Pancreatic ?-cell Function,Mass And Type 2 Diabetes

Regulation of blood glucose and lipid metabolism requires an adequate amount of insulin released by the availability of sufficient number of functional?-cells.Impaired insulin secreation,due in part to the reduction of pancreatic?-cell mass,makes up one of the major underlying mechanisms of Type 2 diabetes.Thus,identification of Type 2 diabetes high-risk subjects with impaired insulin secretion and revealing of?-cell-protective molecules are of great importance to the early interventions and target therapy of diabetes.Two parts are included in the present study.Part I:Association of 2hr-Post OGTT Glucose Levels,Insulin Secretion and Development of Type 2 DiabetesObjective:Impaired insulin secretion is one of the mechanisms leading to Type 2diabetes.It is estimated by United Kingdom Prospective Diabetes Study?UKPDS?that only 50%of normal?-cell function remains at the onset of diabetes,suggesting that?-cell defect precedes the onset of hyperglycemia by some time.The purpose of the study was to determine whether impaired?-cell function exist in Chinese NGT individuals with high-normal 2hr glucose,and these individuals are predisposed to diabetes later in life.Methods:Two sets of population?age 20-80?were included in our study.The cross-sectional study included 1405 subjects,with 843 NGT subjects and 562 isolated impaired glucose tolerance?IGT?patients.The longitudinal study included 1724 NGT subjects.Oral glucose tolerance test?OGTT?was performed to determine the glucose tolerance state of the subjects.NGT subjects were sub-divided into two groups according to group upper quatile:NGT-l?2hPG<125 mg/dl?and NGT-h?2hPG 125–140 mg/dl?.Normal weight subjects were individuals with BMI<25 kg/m²,and overweight were with BMI?25kg/m².1st-and 2nd-phase insulin secretion was assessed using Stumvoll formulas.Considering their dramatic impact on?-cell function,insulin resistance were adjusted and disposition indice were used to assess the insulin secretion related to insulin resistance.Results:In the cross-sectional study,201 out of 843 NGT subjects were included in the NGT-h group,who showed a similar insulin secretion level of both 1st-and 2nd-phase with NGT-l subjects.In normal weight stratum,the relative 1st-and 2nd-phase insulin secretion indices were significantly higher in NGT-h subjects compared with IGT patients,though they were still lower than those in NGT-l subjects.However,in overweight stratum,the relative 1st-phase insulin secretion index in NGT-h subjects was similar to that in IGT patients,and significantly lower than that in NGT-l subjects.The relative 2nd-phase insulin secretion was comparable between NGT-h and NGT-l subjects.The results indicating that impaired 1st-phase insulin secretion related to insulin resistance could exist in overweight NGT-h subjects.After an average follow-up of 43.80±11.25 months,totally 25?1.5%?NGT subjects at baseline developed diabetes.The incidence rate of diabetes was higher in NGT-h overweight subjects?9.2%?than in NGT-l overweight subjects?1.5%?with a risk ratio?RR?reaching 6.655?95%CI 2.347-18.867?.This risk remained after adjustment for sex,age,BMI,systolic pressure and diastolic pressure?RR8.315,95%CI 2.649-26.108?.Conclusion:Overweight NGT adults with high-normal 2hPG??125 mg/dl?had a defect in relative 1st-phase insulin secretion similar to IGT patients and were with increasing risk for developing new diabetes.Part II:Role and Mechanism of?-Arrestin2 in?-Cell Expansion under Metabolic StressObjective:?-Arrestin2??arr2?,an adopter protein,is ubiquitously expressed in cells and modulates G-protein-coupled receptors desensitization and internalization.It also functions as a scaffold which recruits numerous signaling molecules and involved in the regulation of cell biological functions.We reported previously that?arr2 was abundantly expressed in mouse pancreatic?-cells,and its expression was significantly decreased in obese and diabetic mouse models.Loss of?arr2 led to a defect in acute and late phase insulin secretion and decrease in the number of docked insulin granules in?-cells.In the present study,we aimed to in vivo explore the dynamic changes of?-cell mass in?arr2deficiency mice and its underlying mechanisms.Methods:MIP-TF mice,a mice with luciferase transgene,were interbred with?arr2^-/-mice,which made the expression of luciferase exclusively in?-cells of?arr2^-/-mice.Obese mice models with increased insulin resistance were generated by feeding the mice with a high fat diet?HFD?.?-Cell mass was determined either by in vivo noninvasive bioluminescence imaging technique from 4 to 20 weeks,or by morphometric analysis.BrdU-and Ki67-staining was performed to examine cell proliferation.PI/HO staining was used to evaluate cell death.RT-PCR was conducted to analyse gene expression.Results:Loss of?arr2 in mice resulted in impaired glucose metabolism under HFD.In wildtype mice,HFD induced a pronounced adaptive increase of?-cell mass represented by bioluminescence intensity which reached the plateau at 16-week with 7.5-fold higher than that before feeding the HFD.However,knocking out of?arr2 led to a decompensation of?-cell mass since 12 weeks old with only half of the peak value in their wildtype controls.Moreover,knocking out of?arr2 decreased the BrdU-and Ki67-positive cell counts in islets,with only 40%or 53%of the positive rate in their wildtype littermates.Exposure of?arr2^-/-islets to high levels of glucose and free fat acid?FFA?exacerbated cell death.Conversely,overexpression of?arr2 protected?-cells against high levels of glucose-and FFA-induced cell death and elevated mRNA expression of cyclin D2 by 2.5 fold.Conclusion:?arr2 plays an important role in the regulation of?-cell mass under metabolic stress through protection of?-cell against glucolipotoxicity induced cell-death,and modulation of?-cell proliferation by regulation cell cycle gene transcription.Loss of?arr2 leads to earlier and severer decompensation in beta-cell mass under metabolic stress.