Insulin secretion in type 1 diabetes.

Type 1 diabetes, a chronic autoimmune disease, causes destruction of insulin-producing beta-cells over a period of years. Although many markers of the autoimmune process have been described, none can convincingly predict the rate of disease progression. Moreover, there is relatively little information about changes in insulin secretion in individuals with type 1 diabetes over time. Previous studies document C-peptide at a limited number of time points, often after a nonphysiologic stimulus, and under non-steady-state conditions. Such methods do not provide qualitative information and may not reflect physiologic responses. We have studied qualitative and quantitative insulin secretion to a 4-h mixed meal in 41 patients with newly diagnosed type 1 diabetes and followed the course of this response for 24 months in 20 patients. Newly diagnosed diabetic patients had an average total insulin secretion in response to a mixed meal that was 52% of that in nondiabetic control subjects, considerably higher than has been described previously. In diabetic patients there was a decline of beta-cell function at an average rate of 756 +/- 132 pmol/month to a final value of 28 +/- 8.4% of initial levels after 2 years. There was a significant correlation between the total insulin secretory response and control of glucose, measured by HbA(1c) (P = 0.003). Two persistent patterns of insulin response were seen depending on the peak insulin response following the oral meal. Patients with an early insulin response (i.e., within the first 45 min after ingestion) to a mixed meal, which was also seen in 37 of 38 nondiabetic control subjects, had a significantly accelerated loss of insulin secretion, as compared with those in whom the insulin response occurred after this time (P < 0.05), and significantly greater insulin secretory responses at 18 and 24 months (P < 0.02). These results, which are the first qualitative studies of insulin secretion in type 1 diabetes, indicate that the physiologic metabolic response is greater at diagnosis than has previously been appreciated, and that the qualitative insulin secretory response is an important determinant of the rate of metabolic decompensation from autoimmune destruction.

[1]  W. Gepts.  Pathologic Anatomy of the Pancreas in Juvenile Diabetes Mellitus , 1965, Diabetes.

[2]  G. Grodsky,et al.  A threshold distribution hypothesis for packet storage of insulin and its mathematical modeling. , 1972, The Journal of clinical investigation.

[3]  H. Kuzuya,et al.  Characterization of Seven C-peptide Antisera , 1978, Diabetes.

[4]  K. M. Erickson,et al.  Prehepatic insulin production in man: kinetic analysis using peripheral connecting peptide behavior. , 1980, The Journal of clinical endocrinology and metabolism.

[5]  L. Regeur,et al.  Insulin secretory reserve in insulin dependent patients at time of diagnosis and the first 180 days of insulin treatment. , 1980, Acta endocrinologica.

[6]  J. McNally,et al.  EVIDENCE FOR A LONG PREDIABETIC PERIOD IN TYPE I (INSULIN-DEPENDENT) DIABETES MELLITUS , 1981, The Lancet.

[7]  Bruce H. Frank,et al.  Use of biosynthetic human C-peptide in the measurement of insulin secretion rates in normal volunteers and type I diabetic patients. , 1986, The Journal of clinical investigation.

[8]  K. Polonsky,et al.  The Limitations to and Valid Use of C-Peptide as a Marker of the Secretion of Insulin , 1986, Diabetes.

[9]  M. Sharf,et al.  Fetal obstructive uropathy [corrected]. , 1988, Lancet.

[10]  K. Polonsky,et al.  Abnormal patterns of insulin secretion in non-insulin-dependent diabetes mellitus. , 1988, The New England journal of medicine.

[11]  Relationship of Insulin Autoantibodies to Presentation and Early Course of IDDM in Children , 1989, Diabetes Care.

[12]  O. Snorgaard,et al.  Homogeneity in Pattern of Decline of β-Cell Function in IDDM: Prospective study of 204 consecutive cases followed for 7.4 yr , 1992, Diabetes Care.

[13]  A. Schiffrin,et al.  Factors Predicting Course of β-cell Function in IDDM , 1992, Diabetes Care.

[14]  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.

[15]  A. Ziegler,et al.  Natural Course of Remission in IDDM During 1st yr After Diagnosis , 1992, Diabetes Care.

[16]  I. Hramiak,et al.  Determinants of Clinical Remission in Recent-Onset IDDM , 1993, Diabetes Care.

[17]  S. Genuth,et al.  The effect of intensive treatment of diabetes on the development and progression of long-term complications in insulin-dependent diabetes mellitus. , 1993, The New England journal of medicine.

[18]  C. Fathman,et al.  β-Cell Destruction May Be a Late Consequence of the Autoimmune Process in Nonobese Diabetic Mice , 1996, Diabetes.

[19]  R. Bretzel,et al.  Persistent GAD 65 antibodies in longstanding IDDM are not associated with residual beta-cell function, neuropathy or HLA-DR status. , 1997, Hormone and metabolic research = Hormon- und Stoffwechselforschung = Hormones et metabolisme.

[20]  Intensive Therapy Preserves Insulin Secretion , 1998, Annals of Internal Medicine.

[21]  E. Bognetti,et al.  Residual beta-cell function and spontaneous clinical remission in type 1 diabetes mellitus: the role of puberty , 1998, Acta Diabetologica.

[22]  E. Bonifacio,et al.  Parameters associated with residual insulin secretion during the first year of disease in children and adolescents with Type 1 diabetes mellitus , 1998, Diabetic medicine : a journal of the British Diabetic Association.

[23]  K. Polonsky,et al.  Increased beta-cell proliferation and reduced mass before diabetes onset in the nonobese diabetic mouse. , 1999, Diabetes.

[24]  Diabetes-associated autoantibodies in relation to clinical characteristics and natural course in children with newly diagnosed type 1 diabetes. The Childhood Diabetes In Finland Study Group. , 1999, The Journal of clinical endocrinology and metabolism.

[25]  C. Mathieu,et al.  Use of an islet cell antibody assay to identify type 1 diabetic patients with rapid decrease in C-peptide levels after clinical onset. Belgian Diabetes Registry. , 2000, Diabetes care.

[26]  Erik Renström,et al.  The Cell Physiology of Biphasic Insulin Secretion. , 2000, News in physiological sciences : an international journal of physiology produced jointly by the International Union of Physiological Sciences and the American Physiological Society.

[27]  Å. Lernmark,et al.  Prognostic Factors for the Course of β Cell Function in Autoimmune Diabetes , 2000 .

[28]  W. Hagopian,et al.  A novel high-throughput method for accurate, rapid, and economical measurement of multiple type 1 diabetes autoantibodies. , 2000, Journal of immunological methods.

[29]  W. Tamborlane,et al.  Augmentation of Alimentary Insulin Secretion despite Similar Gastric Inhibitory Peptide (GIP) Responses in Juvenile Obesity , 2000, Pediatric Research.

[30]  M. Landin-Olsson.  Latent Autoimmune Diabetes in Adults , 2002, Annals of the New York Academy of Sciences.

[31]  K. Lalić,et al.  Relation between Course of Disease in Type 1 Diabetes and Islet Cell Antibodies , 2002, Annals of the New York Academy of Sciences.

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

[33]  D. Harlan,et al.  Anti-CD3 monoclonal antibody in new-onset type 1 diabetes mellitus. , 2002, The New England journal of medicine.

[34]  Y. Altuntas.  A mathematical model for pattern of change in β-cell reserve and factors affecting residual reserve within the first 2 years of Type 1 diabetes , 2002, Journal of endocrinological investigation.

[35]  M. Steffes,et al.  Beta-cell function and the development of diabetes-related complications in the diabetes control and complications trial. , 2003, Diabetes care.

[36]  J. Bluestone,et al.  Activation of human T cells by FcR nonbinding anti-CD3 mAb, hOKT3γ1(Ala-Ala) , 2003 .

[37]  Å. Lernmark,et al.  Factors influencing the magnitude, duration, and rate of fall of B-cell function in Type 1 (insulin-dependent) diabetic children followed for two years from their clinical diagnosis , 1988, Diabetologia.

[38]  L. Regeur,et al.  Effect of strict blood glucose control on residual B-cell function in insulin-dependent diabetics , 1981, Diabetologia.

[39]  S. Grundy,et al.  Hyperglycaemia as an inducer as well as a consequence of impaired islet cell function and insulin resistance: implications for the management of diabetes , 1985, Diabetologia.

[40]  O. Faber,et al.  B-cell function and blood glucose control in insulin dependent diabetics within the first month of insulin treatment , 1977, Diabetologia.