Pancreatic β-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 functionalβ-cells.Impaired insulin secreation,due in part to the reduction of pancreaticβ-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 ofβ-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 normalβ-cell function remains at the onset of diabetes,suggesting thatβ-cell defect precedes the onset of hyperglycemia by some time.The purpose of the study was to determine whether impairedβ-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 onβ-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 ofβ-Arrestin2 inβ-Cell Expansion under Metabolic StressObjective:β-Arrestin2（βarr2）,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 thatβarr2 was abundantly expressed in mouse pancreaticβ-cells,and its expression was significantly decreased in obese and diabetic mouse models.Loss ofβarr2 led to a defect in acute and late phase insulin secretion and decrease in the number of docked insulin granules inβ-cells.In the present study,we aimed to in vivo explore the dynamic changes ofβ-cell mass inβarr2deficiency mice and its underlying mechanisms.Methods:MIP-TF mice,a mice with luciferase transgene,were interbred withβarr2^-/-mice,which made the expression of luciferase exclusively inβ-cells ofβarr2^-/-mice.Obese mice models with increased insulin resistance were generated by feeding the mice with a high fat diet（HFD）.β-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 ofβarr2 in mice resulted in impaired glucose metabolism under HFD.In wildtype mice,HFD induced a pronounced adaptive increase ofβ-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 ofβarr2 led to a decompensation ofβ-cell mass since 12 weeks old with only half of the peak value in their wildtype controls.Moreover,knocking out ofβarr2 decreased the BrdU-and Ki67-positive cell counts in islets,with only 40%or 53%of the positive rate in their wildtype littermates.Exposure ofβarr2^-/-islets to high levels of glucose and free fat acid（FFA）exacerbated cell death.Conversely,overexpression ofβarr2 protectedβ-cells against high levels of glucose-and FFA-induced cell death and elevated mRNA expression of cyclin D2 by 2.5 fold.Conclusion:βarr2 plays an important role in the regulation ofβ-cell mass under metabolic stress through protection ofβ-cell against glucolipotoxicity induced cell-death,and modulation ofβ-cell proliferation by regulation cell cycle gene transcription.Loss ofβarr2 leads to earlier and severer decompensation in beta-cell mass under metabolic stress.