Trends and cyclical variation in the incidence of childhood type 1 diabetes in 26 European centres in the 25 year period 1989-2013: a multicentre prospective registration study.

AIMS/HYPOTHESIS: Against a background of a near-universally increasing incidence of childhood type 1 diabetes, recent reports from some countries suggest a slowing in this increase. Occasional reports also describe cyclical variations in incidence, with periodicities of between 4 and 6 years. METHODS: Age/sex-standardised incidence rates for the 0- to 14-year-old age group are reported for 26 European centres (representing 22 countries) that have registered newly diagnosed individuals in geographically defined regions for up to 25 years during the period 1989-2013. Poisson regression was used to estimate rates of increase and test for cyclical patterns. Joinpoint regression software was used to fit segmented log-linear relationships to incidence trends. RESULTS: Significant increases in incidence were noted in all but two small centres, with a maximum rate of increase of 6.6% per annum in a Polish centre. Several centres in high-incidence countries showed reducing rates of increase in more recent years. Despite this, a pooled analysis across all centres revealed a 3.4% (95% CI 2.8%, 3.9%) per annum increase in incidence rate, although there was some suggestion of a reduced rate of increase in the 2004-2008 period. Rates of increase were similar in boys and girls in the 0- to 4-year-old age group (3.7% and 3.7% per annum, respectively) and in the 5- to 9-year-old age group (3.4% and 3.7% per annum, respectively), but were higher in boys than girls in the 10- to 14-year-old age group (3.3% and 2.6% per annum, respectively). Significant 4 year periodicity was detected in four centres, with three centres showing that the most recent peak in fitted rates occurred in 2012. CONCLUSIONS/INTERPRETATION: Despite reductions in the rate of increase in some high-risk countries, the pooled estimate across centres continues to show a 3.4% increase per annum in incidence rate, suggesting a doubling in incidence rate within approximately 20 years in Europe. Although four centres showed support for a cyclical pattern of incidence with a 4 year periodicity, no plausible explanation for this can be given.

Why boys will be boys: two pathways of fetal testicular androgen biosynthesis are needed for male sexual differentiation.

Human sexual determination is initiated by a cascade of genes that lead to the development of the fetal gonad. Whereas development of the female external genitalia does not require fetal ovarian hormones, male genital development requires the action of testicular testosterone and its more potent derivative dihydrotestosterone (DHT). The "classic" biosynthetic pathway from cholesterol to testosterone in the testis and the subsequent conversion of testosterone to DHT in genital skin is well established. Recently, an alternative pathway leading to DHT has been described in marsupials, but its potential importance to human development is unclear. AKR1C2 is an enzyme that participates in the alternative but not the classic pathway. Using a candidate gene approach, we identified AKR1C2 mutations with sex-limited recessive inheritance in four 46,XY individuals with disordered sexual development (DSD). Analysis of the inheritance of microsatellite markers excluded other candidate loci. Affected individuals had moderate to severe undervirilization at birth; when recreated by site-directed mutagenesis and expressed in bacteria, the mutant AKR1C2 had diminished but not absent catalytic activities. The 46,XY DSD individuals also carry a mutation causing aberrant splicing in AKR1C4, which encodes an enzyme with similar activity. This suggests a mode of inheritance where the severity of the developmental defect depends on the number of mutations in the two genes. An unrelated 46,XY DSD patient carried AKR1C2 mutations on both alleles, confirming the essential role of AKR1C2 and corroborating the hypothesis that both the classic and alternative pathways of testicular androgen biosynthesis are needed for normal human male sexual differentiation.

Interleukin-6 contributes to early fasting-induced free fatty acid mobilization in mice.

Contracting muscle releases interleukin-6 (IL-6) enabling the metabolic switch from carbohydrate to fat utilization. Similarly, metabolism is switched during transition from fed to fasting state. Herein, we examined a putative role for IL-6 in the metabolic adaptation to normal fasting. In lean C57BL/6J mice, 6 h of food withdrawal increased gene transcription levels of IL-6 in skeletal muscle but not in white adipose tissue. Concomitantly, circulating IL-6 and free fatty acid (FFA) levels were significantly increased, whereas respiratory quotient (RQ) was reduced in 6-h fasted mice. In white adipose tissue, phosphorylation of hormone-sensitive lipase (HSL) was increased on fasting, indicating increased lipolysis. Intriguingly, fasting-induced increase in circulating IL-6 levels and parallel rise in FFA concentration were absent in obese and glucose-intolerant mice. A causative role for IL-6 in the physiological adaptation to fasting was further supported by the fact that fasting-induced increase in circulating FFA levels was significantly blunted in lean IL-6 knockout (KO) and lean C57BL/6J mice treated with neutralizing IL-6 antibody. Consistently, phosphorylation of HSL was significantly reduced in adipose tissue of IL-6-depleted mice. Hence, our findings suggest a novel role for IL-6 in energy supply during early fasting.

Fas activates lipolysis in a Ca2+-CaMKII-dependent manner in 3T3-L1 adipocytes.

Fas (CD95) is a member of the tumor necrosis factor (TNF) receptor superfamily and plays a crucial role in the induction of apoptosis. However, like TNF, Fas can induce nonapoptotic signaling pathways. We previously demonstrated that mice lacking Fas specifically in adipocytes are partly protected from diet-induced insulin resistance, potentially via decreased delivery of FAs to the liver, as manifested by lower total liver ceramide content. In the present study, we aimed to delineate the signaling pathway involved in Fas-mediated adipocyte lipid mobilization. Treatment of differentiated 3T3-L1 adipocytes with membrane-bound Fas ligand (FasL) significantly increased lipolysis after 12 h without inducing apoptosis. In parallel, Fas activation increased phosphorylation of ERK1/2, and FasL-induced lipolysis was blunted in the presence of the ERK-inhibitor U0126 or in ERK1/2-depleted adipocytes. Furthermore, Fas activation increased phosphorylation of the Ca(2+)/calmodulin-dependent protein kinases II (CaMKII), and blocking of the CaMKII-pathway (either by the Ca(2+) chelator BAPTA or by the CaMKII inhibitor KN62) blunted FasL-induced ERK1/2 phosphorylation and glycerol release. In conclusion, we propose a novel role for CaMKII in promoting lipolysis in adipocytes.

Adipose tissue inflammation contributes to short-term high-fat diet-induced hepatic insulin resistance.

High-fat feeding for 3-4 days impairs glucose tolerance and hepatic insulin sensitivity. However, it remains unclear whether the evolving hepatic insulin resistance is due to acute lipid overload or the result of induced adipose tissue inflammation and consequent dysfunctional adipose tissue-liver cross-talk. In the present study, feeding C57Bl6/J mice a fat-enriched diet [high-fat diet (HFD)] for 4 days induced glucose intolerance, hepatic insulin resistance (as assessed by hyperinsulinemic euglycemic clamp studies), and hepatic steatosis as well as adipose tissue inflammation (i.e., TNFα expression) compared with standard chow-fed mice. Adipocyte-specific depletion of the antiapoptotic/anti-inflammatory factor Fas (CD95) attenuated adipose tissue inflammation and improved glucose tolerance as well as hepatic insulin sensitivity without altering the level of hepatic steatosis induced by HFD. In summary, our results identify adipose tissue inflammation and resulting dysfunctional adipose tissue-liver cross-talk as an early event in the development of HFD-induced hepatic insulin resistance.

Transient severe non-proliferative retinopathy in an adolescent with type 1 diabetes and chronic myeloid leukemia.

The onset of diabetic retinopathy correlates with the long-term quality of glycemic control. A 17-yr-old adolescent with type 1 diabetes presented unexpectedly with acute non-proliferative retinopathy despite good glycemic control. Two months later chronic myeloid leukemia (CML) was diagnosed. Chemotherapy was initiated and within a few weeks the patient was in full remission concerning leukemia. Retinopathy completely resolved within 8 months. The patient was in good metabolic control throughout the course. To our knowledge, this is the first report of CML-triggered retinopathy in a well-controlled diabetic adolescent. In case of unexpected retinopathy in patients with type 1 diabetes, other potential causes of retinopathy should be considered.

Metabolic outcomes in young children with type 1 diabetes differ between treatment centers: the Hvidoere Study in Young Children 2009.

OBJECTIVE: To investigate whether center differences in glycemic control are present in prepubertal children <11 yr with type 1 diabetes mellitus. RESEARCH DESIGN AND METHODS: This cross-sectional study involved 18 pediatric centers worldwide. All children, <11 y with a diabetes duration ≥12 months were invited to participate. Case Record Forms included information on clinical characteristics, insulin regimens, diabetic ketoacidosis (DKA), severe hypoglycemia, language difficulties, and comorbidities. Hemoglobin A1c (HbA1c) was measured centrally by liquid chromatography (DCCT aligned, range: 4.4-6.3%; IFFC: 25-45 mmol/mol). RESULTS: A total of 1133 children participated (mean age: 8.0 ± 2.1 y; females: 47.5%, mean diabetes duration: 3.8 ± 2.1 y). HbA1c (overall mean: 8.0 ± 1.0%; range: 7.3-8.9%) and severe hypoglycemia frequency (mean 21.7 events per 100 patient-years), but not DKA, differed significantly between centers (p < 0.001 resp. p = 0.179). Language difficulties showed a negative relationship with HbA1c (8.3 ± 1.2% vs. 8.0 ± 1.0%; p = 0.036). Frequency of blood glucose monitoring demonstrated a significant but weak association with HbA1c (r = -0.17; p < 0.0001). Although significant different HbA1c levels were obtained with diverse insulin regimens (range: 7.3-8.5%; p < 0.001), center differences remained after adjusting for insulin regimen (p < 0.001). Differences between insulin regimens were no longer significant after adjusting for center effect (p = 0.199). CONCLUSIONS: Center differences in metabolic outcomes are present in children <11 yr, irrespective of diabetes duration, age, or gender. The incidence of severe hypoglycemia is lower than in adolescents despite achieving better glycemic control. Insulin regimens show a significant relationship with HbA1c but do not explain center differences. Each center's effectiveness in using specific treatment strategies remains the key factor for outcome.

Inverse regulation of basal lipolysis in perigonadal and mesenteric fat depots in mice.

Given the strong link between visceral adiposity and (hepatic) insulin resistance as well as liver steatosis, it is crucial to characterize obesity-associated alterations in adipocyte function, particularly in fat depots drained to the liver. Yet these adipose tissues are not easily accessible in humans, and the most frequently studied depot in rodents is the perigonadal, which is drained systemically. In the present study, we aimed to study alterations in lipolysis between mesenteric and perigonadal adipocytes in mice. Basal free fatty acid and glycerol release was significantly lower in perigonadal compared with mesenteric adipocytes isolated from chow-fed C57BL/6J mice. However, this difference completely vanished in high-fat diet-fed mice. Consistently, protein levels of the G(0)/G(1) switch gene 2 (G0S2), which were previously found to be inversely related to basal lipolysis, were significantly lower in mesenteric compared with perigonadal fat of chow-fed mice. Similarly, perilipin was differently expressed between the two depots. In addition, adipocyte-specific overexpression of G0S2 led to significantly decreased basal lipolysis in mesenteric adipose tissue of chow-fed mice. In conclusion, lipolysis is differently regulated between perigonadal and mesenteric adipocytes, and these depot-specific differences might be explained by altered regulation of G0S2 and/or perilipin.

Ovaries and female phenotype in a girl with 46,XY karyotype and mutations in the CBX2 gene.

A girl with a prenatal 46,XY karyotype was born with a completely normal female phenotype, including uterus and histologically normal ovaries. In mice with a similar phenotype, the ablation of M33, an ortholog of Drosophila Polycomb, causes male-to-female sex reversal. The analysis of the human homolog of M33, Chromobox homolog 2 (CBX2), in this girl revealed loss-of-function mutations that allowed us, by placing CBX2 upstream of SRY, to add an additional component to the still incomplete cascade of human sex development.

Aromatase deficiency owing to a functional variant in the placenta promoter and a novel missense mutation in the CYP19A1 gene.

CONTEXT: Aromatase deficiency in women is a rare 46, XX disorder of sex differentiation characterized by a defect in catalysing oestrogens from androgens. OBJECTIVE: To better understand this rare disorder, we searched for mutations in the CYP19A1 gene of an affected girl and analysed their functional consequences. DESIGN AND PATIENT: We examined a girl presenting with clitoral hypertrophy at birth and mild maternal virilization (acne) during pregnancy. MAIN OUTCOME MEASUREMENT: A genotype-phenotype correlation was found. RESULTS: By direct sequencing of the CYP19A1 gene, we identified a heterozygous A>G mutation (c. A1374G) mutation in exon IX, leading to the missense p.N411S in the P450Aro protein and a heterozygous placenta promoter variant -41 base pairs upstream of exon I.1. Aromatase enzyme activity was completely lost when the mutant p.N411S protein was expressed in COS-1 cells. The placenta promoter variant had a significantly reduced (-50%) transactivation ability compared to wild-type. CONCLUSION: Our data describe a novel loss-of-function missense mutation in CYP19A1 combined with the first-described variant of the placenta promoter with a significant reduction in function, likely to be the molecular basis of this rare 46, XX disorder of sex development. This seems to represent a unique case of aromatase deficiency occurring in utero only.

Improved glycemic control and lower frequency of severe hypoglycemia with insulin detemir; long-term experience in 105 children and adolescents with type 1 diabetes.

OBJECTIVE: To assess the effect of the insulin analog detemir on glycemic control and severe hypoglycemia in children and adolescents with type 1 diabetes. RESEARCH DESIGN AND METHODS: A retrospective chart analysis was performed in 105 patients with type 1 diabetes after switching to insulin detemir between 2004 and 2007. In children below 12 yr of age (n = 53), evening neutral protomin hagedorn (NPH) insulin was replaced by insulin detemir if therapeutic goals were not reached and blood glucose levels were unpredictable or hardly controllable. In adolescents above 12 yr of age (n = 52), insulin detemir was started when changing to intensified insulin therapy. RESULTS: In children below 12 yr of age, hemoglobin A1c (HbA1c) at start was 8.3 +/- 0.8% and after 12 months of treatment with insulin detemir significantly lowered (7.6 +/- 0.6%, p < 0.001). In the age-group above 12 yr of age at the start of the study, the improvement of HbA1c after 12 months of treatment was less pronounced (8.0 +/- 1.2 vs. 7.6 +/- 1.0%) but still significant (p < 0.01). The risk for severe hypoglycemia was significantly decreased compared with patients attending the outpatient clinic between 1995 and 2003 (4.8/100 patient years vs. 7.6/100 patient years, p = 0.003). From the beginning to the end of the follow-up period, body mass index dropped significantly in children below 12 yr of age but no effect was observed in adolescents. CONCLUSIONS: Use of insulin detemir allows a safe nocturnal glycemic control in children and adolescents with type 1 diabetes and is associated with significantly improved HbA1c levels and fewer severe hypoglycemic events. This makes insulin detemir a most valuable new tool for the treatment of children and adolescents with type 1 diabetes.

A WNT4 mutation associated with Müllerian-duct regression and virilization in a 46,XX woman.

WNT4, a secreted protein that suppresses male sexual differentiation, is thought to repress the biosynthesis of gonadal androgen in female mammals. An 18-year-old woman presented with primary amenorrhea and an absence of müllerian-derived structures, unilateral renal agenesis, and clinical signs of androgen excess--a phenotype resembling the Mayer-Rokitansky-Küster-Hauser syndrome and remarkably similar to that of female Wnt4-knockout mice. A genetic evaluation revealed a loss-of-function mutation in the WNT4 gene. WNT4 appears to be important in the development and maintenance of the female phenotype in women, by means of the regulation of müllerian-duct formation and control of ovarian steroidogenesis.

Clinical follow-up of the first SF-1 insufficient female patient.

OBJECTIVE: Steroidogenic factor 1 (SF-1/NR5A1) plays a crucial role in regulating adrenal development, gonad determination and differentiation, and in the hypothalamic-pituitary control of reproduction and metabolism. In men (46, XY), it is known that mutations in SF-1/NR5A1 gene cause a wide phenotypic spectrum with variable degrees of undervirilization. In recent years, the role of SF-1 in the ovarian function was increasingly discussed and alterations in the gene were related to primary ovarian insufficiency. We describe the follow-up of a 46, XX affected woman with a SF-1 mutation and by comparing our case with the known manifestations reported in the literature, we try to further elucidate the function of SF-1 in the ovary. RESULTS: During infancy, adrenal insufficiency was the only clinical sign of the loss-of-function as ovarian development and function seemed normal. To date, this young woman aged 16.5 years shows normal growth, normal BMI and psychomotor development, has a normal puberty and regular menstruation. CONCLUSION: This report shows one, to date uniquely described, phenotypic variant of SF-1 mutation in a 46, XX affected person with adrenocortical insufficiency but no ovarian dysfunction nor disturbance of pubertal development. To follow the natural history of SF-1 mutation in a 46, XX individual will further shed light on its role in the ovarian function and thus will help to counsel affected patients in future.

Loss of kinase activity in a patient with Wolcott-Rallison syndrome caused by a novel mutation in the EIF2AK3 gene.

Wolcott-Rallison syndrome (WRS) is an autosomal recessive disorder characterized by neonatal or early infancy type 1 diabetes, epiphyseal dysplasia, and growth retardation. Mutations in the EIF2AK3 gene, encoding the eukaryotic initiation factor 2alpha-kinase 3 (EIF2AK3), have been found in WRS patients. Here we describe a girl who came to our attention at 2 months of age with severe hypertonic dehydration and diabetic ketoacidosis. A diagnosis of type 1 diabetes was made and insulin treatment initiated. Growth retardation and microcephaly were also present. Anti-islet cell autoantibodies were negative, and mitochondrial diabetes was excluded. Imaging revealed a hypoplastic pancreas and typical signs of spondylo-epiphyseal dysplasia. The diagnosis of WRS was therefore made at age 5 years. Sequencing analysis of her EIF2AK3 gene revealed the presence of a homozygous T to C exchange in exon 13 leading to the missense serine 877 proline mutation. The mutated kinase, although it partly retains the ability of autophosphorylation, is unable to phosphorylate its natural substrate, eukaryotic initiation factor 2alpha (eIF2alpha). This is the first case in which the pathophysiological role of EIF2AK3 deficiency in WRS is confirmed at the molecular level. Our data demonstrate that EIF2AK3 kinase activity is essential for pancreas islet function and bone development in humans, and we suggest EIF2AK3 as a possible target for therapeutic intervention in diabetes.

The Aldosterone/Renin Ratio as a Diagnostic Tool for the Diagnosis of Primary Hypoaldosteronism in Newborns and Infants.

BACKGROUND/AIMS: Primary hypoaldosteronism is a rare inborn disorder with life-threatening symptoms in newborns and infants due to an aldosterone synthase defect. Diagnosis is often difficult as the plasma aldosterone concentration (PAC) can remain within the normal range and thus lead to misinterpretation and delayed initiation of life-saving therapy. We aimed to test the eligibility of the PAC/plasma renin concentration (PRC) ratio as a tool for the diagnosis of primary hypoaldosteronism in newborns and infants. Meth ods: Data of 9 patients aged 15 days to 12 months at the time of diagnosis were collected. The diagnosis of primary hypoaldosteronism was based on clinical and laboratory findings over a period of 12 years in 3 different centers in Switzerland. To enable a valid comparison, the values of PAC and PRC were correlated to reference methods. RESULTS: In 6 patients, the PAC/PRC ratio could be determined and showed constantly decreased values <1 (pmol/l)/(mU/l). In 2 patients, renin was noted as plasma renin activity (PRA). PAC/PRA ratios were also clearly decreased. The diagnosis was subsequently genetically confirmed in 8 patients. CONCLUSION: A PAC/PRC ratio <1 pmol/mU and a PAC/PRA ratio <28 (pmol/l)/(ng/ml × h) are reliable tools to identify primary hypoaldosteronism in newborns and infants and help to diagnose this life-threatening disease faster.

Opposing effects of reduced kidney mass on liver and skeletal muscle insulin sensitivity in obese mice.

Reduced kidney mass and/or function may result in multiple metabolic derangements, including insulin resistance. However, underlying mechanisms are poorly understood. Herein, we aimed to determine the impact of reduced kidney mass on glucose metabolism in lean and obese mice. To that end, 7-week-old C57BL/6J mice underwent uninephrectomy (UniNx) or sham operation. After surgery, animals were fed either a chow (standard) diet or a high-fat diet (HFD), and glucose homeostasis was assessed 20 weeks after surgery. Intraperitoneal glucose tolerance was similar in sham-operated and UniNx mice. However, insulin-stimulated glucose disposal in vivo was significantly diminished in UniNx mice, whereas insulin-stimulated glucose uptake into isolated skeletal muscle was similar in sham-operated and UniNx mice. Of note, capillary density was significantly reduced in skeletal muscle of HFD-fed UniNx mice. In contrast, hepatic insulin sensitivity was improved in UniNx mice. Furthermore, adipose tissue hypoxia-inducible factor 1α expression and inflammation were reduced in HFD-fed UniNx mice. Treatment with the angiotensin II receptor blocker telmisartan improved glucose tolerance and hepatic insulin sensitivity in HFD-fed sham-operated but not UniNx mice. In conclusion, UniNx protects from obesity-induced adipose tissue inflammation and hepatic insulin resistance, but it reduces muscle capillary density and, thus, deteriorates HFD-induced skeletal muscle glucose disposal.

High reliability of neonatal screening for congenital adrenal hyperplasia in Switzerland.

Newborn screening for congenital adrenal hyperplasia (CAH) is justified by the sometimes difficult clinical diagnosis and the risks associated with missed diagnosis, particularly the life-threatening salt-wasting crisis. In Switzerland, nationwide screening for CAH by measuring 17-hydroxyprogesterone levels in dried blood spots was introduced in 1992. At the Zurich University Children's Hospital, 50% of the population of Switzerland is screened. The aim of the study was to evaluate the efficiency of the Zurich screening program. Between January 1, 1993, and May 31, 2001, 333,221 newborns were screened for CAH. Thirty-one newborns had CAH (incidence, 1 in 10,749); 30 were detected through screening (sensitivity, 97%). A recall for suspected CAH was performed in only 60 cases, corresponding to a very low recall rate (0.0018%). In 30 recalls CAH was confirmed (positive predictive value, 50%; specificity, 99.99%). Fifteen of 31 patients profited from screening, as CAH had not been recognized clinically. The timely availability of screening results made therapy possible within the first week of life in most cases and helped in preventing salt-wasting crisis in all patients. With a sensitivity of 97%, a specificity of 99.99%, and a positive predictive value of 50%, the Zurich neonatal screening program for CAH can be considered highly reliable.

Complete androgen insensitivity syndrome caused by a novel mutation in the ligand-binding domain of the androgen receptor: functional characterization.

Mutations in the X-linked androgen receptor (AR) gene cause the androgen insensitivity syndrome by impairing androgen-dependent male sexual differentiation to varying degrees. Complete androgen insensitivity (CAIS) yields an external female phenotype, whereas affected cases of partial androgen insensitivity have various ambiguities of the genitalia. Here we describe a 46,XY phenotypically female patient with all of the characteristics of CAIS, i.e. primary amenorrhea, no axillary or pubic hair, female external genitalia, no uterus, and undescended testes. Defects in testosterone and dihydrotestosterone synthesis were excluded. The molecular basis of the disease was clarified by means of direct sequencing of PCR-amplified exonic fragments of the AR gene. An A to C transition in exon 4 of the AR gene led to a novel missense His(689)Pro mutation in the ligand-binding domain of the AR protein. Functional studies demonstrated that the mutated AR is unable to efficiently bind its natural ligand dihydrotestosterone and to trans-activate known androgen response elements. Analysis of the structural consequences of the His(689)Pro substitution suggests that this mutation is likely to perturb the conformation of the second helix of the AR ligand-binding domain, which contains residues critical for androgen binding.

Comparative trial between insulin glargine and NPH insulin in children and adolescents with type 1 diabetes mellitus.

The objective of this study was to compare the efficacy and safety of insulin glargine, a long-acting insulin analog, with NPH insulin in children and adolescents with type 1 diabetes mellitus (T1DM). In a multicenter, open-label, randomized, 6-month study, 349 patients with TIDM, aged 5-16 years, received insulin glargine once daily or NPH insulin either once or twice daily, based on their prior treatment regimen. Although there was no significant difference between the NPH insulin and insulin glargine treatment groups with respect to baseline to endpoint change in HbA1c levels, fasting blood glucose (FBG) levels decreased significantly more in the insulin glargine group (-1.29 mmol/l) than in the NPH insulin group (-0.68 mmol/L, p = 0.02). The percentage of symptomatic hypoglycemic events was similar between groups; however, fewer patients in the insulin glargine group reported severe hypoglycemia (23% vs 29%) and severe nocturnal hypoglycemia (13% vs 18%), although these differences were not statistically significant (p = 0.22 and p = 0.19, respectively). Fewer serious adverse events occurred in the insulin glargine group than in the NPH insulin group (p < 0.02). A once-daily subcutaneous dose of insulin glargine provides effective glycemic control and is well tolerated in children and adolescents with T1DM.

Short-term HFD does not alter lipolytic function of adipocytes.

A short bout of high fat diet (HFD) impairs glucose tolerance and hepatic insulin sensitivity. We recently identified adipose tissue inflammation and resulting dysfunctional adipose tissue-liver cross-talk as an early event in the development of HFD-induced hepatic insulin resistance. In particular, reducing white adipose tissue (WAT) inflammation by adipocyte-specific depletion of Fas/CD95 protected mice from developing hepatic insulin resistance but not hepatic steatosis. Herein, we expanded our previous work and determined the impact of four days of HFD on lipolytic activity of isolated adipocytes. Compared with chow-fed mice, the degree of basal and isoproterenol-stimulated free fatty acid (FFA) and glycerol release was similar in HFD-fed animals. Moreover, insulin's ability to suppress lipolysis remained intact, suggesting retained insulin sensitivity. Despite unaltered lipolysis, circulating FFA concentrations were greatly increased in non-fasted HFD-fed mice. In conclusion, a short-term HFD challenge does not affect lipolytic function of adipocytes. The observed increase of circulating FFA levels in randomly fed animals may rather be the result of increased dietary fat supply.