Critical Reduction in β-Cell Mass Results in Two Distinct Outcomes over Time

We have proposed that hyperglycemia-induced dedifferentiation of β-cells is a critical factor for the loss of insulin secretory function in diabetes. Here we examined the effects of the duration of hyperglycemia on gene expression in islets of partially pancreatectomized (Px) rats. Islets were isolated, and mRNA was extracted from rats 4 and 14 weeks after Px or sham Px surgery. Px rats developed different degrees of hyperglycemia; low hyperglycemia was assigned to Px rats with fed blood glucose levels less than 150 mg/dl, and high hyperglycemia was assigned above 150 mg/dl. β-Cell hypertrophy was present at both 4 and 14 weeks. At the same time points, high hyperglycemia rats showed a global alteration in gene expression with decreased mRNA for insulin, IAPP, islet-associated transcription factors (pancreatic and duodenal homeobox-1, BETA2/NeuroD, Nkx6.1, and hepatocyte nuclear factor 1α), β-cell metabolic enzymes (glucose transporter 2, glucokinase, mitochondrial glycerol phosphate dehydrogenase, and pyruvate carboxylase), and ion channels/pumps (Kir6.2, VDCCβ, and sarcoplasmic reticulum Ca2+-ATPase 3). Conversely, genes normally suppressed in β-cells, such as lactate dehydrogenase-A, hexokinase I, glucose-6-phosphatase, stress genes (heme oxygenase-1, A20, and Fas), and the transcription factor c-Myc, were markedly increased. In contrast, gene expression in low hyperglycemia rats was only minimally changed at 4 weeks but significantly changed at 14 weeks, indicating that even low levels of hyperglycemia induce β-cell dedifferentiation over time. In addition, whereas 2 weeks of correction of hyperglycemia completely reverses the changes in gene expression of Px rats at 4 weeks, the changes at 14 weeks were only partially reversed, indicating that the phenotype becomes resistant to reversal in the long term. In conclusion, chronic hyperglycemia induces a progressive loss of β-cell phenotype with decreased expression of β-cell-associated genes and increased expression of normally suppressed genes, these changes being present with even minimal levels of hyperglycemia. Thus, both the severity and duration of hyperglycemia appear to contribute to the deterioration of the β-cell phenotype found in diabetes. We have proposed that hyperglycemia-induced dedifferentiation of β-cells is a critical factor for the loss of insulin secretory function in diabetes. Here we examined the effects of the duration of hyperglycemia on gene expression in islets of partially pancreatectomized (Px) rats. Islets were isolated, and mRNA was extracted from rats 4 and 14 weeks after Px or sham Px surgery. Px rats developed different degrees of hyperglycemia; low hyperglycemia was assigned to Px rats with fed blood glucose levels less than 150 mg/dl, and high hyperglycemia was assigned above 150 mg/dl. β-Cell hypertrophy was present at both 4 and 14 weeks. At the same time points, high hyperglycemia rats showed a global alteration in gene expression with decreased mRNA for insulin, IAPP, islet-associated transcription factors (pancreatic and duodenal homeobox-1, BETA2/NeuroD, Nkx6.1, and hepatocyte nuclear factor 1α), β-cell metabolic enzymes (glucose transporter 2, glucokinase, mitochondrial glycerol phosphate dehydrogenase, and pyruvate carboxylase), and ion channels/pumps (Kir6.2, VDCCβ, and sarcoplasmic reticulum Ca2+-ATPase 3). Conversely, genes normally suppressed in β-cells, such as lactate dehydrogenase-A, hexokinase I, glucose-6-phosphatase, stress genes (heme oxygenase-1, A20, and Fas), and the transcription factor c-Myc, were markedly increased. In contrast, gene expression in low hyperglycemia rats was only minimally changed at 4 weeks but significantly changed at 14 weeks, indicating that even low levels of hyperglycemia induce β-cell dedifferentiation over time. In addition, whereas 2 weeks of correction of hyperglycemia completely reverses the changes in gene expression of Px rats at 4 weeks, the changes at 14 weeks were only partially reversed, indicating that the phenotype becomes resistant to reversal in the long term. In conclusion, chronic hyperglycemia induces a progressive loss of β-cell phenotype with decreased expression of β-cell-associated genes and increased expression of normally suppressed genes, these changes being present with even minimal levels of hyperglycemia. Thus, both the severity and duration of hyperglycemia appear to contribute to the deterioration of the β-cell phenotype found in diabetes. glucose-induced insulin secretion hepatocyte nuclear factor lactate dehydrogenase partially pancreatectomized low hyperglycemia high hyperglycemia nonesterified fatty acid(s) pancreatic and duodenal homeobox-1 glucose transporter 2 Zucker diabetic fatty TATA-binding protein Pancreatic β-cells maintain specialized pathways of metabolism that efficiently couple the secretion of insulin to circulating glucose levels (1Deeney J.T. Prentki M. Corkey B.E. Semin. Cell Dev. Biol. 2000; 11: 267-275Google Scholar, 2Newgard C.B. Matschinsky F.M. Jefferson L.S. Cherrington A.D. Handbook of Physiology, Section 7: The Endocrine System. American Physiological Society, Oxford University Press, New York2000: 125-151Google Scholar). With the increased demand of insulin resistance and obesity, an adaptation in β-cell mass and secretion can keep glucose levels within a narrow range (3Bruning J.C. Winnay J. Bonner-Weir S. Taylor S.I. Accili D. Kahn C.R. Cell. 1997; 88: 561-572Google Scholar, 4Pick A. Clark J. Kubstrup C. Levisetti M. Pugh W. Bonner-Weir S. Polonsky K.S. Diabetes. 1998; 47: 358-364Google Scholar, 5Weir G.C. Laybutt D.R. Kaneto H. Bonner-Weir S. Sharma A. Diabetes. 2001; 50 Suppl. 1: 154-159Google Scholar). The failure of β-cells to adequately adapt to increased demand is fundamental to the pathogenesis of all forms of diabetes. We have hypothesized that abnormal β-cell function in diabetes is due to the loss of the unique expression pattern of genes that optimize glucose-induced insulin secretion (GIIS)1 and insulin synthesis (5Weir G.C. Laybutt D.R. Kaneto H. Bonner-Weir S. Sharma A. Diabetes. 2001; 50 Suppl. 1: 154-159Google Scholar). The development of the endocrine pancreas and the maintenance of β-cell differentiation is regulated by a network of transcription factors, which includes pancreatic and duodenal homeobox-1 (PDX-1), BETA2/NeuroD, Nkx6.1, and hepatocyte nuclear factors (HNFs). These factors regulate transcription of the insulin gene and genes involved in β-cell glucose sensing such as GLUT2 and glucokinase (6Waeber G. Thompson N. Nicod P. Bonny C. Mol. Endocrinol. 1996; 10: 1327-1334Google Scholar, 7Ahlgren U. Jonsson J. Jonsson L. Simu K. Edlund H. Genes Dev. 1998; 12: 1763-1768Google Scholar, 8Naya F.J. Huang H.P. Qiu Y. Mutoh H. DeMayo F.J. Leiter A.B. Tsai M.J. Genes Dev. 1997; 11: 2323-2334Google Scholar, 9Sander M. German M.S. J. Mol. Med. 1997; 75: 327-340Google Scholar, 10Sander M. Sussel L. Conners J. Scheel D. Kalamaras J. Dela Cruz F. Schwitzgebel V. Hayes-Jordan A. German M. Development. 2000; 127: 5533-5540Google Scholar, 11Huang H.P. Tsai M.J. J. Biomed. Sci. 2000; 7: 27-34Google Scholar, 12Schwitzgebel V.M. Scheel D.W. Conners J.R. Kalamaras J. Lee J.E. Anderson D.J. Sussel L. Johnson J.D. German M.S. Development. 2000; 127: 3533-3542Google Scholar). Optimal β-cell function is dependent on expression of these genes and the suppression of other genes, including lactate dehydrogenase-A (LDH-A), hexokinase I, and enzymes required for gluconeogenesis, that can be predicted to interfere with optimal In we have the of the diabetic on β-cell differentiation in the (Px) of diabetes J.C. Sharma A. W. H. G. Laybutt Bonner-Weir S. G.C. J. Biol. Scholar, D.R. Kaneto H. W. S. J.C. A. C. Bonner-Weir S. Sharma A. G.C. Diabetes. Scholar, D.R. Sharma A. J. Bonner-Weir S. G.C. J. Biol. Scholar). is the but by 14 the of the pancreas to is at time We have found that at the time after is a loss of β-cell differentiation with insulin secretory and β-cell hypertrophy J.C. Sharma A. W. H. G. Laybutt Bonner-Weir S. G.C. J. Biol. Scholar, D.R. Kaneto H. W. S. J.C. A. C. Bonner-Weir S. Sharma A. G.C. Diabetes. Scholar, D.R. Sharma A. J. Bonner-Weir S. G.C. J. Biol. Scholar, S. G.C. J. Scholar, G. Bonner-Weir S. Diabetes. Scholar). have as to time a of adaptation to the diabetic or the from these phenotype and were examined at both 4 and 14 weeks rats were to Px or sham Px as J.C. Sharma A. W. H. G. Laybutt Bonner-Weir S. G.C. J. Biol. Scholar, S. Diabetes. Scholar). was by with the pancreas within of the pancreatic and from the to the of the The of the was to Px rats that different degrees of hyperglycemia J.C. Sharma A. W. H. G. Laybutt Bonner-Weir S. G.C. J. Biol. Scholar). sham the pancreatic was only of being were and blood was in from of fed rats glucose levels were with a were to blood glucose levels from weeks after low hyperglycemia was assigned to Px rats with blood glucose levels less than 150 mg/dl, and high hyperglycemia was assigned above 150 mg/dl. the effects of the duration of hyperglycemia on gene rats were at 4 and 14 weeks after and islets were with of the pancreatic or sham Islets were with a and a Islets of were for of In was to islets from Px rats with levels to an that was for were with to and were by the was extracted from islets to the and by was in a of the and of 50 of and of transcription were for at at and at were with 50 of to a to of were in a of of of of of and of of and with for gene were in a in which a by the of for of at at the in I, and at The was at were by in The of was with a and with The of was to the gene of These were to the of sham expression for Px in the same We have J.C. Sharma A. W. H. G. 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Scholar). nonesterified fatty were by a were with a glycerol as a Px rats were with for the 2 weeks of the was in and a and at a of of as Px rats. β-Cell was in of pancreas from sham and Px rats with of M. and with as G. Bonner-Weir S. Diabetes. Scholar). The of were of for were and the of these was β-cell was as the of the by the of of were the of hyperglycemia on gene expression in rats were for 4 with glucose or as N. J.C. Sharma A. Bonner-Weir S. G.C. J. 2001; Scholar, J.C. Laybutt D.R. N. M. G.C. J.C. J. Biol. 2001; Scholar). The glucose was to maintain the blood glucose at mg/dl, with At the of the islets were isolated, and was extracted for were on from rats in J.C. Laybutt D.R. N. M. G.C. J.C. J. Biol. 2001; Scholar). as were or of changes in blood glucose levels after Px in J.C. Sharma A. W. H. G. Laybutt Bonner-Weir S. G.C. J. Biol. Scholar, D.R. Kaneto H. W. S. J.C. A. C. Bonner-Weir S. Sharma A. G.C. Diabetes. Scholar, D.R. Sharma A. J. Bonner-Weir S. G.C. J. Biol. in the of pancreas in rats with different degrees of hyperglycemia after 4 blood glucose levels from to mg/dl. after 14 weeks, the range of blood glucose levels in Px rats with low or high levels of hyperglycemia Px rats were to fed blood glucose 150 and above 150 mg/dl. The time changes in and fed blood glucose in and rats in J.C. Sharma A. W. H. G. Laybutt Bonner-Weir S. G.C. J. Biol. Scholar, S. Diabetes. in Px rats was decreased the after in significantly at Px rats at the same as sham Px rats. weeks, rats significantly different from sham whereas rats the fed blood glucose levels from to in sham from to in and from to in rats. The blood glucose levels of rats were significantly increased by after and significantly with sham and rats the glucose levels of rats were different from sham at after the blood glucose levels in rats were significantly than sham changes in and fed blood glucose levels in Px rats to blood glucose levels for sham and The expression of islet-associated transcription factors, specialized β-cell metabolic and ion channels/pumps with other normally suppressed metabolic enzymes and stress genes were in islets from and rats 4 and 14 weeks after surgery. of the gene to an gene or mRNA levels in and islets were as a of sham The expression levels of transcription factors as and β-cell 2 Nkx6.1, and hepatocyte nuclear factor for pancreas and development and the maintenance of β-cell differentiation were in Px 4 weeks, the mRNA levels of BETA2/NeuroD, Nkx6.1, and were in islets from whereas in rats were by with sham 14 weeks, the mRNA levels for Nkx6.1, and were significantly in rats and were in rats Thus, expression levels in rats were at 4 weeks but significantly after 14 weeks. the of islet-associated transcription factors after Px showed an with blood glucose levels and the duration of hyperglycemia. the other is a transcription factor minimally in which is with low expression in islets J.C. Sharma A. W. H. G. Laybutt Bonner-Weir S. G.C. J. Biol. Scholar, M. M. M. K. Scholar). 4 weeks, mRNA levels were in rats but were increased in rats 14 weeks, mRNA levels were significantly increased in rats and were increased in rats with sham rats the of was with blood glucose levels and the duration of in gene mRNA levels in rats with different degrees of hyperglycemia 4 and 14 weeks after glucose factors enzymes channels/pumps genes in a and expression were after Px with a on the and duration of hyperglycemia. 4 weeks, both insulin and mRNA levels were in rats but were in rats 14 weeks, both genes were significantly in rats and were in rats by In contrast, the mRNA levels for the and the were in Px rats at both time and showed with the of β-cell-associated metabolic enzymes (glucose transporter 2 glucokinase, mitochondrial glycerol phosphate dehydrogenase, and pyruvate after Px showed a with blood glucose and the duration of hyperglycemia. 4 weeks, mRNA levels were in rats but were by in rats 14 weeks, the β-cell-associated metabolic enzymes significantly changed in rats. the mRNA levels for of genes glucokinase, mitochondrial glycerol phosphate dehydrogenase, and pyruvate were for the mRNA levels in rats were significantly with sham were in rats at 14 weeks. In contrast, metabolic enzymes normally suppressed in β-cells I, and the were markedly increased in rats at 4 and 14 weeks In hexokinase I, and were at 4 weeks. at 14 weeks, mRNA levels were significantly and hexokinase and to be The expression of ion for the of secretion were in Px rats the mRNA levels of the of the the of and sarcoplasmic reticulum Ca2+-ATPase were significantly in rats at 4 or 14 weeks. mRNA levels for of ion (Kir6.2, the of and sarcoplasmic reticulum Ca2+-ATPase for were significantly in rats at 14 weeks but at 4 weeks. In the mRNA levels of the of the and sarcoplasmic reticulum Ca2+-ATPase were to a at both 4 and 14 weeks. gene mRNA levels in β-cells than in the and other N. J. M. A. C. Mol. Med. 1: Scholar, M. S. J. S. Diabetes. 1997; Scholar). mRNA levels of the were in rats at 4 weeks but were significantly increased at 14 weeks. of both genes, and were markedly increased in islets of rats at 4 and 14 weeks. mRNA levels of the A20, were in rats but were increased in rats at 4 weeks. At 14 weeks, expression was increased to a in and rats. expression of the was was in but increased in rats at 4 weeks and increased to levels in and rats at 14 weeks. in insulin, and levels 4 and 14 weeks after in At both time points, insulin levels to be decreased in Px rats but were only significantly in rats. and levels were at 4 weeks of the of hyperglycemia. At 14 weeks, and levels were in rats but increased in rats. We the of the changes in mRNA levels by an of glucose in the the in the of the and the of circulating glucose We showed J.C. Sharma A. W. H. G. Laybutt Bonner-Weir S. G.C. J. Biol. Scholar, D.R. Kaneto H. W. S. J.C. A. C. Bonner-Weir S. Sharma A. G.C. Diabetes. Scholar, D.R. Sharma A. J. Bonner-Weir S. G.C. J. Biol. that expression levels of transcription factors, metabolic ion and stress genes were completely in Px rats after with we the gene expression in Px rats be with glucose levels in Px rats were completely of the transcription factors, and Nkx6.1, to be with of Px rats J.C. Sharma A. W. H. G. Laybutt Bonner-Weir S. G.C. J. Biol. were only partially at 14 weeks, significantly with sham levels insulin and GLUT2 expression were partially after GLUT2 mRNA levels were significantly decreased in Px rats with The expression of c-Myc, and in Px rats to be partially after and mRNA levels were significantly increased in Px rats with In all in the on gene expression in rats. were for the other genes in of changes in gene expression after mRNA levels were by in of sham sham Px and Px rats after 14 weeks. of the gene to an gene or mRNA levels were as a of sham for We found hypertrophy of β-cells in Px rats J.C. Sharma A. W. H. G. Laybutt Bonner-Weir S. G.C. J. Biol. Scholar, G. Bonner-Weir S. Diabetes. Scholar). Here we these and the β-cell 14 weeks after sham or Px β-cell was increased by in Px rats. Thus, β-cell was increased at 4 and 14 weeks after is that of the Px rats of the all of with being but a fed blood glucose of only of chronic hyperglycemia on β-cell 4 and 14 weeks after blood in a The of hyperglycemia on gene expression was glucose expression levels after glucose glucose at to rats in In to the effects of long hyperglycemia in Px rats hyperglycemia by glucose in gene expression mRNA levels were after glucose and and mRNA were mRNA levels were after glucose whereas mRNA levels were increased with in rats N. J.C. Sharma A. Bonner-Weir S. G.C. J. 2001; Scholar). mRNA levels were after glucose whereas mRNA was due the in β-cells, to a in the of expression of β-cell metabolic ion channels/pumps and stress genes were in expression was found for and We found increased expression after glucose J.C. Laybutt D.R. N. M. G.C. J.C. J. Biol. 2001; Scholar). as a to the the effects of hyperglycemia in the after glucose and the long after insulin levels were glucose J.C. Laybutt D.R. N. M. G.C. J.C. J. Biol. 2001; whereas to be after of glucose on gene factors genes glucose was to maintain the blood glucose at mg/dl, with in a The glucose was to maintain the blood glucose at mg/dl, with In we have the of the diabetic on β-cell differentiation in the Px of diabetes J.C. Sharma A. W. H. G. Laybutt Bonner-Weir S. G.C. J. Biol. Scholar, D.R. Kaneto H. W. S. J.C. A. C. Bonner-Weir S. Sharma A. G.C. Diabetes. Scholar, D.R. Sharma A. J. Bonner-Weir S. G.C. J. Biol. Scholar). Here we that the changes in β-cell gene expression in Px rats with both the severity and duration of hyperglycemia with the of normally suppressed genes and decreased expression of genes that optimize β-cell The global of gene expression over resistant to reversal and even with minimal the critical of hyperglycemia in the loss of β-cell chronic hyperglycemia and β-cell dedifferentiation a for the β-cell found in diabetes. is of that critical of β-cell mass in after 14 weeks. We a with islets that an of islets or diabetic with being K. Bonner-Weir S. N. J. G.C. 1998; Scholar). In the present Px a in the of pancreas have for the rats a range of blood glucose levels from low to and high over blood glucose levels rats maintain glucose levels that be with the of glucose in The other rats with rats glucose levels in the range glucose levels to high by the of at the β-cell and by and on insulin to insulin with 2 diabetes present with hyperglycemia and with diabetes can hyperglycemia and the stress the and rats different of diabetes We the for a of the same changes in gene expression as which to with hyperglycemia. is that the less phenotype be and long be to and J.C. Sharma A. W. H. G. Laybutt Bonner-Weir S. G.C. J. Biol. Scholar, D.R. Kaneto H. W. S. J.C. A. C. Bonner-Weir S. Sharma A. G.C. Diabetes. Scholar, D.R. Sharma A. J. Bonner-Weir S. G.C. J. Biol. Scholar, Y. J. J. M. J. Polonsky K.S. Diabetes. that β-cell to the diabetic is with a global in β-cell gene expression than with gene as with diabetes of the and mitochondrial diabetes. Thus, the of β-cells decreased expression of a of genes for insulin secretion and the of β-cell gene Genes that in β-cells such as insulin, glucokinase, mitochondrial glycerol phosphate dehydrogenase, pyruvate and and islet-associated transcription factors a in mRNA levels in Px rats. the other of normally suppressed genes hexokinase I, glucose-6-phosphatase, stress genes, and the transcription to be an of the in β-cell phenotype with diabetes. in of diabetes by such as the Zucker diabetic fatty to diabetes is with a global alteration in β-cell gene expression Y. J. J. M. J. Polonsky K.S. Diabetes. Scholar). The loss of in only 2 and diabetes but in J.D. J. Endocrinol. Scholar, S. Diabetes. Scholar, Bonner-Weir S. G.C. Scholar, P. L. C. D. Scholar, Y. Y. Bonner-Weir S. G.C. Diabetes. Scholar). Islets from Px rats a in S. G.C. J. Scholar, Bonner-Weir S. G.C. Scholar). The of islet-associated transcription factors BETA2/NeuroD, and after Px contribute to the expression of genes for of the transcription factors were completely in Px but the of in the of β-cell gene expression G. S. A. Edlund H. D.J. D. N. Diabetes. 2001; Scholar, M. M. M. D.W. J. Biol. Scholar). of can induce insulin gene expression in which can glucose in diabetic S. A. H. Y. J. N. A. Med. 2000; Scholar). In Px the of these and other transcription factors the decreased expression of metabolic enzymes glucokinase, mitochondrial glycerol phosphate dehydrogenase, and pyruvate The expression of these genes the of glucose to and the of metabolic such as that to an insulin secretory to an glucose C.B. Matschinsky F.M. Jefferson L.S. Cherrington A.D. Handbook of Physiology, Section 7: The Endocrine System. American Physiological Society, Oxford University Press, New York2000: 125-151Google Scholar, 5Weir G.C. Laybutt D.R. Kaneto H. Bonner-Weir S. Sharma A. Diabetes. 2001; 50 Suppl. 1: 154-159Google Scholar). decreased expression with of normally suppressed metabolic genes be to interfere with unique and glucose In the increased expression of genes such as and metabolic pathways to β-cell metabolism and the of and the of to for and C. Diabetes. 2000; Scholar, M. S. J. 2000; Scholar). glucose is efficiently by and mitochondrial with to lactate N. V. J. M. S. M.J. C.B. J. Biol. Scholar, A. S. K. D. Prentki M. J. Biol. 1997; Scholar). can be a to increased demand in of β-cells found in Px rats J.C. Sharma A. W. H. G. Laybutt Bonner-Weir S. G.C. J. Biol. Scholar, G. Bonner-Weir S. Diabetes. rats with glucose A. Clark J. Kubstrup C. Levisetti M. Pugh W. Bonner-Weir S. Polonsky K.S. Diabetes. 1998; 47: 358-364Google and in L. Bonner-Weir S. Scholar). The of be in the of β-cells, factor can to hypertrophy in the of M. M.S. A. A. D. F. Biol. Scholar). The development of β-cell hypertrophy is to be dependent the of such as factors that and D.R. Kaneto H. W. S. J.C. A. C. Bonner-Weir S. Sharma A. G.C. Diabetes. Scholar, D.R. G.C. Kaneto H. J. Sharma A. Bonner-Weir S. Diabetes. Scholar, S. M. Cell. Scholar). β-Cell hypertrophy was 14 weeks after Px and to the in of the endocrine pancreas that in the after S. Diabetes. Scholar). the that β-cell hypertrophy a to the diabetic metabolic hyperglycemia as a of β-cell (5Weir G.C. Laybutt D.R. Kaneto H. Bonner-Weir S. Sharma A. Diabetes. 2001; 50 Suppl. 1: 154-159Google Scholar, Bonner-Weir S. G.C. Scholar, Y. Y. Bonner-Weir S. G.C. Diabetes. Scholar). In with that the glucose to in insulin secretion K. Y. Scholar, J. Diabetes. Scholar). that the severity of hyperglycemia a critical in the progressive loss of β-cell differentiation with diabetes. were in Px rats at 4 weeks or in rats at 14 weeks, that the changes in β-cell gene expression in the Px have that fatty can to in β-cell gene expression S. Bonny C. G. J. Biol. 1997; Scholar, J.D. J. 1998; Scholar, M. M. Sci. U. S. A. 1998; Scholar, H. Y. Y. F. H. 2001; and the changes in rats have with circulating fatty M. M. Sci. U. S. A. 1998; Scholar, Y. H. M. Johnson J.D. Sci. U. S. A. Scholar). a in rats found and to be with the decreased insulin gene expression in of diabetes Y. V. Diabetes. 2001; Scholar). β-cell in Px and rats be by chronic hyperglycemia. These an for pathways in the β-cell of diabetes. changes be by the effects of high glucose in with fatty by levels of circulating fatty The duration of to hyperglycemia a critical factor in the deterioration of the β-cell phenotype as by the hyperglycemia by glucose in β-cell gene expression whereas long hyperglycemia after Px global changes in β-cell gene expression were with of Px rats at 4 weeks J.C. Sharma A. W. H. G. Laybutt Bonner-Weir S. G.C. J. Biol. Scholar, D.R. Kaneto H. W. S. J.C. A. C. Bonner-Weir S. Sharma A. G.C. Diabetes. Scholar, D.R. Sharma A. J. Bonner-Weir S. G.C. J. Biol. but at 14 weeks and low levels of hyperglycemia in Px rats changes in gene expression after 14 weeks but at 4 weeks These a the duration of hyperglycemia and the deterioration of the β-cell phenotype with diabetes. is that at 4 and 14 weeks, rats with such minimal hyperglycemia have such in β-cell The β-cell hypertrophy of time is β-cell mass was These the of β-cells with markedly phenotype to maintain insulin to keep glucose levels in the range for long of time. be β-cells can adapt to deterioration to diabetes. is that the β-cell changes in of with the of glucose a of hyperglycemia that can for deterioration to the of 2 diabetes. In conclusion, the of with that a critical loss of β-cell differentiation to the β-cell found in diabetes (5Weir G.C. Laybutt D.R. Kaneto H. Bonner-Weir S. Sharma A. Diabetes. 2001; 50 Suppl. 1: 154-159Google Scholar). a loss in β-cell insulin can be to keep glucose levels in a to We the for the insulin and we the