This document discusses different types of iatrogenic (medically induced) diabetes, including: 1) Pancreatogenic diabetes caused by pancreatic diseases or procedures that damage the pancreas. 2) Drug-induced diabetes caused by medications like corticosteroids, antipsychotics, immunosuppressants, protease inhibitors, and chemotherapy drugs. 3) Post-transplant diabetes that develops in some organ transplant recipients due to immunosuppressant drugs and other risk factors. The document provides details on the mechanisms and risk factors for each type of iatrogenic diabetes.

1. Iatrogenic Diabetes
Dr. Veerendra Singh
MD, FICP,FIACM,FDI, FUPDA
Chairman API UP Chapter

2. Iatrogenic diabetes mellitus
New onset diabetes due to human intervention

3. Inbar Zucker et al;Cardiovasc Diabetol. 2017; 16: 105.
Survival plot according to diabetes status

4.  Pancreatogenic diabetes
 Drug induced NOD
 Post Transplant DM
 ART Induced DM
 Stress induced Diabetes
 Diet induced NOD
 Environmental pollutants induced NOD
Iatrogenic diabetes

5. Pancreatogenic diabetes: (T3cDM)
• Pancreatectomy (pancreatic resection),
• Chronic pancreatitis , hemochromatosis, cystic
fibrosis, fibrocalculous pancreatopathy,
pancreatic trauma, pancreatic agenesis and
pancreatic cancer

6. Pancreatogenic diabetes: (T3cDM)
Brittle diabetes
Unsupressed hepatic
glucose production due
to PP deficiency
Hyperglycemia
Enhanced peripheral
insulin sensitivity and
glucagon deficiency
Hypoglycemia
Pancreatology. 2011;11(2):268-76,

7. Drug induced diabetes

8. • Streptozotocin,
• alloxan,
• vacor
• pentamidine
Beta cell poisons
• Steroids
• Antipsychotics
• Immunosuppressive
• Diazoxide
Strong diabetogenic
• Statins
• Thiazides
• Beta blockers
Weak diabetogenic
• Salbutamol,terbutaline and retoridine
• Anti cancer drugs asperginase
• Nicotinic acid, isoniazid, NSAIDs, phenytoin,
nalidixic acid, carbamazepine, encainide,
benzodiazepines and mianserine
Other common drugs
Drug-induced diabetes

9. • 14-28% of subjects on corticosteroids
• All corticosteroids In high doses > 30 mg cause DM
• Topical steroids over large areas of damaged skin
and under occlusive dressings
• Reversible on withdrawing the drug.
Strong Diabetogenics
Corticosteroids

10. Corticosteroids_______
Induce insulin resistance in liver, muscle, and adipose
tissue by
•↑ hepatic gluconeogenesis
• ↓ glucose disposal in muscle and adipose tissue
• Suppress insulin secretion from beta cells

11. Consensus is that
• Glinides, thiazolidinediones, GLP‐1 analogs, or
DPP‐4 inhibitors preferred
• Metformin is not recommended as many
patients taking glucocorticoid have renal failure
or may be prone to lactic acidosis

12. Strong Diabetogenics
Antipsychotics
Weight gain and consequent insulin resistance

13. • High association
- clozapine and olanzapine
•Lower association
- Risperidone and quetiapine
•Least association
- Aripiprazole and ziprasidone
Lifestyle modification and metformin
Antipsychotic induced NOD________

14. Antipsychotic drug users
Antidepressant drug users
Anxiolytic drug users
Medicine (Baltimore). 2015 Jun; 94(23): e919.
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New onset diabetes with antipsychotic drugs

15. JAMA Psychiatry. 2016 Mar;73(3):247-59. doi: 10.1001/jamapsychiatry.2015.2923.
Type 2 Diabetes Mellitus in Youth Exposed to Antipsychotics: A
Systematic Review and Meta-analysis.
Galling B1, Roldán A2, Nielsen RE3, Nielsen J4, Gerhard T5
13 studies including 185 105 youth exposed to antipsychotics
Antipsychotic-exposed youth had a cumulative T2DM risk of 5.72 per 1000
patients. Greater cumulative T2DM risk was associated with longer follow-up,
olanzapine , and male sex.

16. This updated meta-analysis confirms the association between AD use and
incident diabetes. While it still remains a matter of debate whether this
association is causal or not.

17. The US FDA warning
U.S. Food and Drug Administration (FDA) recommends
baseline screening and routine ongoing monitoring
of risk of DM throughout antipsychotic therapy in all
ages with a risk of DM.
Medicine (Baltimore). 2015 Jun; 94(23): e919.

18. Strong Diabetogenics
Immunosuppressives

19. Calcineurin inhibitors
• 16.6% with tacrolimus vs 9.8% with ciclosporin
• These agents affect β-cell growth, proliferation
and function.
• This limits the application of these agents in the
prevention of type 1 diabetes
Am J Transplant 2004

20. PLoS One. 2014; 9(6): e99406.
Influence of immunosuppressant conversion on FPG
level and NODAT

21. World J Gastroenterol. 2016 Feb 14;22(6):2133-41.
• Switching from tacrolimus to cyclosporine allowed
50% patients to withdraw from insulin.¹
Transplant Proc. 2014 Apr;46(3):865-9.
• A minimal tacrolimus regimen can decrease the risk of
long-term NOD after liver transplant.²

22. Protease inhibitors
• 14% of HAART treated men developed diabetes
Multicenter AIDS Cohort Study.
Arch Intern Med 2005
• Ritonavir an important drug in highly active antiretroviral
therapy (HAART) strongly predisposes to NOD
J Int AIDS Soc. 2012 Oct 10;15(2):17426.

23. Chemotherapy induced NOD________

24. Timing of hyperglycemia after CPI treatment.
Angeliki M. Stamatouli et al. Diabetes 2018;67:1471-1480
©2018 by American Diabetes Association
Monoclonal antibodies that block immune inhibitory ligands CTLA-4 and PD-1,
known as immune checkpoint inhibitors (CPI)

25. BMJ Case Rep. 2018 Jan 29;2018. pii: bcr-2017-220999. doi: 10.1136/bcr-2017-220999.
New onset diabetes after nivolumab treatment.
Capitao R1, Bello C1, Fonseca R1, Saraiva C1.
25 days after initiation of nivolumab (3 mg/kg) for stage 4 lung adenocarcinoma patient was admitted to the emergency
department, with hyperglycaemia-related signs and symptoms. Blood tests showed hyperglycaemia (1060 mg/dL),
hyperketonaemia (beta-hydroxybutyrate: 6.6 mmol/dL), elevated total serum osmolality (389 mOsm/kg), low serum and urinary
C-peptide and positive antiglutamic acid decarboxylase antibodies.
J Immunother Cancer. 2017 May 16;5:40. doi: 10.1186/s40425-017-0245-2. eCollection 2017.
Nivolumab-induced autoimmune diabetes mellitus presenting as diabetic ketoacidosis in a patient with
metastatic lung cancer.
Godwin JL1, Jaggi S2, Sirisena I2, Sharda P3, Rao AD2, Mehra R4, Veloski C3
After receiving two doses of nivolumab, the patient developed abrupt onset of hyperglycemia and diabetic ketoacidosis.
Autoimmune diabetes was diagnosed on the basis of undetectable C-peptide levels, seropositivity of three diabetes related
(islet) autoantibodies and absolute insulin dependence.
J Chin Med Assoc. 2018 Aug 9. pii: S1726-4901(18)30200-4. doi: 10.1016/j. [Epub ahead of print]
Hyperglycemia crisis in head and neck cancer patients with platinum-based chemotherapy.
Huang CY1, Lin YS2, Liu YH1, Lin SC1, Kang BH3.
A total of 185 patients were enrolled, of which seven patients (3.8%) had developed type 2 DM after initiation of platinum-
based chemotherapy.

26. Weak diabetogenics
Statins

27. Ridker PM,et al; JUPITER Study Group. N Engl J Med. 2008 Nov 20; 359(21):2195-207

28. Figure 1
Incidence rates of physician diagnosed diabetes in the JUPITER trial according to baseline fasting glucose levels.
Numbers in parentheses indicate the absolute number of individuals who developed diabetes in each group.
Lancet. Aug 11, 2012 Volume 380(9841):565-571.

29. Fig: Cumulative incidence of NODM between statin users and nonstatin users
Ther Clin Risk Manag. 2016; 12: 1533–1543.

30. Hailong Li,1 et al ; Therapeutics and Clinical Risk Management Volume 2018:14 Pages 823—832

31. Figure 4
Hazard ratios and 95% confidence intervals for specific vascular events, total mortality, and diabetes in subgroup
analyses
Lancet. Aug 11, 2012 Volume 380 (9841):565-571.

32. Can J Diabetes. 2016 Jun;40(3):264-9. doi: 10.1016/j.jcjd.2015.12.006. Epub 2016 Mar 15.
Statin Use and the Risk for Incident Diabetes Mellitus in Patients with Acute Coronary Syndrome after PTCA.
Lin ZF1, Wang CY2, Shen LJ1, Hsiao FY3, Lin Wu FL4.
Statin use was associated with a significant increase of 27% in the risk for new-onset diabetes mellitus .
ACC.I2 Interventional Cardiology |Volume 67, Issue 13_S, April 2016
IMPACT OF PITAVASTATIN ON NEW-ONSET DIABETES IN ACUTE MYOCARDIAL INFARCTION
Cheol Ung Choi; Sung Hun Park; et al.
298 patients (3.6%) had a NODM. No significant differences associated with pitavastatin. However, there
were significant differences associated with rosuvastatin and atorvastatin.
Ther Clin Risk Manag, 2018 May 03; Vol. 14, pp. 823-832;
Statins use and risk of new-onset diabetes in hypertensive patients: a population-based
retrospective cohort study.
Li H; Lin H; Zhao H; Xu Y; Cheng Y; Shen P; Zhan S;
Statin use was associated with a significant increased risk for T2DM in the matched cohort (adjusted
hazard ratio: 1.54; 95% confidence interval: 1.41-1.67.

33. The National Lipid Association (NLA)
Note on use of statins
• The cardiovascular benefit of statin therapy outweighs
the risk for developing diabetes.
• Statins should be prescribed on the basis of CVD risk
and individual patient characteristics
• Diet and lifestyle interventions should be emphasized
to help mitigate the risk of NODM
Endocrinol Metab Clin North Am. 2016 Mar;45(1):87-100

34. Weak diabetogenics
Antihypertensives

35. J Cardiometab Syndr. 2008 Winter;3(1):18-25.
Impaired glycemic control can be reversed by switching to a regimen without a
diuretic

36. Figure 1 Development of new onset diabetes
Carvedilol Or Metoprolol European Trial (COMET) Heart. 2007 Aug; 93(8): 968–973.

37. Am J Cardiol. 2011 Jun 15; 107(12): 1705–1709.

38. Development of New Onset Diabetes (NOD) in patients assigned to
trandolapril and placebo.

39. Impact of ACIs versus ARBs on Incidence of New-Onset Diabetes Mellitus in
Asian
The cumulative incidence of new-onset diabetes were significantly higher in the ARB group
(black) than in the ACEI group (gray)
Yonsei Med J. 2016 Jan 1; 57(1): 180–186.

40. Post Transplant Diabetes Mellitus (PTDM)

41. New onset diabetes develops in:
• In 15% of liver transplant recipients.¹
• In 15-20% of renal transplant patients.²
• In 2% to 53% of all solid organ transplants.³
1.Liver Transpl. 2005 Jun;11(6)
2.Clin Transplant. 2006 Nov-Dec;20(6)
3.Diabetes Metab Syndr Obes. 2011; 4

42. Risk factors for NODAT.

43. Association between impaired fasting glucose and new-onset
diabetes mellitus.
The pooled OR indicated a significant association between pre-transplant impaired
fasting glucose and the risk of new-onset diabetes mellitus after liver transplantation.
World J Gastroenterol. 2015 May 28; 21(20): 6329–6340.

44. Living donor transplant and induction therapy were
associated with a decreased risk of NODM.
Transplantation. 2010 May 15;89(9):1134-40.
NODM in adult liver transplant recipients

45. Nephrol Dial Transplant. 7 April 2016;31(3):495-505.
Prevalence of
(B) Diverse subtypes
of prediabetes
Prevalence of
(A) PTDM and
prediabetes
Evolution of Post-transplant Diabetes Mellitus In Renal Transplant
At 3 months 27% patients developed PTDM 26% had
prediabetes and 47% had normal glucose metabolism

46. PTDM after renal transplant
• More frequently men, older, with higher BMI, triglyceride and
proteinuria.
• 70% received triple therapy with tacrolimus, steroids and
mycophenolate.
• Bimodal evolution
i. Early PTDM during the first 3 months
ii. Late PTDM onset after 3 months
Nephrol Dial Transplant. 7 April 2016;31(3):495-505.

47. NODM in adult heart transplant recipients
• NODM in 28.6% of the 3763 recipients
• Older age > 50
• Non-white race
• Body mass index > 25
• Ischemic heart disease
• Recipient cytomegalovirus positivity
• Tobacco
• Tacrolimus or steroid
Transplantation. 2010 Jun 27;89(12):1526-32.

48. CKD: hemodialysis vs. peritoneal dialysis
Patients on hemodialysis are more at risk for new
onset diabetes than those on peritoneal dialysis .
PLoS One. 2014 Feb 4;9(2)

49. NODM after Assisted Reproduction Technology
(ART)

50. Higher prevalence of gestational diabetes mellitus
following assisted reproduction technology.
The prevalence of GDM was 7.6% for ART mothers and 5.0% for non-
ART mothers. Mothers who had twins had higher prevalence of GDM than
those who gave births to singletons (8.8 versus 7.5% for ART mothers; and 7.3
versus 5.0% for non-ART mothers). Overall, ART mothers had a 28% increased
likelihood of GDM.
Hum Reprod. 2013 Sep;28(9):2554-61. Epub 2013 Jun 27.

51. The incidence of GDM was significantly higher in the IVF/ICSI
and IUI groups (43% and 26%, respectively) compared with the
spontaneous pregnancy group (10%).

52. When compared to NC group, significantly increased rates
of gestational diabetes mellitus (GDM) (p<0.01),
preeclampsia (PE) (p<0.01) and intrahepatic cholestasis of
pregnancy (ICP) (p˂0.01) were observed in ART group

53. Among the 8,948 pregnancies, risks were significantly higher
among twins (PIH 2.58, GDM 1.30, CS 5.83, PTB 11.84, LBW
10.68, SGA 2.17, BD 2.54),

54. The prevalence and prognosis of gestational diabetes
mellitus after assisted reproductive technology
Analysis of the prevalence of GDM and of GDM-related events (preeclampsia or birth weight
≥4000 g or shoulder dystocia) in the 18.305 women without known diabetes.
The greater rate of GDM after ART than after natural
pregnancies (17.6 vs 14.2%, p<0.05) was driven by ART
procedures (18.3%) rather than by ovulation inductions (15.5%)..
EASD 2015 Presentation Number:146: Sep 17, 2015,

55. Stress induced NODM

56. Perceived psychosocial stress and glucose intolerance
among pregnant Hispanic women.
An increase in stress from early to mid-pregnancy had a
2.6-fold increased odds of gestational diabetes mellitus .
Diabetes Metab. 2014 Dec;40(6): Epub 2014 Jun 16.

57. Posttraumatic stress disorder and new-onset diabetes among
adult survivors of the World Trade Center disaster.
PTSD, a common 9/11-related health outcome, was a
risk factor for self-reported diabetes. Clinicians treating
survivors of both the WTC attacks and other disasters
should be aware that diabetes may be a long-term
consequence
Prev Med. 2014 Sep;66:34-8. doi: 10.1016/ Epub 2014 May 28.

58. Association between occupational stressors and type
2 diabetes among Chinese police officers: a 4-year
follow-up study in Tianjin, China.
A total of 3.1% of the participants (n = 179) developed NOD.
Role overload (RO), role boundary (RB), physical environment
(PE), interpersonal strain (IS), and physical strain (PHS) were
associated with the incidence of T2DM
Int Arch Occup Environ Health. 2016 Feb;89(2):277-88.

59. Dairy Products and Diabetes
Role of Fatty Acids in NODM

60. The epidemics of diabetes, cardiovascular
disease and related conditions in India have been
iatrogenic, a product of diets high in linoleic acid,
as a result of “chasing the phantom of cholesterol”.
Raheja B.S., J Assoc Physicians India. 1994 May;42(5):385-90, 395-6.

61. Processed foods labelled ‘low fat’, ‘lite’, ‘low cholesterol’
or “proven to lower cholesterol” should be avoided.
Replacing saturated fat with omega 6 containing
vegetable oils lowers cholesterol but does NOT
improve cardiovascular mortality. [18] Worryingly,
studies revealed a trend towards increased mortality.
Dietary fats: a new look at old data challenges established wisdom
BMJ 2016; 353 :i1512

62. Traditional Indian diet
• 39% fat
• 20.3% as saturated fats
mainly from ghee
• 5% from linoleic acid.
Modern urban diet
• 31.9% fat
• 5.6% as saturated fat
mainly linoleate oils
• 16.9% linoleic acid

63. Dietary unsaturated fatty acids in type
2 diabetes
Fasting blood glucose was significantly higher on the
linoleic acid diet compared with the oleic acid diet (P <
0.01 and P < 0.002, respectively)
Diabetes Care. 2000 Oct;23(10):1472-7.

64. Trans-palmitoleic acid, metabolic risk factors, and new-
onset diabetes in U.S. adults: a cohort study.
Whole fat dairy consumption were associated with higher HDL
levels, lower triglyceride levels, a lower total cholesterol-HDL
cholesterol ratio, lower insulin resistance and a substantially
lower incidence of diabetes.
Diabetes Care. 2000 Oct;23(10):1472-7.

65. Dairy consumption (Trans-palmitoleate (trans 16:1n-7)
is associated with a more favorable metabolic profile
and less incident diabetes

67. Trans fatty acids and incident type 2 diabetes in older
adults: the Cardiovascular Health Study.
Plasma phospholipid t-16:1n9 and t-18:1 levels were
positively related to DM.
Diabetes Care. 2015 Jun;38(6):1099-107.

68. Am J Clin Nutr 2015;101:775–82.
Dairy intake, especially fermented dairy, was inversely associated with measures of
glycemia and insulinemia.

69. Fatty acids in the de novo lipogenesis pathway with risk
of type 2 diabetes: Cardiovascular Health Study
Circulating palmitic acid and stearic acid were
associated with higher diabetes risk.
Am J Clin Nutr. 2015 Jan;101(1):153-63.

70. Environmental factors and NODM

71. Environmental contaminants as etiologic factors for
diabetes
• Arsenic and 2,3,7,8-tetrachlorodibenzo-p-dioxin had a
direct association with type 2 diabetes
Environ Health Perspect. 2001 Dec;109 Suppl 6:871-6.

72. Dioxin exposure:
• An overall increase in diabetes was reported, notably
among women (RR = 2.4, 95% CI: 1.2, 4.6). exposed to
dioxin after the 1976 accident in Seveso, Italy¹
1. Am J Epidemiol. 2001 Jun 1;153(11):1031-44.

73. Pesticide Exposure and Gestational Diabetes Mellitus in the
Agricultural Health Study
Four herbicides (2,4,5-T; 2,4,5-TP; atrazine; or butylate) and
three insecticides (diazinon, phorate and carbofuran)
were associated with GDM.
Diabetes Care. 2007 Mar; 30(3): 529–534.

74. Endocrine-disrupting chemicals in the European Union
and probability to NODM
• Dichlorodiphenyldichloroethylene 20-39%
• Phthalate 40% to 69%
• Prenatal bisphenol A 20% to 69%
J Clin Endocrinol Metab. 2015 Apr;100(4):1278-88

75. Environ Health Perspect. 2002 Sep;110(9):853-8.
The public health significance of such an association
is that all populations are exposed to measurable
levels of dioxin like compounds (DLCs) which may
hasten the onset of adult-onset diabetes.

76. Take home message
• Iatrogenic diabetes is an established entity today
• Awareness of the clinician is vital.
• The list of drugs inducing NOD is increasing

77. In subjects at increased risk of NOD
(impaired fasting glucose, obesity, metabolic syndrome)
• Drugs be used cautiously with the lowest doses
• Metabolic parameters be checked periodically
• Early identification of modifiable risk factors will
prevent new onset diabetes after organ transplant.

78. Faizaba
d
Thank you