Impaired Glucose Tolerance and Risk for Morbidity

1
Impaired Glucose Tolerance and Risk for Morbidity

• Yolanda Y. Clay-Po, M.D.
• Resident Grand Rounds
• April 6, 1999

2
Case Presentation

• H.N. is a 44 year old African-American male who
  presented to Reynolds Health Center walk-in
  clinic requesting a 3-hour glucose tolerance test
  because he wanted to make sure he was not a
  diabetic. He had been told that he had an
  elevated blood sugar at an outside hospital one
  week previously
• The patient was told that glucose tolerance
  testing was not necessary to diagnose diabetes.

3
Case presentation

• ROS-negative for polyuria,polydipsia,or
  polyphagia
  
• PMH-none
• PSH-none
• FH-positive for Diabetes mellitus in mother
  maternal aunts and uncles
  

• SH-no tobacco, no ETOH, no illegal drugs currently

4
Case presentation

• Vitals BP 124/74 weight 240 lb.
  Afebrile
  
• Physical exam-General mildly obese male in no
  distress
  
• HEENT no scleral icterus,mucosa moist
• neck no JVD, no thyromegaly
• chest clear to auscultation
• CVS regular rhythm,rate normal, no murmurs
• Abdomen obese,bowel sounds present,non-tender
  no organomegaly appreciated
  
• extremities without edema

5
Case Presentation

• At the patients request, a 3-h OGTT was
  performed
  

6
Laboratory Data
7
Patient questions

• Am I a diabetic?
• What do you mean I have glucose intolerance?
• What can I do to prevent diabetes

8
Clinical Questions?

• What is diabetes mellitus type 2?
• How is diabetes diagnosed?
• What are the screening criteria?

9
Diabetes mellitus diagnostic criteria

• Diagnostic criteria for Diabetes mellitus type 2
  (DM 2) have recently been redefined by the Expert
  Committee on diagnosis and Classification of
  Diabetes
• there were no changes made in the treatment of
  diabetes or the treatment goals for diabetes
  
• changes were made in an attempt to diagnose
  diabetes earlier and to prevent the complications
  of diabetes from occurring

10
How to Diagnose Diabetes Mellitus

• There are three ways to diagnose diabetes
  mellitus
  
• Symptoms random glucose 200mg/dl
• Fasting Glucose 126mg/dl
• Oral glucose tolerance testing with a 2-hour post
  glucose load of 200mg/dl
  

11
Who should be Screened for Diabetes?

• 45 years
• diabetes
  
• obesity
• first degree relative with DM
• member of a high risk population
• gestational diabetes or delivery of an infant
  9lbs.
  
• History of impaired glucose tolerance or impaired
  fasting glucose
  
• hypertension or hypertriglyceridemia 250mg/dl

12
Diagnosis of Diabetes Mellitus

• Hemoglobin A1c(Hba1c) has been studied for use in
  the diagnosis of diabetes but is not recommended
  as a diagnostic test because of
  
• wide variability in the methods used in studies
• difficulty in assigning cutpoints as with glucose
  levels
  
• variability of normal ranges

13
Why were criteria revised?

• FPG was found to be identical to 2-hPG in
  measuring the development of retinopathy in Pima
  Indians
  
• FPG was an easier test to administer
• FPG had easily reproducible results
• low cost screening test

14
Pathophysiology of Insulin Resistance
15
Progression to Diabetes Mellitus

• The mechanism of conversion from IGT to diabetes
  is not known
  
• It is suspected that it is a two part mechanism
• insulin resistanceinc.glucose
  concentrationsincreased insulin secretion
  beta cell failure

16
Diagnosis of Impaired Glucose Tolerance

• Impaired glucose tolerance was defined by the
  Expert Committee as
  
• Fasting Plasma glucose of 110-125mg/dl
• 2-hour post glucose load 140-199mg/dl

17
Clinical questions

• Is glucose intolerance a risk factor for other
  diseases?
  
• How will this evidence help me in advising my
  patient?
  
• Should glucose intolerance be treated as a true
  disease state?
  

18
Impaired Glucose Tolerance and Coronary Artery
Disease
19
Diabetes Mellitus and CAD risk

• Pan et al. Am J Epidem vol 123,vol. 3 504-516
  also examined the relationship between
  hyperglycemia and the risk of CAD
  
• objective to ascertain if a sex differential
  existed in the risk of death from CAD
  
• study type epidemiological
• subjects 19,252 Caucasians without previous MI
  selected from a cohort of the Chicago Heart
  Association Detection Project in Industry

20
Diabetes Mellitus and CAD risk

• Methods 19,252 persons (11,220 males, 8030
  females) were screened with a 50-g glucose load
  
• other CAD risk factors were screened for
  including cholesterol levels, blood pressure and
  EKG abnormalities

21
Diabetes Mellitus and CAD

• Relative Risk
• Normal men normal women 4.87
• DM men DM women 3.27
• DM menNormal women 5.91
• DM women/Normal men 1.06

22
Diabetes Mellitus and CAD risk

• Men were more vulnerable than women to heart
  disease
  
• Men with DM 2 had an increased risk of dying
  compared to non-diabetic males
  
• age-adjusted risk of a woman with DM 2 was the
  same as that of a man without DM 2

23
Diabetes Mellitus and CAD risk

• Problems
• Standard dosing of 75-g load was not used
• patients divided into groups based on a single
  value from a test known to have widely variable
  responses
  
• excluded population of interest

24
Impaired Glucose Tolerance and Coronary Artery
disease Risk

• Meigs et al. Ann. Int. Med. 128 524-533 1998
  (Framingham Offpring study)
  
• study type cross-sectional study
• study goal examine the relationship between
  metabolic risk factors for CAD and glucose
  intolerance
  
• participants 2874 members of the cohort not
  known to have diabetes
  

25
IGT and CAD risk

• Method 75-g glucose tolerance test performed on
  participants without diabetes
  
• glucose tolerance determined using 1980 WHO
  criteria
  
• risk factors for CAD were assessed including
• blood pressure
• body mass index
• HDL cholesterol and triglyceride levels
• serum insulin levels
• cigarette smoking

26
IGT and CAD risk

• 2.5 of NGT women and 3.8 of NGT men had 4 risk
  factors
  
• 17.7 of IGT women and 29.2 of IGT had 4 risk
  factors
  
• 38.9 of DM 2 women and 43.7 of DM 2 men had 4
  risk factors
  
• these data imply that persons with IGT are in an
  intermediate risk category for CAD

27
IGT and CAD risk

• Levels of all Metabolic risk factors increased
  with each incremental change by quintiles in
  glucose tolerance
  
• Those found to have previously undiagnosed DM 2
  had higher levels of all risk factors
  
• The number of persons with 4 risk factors
  increased with increasing glucose tolerance
  
• There was no distinct threshold above which
  metabolic risk increased

28
IGT and CAD

• Follow-up for this group of patients is very
  complete
  
• Participants are from a community not a tertiary
  referral center so referral bias is not likely
  
• unbiased criteria were used to measure outcome
  (HTN,BMI etc.)
  
• age adjustment was performed for important risk
  factors

29
Problems

• Average age of patients studied was 54 years
• population was predominantly Caucasian
• criteria used for diagnosis of DM 2 had lower
  cutpoints

30
Progression to Diabetes
31
Progression to Diabetes

• The mechanism of conversion from IGT to diabetes
  is not known
  
• It is suspected that it is a two part mechanism
• insulin resistance inc.glucose concentrations
  increased insulin secretion beta cell
  failure

32
Progression to Diabetes

• Viswanathan et al Diabetes Res and Clin Prac 35
  (1997) 107-112
  
• investigated the relationship between weight loss
  and progression to diabetes
  
• 119 non-diabetic offspring of diabetic parents
  underwent 2-h GTT with a 75-g glucose load to
  establish glucose tolerance status
  
• The participants were then given dietary advice
  based on their body mass index

33
Progression to Diabetes

• Dietary advice
• 60 carbohydrate
• 20 protein
• 20 fat
• avoid sweets, refined sugar

• Exercise advice
• walking
• jogging
• aerobics

34
Progression to Diabetes

• All participants had individualized physician
  and registered dietician follow-up to assess
  compliance for the entire study period

35
Progression to Diabetes

• Results
• progression to diabetes occurred in 14.5 of
  study participants
  
• In the normal group 6 progressed to diabetes
  while 19.3 became IGT
  
• In the EGI group16.1 became diabetics and 26
  progressed to IGT
  
• In the IGT group 30.4 became diabetics and 21.4
  had normal glucose tolerance
  

36
Progression to Diabetes

• Rate of development of diabetes was greatest in
  those who gained weight (p
• Weight gain most commonly occurred in
  noncompliant persons
  
• NGT was most common in those who maintained their
  body weight or lost weight
  

37
Progression to Diabetes

• Limitations
• waist-to-hip ratio was not measured in this study
  which may underestimate the role of increased
  abdominal fat in the progression to diabetes
  
• The effect of change in fat distribution could
  not be evaluated

38
Progression to Diabetes

• Pan et al Diabetes Care vol 20 no. 4,April 1997
• Clinical Question Do diet and exercise
  interventions delay the progression of IGT to
  diabetes?
  
• Methods 110,660 people screened for IGT and
  diabetes with a fasting PG and 2h GTT
  
• 577 identified as IGT
• 530 subjects (283 male/247 female)were followed
  for a 6-year period
  

39
Progression to Diabetes

• Clinics were randomized to interventions
• diet only
• exercise only
• diet and exercise
• control group

40
Progression to Diabetes

• Exercise advice
• counselling
• increase level of exercise
• type of exercise and rate dependent on age and
  exercise patterns
  
• indoor exercise in winter

• Diet advice
• 55-65 carbohydrate
• 10-15 protein
• 25-30 fat
• inc. vegetables
• moderate ETOH
• dec. sweets
• regularly scheduled counseling sessions

41
Progression to Diabetes

• Diet Exercise
• similar to previous diet and exercise groups

• Control Group
• general informations on diabetes given
• Clinic M.D.s dispensed brochures on diet and
  exercise
  
• No counseling

42
Progression to Diabetes

• Subjects systematically followed with general
  medical exam in 2 year intervals with repeat FPG
  and 2-h GTT
  
• Those with diabetes had reached the endpoint of
  the study
  
• each group was analyzed separately and compared
  by several variables

43
Progression to Diabetes

• Results
• the incidence of diabetes in the control group
  was higher than any of the intervention groups at
  15.7/100 person years (95 CI, 12.7-18.7)
  
• NO significant difference was found between the
  intervention groups
  
• diet group10/100 py (95 CI, 7.5-12.5)
• exercise group8.3/100 py (95 CI, 6.4-10.3)
• diet exercise group 9.6/100 py (95 CI,7.2-12.0)

44
Progression to Diabetes

• Baseline physical activity was not predictive in
  the development of diabetes
  
• The rate of development of diabetes was greater
  in the obese subjects compared with the lean
  subjects across all intervention groups

45
Progression to Diabetes

• When compared with the control group there was
  a
  
• 33 reduction in the incidence of diabetes in the
  diet only group (p
  
• 47 reduction in the exercise only group(pRR.53
  
• 38 reduction in the diet exercise group RR.62

46
Progression to Diabetes

• Conclusions
• lifestyle interventions can be effective in
  reducing the incidence of diabetes mellitus in
  persons with IGT
  
• There was no significant difference between the
  effectiveness of the different interventions
  

47
Progression to Diabetes

• Concerns
• Subjects were assigned to clinics who then
  administered the interventions
  
• can results be generalized to my patient?

48
Progression to Diabetes

• EAT LESS
• MOVE MORE

49
Impaired Glucose Tolerance and Retinopathy
50
IGT and Retinopathy

• Rajala et al. Diabetes Care vol 21,no.10, Oct.
  1998
  
• Study type cross sectional study
• Objective appraise the ability of the new
  diabetes criteria to distinguish between those at
  high risk for retinopathy and those at low risk
  
• subjects 1,008 persons born in 1935 in Oulu,
  Finland were screened

51
IGT and Retinopathy

• Method 780 participants were screened with a
  random glucose level
  
• further testing was done if the screen showed a
  glucose level of 144mg/dl (8.0 mmol/l)
  
• fasting 121mg/dl (6.7 mmol/l) the patient was
  diabetic and referred for treatment
  
• 51 people refused this first phase but
  participated in the second phase
  
• participants also had cholesterol, HDl, and
  triglycerides measured

52
IGT and Retinopathy

• 831 subjects underwent phase 2 of the trial which
  included retinal fundus photography and 2-h GTT
  testing
  
• 790 photos were evaluated by an ophthalmologist
  specializing in retinal disease
  
• retinas were scored on a scale of 1-4 (1 no
  retinopathy,4 proliferative retinopathy)
  
• 2-h GTT was performed to identify glucose
  tolerance

53
IGT and Retinopathy

• Results
• retinopathy was seen on 28 of the 790 gradeable
  photos
  
• 32 subjects had diabetes of 7 years duration
• 36 subjects were diagnosed with diabetes
• 207 subjects had IGT
• 519 subjects had normal glucose tolerance (NGT)

54
IGT and Retinopathy

• Results(contd)
• When stratified by level of glycemia the
  prevalence of retinopathy was
  
• Diabetics 7 (25 ) 95 CI 10.7-44.9
• new diabetics 1 (2.9) 95 CI 0.1-15.3
• IGT 4 (2) 95 CI 0.5-4.9
• NGT 15 (2.9) 95 CI 1.6-4.7

55
IGT and Retinopathy

• Results(contd)
• When retinopathy was stratified according to
  level of glycemia in FBG
  
• 14.3 for FBG 121mg/dl
• 5.1 for FBG 110-119mg/dl
• 2.6 for FBG

• When the groups were dichotomized into FBG and 110
  
• 10.2 for FBG 110
• 2.9 for FBG

56
IGT and Retinopathy

• Rajala et al concluded that the new criteria were
  indeed useful in identifying those at risk for
  retinopathy
  
• Limitations
• some data missing in 6 of participants who
  dropped out of phase one
  
• variability in other studies using different
  methods to photo retina

57
IGT and Retinopathy

• Klein et al Diabetes Care.vol.14,no.10, Oct
  1991
  
• performed a similar study on the Rancho Bernardo
  cohort
  
• Study type cross sectional
• Subjects 1959 Caucasian adults 55 years whose
  glucose tolerance status was known

58
IGT and Retinopathy

• Methods
• Visual acuity was measured with a standard eye
  chart at 15m
  
• fundus photos were taken through dilated pupils
• photo grader was masked to any information about
  subjects

59
IGT and Retinopathy

• Results
• visual impairment was more prevalent with
  increasing age (brilliant!)
  
• NGT participants were found to have the highest
  frequency of retinopathy
  
• women with IGT were found to have higher rates of
  visual impairment than women with NGT
  
• Men with IGT had a higher rate of visual
  impairment than diabetic males but this was
  attributed to the higher death rate of diabetic
  males in this cohort

60
IGT and Nephropathy

• The Diabetes Control and Complication Trial
  (DCCT)Kidney Int vol 47 (1995) 1703-1720
  
• The DCCT research group showed that the
  development and progression of complications of
  Type 1 diabetes mellitus could be altered with
  intensive insulin therapy
• The incidence of microalbuminuria was also
  diminished with tighter glycemic control
  
• There have been few randomized controlled trials
  showing a similar relationship between IGT and
  the development of nephropathy

61
IGT and Nephropathy

• Wasada et al Diabetes Res and Clin Prac 34
  (1997) 157-162
  
• studied the relationship between urinary albumin
  excretion rates (UAER) and insulin resistance
  
• Study type Experiment
• Method 53 diagnosed with IGT after a 2-h GTT
• the group was then divided into hypertensive (SBP
  140mmHg, DBP 90 mmHg) and normotensive
  
• subjects underwent measurement of glucose
  infusion rate (GIR), a measure of insulin
  sensitivity,by the euglycemic clamp method
  
• Insulin infused at 1.12mU/kg/min along with 10
  glucose solution to keep glucose at 80 mg/dl
  
• a 24 hour urine collection was made for albumin
  C-peptide, plasma insulin and BMI were measured

62
IGT and Nephropathy

• Results
• In the Normotensive group
• glucose infusion rate (GIR)levels were lowest in
  subjects with the highest BMI ( low insulin
  sensitivity in overweight subjects) (p0.0204)
  
• Plasma insulin levels were highest in the lowest
  GIR group (hyperinsulinemia) (p0.0112)
  
• UAER was found to be inversely proportional to
  the GIR level (p0.0007)
  

63
IGT and Nephropathy

• In the Hypertensive group
• UAER was not higher with lower GIR
• lower levels for GIR were seen
• BMI was higher in the lower GIR group
• Plasma insulin levels were also higher in the
  lower GIR group

64
IGT and Nephropathy

• Conclusions
• increased UAER was a feature of insulin
  resistance in subjects at risk for diabetes
  
• UAER was correlated with lower GIR (p0.0007)
• Plasma insulin levels were higher in the lower
  GIR group (p0.0112)
  

65
Conclusions

• IGT is an intermediate state between normal
  glucose tolerance and diabetes mellitus type 2
  
• Individuals at risk for Diabetes should be
  screened for IGT
  
• IGT is likely a risk factor for CAD, nephropathy
  and retinopathy but in the studies reviewed most
  subjects would be reclassified using the new
  criteria
• Increased activity and weight loss are key in
  reducing insulin resistance which is a herald of
  eventual pancreatic failure
  
• Medical management of IGT may become common
  practice in the future
  

66
Case conclusion

• H.N was told
• that he was a high risk for developing diabetes
• weight loss was key in preventing progression
• detailed information about dietary and lifestyle
  modifications
  
• that he could have a referral to In Control and
  to the nutritionist
  

67
Case Conclusion

• Ideally this patient also should have had another
  2h GTT in 2-3 weeks to evaluate his glucose
  tolerance
  
• An elevated blood glucose in the diabetic range
  would warrant starting an oral agent, such as
  metformin
  

68
Case conclusion

• Patient did not keep several follow-up
  appointments and was lost to follow-up

69
Special Thanks to

• Dr. Sandra Werbel
• Dr. Michael Pursely
• Dr. Amanda Ebright
• Dr. Scott Landry