Diabetes in Chronic Pancreatitis: When is it type 3c? Melena Bellin, MD Associate Professor, Pediatrics & Surgery Schulze Diabetes Institute

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1 Diabetes in Chronic Pancreatitis: When is it type 3c? Melena Bellin, MD Associate Professor, Pediatrics & Surgery Schulze Diabetes Institute

2 Disclosure Information Melena D. Bellin Disclosure of Relevant Financial Relationships (3 yrs) I have the following financial relationships to disclose: Consultant for: NovoNordisk, AbbVie Grant/Research support from: Merck, Medtronic, Dompe, Viacyte Disclosure of Off-Label and/or investigative Uses I will not discuss off label use and/or investigational use in my presentation.

3 Content Prevalence and pathophysiology of pancreatogenous (T3c) diabetes Overlap of T3c and T2DM Distinguishing T3c from T2 and T1DM

4 Distribution of Type 3c DM

5 Diabetes Related to Benign Pancreatic Disease Acute pancreatitis? Recurrent acute pancreatitis? Cystic Fibrosis Chronic pancreatitis

6 Prevalence Diabetes is common in chronic pancreatitis 26-76% diabetes or impaired glucose tolerance Depends on: Study population Disease etiology Duration of disease Wang et al, Pancreas 2011; 40: 206 Rebours et al, Gut 2009; 58:97 Howes et al, Clin Gastro Hepatol 2004; 2:252 Larsen S, Lægeforeningens Forlag, 1992

7 Pathophysiology: Insulin Deficiency Reduced beta cell mass in diabetic CP Fibrosis-> islet injury Reduced C-peptide/ insulin secretion Correlation between exocrine insufficiency & endocrine insufficiency ( C-peptide) Andersen et al, Diabetologia 1982; 23:86 Domshcke et al, Hepatogastroenterol 1985; 32:27 Schrader et al, Diabetologia 2010; 53:1062 Kobayashi et al, Pancreas 2011; 40:193

8 Pathophysiology: β cell Dysfunction Intrapancreatic cytokines are increased in CP with or without diabetes INF-γ is highly increased in CP w/dm > CP w/odm Reduces glucose stimulated insulin secretion in vitro

9 Pathophysiology: insulin sensitivity, incretin hormones, & glucagon Possible insulin sensitivity Hepatic insulin resistance Peripheral insulin sensitivity M on euglycemic clamp vs T1DM Nl or insulin resistant in other studies Abnormal glucagon suppression on OGTT? Incretin hormones Nl,, or GIP Improved GIP and GLP with pancreatic enzyme replacement

10 Progressive deficits precede IVGTT onset of diabetes

11 Progressive deficits precede IVGTT onset of diabetes MMTT

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13 Type 3c vs Types 1 or 2 DM

14 Type 2 Diabetes is Common! ~9% of the U.S. population has T2DM Crude and Age-Adjusted Rates of Diagnosed Diabetes per 100 Civilians Chronic pancreatitis and type 2 DM are not mutually exclusive

15 Traditional T2DM Risk Factors Increase Risk for DM in CP Double hit hypothesis Obesity OR 2.48 FamHx+ OR 1.48

16 Where are the challenges in diagnosis? In the patient with known chronic pancreatitis, distinguishing type 3c from type 1 or type 2 DM In the patient with chronic abdominal pain but no pancreatitis diagnosis, recognizing possible type 3c DM

17 Barriers to correct classification Unfamiliarity with T3cDM (endocrine/ primary medicine) Lack of adequate ICD-coding Overlap of exocrine insufficiency in T1 and T2DM & pancreatic atrophy in T1 Lack of definitive diagnostic testing

18 Distinguishing Type 3c from Type 2 DM Insulin/C-peptide (stimulated) PP in type 3c/ in type 2 in type 3c/ in type 2 Challenges/Gaps: No direct comparison Overlap syndrome, double DM Lacks validation, cut off Clinical availability limited Belinova et al, PLOS One, 4/17

19 Distinguishing Type 3c from Type 1 DM? Islet antibodies suggest T1D GAD, IA-2, insulin Ab, ZnT8, ICA GAD+ observed at low levels in non-t1 May wane with long duration of DM Absolute insulin deficiency (C-peptide undetectable) Clinical onset with DKA

20 It s all diabetes: Why does it matter? Affects treatment selection Insulin and/or metformin usual treatments for Type 3c DM (insulin late stage) Other oral agents/ insulin sensitizers- T2D Use/avoidance of GLP1 Affects prognosis Rapid progression to insulin deficiency in T1D Appropriate dx and management of pancreatitis

21 Conclusions Type 3c DM characterized by insulin deficiency, beta cell dysfunction, and possible hepatic insulin resistance Risk factors for T2DM may increase risk of DM in CP Determining T2DM from T3c may depend on insulin and PP response to meal, but validation is needed Determining T1 from T3cDM relies on antibodies (early), C-peptide (late)

22 Acknowledgements