Prediabetic Phenotypes Research Articles

Dynamic assessment of insulin secretion and insulin resistance in Asians with prediabetes

Aims/hypothesisPrediabetes and type 2 diabetes are highly prevalent in Asia. Understanding the pathophysiology of abnormal glucose homeostasis in Asians will have important implications for reducing disease burden, but there have been conflicting reports on the relative contributions of insulin secretion and action in disease progression. In this study, we aimed to assess the contribution of β-cell dysfunction and insulin resistance in the Asian prediabetes phenotype. MethodsWe recruited 1679 Asians with prediabetes (n = 659) or normoglycemia (n = 1020) from a multi-ethnic population in Singapore. Participants underwent an oral glucose tolerance test, an intravenous glucose challenge, and a hyperinsulinemic-euglycemic clamp procedure to determine glucose tolerance, β-cell responsivity, insulin secretion, insulin clearance and insulin sensitivity. ResultsParticipants with prediabetes had significantly higher glucose concentrations in the fasting state and after glucose ingestion than did normoglycemic participants. Insulin sensitivity (M/I ratio) was ~15% lower, acute insulin response (AIR) to intravenous glucose and β-cell responsivity to oral glucose were ~35% lower, but total insulin secretion rate in the fasting state and after glucose ingestion was ~10% greater in prediabetic than in normoglycemic participants. The decrease in β-cell function with worsening glucose homeostasis in Asians with prediabetes was associated with progressively greater defects in AIR rather than M/I. However, analysis using static surrogate measures (HOMA indices) of insulin resistance and β-cell function revealed a different pattern. ConclusionsLower AIR to intravenous glucose and β-cell responsivity to oral glucose, on a background of mild insulin resistance, are the major contributors to the dysregulation of glucose homeostasis in Asians with prediabetes.

Abstract 10233: Interruption of Perirenal Adipose Tissue Thromboinflammation Reverses Prediabetic Kidney Impairment

Introduction: Mounting evidence suggests that micro- and macrovascular complications typically seen in diabetic patients commence in prediabetes. In absence of protracted hyperglycemia and its downstream pathological pathways, alternative mechanisms contribute to the observed cardiorenal involvement. Recent work from our laboratory implicated localized adipose inflammation in the detrimental phenotype in early metabolic deterioration, where inflammatory changes in perirenal adipose tissue triggered kidney functional and vascular deterioration. Significantly, thromboinflammatory processes involving increased factor Xa activity contribute to the low-grade adipose tissue inflammation resulting in vascular remodeling, vascular injury, atherosclerosis and organ damage, acting in a positive feedback loop further exacerbating tissue damage. Hypothesis: As such, we hypothesize factor Xa inhibition in a non-obese prediabetic rat model of localized perirenal adipose inflammation will mitigate the functional and renovascular derangements associated with metabolic dysfunction. Methods: Our rat model is induced by twelve weeks of high-caloric diet feeding to evoke a non-obese normoglycemic prediabetic phenotype. Prediabetic rats received daily oral rivaroxaban (20 mg/Kg) for the last two weeks of feeding. Renal function was assessed by measuring urinary protein excretion and glomerular filtration rate. Renovascular reactivity was examined in isolated perfused kidney preparations. Markers of inflammation, oxidative stress, and structural damage were studied in perirenal adipose and renal cortices. Results: High-calorie diet induced local adipose tissue inflammation and subsequent renovascular deterioration evident by an impaired renovasular endothelial feedback. This was associated with augmented oxidative stress and interstitial fibrosis. Rivaroxaban treatment decreased markers of perirenal adipose inflammation, oxidative stress and improved kidney structure and function. Conclusion: Our results highlight a pleotropic effect of the factor Xa inhibitor, rivaroxaban, in decreasing perirenal adipose tissue inflammation and subsequent amelioration of the deteriorated kidney function in prediabetes.

Profiles of Glucose Metabolism in Different Prediabetes Phenotypes, Classified by Fasting Glycemia, 2-Hour OGTT, Glycated Hemoglobin, and 1-Hour OGTT: An IMI DIRECT Study.

Differences in glucose metabolism among categories of prediabetes have not been systematically investigated. In this longitudinal study, participants (N = 2,111) underwent a 2-h 75-g oral glucose tolerance test (OGTT) at baseline and 48 months. HbA1c was also measured. We classified participants as having isolated prediabetes defect (impaired fasting glucose [IFG], impaired glucose tolerance [IGT], or HbA1c indicative of prediabetes [IA1c]), two defects (IFG+IGT, IFG+IA1c, or IGT+IA1c), or all defects (IFG+IGT+IA1c). β-Cell function (BCF) and insulin sensitivity were assessed from OGTT. At baseline, in pooling of participants with isolated defects, they showed impairment in both BCF and insulin sensitivity compared with healthy control subjects. Pooled groups with two or three defects showed progressive further deterioration. Among groups with isolated defect, those with IGT showed lower insulin sensitivity, insulin secretion at reference glucose (ISRr), and insulin secretion potentiation (P < 0.002). Conversely, those with IA1c showed higher insulin sensitivity and ISRr (P < 0.0001). Among groups with two defects, we similarly found differences in both BCF and insulin sensitivity. At 48 months, we found higher type 2 diabetes incidence for progressively increasing number of prediabetes defects (odds ratio >2, P < 0.008). In conclusion, the prediabetes groups showed differences in type/degree of glucometabolic impairment. Compared with the pooled group with isolated defects, those with double or triple defect showed progressive differences in diabetes incidence.

Distinct Effects of a High Fat Diet on Bone in Skeletally Mature and Developing Male C57BL/6J Mice.

Increased risks of skeletal fractures are common in patients with impaired glucose handling and type 2 diabetes mellitus (T2DM). The pathogenesis of skeletal fragility in these patients remains ill-defined as patients present with normal to high bone mineral density. With increasing cases of glucose intolerance and T2DM it is imperative that we develop an accurate rodent model for further investigation. We hypothesized that a high fat diet (60%) administered to developing male C57BL/6J mice that had not reached skeletal maturity would over represent bone microarchitectural implications, and that skeletally mature mice would better represent adult-onset glucose intolerance and the pre-diabetes phenotype. Two groups of developing (8 week) and mature (12 week) male C57BL/6J mice were placed onto either a normal chow (NC) or high fat diet (HFD) for 10 weeks. Oral glucose tolerance tests were performed throughout the study period. Long bones were excised and analysed for ex vivo biomechanical testing, micro-computed tomography, 2D histomorphometry and gene/protein expression analyses. The HFD increased fasting blood glucose and significantly reduced glucose tolerance in both age groups by week 7 of the diets. The HFD reduced biomechanical strength, both cortical and trabecular indices in the developing mice, but only affected cortical outcomes in the mature mice. Similar results were reflected in the 2D histomorphometry. Tibial gene expression revealed decreased bone formation in the HFD mice of both age groups, i.e., decreased osteocalcin expression and increased sclerostin RNA expression. In the mature mice only, while the HFD led to a non-significant reduction in runt-related transcription factor 2 (Runx2) RNA expression, this decrease became significant at the protein level in the femora. Our mature HFD mouse model more accurately represents late-onset impaired glucose tolerance/pre-T2DM cases in humans and can be used to uncover potential insights into reduced bone formation as a mechanism of skeletal fragility in these patients.

Predictors of Normalization of Fasting Glucose in Patients With Prediabetes Using Remote Continuous Care Emphasizing Low Carbohydrate Intake

Background: Prediabetes phenotypes differ based on whether an individual exhibits impaired glucose tolerance (IGT), impaired fasting glucose (IFG), or both. The traditional diabetes prevention approach focused on weight loss via fat/caloric restriction and exercise appears less effective in those with IFG. Given that even transient regression to normal glucose regulation is associated with reduced risk of progression to type 2 diabetes, interventions that elicit normal fasting glucose (NFG) may be beneficial. Here, we explored predictors of normalization of fasting glucose (FG) over one-year treatment with carbohydrate restricted nutrition therapy (Carb-R) delivered via a continuous remote care model. Methods: Data were obtained from medical records of adults with prediabetes who were treated at least one year at time of analysis. Of 738 patients with an antecedent prediabetes diagnosis, 460 had IFG (100mg/dL to 125mg/dL) at enrollment in the clinic and were included in this analysis. Patients were counseled on Carb-R targeting nutritional ketosis (NK) and reported fasting blood glucose, blood beta-hydroxybutyrate (BHB), and weight via an app facilitating remote monitoring and medical/coaching support. BHB ≥0.5 mM indicated NK. Cox proportional hazard regression was used to model time of first incidence of NFG at 3, 6, 9, and 12 months and to assess if normalization of fasting glucose was associated with baseline factors, weight change, metformin use, and degree or frequency of NK achieved, analyzed separately. Mean±SE is reported. Results: Patients with IFG were 53.9±0.4 years of age, 64.0% female, HbA1c 5.92±0.02%, and fasting glucose 114.5±0.8 mg/dL at enrollment. During treatment, 199 (43.3%) patients normalized FG at ≥1 time point with mean weight loss of 10.0±0.4 kg (-8.9%) at time of normalization, 192 (41.7%) did not, and 69 (15.0%) were missing glucose data. In an adjusted multivariate model, lower baseline HbA1c (HR 0.60, p=0.03), female sex (HR 1.39, p=0.04), and greater mean BHB value (HR 1.83, p<0.001) or higher proportion of days on which NK was reported (HR 3.23, p<0.001) were associated with reversion to NFG. Age, metformin use, weight change, and baseline fasting glucose, weight, triglycerides, HDL-C, and LDL-C were not associated with reversion to NFG (p>0.05). Conclusions: Greater adherence to Carb-R indicated by greater BHB values and a greater proportion of days in NK were strongly associated with normalization of FG in prediabetes patients with IFG. Weight loss, a common goal for diabetes prevention, was not associated with reversion to NFG. Future studies should assess the effects of Carb-R including NK in other prediabetes phenotypes and on progression to type 2 diabetes.

Comparing the effects of 12 months aerobic exercise and resistance training on glucose metabolism among prediabetes phenotype: A explorative randomized controlled trial

AimsThe pathophysiology of each phenotype of prediabetes is unique that promotes different levels of diabetes and cardiovascular disease risks. Exercise guidelines for individuals with prediabetes including both aerobic and resistance training could improve metabolic control, but its effects on different prediabetes subtypes are unclear. The aim of this explorative randomized controlled trial was to evaluate the effects of aerobic training (AT) or resistance training (RT) on glucose metabolism and lipid profile by different prediabetes subtypes with. MethodsA randomized controlled trial in which 128 individuals with isolated impaired fasting glucose (i-IFG; n = 39), isolated impaired glucose tolerance (i-IGT; n = 29), combined glucose tolerance (CGI; n = 27) and isolated elevated HbA1c (n = 33) were randomly assigned to the control group, AT group and RT group, respectively. Supervised exercise training, including AT and RT were completed at moderate intensity for 60 min per day, three non-consecutive days per week for 12 months. The primary outcome was improvement in glucose metabolism. Secondary outcomes included measure of lipid profile and if these effects were moderated by the prediabetes phenotype. ResultsOf the initial 128 participants, 118 finished the study, but all participants were included in the intention-to-treat analyses. The improvement in 2 h postprandial plasma glucose (2 hPG) between group difference (AT vs. RT) at 12 months was 0.87 (95% CI, -1.59 to-0.16; p < 0.05). Compared with RT group, AT significantly decreased the 2hPG in participants with i-IGT at 12 months (-1.66, 95% CI -3.04 to -0.28; p < 0.05). ConclusionsAT program conferred benefits in improving 2 h PG and HbA1c compared with RT for prediabetes. These findings may moderate by prediabetes phenotype, and AT appeared more effective in i-IGT. A future trial with large sample size and long time follow up of prediabetes phenotype groups are needed.

Heterozygous disruption of ALAS1 in mice causes an accelerated age-dependent reduction in free heme, but not total heme, in skeletal muscle and liver

5-Aminolevulinic acid (ALA) is the rate-limiting intermediate in heme biosynthesis in vertebrate species; a reaction catalyzed by the mitochondrial ALA synthase 1 (ALAS1) enzyme. Previously we reported that knockdown of the ubiquitously expressed ALAS1 gene in mice disrupts normal glucose metabolism, attenuates mitochondrial function and results in a prediabetic like phenotype when animals pass 20-weeks of age (Saitoh et al., 2018). Contrary to our expectations, the cytosolic and mitochondrial heme content of ALAS1 heterozygous (A1+/-) mice were similar to WT animals. Therefore, we speculated that regulatory “free heme” may be reduced in an age dependent manner in A1+/- mice, but not total heme.Here, we examine free and total heme from the skeletal muscle and liver of WT and A1+/- mice using a modified acetone extraction method and examine the effects of aging on free heme by comparing the amounts at 8–12 weeks and 30–36 weeks of age, in addition to the mRNA abundance of ALAS1. We found an age-dependent reduction in free heme in the skeletal muscle and liver of A1+/- mice, while WT mice showed only a slight decrease in the liver. Total heme levels showed no significant difference between young and aged WT and A1+/- mice. ALAS1 mRNA levels showed an age-dependent reduction similar to that of free heme levels, indicating that ALAS1 mRNA expression levels are a major determinant for free heme levels. The free heme pools in skeletal muscle tissue were almost 2-fold larger than that of liver tissue, suggesting that the heme pool varies across different tissue types. The expression of heme oxygenase 1 (HO-1) mRNA, which is expressed proportionally to the amount of free heme, were similar to those of free heme levels. Taken together, this study demonstrates that the free heme pool differs across tissues, and that an age-dependent reduction in free heme levels is accelerated in mice heterozygous for ALAS1, which could account for the prediabetic phenotype and mitochondrial abnormality observed in these animals.

Elevated triglyceride-glucose (TyG) index predicts incidence of Prediabetes: a prospective cohort study in China

BackgroundPrediabetes has become a pandemic. This study aimed to identify a better predictor for the incidence of prediabetes, which we hypothesize to be the triglyceride-glucose (TyG) index, a simplified insulin resistance index. We compared its predictive value with the other common risk factors of prediabetes.MethodsThe participants of this analysis were derived from the Risk Evaluation of cAncers in Chinese diabeTic Individuals: a lONgitudinal (REACTION) study. A total of 4543 participants without initial prediabetes or diabetes were followed up for 3.25 years. Using multivariate logistic regression model, the associations between baseline obesity, lipid profiles and non-insulin-based insulin resistance indices with the incidence of prediabetes were analyzed. To assess which is better predictor for the incidence of prediabetes, the area under curves (AUCs) calculated from the receiver operating characteristic curve analyses were used to evaluate and compare with the predictive value of the different indices.ResultsDuring the 3.25 years, 1071 out of the 4543 participants developed prediabetes. Using the logistic regression analysis adjusted for some potential confounders, the risk of incidence of prediabetes increased 1.38 (1.28–1.48) fold for each 1–SD increment of TyG index. The predictive ability (assessed by AUCs) of TyG index for predicting prediabetes was 0.60 (0.58–0.62), which was superior to the indices of obesity, lipid profiles and other non-insulin-based insulin resistance indices. Although the predictive ability of the TyG index was overall similar to fasting plasma glucose (FPG) (P = 0.4340), TyG index trended higher than FPG in females (0.62 (0.59–0.64) vs. 0.59 (0.57–0.61), P = 0.0872) and obese subjects (0.59 (0.57–0.62) vs. 0.57 (0.54–0.59), P = 0.1313). TyG index had superior predictive ability for the prediabetic phenotype with isolated impaired glucose tolerance compared with FPG (P < 0.05) and other indices. Furthermore, TyG index significantly improved the C statistic (0.62 (0.60–0.64)), integrated discrimination improvement (1.89% (1.44–2.33%)) and net reclassification index (28.76% (21.84–35.67%)) of conventional model in predicting prediabetes than other indices.ConclusionsTyG could be a potential predictor to identify the high risk individuals of prediabetes.

Exenatide, Metformin, or Both for Prediabetes in PCOS: A Randomized, Open-label, Parallel-group Controlled Study.

Up to 40% of patients with polycystic ovary syndrome (PCOS) have prediabetes; an optimal pharmacotherapy regimen for diabetes prevention in PCOS is yet to be established. To evaluate clinical efficacy of exenatide (EX), metformin (MET), or combination (COM) for prediabetes in PCOS. Randomized, open-label, parallel-group controlled trial. Renji Hospital Affiliated to Shanghai Jiaotong University School of Medicine. PCOS with prediabetes (fasting plasma glucose 5.6-6.9 mmol/L and/or 2 hour post glucose 7.8-11.0 mmol/L on oral glucose tolerance test [OGTT]). A total of 150 out of 183 eligible enrollees completed the study. EX (10-20μg daily), MET (1500-2000 mg daily), or COM (EX plus MET) for 12 weeks. Sustained remission rate of prediabetes (primary endpoint, a normal OGTT after 12 weeks of treatment followed by 12 weeks of washout on no drug treatment) along with anthropometric, hormonal, metabolic, and pancreatic β-cell function parameters (secondary endpoints) and potential mechanisms were assessed. Impaired glucose tolerance was found the dominant prediabetes phenotype. Overall sustained prediabetes remission rate was 50.7%. Remission rate of COM group (64%, 32/50) or EX group (56%, 28/50) was significantly higher than that of the MET group (32%, 16/50) (P = .003 and .027, respectively). EX was associated with superior suppression of 2-hour glucose increment in OGTT. A 2-step hyperglycemic clamp study revealed that EX had led to higher postprandial insulin secretion than MET, potentially explaining the higher remission rate. Compared with MET monotherapy, EX or COM achieved higher rate of remission of prediabetes among PCOS patients by improving postprandial insulin secretion.

Abstract MP04: High Fat Diet Exposure Induces Epigenetic Modulation In The Brain Renin Angiotensin System

Cardiometabolic Diseases (CMD) are one of the highest causes of morbidity and mortality worldwide. In-utero, environmental insults can program brain’s progeny through changes in gene expression level affecting cardiometabolic functions. Methylation and demethylation of DNA take place by DNA methyltransferase (DNMT) and Ten eleven translocation (TET) enzymes, respectively. Expression of renin angiotensin system (RAS) on pre-autonomic neurons in the hypothalamus is believed to play a pivotal role in sympathetic activity controlling metabolic and blood pressure (BP) homeostasis. We hypothesize that perinatal exposure to high fat high sucrose diet (HFHSD) programs the brain RAS through methylation mechanisms that lead to autonomic dysfunction and hypersensitivity to CMD. C57BL6/J dams were fed HFHSD or regular diet (RD) and mated with RD sires. After weaning, offspring were raised on RD. Three-month old progeny underwent 24 h BP recording (telemetry), measurement of fasted blood glucose (FBG), assessment of autonomic function (pharmacological) and baroreflex sensitivity (sequence method). Mice were then sacrificed, and brains harvested for quantification of mRNA levels of DNMT, TET and RAS components in the hypothalamus. HFHSD-exposed male offspring showed elevation in systolic BP (140.2 ±1.9 vs. 131.2 ±2.4 mmHg, p=0.006), heart rate (611.3 ±7.8 vs 562.5 ±7 bpm, p&lt;0.0001) and FBG (172.7 ±6.3 vs. 142.6 ±6.3 mg/dl, p=0.018) but not females. Cardiac sympathetic activity was higher in HFHSD-exposed mice (-148 ±11.5 vs. -35.2 ±4.7 bpm, p&lt;0.05). Surprisingly, sympathetic vascular tone was only increased in HFHSD-exposed females (-64.6 ±5.7 vs. -36.7 ±2.9 mmHg, p&lt;0.05) while spontaneous baroreflex gain was improved in HFHSD-exposed males (5.3 ±0.7 vs. 2.6 ±0.4 msec/mmHg, p&lt;0.05). In the brain, DNMT1, DNMT3a and TET1, 2 and 3 mRNA expression were downregulated (p&lt;0.05) while AT 1a R and ACE2 genes were upregulated (p=0.02) in HFHSD-exposed mice. We conclude that perinatal exposure to a hypercaloric diet epigenetically programs the progeny’s brain through methylation leading to a pre-hypertensive and pre-diabetic phenotype associated with changes in the expression of RAS genes which could eventually result in increased susceptibility to CMD.

PREDIABETES PHENOTYPE DOES NOT EXACERBATE MICROVASCULAR INSULIN SENSITIVITY IN METABOLIC SYNDROME

Metabolic syndrome (MetS) and elevated glucose each promote microvascular dysfunction. Whether in combination these two conditions create increased dysfunction is not clear. Here, we tested whether glucose status worsens microvascular insulin sensitivity in MetS. Thirty-two sedentary, obese adults (54.2±1.2yrs; 35.9±1.3kg/m2; VO2max: 19.9±1.3ml/kg/min) with MetS (≥3 ATP III criteria) were classified as normal glucose tolerant (NGT, n=8; 6F), impaired fasting glucose (IFG; n=10; 7F) or IFG+IGT (n=14; 11F) according to ADA criteria using a 75g OGTT. Capillary perfusion (microvascular blood volume, MBV), filling rate (microvascular flow velocity, MFV) and blood flow (MBF=MBV*MFV) were assessed as the change before and after a 2hr euglycemic-hyperinsulinemic clamp (90mg/dl, 40mU/m2/min) using contrast enhanced ultrasound. Glucose infusion rate (GIR) was used to determine metabolic insulin sensitivity while carbohydrate oxidation (CHOox) was measured before and after the clamp to understand nutrient utilization. T-tests, repeated measures ANOVAs and correlations were used when appropriate. Significance was accepted as P≤0.05. There were no differences in age, BMI, VO2max or GIR (NGT: 2.26±0.48 vs. IFG: 2.66±0.46 vs. IFG+IGT: 1.91±0.37mg/kg/min, P=0.44) among groups. Insulin did not stimulate capillary perfusion (NGT: 0.16±0.19 vs. IFG: -0.02±0.14 vs. IFG+IGT: 0.08±0.12AI, P=0.40), filling rate (NGT: 0.006±0.005 vs. IFG: 0.003±0.004 vs. IFG+IGT: 0.004±0.004sec-1, P=0.11) or blood flow (NGT: 0.02±0.02 vs. IFG: 0.01±0.01 vs. IFG+IGT: 0.01±0.01AI/sec, P=0.21). CHOox was likewise unresponsive to insulin (P=0.34). Although age, BMI, fasting and 2hr glucose concentrations did not relate to insulin effects on microvascular function, fasting triglycerides was related to insulin-stimulated MBF (r=-0.39, P=0.03). Prediabetes phenotype does not worsen microvascular insulin sensitivity in adults with MetS. Future work is warranted to examine the effects of different therapies (lifestyle, medication) on microvascular function. Funding was supported by the National Institutes of Health RO1-HL130296.

Psoriatic skin inflammation induces a pre-diabetic phenotype via the endocrine actions of skin secretome

ObjectivePsoriasis is a chronic inflammatory skin disease that is thought to affect ∼2% of the global population. Psoriasis has been associated with ∼30% increased risk of developing type 2 diabetes (T2D), with numerous studies reporting that psoriasis is an independent risk-factor for T2D, separate from underlying obesity. Separately, studies of skin-specific transgenic mice have reported altered whole-body glucose homeostasis in these models. These studies imply a direct role for skin inflammation and dysfunction in mediating the onset of T2D in psoriasis patients, potentially via the endocrine effects of the skin secretome on key metabolic tissues. We used a combination of in vivo and ex vivo mouse models and ex vivo human imiquimod (IMQ) models to investigate the effects of psoriasis-mediated changes in the skin secretome on whole-body metabolic function. MethodsTo induce psoriatic skin inflammation, mice were topically administered 75 mg of 5% IMQ cream (or Vaseline control) to a shaved dorsal region for 4 consecutive days. On day 5, mice were fasted for glucose and insulin tolerance testing, or sacrificed in the fed state with blood and tissues collected for analysis. To determine effects of the skin secretome, mouse skin was collected at day 5 from IMQ mice and cultured for 24 h. Conditioned media (CM) was collected and used 1:1 with fresh media to treat mouse explant subcutaneous adipose tissue (sAT) and isolated pancreatic islets. For human CM experiments, human skin was exposed to 5% IMQ cream for 20 min, ex vivo, to induce a psoriatic phenotype, then cultured for 24 h. CM was collected, combined 1:1 with fresh media and used to treat human sAT ex vivo. Markers of tissue inflammation and metabolic function were determined by qPCR. Beta cell function in isolated islets was measured by dynamic insulin secretion. Beta-cell proliferation was determined by measurement of Ki67 immunofluorescence histochemistry and BrDU uptake, whilst islet apoptosis was assessed by caspase 3/7 activity. All data is expressed as mean ± SEM. ResultsTopical treatment with IMQ induced a psoriatic-like phenotype in mouse skin, evidenced by thickening, erythema and inflammation of the skin. Topical IMQ treatment induced inflammation and signs of metabolic dysfunction in sub-cutaneous and epidydimal adipose tissue, liver, skeletal muscle and gut tissue. However, consistent with islet compensation and a pre-diabetic phenotype, IMQ mice displayed improved glucose tolerance, increased insulin and c-peptide response to glucose, and increased beta cell proliferation. Treatment of sAT with psoriatic mouse or human skin-CM replicated the in vivo phenotype, leading to increased inflammation and metabolic dysfunction in mouse and human sAT. Treatment of pancreatic islets with psoriatic mouse skin-CM induced increases in beta-proliferation and apoptosis, thus partially replicating the in vivo phenotype. ConclusionsPsoriasis-like skin inflammation induces a pre-diabetic phenotype, characterised by tissue inflammation and markers of metabolic dysfunction, together with islet compensation in mice. The in vivo phenotype is partially replicated by exposure of sAT and pancreatic islets to psoriatic-skin conditioned media. These results support the hypothesis that psoriatic skin inflammation, potentially via the endocrine actions of the skin secretome, may constitute a novel pathophysiological pathway mediating the development of T2D.

Risk of chronic kidney disease defined by decreased estimated glomerular filtration rate in individuals with different prediabetic phenotypes: results from a prospective cohort study in China

ObjectiveWe aimed to investigate the effects of prediabetes and its phenotypes of impaired fasting glucose (IFG), impaired glucose tolerance (IGT) and elevated glycated hemoglobin A1c (EHbA1c) on chronic kidney disease...

Obesity-Induced Regulator of Calcineurin 1 Overexpression Leads to β-Cell Failure Through Mitophagy Pathway Inhibition.

Aims: Type 2 diabetes (T2D) is associated with pancreatic β-cell dysfunction, manifested by reduced glucose-stimulated insulin secretion (GSIS). The regulator of calcineurin 1 (RCAN1) in islets is an endogenous inhibitor of calcium-activated protein phosphatase. Previous studies have indicated that global RCAN1 overexpression under high nutrient stress is involved in insulin resistance in T2D. However, the specific role and mechanism of this gene's overexpression in pancreatic β-cells have not been thoroughly elucidated to date. Results: In this study, we showed that mice overexpressing islet-specific RCAN1 exhibited a prediabetic phenotype with markedly reduced GSIS under nutrient stress. Overexpression of RCAN1 increased the autophagy-associated DNA methylation level of Beclin-1 suppressing the induction of autophagy, affected the protein kinase B, and downregulated the activation of mammalian target of rapamycin, leading to Miro1-mediated mitophagy deficiency. Furthermore, the exacerbated impairment of autophagy induction and mitophagy flux failures induced β-cell apoptosis, resulting in GSIS impairment, lipid imbalance, and NOD-like receptor 3 proinflammation under high nutrient stress in mice. Innovation: Our present data identify a detrimental effect of RCAN1 overexpression on Miro1-mediated mitophagy deficiency and β-cell dysfunction in high-fat diet-fed RCAN1 overexpressing mice. Conclusion: Our results revealed that strategies targeting RCAN1 in vivo may provide a therapeutic target to enhance β-cell mitophagy quality and may determine the crucial factor in T2D development.

Phenotypes of prediabetes: pathogenesis and consequences for prediction and prevention of type 2 diabetes and cardiovascular diseases

The prevalence of type 2 diabetes is increasing world-wide. Thus, it is necessary to better understand its pathogenesis, the risk of diabetes-associated complications and effective treatment strategies. Because type 2 diabetes is a very heterogenous disease, both, related to its pathogenesis and risk of complications, phenotyping strategies in diabetes may help to tailor the preventive strategies based on the individuals risk. As the the hyperglycemic state of prediabetes is already associated with an increased risk of cardiometabolic diseases it is necessary to investigate the impact of phenotypes for predictive and preventive outcomes already in this early state of hyperglycemia. In this review artice I discuss how important phenotypes of prediabetes, such as nonalcoholic fatty liver disease, visceral obesity, insulin secretion defect and insulin resistance can be used to improve the prediction and prevention of type 2 diabetes and cardiovascular disease.

Benefit of lifestyle-based T2DM prevention is influenced by prediabetes phenotype.

The prevention of type 2 diabetes mellitus (T2DM) is a target priority for the WHO and the United Nations and is a key priority in the 2018 Berlin Declaration, which is a global call for early actions related to T2DM. Health-care policies advocate that individuals at high risk of developing T2DM undertake lifestyle modification, irrespective of whether the prediabetes phenotype is defined by hyperglycaemia in the postprandial state (impaired glucose tolerance) and/or fasting state (impaired fasting glucose) or by intermediate HbA1c levels. However, current evidence indicates that diabetes prevention programmes based on lifestyle change have not been successful in preventing T2DM in individuals with isolated impaired fasting glucose. We propose that further research is needed to identify effective lifestyle interventions for individuals with isolated impaired fasting glucose. Furthermore, we call for the identification of innovative approaches that better identify people with impaired glucose tolerance, who benefit from the currently available lifestyle-based diabetes prevention programmes.

Insulin resistance, beta-cell function, adipokine profiles and cardiometabolic risk factors among Chinese youth with isolated impaired fasting glucose versus impaired glucose tolerance: the BCAMS study

ObjectiveImpaired fasting glucose (IFG) and impaired glucose tolerance (IGT) may convey disparate risks of metabolic consequences. Fasting plasma glucose (FPG), while an expedient screening procedure, may not adequately assess metabolic...

Impact Of Short-term Exercise Training And Diet On Glucose Effectiveness Between Prediabetes Phenotypes

PURPOSE: Although exercise improves glucose effectiveness (GE) in adults with type 2 diabetes, the influence of exercise on GE across the prediabetes phenotypes is unknown. Additionally, the impact of dietary intake on GE after an exercise intervention is limited. The purpose of this study was to examine the effect of short-term exercise training and habitual dietary intake on GE in adults with impaired fasting glucose (IFG) compared with IFG plus impaired glucose tolerance (IFG+IGT). METHODS: Female subjects (Age 59.4±7.2 yrs.; BMI 34.4±1.4 kg/m2) were screened for IFG (n=7, FPG: 103.9±2.3 mg/dl; 2-hr glc: 116.7±7.2 mg/dl) and IFG+IGT (n=10 FPG: 99.1±3.5 mg/dl; 2-hr glc: 152.9±11.0 mg/dl) using ADA criteria (120 min 75g OGTT). Subjects underwent 12 bouts of exercise at ~70% of HRpeak for 60 min/d over 2-weeks. A 180 min, 75g OGTT was used to collect glucose and insulin to determine GE via a validated minimal model before and after training. VO2peak and body composition (BIA) were also tested. Energy expenditure during training was calculated using a linear regression equation based on VO2 and heart rate. Subjects were also asked to record their diet before and after the intervention using 3-d food logs. RESULTS: Exercise training reduced BMI (P<0.05), but had no effect on lean body mass (LBM) or VO2peak; and there was no difference in exercise energy expenditure in either group (all, P>0.72). However, adults with IFG+IGT increased GE post-training (within effect; P=0.02), and this rise in GE tended to be greater in IFG+IGT than IFG (0.23±0.08 vs. 0.00±0.08 mg/dl per min; P=0.059). Increased GE correlated with elevated LBM (r=0.42, P=0.09), but not reduced BMI (r=-0.08, P=0.75) or increased fitness (r=0.02, P=0.95). While dietary protein reduction was linked with increased GE (r=-0.49, P=0.05), no association was seen between GE and carbohydrates (r=-0.24, P=0.37), fat (r=-0.17, P=0.53) or total kcal (r=-0.23, P=0.40). CONCLUSION: Independent of weight loss and fitness, short-term exercise training increased GE in adult women with IFG+IGT but not those with IFG. The results also suggest dietary protein may modulate the exercise effect on GE. Future work is needed to examine how nutrition can optimize exercise induced glucose regulation in individuals with prediabetes.

Circulating Lactate Is Elevated in Prediabetes Phenotypes Compared with Normal Glucose Tolerant Counterparts

PURPOSE: Prediabetes can be characterized as impaired fasting glucose (IFG) with or without impaired glucose tolerance (IGT; 2-hr blood glucose). IFG is depicted by impaired liver insulin sensitivity, while IFG+IGT is related to reduced liver and muscle insulin sensitivity. Lactate is a byproduct of non-oxidative glycolysis that may mediate altered glucose regulation. However, whether people with IFG and/or IFG+IGT have elevated lactate concentrations compared to normal glucose tolerant (NGT) controls is unclear. We hypothesized that individuals with IFG and IFG+IGT would have higher lactate levels than NGT controls in relation to glucose metabolism. METHODS: Forty-one obese adults (Age: 54.8±2.0yrs; BMI: 36.0±1.0kg/m2; 34F/7M) were screened for NGT, IFG, or IFG+IGT (75g OGTT, ADA criteria) following an overnight fast. Plasma lactate, glucose, and insulin were measured during a 120min 75g OGTT. The oral minimal model was used as an estimate for insulin sensitivity. Aerobic fitness (VO2peak), fasting substrate oxidation (respiratory exchange ratio (RER), indirect calorimetry) and body composition (bioelectrical impedance) were also tested. RESULTS: There were no differences in VO2peak, body fat or fasting RER across groups. Individuals with IFG+IGT had lower insulin sensitivity compared with IFG and NGT (P<0.01). However, both IFG and IFG+IGT had increased lactate tAUC compared to NGT (P<0.01 and P=0.01, respectively). Increased lactate tAUC correlated with fasting glucose (r=0.33, P=0.03) and reduced VO2peak (r=-0.34, P=0.03). Fasting lactate also related to fasting RER (r=0.31, P=0.04). CONCLUSION: Despite no differences between prediabetes phenotypes, adults with IFG and IFG+IGT have elevated lactates compared to NGT controls. Lactate tAUC directly associates with fasting glucose and fitness, but not insulin sensitivity. These data suggest that fitness may mediate lactate metabolism via the liver. Future work is warranted to determine the mechanism by which lactate influences type 2 diabetes risk.

The influence of the prediabetes phenotype on the efficacy of lifestyle interventions to improve glycemia, insulin resistance and postprandial hyperinsulinaemia

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