Full title: Impact of a mild decrease in fasting plasma glucose on β-cell

1 Department of Clinical & Experimental Medicine, University of Pisa, Italy 11 2 CNR Institute of Neuroscience, Padua, Italy 12 3 CNR Institute of Clinical Physiology, Pisa, Italy 13 14 15 Corresponding author: Marta Seghieri, Department of Clinical & Experimental Medicine, 16 University of Pisa, Via Roma, 67, 56122, Pisa, Italy. Tel: 050/992151; fax: 050/553235; E-mail: 17 martaseghieri@gmail.com 18 19 20 21 22 23 24 25 26 27 28 29 Articles in PresS. Am J Physiol Endocrinol Metab (April 12, 2016). doi:10.1152/ajpendo.00428.2015

[1]  J. Halter,et al.  The regulation of glucose-induced insulin secretion by Pre-stimulus glucose level and tolbutamide in normal man , 1981, Diabetologia.

[2]  M. Walker,et al.  Influence of Hyperinsulinemia and Insulin Resistance on In Vivo β-Cell Function , 2011, Diabetes.

[3]  M. Matsuda,et al.  Effect of sustained physiologic hyperinsulinaemia and hyperglycaemia on insulin secretion and insulin sensitivity in man , 1994, Diabetologia.

[4]  T. Vilsbøll,et al.  Four weeks of near-normalisation of blood glucose improves the insulin response to glucagon-like peptide-1 and glucose-dependent insulinotropic polypeptide in patients with type 2 diabetes , 2009, Diabetologia.

[5]  C. Cobelli,et al.  Insulin secretory responses to rising and falling glucose concentrations are delayed in subjects with impaired glucose tolerance , 2002, Diabetologia.

[6]  J. P. Moulin,et al.  The defective glucose sensitivity of the B cell in non insulin dependent diabetes. Improvement after twenty hours of normoglycaemia. , 1982, Metabolism: clinical and experimental.

[7]  R. Rizza,et al.  β-Cell Mass and Turnover in Humans , 2012, Diabetes Care.

[8]  J. Halter,et al.  Potentiation of insulin secretory responses by plasma glucose levels in man: evidence that hyperglycemia in diabetes compensates for imparied glucose potentiation. , 1979, The Journal of clinical endocrinology and metabolism.

[9]  J. Holst,et al.  Mechanisms for the antihyperglycemic effect of sitagliptin in patients with type 2 diabetes. , 2012, The Journal of clinical endocrinology and metabolism.

[10]  G. Boden,et al.  Effects of prolonged glucose infusion on insulin secretion, clearance, and action in normal subjects. , 1996, The American journal of physiology.

[11]  Jeppe Sturis,et al.  Estimation of Insulin Secretion Rates from C-Peptide Levels: Comparison of Individual and Standard Kinetic Parameters for C-Peptide Clearance , 1992, Diabetes.

[12]  Robert A. Rizza,et al.  β-Cell Deficit and Increased β-Cell Apoptosis in Humans With Type 2 Diabetes , 2003, Diabetes.

[13]  M. Noda,et al.  Identification of the docked granule pool responsible for the first phase of glucose-stimulated insulin secretion. , 1999, Diabetes.

[14]  P. Rorsman,et al.  Insulin granule dynamics in pancreatic beta cells , 2003, Diabetologia.

[15]  J. Rowe,et al.  Effect of experimental potassium deficiency on glucose and insulin metabolism. , 1980, Metabolism: clinical and experimental.

[16]  H. Itoh,et al.  Change in β-cell mass in Japanese nondiabetic obese individuals. , 2013, The Journal of clinical endocrinology and metabolism.

[17]  G. Sharp,et al.  Hypothesis: one rate-limiting step controls the magnitude of both phases of glucose-stimulated insulin secretion. , 2004, American journal of physiology. Cell physiology.

[18]  R. DeFronzo,et al.  Regulation of Splanchnic and Peripheral Glucose Uptake by Insulin and Hyperglycemia in Man , 1983, Diabetes.

[19]  G. Lewis,et al.  Prolonged increase of plasma non-esterified fatty acids fully abolishes the stimulatory effect of 24 hours of moderate hyperglycaemia on insulin sensitivity and pancreatic beta-cell function in obese men , 2004, Diabetologia.

[20]  E. Ferrannini,et al.  A model for glucose control of insulin secretion during 24 h of free living. , 2001, Diabetes.

[21]  J. Kerr-Conte,et al.  Dynamics of glucose-induced insulin secretion in normal human islets. , 2015, American journal of physiology. Endocrinology and metabolism.

[22]  E. Ferrannini,et al.  Relationship between insulin release, antinatriuresis and hypokalaemia after glucose ingestion in normal and hypertensive man. , 1993, Clinical science.

[23]  C. Sempoux,et al.  Pancreatic β‐cell mass in European subjects with type 2 diabetes , 2008, Diabetes, obesity & metabolism.

[24]  C. Kahn,et al.  Insulin Augmentation of Glucose-Stimulated Insulin Secretion Is Impaired in Insulin-Resistant Humans , 2012, Diabetes.

[25]  E. Ferrannini,et al.  Effect of acute hyperglycemia on insulin secretion in humans. , 2002, Diabetes.

[26]  N. Scopinaro,et al.  Biliopancreatic diversion in nonobese patients with type 2 diabetes: impact and mechanisms. , 2013, The Journal of clinical endocrinology and metabolism.

[27]  R. Hamman,et al.  The Effect of Insulin Treatment on Insulin Secretion and Insulin Action in Type II Diabetes Mellitus , 1985, Diabetes.

[28]  E. Ferrannini,et al.  β-Cell function in type 2 diabetes. , 2014, Metabolism: clinical and experimental.

[29]  Geetha Shanmugam,et al.  Stimulation of insulin release by glucose is associated with an increase in the number of docked granules in the beta-cells of rat pancreatic islets. , 2004, Diabetes.

[30]  J. Halter,et al.  Diminished B cell secretory capacity in patients with noninsulin-dependent diabetes mellitus. , 1984, The Journal of clinical investigation.