Case- history. Lab results

Transcription

1 Neda Rasouli, M.D. Associate Professor of Medicine Division of Endocrinology, UC Denver VA_ Eastern Colorado Health Care System Case- history 46 y/o AA male with BMI 37 presented in Oct 2001 with polyuria, polydipsia and blurry vision for 2-4 weeks. Weight loss of 10 lbs/ over one month. PMH: hypothyroidism after I131 Tx. Dyslipidemia Slightly elevated in liver enzyme FH: (strong FH of diabetes) Mother with T2DM age 60 with CRF Older brother with T2DM age 49 y/o with CRF on insulin Two maternal aunts with DM Cousin with DM age 46, now on insulin Lab results Glucose 655 Bicarb 27 NA 134 K 4.7 AG 16 Serum Acetone + U/A neg for infection Cardiac enzymes nl A1c 13.7% GAD Ab <1

2 Hospitalization course Pt was treated with insulin drip during hospitalization and was sent home on insulin N + R (total daily dose of 60 units). Pt developed hypoglycemia 3 weeks after discharge from hospital and present to ED with BG of 30 s. Insulin was stopped and he was sent home on low dose metformin. Near Normoglycemic Remission in less than a month after crisis Fact or Fiction? Continuous Glucose Monitoring indicative of near normoglycemic remission

3 Near nomoglycemic remission Weight : lbs Questions 1. What type of diabetes this patient has? 2. What is the risk for the recurrence of hyperglycemic crisis? 3. What are the predictive factors for near normoglycemic remission? 4. What are the underlying mechanisms for the transient insulin deficiency? Q 1: What type of diabetes this patient has? Obese AA male hyperglycemic crisis, Unprovoked ketosis Near nomoglycemic remission features of metabolic syndrome Strong FH of T2D. Negative GAD Ab

4 Expert Committee Report on Dx. & Classification of Diabetes in 1997: Type 1 Diabetes Immune type Idiopathic diabetes Type 2 Diabetes Other specific types Genetic defects of beta cell function, or IR Diseases of exocrine pancreas Endocrinopathies Drug- or chemical- induced Infections Gestational diabetes Mellitus Diabetes Care 20: , 1997 Q1: What type of diabetes this patient has? Because of the mixed features of type 1 and type 2 diabetes, this variant of diabetes has been referred to Idiopathic T1DM T3DM or Type 1.5 Diabetes Flatbush Diabetes Ketosis prone T2DM Atypical diabetes Atypical presentations of DM Banerji et al described overweight, adult Afro- Caribbean patients who had clinical characteristics of type 2 diabetes but presented with DKA; and developed near normoglycemic remission. The term Flatbush diabetes entered the literature at this point. Banerji et al, 1994 Diabetes 43:

5 Flatbush Diabetes (case series, n=79) Near normoglycemic remission Sex (male/female) 51/28 Age 45.4 ± 10.4 FH of DM 78.5% Glucose at presentation 680±350 ( ) mg Presenting in DKA 27% GAD (- ) Banerji et al, diabetes vol 45, March 1996 Umpierrez et al. carefully characterized obese African- American patients presenting with DKA. They noted that β- cell functional reserve was higher at baseline in these obese patients than in typical lean patients who developed DKA, and that it improved further after 12 wk of treatment. Obese DKA Glucose: 36 mmol= 648 mg/dl Umpierrez et al, Diabetes Care Vol 22(9), Sep.1999,

6 Obese DKA Umpierrez et al, Diabetes Care Vol 22(9), Sep.1999, F/U on obese DKA patients Only 43% required insulin at F/U A1c decreased to from 13% to 6.8% ± 0.2 within a year after crisis Umpierrez et al, Annals of Internal Medicine, 2009 A recent longitudinal study reported that after 10 years after diabetes onset, 40% of patients with KPDM are still insulin independent. Mauvais- Jarvis F et al, Diabetes 2004;53: Mauvais-Jarvis F et al, Diabetes 2004;53:

7 Risk of Relapse F/U (n=72) ~8.8 y ( y): Relapse: 27 (39%) Remission: 44 (61%) Risk of relapse increased with higher glucose levels at presentation Banerji et al, Diabetes vol 45, March 1996 Q3. What are the predictive factors for near normoglycemic remission? Ketosis- prone diabetes ADA classification a BMI- based system a modified ADA classification the Aβ system

8 The Aβ system Autoimmunity Patients were classified as antibody positive (A+) if the antibody index for at least one of the measured serum antibodies (GAD 65, GAD 67 and IA- 2) exceeded the ethnic- specific 99th percentile, or antibody negative (A- ) if the index for every antibody was below the 99th percentile. Beta cell function ß- Cell functional reserve was defined as : Fasting c- peptide > 1 ng/dl the peak C- peptide after glucagon> 1.5 ng/dl (glucagon stim test: 1 mg of glucagon iv, then serum C- peptide concentrations at 0, 5, and 10 min). Aβ classification All subjects with DKA ( ) in Tx N=103 56% male Mean age 39 y/o 40% H, 44% AA, 15% C, 1% Asian 40% new onset DM beta cell function, autoimmunity, HLA Glucagon stimulation test (1 wk) after correction of 6 and 12 month Maldonado et al, JCEM Vol. 88, No

9 Maldonado et al, 2003, JCEM Vol. 88, No AUC of c-peptide Fasting c-peptide Maldonado et al, JCEM 2003 Vol. 88, No Maldonado et al, JCEM Vol. 88, No

10 Comparing 4 classification schemes of KPD 294 consecutive patients who presented with DKA ( ) F/U for a mean duration of 31 months ( 12 60) BMI, ß- cell autoantibodies and ß- cell function at baseline and again 6 12 months later Maldonado group, Diabetes Care, 2006, 29: The Aβ system was the most accurate in predicting preserved β- cell function 12 months after the index DKA Maldonado group, Diabetes Care, 2006, 29: Q 4: What is the underlying mechanism for the hyperglycemic crisis & remission?

11 Pathophysiology of disease Glucotoxicity / lipotoxicty impaire the intracellular pathway leading to insulin secretion Summary of the protocol Intensive Conventional Insulin Therapy Baseline 1 wk 2 wk 3 wk 3 mon Overnight visit FSIGT Glucagon test DEXA A1c Fructosamine Adjusting insulin dose Continuous glucose monitoring Overnight visit FSIGT Glucagon test Fructosamine Overnight visit FSIGT Glucagon test DEXA A1c Fructosamine Rasouli et al, JCEM Vol. 89, No

12 Rasouli et al, JCEM Vol. 89, No Rasouli et al, JCEM Vol. 89, No Correlation of change in AIRg and baseline C peptide response to glucagon (AUC). The changes in AIRg correlated significantly (r = 0.78; P = 0.05) with the basal AUC of C peptide in the GST. Rasouli et al, JCEM Vol. 89, No

13 Glucotoxicity as the cause of beta cell failure? Subjects: Pt with ketosis prone diabetes were tested after 1 week after discontinuation of insulin therapy. (newly diagnosed DM) Ketosis resistant diabetes (newly diagnosed) Control (obese non diabetic) Intervention: Dextrose 10% infusion for 20 h at 200 mg per m 2 /min (250 ml/hr). noon until 8 AM in addition to diet (2000 Kcal/d) Outcome :Beta cell function was measured before/after infusion using arginine stimulation test & glucose potentiated arginine stim test. Diabetes Care April 2010 vol. 33 no Diabetes Care April 2010 vol. 33 no Glucose infusion did not cause beta cell failure in any of these 3 groups. Diabetes Care April 2010 vol. 33 no

14 Diabetes Care April 2010 vol. 33 no Summary of the study Remarkable recovery of basal and stimulated insulin secretion during the near- normoglycemic remission in patients with newly diagnosed KPD, The lack of β- cell failure (glucotoxicity) after a short- term intravenous dextrose infusion. Lipotoxicity as the cause of beta cell failure? Subjects: Pt with ketosis prone diabetes were tested after 1 week after discontinuation of insulin therapy. (newly diagnosed DM) Ketosis resistant diabetes (newly diagnosed) Control (obese non diabetic) Intervention: infusion of 20% intralipid at 40 ml/h for 48- hr Outcome: Beta cell function was measured before/after infusion using arginine stimulation test & glucose potentiated arginine stim test.

15 , KPDM;,hyperglycemia, control.

16 Summary of lipotoxicty study short- term high FFA levels are not primary pathophysiologic factor(s) in the development of β- cell decompensation in KPDM patients. Other potential causes Increased glucagon Viral infection reduced protection against oxidative stress, glucose- 6- phosphate dehydrogenase deficiency JCEM 2005, 90: (Mauvais- Jarvis group) a polymorphism leading to an amino acid substitution (R133W) in PAX4, (a transcription factor essential for islet morphogenesis β- cell development) Hum Mol Genet, : Summary Ketosis prone diabetes: severe hyperglycaemia with ketosis or ketoacidosis at diagnosis. Sx of hyperglycemia, polyuria, polydipsia, and weight loss, near- normoglycaemic remission within days or weeks after initial insulin The cause of acute onset and remission and the underlying insulin secretion dysfunction is unknown

17 Is beta cell remission unique to this subtype of diabetes? 436 patients with newly diagnosed type 2 diabetes ( ) FBG: mg/dl Randomization: MDI CSII Oral agents Tx was stopped after normoglycaemia was maintained for 2 weeks. F/U on diet and exercise. Wang et al, Lancet 2008;371: Target glycemic control: FBG<140 CSII : 97% in 4 days MDI: 95% in 5.6 days oral hypoglycaemic agents : 83.5 in 9.3 days Subjects continued TX for 2 weeks after the glycemic control was achieved

18 Wang et al, Lancet 2008;371: Summary Weng et al. recently reported that 1 week of intensive insulin administration in patients with newly diagnosed type 2 diabetes resulted in remission of diabetes in half of the patients after 1 year of follow- up. Wang et al, Lancet 2008;371: