My Journey in Endocrinology Samuel Cataland M.D. 1968-2015
Drs Berson M.D. Yalow phd Insulin Radioimmunoassay
Nobel Prize Physiology or Medicine 1977 Rosalyn Yalow: Radioimmunoassay Technology Andrew Schally and Roger Guillemin: Hypothalamic releasing factors
Cause of Long-term Complications of Diabetes Metabolic Concept Genetic Concept Siperstein basement membrane controversy, 1968 Glucose control in 1960 s monitored by qualitative urine testing and periodic blood glucose during office visits. Tes Tape for home urine testing was a minor breakthrough requiring only a few drops of urine applied to the tape.
University Group Diabetes Program (UGDP)1961-1968 Glucose Control and Vascular Complications 12 medical centers Type 2 diabetes patients Treatment arms (all on diet): -placebo -insulin std. dose -tolbutamide -insulun var. -phenformin added 1 year later Because of excess CV deaths in tolbutamide arm it was discontinued in 1969 and phenformin the following year
Gut-Pancreas Interaction Incretin hormones: gut hormones released in response to nutrient ingestion,especially glucose which potentiates pancreatic hormones Enteroinsular axis: Concept of intestinal factors(hormone,neural nuttrients) connecting with islet cells
Incretin Concept Incretin Concept Conce;pt Lancet McIntyre et al New interpretation of oral glucose tolerance 2:20,1964
Plans for Year 2 Develop a radioimmunoassay Dr. Zollinger( gastrinoma fame) wanted a secretin RIA for diagnosing WDHA syndrome
Secretin Radioimmunoassay -Rabbits were Immunized monthly with Jorpes/Mutt purified porcine secretin extract. -In 7 months we fortunately found one rabbit with a sensitive antibody -Synthetic secretin was used for iodination and standard curves
Gastric Imhibitory Polypeptide (GIP) John Brown et al 1970 isolated a peptide(enterogastrone) from porcine gut extracts which inhibited gastric acid secretion in animals.
Enteroinsular Axis Revisited EntEnteroeroinsular
Glucose-Dependent Insulinotropic Polypeptide Studies showed GIP stimulated insulin secretion in the presence of hyperglycemia and was renamed Glucose-dependent Insulinotropic Polypeptide
JCEM Dupre J.et al 37:826,1973 JCEM
Glucose-dependent Insulinotropic polypeptide RIA Brown et al developed a RIA for GIP We at OSU also established an assay Dr Brown kindly provided us with highly purified porcine GIP for labeling and standards
Diabetologia((1986) 29:46
Crockett,Mazzaferri,Cataland Diabetes,25,1976 Crockett,Mazzaferri,
Best Practice& Research Clinical Endo.& Metab. Meier,Nauck 18(4) 587,2004
Is GIP the sole incretin?
Another incretin was identified after cloning and sequencing the proglucagon gene was designated Glucagon-like peptide-1 (GLP-1)
Creutzfeldt,W Exp Clin Endocrinol Diabetes 109(2001) Suppl 2:S288
Incretin Effect in T2DM GIP secretion normal or increased in response to nutrient ingestion The insulinotropic action of GIP is diminished GLP-1 secretion is decreased/normal in response oral nutrients Insulinotropic action of GLP-1 is preserved GLP-1 Inhibits glucagon secretion
Incretin-Based Treatment in T2DM GIP & GLP-1 undergo a rapid degradation by dipeptidyl peptidyl peptidase (DPP-4) ~7 & 2 min. T/2 respectively GIP therapy for T2DM was discouraged because of reduced insulinotropic action and enhansement in postprandial glucagon Since the insulinotropic effect of GLP-1 is preserved, DPP-4 inhibitors and GLP- 1receptor agonists were developed eg. sitagliptin and exenatide etc
The issue of chronic complications of diabetes and glucose control.
Diabetes Control Complications Trial (DCCT) T1DM 1983-1993 In T1DM patients,intensive therapy resulted in a delay in onset and progression of microvascular and neuropathic complications. Risk for eye complications reduced 76%,renal 50%, and 60% for neuropathy
United Kingdom Prospective Study in T2DM (1977-1997) Intensive blood glucose control by either sulfonylurea or Insulin, reduced microvascular complications Blood pressure control showed a delay in progression of retinopathy and nephropathy
DCCT/UKPDS Post Trial Studies Glucose control early in new onset diabetes reduces microvascular disease and probably macrovascular disease due to a metabolic memory or legacy effect. Should we strive for an earlier diagnosis like pre.diabetes?
A major advance in diabetes has been education in self-care provided by: nurse specialists,dietitians,diabetes educators and physicians