Effects of nonsurgical periodontal treatment on glycated haemoglobin on type 2 diabetes patients (PARODIA 1 study): a randomized controlled trial in a sub-Saharan Africa population.

BACKGROUND: There is a burglar association between diabetes and periodontitis. Many studies has shown that periodontitis treatment can help improving glycemic control in diabetes patients but little evidence of non-surgical treatment benefit is available in sub Saharan african diabetes patients. We aimed to assess the effects of non-surgical periodontal treatment (NSPT) of chronic periodontitis on glycaemic control in poorly controlled type 2 diabetes patients (T2D) in a sub-Saharan Africa urban setting. METHODS: A total of 34 poorly controlled T2D patients with chronic periodontitis aged 51.4 ± 8.8 years (mean ± SD), with known duration of diabetes of 55.5 ± 42.6 months, and HbA1c of 9.3 ± 1.3% were randomly assigned to two groups. The treatment group (Group 1, n = 17) received immediate ultrasonic scaling, scaling and root planning along with subgingival 10% povidone iodine irrigation, whereas the control group (Group 2, n = 17) was assigned to receive delayed periodontal treatment 3 months later. Pharmacological treatment was unchanged and all participants received the same standardized education session on diabetes management and dental hygiene. The primary outcome was the 3-month change in HbA1c from baseline. Plaque index (PI), gingival bleeding index (GBI), pocket depth (PD), clinical attachment loss (CAL) were also assessed prior to, at 6 and 12 weeks after enrolment. RESULTS: Two subjects in each group were excluded from the study. Data were analyzed on thirty patients (15 per group). Non-surgical periodontal treatment with education for better dental hygiene (group 1) significantly improved all periodontal parameters whereas education only (group 2) improved only the plaque index among all periodontal parameters. Immediate non-surgical periodontal treatment induced a reduction of HbA1c levels by 3.0 ± 2.4 points from 9.7 ± 1.6% at baseline to 6.7 ± 2.0% 3 months after NSPT, (p ˂ 0.001) but the change was not significant in group 2, from mean 8.9 ± 0.9% at baseline vs 8.1 ± 2.6% after 3 months (p = 0.24). CONCLUSION: Non-surgical periodontal treatment markedly improved glycaemic control with an attributable reduction of 2.2 points of HbA1c in poorly controlled T2D patients in a sub Saharan setting. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT02745015 Date of registration: July 17, 2016 'Retrospectively registered'.

Use of medical services and medicines attributable to type 2 diabetes care in Yaoundé, Cameroon: a cross-sectional study.

BACKGROUND: The increasing numbers of people with type 2 diabetes (T2D) is a global concern and especially in sub-Saharan Africa, where diabetes must compete for resources with communicable diseases. Diabetes intensifies health care utilisation and leads to an increase in medical care costs. However, In Cameroon like in most developing countries, data on the impact of diabetes on the medical health system are scarce. We aimed to analyse the use of medical services and medicines attributable to T2D care in Yaoundé, Cameroon. METHODS: We conducted a cross-sectional study comparing the use of medical services and medicines on 500 people with T2D attending the diabetic outpatient units of three hospitals in Yaoundé and 500 people without diabetes matched for age, sex and residence. We performed multivariate logistic and quantile regressions to assess the effect of diabetes on the use of medical services and medicines and the presence of other chronic health problems. Models were adjusted for age, educational level, marital status, occupation and family income. RESULTS: Overall, the rate of use of health services was found to be greater in people with T2D than those without diabetes. People with T2D had greater odds of having an outpatient visit to any clinician (OR 97.1 [95% CI: 41.6-226.2]), to be hospitalised (OR 11.9 [95% CI: 1.6-87.9]), to take at least one medicine (OR 83.1 [37.1-185.8]) compared with people without diabetes. We also observed an association between diabetes and some chronic diseases/diabetes complications including hypertension (OR 9.2 [95% CI: 5.0-16.9]), cardiovascular diseases (OR 1.9 [95% CI: 0.8-4.9]), peripheral neuropathy (OR 6.2 [95% CI: 3.4-11.2]), and erectile dysfunction (OR 5.8 [95% CI: 2.7-12.1]). CONCLUSIONS: This study showed that the presence of diabetes is associated with an increased use of health care services and medicines as well as with some chronic diseases/diabetes complications.

Seasonality in diabetes in Yaounde, Cameroon: a relation with precipitation and temperature.

BACKGROUND: Diabetes is a growing health concern in developing countries, with Cameroon population having an estimated 6% affected. Of note, hospital attendees appear to be increasing all over the country, with fluctuating numbers throughout the annual calendar. The aim of the study was to investigate the relationship between diabete hospitalization admission rates and climate variations in Yaounde. METHODS: A retrospectively designed study was conducted in four health facilities of Yaounde (Central Hospital, University teaching hospital, Biyem-Assi and Djoungolo District Hospitals), using medical records from 2000 to 2008. A relationship between diabetes (newly diagnosed diabetes patients or decompensated diabetics) hospitalization admissions and climate variations was determined using the "2000-2008" national meteorological database (precipitation and temperature). RESULTS: The monthly medians of precipitation and temperature were 154mm and 25 °C, respectively. The month of October received 239mm of precipitation. The monthly medians of diabetic admissions rates (newly diagnosed or decompensated diabetes patients) were 262 and 72 respectively. October received 366 newly diagnosed diabetics and 99 decompensated diabetics. Interestingly, diabetic hospitalization admissions rates were higher during the rainy (51 %, 1633/3232) than the dry season, though the difference was non-significant. The wettest month (October) reported the highest cases (10 %, 336/3232) corresponding to the month with the highest precipitation level (239mm). Diabetes hospitalization admissions rates varied across health facilities [from 6 % (189/3232) in 2000 to 15 % (474/3232) in 2008]. CONCLUSION: Diabetes is an important epidemiological disease in the city of Yaounde. The variation in the prevalence of diabetes is almost superimposed to that of precipitation; and the prevalence seems increasing during raining seasons in Yaoundé.

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.

Diabetes mellitus and inflammation.

Type 2 diabetes mellitus (T2DM) is increasingly common worldwide. Related complications account for increased morbidity and mortality, and enormous healthcare spending. Knowledge of the pathophysiological derangements involved in the occurrence of diabetes and related complications is critical for successful prevention and control solutions. Epidemiologic studies have established an association between inflammatory biomarkers and the occurrence of T2DM and complications. Adipose tissue appears to be a major site of production of those inflammatory biomarkers, as a result of the cross-talk between adipose cells, macrophages, and other immune cells that infiltrate the expanding adipose tissue. The triggering mechanisms of the inflammation in T2DM are still ill-understood. Inflammatory response likely contributes to T2DM occurrence by causing insulin resistance, and is in turn intensified in the presence of hyperglycemia to promote long-term complications of diabetes. Targeting inflammatory pathways could possibly be a component of the strategies to prevent and control diabetes and related complications.

Geographic distribution of metabolic syndrome and its components in the general adult population: A meta-analysis of global data from 28 million individuals.

AIMS: Better knowledge of the global metabolic syndrome (MetS) prevalence and its components is a prerequisite to curb the related burden. METHODS: We systematically searched PubMed, EMBASE, Web of Knowledge, Africa Journal Online, Global Index Medicus up to May 23, 2021. Prevalence pooling was done with a random-effects meta-analysis. RESULTS: In total, 1,129 prevalence data (28,193,768 participants) were included. The MetS global prevalence varied from 12.5% (95 %CI: 10.2-15.0) to 31.4% (29.8-33.0) according to the definition considered. The prevalence was significantly higher in Eastern Mediterranean Region and Americas and increased with country's level of income. The global prevalence was 45.1% (95 %CI: 42.1-48.2) for ethnic-specific central obesity, 42.6% (40.3-44.9) for systolic blood pressure (BP) ≥ 130 mmHg and/or diastolic BP ≥ 85 mmHg, 40.2% (37.8-42.5) for HDL-cholesterol < 1.03 for men or < 1.29 mmol/L for women, 28.9% (27.4-30.5) for serum triglycerides ≥ 1.7 mmol/L, and 24.5% (22.5-26.6) for fasting plasma glucose ≥ 5.6 mmol/L. CONCLUSIONS: This study reveals that MetS and its related cardiometabolic components are highly prevalent worldwide. This study calls for more aggressive and contextualized public health interventions to tackle these conditions.

Global, regional, and country estimates of metabolic syndrome burden in children and adolescents in 2020: a systematic review and modelling analysis.

BACKGROUND: Halting the rise in cardiometabolic risk factors in children and adolescents is crucial to curb the global burden of cardiovascular diseases. We aim to provide global, regional, and national estimates of the prevalence of metabolic syndrome in children and adolescents to support the development of evidence-based prevention strategies. METHODS: In this systematic review with modelling analysis, we searched PubMed, Embase, Africa Journal Online, and Global Index Medicus from database inception to Jan 30, 2021, with no restriction on language or geographical location. We included community-based and school-based cross-sectional studies and cross-sectional analysis of cohort studies that reported prevalence of metabolic syndrome in the general population of children (6-12 years) and adolescents (13-18 years). Only studies with a low risk of bias were considered. Eligible studies included at least 200 participants and used probabilistic-based sampling. Diagnosis of metabolic syndrome had to meet at least three of the following criteria: high systolic or diastolic blood pressure (≥90th percentile for age, sex, and height); waist circumference in at least the 90th percentile for age, sex, and ethnic group; fasting plasma glucose 5·6 mmol/L or greater; fasting plasma triglycerides 1·24 mmol/L or greater; and fasting plasma high density lipoprotein cholesterol 1·03 mmol/L or less. Independent investigators selected eligible studies and extracted relevant data. The primary outcome was a crude estimate of metabolic syndrome prevalence, assessed using a Bayesian hierarchical model. FINDINGS: Our search yielded 6808 items, of which 169 studies were eligible for analysis, including 306 prevalence datapoints, with 550 405 children and adolescents from 44 countries in 13 regions. The between-study variance (τ2) was 0·52 (95% CI 0·42-0·67), which could reflect the measurement of each component of the metabolic syndrome and covariates as sources of between-study heterogeneity. We estimated the global prevalence of metabolic syndrome in 2020 at 2·8% (95% uncertainty interval [UI] 1·4-6·7) for children and 4·8% (2·9-8·5) for adolescents, equating to around 25·8 (12·6-61·0) million children and 35·5 (21·3-63·0) million adolescents living with metabolic syndrome. In children, the prevalence of metabolic syndrome was 2·2% (95% UI 1·4-3·6) in high-income countries, 3·1% (2·5-4·3) in upper-middle-income countries, 2·6% (0·9-8·3) in lower-middle-income countries, and 3·5% (1·0-8·0) in low-income countries. In adolescents, the prevalence of metabolic syndrome was 5·5% (4·1-8·4) in high-income countries, 3·9% (3·1-5·4) in upper-middle-income countries, 4·5% (2·6-8·4) in lower-middle-income countries, and 7·0% (2·4-15·7) in low-income countries. Prevalence in children varied from 1·4% (0·6-3·1) in northwestern Europe to 8·2% (6·9-10·1) in Central Latin America. Prevalence for adolescents ranged from 2·9% (95% UI 2·6-3·3) in east Asia to 6·7% (5·9-8·3) in high-income English-speaking countries. The three countries with the highest prevalence estimates in children were Nicaragua (5·2%, 2·8-10·4), Iran (8·8%, 8·0-9·6), and Mexico (12·3%, 11·0-13·7); and the three countries with the highest prevalence estimates in adolescents were Iran (9·0%, 8·4-9·7), United Arab Emirates (9·8%, 8·5-10·3), and Spain (9·9%, 9·1-10·8). INTERPRETATION: In 2020, about 3% of children and 5% of adolescents had metabolic syndrome, with some variation across countries and regions. The prevalence of metabolic syndrome was not consistently higher with increasing level of development, suggesting that the problem is not mainly driven by country wealth. The high number of children and adolescents living with metabolic syndrome globally highlights the urgent need for multisectoral interventions to reduce the global burden of metabolic syndrome and the conditions that lead to it, including childhood overweight and obesity. FUNDING: None.

An Atypical Form of Diabetes Among Individuals With Low BMI.

OBJECTIVE: Diabetes among individuals with low BMI (<19 kg/m2) has been recognized for >60 years as a prevalent entity in low- and middle-income countries (LMICs) and was formally classified as "malnutrition-related diabetes mellitus" by the World Health Organization (WHO) in 1985. Since the WHO withdrew this category in 1999, our objective was to define the metabolic characteristics of these individuals to establish that this is a distinct form of diabetes. RESEARCH DESIGN AND METHODS: State-of-the-art metabolic studies were used to characterize Indian individuals with "low BMI diabetes" (LD) in whom all known forms of diabetes were excluded by immunogenetic analysis. They were compared with demographically matched groups: a group with type 1 diabetes (T1D), a group with type 2 diabetes (T2D), and a group without diabetes. Insulin secretion was assessed by C-peptide deconvolution. Hepatic and peripheral insulin sensitivity were analyzed with stepped hyperinsulinemic-euglycemic pancreatic clamp studies. Hepatic and myocellular lipid contents were assessed with 1H-nuclear magnetic resonance spectroscopy. RESULTS: The total insulin secretory response was lower in the LD group in comparison with the lean group without diabetes and the T2D group. Endogenous glucose production was significantly lower in the LD group than the T2D group (mean ± SEM 0.50 ± 0.1 vs. 0.84 ± 0.1 mg/kg · min, respectively; P < 0.05). Glucose uptake was significantly higher in the LD group in comparison with the T2D group (10.1 ± 0.7 vs. 4.2 ± 0.5 mg/kg · min; P < 0.001). Visceral adipose tissue and hepatocellular lipids were significantly lower in LD than in T2D. CONCLUSIONS: These studies are the first to demonstrate that LD individuals in LMICs have a unique metabolic profile, suggesting that this is a distinct entity that warrants further investigation.

Prevalence of asymptomatic or "silent" myocardial ischemia in diabetic patients: Protocol for a systematic review and meta-analysis.

INTRODUCTION: Myocardial ischemia (MI) is a top ranked cause of death among diabetic patients, yet it is mostly asymptomatic or "silent". There is a need for summary epidemiologic measures on this highly lethal and unnoticeable complication of diabetes. The proposed systematic review and meta-analysis aims to estimate of the global prevalence of silent MI among diabetic patients. METHODS AND ANALYSIS: This protocol was prepared according to the preferred reporting items for systematic review and meta-analysis protocols (PRISMA-P) statement. The systematic review will include all observational studies published until March 23, 2021 and reporting on the prevalence of silent MI in diabetic patients. Electronic sources including MEDLINE(PubMed), Embase, Cochrane Library, and Web of Science will be searched for potentially eligible studies, restricted to only studies published in English. Two investigators will select studies and use a pre-pilot tested form to extract data. Further, they will independently perform a qualitative assessment of the risk of bias and overall quality of the selected studies, followed by a quantitative assessment using funnel plots and Egger's tests. The heterogeneity between studies will be assessed with the Cochrane's Q statistic, and the I2 statistic will measure the percentage of variation across studies that is due to their heterogeneity rather than chance; it will decide if a meta-analysis can be conducted. In case a meta-analysis cannot be conducted, a descriptive analysis will be performed. Otherwise, study-specific estimates will be pooled using either a fixed-effects or a random-effects model depending on the value of the I2 statistic. Subgroup and random effects meta-regression analyses will be used to further investigate the potential sources of heterogeneity. Finally, sensitivity analyses will be performed to measure the impact of low-quality studies on the results of the meta-analysis, and power calculations will determine the probability that we will detect a true effect if it does exist. STRENGTHS AND LIMITATIONS OF THIS STUDY: The intended review will provide an up-to-date summary of the global prevalence of silent MI in diabetic patients. We will conduct a thorough literature search for eligible studies, and we will use robust meta-analysis tools to provide reliable estimates of the global prevalence of silent MI in diabetic patients. Two major limitations could be: the predominance of clinical trials that might limit the generalizability of the findings, given that the strict inclusion criteria of these studies might have excluded other patients; the risk of type 1 error emanating from the high number of subgroup and sensitivity analyses. PROSPERO REGISTRATION NUMBER: CRD42019138136.

Effects of non-surgical treatment of chronic periodontitis on insulin resistance and glucose tolerance in subjects without diabetes (PARODIA 2 study).

This study aimed to assess the effects of non-surgical periodontal treatment (NSPT) of chronic periodontitis on insulin sensitivity, glucose tolerance, and serum C reactive protein (CRP) level in individuals without diabetes. Twenty individuals without diabetes with chronic periodontitis underwent NSPT, which consisted of complete scaling, polishing, root planing, and irrigation of the periodontal pockets with a 10% povidone-iodine solution. Periodontal indices (plaque index, gingival bleeding index, pocket depth, and clinical attachment loss), insulin sensitivity using the Short Insulin Tolerance Test index (KITT), glucose tolerance derived from oral glucose tolerance test, and serum CRP level were measured before and 3 months after the intervention. This study was carried out at the National Obesity Center of Yaoundé Central Hospital, Cameroon. After 3 months, we observed significant improvement in periodontal parameters (all p<0.001) and insulin sensitivity (3.72 (2.99-4.17) %/min before treatment vs 4.04 (3.67-4.78) %/min after treatment, p=0.001) and significant decrease in serum CRP level (2.35 (1.46-4.18) mg/L before vs 1.53 (1.03-2.12) mg/L after, p=0.033). There was a trend toward improvement in glucose tolerance, although not statistically significant after the intervention. This study suggests that NSPT of chronic periodontitis in individuals without diabetes is associated with increased insulin sensitivity and decreased serum CRP levels.Trial registration number NCT02830113.

Non-autoimmune diabetes mellitus and the risk of virus infections: a systematic review and meta-analysis of case-control and cohort studies.

A significant number of studies invoked diabetes as a risk factor for virus infections, but the issue remains controversial. We aimed to examine whether non-autoimmune diabetes mellitus enhances the risk of virus infections compared with the risk in healthy individuals without non-autoimmune diabetes mellitus. In this systematic review and meta-analysis, we assessed case-control and cohort studies on the association between non-autoimmune diabetes and viruses. We searched PubMed, Embase, Cochrane Database of Systematic Reviews, Cochrane Central Register of Controlled Trials, and Web of Science with no language restriction, to identify articles published until February 15, 2021. The main outcome assessment was the risk of virus infection in individuals with non-autoimmune diabetes. We used a random-effects model to pool individual studies and assessed heterogeneity (I2) using the χ2 test on Cochrane's Q statistic. This study is registered with PROSPERO, number CRD42019134142. Out of 3136 articles identified, we included 68 articles (90 studies, as the number of virus and or diabetes phenotype varied between included articles). The summary OR between non-autoimmune diabetes and virus infections risk were, 10.8(95% CI: 10.3-11.4; 1-study) for SARS-CoV-2; 3.6(95%CI: 2.7-4.9, I2 = 91.7%; 43-studies) for HCV; 2.7(95% CI: 1.3-5.4, I2 = 89.9%, 8-studies;) for HHV8; 2.1(95% CI: 1.7-2.5; 1-study) for H1N1 virus; 1.6(95% CI: 1.2-2.13, I2 = 98.3%, 27-studies) for HBV; 1.5(95% CI: 1.1-2.0; 1-study) for HSV1; 3.5(95% CI: 0.6-18.3 , I2 = 83.9%, 5-studies) for CMV; 2.9(95% CI: 1-8.7, 1-study) for TTV; 2.6(95% CI: 0.7-9.1, 1-study) for Parvovirus B19; 0.7(95% CI: 0.3-1.5 , 1-study) for coxsackie B virus; and 0.2(95% CI: 0-6.2; 1-study) for HGV. Our findings suggest that, non-autoimmune diabetes is associated with increased susceptibility to viruses especially SARS-CoV-2, HCV, HHV8, H1N1 virus, HBV and HSV1. Thus, these viruses deserve more attention from diabetes health-care providers, researchers, policy makers, and stakeholders for improved detection, overall proper management, and efficient control of viruses in people with non-autoimmune diabetes.

Diabetes mellitus and tuberculosis, a systematic review and meta-analysis with sensitivity analysis for studies comparable for confounders.

INTRODUCTION: Meta-analyses conducted so far on the association between diabetes mellitus (DM) and the tuberculosis (TB) development risk did not sufficiently take confounders into account in their estimates. The objective of this systematic review was to determine whether DM is associated with an increased risk of developing TB with a sensitivity analyses incorporating a wider range of confounders including age, gender, alcohol consumption, smoke exposure, and other comorbidities. METHODS: Pubmed, Embase, Web of Science and Global Index Medicus were queried from inception until October 2020. Without any restriction to time of study, geographical location, and DM and TB diagnosis approaches, all observational studies that presented data for associations between DM and TB were included. Studies with no abstract or complete text, duplicates, and studies with wrong designs (review, case report, case series, comment on an article, and editorial) or populations were excluded. The odds ratios (OR) and their 95% confidence intervals were estimated by a random-effect model. RESULTS: The electronic and manual searches yielded 12,796 articles of which 47 were used in our study (23 case control, 14 cross-sectional and 10 cohort studies) involving 503,760 cases (DM or TB patients) and 3,596,845 controls. The size of the combined effect of TB risk in the presence of DM was OR = 2.3, 95% CI = [2.0-2.7], I2 = 94.2%. This statistically significant association was maintained in cohort (OR = 2.0, CI 95% = [1.5-2.4], I2 = 94.3%), case control (OR = 2.4, CI 95% = [2.0-2.9], I2 = 93.0%) and cross-sectional studies (OR = 2.5, CI 95% = [1.8-3.5], I2 = 95.2%). The association between DM and TB was also maintained in the sensitivity analysis including only studies with similar proportions of confounders between cases and controls. The substantial heterogeneity observed was mainly explained by the differences between geographic regions. CONCLUSIONS: DM is associated with an increased risk of developing latent and active TB. To further explore the role of DM in the development of TB, more investigations of the biological mechanisms by which DM increases the risk of TB are needed. REVIEW REGISTRATION: PROSPERO, CRD42021216815.

Use of capillary ketones monitoring in treatment of mild ketotic crisis in people with ketosis-prone atypical diabetes.

This study was carried out to assess the potential reduction in duration of intensive diabetic ketoacidosis treatment in adults with ketosis-prone atypical diabetes (KPD) when using capillary versus urinary ketones. In this cross-sectional study, we included 20 people with KPD presented at the National Obesity Center of the Yaoundé Central Hospital with hyperglycemic decompensation (random capillary glucose ≥13 mmol/L) and significant ketosis (ketonuria≥++) requiring intensive insulin treatment. In all subjects, intensive insulin treatment was initiated at 10 UI per hour with simultaneous measurement of capillary beta-hydroxybutyrate and ketonuria every 2 hours until disappearance of ketonuria. Time-to-disappearance of urine ketones was compared with the time-to-normalization of capillary ß-hydroxybutyrate concentrations. Subjects were aged 46±13 years with a median duration of diabetes of 1.5 (IQR: 0-2.5) years. On admission, the mean blood glucose was 22.8±5 mmol/L and capillary ketones level was 2.9±2.7 mmol/L. The median time-to-disappearance of ketonuria was 5 (IQR: 3-8) hours compared with the time-to-normalization of capillary ß-hydroxybutyrate of 4 (IQR: 2-6) hours, p=0.0002. The absolute difference in time-to-normalization of ketonuria versus ketonemia was 2 (IQR: 1-3) hours and the relative time reduction of treatment was 32.5%±18.0%. Our results suggested that the use of capillary ketones versus ketonuria would allow a significant reduction in duration of intensive insulin treatment by one third in people with KPD.

Plasma Epinephrine Contributes to the Development of Experimental Hypoglycemia-Associated Autonomic Failure.

BACKGROUND: Recurrent hypoglycemia blunts counter-regulatory responses to subsequent hypoglycemic episodes, a syndrome known as hypoglycemia-associated autonomic failure (HAAF). Since adrenergic receptor blockade has been reported to prevent HAAF, we investigated whether the hypoglycemia-associated rise in plasma epinephrine contributes to pathophysiology and reported interindividual differences in susceptibility to HAAF. METHODS: To assess the role of hypoglycemia-associated epinephrine responses in the susceptibility to HAAF, 24 adult nondiabetic subjects underwent two 2-hour hyperinsulinemic hypoglycemic clamp studies (nadir 54 mg/dL; 0-2 hours and 4-6 hours) on Day 1, followed by a third identical clamp on Day 2. We challenged an additional 7 subjects with two 2-hour infusions of epinephrine (0.03 µg/kg/min; 0-2 hours and 4-6 hours) vs saline on Day 1 followed by a 200-minute stepped hypoglycemic clamp (90, 80, 70, and 60 mg/dL) on Day 2. RESULTS: Thirteen out of 24 subjects developed HAAF, defined by ≥20% reduction in average epinephrine levels during the final 30 minutes of the third compared with the first hypoglycemic episode (P < 0.001). Average epinephrine levels during the final 30 minutes of the first hypoglycemic episode were 2.3 times higher in subjects who developed HAAF compared with those who did not (P = 0.006).Compared to saline, epinephrine infusion on Day 1 reduced the epinephrine responses by 27% at the 70 and 60 mg/dL glucose steps combined (P = 0.04), with a parallel reduction in hypoglycemic symptoms (P = 0.03) on Day 2. CONCLUSIONS: Increases in plasma epinephrine reproduce key features of HAAF in nondiabetic subjects. Marked interindividual variability in epinephrine responses to hypoglycemia may explain an individual's susceptibility to developing HAAF.

Metabolic effects of exposure to pesticides during gestation in female Wistar rats and their offspring: a risk factor for diabetes?

Some pesticides increase the risk of type 2 diabetes, but whether fetal exposure carries transgenerational risk remains unknown. We evaluated the metabolic effects of gestational exposure to chlorpyrifos and imidacloprid in female Wistar rats and their offspring. We studied female nulliparous Wistar rats, including six exposed to imidacloprid (IMI) and six to chlorpyrifos (CPF) once daily throughout gestation at 1/10 lethal dose 50, while six (control group) received distilled water. These were explored 1 month after the birth of the offspring, while their offspring were explored at weaning (4 weeks) and adult age (12 weeks). Blood glucose, insulin and lipid profile were determined at each stage, while glucose transporter 4 (GLUT4) and nuclear factor kappa beta (NFkß) protein expression was measured in skeletal muscle at the end of follow up. Exposure to pesticides was associated with significantly higher fasting glucose (+25.4 to 30.9%) and insulin (> 100%) levels, with > 100% increased insulin resistance (HOMA-IR), - 18.3 to - 21.1% reduced HDL-cholesterol and + 60.9 to + 102.6% increased LDL-cholesterol in mothers. GLUT4 expression was reduced by 28.9-42.3% while NFkß expression increased by 32.8-35.4% in mothers. In offspring, similar abnormalities were observed at weaning (+ 18.4 to 67.4% fasting glucose, + 57.1 to 72.2% LDL-cholesterol, + 72.3 to 78.2% fasting insulin), persisting at adult age with decreased expression of GLUT4 (- 52.8 to 54.5%) and increased expression of NFkß (+ 30.5 to 30.7%). Gestational exposure to imidacloprid and chlorpyrifos induces hyperglycemia, insulin resistance and dyslipidemia in female Wistar rats and their offspring. The effects on offspring persist until adult age, suggesting intergenerational adverse effects.

Insulin-sensitizing effects of vitamin D repletion mediated by adipocyte vitamin D receptor: Studies in humans and mice.

OBJECTIVE: Adipose tissue inflammation and fibrosis appear to contribute to insulin resistance in obesity. Vitamin D receptor (Vdr) genes are expressed by adipocytes, macrophages, and fibroblasts, all of which could potentially play a role in adipose tissue inflammation and fibrosis. As vitamin D has been shown to have direct anti-inflammatory effects on adipocytes, we determined whether specific vitamin D receptor-mediated effects on adipocytes could impact adipose tissue inflammation and fibrosis and ultimately insulin resistance. METHODS: We examined the effects of repleting vitamin D in 25(OH)D-deficient, insulin resistant, overweight-to-obese human subjects (n = 19). A comprehensive assessment of whole-body insulin action was undertaken with stepped euglycemic (∼90 mg/dL) hyperinsulinemic clamp studies both before and after the administration of vitamin D or placebo. Adipose tissue fibrosis and inflammation were quantified by real-time rt-PCR and immunofluorescence in subcutaneous abdominal adipose tissue. To determine whether vitamin D's effects are mediated through adipocytes, we conducted hyperinsulinemic clamp studies (4 mU/kg/min) and adipose tissue analysis using an adipocyte-specific vitamin D receptor knockout (VDR-KO) mouse model (adiponectin-Cre + VDR+/fl) following high-fat diet feeding for 12 weeks. RESULTS: 25(OH)D repletion was associated with reductions in adipose tissue expression of pro-inflammatory and pro-fibrotic genes, decreased collagen immunofluorescence, and improved hepatic insulin sensitivity in humans. Worsening trends after six months on placebo suggest progressive metabolic effects of 25(OH)D deficiency. Ad-VDR-KO mice mirrored the vitamin D-deficient humans, displaying increased adipose tissue fibrosis and inflammation and hepatic insulin resistance. CONCLUSIONS: These complementary human and rodent studies support a beneficial role of vitamin D repletion for improving hepatic insulin resistance and reducing adipose tissue inflammation and fibrosis in targeted individuals, likely via direct effects on adipocytes. These studies have far-reaching implications for understanding the role of adipocytes in mediating adipose tissue inflammation and fibrosis and ultimately impacting insulin sensitivity.

Central KATP Channels Modulate Glucose Effectiveness in Humans and Rodents.

Hyperglycemia is a potent regulator of endogenous glucose production (EGP). Loss of this "glucose effectiveness" is a major contributor to elevated plasma glucose concentrations in type 2 diabetes (T2D). KATP channels in the central nervous system have been shown to regulate EGP in humans and rodents. We examined the contribution of central KATP channels to glucose effectiveness. Under fixed hormonal conditions (studies using a pancreatic clamp), hyperglycemia suppressed EGP by ∼50% in both humans without diabetes and normal Sprague-Dawley rats. By contrast, antagonism of KATP channels with glyburide significantly reduced the EGP-lowering effect of hyperglycemia in both humans and rats. Furthermore, the effects of glyburide on EGP and gluconeogenic enzymes were abolished in rats by intracerebroventricular administration of the KATP channel agonist diazoxide. These findings indicate that about half of the suppression of EGP by hyperglycemia is mediated by central KATP channels. These central mechanisms may offer a novel therapeutic target for improving glycemic control in subjects with T2D.

Gestational Exposure to Pesticides Induces Oxidative Stress and Lipid Peroxidation in Offspring that Persist at Adult Age in an Animal Model.

Pesticide exposure may induce biochemical alterations including oxidative stress and lipid peroxidation. However, in the context of developmental origin of health and disease, putative trans-generational effect of exposure to pesticides are insufficiently studied. We therefore aimed to evaluate the biochemical effect of gestational exposure to four pesticides on female Wistar rats and their offspring at adult age. We studied 30 female nulliparous Wistar rats divided into 5 equal groups. Group 1 served as the control group and received distilled water while group 2, 3, 4 and 5 received orally pesticide 1 (imidacloprid), pesticide 2 (chlorpyrifos), pesticide 3 (imidacloprid + lambda cyhalothrin) and pesticide 4 (oxamyl) respectively once daily throughout gestation at a dose equivalent to 1/10 lethal dose 50. The mothers were followed up until one month post gestation. The offspring were followed up from birth until adult age (12 weeks). In all animals at each time point we evaluated malondialdehyde (MDA), oxidative stress and liver function enzymes. There was similar variation of total body weight in all the groups during and after gestation. However, Female Wistar rats of the exposed groups had significant alterations in liver SOD (-30.8% to +64.1%), catalase (-38.8% to -85.7%) and GSH (-29.2% to -86.5%) and; kidney catalase (> 100%), GSH (> 100%). Moreover, MDA, alanine transaminase (ALT) and aspartate transaminase (AST) levels were significantly higher in pesticide exposed rats compared to the control group. Similar alterations in antioxidant enzymes, MDA and liver function enzymes were observed in offspring of treated rats evidenced at weaning and persisting until adult age. Exposure to pesticides causes oxidative stress and lipid peroxidation in exposed female Wistar rats and their offspring. The persistence in offspring at adult age suggests transgenerational adverse effects.

Potential approaches to prevent hypoglycemia-associated autonomic failure.

Clear health benefits are associated with intensive glucose control in type 1 diabetes mellitus (T1DM). However, maintaining near-normal glycemia remains an elusive goal for many patients, in large part owing to the risk of severe hypoglycemia. In fact, recurrent episodes of hypoglycemia lead to 'hypoglycemia-associated autonomic failure' (HAAF), characterized by defective counter-regulatory responses to hypoglycemia. Extensive studies to understand the mechanisms underlying HAAF have revealed multiple potential etiologies, suggesting various approaches to prevent the development of HAAF. In this review, we present an overview of the literature focused on pharmacological approaches that may prevent the development of HAAF. The purported underlying mechanisms of HAAF include: 1) central mechanisms (opioid receptors, ATP-sensitive K+(KATP) channels, adrenergic receptors, serotonin selective receptor inhibitors, γ-aminobuyric acid receptors, N-methyl D-aspartate receptors); 2) hormones (cortisol, estrogen, dehydroepiandrosterone (DHEA) or DHEA sulfate, glucagon-like peptide-1) and 3) nutrients (fructose, free fatty acids, ketones), all of which have been studied vis-à-vis their ability to impact the development of HAAF. A careful review of the current literature reveals many promising therapeutic approaches to treat or reduce this important limitation to optimal glycemic control.

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.