My Journey in Endocrinology. Samuel Cataland M.D

Transcription

1 My Journey in Endocrinology Samuel Cataland M.D

2 Drs Berson M.D. Yalow phd Insulin Radioimmunoassay

3 Nobel Prize Physiology or Medicine 1977 Rosalyn Yalow: Radioimmunoassay Technology Andrew Schally and Roger Guillemin: Hypothalamic releasing factors

4 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.

5 University Group Diabetes Program (UGDP) 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

6 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

7 Incretin Concept Incretin Concept Conce;pt Lancet McIntyre et al New interpretation of oral glucose tolerance 2:20,1964

8 Plans for Year 2 Develop a radioimmunoassay Dr. Zollinger( gastrinoma fame) wanted a secretin RIA for diagnosing WDHA syndrome

9 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

10 Gastric Imhibitory Polypeptide (GIP) John Brown et al 1970 isolated a peptide(enterogastrone) from porcine gut extracts which inhibited gastric acid secretion in animals.

11 Enteroinsular Axis Revisited EntEnteroeroinsular

12 Glucose-Dependent Insulinotropic Polypeptide Studies showed GIP stimulated insulin secretion in the presence of hyperglycemia and was renamed Glucose-dependent Insulinotropic Polypeptide

13 JCEM Dupre J.et al 37:826,1973 JCEM

14 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

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16 Diabetologia((1986) 29:46

17 Crockett,Mazzaferri,Cataland Diabetes,25,1976 Crockett,Mazzaferri,

18 Best Practice& Research Clinical Endo.& Metab. Meier,Nauck 18(4) 587,2004

19 Is GIP the sole incretin?

20 Another incretin was identified after cloning and sequencing the proglucagon gene was designated Glucagon-like peptide-1 (GLP-1)

21 Creutzfeldt,W Exp Clin Endocrinol Diabetes 109(2001) Suppl 2:S288

22 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

23 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

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25 The issue of chronic complications of diabetes and glucose control.

26 Diabetes Control Complications Trial (DCCT) T1DM 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

27 United Kingdom Prospective Study in T2DM ( ) Intensive blood glucose control by either sulfonylurea or Insulin, reduced microvascular complications Blood pressure control showed a delay in progression of retinopathy and nephropathy

28 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?

29 A major advance in diabetes has been education in self-care provided by: nurse specialists,dietitians,diabetes educators and physicians