Early Insulin Research Articles

Evaluation of Early Insulin Glargine Administration in the Treatment of Pediatric Diabetic Ketoacidosis.

In the management of diabetic ketoacidosis (DKA), the standard of care is to administer insulin glargine after ketoacidosis has resolved and the patient is transitioning from intravenous (IV) insulin to subcutaneous insulin; however, there is evidence to suggest that earlier administration of insulin glargine may accelerate resolution of ketoacidosis. The objective of this research is to determine the efficacy of early subcutaneous insulin glargine on time to resolution of ketoacidosis in children with moderate to severe DKA. This retrospective chart review evaluated children age 2 to 21 years old admitted for moderate to severe DKA who received insulin glargine within 6 hours of hospital admission (early insulin glargine) compared with those who received insulin glargine greater than 6 hours from admission (late insulin glargine). The primary outcome was duration of time the patient received IV insulin. A total of 190 patients were included. The median time on IV insulin was lower in patients who received early insulin glargine compared with those who received late insulin glargine (17.0 [IQR, 14-22.8] vs 22.9 hours [IQR, 4.3-29.3]; p = 0.0006). Resolution of DKA was faster in patients who received early insulin glargine compared with those who received late insulin glargine (median, 13.0 [IQR, 9.8-16.8] vs 18.2 hours [IQR, 12.5-27.6]; p = 0.005). Length of pediatric intensive care unit (PICU) and hospital stay and incidences of hypoglycemia and hypokalemia were similar between the 2 groups. Children with moderate to severe DKA who received early insulin glargine had a significantly lower time on IV insulin, as well as significantly faster time to resolution of DKA when compared with those who received late insulin glargine. There were no significant differences observed in hospital stay and rates of hypoglycemia and hypokalemia.

Distinctive Cranial Abnormalities in Children with Early Infancy Insulin Dependent Diabetes in Connection with Wolcott-Rallison Syndrome

Background: Abnormal craniofacial contour and deformities of the appendicular skeleton of the lower limbs can occur in connection with a long list of skeletal dysplasia. The natural history of chronic/unusual disorders can be a precise key factor towards a successful diagnostic process. Material and Methods: Three unrelated children aged 18-months, 2 and 7 year (two boys and one girl) presented with generalised skeletal mal-development compatible with multiple epiphyseal dysplasia. However, in the early months of life these children have been diagnosed with early infancy insulin dependent diabetes. Strikingly, all manifested Wormian bones over the lambdoid sutures. In addition to Progressive malalignment of the lower limbs and thoracic kyphosis associated with significant growth deficiency were the major skeletal abnormalities. Endochondral ossification was diffusely affected associated with multiple epiphyseal dysplasia and appearance of irregular and fragmented epiphyses. Results: Based on early permanent neonatal or early-infancy insulin-dependent diabetes, associated with the clinical and radiological phenotypic characterizations of multiple epiphyseal dysplasia and growth retardation as the major abnormalities in these children. Wolcott-Rallison syndrome was the highly likely diagnosis. The most interesting findings in this study; The Wormian bones, not only involved the lambdoid sutures, but also extended to involve the occipitomastoid suture. We confirmed our diagnosis via sequence analysis which revealed a homozygous nonsense gene mutation (EIF2AK3) resulting in a premature stop codon (c.2707 C>T, p.R903X). Parents in two families were identified as heterozygous carriers of this mutation. Conclusion: The significance of this study is to point out the importance of analysing the skull bones in children with skeletal dysplasia. Interestingly, for the first time we detected the downward bulging of the occiput because of the abundancy of the Wormian bones (sites of maximal skull bone fragility) along the lambdoid and the occipito-mastoid sutures is by itself a highly alarming sign of progressive weakness of the weight-bearing zone (which is represented by the lambdoid and the occipitomastoid sutures). The exerting load of the cerebrum on these vulnerable and soft sutures can lead to brain swelling (a serious condition). Despite that lower limb defects in children are the most frequent deformities encountered in the departments of paediatric orthopaedics, because of the real or apparent detrimental effect that they have on gait and upright activity, and it draw immediate and alarming attention to parents. But, nevertheless, it is the responsibility of physicians to pay prompt attention for the necessity to scrutinize the skulls and the craniocervical junction in patients with long term bone disorders.

Comparison of Animal Models for the Study of Nonalcoholic Fatty Liver Disease

Nonalcoholic fatty liver disease (NAFLD) is one of the most prevalent chronic liver diseases, and there is still no effective treatment for its advanced stage, nonalcoholic steatohepatitis (NASH). An ideal animal model of NAFLD/NASH is urgently needed for preclinical studies. However, the models reported previously are quite heterogeneous owing to differences in animal strains, feed formulations, and evaluation indicators, among others. In this study, we report 5 NAFLD mouse models we developed in previous studies and comprehensively compared their characteristics. The high-fat diet (HFD) model was time-consuming and characterized by early insulin resistance and slight liver steatosis at 12 weeks. However, inflammation and fibrosis were rare, even at 22 weeks. The high-fat, high-fructose, and high-cholesterol diet (FFC) exacerbates glucose and lipid metabolism disorders, showing distinct hypercholesterolemia, steatosis, and mild inflammation at 12 weeks. An FFC diet combined with streptozotocin (STZ) was a novel model that speeds up the process of lobular inflammation and fibrosis. The STAM model also used a combination of FFC and STZ but used newborn mice and showed the fastest formation of fibrosis nodules. The HFD model was appropriate for the study of early NAFLD. FFC combined with STZ accelerated the pathologic process of NASH and might be the most promising model for NASH research and drug development.

Impaired Early Insulin Response to Glucose Load Predicts Episodic Memory Decline: A 10-Year Population-Based Cohort Follow-Up of 45-74-Year-Old Men and Women.

Diabetes increases the risk for cognitive decline, but the mechanisms behind this association remain unknown. Impaired early insulin secretion in elderly men and insulin resistance, both of which are pathophysiological features of type 2 diabetes, have previously been linked to Alzheimer's disease. To examine if the early insulin response to oral glucose load predicts cognitive performance after 10 years in men and women aged 45-74 years. This study was based on a subpopulation of the Health 2000 Survey, a Finnish nationwide, population-based health examination study, and its follow-up, the Health 2011 Study. In total, 961 45-74-year-old individuals (mean age at baseline 55.6 years, 55.8% women) were examined. An oral glucose tolerance test was performed in 2001-2002, and early insulin response was defined as the ratio of the 30-min increment in insulin concentration to that of glucose concentration. Cognitive function was evaluated at baseline and follow-up with categorical verbal fluency, word-list learning, and word-list delayed recall. Statistical analyses were performed using multivariable linear models adjusted for age, sex, education, APOE&z.epsi;4 genotype, vascular risk factors including diabetes, and depressive symptoms. A lower early insulin response to glucose load predicted lower performance (β: 0.21, p = 0.03) and greater decline (β: 0.19, p = 0.03) in the word-list delayed recall test. Baseline early insulin response did not predict verbal fluency or word-list learning (all p-values≥0.13). Our results suggest that decreased early insulin secretion predicts episodic memory decline in middle-aged to elderly men and women.

An optimised protocol for the investigation of insulin signalling in a human cell culture model of adipogenesis

ABSTRACT While there is no standardized protocol for the differentiation of human adipocytes in culture, common themes exist in the use of supra-physiological glucose and hormone concentrations, and an absence of exogenous fatty acids. These factors can have detrimental effects on some aspects of adipogenesis and adipocyte function. Here, we present methods for modifying the adipogenic differentiation protocol to overcome impaired glucose uptake and insulin signalling in human adipose-derived stem cell lines derived from the stromal vascular fraction of abdominal and gluteal subcutaneous adipose tissue. By reducing the length of exposure to adipogenic hormones, in combination with a physiological glucose concentration (5 mM), and the provision of exogenous fatty acids (reflecting typical dietary fatty acids), we were able to restore early insulin signalling events and glucose uptake, which were impaired by extended use of hormones and a high glucose concentration, respectively. Furthermore, the addition of exogenous fatty acids greatly increased the storage of triglycerides and removed the artificial demand to synthesize all fatty acids by de novo lipogenesis. Thus, modifying the adipogenic cocktail can enhance functional aspects of human adipocytes in vitro and is an important variable to consider prior to in vitro investigations into adipocyte biology.

Glucose Metabolism and Metabolomic Changes in Response to Prolonged Fasting in Individuals with Obesity, Type 2 Diabetes and Non-Obese People-A Cohort Trial.

Metabolic regulation of glucose can be altered by fasting periods. We examined glucose metabolism and metabolomics profiles after 12 h and 36 h fasting in non-obese and obese participants and people with type 2 diabetes using oral glucose tolerance (OGTT) and intravenous glucose tolerance testing (IVGTT). Insulin sensitivity was estimated by established indices and mass spectrometric metabolomics was performed on fasting serum samples. Participants had a mean age of 43 ± 16 years (62% women). Fasting levels of glucose, insulin and C-peptide were significantly lower in all cohorts after 36 h compared to 12 h fasting (p < 0.05). In non-obese participants, glucose levels were significantly higher after 36 h compared to 12 h fasting at 120 min of OGTT (109 ± 31 mg/dL vs. 79 ± 18 mg/dL; p = 0.001) but insulin levels were lower after 36 h of fasting at 30 min of OGTT (41.2 ± 34.1 mU/L after 36 h vs. 56.1 ± 29.7 mU/L; p < 0.05). In contrast, no significant differences were observed in obese participants or people with diabetes. Insulin sensitivity improved in all cohorts after 36 h fasting. In line, metabolomics revealed subtle baseline differences and an attenuated metabolic response to fasting in obese participants and people with diabetes. Our data demonstrate an improved insulin sensitivity after 36 h of fasting with higher glucose variations and reduced early insulin response in non-obese people only.

Skeletal Muscle Insulin Resistance in a Novel Fetal Growth Restriction Model

The abnormal fetal environment exerts long-term effects on skeletal muscle, and fetal growth restriction (FGR) is associated with insulin resistance in adulthood. In this study, we examined insulin resistance in early adulthood and insulin signaling in skeletal muscle using a novel FGR rat model. Ameroid constrictors (AC) were placed on the bilateral uterine and ovarian arteries of rats on day 17 of gestation; placebo surgery was performed on the control group. We measured body weight at birth, 4, 8, and 12 weeks of age and performed oral glucose tolerance tests at 8 and 12 weeks. Rats were dissected at 12 weeks of age. We examined the mRNA and protein expression of insulin signaling pathway molecules in skeletal muscle. FGR rats had a significantly lower birth weight than control rats (p = 0.002). At 12 weeks of age, the incremental area under the curve of blood glucose was significantly higher, and GLUT4 mRNA and protein expression in soleus muscle was significantly lower in the FGR group than in the control group. Reduced placental blood flow in the AC-attached FGR group caused insulin resistance and altered insulin signaling in skeletal muscles. Therefore, FGR causes skeletal muscle insulin resistance in early adulthood.

Clinical characteristics of immune checkpoint inhibitor-related type 1 diabetes mellitus

The clinical data of ten patients with immune checkpoint inhibitor-related type 1 diabetes mellitus were enrolled in the Second Xiangya Hospital of Central South University from January 2020 to October 2022 including 9 males and 1 female, with an average age of (57±8) years. There were 7 cases of fulminant type 1 diabetes and 3 cases of acute type 1 diabetes. Among the 10 patients, there were 5 cases of lung cancer, 2 cases of esophageal cancer, 1 case of gastric carcinom, 1 case of renal cell carcinoma, and 1 case of nasopharyngeal cancer. The drugs used in 10 patients were all programmed cell death receptor 1 (PD-1) inhibitors, including 5 cases of pembrolizumab, 3 cases of sintilimab, 1 case of tanezumab, and 1 case of toripalimab. Among them, 8 patients had diabetic ketoacidosis (DKA), 1 patient had ketosis, and 1 case had no ketosis at onset; 9 patients were negative for diabetes-related antibodies, and 1 patient was positive. All the 10 patients were successfully treated and depended on insulin therapy. Immune checkpoint inhibitors can cause type 1 diabetes, including fulminant type 1 diabetes, which mostly begins with DKA, requiring early identification and aggressive insulin therapy.

Glucagon 100 years. Important, but still enigmatic

Glucagon was discovered in 1923 as a contaminant of early insulin preparations, and its hormonal status was not established until its structure was established in the 1950 s and when the first radioimmunoassay was developed by Roger Unger, providing information about its secretion. Its role in hepatic glucose production was soon established and it was proposed as an essential factor in diabetic hyperglycemia. However, even today a number of issues remain unsolved. For instance, the assays for glucagon are not straightforward, although the development of sandwich ELISAs allowed reasonably accurate measurements also in rodents. The tools for evaluation of glucagon physiology include pancreatectomy, but studies in both humans and experimental animals pointed towards extrapancreatic sources of glucagon. It was demonstrated that glucagon receptor knockout animals do not develop diabetes upon destruction of their beta cells with streptozotocin. However, in patients with type 1 diabetes, glucagon antagonists do not normalize glucose levels; but antagonists do lower glucose levels in patients with in type 2 diabetes. Recent studies in animals and humans have confirmed the essential role of glucagon in glucose metabolism, but have suggested that it may be at least equally important for amino acid and lipid metabolism. In spite of the 100 years, glucagon research is very much alive.

The effects of early short-term insulin treatment vs. glimepiride on beta cell function in newly diagnosed type 2 diabetes with HbA1c above 9.

Type 2 diabetes mellitus (T2D) is a complex metabolic impairment. Beta cell (BC) failure is the most challenging among its pathogenetic mechanisms. Recognizing reversible contributors to BC failure could guide individualized approach to early T2D treatment. The aim of this study was to compare early short-term insulin treatment vs. glimepiride, both added to metformin, on BC function, glycemic and lipid control, during 12-month follow-up. Eighty newly diagnosed T2D patients, 30-65 years of age, presenting with HbA1c ≥ 9% were enrolled in the study. They were randomly assigned to single-month initial insulin therapy (INS) added to metformin, or to glimepiride and metformin (OAD) as only treatment. Subjects assigned to initial insulin intervention were thereafter switched to OAD. C-peptide (C-Pep) was analyzed at baseline and 2 hours after standardized test meal (STM). All subjects were STM-retested after 3 and 12 months. HbA1c, serum lipids, BMI, HOMA IR, and HOMA B were assessed over follow-up. HbA1c was lower in INS vs OAD at 3-months: 6.26 ± 0.18% vs 6.78 ± 0.10% (p = 0.016), remaining so by 12 months (p =0.056). BMI-adjusted ΔC-Pep was greater in INS vs. OAD at 3 months (4.60 ± 0.59 vs. 3.21 ± 0.34 m2 /kg; p = 0.044), persisting by 12months (4.57 ± 0.56 vs. 3.04 ± 0.34 m2/kg; p = 0.023). Average ΔC-Pep improvement from recruitment to 3 months was 100.8% in INS,vs. 51.3% in OAD. Prevalence of STM-ΔC-Pep response greater than 2.4 ng/mL had risen 3.2-fold by 12 months in the INS, vs. 2.4-fold only in the OAD group (p = 0.018). Early short-term insulin intervention in newly diagnosed T2D improves beta cell function more than glimepiride, both added to metformin, resulting in a superior and longer lasting glycemic and lipid control.

Deletion of Jazf1 gene causes early growth retardation and insulin resistance in mice

Single-nucleotide polymorphisms in the human juxtaposed with another zinc finger protein 1 (JAZF1) gene have repeatedly been associated with both type 2 diabetes (T2D) and height in multiple genome-wide association studies (GWAS); however, the mechanism by which JAZF1 causes these traits is not yet known. To investigate the possible functional role of JAZF1 in growth and glucose metabolism in vivo, we generated Jazf1 knockout (KO) mice and examined body composition and insulin sensitivity both in young and adult mice by using 1H-nuclear magnetic resonance and hyperinsulinemic-euglycemic clamp techniques. Plasma concentrations of insulin-like growth factor 1 (IGF-1) were reduced in both young and adult Jazf1 KO mice, and young Jazf1 KO mice were shorter in stature than age-matched wild-type mice. Young Jazf1 KO mice manifested reduced fat mass, whereas adult Jazf1 KO mice manifested increased fat mass and reductions in lean body mass associated with increased plasma growth hormone (GH) concentrations. Adult Jazf1 KO manifested muscle insulin resistance that was further exacerbated by high-fat diet feeding. Gene set enrichment analysis in Jazf1 KO liver identified the hepatocyte hepatic nuclear factor 4 alpha (HNF4α), which was decreased in Jazf1 KO liver and in JAZF1 knockdown cells. Moreover, GH-inducedIGF-1 expression was inhibited by JAZF1 knockdown in human hepatocytes. Taken together these results demonstrate that reduction of JAZF1 leads to early growth retardation and late onset insulin resistance in vivo which may be mediated through alterations in the GH-IGF-1 axis and HNF4α.

Identifying type 1 and 2 diabetes in research datasets where classification biomarkers are unavailable: assessing the accuracy of published approaches

ObjectivesWe aimed to compare the performance of approaches for classifying insulin-treated diabetes within research datasets without measured classification biomarkers, evaluated against two independent biological definitions of diabetes type. Study Design and SettingWe compared accuracy of ten reported approaches for classifying insulin-treated diabetes into type 1 (T1D) and type 2 (T2D) diabetes in two cohorts: UK Biobank (UKBB) n = 26,399 and Diabetes Alliance for Research in England (DARE) n = 1,296. The overall performance for classifying T1D and T2D was assessed using: a T1D genetic risk score and genetic stratification method (UKBB); C-peptide measured at >3 years diabetes duration (DARE). ResultsApproaches’ accuracy ranged from 71% to 88% (UKBB) and 68% to 88% (DARE). When classifying all participants, combining early insulin requirement with a T1D probability model (incorporating diagnosis age and body image issue [BMI]), and interview-reported diabetes type (UKBB available in only 15%) consistently achieved high accuracy (UKBB 87% and 87% and DARE 85% and 88%, respectively). For identifying T1D with minimal misclassification, models with high thresholds or young diagnosis age (<20 years) had highest performance. Findings were incorporated into an online tool identifying optimum approaches based on variable availability. ConclusionModels combining continuous features with early insulin requirement are the most accurate methods for classifying insulin-treated diabetes in research datasets without measured classification biomarkers.

Weight Management, Micronutrients, and Supplements in Diabetes

This year’s 39th International Symposium on Diabetes and Nutrition in Anavyssos, Greece, hosted a series of presentations and plenary lectures with a focus on the effects of weight loss, micronutrients, nutritional supplements, and alternative dietary patterns in the prevention and management of Type 2 diabetes (T2D) and cardiovascular risk reduction. Michael Lean discussed how diabetes remission can be achieved through weight loss using a low-energy diet (LED) or very low-energy diet (VLED), accompanied by continued long-term support from specialised healthcare professionals. Jeffrey Mechanick discussed the importance and impact of early intervention on T2D and cardiovascular disease (CVD). He emphasised that T2D should be seen not just at the point of disease, but on a spectrum from prediabetes to complications, with early interventions having significant impact on not only the progression of T2D, but also into the latter stages.Simin Liu presented an integrative multilevel framework for causal inference to personalise cardiometabolic health, highlighting recent work investigating the roles of dietary minerals, environment metals, and genomics in relation to cardiovascular disease and diabetes. Several of the presentations included discussion of specific interventions. Daniel West discussed the use of whey protein (WP) and how it can help control postprandial glycaemic excursions (PGE) in people with T2D controlled on oral antihyperglycaemic drugs. Following this, Andrea Hawkinson discussed how a new supplement, mulberry leaf (Morus alba) extract (MLE), can significantly lower postprandial glucose response, as well as early insulin response, highlighting the need for further studies to evaluate its efficacy in people with T2D. Philip Atherton showed studies providing evidence that protein and essential amino acid (EAA) supplementation can help support muscle mass, which is especially essential for older people with T2D and sarcopenia. Finally, Jose-María López-Pedrosa spoke about how a supplement containing slow digestible carbohydrates (SDC), arginine, lysine, and β-hydroxy-β-methylbutyric acid (HMB) can help preserve muscle mass, as well as improve insulin resistance, in a rat model of diabetes.

ODP220 Latent Autoimmune Diabetes of Adults and PCOS - an Unusual Combination

Abstract Introduction Latent autoimmune diabetes of adults (LADA) is an adult-onset subtype of autoimmune type 1 diabetes mellitus (T1DM), that is often misdiagnosed as T2DM. We present a case of LADA that was diagnosed in a young female with PCOS (polycystic ovaries syndrome) previously unsuccessfully managed as a T2DM patient. Case report 20-years-old female with past medical history of hyperlipidemia, newly diagnosed PCOS and suspected T2DM, presented to the PCP office for a routine follow up. Patient medication regimen consisted of Metformin 500 mg BID, Spironolactone 50 mg daily and oral contraceptive. Her BMI was 27.1. Routine blood work resulted in A1C 12.6% (estimated average glucose of 306 mg/dL), total cholesterol 278 mg/dL, triglycerides 1216 mg/dL, HDL cholesterol 31 mg/dL. She was also found to be Vitamin D deficient (Vitamin D, 25-OH 9.8 ng/mL). Based on a very young age and unusually elevated A1C she was assessed for LADA and found to have glutamic acid decarboxylase antibody (GAD-65) titer greater than 28.9 IU/mL (normal 0 - 5. 0 IU/mL), C-peptide of 0.8 ng/mL (normal 0.8-3.5 ng/mL) and negative anti pancreatic islet cells antibody level. Based on those results, she was diagnosed with LADA and initiated on insulin therapy (long acting and short - acting mealtime insulin). Metformin and OCP were discontinued given very high cholesterol level, but she started on Fenofibrate 160 mg daily, Vitamin D supplements and continued with Spironolactone 50 mg daily. Within 3 months her HbA1c decreased to 6.9% and she is doing remarkably well with the new medication regimen. Discussion LADA shares similar genetic and autoimmune profiles with T1DM, however LADA insidious presentation overlaps with T2DM, often resulting in misdiagnosis and delaying diagnosis and adequate treatment. Insulin resistance appears to underlie many of the endocrine features of PCOS in most of the patients. The risk of T2DM among PCOS patients is 5- to 10-fold higher than normal, however there is no clear correlation established between PCOS and T1DM, including LADA. Our case warrants newly diagnosed young adults with diabetes should be screened for LADA if there are atypical findings (such as very young age, remarkably elevated A1C, close to normal BMI). Among the anti-islet antibodies, GAD-65 are the most sensitive self-antigen-antibody markers of autoimmune diabetes. Early insulin therapy preserves residual β-cell function, improves glycemic control, and reduces the risk of long-term complications. Presentation: No date and time listed

Common Bean Seeds Obtained by Plant Water Restriction Ameliorates Obesity-Associated Cardiovascular Risk and Insulin Resistance.

The inclusion of beans in the diet has been recommended for obesity control. However, its beneficial effect varies depending on agroclimatic factors acting during plant development. The antiobesogenic capacity of Dalia bean (DB) seeds obtained by water restriction (WR) during the vegetative or reproductive stage of plant growth (50/100 and 100/50% of soil moisture in vegetative/reproductive stage, respectively), during the whole cycle (50/50), and well-watered plants (100/100) was researched. After phytochemical characterization, harvested beans from each experimental unit were pooled among treatments, based on a multivariate canonical discriminant analysis considering concentration of non-digestible carbohydrates (total, soluble and insoluble dietary fiber and resistant starch), phenolic compounds (total phenols, flavonoids, anthocyanins and condensed tannins) and total saponins, which showed no differences among replicas of each treatment. Obesity was induced in rats (UAZ-2015-36851) with a high fat diet (HFD) for fourmonths. Afterwards, rats were fed with the HFD supplemented with 20% of cooked DB for threemonths. During treatment, 100/50 beans, improved blood triglycerides, cholesterol, and glucose, and alleviated early insulin resistance (IR) related to inhibition of lipase, α-amylase and -glucosidase activity. After sacrifice, a hypolipidemic capacity and atherogenic risk reduction was observed, especially from the 100/50 treatment, suggesting that intake of DB obtained from WR may prevent IR and dyslipidemia.

Predictors of acarbose therapeutic efficacy in newly diagnosed type 2 diabetes mellitus patients in China

BackgroundAcarbose is one of the optimal drugs for patients with the first diagnosis of type 2 diabetes mellitus (T2DM). But what kind of emerging patients has the best therapeutic response to acarbose therapy has never been reported. To this end, we investigated predictors of acarbose therapeutic efficacy in newly diagnosed T2DM patients in China.MethodsA total of 346 T2DM patients received acarbose monotherapy for 48 weeks as part of participating in the Study of Acarbose in Newly Diagnosed Patients with T2DM in China (MARCH study) from November 2008 to June 2011. Change in glycated hemoglobin (ΔHbA1c) served as a dependent variable while different baseline variables including sex, age, disease duration, weight, body mass index (BMI), systolic blood pressure (SBP), diastolic blood pressure (DBP), HbA1c, fasting plasma glucose (FPG), 2-h postprandial blood glucose (2 h PG), fasting insulin (FINS), 2-h postprandial insulin (2 h INS), early insulin secretion index (IGI), homeostasis model assessment of insulin resistance index (HOMA-IR), homeostasis model assessment of beta cell function (HOMA-B), area under the curve (AUC) of glucagon, insulin and GLP-1 were assessed as independent predictors. Step-wise multiple linear regression was employed for statistical analysis.ResultsThe results suggested that independent predictors of ΔHbA1c at 12 weeks included baseline body weight (β = − 0.012, P = 0.006), DBP (β = 0.010, P = 0.047), FPG (β = 0.111, P = 0.005) and 2 h PG (β = 0.042, P = 0.043). Independent predictors of ΔHbA1c at 24 weeks included disease duration (β = 0.040, P = 0.019) and FPG (β = 0.117, P = 0.001). Finally, independent predictor of ΔHbA1c at 48 weeks was disease duration (β = 0.038, P = 0.046).ConclusionsAcarbose may be more effective in newly diagnosed T2DM patients with low FPG, low 2 h PG and obesity. The earlier T2DM is diagnosed and continuously treated with acarbose, the better the response to therapy.

Maternal Glycaemic and Insulinemic Status and Newborn DNA Methylation: Findings in Women With Overweight and Obesity.

Maternal dysglycaemia and prepregnancy obesity are associated with adverse offspring outcomes. Epigenetic mechanisms such as DNA methylation (DNAm) could contribute. To examine relationships between maternal glycaemia, insulinemic status, and dietary glycemic indices during pregnancy and an antenatal behavioral-lifestyle intervention with newborn DNAm. We investigated 172 women from a randomized controlled trial of a lifestyle intervention in pregnant women who were overweight or obese. Fasting glucose and insulin concentrations and derived indices of insulin resistance (HOMA-IR), β-cell function (HOMA-%B), and insulin sensitivity were determined at baseline (15) and 28 weeks' gestation. Dietary glycemic load (GL) and index (GI) were calculated from 3-day food diaries. Newborn cord blood DNAm levels of 850K CpG sites were measured using the Illumina Infinium HumanMethylationEPIC array. Associations of each biomarker, dietary index and intervention with DNAm were examined. Early pregnancy HOMA-IR and HOMA-%B were associated with lower DNAm at CpG sites cg03158092 and cg05985988, respectively. Early pregnancy insulin sensitivity was associated with higher DNAm at cg04976151. Higher late pregnancy insulin concentrations and GL scores were positively associated with DNAm at CpGs cg12082129 and cg11955198 and changes in maternal GI with lower DNAm at CpG cg03403995 (Bonferroni corrected P < 5.99 × 10-8). These later associations were located at genes previously implicated in growth or regulation of insulin processes. No effects of the intervention on cord blood DNAm were observed. None of our findings were replicated in previous studies. Among women who were overweight or obese, maternal pregnancy dietary glycemic indices, glucose, and insulin homeostasis were associated with modest changes in their newborn methylome. ISRCTN29316280.

Peripheral blood mononuclear cells-expressed miRNA profiles derived from children with metabolic-associated fatty liver disease and insulin resistance.

miRNA have been proposed as potential biomarkers of metabolic diseases. To identify potential miRNA biomarkers of early metabolic-associated fatty liver disease (MAFLD) and/or insulin resistance (IR) in preadolescent children. A total of 70 preadolescents, aged 8.5-12 years old participated in the study. Hepatic fat was assessed by magnetic resonance imaging. Fasting blood biochemical parameters were measured and HOMA-IR calculated. Peripheral blood mononuclear cells (PBMC)-derived miRNA profiles associated with MAFLD (≥5.5% hepatic fat) and IR (HOMA-IR ≥2.5) were identified using untargeted high-throughput miRNAs sequencing (RNA-seq). A total of 2123 PBMC-derived miRNAs were identified in children with (21.4%) or without MAFLD. Among them, hsa-miR-143-3p, hsa-miR-142-5p and hsa-miR-660-5p were up-regulated, and p-hsa-miR-247, hsa-let-7a-5p and hsa-miR-6823-3p down-regulated. Importantly, children with MAFLD had consistently higher miR-660-5p expression levels than their peers without it (p < 0.01), regardless of weight status. A total of 2124 PBMC-derived miRNA were identified in children with IR (28.6%) versus children without IR, where thirteen of them were dysregulated (p < 0.05) in children with IR. In addition, children with IR showed higher levels of miR-374a-5p and miR-190a-5p (p < 0.01) and lower levels of miR-4284 and miR-4791 (p < 005), than their peers without IR in both the whole sample and in those with overweight or obesity. Our study results suggest circulating miR-660-5p as a potential biomarker of the presence of MAFLD in preadolescent children while circulating miR-320a, miR-142-3p, miR-190a-5p, miR-374a-5p and let-7 family miRNAs could serve as potential biomarkers of IR in children.

Insulinogenic index and early phase insulin secretion predict increased risk of worsening glucose tolerance and of cystic fibrosis-related diabetes

ObjectiveMeasures of stimulated insulin secretion are emerging as important predictors of diabetes mellitus in at-risk populations. We analyzed the utility of clinical estimates of insulin secretion in a prospective cohort at risk for cystic fibrosis-related diabetes (CFRD). MethodsWe divided the profiles of 189 people with CF (pwCF) followed longitudinally in the Montreal CF cohort (mean follow up 6.6 ± 1.2 years) according to quartiles of the insulinogenic index (IGI; (I30-I0)/(G30-G0)); area under the curve for insulin normalized for glucose (AUCins/glu), and HOMA-B at baseline to compare clinical characteristics and risk of CFRD according to quartiles for each measure. We also compared characteristics of 40 pwCF found to have de novo CFRD at baseline. ResultsAt baseline, IGI and AUCins/glu were lower in subjects with de novo CFRD and those who later developed CFRD than those who never developed CFRD (p < 0.0001 for each). Subjects with the lowest quartiles of IGI, AUCins/glu, and AUCins/glu 0–30 had increased risk of developing CFRD by Kaplan-Meier analysis (p = 0.0244, p = 0.0024, and p = 0.0338, respectively). There was no significant difference in risk between quartiles of HOMA-B. Subjects in the lowest quartile of IGI showed a significant increase in 2-hour OGTT glucose and AUCglu between the initial and final study visits (p = 0.0027 and p = 0.0044, respectively). ConclusionIGI is easily measured in a clinical setting and needs to be validated in prospective studies as a potential tool to improve risk stratification in CFRD with direct relevance to pathogenesis.

Disease heterogeneity of adult diabetes based on routine clinical variables at diagnosis: Results from the German/Austrian Diabetes Follow-up Registry.

To cluster adults with diabetes using variables from real-world clinical care at manifestation. We applied hierarchical clustering using Ward's method to 56 869 adults documented in the prospective Diabetes Follow-up Registry (DPV). Clustering variables included age, sex, body mass index (BMI), HbA1c, diabetic ketoacidosis (DKA), components of the metabolic syndrome (hypertension/dyslipidaemia/hyperuricaemia) and beta-cell antibody status. Time until use of oral antidiabetic drugs (OADs), use of insulin, chronic kidney disease (CKD), cardiovascular disease (CVD), retinopathy or neuropathy were assessed using Kaplan-Meier analysis and Cox regression models. We identified eight clusters: four clusters comprised early diabetes onset (median age 40-50 years) but differed with regard to BMI, HbA1c, DKA and antibody positivity. Two clusters included adults with diabetes onset aged in their early 60s who met target HbA1c, but differed in BMI and sex distribution. Two clusters were characterized by late diabetes onset (median age 69 and 77 years) and comparatively low BMI, but differences in HbA1c. Earlier insulin use was observed in adults with high HbA1c, and earlier OAD use was observed in those with high BMI. Time until CKD or CVD was shorter in those with late onset, whereas retinopathy occurred earlier in adults with late onset and high HbA1c, and in adults with early onset, but high HbA1c and high percentage of antibody positivity. Adult diabetes is heterogeneous beyond classical type 1/type 2 diabetes, based on easily available variables in clinical practice using an automated clustering algorithm that allows both continuous and binary variables.