expression of hexokinase II was decreased in type 2 diabetic patients (P < 0.01). In adipose tissue, SREBP-1c (P < 0.01) mRNA expression was reduced in obese (nondiabetic and type 2 diabetic) subjects and was negatively correlated with the BMI of the subjects (r = -0.63, P = 0.02). Insulin (+/-1,000 pmol/l) induced a two- to threefold increase (P < 0.05) in hexokinase II, p85alphaPI3K, and SREBP-1c mRNA levels in muscle and in adipose tissue in control subjects, in insulin-resistant nondiabetic obese patients, and in hyperglycemic type 1 diabetic subjects. Upregulation of these genes was completely blunted in type 2 diabetic patients. This study thus provides evidence for a specific defect in the regulation of a group of important genes in response to insulin in peripheral tissues of type 2 diabetic patients.

Insulin acutely regulates the expression of the peroxisome proliferator-activated receptor-gamma in human adipocytes.

Peroxisome proliferator-activated receptor (PPAR)-gamma is one of the key actors of adipocyte differentiation. This study demonstrates 1) that PPAR-gamma mRNA expression is not altered in subcutaneous adipose tissue (n = 44) or in skeletal muscle (n = 19) of subjects spanning a wide range of BMIs (20-53 kg/m2) and 2) that insulin acutely increases PPAR-gamma mRNA expression in human adipocytes both in vivo and in vitro. The effect of insulin was investigated in abdominal subcutaneous biopsies obtained before and at the end of a 3-h euglycemic-hyperinsulinemic clamp. Insulin significantly increased PPAR-gamma mRNA levels in lean subjects (88 +/- 17%, n = 6), in type 2 diabetic patients (100 +/- 19%, n = 6), and in nondiabetic obese patients (91 +/- 20%, n = 6). Both PPAR-gamma1 and PPAR-gamma2 mRNA variants were increased (P < 0.05) after insulin infusion. In isolated human adipocytes, insulin induced the two PPAR-gamma mRNAs in a dose-dependent manner, with half-maximal stimulation at a concentration of approximately 1-5 nmol/l. However, PPAR-gamma2 mRNA was rapidly (2 h) and transiently increased, whereas a slow and more progressive induction of PPAR-gamma1 was observed during the 6 h of incubation. In explants of human adipose tissue, PPAR-gamma protein levels were significantly increased (42 +/- 3%, P < 0.05) after 12 h of incubation with insulin. These data demonstrate that PPAR-gamma belongs to the list of the insulin-regulated genes and that obesity and type 2 diabetes are not associated with alteration in the expression of this nuclear receptor in adipose tissue.

[How to manage the metabolic syndrome?]. / Comment prendre en charge le syndrome métabolique?

The metabolic syndrome represents the association in a single individual of a cluster of metabolic and hemodynamic factors, leading to an increased risk of type 2 diabetes and/or cardiovascular diseases. Several definitions exist (WHO, EGIR, NCEP-ATP III, AACE), but all of them include a cluster of criteria (hyper glycemia or type 2 diabetes, arterial hypertension, dyslipidemia, abdominal obesity) which increased these risks in parallel to their aggregation. The prevalence of the metabolic syndrome in industrialized countries represents 10 to 30% of the adult population, depending on the definition used and of the range of age, with a regular progression, particularly in women. Thus, it is needed to identify subjects with metabolic syndrome in the general population, and not only in overweight/obese subjects. This review, briefly presents the main definitions, as well as current data on pathophysiology, prevalence and consequences of the metabolic syndrome. Steps to diagnose it and guidance for the therapeutic management of metabolic syndrome in primary care practice are described.

Normal reproductive function in leptin-deficient patients with lipoatropic diabetes.

To further examine the relationships between leptin and female reproductive axis, we conducted hormonal studies in two patients with lipoatropic diabetes that occurred before puberty. Despite complete atrophy of sc and visceral adipose tissue, menarche occurred in these two patients between 11-12 yr of age, followed by regular menstrual cycles. One patient had been pregnant three times, giving birth to children who did not develop the disease. In our two patients, repeated analysis revealed leptin levels below 1 ng/mL (normal range for 20 insulin-treated diabetic women, 2-23 ng/mL for body mass index of 14-39 kg/m2; personal data). We measured peripheral levels of estradiol, progesterone, FSH, LH, free testosterone, and androstenedione within the first 5 days of the menstrual cycle, and we tested the reactivity of pituitary after iv injection of 100 microg GnRH. The variation in body temperature in the morning before arising was also analyzed. We showed that 1) all measured levels of hormones were in the normal range for both patients; and 2) low levels of leptin did not impair the development of reproductive function in one patient and was associated with normal gonadal function in both patients. We conclude that puberty and fertility can occur despite chronic low serum levels of leptin. This suggests that leptin is not fundamental to the maintenance of normal reproductive function in humans.

[News from UKPDS]. / Les nouveautés de l'UKPDS.

Risk factors present in type 2 diabetic patients at the time of their inclusion in the study were related with the occurrence of some complications. Thus, relative risk for coronary heart disease is 1.57 when HbA1c is > 7.5%, 1.41 when LDL-Cholesterol is > 3.89 mmol/l, these factors are not involved in the occurrence of cerebral stroke. Blood pressure and HbA1c were monitored throughout the study and could have been significantly correlated with the occurrence of micro- and macroangiopathy, with a linear-type and even exponential (HbA1c/retinopathy) relationship and a synergistic interaction between these 2 parameters. A treatment allowing a 0.9% decrease of HbA1c and a 10 mmHg decrease of systolic blood pressure is associated with a reduction of complications, more or less important than that expected from the epidemiological analysis of data. Several therapeutic strategies ensue from these observations.

[Mechanisms for weight gain during blood glucose normalization]. / Mécanismes de la prise de poids en cas de normalisation glycémique.

Secondary failure to dietary and maximal oral treatment leads to insulin therapy in type 2 diabetic patients. However, weight gain is a frequent side effect of insulin therapy in these patients. Mechanisms for this weight gain are complex. Insulin 1) reduces glycosuria and its caloric expenditure; 2) stimulates the stockage of fatty acids into triglycerides in adipose tissue, thus favoring an increase in adipose mass; 3) yields a positive nitrogen balance through an inhibition of muscle proteolysis, thus favoring an increase in lean mass. Most studies report an average 6 kg weight gain during the first year following the initiation of insulin therapy in type 2 diabetic patients. Analysing body composition variations shows that weight gain results both from an increase in fat mass (mean 63%) and an increase in lean mass (mean 37%). Preexisting obesity does not influence this weight gain. Finally, the 10 year-follow up of UKPDS showed a beneficial effect of insulin therapy on microangiopathy prevention, without increasing cardiovascular mortality as compared with type 2 diabetic patients on oral treatment. Thus, while weight gain seems mandatory, it should not refrain from initiating insulin therapy in poorly controlled type 2 diabetic patients, as its expected beneficial effects on the prevention of microangiopathy seem well established.

Are conventional targets for metabolic control sufficient to prevent fetal macrosomia during diabetic pregnancy?

We report the case of a 26 year-old woman, with an uncomplicated type 1 IDDM of 17 yr duration followed for her first pregnancy. At conception, HbA1c (measured by HPLC) was 6.5% and fructosamine was 280 u.mol.l (normal range below 285). During the follow-up, 15-days-interval frutosamine never exceeded the normal range and HbA1c values were under 6.5% excepted in the third trimester (7.0 +/- 0.8%) coinciding with a bad control of the 2 hours post-prandial blood glucose. A fetal macrosomy was discovered at 34 weeks of gestation and a heavy-for-date 4680 g baby was delivered by caesarean section at 38 weeks of gestation. Our case report outlines again the need to achieve the recommended target of metabolic control for the diabetic pregnant woman (blood preprandial glucose: 3.9-5.6 mM; post-prandial 2 h < 6.7 mM) specially during the third trimester of pregnancy. The use of computer databases might be helpful for precise monitoring during this narrow window period.