Pioglitazone prevents the increase in plasma ketone concentration associated with dapagliflozin in insulin-treated T2DM patients: Results from the Qatar Study

Because of the unique mechanism of action of sodium-glucose co-transport inhibitors (SGLT2i), which is independent of insulin secretion and insulin action, members of this class of drugs effectively lower plasma glucose concentration when used in combination with all other antidiabetic agents, including insulin. Increased plasma ketone concentration has been reported in association with SGLT2i initiation, which, under certain clinical conditions, has developed into diabetic ketoacidosis. The daily insulin dose often is reduced at the time of initiating SGLT2i therapy in insulin-treated patients to avoid hypoglycaemia. However, reduction of insulin dose can increase the risk of ketoacidosis. In the present study, we examined the effect of the addition of dapagliflozin plus pioglitazone on plasma ketone concentration in insulin-treated T2DM patients and compared the results to the effect of dapagliflozin alone. A total of 18 poorly controlled, insulin-treated T2DM participants in the Qatar Study received dapagliflozin (10 mg) plus pioglitazone (30 mg), and 10 poorly controlled non-insulin-treated T2DM patients received dapagliflozin (10 mg) alone for 4 months. Dapagliflozin plus pioglitazone produced a robust decrease in HbA1c (−1.4%) and resulted in a 50% reduction in daily insulin dose, from 133 to 66 units, while dapagliflozin alone caused a 0.8% reduction in HbA1c. Dapagliflozin caused a four-fold increase in fasting plasma ketone concentration, while the combination of pioglitazone plus dapagliflozin was not associated with a significant increase (0.13 vs 0.15 mM) in plasma ketone concentration or in risk of hypoglycaemia. These results demonstrate that the addition of pioglitazone to dapagliflozin prevents the increase in plasma ketone concentration associated with SGLT2i therapy.     

The Rising Tide of Overweight among Kuwaiti Children: Study from Al-Adan Hospital,Kuwait

Objective

This study was designed to screen patients who sought medical services in the Pediatric Outpatient Department, Al-Adan Hospital, Kuwait for overweight.

Subjects and Methods

Body mass index (BMI) was used to screen 361 children (≤10 years old) for risk of overweight and overweight (BMI between 85th and 94th, and ≥95th percentile, respectively). Overweight children were fully examined and abdominal ultrasound was done for each of them.

Results

Of the 361 children, 52 (14.41%) and 77 (21.33%) were at risk of overweight and overweight, respectively. There was a slight male predominance for overweight (40 males, 51.95%, compared to 37 females, 48.05%) and within the overweight category; 28 males (70%) and 26 females (70.27%) were above 6 years of age. In overweight children over 6 years, 4 (7.41%) had hepatomegaly with fatty changes and 3 (5.56%) had blood pressure above the 95th percentile for age and sex.

Conclusion

Childhood overweight at Al-Adan Hospital was high and increased with age. Hence childhood screening for overweight is recommended at an early age because it is an important risk factor of chronic diseases.Key Words: Body mass index, Child health, Overweight     

Tumor Necrosis Factor-α and Pregnancy Complications: A Prospective Study

Objective

The aim of this study was to compare the levels of tumor necrosis factor-α (TNF-α) produced by peripheral blood mononuclear cells in normal pregnancies and pregnancies with complications.

Materials and Methods

Maternal peripheral blood mononuclear cells from women with a recurrent spontaneous miscarriage (n = 35), premature rupture of fetal membranes (n = 30), preeclampsia (n = 27) and intrauterine fetal growth retardation (IUGR; n = 36) were stimulated with mitogen or antigen, and the levels of TNF-α produced were compared to those produced by peripheral blood mononuclear cells from a normal pregnancy (n = 35).

Results

The median levels of mitogen-induced TNF-α at the 1st, 2nd and 3rd trimester, and at normal delivery were 1,176.4, 4,320.9, 7,307.4 and 2,463.0 pg/ml, respectively, while those produced in the recurrent spontaneous miscarriage, premature rupture of membranes and preeclampsia cases were 4,159.8, 3,489.5 and 4,149.2 pg/ml, respectively. The differences were statistically significantly higher in these pregnancy complications (p = 0.04, 0.024 and 0.014) as compared to the levels in normal pregnancy. Furthermore, antigen-induced TNF-α levels were produced at statistically significantly higher levels by women with IUGR (120.4 pg/ml) compared to women with normal pregnancies (17.9 pg/ml; p = 0.041).

Conclusion

Higher levels of TNF-α seem to play a role in these pregnancy complications, suggesting its pathogenesis in such conditions.Key Words: Cytokines, Intrauterine fetal growth retardation, Preeclampsia, Recurrent spontaneous miscarriage, Tumor necrosis factor-α     

Coexistence of sickle cell disease and severe congenital neutropenia: first impressions can be deceiving

We report an Omani family in whom the propositus had a rare coexistence of sickle cell disease and severe congenital neutropenia associated with a mutation in ELANE. In contrast to his siblings with sickle cell disease, the severity of HbSS-associated complications such as painful crises and acute chest syndrome was significantly reduced. His course of the disease had markedly worsened after initiating G-CSF therapy. These clinical observations suggest that neutropenia may ameliorate inflammatory responses and thus display a modulating factor with respect to the clinical course of sickle cell disease.     

Stage of change of 6 health-related behaviors among patients with type 2 diabetes

AimsAssessing patients’ current stage of change toward 6 healthy behaviors related to diabetes control. Behaviors studied were smoking cessation (2) regular exercise; (3) consuming 5 servings or more of fruits and vegetables; (4) decreasing intake of refined sugar; (5) reducing saturated fat; and (6) self monitoring of blood glucose (SMBG).MethodsStage of change (SOC) for several diabetes control-related behaviors was assessed for 737 patients with type 2 diabetes using a staging algorithm. Socio-demographic data were collected by a structured interview-based questionnaire.ResultsThere was high degree of readiness toward consuming diets with less saturated fat and simple sugar. Very low degree of readiness was reported for self-monitoring of blood glucose on a regular bases and for practicing physical exercise. Half of the participants (50.9%) were in the precontemplation stage for consuming ≥5 servings of fruits and vegetables every day. Significant correlations were obtained between the degree of readiness for several behaviors (p < 0.01). Age, gender, income and education were all related to the stage of change of the studied behaviors (p < 0.01).ConclusionsPatients with diabetes in Jordan are still in the pre-action stages for practicing exercise, consuming 5 servings or more of fruit and vegetable, and self-monitoring of blood glucose. The current finding suggests a need for nutritional education and interventions to raise awareness of lifestyle factors influencing glycemic control among diabetics.     

Sodium–glucose cotransporter‐2 inhibitors induced euglycemic diabetic ketoacidosis: Two case reports and a review of the literature

If not detected early, euglycemic diabetic ketoacidosis can be a serious adverse effect of sodium–glucose cotransporter‐2 (SGLT2) inhibitors. Unfortunately, euglycemic diabetic ketoacidosis is underreported in recent trials and missed because of normal blood sugar levels and nonspecific symptoms on presentation. We present two patients with type 2 diabetes mellitus who developed dapagliflozin‐associated euglycemic diabetic ketoacidosis followed by hyperglycemic ketoacidosis. The second patient had euglycemic ketoacidosis twice despite instructions to stop using the medication dapagliflozin.     

D-bifunctional protein deficiency caused by splicing variants in a neonate with severe peroxisomal dysfunction and persistent hypoglycemia

D -bifunctional protein (DBP) deficiency is a rare, autosomal recessive peroxisomal enzyme deficiency resulting in a high burden of morbidity and early mortality. Patients with DBP deficiency resemble those with a severe Zellweger phenotype, with neonatal hypotonia, seizures, craniofacial dysmorphisms, psychomotor delay, deafness, blindness, and death typically within the first 2 years of life, although patients with residual enzyme function can survive longer. The clinical severity of the disease depends on the degree of enzyme deficiency. Loss-of-function variants typically result in no residual enzyme activity; however, splice variants may result in protein with residual function. We describe a full-term newborn presenting with hypotonia, seizures, and unexplained hypoglycemia, who was later found to have rickets at follow up. Rapid whole genome sequencing identified two HSD17B4 variants in trans; one likely pathogenic variant and one variant of uncertain significance (VUS) located in the polypyrimidine tract of intron 13. To determine the functional consequence of the VUS, we analyzed RNA from the patient's father with RNA-seq which showed skipping of Exon 14, resulting in a frameshift mutation three amino acids from the new reading frame. This RNA-seq analysis was correlated with virtually absent enzyme activity, elevated very-long-chain fatty acids in fibroblasts, and a clinically severe phenotype. Both variants are reclassified as pathogenic. Due to the clinical spectrum of DBP deficiency, this provides important prognostic information, including early mortality. Furthermore, we add persistent hypoglycemia to the clinical spectrum of the disease, and advocate for the early management of fat-soluble vitamin deficiencies to reduce complications.