1. Control of delta (d) glucose is determinant of renal preservation in diabetes
Anil K. Mandal
MB. BS. FACP, FASN, FICP
Fulbright Scholar
Mandal Diabetes Research Foundation of USA
Harbhajan Singh-Mandal Diabetes Foundation of India
Deliver at
All India Institute of Medical Sciences, New Delhi -August 28, 2015
Centenary Celebration Lecture, Banaras Hindu University
October 8-10, 2015

2. Presentation Categories
Historical Perspective of Diabetes
Inconsistency in Diabetes Care
Relationship of post prandial hyperglycemia to outcome measures (cardiovascular) in diabetes
Glycemic control with Intensive Insulin treatment Fundamental to Renal Preservation in Diabetes
Novelty of dglucose
Pearl of Wisdom

3. A. Historical perspective of diabetes and discovery of insulin
In 1916, the Romanian scientist Nicolae Paulescu ( ) found that injection of aqueous pancreatic extract normalized blood sugar in a diabetic dog.
In 1922, Frederick Banting and Charles Best reported use of a pancreatic extract for normalizing blood sugar levels in a diabetic dog

4. Historical Perspective (Cont.)
Historical patient Leonard Thompson, a 14 years boy first one to receive pancreatic extract. He had diabetes since His blood sugar returned to normal, he became brighter and stronger.

5. Historical Perspective (Cont.)
August Krogh began insulin purification in Copenhagen, Denmark in December Assisted by Danish Physician H.C. Hagedorn Krogh founded Nordic Insulin Laboratory, to produce insulin NPH (Neutral protamine Hagedorn,) an intermediate acting insulin in Eli Lilly and Company began commercial production of insulin called Isletin insulin in Indianapolis, Indiana, USA

6. B. Inconsistency of Diabetes Care
Fasting blood glucose (FBG)
2-hour postprandial glucose (2hPPG) in a random fashion or in a 4-hour oral glucose tolerance test (OGTT)
Glycosylated hemoglobin (HbA1c)

7. Inconsistency of Diabetes Care (Contd)
A recent opinion piece in JAMA concluded that HbA1c remains the only test that predicts the microvascular complications of diabetes (1)
(1) JAMA 2014; 34:

8. Inconsistency in Diabetes Care (Contd.)
2. Pharmacologic Interventions in diabetes directed at lowering FBG and HbA1c. Historical Reasons:
Testing under fasting conditions convenient for clinical and research settings.
To establish clinical guidelines for diabetes management and for rating efficacy of management.
FBG and HbA1c used as primary endpoints in landmark studies of diabetes

9. Inconsistency of Diabetes Care (Contd.)
In 1995, the authors of landmark DCCT wrote “Mean HbA1c not the complete expression of degree of hyperglycemia. For example, the risk of complication more highly dependent on the extent of post prandial glycemic excursion.

10. US RENAL DATA SYSTEM Incidence of ESRD by Primary Diagnosis
QUESTION: Again Why and How?

11. Fallacious overestimation of DM and artificial epidemic of dm
Example
Fortuitous Epidemic of Diabetes
Patient #1: 64y AAM
Referred for uncontrolled hypertension + hypokalemia
Medication:
Diltiazem CD 360mg x 1 daily
Amlodipine 10mg x 1 daily
Triam/HCTZ 37.5/25mg x 1 daily
Kcl 20mEQ t.i.d.
Triam = Triamterene/HCTZ = Hydrochlorothiazide
Probably Hydrochlorthiazide the most common cause of epidemic of DM
Glucose levels next

12. Patient 1 (cont.) Year 2009 2010 2011 Glucose mg/d (mmol/L) Oct 26
Random
186 (10.3)
Nov 6
Triam/HCTZ
discontinued
Nov 17
Fasting
113 (6.2)
2hPP
153 (8.5)
HbA₁c
6.1%
Dec 30
147 (8.1)
5.9%
July 1
Fasting 104 (5.7)
2hPP 109 (6)*
Sept 15
2hPP 119 (6.6)*
No Diabetes
* Hyperglycemia induced by HCTZ
* 2hPP lower than normal (140mg/dL) due to high insulin response. Serum insulin (2hPP) = 62.7 luo/L *(n = ) Potential for overt diabetes.
Prevention: Low Carbohydrate diet

13. Undiagnosed NIDDM: Clinical and Public Health Issues MI Harris, Diabetes Care 1993; 16: 642-652
A splendid article in understanding the definition of diabetes and its risk profile.
2hPPG≥200mg/dL (≥11.1mmol/L) with normal fasting blood glucose portend highest risk of developing complications.
National Diabetes Data Group: Elevated 1h post challenge glucose value ≥200mg/dL in addition to an elevated 2hPPG required for diagnosis of diabetes [1].
2h post-challenge glucose ≥200mg/dL is the key for diagnosis of diabetes.
[1] National Diabetes Data Group: Classification and diagnosis of diabetes mellitus and other categories of glucose intolerance. Diabetes 1979; 28:

14. Screening for Undiagnosed NIDDM
Screening Test
Sensitivity (%)
Specificity (%)
Positive Predictive Value (%)
OGTT
2-H ≥ 200mg/dL 97
100
FPG
≥ 100 mg/dL 83 76 21
≥ 120 mg/dL 54 98
≥ 140 mg/dL 31
NHANES II, yrs. of age
Adapted from: MI Harris, Diabetes Care 1993; 16:

15. C. Postprandial Hyperglycemia Importance and Consequences Lebovitz He
C. Postprandial Hyperglycemia Importance and Consequences Lebovitz He. Diab Res Clin Pract 1998; 40 (Suppl): S27-S28
Approximately 50% of individuals with undiagnosed diabetes have FBG of <7.0mmol/L (126mg/dL) but 2hPPG exceeding 11.1mmol/L (>200mg/dL)
PPG persists for several years before fasting hyperglycemia develops.
Thus, earliest abnormality in diabetes is postprandial hyperglycemia.

16. Culture of 2hPPG (cont.) Cardiovascular Mortality
From six population-based studies
Study
Population,
Age (y)
Duration of Follow-up (y)
Risk of Postprandial Hyperglycemia
Hoorn
2,363 Dutch males & females, 50-75 8
CV mortality: 3.3 in patients w/ 2hPG≥11.1mmol/L
Shaw et al.
9,179 males & females from Mauritius, Fiji, and Nauru, ≥20
5-12
CV mortality: 2.6 in patients w/ 2hPG≥11.1mmol/L
Honolulu Heart
8,006 Japanese American males, 45-68 23
CHD mortality: 2.01 in patients w/ 1hPG≥11.1mmol/L
Rancho Bernado
1,704 males & females, 50-89 7
CV mortality: 2.6 in women w/ 2hPG≥11.1mmol/L (women patients)
Cardiovascular Health
4,515 American males & females
CV mortality: 1.22 in glucose intolerant
Chicago Heart Assn/ Detection Project in Industry
11,554 white & 666 black males, 35-64 22
CV mortality: 1.18 in white males w/ 2hPG≥11.1mmol/L (white male patients)
hPG = hours post-glucose challenge; CV = cardiovascular; CHD = coronary heart disease
Adapted from Charpentier G, et al. Should postprandial hyperglycemia in prediabetic and type 2 diabetic patients be treated?
Drugs 2006; 66 (3):

17. Culture of 2hPPG Glucose Intolerance and Cardiovascular Mortality (CONT)
Comparison of Fasting and 2-hour diagnostic criteria. Arch Intern Med 2001; 161:
DECODE Study Group, the European Diabetes Epidemiology Group.
DECODE confirmed PPG’s major role, grouping 10 European studies totaling 22,514 subjects aged years with a median follow-up of 8.8 years.
Addition of FBG didn’t improve results.
2hPPG alone was predictive of cardiovascular risk
Patients with 2hPPG ≥11.1mmol/L had a hazard ration of for death from coronary artery disease and 1.29 for death from stroke.

18. Duration of Follow-up = 14.2 months (1.5-115 months)
Glycemic control with Intensive Insulin Therapy Fundamental in Diabetes
Current Trends in Endocrinol 2014; 7: 15-22
46 patients
F=28 M =18
Duration of Follow-up = months
( months)

19. Therapy
Glargine or detemir insulin after breakfast and dinner. Regular insulin by finger stick 2-h post meal and bedtime
Blood pressure control with antihypertensive drugs with exclusion of ACEI/ARB drugs.

20. Purpose of this study
Many studies in the past documented benefits of glucose control in prevention of microvascular and macrovascular complications.
DCCT only reported long term follow-up into ESRD.
Our purpose to determine the efficacy of control of 2hPPG (post prandial hyperglycemia) in reducing the risk of diabetes-related ESRD.

21. Average Fasting (F) , 2hPP and dglucose (2hPP-F)
First Visit
mmol/L
Last Visit *P
values
All patients
n=46 F
10.3±0.7
8.4±0.6
0.017
2hPP
15.2±0.9
14.0±0.80
0.281 d
5.6±0.6
0.975
>11.1 mmol/L
n=31
11.2±0.8
9.6±0.8
0.124
16.1±1.1
16.4±0.7
0.839
5.7±0.7
6.7±0.6
0.262
<11.1 mmol/L
n=15
8.4±1.2
5.7±0.3
0.048
13.5±1.6
8.9±0.6
0.009
5.3±1.2
3.3±0.5
0.073

22. Serum Creatinine (Scr), FScr, 2hPPScr and dScr
First Visit
µmol/L
Last Visit *P
values
All patients
n=46 F
110.9±7.8
100.3±5.2
0.013
2hPP
109.4±6.1
106.0±5.6
0.167 d
6.0±1.3
5.8±1.0
0.846
>11.1 mmol/L
n=31
99.1±7.4
95.8±6.3
0.214
105.6±7.9
101.2±6.8
0.149
6.6±1.6
5.4±1.2
0.539
n=15
113.8±8.8
111.0±9.2
0.552
118.5±8.4
117.6±9.7
0.823
4.8±2.3
6.6±2.1
0.438

23. eGFR

24. Glycosylated hemoglobin at First and Last Visit
First visit
Last Visit
P Values
HbA1c%
All patients
9.15±0.32
8.61±0.29
0.1785
>11.1 mmol/L
9.16±0.41
9.12±0.33
0.9356
< 11.1mmol/L
9.14±0.52
7.60±0.45
0.0148

25. Average Systolic, Diastolic and Mean Blood Pressures at first and last visits in all patients and when 2hPP Glucose is > or < 11.1 mmol/L
First Visit
mmHg
Last Visit *P
First visit vs Last
All patients
n=46
Systolic
136.2 ± 3.3
± 2.6
0.4777
Diastolic
81.6 ± 1.9
77.0 ± 1.5
0.0297
Mean
99.8 ± 2.0
77.0 ± 1.5
0.0806
>11.1 mmol/L
n=31
± 4.2
± 2.7
0.5495
± 2.3
77.6 ± 1.7
0.0795
99.9 ± 2.6
96.1 ± 1.4
0.1383
<11.1 mmol/L
n=15
± 5.4
± 5.8
0.7154
80.9 ± 3.5
75.7 ± 3.2
0.2233
99.9 ± 3.4
95.3 ± 3.4
0.3644
* Two-tailed paired t-test

26. E. Novel Approach with Introduction of dglucose
delta (d) glucose = (2hPPG-FBG)
Correlation of dglucose to same calcuted differences (2hPP-F) fBUN (dBUN), serum creatinine (dSCr) and estimated glomerular filtration rate (deGFR)
Analysis of 56 adults with diabetes (F=29, M=27) Mean age 68.7 ± 13.5 years (R=19-91)
Therapy: Insulin, combination of short-acting on a sliding scale and long acting Lantus after breakfast and dinner. Fewer than 5 patients also received oral agents.

27. A strong positive correlation seen between dglucose and dScr when 2hPPG greater than 200mg/dL (r=0.0523, p=0.0018) but not in patients with 2PPG less than 200mg/dL ( r=0.142 p= )
Similarly a strong negative correlation seen between dglucose and deGFR in patients with 2PPG greater than 200mg (r=0.513, P=0.0023) but not in those with 2hPPG less than 200mg/dL (r= 0.064, p =0.7723)
Shown The next slide

28. Elucidation (cont.) Correlation of dSCR (2hPP-F) with dGlucose (2hPP-F)
Correlation between dScr and dglucose and correlation coefficients and p values are shown for all 56 patients (dashed line, all data points), for patients whose 2hPP glucose is greater than 200 mg/dL (solid line, black circles, n = 33) and for patients whose 2hPP glucose is less than 200 mg/dL (dotted line, open circles, n = 23)
Correlation between deGFR and dglucose and correlation coefficients and p values are shown for all 56 patients (dashed line, all data points), for patients whose 2hPP glucose is greater than 200 mg/dL (solid line, black circles, n = 33) and for patients whose 2hPP glucose is less than 200 mg/dL (dotted line, open circles, n = 23).
Figures Adapted from Mandal AK and colleagues. Diab Res Clin Pract 2011; 91:

29. Conclusion of this Study
Our novel glycemic parameter of dglucose below 5.5mmol/L (99mg/dL) is a stronger predictor of renal protection than 2hPPG.
This study recommends paired testing of fasting and 2hPP Basic Metabolic Panel for glucose level and renal function test

30. Control of dglucose is determinant of renal preservation in diabetes (unpublished)
This study is an expansion of a previous study but with longer duration
Eighty five diabetic patients treated with a combination of glargine or detemir and regular or fast acting insulin for 26.3 ± 24.5 (SD) months
Angiotensin converting enzyme inhibitors and receptors blockers (ACEI/ARB) excluded inorder to reduce the risk of acute and chronic renal failure
* Presented in American Society of Nephrology Annual Meeting, Philadelphia, November 15, 2014

31. Fasting (F) and 2-hour post prandial (2hPP) glucose, serum creatinine (Scr) and estimated glomerular filtration rate (eGFR), HbA1c, sitting and diastolic BP were recorded for first and last visits.
Mean blood pressure (systolic + 2 diastolic/3) and differences (d, 2hPP-F) calculated for glucose, Scr and eGFR.
Parameters between first and last visits compared using a paired t-test adjusted for age, gender and duration of treatment with P < considered significant

32. Changes in blood glucose, HbA1c, Scr and eGFR in a population of 85 diabetic patients
Variable No
First Visit
Mean SD
Last Visit
Mean SD
First
Vs Last P*
Change
Mean SD
Fasting Glucose (mg/dL) 59
175.2
83.6
166.2
87.9
0.5243
-9.7
107.6
2hPP Glucose
(mg/dL) 57
244.0
98.2
217.2
94.8
0.1119
-26.8
124.2
dGlucose (mg/dL) 41
63.5
67.2
36.6
64.8
0.0449
-26.9
82.2

33. Sitting and standing blood pressures
Variable No
First Visit
Mean SD
Last Visit
Mean SD
First
Vs Last P*
Change
Mean SD
Sitting Systolic Pressure (mmHg) 74
133.1
171.1
128.4
13.9
0.0319
-4.8
18.5
Sitting Diastolic Pressure (mmHg)
81.8
11.9
78.9
12.4
0.0546
-2.9
12.7
Sitting mean Pressure (mmHg)
98.9
11.3
95.4
10.9
0.0151
-3.5
12.0

34. Correlation between HbA1c and fasting glucose (A), 2hPPG (B) and HbA1c (C). Significant correlation obtained between HbA1c and fasting and 2hPP glucose levels

35. Correlation between HbA1c and fasting Scr , 2hPP Scr and dSCr
Correlation between HbA1c and fasting Scr , 2hPP Scr and dSCr. Significant correlation obtained between HbA1c and dScr only

36. Correlation between dglucose and dScr. Pretreatmenr values combined
Correlation between dglucose and dScr. Pretreatmenr values combined. Significant correlation obtained between dglucose and dScr dglucose (2hPPG- FBG) higher than 50 likely associated with increase in serum creatinine.

37. Confirms the relationship between dglucose and dScr
Patient1
Fglucose
2hPP
Glucose
dglucose
mg/dl
FScr
Scr
dScr 1
151
178 27
1.6 2
141
270
129
1.7
0.1 3
193
214 21 4
207
1.00 5
109
232
123
1.28
1.49
0.21

38. Analysis of the Previous Slide
As stated early, dglucose of 50mg/dL or less is associated with slight or no change in renal function.
dglucose of above 50mg/dL is associated with worsening of renal function.
Thus, keeping 2hPPG < 200mg/dL is fundamental to preservation of renal function.

39. Pearl of Wisdom
Studies by the authors validate dglucose as the strongest predictor of renal function change
Since dglucose is the difference between 2hPPG and FBG, reduction of 2hPPG will decrease dglucose
2hPPG relates to diabetes complications, thus our finding of dglucose amplifies the validity of 2hPPG

40. Pearl of Wisdom
4. Thus keeping 2hPPG, under tight control (< 200mg/dL) with intensive insulin therapy is fundamentally important. 5. Finally blood pressure control avoiding the use of ACEI/ARB is additive to glycemic control for renal protection in diabetes.

41. Acknowledgement Noteworthy contribution by these co-workers
Linda Hiebert PhD
University if Saskatchewan, Saskatoon, Canada
2. Harry Khamis, PhD
Wright State University,Dayton, Ohio, USA
Moustafa Eldick, MD
Putnam Community Medical Center, Florida, USA
Janice Pimentel, MA
Mandal Diabetes Research Foundation, St. Augustine, Florida, USA

42. The practice of medicine is an art of observation and not all science.
Thank You