1. METABOLIC SYNDROME
Donald Felitto, M.D.

2. DEFINITIONS

3. WHO Definition 1999
Diabetes or impaired fasting glycemia or IGT or insulin resistance
Plus any two:
Obesity: BMI > 30, WTH ratio>0.9 male or >0.85 female.
Dyslipidemia: TG >or= 1.7mmol/liter or HDL cholesterol <0.9 mmol/l male or <1.0mmol/l female.
Hypertension: BP > 140/90 mmHg
Microalbuminuria: albumin excretion >20mcg/min

4. European Group for the Study of Insulin Resistance 1999
Insulin Resistance: hyperinsulinemia: top 25% of the fasting insulin values from the non-diabetic population.
Plus 2 or more of the following:
Central obesity: waist circumference > or = to 94 cm for male and 84 cm female
Dyslipidemia: TG > 2.0mmol/L or HDL cholesterol > 1.0mmol/L
Hypertension: BP 140/90 and/or medication
Fasting plasma glucose > 6.1mmol/l

5. National Cholesterol Education Program’s Adult Treatment Panel III (2001)
Three or more of the following:
Central Obesity: waist > 40 in. male and waist > in. female.
TG > or = to 150
Low HDL cholesterol: < 40 male and less than female.
Hypertension: BP > or = 135/85mm/Hg
Fasting plasma glucose > 110

6. American Association of Endocrinology - Statement Insulin Resistance Syndrome (2002)
Four Identifying Abnormalities:
High Triglycerides
Low HDL cholesterol
Hypertension
Elevated fasting or post load (75g)
glucose.
OBESITY is not a component of the definition.

7. Comparison of Definitions
WHO 1999
Risk Factor
Impaired glucose regulation (+2 other risks,) IR, IGT, DM Central Obesity BP > 140/90 TG >150 or HDL. M <35, F <39
Mcroalbuminuria
ATP III 2001
Risk Factor (any 3 of 5 risk factors)
Blood Sugar >/= 100
Central obesity
BPS >/=130, BPD >/= 85
Triglyceride >/= 150
HDL <40M, <50F
Am. Assoc. of Endo 2002
Risk factor
Elevated fasting or post load (75g) glucose
Hypertension
Elevated Triglycerides
Low HDL
(no mention of obesity)
International Diabetes Federation 2005
Central Obesity (plus >/= 2 factors)
BS>/=100 or DM
BPS>/=135, BPD >/=85
TG > 150
HDL <40M, ,50F

9. Table 2: AHA/NHLBI criteria for diagnosis of metabolic syndrome

10. Commonalities A large waistline: Central Obesity/ Visceral Obesity
For women a waistline > 35” and for men >40”
Dyslipidemia: High Triglyceride and low HDL in the blood
Hypertension: 135/85 or 140/90
Some form of insulin resistance

11. Case Report
Mr. B. is a 63 year old man with a past medical history for Hypertension, Dyslipidemia, Obesity and family history of Type 2 Diabetes Mellitus was evaluated for weight loss.
The BMI was 36 kg/m2, BP was 144/84, fasting blood sugar was 125, TC was 183, LDL cholesterol 112, TG 171, HDL cholesterol 37.
The EKG showed old MI.

12. Prevalence of Metabolic Syndrome
USA Native Americans 45-49y/o: (58% women and 45% men)
USA Filipina-Americans: 50-69y/o (35%)
USA 30-79y/o: 25+% (>60y/o 40+%)
USA non-Hispanic white:30-79y/o (25%)
USA Mexican American 30-79y/o (30%)

13. Prevalence of Metabolic Syndrome
Weiss et al. (2004)
Severely obese children/adolescents, the prevalence is 50%!
NHANES III 12-19y/o using ATPIII criteria for metabolic syndrome – the prevalence is 4.2%.

14. Risk factors for developing Metabolic Syndrome
Overweight
Obesity
Lack of physical activity (sedentary lifestyle)
Insulin resistance
Genetics
Older age
NHLBI 2007

15. Conditions that may play a role
Fatty Liver (NASH)
Polycystic Ovarian Syndrome
Gallstones
Sleep Apnea
NHLBI 2007

16. The diagnosis of metabolic syndrome requires a tape measure or accurate eye; fasting lipogram and plasma glucose measurements; and BP measurements.
The diagnosis of metabolic syndrome requires a tape measure or accurate eye; fasting lipogram and plasma glucose measurements; and BP measurements. A-II indicates angiotensin-II; FFA, free fatty acids; BP, blood pressure; FPG, fasting plasma glucose; TG, triglycerides; and HDL, high-density lipoproteins. Figure modified with permission from Opie LH. The metabolic syndrome, does it exist? In: Opie LH, Kasuga M, Yellon DM, eds. Diabetes at the Limits. Cape Town, South Africa: University of Cape Town Press; 2006:95–110.
Opie L H Circulation. 2007;115:e32-e35
Copyright © American Heart Association, Inc. All rights reserved.

17. Mechanisms
Abdominal adipose tissue is an endocrine organ which releases into circulation FFA, Angiotensin II and adipokines.
Increased FFA in the blood inhibit uptake of glucose by muscle.
Excess FFA and AT II damage the pancreas. The pancreas makes extra insulin, it is an insufficient to counter hyperglycemia
So, there is increased insulin levels and increased glucose. This is insulin resistance.
AT II increases BP through vasoconstriction.
Inflammatory cytokines are responsible IR and Hypertension
Hyperglycemia and increased circulating FFA contribute to increased manufacture of TG by the liver. Circulating TG increase so that lipoproteins carry more TG and less HDL.
Circulation 2007;115:e32-e35

18. Mechanisms Insulin resistance:
Increased postprandial insulin to maintain euglycemia.
Increased fasting insulin secretion to maintain euglycemia.
Eventually, hyperglycemia in many.
Hyperglycemia and increased FFA will increase insulin levels further.
Beta cell dysfunction, defective insulin secretion

19. Pathophysiology AT II increases Blood Pressure
The adipose tissue liberates Tumor Necrosis Factor alpha and interleukins that provoke an inflammatory reaction which promotes insulin resistance and promotes and promotes hypertension.
Hyperglycemia and elevated levels of circulating FFA foster the manufacture of triglycerides by the liver. Lipoproteins carry triglyceride and TG level rises.
HDL molecules are small and they are easily secreted.
These physiologic reactions cause the high TG: HDL lipid abnormality.
Opie L H Circulation. 2007;115:e32-e35

20. Inflamation Inflammation associated with Insulin resistance:
IL 6, TNF a, CRP, are increased.
IL 6 and other cytokines increase hepatic glucose production, inc. hepatic production of VLDL and increase insulin resistance in muscle tissue.
Cytokines plus FFA increase fibrinogen and plasminogen activator inhibitor 1 (from the liver) promote a prothrombotic state.

21. Adiponectin Adiponectin:
Anti-inflammatory cytokine produced by adipose tissue.
Enhances insulin sensitivity and inhibits
the inflammatory process.
Inhibits hepatic glucose production.
Enhances glucose transport to muscle.
It is reduced with insulin resistance.
Some associate low concentrations with progression of subclinical CAD and MI.

22. The diagnosis of metabolic syndrome requires a tape measure or accurate eye; fasting lipogram and plasma glucose measurements; and BP measurements.
The diagnosis of metabolic syndrome requires a tape measure or accurate eye; fasting lipogram and plasma glucose measurements; and BP measurements. A-II indicates angiotensin-II; FFA, free fatty acids; BP, blood pressure; FPG, fasting plasma glucose; TG, triglycerides; and HDL, high-density lipoproteins. Figure modified with permission from Opie LH. The metabolic syndrome, does it exist? In: Opie LH, Kasuga M, Yellon DM, eds. Diabetes at the Limits. Cape Town, South Africa: University of Cape Town Press; 2006:95–110.
Opie L H Circulation. 2007;115:e32-e35
Copyright © American Heart Association, Inc. All rights reserved.

24. Manifestations Obesity and Physical Inactivity Dyslipidemia
Insulin Resistance/IGT/Hyperinsulinemia (Na retention, SNS stimulation, HTN, increased circulating FFA).
Prothrombotic state
Pro-inflammatory state
Hyperuricemia defects in insulin action on the renal tubular reabsorption of uric acid.
Asymmetric dimethylarginine (endothelial dysfunction)
Homocysteinemia
Microalbuminuria
Non-alcoholic fatty liver
OSA
? Leptin deficiency/dysfunction (TG accumulation and ?hyperinsulinism)
NHLBI 2007

25. Diagnosis of Metabolic Syndrome
Large waistline
High TG and low HDL (3:1)
Blood Pressure >130/85
High FBS
About 85% of people with Type 2 Diabetes Mellitus have Metabolic Syndrome
NHLBI 2007

26. Case Report
A 45 year old man with a PHx significant for MCD, Obesity, Hyperlipidemia, HTN who despite counseling developed Type 2 DM.
BP controlled with ACEI.
Total cholesterol 303, TG 1498, Abnormal LFT’s, TC/HDL cholesterol 9.2

27. A patient is found to have Metabolic Syndrome; so what?

28. Metabolic Syndrome Metabolic Syndrome Obesity Type 2 Diabetes Mellitus
Hypertension
Insulin Resistance
Hyperlipidemia
Lifestyle
High Sodium Intake
High Caloric Intake
Atherogenic diet
Carbohydrate abuse
Sedentary living
plus
Predisposition
Type 2
Diabetes
Mellitus
Neuropathy
Nephropathy
Retinopathy
Vasculopathy
Premature
Coronary
Heart Disease
Tobacco
Abuse

29. Metabolic Syndrome is associated with risk of cardiovascular disease
The risk of vascular complications (CHD, Type 2 Diabetes Mellitus and Stroke) increase with the number of risk factors.
People with Metabolic Syndrome are twice as likely to develop CHD and 5 times as likely to develop Type 2 Diabetes Mellitus when compared to patients who do not have Metabolic Syndrome.
Coagulopathy (propensity for blood clotting) and inflammation (elevated C-Reactive Protein)
The risk must be added to finding of high LDL and smoking
NHLBI 2007

30. Risk of Metabolic Syndrome
Although the metabolic syndrome unequivocally predisposes to type 2 diabetes mellitus,48,58–62 many investigators of cardiovascular diseases consider this syndrome to be a multidimensional risk factor for ASCVD.1,58 Several recent reports show that the metabolic syndrome is associated with greater risk for cardiovascular disease,63–73 but once type 2 diabetes mellitus emerges, cardiovascular risk increases even more.
Ann Intern Med. doi: /M

31. Metabolic Syndrome-Risk
Other metabolic risk factors likewise appear individually to be: atherogenic diet
Hypertension
Elevated blood glucose
prothrombotic state
proinflammatory state.
Indeed, 3 of the metabolic risk factors—elevated apoB-containing lipoproteins,1 low HDL-C levels,1 and hypertension91—are well established, major risk factors. Each imparts increased risk even when only marginally abnormal.
Ann Intern Med. doi: /M

32. THERAPY

33. Treatments Healthy Lifestyle Eating a healthy diet/losing weight
Increasing physical activity
Quitting the cigarette smoking habit

34. The Diabetes Prevention Program
A randomized clinical trial testing strategies to prevent Type 2 Diabetes Mellitus.
High risk individuals with elevated fasting glucose and impaired glucose tolerance.
3,234 participants 27 centers in the U.S.- 20% of whom were over 65y/o.
Mean age 51y/o, BMI 34m/kg2.
Three interventions: intensive lifestyle intervention, Metformin, Placebo.

35. Diabetes Prevention Program
Primary outcome was development of Type 2 DM
Secondary outcomes: CVD, changes in glycemia, Beta cell function, insulin sensitivity, obesity, diet, physical activity, health related QOL, occurrence of adverse events.

36. Diabetes Prevention Program
Inclusion Criteria:
Age greater than or equal to 25y/o.
BMI >/= 24kg/m2.
IGT 2h plasma glucose
Elevated FPG (95-125mg/dl)

37. Diabetes Prevention Program
ILS reduced the incidence of Type 2 DM by 58%.
Metformin reduced the incidence of Type 2 DM by 31% over years.
6.9 participants with IGT would need to be treated with ILS for 3 years to prevent one case of Type 2 DM.
For Metformin 14.3 participants for 3 yrs to prevent one case Type 2 DM.
Cost analysis shows both therapies to be cost effective.
Diabetes Care 9/03

38. Lifestyle changes Losing weight Reduce salt in the diet
DASH diet (Dietary Approaches to Stop Hypertension)
Increase activity/Fitness

40. Therapy: Finnish Study
Study design:
Reduce fat intake
Reduce saturated fat
Increase Fiber
Increase exercise
Yield was a 60% reduction of Type II Diabetes.
Finnish Diabetes Prevention Study Group. Prevention of type-2 diabetes mellitus by changes in lifestyle among subjects with impaired glucose tolerance .Tuomilehto et al. N Engl J Med. 2001;344:1343–1350

41. Treatment of Metabolic Syndrome
Therapeutic Strategies:
1. Lifestyle changes, exercise, adherence to the Mediterranean diet, and weight loss
less new diabetes
2. Metformin (less new diabetes, not as good as lifestyle changes)
3. Glitazones, for non-diabetics with high cardiovascular risk: reduce fatty free acids, reduce insulin resistance, Increase HDL, must balance these against possible weight gain and heart failure
4. Choice of antihypertensives: -blocker/diuretic much more likely to cause metabolic syndrome than calcium channel blockers/angiotensin- converting enzyme inhibitors32
Opie L H Circulation. 2007;115:e32-e35

42. BEHAVIORAL COUNSELING TO PROMOTE A HEALTHFUL DIET AND PHYSICAL ACTIVITY FOR CARDIOVASCULAR DISEASE PREVENTION IN ADULTS WITH CARDIOVASCULAR RISK FACTORS CLINICAL SUMMARY OF U.S. PREVENTIVE SERVICES TASK FORCE RECOMMENDATION
Ann Intern Med. doi: /M

43. Importance of the Recommendations
Obesity is associated with increased CVD mortality
Adults who adhere to national guidelines for a healthy diet and physical activity have a lower cardiovascular morbidity and mortality than those who do not
All persons, regardless of CVD risk status, can accrue the health of improved nutrition, healthy eating behaviors and increased physical activity.
AnnInternMed.doi: /M

44. Proof of Efficacy
The task force found adequate evidence that intensive behavioral counseling interventions have moderate benefits for CVD risk in overweight or obese adults who are at increased risk for CVD, including:
Decreases in blood pressure, lipid and fasting glucose levels, and body mass index (BMI).
Increases in levels of physical activity.
The reduction in glucose levels was large enough to decrease the incidence of a diabetes diagnosis.
Ann Intern Med. doi: /M

46. Case Report
A 45 year old man with a PHx significant for MCD, Obesity, Hyperlipidemia, HTN who despite counseling developed Type 2 DM.
BP controlled with ACEI.
Total cholesterol 303, TG 1498, Abnormal LFT’s, TC/HDL cholesterol 9.2

47. Case Report: 57lb. Weight Loss
Total Protein 1.6g/24h
Cholesterol 303mg/dl HDL 32.9
Tc/HDL 9.2
LDL CNC
TG 1498
320mg/24h
Cholesterol 191mg/dl
HDL 49mg/dl
Tc/HDL 3.89
LDL 95mg/dl
TG 236mg/dl

48. Treatments/Medications
If lifestyle changes are inadequate; medication may be necessary:
Hypertension (Ace Inhibitors/Angiotensin Receptor Blockers)
Dyslipidemia (Statins and fibrates)
High Blood Sugar (Metformin)
Excessive blood clotting (ASA may be indicated)
Ann Intern Med. doi: /M

49. Disease Burden
Cardiovascular disease is the leading cause of death in the US
CVD risk factors are common in adults
Ann Intern Med. doi: /M

50. Disease Burden
The Center for Disease Control and Prevention estimates that nearly half of all U.S. adults aged 20 years or older have at least of the following CVD risk factors:
Uncontrolled hypertension
Elevated low density lipoprotein
Current smoking
Nearly 70% of U.S. adults are either overweight or obese
Ann Intern Med. doi: /M

51. Low carbohydrate vs. Low fat diet
1.Foster GD, et al. A randomized trial of a low-carbohydrate diet for obesity. New England Journal of Medicine, 2003.
Details: 63 individuals were randomized to either a low-fat diet group, or a low-carb diet group. The low-fat group was calorie restricted. This study went on for 12 months.
Weight Loss: The low-carb group lost more weight, 7.3% of total body weight, compared to the low-fat group, which lost 4.5%. The difference was statistically significant at 3 and 6 months, but not 12 months.
Conclusion: There was more weight loss in the low-carb group, significant at 3 and 6 months, but not 12. The low-carb group had greater improvements in blood triglycerides and HDL, but other biomarkers were similar between groups.
authoritynutrition.com

52. Low carbohydrate vs. Low fat diet
2. Samaha FF, et al. A low-carbohydrate as compared with a low-fat diet in severe obesity. New England Journal of Medicine, 2003.
Details: 132 individuals with severe obesity (mean BMI of 43) were randomized to either a low-fat or a low-carb diet. Many of the subjects had metabolic syndrome or type II diabetes. The low-fat dieters were calorie restricted. Study duration was 6 months.
Weight Loss: The low-carb group lost an average of 5.8 kg (12.8 lbs) while the low-fat group lost only 1.9 kg (4.2 lbs). The difference was statistically significant.
authoritynutrition.com

53. Low carbohydrate vs. Low carbohydrate diet
Conclusion: The low-carb group lost significantly more weight (about 3 times as much). There was also a statistically significant difference in several biomarkers:
Triglycerides went down by 38 mg/dL in the LC group, compared to 7 mg/dL in the LF group.
Insulin sensitivity improved on LC, got slightly worse on LF.
Fasting blood glucose levels went down by 26 mg/dL in the LC group, only 5 mg/dL in the LF group.
Insulin levels went down by 27% in the LC group, but increased slightly in the LF group.
Overall, the low-carb diet had significantly more beneficial effects on weight and key biomarkers in this group of severely obese individuals.
authoritynutrition.com

54. Low carbohydrate vs. Low fat diet
8. Meckling KA, et al. Comparison of a low-fat diet to a low- carbohydrate diet on weight loss, body composition, and risk factors for diabetes and cardiovascular disease in free-living, overweight men and women. The Journal of Clinical Endocrinology & Metabolism,
Details: 40 overweight individuals were randomized to a low-carb and a low-fat diet for 10 weeks. The calories were matched between groups.
Weight Loss: The low-carb group lost 7.0 kg (15.4 lbs) and the low-fat group lost 6.8 kg (14.9 lbs). The difference was not statistically significant.
authoritynutrition.com

55. Low carbohydrate vs. Low fat diet
Conclusion: Both groups lost a similar amount of weight.
A few other notable differences in biomarkers:
Blood pressure decreased in both groups, both systolic and diastolic.
Total and LDL cholesterol decreased in the LF group only.
Triglycerides decreased in both groups.
HDL cholesterol went up in the LC group, but decreased in the LF group.
Blood sugar went down in both groups, but only the LC group had decreases in insulin levels, indicating improved insulin sensitivity.
authoritynutrition.com

56. Low carbohydrate vs. Low Carbohydrate diet
19. Volek JS, et al. Carbohydrate restriction has a more favorable impact on the metabolic syndrome than a low fat diet. Lipids, 2009.
Details: 40 subjects with elevated risk factors for cardiovascular disease were randomized to a low-carb or a low-fat diet for 12 weeks. Both groups were calorie restricted.
Weight Loss: The low-carb group lost 10.1 kg (22.3), while the low-fat group lost 5.2 kg (11.5 lbs).
authoritynutrition.com

57. Low carbohydrate vs. Low fat diet
Conclusion: The low-carb group lost almost twice the amount of weight as the low-fat group, despite eating the same amount of calories.
This study is particularly interesting because it matched calories between groups and measured so-called “advanced” lipid markers. Several things are worth noting:
Triglycerides went down by 107 mg/dL on LC, but 36 mg/dL on the LF diet.
HDL cholesterol increased by 4 mg/dL on LC, but went down by 1 mg/dL on LF.
Apolipoprotein B went down by 11 points on LC, but only 2 points on LF.
LDL size increased on LC, but stayed the same on LF.
On the LC diet, the LDL particles partly shifted from small to large (good), while they partly shifted from large to small on LF (bad).
authoritynutrition.com

58. Case Report
Mrs. D. is a 46 year old woman with a PMH significant for Type 2 Diabetes Mellitus, Hypertension, Dyslipidemia, microalbuminuria, and morbid obesity who was seen in the clinic for weight loss management.
BP was 126/80, BMI 54.3kg/m2,
: HbA1C 7.6
: TC 163, LDL 89, HDL 56, TG 90
: weight 356 lbs
After weight loss of 60lbs, 70/30 insulin requirement has dropped.
From 70/ units bid to 30 units bid
: HbA1C has likewise dropped to 6.4

59. Physical Activity

60. Figure 1. A, Joint associations of waist circumference and physical activity with CHD, the Nurses’ Health Study 1986 to *Adjusted for age (<50, 50 to 54, 55 to 59, 60 to 64, ≥65), parental history of CHD, postmenopausal status and hormone use (never-use, past, current), physical activity (5 categories), aspirin use (<1, 1 to 2, 3 to 6, 7 to 14, 15+/wk), BMI (<25, 25 to 29.9, ≥30 kg/m2), and alcohol consumption (0, 0.1 to 4.9, 5 to 14.9, ≥15 g/d).
Figure 1. A, Joint associations of waist circumference and physical activity with CHD, the Nurses’ Health Study 1986 to *Adjusted for age (<50, 50 to 54, 55 to 59, 60 to 64, ≥65), parental history of CHD, postmenopausal status and hormone use (never-use, past, current), physical activity (5 categories), aspirin use (<1, 1 to 2, 3 to 6, 7 to 14, 15+/wk), BMI (<25, 25 to 29.9, ≥30 kg/m2), and alcohol consumption (0, 0.1 to 4.9, 5 to 14.9, ≥15 g/d). B, Joint associations of WHR and physical activity with CHD, the Nurses’ Health Study 1986 to *Adjusted for age (<50, 50 to 54, 55 to 59, 60 to 64, ≥65), parental history of CHD, postmenopausal status and hormone use (never-use, past, current), physical activity (5 categories), aspirin use (<1, 1 to 2, 3 to 6, 7 to 14, 15+/wk), BMI (<25, 25 to 29.9, ≥30 kg/m2), and alcohol consumption (0, 0.1 to 4.9, 5 to 14.9, ≥15 g/d).
Li T Y et al. Circulation. 2006;113:
Copyright © American Heart Association, Inc. All rights reserved.

61. Figure 2. Joint associations of WHR and BMI and CHD, the Nurses’ Health Study 1986 to *Adjusted for age (<50, 50 to 54, 55 to 59, 60 to 64, ≥65), parental history of CHD, postmenopausal status and hormone use (never-use, past, current), physical activity (5 categories), aspirin use (<1, 1 to 2, 3 to 6, 7 to 14, 15+/wk), and alcohol consumption (0, 0.1 to 4.9, 5 to 14.9, ≥15 g/d).
Figure 2. Joint associations of WHR and BMI and CHD, the Nurses’ Health Study 1986 to *Adjusted for age (<50, 50 to 54, 55 to 59, 60 to 64, ≥65), parental history of CHD, postmenopausal status and hormone use (never-use, past, current), physical activity (5 categories), aspirin use (<1, 1 to 2, 3 to 6, 7 to 14, 15+/wk), and alcohol consumption (0, 0.1 to 4.9, 5 to 14.9, ≥15 g/d).
Li T Y et al. Circulation. 2006;113:
Copyright © American Heart Association, Inc. All rights reserved.

62. Goals of Therapy Prevent risk of heart disease
Prevent Type 2 Diabetes Mellitus
Manage risk factors that can be controlled (weight and sedentary lifestyle) and smoking
Ann Intern Med. doi: /M

63. Prevention and Delay of Metabolic Syndrome
Regular follow up with the primary care physician
A lifelong commitment to a healthy lifestyle (eating habits and exercise)
Long-term effort
Because of the rise in the prevalence of obesity, Metabolic Syndrome may overtake smoking as the leading cause of Coronary Heart Disease.
Ann Intern Med. doi: /M

64. Summary Onset of Type 2 DM can be delayed.
The results have been replicated in Finland and China.
Assess CVD risks in each patient
Managing each cardiac risk factor with ILS interventions and the appropriate medications can reduce CVD morbidity and mortality.

65. Thank you…….

66. Pathophysiology
Adipose tissue is an endocrine organ. It liberates excess FFA, AT II and adipokines
The rise of FFA in the blood inhibit uptake of glucose by muscle.
Excess FFA + AT II damage the pancreas (Lipotoxicity)
Pancreas increases insulin but not enough to counter the rise of blood sugar, therefore; both insulin and blood sugar rise.
Opie L H Circulation. 2007;115:e32-e35