Long-term Metabolic and Socioeducational Outcomes of Transient Neonatal Diabetes: A Longitudinal and Cross-sectional Study.

OBJECTIVE: Transient neonatal diabetes mellitus (TNDM) occurs during the 1st year of life and remits during childhood. We investigated glucose metabolism and socioeducational outcomes in adults. RESEARCH DESIGN AND METHODS: We included 27 participants with a history of TNDM currently with (n = 24) or without (n = 3) relapse of diabetes and 16 non-TNDM relatives known to be carriers of causal genetic defects and currently with (n = 9) or without (n = 7) diabetes. Insulin sensitivity and secretion were assessed by hyperinsulinemic-euglycemic clamp and arginine-stimulation testing in a subset of 8 TNDM participants and 7 relatives carrying genetic abnormalities, with and without diabetes, compared with 17 unrelated control subjects without diabetes. RESULTS: In TNDM participants, age at relapse correlated positively with age at puberty (P = 0.019). The mean insulin secretion rate and acute insulin response to arginine were significantly lower in TNDM participants and relatives of participants with diabetes than in control subjects (median 4.7 [interquartile range 3.7-5.7] vs. 13.4 [11.8-16.1] pmol/kg/min, P < 0.0001; and 84.4 [33.0-178.8] vs. 399.6 [222.9-514.9] µIU/mL, P = 0.0011), but were not different between participants without diabetes (12.7 [10.4-14.3] pmol/kg/min and 396.3 [303.3-559.3] µIU/mL, respectively) and control subjects. Socioeducational attainment was lower in TNDM participants than in the general population, regardless of diabetes duration. CONCLUSIONS: Relapse of diabetes occurred earlier in TNDM participants compared with relatives and was associated with puberty. Both groups had decreased educational attainment, and those with diabetes had lower insulin secretion capacity; however, there was no difference in insulin resistance in adulthood. These forms of diabetes should be included in maturity-onset diabetes of the young testing panels, and relatives of TNDM patients should be screened for underlying defects, as they may be treated with drugs other than insulin.

Exposure to Glucocorticoids in the First Part of Fetal Life is Associated with Insulin Secretory Defect in Adult Humans.

OBJECTIVE: High glucocorticoid levels in rodents inhibit development of beta cells during fetal life and lead to insulin deficiency in adulthood. To test whether similar phenomena occur in humans, we compared beta-cell function in adults who were exposed to glucocorticoids during the first part of fetal life with that of nonexposed subjects. RESEARCH DESIGN AND METHODS: The study was conducted in 16 adult participants exposed to glucocorticoids during the first part of fetal life and in 16 nonexposed healthy participants with normal glucose tolerance who were matched for age, sex, and body mass index (BMI). Exposed participants had been born to mothers who were treated with dexamethasone 1 to 1.5 mg/day from the sixth gestational week (GW) to prevent genital virilization in children at risk of 21-hydroxylase deficiency. We selected offspring of mothers who stopped dexamethasone before the 18th GW following negative genotyping of the fetus. Insulin and glucagon secretion were measured during an oral glucose tolerance test (OGTT) and graded intravenous (IV) glucose and arginine tests. Insulin sensitivity was measured by hyperinsulinemic-euglycemic-clamp. RESULTS: Age, BMI, and anthropometric characteristics were similar in the 2 groups. Insulinogenic index during OGTT and insulin sensitivity during the clamp were similar in the 2 groups. In exposed subjects, insulin secretion during graded IV glucose infusion and after arginine administration decreased by 17% (P = 0.02) and 22% (P = 0.002), respectively, while glucagon secretion after arginine increased. CONCLUSION: Overexposure to glucocorticoids during the first part of fetal life is associated with lower insulin secretion at adult age, which may lead to abnormal glucose tolerance later in life.

Checkpoint inhibitor treatment induces an increase in HbA1c in nondiabetic patients.

Immunotherapy greatly improves clinical outcomes in treated patients with cancer. However, the long-lasting immune response and long duration of therapy could induce long-term adverse effects owing to the chronic inflammation induced. Type 2 diabetes is now recognized as an inflammatory disease. In addition, immunotherapy is concerned with increase in the production of tumor necrosis factor-α, interleukin-2, and interferon-γ, which are involved in the inflammatory process. Based on these observations, we hypothesized that anti-programmed cell death-1 (anti-PD-1) and/or anticytotoxic T-lymphocyte-associated protein-4 therapy could contribute to type 2 diabetes genesis in treated patients. Therefore, to evaluate this hypothesis, we studied HbA1c levels during follow-up in patients treated with anti-PD-1 and/or anticytotoxic T-lymphocyte-associated protein-4 therapy. A prospective and observational study was performed in an oncodermatology department (Saint-Louis Hospital, Paris, France) from March 2015 to February 2017. Sixty-two patients meeting the inclusion criteria were enrolled. Forty-three patients had paired HbA1c measurements during their follow-up period and were analyzed. The median follow-up was 3 months. We noted an increase in HbA1c levels from 5.3% [interquartile range (IQR): 5.1-5.5; range: 4.5-6.2) to 5.45% (IQR: 5.2-5.7; range: 4.7-6.2; P=0.037). This observation was confirmed in the subgroup of patients who did not receive concomitant glucocorticoids; their median HbA1c levels increased from 5.3% (IQR: 5.1-5.5; range: 4.7-6.2) to 5.5% (IQR: 5.2-5.7; range: 4.7-6.3; P=0.025). Variables such as age, BMI, and sex were not associated with the HbA1c level increase, but a tendency toward rising HbA1c levels was observed in treatments longer than 12 months. This study demonstrates that treatment with anti-PD-1 antibodies may impair glucose metabolism, as measured by increasing HbA1c levels.

Acute phase ketosis-prone atypical diabetes is associated with a pro-inflammatory profile: a case-control study in a sub-Saharan African population.

BACKGROUND: It is unknown whether inflammation plays a role in metabolic dysfunction on ketosis-prone diabetes (KPD). We aimed to assess the inflammatory profile in sub-Saharan African patients with KPD during the acute ketotic phase as well as during non-ketotic hyperglycemic crises. METHODS: We studied 72 patients with non-autoimmune diabetes: 23 with type 2 diabetes mellitus (T2D), and 49 with KPD, all admitted in hyperglycemic crisis (plasma glucose ≥250 mg/dl). The T2D and KPD groups were matched by sex, age, and Body Mass Index. KPD was sub-classified into new-onset ketotic phase (n = 34) or non-ketotic phase (n = 15). We measured TNF-α, MCP-1, MIP1-α, IL-8, MIP1-ß, and VEGF in the serum of all participants. RESULTS: TNF-α and IL-8 were higher in participants with KPD compared to those with T2D (p = 0.02 TNF-α; p = 0.03 IL-8). TNF-α and IL-8 were also higher in the ketotic phase KPD group compared to the T2D group (p = 0.03 TNF-α; p < 0.001 IL-8) while MIP1-α was lower in people with ketotic phase KPD compared to their T2D counterparts (p = 0.03). MIP1-α was lower in the ketotic phase KPD group compared to the non-ketotic phase KPD group (p = 0.04). MCP-1 was lower in non-ketotic phase KPD compared to T2D (p = 0.04), and IL-8 was higher in non-ketotic phase KPD compared to T2D (p = 0.02). CONCLUSIONS: Participants with KPD had elevated pro-inflammatory cytokines compared to their T2D counterparts. Ketotic phase KPD is associated with a different pro-inflammatory profile compared to non-ketotic phase KPD, and the inflammatory profile appears to be comparable between non-ketotic phase KPD and T2D patients.

Occurrence of type 1 and type 2 diabetes in patients treated with immunotherapy (anti-PD-1 and/or anti-CTLA-4) for metastatic melanoma: a retrospective study.

Anti-PD-1 and anti-CTLA-4 antibodies cause immune-related side effects such as autoimmune type 1 diabetes (T1D). It has also been suggested that by increasing TNF-α, IL-2 and IFN-γ production, anti-PD-1 and/or anti-CTLA-4 treatment could affect pancreatic beta cell function and insulin sensitivity. This study was based on a retrospective observational analysis from 2 July 2014 to 27 June 2016, which evaluated the occurrence of T1D and changes in glycemia and C-reactive protein (CRP) plasma concentrations in patients undergoing anti-PD-1 and/or anti-CTLA-4 treatment for melanoma at the Saint Louis Hospital. All cases of T1D that developed during immunotherapy registered in the French Pharmacovigilance Database (FPVD) were also considered. Among the 132 patients included, 3 cases of T1D occurred. For the remaining subjects, blood glucose was not significantly affected by anti-PD-1 treatment, but CRP levels (mg/l) significantly increased during anti-PD-1 treatment (p = 0.017). However, 1 case of type 2 diabetes (T2D) occurred (associated with a longer therapy duration). Moreover, glycemia of patients pretreated (n = 44) or concomitantly treated (n = 8) with anti-CTLA-4 tended to increase during anti-PD-1 therapy (p = 0.068). From the FPVD, we obtained 14 cases of T1D that occurred during immunotherapy and were primarily characterized by the rapidity and severity of onset. In conclusion, in addition to inducing this rare immune-related diabetes condition, anti-PD-1 treatment appears to increase CRP levels, a potential inflammatory trigger of insulin resistance, but without any short-term impact on blood glucose level.

Human herpesvirus 8 infection DNA positivity is associated with low insulin secretion: A case-control study in a sub-Saharan African population with diabetes.

BACKGROUND: Viruses have been considered potential triggers for the development of diabetes. This study assessed insulin secretion and insulin sensitivity in human herpesvirus 8 (HHV8)-infected and uninfected sub-Saharan African people with diabetes. METHODS: In all, 173 people with non-autoimmune diabetes were enrolled consecutively: 124 with type 2 diabetes mellitus (T2DM) and 49 with ketosis-prone diabetes (KPD) admitted in hyperglycemic crisis. Those with KPD were further subdivided into those with new-onset ketotic-phase KPD (n = 34) or non-ketotic phase KPD (n = 15). All participants were screened for HHV8-specific antibodies and genomic DNA. Blood samples were collected for analysis of fasting glucose, HbA1c, lipid profile, and C-peptide, with insulin resistance and secretion estimated by homeostasis model assessment. RESULTS: Among the 173 diabetic participants, 88 (50.9%) were positive for HHV8 antibodies (Ac-HHV8+), including 15 (8.7%) positive for HHV8 DNA (DNA-HHV8+). The seroprevalence of HHV8 was similar between T2DM (55.6%) and KPD (61.2%) subjects. Of those with and without ketotic-phase KPD, 35.3% and 46.7% were Ac-HHV8+, respectively. Body mass index was significantly in lower DNA-HHV8+ than DNA-HHV8- subjects. Low-density lipoprotein and total cholesterol were significantly higher, but C-peptide and homeostatic model assessment of ß-cell function (HOMA-ß) were significantly lower in DNA-HHV8+ than DNA-HHV8- participants. After excluding DNA-HHV8+ participants, triglyceride concentrations were significantly higher in Ac-HHV8+ (n = 73) than Ac-HHV8- (n = 85) subjects. In contrast, HOMA-ß was significantly higher among Ac-HHV8+ than Ac-HHV8- participants. CONCLUSIONS: In the present study, HHV8 DNA positivity was associated with low insulin secretion in this sub-Saharan African diabetes population.

Sex Difference In the Effect of Fetal Exposure to Maternal Diabetes on Insulin Secretion.

We previously showed that fetal exposure to maternal type 1 diabetes (T1D) is associated with altered glucose-stimulated insulin secretion in adult offspring. Here, we investigated whether this ß-cell defect displays a sex dimorphism. Twenty-nine adult nondiabetic offspring of T1D mothers (ODMs) were compared with 29 nondiabetic offspring of T1D fathers. We measured early insulin secretion in response to oral glucose and insulin secretion rate in response to intravenous glucose ramping. Insulin sensitivity and body composition were assessed by a euglycemic, hyperinsulinemic clamp and dual-energy X-ray absorptiometry, respectively. In response to oral glucose, male and female ODMs displayed a reduced insulin secretion. In contrast, in response to graded intravenous glucose infusion, only female ODMs (not males) exhibited decreased insulin secretion. There was no defect in response to combined intravenous arginine and glucose, suggesting that male and female ODMs exhibit a functional ß-cell defect rather than a reduced ß-cell mass. In conclusion, fetal exposure to maternal diabetes predisposes to ß-cell dysfunction in adult male and female offspring. This ß-cell defect is characterized by a sexual dimorphism following intravenous glucose stimulation.

Association of the leptin-to-adiponectin ratio with metabolic syndrome in a sub-Saharan African population.

BACKGROUND: Worldwide there is an increased prevalence of metabolic syndrome mainly due to life-style modifications, and Africans are not saved of this situation. Many markers have been studied to predict the risk of this syndrome but the most used are leptin and adiponectin. Data on these metabolic markers are scare in Africa and this study aimed to assess the association between the leptin-to-adiponectin ratio (LAR) with metabolic syndrome in a Cameroonian population. METHODS: This was a cross-sectional study that included 476 adults among a general population of Cameroon. Data collected concerned the body mass index, waist circumference, systolic blood pressure, diastolic blood pressure, fasting blood glucose, plasma lipids, adiponectin, leptin, insulin and homeostasis model for assessment of insulin resistance (HOMA-IR). To assess correlations we used Spearman's analyses and association of the studied variables with metabolic syndrome were done using binary logistic regression analysis. RESULTS: The leptin to adiponectin ratio was significantly and positively correlated with the body mass index (r = 0.669, p < 0.0001), waist circumference (r = 0.595, p < 0.0001), triglycerides (r = 0.190, p = 0.001), insulin levels (r = 0.333, p < 0.0001) and HOMA-IR (r = 0.306, p < 0.0001). Binary logistic regression analysis revealed that leptin, adiponectin and LAR were significantly associated with metabolic syndrome with respective unadjusted OR of 1.429, 0.468 and 1.502. After adjustment, for age and sex, the associations remained significative; LAR was also found to be significantly associated with metabolic syndrome (OR = 1.573, p value =0.000) as well as lower levels of adiponectin (OR = 0.359, p value =0.000) and higher levels of leptin (OR = 1.469, p value =0.001). CONCLUSION: This study revealed that LAR is significantly associated with metabolic syndrome in sub-Saharan African population, independently to age and sex.

Autoimmune diabetes induced by PD-1 inhibitor-retrospective analysis and pathogenesis: a case report and literature review.

Anti-PD-1 antibody treatment is approved in advanced melanoma and provides median overall survival over 24 months. The main treatment-related side effects are immune-related adverse events, which include rash, pruritus, vitiligo, thyroiditis, diarrhoea, hepatitis and pneumonitis. We report a case of autoimmune diabetes related to nivolumab treatment. A 73-year-old man was treated in second line with nivolumab at 3 mg/kg every two weeks for metastatic melanoma. At 6 weeks of treatment, he displayed diabetic ketoacidosis. Nivolumab was withheld 3.5 weeks and insulin therapy was initiated, enabling a normalization of glycaemia and the disappearance of symptoms. Laboratory investigations demonstrated the presence of islet cell autoantibodies, while C-peptide was undetectable. Retrospective explorations on serum banked at week 0 and 3 months before the start of nivolumab, already showed the presence of autoantibodies, but normal insulin, C-peptide secretion and glycaemia. Partial response was obtained at month 3, and nivolumab was then resumed at the same dose. The clinical context and biological investigations before, at and after nivolumab initiation suggest the autoimmune origin of this diabetes, most likely induced by anti-PD-1 antibody in a predisposed patient. The role of PD-1/PD-L1 binding is well known in the pathogenesis of type 1 diabetes. Therefore, this rare side effect can be expected in a context of anti-PD-1 treatment. Glycaemia should be monitored during PD-1/PD-L1 blockade. The presence of autoantibodies before treatment could identify individuals at risk of developing diabetes, but systematic titration may not be relevant considering the rarity of this side effect.

Zinc transporter 8 autoantibodies assessment in daily practice.

OBJECTIVES: Zinc transporter 8 (ZnT8) is specifically expressed in the pancreatic ß-cell and is more restricted in its tissue distribution than other auto-antigens as glutamic acid decarboxylase 65 (GAD65) and insulinoma-associated antigen-2 (IA2). ZnT8 autoantibodies (ZnT8A) assessment allows identifying rapid progression to clinical onset of the disease. We evaluated the prevalence of ZnT8A in adults of different ethnic and phenotypic groups and analyzed its potential utility as additional marker of autoimmunity in daily practice. METHODS: ZnT8A, GADA and IA2A were assessed using enzyme-linked immune-sorbent assay (ELISA) in 160 controls and 216 diabetic subjects. 105 were of type 1 diabetes (T1D), 17 had Latent Autoimmune Diabetes of Adults (LADA), 38 were type 2 diabetic (T2D) and 56 had ketosis-prone diabetes (KPD). 82 patients were newly diagnosed cases. RESULTS: ZnT8A were detected in 1% of controls and were not found in any of our 38 T2D subjects or 56 KPD subjects. In contrast, ZnT8A were detected in 18% of LADA subjects and in 38% of T1D subjects. A slight difference of percentage of ZnT8A positivity was found among our T1D ethnic groups. ZnT8A were positive in 41% of patients positive for GADA and 67% of patients positive for IA2A. The percentage of stratification achieved 91% when GADA, IA2A and ZnT8A were assessed simultaneously. CONCLUSIONS: Results obtained for ZnT8A measurement using ELISA were consistent with previous data. Such investigation could improve the risk stratification and would be integrated in our daily practice.

Association of serum leptin and adiponectin with anthropomorphic indices of obesity, blood lipids and insulin resistance in a Sub-Saharan African population.

BACKGROUND: There is little data on the metabolic effects of adipokines in sub-Saharan African populations. This study aimed to explore the potential relationship of leptin and adiponectin, with obesity, plasma lipids and insulin resistance in a Cameroonian population. METHODS: We enrolled 167 men and 309 women aged ≥18 years from the general population in Cameroon. Data were collected on waist circumference (WC), body mass index (BMI), waist-to-hip ratio (WHR), body fat (BF%), fasting blood glucose, plasma lipids, adiponectin, leptin, insulin and homeostasis model for assessment of insulin resistance (HOMA-IR). Pearson's correlation and multiple stepwise linear regression analyses were used to determine correlates of leptin and adiponectin serum levels. RESULTS: The prevalence of obesity was higher in women compared to men (p < 0.0001), and Central obesity which is more prevalent particularly in women (WC = 42.4%, WHR = 42.3%), is almost for 90% comparable to %BF (42.7%). Adiponectin negatively with BMI (r = -0.294, p < 0.0001), WC (r = -0.294, p < 0.0001), %BF (r = -0.122, p = 0.028), WHR (r = -0.143, p = 0.009), triglycerides (r = -0.141, p = 0.011), HOMA-IR (r = -0.145, p = 0.027) and insulin (r = -0.130, p = 0.048). Leptin positively correlated with BMI (r = 0.628), WC (r = 0.530), BF% (r = 0.720), (all p < 0.0001); with DBP (r = 0.112, p = 0.043), total cholesterol (r = 0.324, p < 0.0001), LDL-cholesterol (r = 0.298, p < 0.0001), insulin (r = 0.320, p < 0.001 and HOMA-IR (r = 0.272, p < 0.0001). In multiple stepwise regression analysis, adiponectin was negatively associated with WC (ß = -0.38, p = 0.001) and BF% (ß = 0.33, p < 0.0001), while leptin was positively associated with BF% (ß = 0.60, p < 0.0001), total cholesterol (ß = 0.11, p = 0.02) and HOMA-IR (ß = 0.11, p = 0.02). When controlled for gender, HOMA-IR was found significantly associated to adiponectin (ß = 0.13, p = 0.046), but not BF%, while the association previously found between leptin and HOMA-IR disappeared; BMI and WC were significantly associated with leptin (ß = 0.18, p = 0.04 & ß = 0.19, p = 0.02 respectively). CONCLUSION: This study, which includes a population who was not receiving potentially confounding medications, confirms the associations previously observed of adiponectin with reduced adiposity especially central adiposity and improved insulin sensitivity. Confirmatory associations were also observed between leptin and obesity, blood lipids and insulin resistance for the first time in an African population. Gender was significant covariate interacting with insulin sensitivity/insulin resistance and obesity indexes associations in this population.

Kidney Dysfunction in Adult Offspring Exposed In Utero to Type 1 Diabetes Is Associated with Alterations in Genome-Wide DNA Methylation.

BACKGROUND: Fetal exposure to hyperglycemia impacts negatively kidney development and function. OBJECTIVE: Our objective was to determine whether fetal exposure to moderate hyperglycemia is associated with epigenetic alterations in DNA methylation in peripheral blood cells and whether those alterations are related to impaired kidney function in adult offspring. DESIGN: Twenty nine adult, non-diabetic offspring of mothers with type 1 diabetes (T1D) (case group) were matched with 28 offspring of T1D fathers (control group) for the study of their leukocyte genome-wide DNA methylation profile (27,578 CpG sites, Human Methylation 27 BeadChip, Illumina Infinium). In a subset of 19 cases and 18 controls, we assessed renal vascular development by measuring Glomerular Filtration Rate (GFR) and Effective Renal Plasma Flow (ERPF) at baseline and during vasodilatation produced by amino acid infusion. RESULTS: Globally, DNA was under-methylated in cases vs. controls. Among the 87 CpG sites differently methylated, 74 sites were less methylated and 13 sites more methylated in cases vs. controls. None of these CpG sites were located on a gene known to be directly involved in kidney development and/or function. However, the gene encoding DNA methyltransferase 1 (DNMT1)--a key enzyme involved in gene expression during early development--was under-methylated in cases. The average methylation of the 74 under-methylated sites differently correlated with GFR in cases and controls. CONCLUSION: Alterations in methylation profile imprinted by the hyperglycemic milieu of T1D mothers during fetal development may impact kidney function in adult offspring. The involved pathways seem to be a nonspecific imprinting process rather than specific to kidney development or function.

Osteoprotegerin in relation to insulin resistance and blood lipids in sub-Saharan African women with and without abdominal obesity.

BACKGROUND: Osteoprotegerin (OPG), a soluble member of the tumor necrosis factor receptor superfamily that inhibits bone resorption, has been suggested as a potential marker of cardiovascular risk. This study aimed to assess the relationship between insulin resistance, lipid profile and OPG levels in obese and non-obese sub-Saharan African women. METHODS: Sixty obese (44) and non-obese (16) volunteer women aged 18 to 40 years were recruited in this cross-sectional study. Their clinical (age, height, weight, waist circumference, systolic and diastolic blood pressures) and biochemical parameters (fasting blood glucose, total cholesterol, high density lipoprotein-cholesterol (HDL-C)) were measured using standard methods. Insulin levels were measured using an electrochemiluminescence immunoassay, while OPG levels were measured using the ELISA technique. Low density lipoprotein-cholesterol (LDL-C), body mass index (BMI) and Homeostasis Model Assessment of Insulin Resistance (HOMA-IR) were calculated using standard methods. Abdominal obesity was defined as a waist circumference ≥ 80 cm. RESULTS: OPG levels were higher in obese than in normal subjects, though the difference was not significant (p = 0.9). BMI, waist circumference, percent body fat and systolic blood pressure were significantly higher in obese than in non-obese subjects (p < 0.05). In these subjects, only age significantly correlated with OPG levels (r = 0.831, p = 0.003), while none of the anthropometric nor metabolic parameter did, even after adjustment for age. In obese subjects, OPG levels fairly correlated with HDL-C (r = 0.298, p = 0.058), and significantly correlated with HOMA-IR (r = -0.438, p = 0.018). After adjustment for age, OPG levels remained negatively correlated to HOMA-IR (r = -0.516, p = 0.020) and LDL-C (r = -0.535, p = 0.015) and positively correlated to HDL-C (r = 0.615, p = 0.004). In multiple linear regression analysis, age was a main determinant of OPG levels in non-obese (ß = 0.647, p = 0.006) and obese (ß = 0.356, p = 0.044) women. HDL-C was also associated to OPG levels in obese women (ß = 0.535, p = 0.009). CONCLUSION: The positive correlation of OPG with HDL-C and HOMA-IR, and its negative correlation with LDL-C suggest that it may be a marker of insulin sensitivity/resistance and atherogenic risk in obese African women.

Evaluation of a new automated assay for the measurement of circulating 1,25-dihydroxyvitamin D levels in daily practice.

BACKGROUND AND OBJECTIVE: 1,25-dihydroxyvitamin D [1,25(OH)2D] is the most important vitamin D metabolite in regulating calcium and phosphorus metabolism and bone resorption. It is measured in plasma for diagnosis and management of patients with disorders influencing vitamin D metabolism. The most common methods for 1,25(OH)2D quantification are competitive isotopic I(125) immunoassays. The purpose of this work is to compare the IDS isotopic immunoassay (IDS RIA) and the nonisotopic iSYS immunoassay (IDS iSYS) for 1,25(OH)2D measurement in human serum and in control samples obtained from the Vitamin D External Quality Assessment Scheme (DEQAS). METHODS: 1,25(OH)2D concentrations in 180 serum samples (87 females and 93 males) and in 25 samples from the DEQAS were assayed using IDS RIA and IDS iSYS methods. Both assays were performed after delipidation and immunoextraction steps. Measurement range was 9.0-348.0pmol/L and 15.6-504.0pmol/L for IDS RIA and IDS iSYS assay, respectively. 'Normal adult' reference ranges of 1,25(OH)2D were 43-168pmol/L for IDS RIA and 63-228pmol/L for IDS iSYS. RESULTS: The equation of the Deming regression analysis demonstrated that IDS iSYS tended to give lower 1,25(OH)2D concentrations by a mean of 20% over the tested concentration range when compared to IDS RIA. Both assays would easily meet the DEQAS goal of 80% of survey samples within 30% of the All-Laboratory Trimmed Mean "ALTM". Results of 1,25(OH)2D obtained using IDS iSYS in samples distributed by DEQAS were closely related to those by LC-MS/MS method. CONCLUSIONS: The concentrations of 1,25(OH)2D measured by the IDS iSYS tended to be lower than those of IDS RIA in patients, but quite comparable to those of LC-MS/MS and ALTM in DEQAS samples.

Fasting insulin sensitivity indices are not better than routine clinical variables at predicting insulin sensitivity among Black Africans: a clamp study in sub-Saharan Africans.

BACKGROUND: We aimed to evaluate the predictive utility of common fasting insulin sensitivity indices, and non-laboratory surrogates [BMI, waist circumference (WC) and waist-to-height ratio (WHtR)] in sub-Saharan Africans without diabetes. METHODS: We measured fasting glucose and insulin, and glucose uptake during 80/mU/m2/min euglycemic clamp in 87 Cameroonians (51 men) aged (SD) 34.6 (11.4) years. We derived insulin sensitivity indices including HOMA-IR, quantitative insulin sensitivity check index (QUICKI), fasting insulin resistance index (FIRI) and glucose-to-insulin ratio (GIR). Indices and clinical predictors were compared to clamp using correlation tests, robust linear regressions and agreement of classification by sex-specific thirds. RESULTS: The mean insulin sensitivity was M = 10.5 ± 3.2 mg/kg/min. Classification across thirds of insulin sensitivity by clamp matched with non-laboratory surrogates in 30-48% of participants, and with fasting indices in 27-51%, with kappa statistics ranging from -0.10 to 0.26. Fasting indices correlated significantly with clamp (/r/=0.23-0.30), with GIR performing less well than fasting insulin and HOMA-IR (both p < 0.02). BMI, WC and WHtR were equal or superior to fasting indices (/r/=0.38-0.43). Combinations of fasting indices and clinical predictors explained 25-27% of variation in clamp values. CONCLUSION: Fasting insulin sensitivity indices are modest predictors of insulin sensitivity measured by euglycemic clamp, and do not perform better than clinical surrogates in this population.

Osteoprotegerin is not a determinant of metabolic syndrome in sub-Saharan Africans after age adjustment.

OBJECTIVES: Osteoprotegerin (OPG), a soluble member of tumor necrosis factor receptor superfamily that inhibits bone resorption, has been suggested as a cardiovascular risk factor in humans. In this study, we aim to investigate the potential relationship between OPG and MetS (MetS) in a sub-Saharan African population. METHODS: Four hundred and eleven volunteers (152 men, 259 women) aged ≥18 years recruited from the general population in Douala and Edea, Cameroon participated in this study. Anthropometric parameters measured and blood samples were collected for glucose, serum lipids and OPG concentrations measurements. Mean differences of the variables in different groups were compared using Students' t test. We performed logistic regressions to analyze the impact of independent factors on the relation between OPG and MetS outcome. MetS was defined using the Joint Interim Statement 2009. RESULTS: OPG levels did not vary significantly between both men and women with and without MetS (both P>0.05). However, with high fasting blood glucose (≥5.6 mmol/L) had a significantly higher OPG level than those with lower glucose level (P=0.014). In multiple logistic regression analysis, MetS did not show any significant association with serum OPG levels in men and women after adjusting for age, physical activity, alcohol consumption and menopausal status in women (P=0.720 and P=0.930 respectively). CONCLUSION: This study failed to demonstrate any relationship between OPG and MetS. Nevertheless, the positive association between blood glucose and OPG levels reveals that OPG might be involved in cardiovascular risk development in this sub-Saharan African population.

ß- and α-cell dysfunctions in africans with ketosis-prone atypical diabetes during near-normoglycemic remission.

OBJECTIVE: Ketosis-prone atypical diabetes (KPD) is a subtype of diabetes in which the pathophysiology is yet to be unraveled. The aim of this study was to characterize ß- and α-cell functions in Africans with KPD during remission. RESEARCH DESIGN AND METHODS: We characterized ß- and α-cell functions in Africans with KPD during remission. The cohort comprised 15 sub-Saharan Africans who had been insulin-free for a median of 6 months. Patients in remission were in good glycemic control (near-normoglycemic) and compared with 15 nondiabetic control subjects matched for age, sex, ethnicity, and BMI. Plasma insulin, C-peptide, and glucagon concentrations were measured in response to oral and intravenous glucose and to combined intravenous arginine and glucose. Early insulin secretion was measured during a 75-g oral glucose tolerance test. Insulin secretion rate and glucagon were assessed in response to intravenous glucose ramping. RESULTS: Early insulin secretion and maximal insulin secretion rate were lower in patients compared with control participants. In response to combined arginine and glucose stimulation, maximal insulin response was reduced. Glucagon suppression was also decreased in response to oral and intravenous glucose but not in response to arginine and insulin. CONCLUSIONS: Patients with KPD in protracted near-normoglycemic remission have impaired insulin response to oral and intravenous glucose and to arginine, as well as impaired glucagon suppression. Our results suggest that ß- and α-cell dysfunctions both contribute to the pathophysiology of KPD.

Fertility in women with nonclassical congenital adrenal hyperplasia due to 21-hydroxylase deficiency.

OBJECTIVE: In contrast to subfertility often reported in women suffering from the classical form of congenital adrenal hyperplasia (CAH) due to 21-hydroxylase deficiency, fertility in nonclassical CAH (NC-CAH) has been rarely studied. Our objective was to evaluate fertility in NC-CAH women. MATERIAL AND METHODS: We studied 190 NC-CAH women (161 probands + 29 first degree relatives). Only 20 probands had consulted for infertility (12%), either alone or associated with hirsutism or menstrual cycle disorders. The diagnosis was established on post-ACTH 17-hydroxyprogesterone 10 ng/ml or greater and further characterized by CYP21A2 gene analysis. RESULTS: Ninety-five of the 190 women wanted pregnancy (aged 26.7 +/- 8.9 yr); 187 pregnancies occurred in 85 women, which resulted in 141 births in 82 of them. Ninety-nine pregnancies (52.9%) occurred before the diagnosis of NC-CAH (96 spontaneously and three with ovulation inducers) whereas 98 occurred after diagnosis (11 spontaneously and 77 with hydrocortisone treatment); 83% of pregnancies were obtained within 1 yr. The rate of miscarriages was 6.5% for pregnancies obtained with glucocorticoid treatment vs. 26.3% without. Two of the 141 infants (1.5%) were born with classical CAH. CONCLUSION: Subfertility is mild in NC-CAH. However, the rate of miscarriages is lower in pregnancies occurring with glucocorticoid treatment and argues for treating NC-CAH women wanting pregnancy. In addition, considering the high rate of heterozygotes for CYP21A2 mutations in the general population, it is essential to genotype the partner of patients with a severe mutation to predict the risk of classical CAH and offer genetic counseling.

Potential utility of high preoperative levels of serum type I collagen markers in postmenopausal women with primary hyperparathyroidism with respect to their short-term variations after parathyroidectomy.

We evaluated short-term changes in serum amino-terminal procollagen propeptide (P1NP) and cross-linked C-terminal telopeptide (betaCTX) of type I collagen after parathyroidectomy (PTX) in 41 postmenopausal women with primary hyperparathyroidism (PHPT). Serum levels of 25-hydroxyvitamin D, intact PTH, calcium, phosphate, albumin, creatinine, P1NP, and betaCTX were measured before and 2 days after PTX. Their P1NP and betaCTX levels were compared with those measured in 41 normally menstruating and 30 postmenopausal controls. Fifteen of these 41 women had both pre-surgery P1NP and betaCTX concentrations above the upper limit noted in our postmenopausal controls [high turnover (HT) subgroup], while betaCTX levels were solely above the upper limit lastly mentioned in 11 women [high bone resorption (HBR) subgroup]. In addition, these two markers were within the postmenopausal control range in 12 of them [normal turnover (NT) subgroup]. A more significant decrease in postoperative betaCTX levels was observed in the 15 HT compared with the 12 NT PHPT women. The significant postoperative increase in P1NP levels observed in the 15 HT as well as in the 11 HBR was no longer significant in the 12 NT women. In conclusion, higher pre-surgery P1NP and betaCTX levels in post-menopausal PHPT women are associated with a preferential activation of bone formation over bone resorption after PTX.

Multitissue insulin resistance despite near-normoglycemic remission in Africans with ketosis-prone diabetes.

OBJECTIVE: To characterize insulin action in Africans with ketosis-prone diabetes (KPD) during remission. RESEARCH DESIGN AND METHODS: At Saint-Louis Hospital, Paris, France, 15 African patients with KPD with an average 10.5-month insulin-free near-normoglycemic remission period (mean A1C 6.2%) were compared with 17 control subjects matched for age, sex, BMI, and geographical origin. Insulin stimulation of glucose disposal, and insulin suppression of endogenous glucose production (EGP) and nonesterified fatty acids (NEFAs), was studied using a 200-min two-step (10 mU x m(-2) body surface x min(-1) and 80 mU x m(-2) x min (-1) insulin infusion rates) euglycemic clamp with [6,6-(2)H(2)]glucose as the tracer. Early-phase insulin secretion was determined during an oral glucose tolerance test. RESULTS: The total glucose disposal was reduced in patients compared with control subjects (7.5 +/- 0.8 [mean +/- SE] vs. 10.5 +/- 0.9 mg x kg(-1) x min(-1); P = 0.018). EGP rate was higher in patients than control subjects at baseline (4.0 +/- 0.3 vs. 3.0 +/- 0.1 mg x kg(-1) x min(-1); P = 0.001) and after 200-min insulin infusion (10 mU x m(-2) x min(-1): 1.6 +/- 0.2 vs. 0.6 +/- 0.1, P = 0.004; 80 mU x m(-2) x min(-1): 0.3 +/- 0.1 vs. 0 mg x kg(-1) x min(-1), P = 0.007). Basal plasma NEFA concentrations were also higher in patients (1,936.7 +/- 161.4 vs. 1,230.0 +/- 174.1 micromol/l; P = 0.002) and remained higher after 100-min 10 mU x m(-2) x min(-1) insulin infusion (706.6 +/- 96.5 vs. 381.6 +/- 55.9 micromol/l; P = 0.015). CONCLUSIONS: The triad hepatic, adipose tissue, and skeletal muscle insulin resistance is observed in patients with KPD during near-normoglycemic remission, suggesting that KPD is a form of type 2 diabetes.