Diabetes Mellitus. Approach to Insulin Resistance

Transcription

1 Diabetes Mellitus Approach to Insulin Resistance

2 David Bruyette, DVM, DACVIM VCA West Los Angeles Animal Hospital 1818 South Sepulveda Blvd Los Angeles, CA (ext 226)

3 Insulin Resistance What is the definition? 1) Greater than 1.5 units/kg of insulin BID 2) Glucoses > 300 mg/dl during BG curve 3) Glycemic control is erratic 4) Insulin requirements fluctuate

4 Insulin Resistance Resulting from Insulin Therapy 1) Inactive insulin 2) Diluted insulin 3) Improper administration 4) Inadequate dose 5) Somogyi

5 Insulin Resistance Resulting from Insulin Therapy 6) Inadequate frequency of administration 7) Impaired insulin absorption 8) Anti-insulin antibodies 9) Act of God

6 Insulin Resistance Resulting from Concurrent Disorder 1) Diabetogenic drugs 2) Hyperadrenocorticism 3) Diestrus (canine) 4) Acromegaly (feline) 5) Infections (skin, urinary, oral cavity)

7 Insulin Resistance Resulting from Concurrent Disorder 6) Hypo and hyperthyroidism 7) Renal insufficiency 8) Hepatic insufficiency 9) Heart disease 10) Glucagonoma (canine)

8 Insulin Resistance Resulting from Concurrent Disorder 11) Pheochromocytoma 12) IBD 13) Pancreatitis/triaditis 14) EPI 15) Obesity

9 Insulin Resistance Resulting from Concurrent Disorder 16) Hyperlipidemia 17) Neoplasia 18) Act of God

10 Insulin Resistance Diagnostic Approach History Presence of obesity? Concurrent medications? Is the pet spayed? When was last estrus? Signs of infection?

11 Insulin Resistance Diagnostic Approach Physical Examination Obesity (BCS) Rectal examination, thyroid evaluation Abdominal palpation Thoracic auscultation

12 Insulin Resistance Diagnostic Approach Laboratory testing CBC, chemistry panel, UA, UMIC Serum progesterone Abdominal US Thoracic radiographs

13 Insulin Resistance Diagnostic Approach Laboratory testing Hormonal Evaluation TT4, ft4ed ACTH stimulation/ldds IGF-1

14 Insulin Resistance Diagnostic Approach Laboratory testing PLI TLI CT/MRI of pituitary

15 Obesity

16 Obesity

17 Diabetes Mellitus Dietary Management (Canine) Maintain ideal weight High CHO (50%), low fat (<20%), high fiber (15-25%) Complex carbohydrates Increase insulin sensitivity, increase insulin receptors, post-receptor effects

18 Diabetes Mellitus Dietary Management High Fiber Reduces insulin resistance Decreases post-prandial hyperglycemia Delays gastric emptying

19 Diabetes Mellitus Dietary Management J Small Anim Pract Nov;50(11): Lack of advantage of high-fibre, moderate-carbohydrate diets in dogs with stabilized diabetes.

20 Diabetes Mellitus Dietary Management Domest Anim Endocrinol Nov;37(4): Improvement in insulin resistance and reduction in plasma inflammatory adipokines after weight loss in obese dogs.

21 Diabetes Mellitus Dietary Management (Feline) High protein diets Purina DM, Hill s Feline Growth Canned foods Low CHO (6%) Mimics diet in wild Once daily vs free feeding?

22 Diabetes Mellitus Progesterone and Insulin Resistance Pregnancy, diestrus (dog) or adrenal neoplasia (dog, cat) Reduces insulin binding Reduced glucose transport in tissue Increased mammary production of GH Decreased number of insulin receptors Decreased expression of glucose transporter genes Rapid decrease in GH and resistance following OHE

23 Diabetes Mellitus Hyperadrenocorticism and Insulin Resistance Most common cause in dogs 38 % 2 nd most common cause in cats 17 % Antagonize insulin in liver and muscle cells Decrease number and/or efficacy of glucose transporters Increase glucagon and fatty acids Which came first the diabetes or the Cushing s syndrome?

24 Diagnosis of Canine Cushing s Disease Screening Tests to Diagnose Cushing s: ACTH Stimulation Test Low Dose Dexamethasone Suppression Test (LDDS) Urine Cortisol:Creatinine Ratio (UCCR)

25 Screening Tests Urine Cortisol:Creatinine Ratio Sampling errors High sensitivity Low specificity High number of false positives

26 Screening Tests Low Dose Dexamethasone Suppression Test Diagnostic in 90% of dogs with PDH or ADH Requires 8 hour testing period Cannot be used to diagnose iatrogenic Cushing s disease

27 Screening Tests LDDS Elevated 8 hour sample = HAC Compare 4 and 8 hour levels to Pre 50% suppression = PDH

28 Screening Tests ACTH Stimulation Test Diagnostic in 80-85% of dogs with PDH or ADH Can be used to diagnose iatrogenic Cushing s Requires a baseline sample and 1 hour (Cortrosyn) or 2 hour (IM gel) sample post ACTH administration

29 Feline Hyperadrenocorticism Dexamethasone Suppression Testing Cats are not like dogs Inconsistent suppression in normal cats with 0.01 mg/kg IV DexNaPO4 Doses evaluated have ranged from mg/kg

30 Feline Hyperadrenocorticism Dexamethasone Suppression Testing Non-adrenal illness In PDH the most reliable dose is: 0.1 mg/kg IV with pre, 4 and 8 hour post; 89 % sensitive

31 Vetoryl - Diabetes Mellitus 1. Unstable diabetics may be positive on ACTH stimulation test and LDDST 2. Diabetic with positive HAC tests - stabilize diabetes 1 month 3. Once stable repeat HAC tests, if tests confirm HAC start trilostane. 4. Reduce insulin dose by 50% at start of trilostane therapy.

32 Insulin Resistance Bacterial Infections 2 nd most common cause in dogs 16 % 4 th most common cause in cats 9 % Skin, urinary and oral cavity

33 Insulin Resistance Bacterial Infections Diabetics pre-disposed to infections: Decreased blood supply Impaired humoral immunity Abnormal chemotaxis of neutrophils Defects in phagocytosis

34 Insulin Resistance The EMBO Journal (2010) 29,

35 Insulin Resistance Renal Insufficiency 3 rd most common cause in cats 15 % Poor and/or erratic glycemic control Increased insulin sensitivity Decreased insulin clearance Decreased renal glucose production

36 Renal Insufficiency Insulin Resistance Decreased insulin sensitivity Common clinical signs Primary focus is on managing the renal disease

37 Insulin Resistance Chronic Pancreatitis Identified at necropsy in 35 % of diabetic dogs and 50 % of diabetic cats Poor glycemic control and persistent hyperglycemia Fluctuating insulin requirements Lethargy and inappetence (ADR)

38 Insulin Resistance Exocrine Pancreatic Insufficiency EPI with diabetes in juvenile patients - pancreatic atrophy As a result of chronic pancreatitis - Signs of EPI become more pronounced

39 Hypothyroidism Insulin Resistance 4 th most common cause in dogs 9 % Post receptor defect in glucose transport Obesity Hypertriglyceridemia Insulin requirement decreased by 50-60% after 2 weeks of supplementation

40 FIG. 1. Relationships among TC (A), HDL-C (B), TC/HDL-C (C), and TGs (D), and TSH and HOMA-S Chubb, S. A. P. et al. J Clin Endocrinol Metab 2005;90: Copyright 2005 The Endocrine Society

41 Canine Hypothyroidism Role of Thyroid Function Testing Total T4 Diagnostic if normal (> 1.5 ug/dl) Low values can be seen with: Non-thyroidal illness Time of day Medications

42 Canine Hypothyroidism Role of Thyroid Function Testing Total T4 Time of day % of normal dogs have concentrations below the reference range at some time during the day

43 Canine Hypothyroidism Role of Thyroid Function Testing Total T4 Effect of age TT4 two to 5 times higher in first 3 months Age dependent decline in resting and post TSH TT4 Decline in TSH response to TRH in aged dogs

44 Canine Hypothyroidism Role of Thyroid Function Testing Total T4 Breed related normals Greyhounds, sight hounds, basenji s TT4 about 50% of normal ft4 also lower

45 Canine Hypothyroidism Role of Thyroid Function Testing Assessment of criteria used by veterinary practitioners to diagnose hypothyroidism in sighthounds and investigation of serum thyroid hormone concentrations in healthy Salukis. J Am Vet Med Assoc Feb 1;236(3): % diagnosed with hypothyroidism based on low TT4 7.5 % diagnosed with hypothyroidism with normal results 83.6 % incorrectly diagnosed

46 Canine Hypothyroidism Role of Thyroid Function Testing Total T4 Non-thyroidal illness Euthyroid sick syndrome Low T3 syndrome Low T4 state of medical illness Predictor of mortality in man and cats

47 Canine Hypothyroidism Role of Thyroid Function Testing Total T4 Non-thyroidal illness Hyperadrenocorticism Diabetes mellitus Hypoadrenocorticism Chronic renal failure Hepatic disease Intensive care

48 Canine Hypothyroidism TT4 and Medications Lowering TT4 Steroids ( in TT4, or = ft4ed, = or ( ) TSH) Phenobarbital (= or TT4 and ft4ed, = or TSH) Sulfonamides ( TT4 and ft4ed, TSH) Rimadyl ( TT4, = or ( ) ft4ed, TSH Clomipramine ( TT4 and ft4ed)

49 Canine Hypothyroidism TT4 (low TT4) Sensitivity % Specificity % Accuracy 85 %

50 Canine Hypothyroidism Free Thyroid Hormone Measurement Free Hormone Hypothesis (Mendel) Linear correlation of ft4 and metabolic rate Inversely correlated with the log of TSH

51 Canine Hypothyroidism ft4ed (low ft4ed) Sensitivity 98 % Specificity 94% Accuracy 95 %

52 Canine Hypothyroidism Canine ctsh Assays History Experimental models TRH testing Supplementation Real world 25% of confirmed hypothyroid dogs have normal ctsh

53 Canine Hypothyroidism Canine ctsh Assays (high ctsh) Sensitivity % Specificity % Accuracy 84 %

54 Canine Hypothyroidism Low ft4ed/high ctsh Low ft4ed Sensitivity 74 80% % Specificity * 97 98% % Accuracy 86 % 95 % *

55 Canine Hypothyroidism Can We Evaluate Thyroid Function in Sick Dogs?? In the sick dogs, serum TT4 and ft4 concentrations were less than reference range values in 39 (59%) and 21 (32%) dogs, respectively; only 5 (8%) dogs had high TSH concentrations J Am Vet Med Assoc 2001;219: J Am Vet Med Assoc 2003;222:

56 Insulin Resistance Neoplasia Insulin resistance is 5 10 % of dogs Pheochromocytoma, glucagonoma, LSA, mast cell Excess secretion of catecholamines and glucagon Inc hepatic gluconeogenesis Inhibit glucose uptake in muscle

57 Insulin Resistance Hypertriglyceridemia Impairs insulin binding to receptors Post-receptor defects Increased hepatic gluconeogenesis Down regulates insulin receptors Schanauzers and hypothyroidism

58 Insulin Resistance Hypertriglyceridemia Which came first? In general, triglycerides < 500 mg/dl > 800 raises suspicion for an underlying disorder

59 Feline Acromegaly Insulin Resistance # 1 cause in cats 184 cats with variably controlled diabetes 59 (32.1%) had markedly high IGF-1 concentrations 18 were subsequently examined, and acromegaly was confirmed by demonstration of a pituitary mass on CT imaging in 17

60 Feline Acromegaly Insulin Resistance Loki 14 yr MC DSH Diabetes mellitus x 6 months Increased insulin dose from 2 15 units glargine BID Persistent pu/pd

61 Feline Acromegaly Insulin Resistance CBC, chemistry panel,tt4, UA, UMIC Thoracic radiographs Serum IGF-1 > 560 nmol/l (12 92) MRI

62 Insulin Resistance

63 Insulin Resistance

64 Insulin Resistance

65 Feline Acromegaly Insulin Resistance Transsphenoidal surgery

66 Feline Acromegaly Insulin Resistance Transsphenoidal surgery 4 weeks post-op off insulin 8 weeks post off all hormone replacement therapy MRI and repeat IGF-1 at 6 and 12 months

67 Feline Acromegaly Insulin Resistance Studies on pathogenesis Role of somatostatin analogues GH receptor antagonists Dopaminergic therapy

68 Insulin Resistance Most common complication of insulin therapy Logical diagnostic approach Good clinical outcome Rewarding cases to work-up