Compensatory Insulin Secretion Research Articles

7718 Dysregulated BCAA catabolism and insulin secretory response in the early stages of insulin resistance in mature adolescents

Abstract Disclosure: A. Basin: None. Q. Wang: None. H. Hong: None. O. Ilkayeva: None. M. Muehlbauer: None. D. Hsia: None. D.A. D'Alessio: None. C.B. Newgard: None. M. Freemark: None. P. Gumus Balikcioglu: None. Objective: We recently showed that surrogate markers of insulin resistance (IR) and insulin secretion are differentially associated with branched-chain amino acids (BCAAs) and their catabolites the branched-chain ketoacids (BCKAs). In this longitudinal study, we determined if baseline levels of BCAAs, BCKAs or the BCKA/BCAA ratio are associated with changes in IR, insulin secretion, and insulin secretion adjusted for IR after a one year follow up in adolescents aged 18-21 yr without Type 2 diabetes. Methods: We performed frequently sampled oral glucose tolerance tests (OGTT) at baseline and one year follow up in 10 adolescents with normal weight and 10 adolescents without Type 2 diabetes but with overweight/obesity and mild IR. After an overnight fast of 8-12 hours, participants had fasting blood samples drawn and consumed 1.75 g/kg, to a maximum of 75 g glucose solution as the initiation of an OGTT. Glucose (G) and insulin (I) were measured at times -15, 0, 10, 15, 30, 45, 60, 90, 120, and 180 minutes. Plasma metabolomic profiles were obtained at time 0. HOMA-IR, Matsuda Index, AUC glucose, AUC insulin, insulinogenic index (IGI) and disposition index (DI) at 15 and 30 min were calculated. % Body fat was measured by TANITA. Results: At one year follow up groups were comparable in age, sex, race, ethnicity and pubertal status. Participants with overweight/obesity had higher BMI (22.5±1.3 vs 36.2±9.7), BF% (16.8±8.4 vs 37.9±10.2), leptin, and diastolic blood pressure than lean participants. They were also more insulin resistant as evidenced by higher HOMA-IR . AUC glucose,AUC insulin, and IGI were comparable across groups, as were fasting BCAA levels and BCKA/BCAA ratio. As with baseline levels, follow-up BCAA levels correlated positively with AUC insulin, HOMA-IR, and IGI at 30 min and negatively with totaland HMW-adiponectin, and Matsuda Index, but did not correlate with BMI or % body fat. Likewise at follow up, BCKAs correlated negatively with total and HMW-adiponectin and did not correlate with Matsuda Index, or HOMA-IR. In association models adjusted for baseline age, sex, and BMI, higher baseline levels of the BCKA, α-keto-β-methylvalerate (KMV, isoleucine catabolite), and a higher BCKA/BCAA ratio were associated with a relative reduction in acute insulin secretion as reflected in a reduction in 15 min IGI at 1 year follow up. Conclusions: In this cohort of adolescents without Type 2 diabetes and with varying degrees of adiposity and insulin sensitivity, we identified KMV as a marker associated with a subsequent reduction in acute glucose-stimulated insulin secretion at one year follow up.These findings suggest that dysregulated BCAA catabolism is associated with loss of compensatory insulin secretion in the face of IR and may play a role in progression to impaired glucose tolerance and development of Type 2 diabetes. Presentation: 6/1/2024

Seropositivity of Anti-Toxoplasma gondii IgG among type 2 diabetes mellitus patients

Introduction. An estimated one-third of people worldwide are thought to be affected by toxoplasmosis, a common tropical disease with a wide geographic spread. The most common form of DM, namely type 2 diabetes arises from a combination of insulin resistance and inadequate compensatory insulin secretion. Methods. A case-control study was conducted from November 2022 to January 2023 from type 2 diabetic patients who attended outpatient clinics. Overall 96 patients who diabetes patients were screened for T. gondii seroprevalence. Results. By the ELISA method, the IgG antibodies in those were 90.63% and compared with a control group which the positive for T. gondii IgG antibodies 28%. The seropositivity of T. gondii IgG revealed that the patients living in urban areas were slightly higher than those in rural areas 58.3%, and 32.3%. The results showed that diabetic patients >60 years old had the highest rate of seropositive T. gondii infections (40.23%), while those ≤30 years old had the lowest rate (4.60%) with the mean of T2DM patients is 7.15 ± 1.94. Conclusion The current study revealed a high prevalence of T. gondii IgG among T2DM patients. The rate of seropositivity for T. gondii among patients living in the urban areas was slightly higher than in those in rural areas. The objective of the research was to ascertain whether T. gondii seropositivity and type 2 diabetes might be related.

Two Distinct Groups Are Shown to Be at Risk of Diabetes by Means of a Cluster Analysis of Four Variables.

Recent attempts to classify adult-onset diabetes using only six diabetes-related variables (GAD antibody, age at diagnosis, BMI, HbA1c, and homeostatic model assessment 2 estimates of b-cell function and insulin resistance (HOMA2-B and HOMA2-IR)) showed that diabetes can be classified into five clusters, of which four correspond to type 2 diabetes (T2DM). Here, we classified nondiabetic individuals to identify risk clusters for incident T2DM to facilitate the refinement of prevention strategies. Of the 1167 participants in the population-based Iwaki Health Promotion Project in 2014 (baseline), 868 nondiabetic individuals who attended at least once during 2015-2019 were included in a prospective study. A hierarchical cluster analysis was performed using four variables (BMI, HbA1c, and HOMA2 indices). Of the four clusters identified, cluster 1 (n = 103), labeled as "obese insulin resistant with sufficient compensatory insulin secretion", and cluster 2 (n = 136), labeled as "low insulin secretion", were found to be at risk of diabetes during the 5-year follow-up period: the multiple factor-adjusted HRs for clusters 1 and 2 were 14.7 and 53.1, respectively. Further, individuals in clusters 1and 2 could be accurately identified: the area under the ROC curves for clusters 1and 2 were 0.997 and 0.983, respectively. The risk of diabetes could be better assessed on the basis of the cluster that an individual belongs to.

Glucose-Induced Hemodynamic and Metabolic Response of Skeletal Muscle in Heart Failure Patients with Reduced vs. Preserved Ejection Fraction-A Pilot Study.

(1) Background: Insulin resistance (IR) is a characteristic pathophysiologic feature in heart failure (HF). We tested the hypothesis that skeletal muscle metabolism is differently impaired in patients with reduced (HFrEF) vs. preserved (HFpEF) ejection fraction. (2) Methods: carbohydrate and lipid metabolism was studied in situ by intramuscular microdialysis in patients with HFrEF (59 ± 14y, NYHA I-III) and HFpEF (65 ± 10y, NYHA I-II) vs. healthy subjects of similar age during the oral glucose load (oGL); (3) Results: There were no difference in fasting serum and interstitial parameters between the groups. Blood and dialysate glucose increased significantly in HFpEF vs. HFrEF and controls upon oGT (both p < 0.0001), while insulin increased significantly in HFrEF vs. HFpEF and controls (p < 0.0005). Muscle tissue perfusion tended to be lower in HFrEF vs. HFpEF and controls after the oGL (p = 0.057). There were no differences in postprandial increases in dialysate lactate and pyruvate. Postprandial dialysate glycerol was higher in HFpEF vs. HFrEF and controls upon oGL (p = 0.0016); (4) Conclusion: A pattern of muscle glucose metabolism is distinctly different in patients with HFrEF vs. HFpEF. While postprandial IR was characterized by impaired tissue perfusion and higher compensatory insulin secretion in HFrEF, reduced muscle glucose uptake and a blunted antilipolytic effect of insulin were found in HFpEF.

Iron Supplementation in Pregnancy and Risk of Gestational Diabetes: A Narrative Review.

Pregnant women frequently supplement their diets with iron to treat any cryptic anemia, on the assumption that if anemia is not present, there will be no negative consequences. However, in women who are already iron-replete, it has been suggested that this can lead to iron overload and an increased risk of certain pregnancy complications. One such complication is gestational diabetes. Fourteen clinical trials, case-control or cohort studies (found using Pubmed/Scopus/Web of Science) have investigated links between iron supplementation in pregnancy and risk of gestational diabetes, several of them finding significant associations with increased risk. Potential mechanisms include increased oxidative stress leading to insulin resistance and inadequate compensatory insulin secretion. Current evidence suggests that dietary supplementation with iron in pregnancy may increase a pregnant woman's chance of developing gestational diabetes, although available evidence is somewhat contradictory, and the magnitude of any increased risk appears relatively small. Meta-analyses have suggested the presence of significant heterogeneity in results between studies, urging a degree of caution in interpreting these results. It is currently suggested that advice to pregnant women about whether to supplement their diets with iron or not should consider both their current iron status and their other established risk factors for gestational diabetes.

363-OR: Weight Loss, Lifestyle Intervention, and Metformin Effects on the Longitudinal Relationship between Insulin Secretion and Sensitivity in the Diabetes Prevention Program (DPP)

Insulin secretion and sensitivity regulate glycemia, with inadequately compensated deficiencies in either or both leading to diabetes. Using data from 2931 participants in the DPP repository, we investigate the effects of lifestyle and metformin interventions and of weight loss on the relationship between insulin secretion and sensitivity. Insulin secretion and sensitivity were estimated from insulin concentrations in fasting and 30-minute post-load serum samples at baseline and at 1, 2, and 3 years after randomization during the active intervention phase of the DPP. The relationship of secretion and sensitivity was evaluated by standardized major axis regression and was found to change over time for participants in the lifestyle and metformin interventions. Distances along and away from the regression line were taken to characterize insulin secretory demand and insulin secretion in compensation to the demand, respectively. Both the metformin and lifestyle interventions decreased secretory demand while increasing compensatory insulin secretion, with greater effects of the lifestyle intervention. Improvements were directly related to the amount of weight loss; decreases in weight significantly reduced secretory demand [b=-0.088 SD (-0.102, -0.074) /5 kg loss] and increased compensatory insulin secretion [b=0.169 SD (0.149, 0.189) /5 kg loss]. In time-dependent hazard models, increasing secretory demand associated with increased diabetes risk [hazard ratio (HR) =1.189 per baseline SD (1.004, 1.413) ] while increasing compensatory insulin secretion associated with lower risk [HR=0.1 (0.080, 0.145) ]. These results are consistent with earlier observations in the DPP that diabetes risk reduction was directly related to the amount of weight loss and suggest that this effect is mediated by lowered insulin secretory demand coupled with improved compensatory insulin secretion. Disclosure W.C. Knowler: None. R.L. Hanson: None.

Evaluation of insulin resistance and beta-cell dysfunctions in newly diagnosed polycystic ovarian syndrome patients

Introduction: Women with polycystic ovary syndrome (PCOS) are at increased risk of developing glucose intolerance and diabetes attributed to increased insulin resistance (IR). However, it is not clear whether β-cell dysfunction has a central role in pathogenesis. The distinction has important implications for the prevention of type 2 diabetes in PCOS with interventions that ameliorate IR. This study aimed to find if IR differs among the various phenotypes of PCOS and perform a quantitative estimation of β-cell dysfunction versus IR in patients of PCOS participants. Materials and Methods: This case–control study was conducted for 1 year in the Endocrinology and Gynaecology outpatient departments at Gauhati Medical College. Fifty women newly diagnosed with PCOS, as per the Rotterdam criteria, were considered cases. Fifty, age- and body mass index-matched healthy females were taken as controls. Fasting and postprandial blood glucose, serum insulin, testosterone, and oral glucose tolerance test values were taken. Impaired fasting glucose, impaired glucose tolerance (IGT), and type 2 diabetes mellitus T2DM were diagnosed according to ADA 2011 criteria. IR and β-cell function were determined by “homeostasis model assessment (HOMA)”. Results: We observed an altered relationship between IR and insulin secretion, consistent with an intrinsic β-cell defect, wherein IR led to a decreased amount of compensatory insulin secretion in PCOS compared with normal women. The correlation coefficients relating HOMA%B to HOMA-IR were lower in PCOS, indicating less compensatory insulin secretion for a given increment in IR. Conclusion: PCOS patients are at increased risk of developing glucose intolerance and diabetes.

Effects of Different Intensity Exercise on Glucose Metabolism and Hepatic IRS/PI3K/AKT Pathway in SD Rats Exposed with TCDD.

The objective of the study was to investigate the effects of different intensity exercise and 2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) exposure on glucose metabolism in Sprague Dawley (SD) rats, as well as the action of insulin receptor substrate (IRS)/phosphatidylinositol-3-kinases (PI3K)/protein kinase (AKT) signaling pathway in it. Besides that, we explored whether exercise can alleviate the toxicity induced by TCDD. Sixty male SD rats (8 weeks old) were randomly divided into non-exercise group, none-exercise toxic group, moderate-intensity exercise group, moderate-intensity exercise toxic group, high-intensity exercise group, high-intensity exercise toxic group. The toxic groups were intraperitoneally injected with TCDD, which the dose was 6.4 µg/kg· BW for the first week, then 21% of the above week dose for continuous 8 weeks. The 8-week treadmill running of moderate intensity (15 m/min, 60 min/day) and high intensity (26 m/min, 35 min/day) were implemented separately in exercise groups five times a week. After detecting the concentration of fasting serum glucose, insulin and C-peptide, the index of the homeostasis model assessment of insulin resistance (HOMA-IR) and islet β-cell secretion (HOMA-β) were calculated. We measured the hepatic mRNA expression levels of IRS2, phosphatidylinositol-3-kinases catalytic subunit alpha (PIK3CA), AKT by real-time PCR. The protein expression of total IRS2 (tIRS2), phosphorylated IRS2 at Ser731 (pSer731), total PIK3CA (tPIK3CA), total Akt (tAkt), phosphorylated Akt at Thr308 (pThr308) in liver were analyzed by western blot. We observed that compared to the non-exercise group, insulin and HOMA-IR index were significantly higher in the none-exercise toxic group (p < 0.05), while glucose, insulin, C-peptide and HOMA-IR index were significantly lower in the moderate-intensity exercise group (p < 0.05). In the high-intensity exercise group, the HOMA-IR index was significantly lower and the gene expression of IRS2 was significantly higher than in the non-exercise group (p < 0.05). Besides that, the HOMA-β index in the moderate-intensity exercise toxic group was significantly higher compared to the none-exercise toxic group and moderate-intensity exercise group (p < 0.05). The level of IRS2mRNA was significantly lower in the high-intensity exercise toxic group than in the high-intensity exercise group (p < 0.05). Our results demonstrated that 8-week TCDD exposure could induce insulin resistance in rats, while exercise could improve insulin sensitivity in which moderate intensity was more obvious than high intensity exercise. Meanwhile, both intensity exercise could not effectively alleviate the insulin resistance induced by TCDD, but high intensity exercise could promote compensatory insulin secretion to maintain glucose homeostasis. Although the gene expression of IRS2 was changed in high-intensity exercise groups, the mediation role of the hepatic IRS2/PI3K/AKT pathway in the effects of exercise and TCDD exposure on glucose metabolism remains very limited.

Relationship Between Insulin Secretion and Insulin Sensitivity and its Role in Development of Type 2 Diabetes Mellitus: Beyond the Disposition Index.

We assessed whether the relationship between insulin secretion and sensitivity predicted development of type 2 diabetes in American Indians participating in a longitudinal epidemiologic study. At baseline, when all subjects did not have diabetes, 1566 participants underwent oral tests and 420 had intravenous measures of glucose regulation with estimates of insulin secretion and sensitivity. Standardized major axis regression was used to study the relationship of secretion and sensitivity. Distances away from and along the regression line estimated compensatory insulin secretion and secretory demand, respectively. This relationship differed according to glucose tolerance and BMI categories. The distance away from the line is similar to the disposition index (DI) defined as the product of estimated secretion and sensitivity, but the regression line may differ from a line with constant DI (i.e., it is not necessarily hyperbolic). Subjects with the same DI but different levels of insulin secretion and sensitivity had different incidence rates of diabetes; lower sensitivity with higher secretory demand was associated with greater diabetes risk. Insulin secretion and insulin sensitivity, analyzed together, predict diabetes better than DI alone. Physiologically, this may reflect long-term risk associated with increased allostatic load resulting from the stimulation of insulin hypersecretion by increased glycemia.

Poor In Utero Growth, and Reduced β-Cell Compensation and High Fasting Glucose From Childhood, Are Harbingers of Glucose Intolerance in Young Indians.

India is a double world capital of early-life undernutrition and type 2 diabetes. We aimed to characterize life course growth and metabolic trajectories in those developing glucose intolerance as young adults in the Pune Maternal Nutrition Study (PMNS). PMNS is a community-based intergenerational birth cohort established in 1993, with serial information on parents and children through pregnancy, childhood, and adolescence. We compared normal glucose-tolerant and glucose-intolerant participants for serial growth, estimates of insulin sensitivity and secretion (HOMA and dynamic indices), and β-cell compensation accounting for prevailing insulin sensitivity. At 18 years (N = 619), 37% of men and 20% of women were glucose intolerant (prediabetes n = 184; diabetes n = 1) despite 48% being underweight (BMI <18.5 kg/m2). Glucose-intolerant participants had higher fasting glucose from childhood. Mothers of glucose-intolerant participants had higher glycemia in pregnancy. Glucose-intolerant participants were shorter at birth. Insulin sensitivity decreased with age in all participants, and those with glucose intolerance had consistently lower compensatory insulin secretion from childhood. Participants in the highest quintile of fasting glucose at 6 and 12 years had 2.5- and 4.0-fold higher risks, respectively, of 18-year glucose intolerance; this finding was replicated in two other cohorts. Inadequate compensatory insulin secretory response to decreasing insulin sensitivity in early life is the major pathophysiology underlying glucose intolerance in thin rural Indians. Smaller birth size, maternal pregnancy hyperglycemia, and higher glycemia from childhood herald future glucose intolerance, mandating a strategy for diabetes prevention from early life, preferably intergenerationally.

995-P: Glucagon-Like Peptide-1 (GLP-1) Levels following OGTT Mirror Insulin Resistant States (IRS) in Prediabetes Subjects: A Multi-Ethnic Comparative Study

Introduction: IRS is a precursor to the development of prediabetes which manifests itself in the form of compensatory insulin secretion. The role of GLP-1 in this compensatory mechanism has not been well studied especially among various ethnic groups.Aim: To assess differences in GLP-1 responses to OGTT and its relationship to insulin resistance indices (HOMA-IR) among 3 major ethnic groups with prediabetes.Methods: Fifty-four prediabetes subjects (21 Malays, 17 Chinese and 16 Indians) matched for age, gender, BMI and waist circumference underwent a 75-g OGTT. Plasma glucose and total GLP-1 concentrations were measured at 0, 30 and 120 minutes. Fasting glucose and insulin were obtained for the HOMA analyses.Results: Indians were the most insulin resistant. This is mirrored by Indians having the highest GLP-1 levels at 0, 30 and 120 minutes. Similarly, the area under the curve for GLP-1 was 59% higher in Indians and 50% higher in Chinese compared to the Malays. GLP-1 level was positively correlated with HOMA-IR (r=0.576, p<0.001). Ethnicity was a significant determinant of GLP-1 level with Indians exhibiting the strongest positive correlation (B=7.02, p<0.001).Conclusions: In prediabetes, GLP-1 responses post-OGTT increased proportionately to IRS, evidenced by the augmented GLP-1 responses in the Indians who possessed the highest HOMA-IR indices.View largeDownload slideView largeDownload slide DisclosureS. C. Chong: None. N. Sukor: None. S. Robert: None. K. F. Ng: None. N. A. Kamaruddin: None.FundingNational University of Malaysia Medical Centre (GUP-2017-066); Malaysian Endocrine & Metabolic Society (L12-MEMS6)

Trehalose Protects against Insulin Resistance-Induced Tissue Injury and Excessive Autophagy in Skeletal Muscles and Kidney.

Insulin resistance refers to a pathological state of compromised sensitivity of insulin to promote glucose uptake and utilization, resulting in compensatory excessive insulin secretion and hyperinsulinemia in an effort to maintain glucose homeostasis. Akt2 represents an important member of the Akt family and plays an essential role in the maintenance of insulin signaling. This study was designed to examine the effects of trehalose on kidney and skeletal muscle (rectus femoris muscle) injury in an Akt2 knockout-induced model of insulin resistance. Akt2 knockout (Akt2-/-) and adult WT mice were treated with trehalose (1 mg/g/d) intraperitoneally for 2 days, followed by providing 2% trehalose in drinking water for 2 months. Intraperitoneal glucose tolerance test (IPGTT), protein carbonyl content and mitochondrial function (aconitase activity) were examined. Apoptosis and autophagy protein markers were monitored using western blot analysis. Akt2 ablation impaired glucose tolerance, promoted protein carbonyl formation and decreased aconitase activity in kidney and skeletal muscles, associated with pronounced apoptosis and overt autophagy, the effects of which, with the exception of IPGTT, were greatly ameliorated or negated by trehalose treatment. Moreover, phosphorylation of mTOR was downregulated in both kidney and skeletal muscles from Akt2-/- mice, the effect of which was attenuated by trehalose. Levels of Akt (pan and Akt2) were much lower in Akt2-/- mice, the effect of which was unaffected by trehalose treatment although trehalose itself upregulated Akt levels. These data suggest that the autophagy inducer trehalose rescued against insulin resistance-induced kidney and skeletal muscle injury, apoptosis and excessive autophagy, possibly in association with restored mTOR phosphorylation without affecting Akt.

1835-P: Deletion of Insulin Receptor Substrate 2 in AGRP Neurons Causes Beta-Cell Dysfunction

In humans, type 2 diabetes progresses when beta-cells fail to compensate peripheral insulin resistance. Insulin receptor substrate (IRS) proteins mediate a variety of the metabolic and growth-promoting actions of insulin and IGF-1, and are important integrators of heterologous regulation. Systemic ablation of the Irs2 gene in mice causes β-cell dysfunction that prevents compensatory insulin secretion while insulin resistance progresses to life threatening hyperglycemia. Upregulation of IRS2 in pancreatic β-cell using rat insulin-2 promoter (Irs2RIP) promotes sufficient hyperinsulinemia to prevent diabetes. Targeted Irs2 deletion using CreRIP also causes beta-cell failure and hyperglycemia, but the mechanism is unclear because CreRIP drives deletion in beta-cells and hypothalamus—especially in the arcuate nucleus (ARC). AGRP neurons in the ARC play an important role in regulating energy homeostasis, but it is unknown whether IRS2 in the AGRP neurons might also affect beta-cell function. Here we show that disruption of Irs2 (but not Irs1) in AGRP neurons (Irs2f/fCreAgrp-mice) reduced islet mass by 45%. To test insulin secretory function, we subjected mice to hyperglycemic clamps. The glucose infusion rate to maintain steady-state hyperglycemia decreased significantly. Moreover, insulin secretion failed to respond to L-arginine treatment in aged Irs2f/fCreAgrp-mice. Moreover, Irs2f/fCreAgrp-mice displayed progressive deterioration of glucose homeostasis and a lack of beta -cell compensation during high fat diet. Overall, our results indicate that dysfunction of Irs2 in AGRP neurons might contribute to the pathophysiology of type 2 diabetes. Disclosure R. Tao: None. K.D. Copps: None. M.F. White: Advisory Panel; Self; Housey Pharmaceutical Research Laboratories. O. Stoehr: None. Funding National Institutes of Health (5R01DK098655-06)

Glutamate decarboxylase 67 contributes to compensatory insulin secretion in aged pancreatic islets

ABSTRACTPancreatic islets play an essential role in regulating blood glucose levels. Age-dependent development of glucose intolerance and insulin resistance results in hyperglycemia, which in turn stimulates insulin synthesis and secretion from aged islets, to fulfill the increased demand for insulin. However, the mechanism underlying enhanced insulin secretion remains unknown. Glutamic acid decarboxylase 67 (GAD67) catalyzes the conversion of glutamate into γ-aminobutyric acid (GABA) and CO2. Both glutamate and GABA can affect islet function. Here, we investigated the role of GAD67 in insulin secretion in young (3 month old) and aged (24 month old) C57BL/6J male mice. Unlike young mice, aged mice displayed glucose-intolerance and insulin-resistance. However, aged mice secreted more insulin and showed lower fed blood glucose levels than young mice. GAD67 levels in primary islets increased with aging and in response to high glucose levels. Inhibition of GAD67 activity using a potent inhibitor of GAD, 3-mercaptopropionic acid, abrogated glucose-stimulated insulin secretion from a pancreatic β-cell line and from young and aged islets. Collectively, our results suggest that blood glucose levels regulate GAD67 expression, which contributes to β-cell responses to impaired glucose homeostasis caused by advanced aging.

MESA 3: DIABETES MELLITUS TIPO 2 Y ACTIVIDAD FÍSICA

La prevalencia de diabetes mellitus (DM) actividad física es cada vez mayor asociada a bajos niveles de actividad física (AF) y aumento de sobrepeso-obesidad.Los beneficios de la AF incluyen la prevención de la DM, reducción de hemoglobina glicosilada y glucemia postprandial, mejoría del perfil cardiovascular (descenso Presión arterial y triglicéridos, aumento de colesterol HDL), descenso significativo de biomarcadores proinflamatorios. Además, la AF mejora la disfunción sexual, la función endotelial, el óxido nítrico biodisponible y la insulinosensibilad, incrementa la testosterona, mejora el humor y la autoestima, la ansiedad y la depresión.El ejercicio incrementa la producción de glucosa, la secreción de insulina compensatoria está alterada y se exacerba por una mayor secreción de catecolaminas. Las personas con insulinopenia marcada tienen riesgo de cetosis. El aumento de hipoglucemias está dado por una mayor captación de glucosa. La AF mejora la polineuropatía y la neuropatía autonómica cardíaca, previene la enfermad renal crónica y se asocia a menores niveles de retinopatía diabética. En pacientes con retinopatía preproliferativa y proliferativa o degradación macular, se desaconsejan las actividades que aumentan considerablemente la presión intraocular. Está contraindicado el ejercicio en caso de hemorragia vítrea.El requerimiento energético depende del tipo, intensidad y duración del ejercicio. Se debe considerar el cuidado del pie. Las recomendaciones son disminuir el tiempo sedentario, ejercicio aeróbico al menos 150 min/semana y ejercicio de resistencia.Al aumentar la intensidad o ante riesgo elevado se debe realizar chequeo que incluya electrocardiograma y test de esfuerzo. Considerar ecocardiograma bidimensional y doppler.

Too Late and Not Enough: School Year Sleep Duration, Timing, and Circadian Misalignment Are Associated with Reduced Insulin Sensitivity in Adolescents with Overweight/Obesity

To examine the relationship between insulin resistance (IR) and sleep/circadian health in overweight/obese adolescents. We hypothesized that insufficient and delayed sleep would be associated with IR in this population. Thirty-one adolescents (mean age, 16.0 ± 1.4 years; 77% female) with body mass index ≥90th percentile for age/sex were recruited from outpatient clinics at a children's hospital. Participants underwent 1 week of objective home sleep monitoring with wrist actigraphy during the academic year. A 3-hour oral glucose tolerance test was conducted, followed by in-laboratory salivary dim-light melatonin sampling every 30-60 minutes from 5 p.m. to noon the next day. Regression analyses between sleep and circadian variables with IR were examined. Longer sleep time and time in bed on weekends and weekdays and earlier weekday bedtime were significantly associated with better insulin sensitivity. Participants who obtained less than the median duration of sleep per night (6.6 hours) had evidence of IR with compensatory insulin secretion compared with those obtaining ≥6.6 hours of sleep. A wider phase angle between bedtime and melatonin onset, indicating a later circadian timing of sleep onset, was significantly associated with IR. Short sleep duration, later weekday bedtime, and later circadian timing of sleep were associated with IR in a cohort of adolescents with overweight/obesity during the school year. Further research is needed to better understand the physiology underlying these observations and to evaluate the impact of improved sleep and circadian health on metabolic health in this at-risk population.

Evaluation and Management of Youth-Onset Type 2 Diabetes: A Position Statement by the American Diabetes Association.

Although all types of diabetes result in hyperglycemia, the pathophysiology of each type of diabetes is different. These guidelines summarize available data specific to the comprehensive care of youth with type 2 diabetes. The objective is to enrich the recognition of type 2 diabetes in youth, its risk factors, its pathophysiology, its management, and the prevention of associated complications. Glucose homeostasis is maintained by a balance between insulin secretion from the pancreatic β-cells and sensitivity to insulin in skeletal muscle, adipose tissue, and liver (1). When insulin sensitivity declines, insulin secretion must increase to maintain glucose tolerance, and, in most youth, decreased insulin sensitivity due to puberty and/or obesity is compensated by increased insulin secretion. However, when β-cells cannot secrete sufficient insulin to compensate for insulin resistance, abnormalities in glucose homeostasis ensue, potentially progressing to prediabetes and type 2 diabetes as β-cell function deteriorates further (2–9). The relationship between β-cell function and insulin sensitivity in adults and youth has been demonstrated to be a hyperbolic function and can be described mathematically as the product of insulin sensitivity and β-cell function, called the disposition index (DI) (1). The DI essentially expresses the amount of insulin being secreted relative to the degree of insulin resistance and is a constant for a given degree of glucose tolerance in any one individual. Overweight and obesity are major acquired contributors to the development of insulin resistance, particularly in the face of the physiologic insulin resistance characteristic of puberty. Robust pancreatic β-cell compensatory insulin secretion maintains normal glucose homeostasis. However, in adolescents with obesity who develop type 2 diabetes, there is severe peripheral and hepatic insulin resistance, with ∼50% lower peripheral insulin sensitivity than peers with obesity without diabetes, along with increased fasting hepatic glucose production and inadequate first- and second-phase insulin secretion, resulting …

Effects of dry period energy intake on insulin resistance, metabolic adaptation, and production responses in transition dairy cows on grass silage–based diets

High energy intake in the dry period has reportedly had adverse effects on mobilization of body reserves, dry matter intake, and productivity of dairy cows. We investigated whether grass silage (GS) fed ad libitum (high energy intake, HEI; 141% of daily metabolizable energy requirements) in an 8-wk dry period affects metabolic adaptation-specifically, peripheral insulin resistance-compared with a total mixed ration consisting of GS, wheat straw, and rapeseed meal (55/40/5%; controlled energy intake, CEI; 108% of metabolizable energy/d) fed ad libitum. Multiparous Ayrshire dairy cows (n = 16) were used in a randomized complete block design until 8 wk after parturition. Commercial concentrates were fed 1 and 2 kg/d during the last 10 to 6 and 5 to 0 d before the expected calving date, respectively. Postpartum, a similar lactation diet with ad libitum access to GS and increasing concentrate allowance (maximum of 16 kg/d) was offered to all. The HEI group gained more body weight and had higher plasma insulin, glucose, and β-hydroxybutyrate concentrations than the CEI group prepartum. Postpartal plasma glucose tended to be higher and milk yield was greater from wk 5 onward for HEI compared with CEI cows. An intravenous glucose tolerance test (IVGTT) was performed at -13 ± 5 d and 9 ± 1 d relative to calving. The HEI cows had greater insulin response to glucose load and smaller area under the response curve for glucose than CEI cows in prepartal IVGTT. Thus, compensatory insulin secretion adapted to changes in insulin sensitivity of the peripheral tissues, preserving glucose tolerance of HEI cows. Higher insulin levels were needed in HEI cows than in CEI cows to elicit a similar decrement of nonesterified fatty acid concentration in prepartal IVGTT, suggesting reduced inhibition of lipolysis by insulin in HEI cows before parturition. In conclusion, high energy intake of moderately digestible GS with low concentrate feeding in the close-up dry period did not have adverse effects on metabolic adaptation, insulin sensitivity, and body mobilization after parturition. Instead, this feeding regimen was more beneficial to early-lactation performance than GS-based total mixed ration diluted with wheat straw.

The mTORC2/PKC pathway sustains compensatory insulin secretion of pancreatic β cells in response to metabolic stress

BackgroundCompensation of the pancreatic β cell functional mass in response to metabolic stress is key to the pathogenesis of Type 2 Diabetes. The mTORC2 pathway governs fuel metabolism and β cell functional mass. It is unknown whether mTORC2 is required for regulating metabolic stress-induced β cell compensation. MethodsWe challenged four-week-old β-cell-specific Rictor (a key component of mTORC2)-knockout mice with a high fat diet (HFD) for 4weeks and measured metabolic and pancreatic morphological parameters. We performed ex vivo experiments to analyse β cell insulin secretion and electrophysiology characteristics. Adenoviral-mediated overexpression and lentiviral-ShRNA-mediated knocking down proteins were applied in Min6 cells and cultured primary mouse islets. ResultsβRicKO mice showed a significant glucose intolerance and a reduced plasma insulin level and an unchanged level β cell mass versus the control mice under HFD. A HFD or palmitate treatment enhanced both glucose-induced insulin secretion (GIIS) and the PMA (phorbol 12-myristate 13-acetate)-induced insulin secretion in the control islets but not in the βRicKO islets. The KO β cells showed similar glucose-induced Ca2+ influx but lower membrane capacitance increments versus the control cells. The enhanced mTORC2/PKC proteins levels in the control HFD group were ablated by Rictor deletion. Replenishing PKCα by overexpression of PKCα-T638D restored the defective GIIS in βRicKO islets. ConclusionsThe mTORC2/Rictor pathway modulates β cell compensatory GIIS under nutrient overload mediated by its phosphorylation of PKCα. General significanceThis study suggests that the mTORC2/PKC pathway in β cells is involved in the pathogenesis of T2D.

Sensitivity to insulin and its kinetics.

Sensitivity to insulin and its kinetics.