Quantifiying OGTT Glucose Appearance in Forms of Prediabetes John S. Melish, M.D. Professor of Medicine John A. Burns School of Medicine Honolulu, HI Endocrine Society 2017 Meeting: Abstract Poster # MON625

Objective Compare patients with normal glucose tolerance (NGT); impaired fasting glucose (IFG); impaired glucose tolerance (IGT); and combined (IFG + IGT) individuals in regard to dietary glucose appearance in the post-hepatic space. Provide a method for the future for quantifying glucose appearance after a carbohydrate meal so that Type 1 and Type 2 diabetics can better determine carbohydrate/insulin ratios In future, provide a basis for quantifying glucose appearance after a mixed meal of carbohydrate, protein, and fat so that diabetics can better determine carbohydrate/insulin ratios.

Hypothesis Model Assumptions A Pharmacokinetic Model Can Assist and Assess Diabetes Management Using Frequently Sampled Glucose Data from High Carbohydrate and from Mixed Meals in Place of Carbohydrate Counting by Determining a Glucose Volume of Distribution and Total Glucose Appearance. Model Assumptions Zero order glucose appearance First order glucose disposal Glycogenolysis is rapidly stopped by insulin Gluconeogenesis continues despite Insulin Glucose disposal is equivalent for dietary and basal glucose Glucose production returns as glucose concentration falls Fat and protein in mixed meals contributes to glucose production through gluconeogenesis In all forms of glucose intolerance (including fasting hyperglycemia, IFG), first pass hepatic glucose uptake is impaired.

Method Frequently sampled glucose concentration curve vs. time after a glucose challenge or high CHO meal. Estimate of dietary CHO intake (to confirm method). Body weight (kg). Hematocrit to estimate corrected extracellular volume, where uncorrected volume = 0.20*kg or 200ml/kg or 2dL/kg. Volume of Distribution (Vd) = kg*(.15+(1-Hct)(0.05))*10. Post-challenge Gl concentration change (PGlC)= [Peak Gl]*e – [Baseline Gl]*e-1 where e = 2.718 7. Vd*PGlC = Total dietary glucose appearing in extracellular space. Further calculations needed for mixed meal taking into account glucose production from fat and protein. Data taken from published study OGTT curves from patients with normal glucose tolerance (NGT), impaired fasting glucose (IFG), impaired glucose tolerance (IGT), and combined glucose intolerance (IFG + IGT) = CGI

Varghese R, et al. JCEM 101;12:4816

Pk = 439 mg/dL Varghese R, et al. JCEM 101;12:4816

BL/e = 33 mg/dL Varghese R, et al. JCEM 101;12:4816

Oral GTT Data: 75 g Glucose in NFG/NGT vs. NFT/IGT Patient Type Peak Gl*e- BL*e-1 = Total Gl Change (mg/dL) Weight (kg) Corrected Extra-cellular Volume = kg*10* 0.1825 dL/kg = (dL) Total Glucose In (g) Total Glucose Calculated Fraction Remaining After First Pass Hepatic Uptake NFG/NGT (n=19,5/14) 407 79 (+/-3) 144 75 58.7 0.78 NFG/IGT (n=25,9/16) 475 84 (+/-4) 151 72.8 0.97 Assumes a total extracellular space of 200 mL/kg body weight Fraction of accessible space in paper 0.65 = 1.0-0.35 75 gram oral glucose tolerance test randomly administered on two occasions Varghese R, et al. JCEM 101;12:4816

Kamat M., et al. Acta Diabetol 2011; 48: 209-217

Kamat M., et al. Acta Diabetol 2011; 48: 209-217

Pk = 460 mg/dL BL/e = 33 mg/dL Kamat M., et al. Acta Diabetol 2011; 48: 209-217

Pk = 459 mg/dL BL/e = 33 mg/dL Kamat M., et al. Acta Diabetol 2011; 48: 209-217

Pk = 537 mg/dL Pk*e – BL/e = 498 mg/dL Concentration Appearance Change; Vd = 173.9 dL Total Appearance: 86.6 g. Fraction Remaining: 1.15 BL/e = 39 Kamat M., et al. Acta Diabetol 2011; 48: 209-217

Total Carbo-hydrate in Diet (g) Normal Glucose Tolerance, Impaired Fasting Glucose, Impaired Glucose Tolerance, Combined Glucose Intolerance* Patient: Peak Gl*e- BL*e-1 = Total Gl Change (mg/dL) Weight (kg) Esti- mated From BMI Corrected Extra-cellular Volume = kg*10* 0.1825 dL/kg = (dL) Total Carbo-hydrate in Diet (g) Total Glucose In Calculated (g) Fraction Remaining After First Pass Hepatic Uptake NGT / n =101 (m/f) 30/71 360 89.8 164.0 75 59.0 0.79 IFG / n = 24 (m/f) 11/13 427 87.1 159.0 68.0 0.91 IGT / n = 64 (m/f) 11/53 428 92.6 168.9 72.1 0.97 CGI / n = 48 (m/f) 18/30 498 95.3 174.9 86.6 1.15 Kamat M., et al. Acta Diabetol 2011; 48: 209-217 * Not on glucose lowering medication

Discussion: Varghese data suggest that with a pure OGTT challenge, there is little first pass hepatic glucose uptake in subjects with Normal Fasting Glucose and Impaired Glucose Tolerance compared with Normal Glucose Tolerance individuals. Similar response was seen when this methodology was applied to patients with pre-diabetes compared with normal in Kamat’s study (progressive first pass abnormalities). This approach suggests an easier, more quantitative approach to assessing glucose/insulin ratios than the usual current meal assessment although it has not been applied to mixed meals with high fat and/or high protein in addition to CHO.

Estimates of the extracellular space are important in defining glucose excursions in individual patients and may be useful in defining individual pharmacokinetic responses to medication, diet, and exercise and glucose/insulin ratios. Attention to Volume of Distribution will be useful in patients with continuous glucose monitoring where pharmacokinetic assessment has been missing. Description should be placed more on assessment of meal-related glucose responses rather than creating indices that further describe populations of patients (e.g., Sensitivity Index, Disposition Index, etc.), which are of interest in defining populations with glucose intolerance but contribute little to patient diabetic management. More studies should include kg body wt, Hct vs. BMI.

Abstract # MON625: Glucose (GL) Appearance in Impaired Glucose Tolerance (IGT) from a 75 G Oral Glucose Tolerance Test (GTT) Is Similar to That in Overt Diabetes and Is an Additional Reason for Hyperglycemia in IGT Patients John Stephens Melish John A. Burns School of Medicine, University of Hawaii at Manoa Carbohydrate counting (CC) is the basis for teaching insulin administration to patients with diabetes mellitus. However, to create an effective GL: insulin ratio, CC requires expertise, time, practice, and extra data resources. Studies show well-instructed diabetic patients performed poorly in CC. This study uses quantitative pharmacokinetic estimates of GL appearance using frequently sampled glucose tolerance data as an alternative way to determine CC and insulin need. This method quantitates extracellular GL appearance for both mainly CHO diets by determining a GL volume of distribution (Vd). This may be estimated from population data or from patient specific data such as kilogram body weight, hematocrit, and the general estimate of extracellular fluid volume (200 mL/kg body weight). GL appearance (Ka, milligrams/dL) can be estimated from the peak GL concentration and the baseline concentration multiplied by "e" and "e-1", respectively. The sum these concentration values / 1/Vd (numerically equivalent to 1/time) = GL appearance (mg). This novel methodology was applied to data presented by Varghese, et al (JCEM 2016) who studied volunteers with normal or impaired glucose tolerance. Baseline and peak glucose values were obtained from frequently monitored 2 hour 75 g glucose tolerance data. With an estimated hematocrit of 35% the Vd was determined to be 18.25% of kilogram body weight (79 kg normal; 84 kg prediabetic). Only 78 % of the glucose ingested by normal patients could be accounted for in the Vd whereas 97% appeared in the pre-diabetic

Abstract Title: Glucose (GL) Appearance in Impaired Glucose Tolerance (IGT) from a 75 G Oral Glucose Tolerance Test (GTT) Is Similar to That in Overt Diabetes and Is an Additional Reason for Hyperglycemia in Igt Patients Authors Presenting Author John Stephens Melish John A. Burns School of Medicine, University of Hawaii at Manoa Abstract Text:                         Carbohydrate counting (CC) is the basis for teaching insulin administration to patients with diabetes mellitus. However, to create an effective GL: insulin ratio, CC requires expertise, time, practice, and extra data resources. Studies show well-instructed diabetic patients performed poorly in CC. This study uses quantitative pharmacokinetic estimates of GL appearance using frequently sampled glucose tolerance data as an alternative way to determine CC and insulin need.. This method quantitates extracellular GL appearance for both mainly CHO diets by determining a GL volume of distribution (Vd). This may be estimated from population data or from patient specific data such as kilogram body weight, hematocrit, and the general estimate of extracellular fluid volume (200 mL/kg body weight). GL appearance (Ka, milligrams/dL) can be estimated from the peak GL concentration and the baseline concentration multiplied by "e" and "e-1", respectively. The sum these concentration values / 1/Vd (numerically equivalent to 1/time) = GL appearance (mg). This novel methodology was applied to data presented by Varghese, et al (JCEM 2016) who studied volunteers with normal or impaired glucose tolerance. Baseline and peak glucose values were obtained from frequently monitored 2 hour 75 g glucose tolerance data. With an estimated hematocrit of 35% the Vd was determined to be 18.25% of kilogram body weight (79 kg normal; 84 kg prediabetic). Only 78 % of the glucose ingested by normal patients could be accounted for in the Vd whereas 97% appeared in the pre-diabetic patients. When applied to a separate study by Wolpert, et al. Type 1 patients on a high CHO low fat, low protein diet exhibited the same phenomenon with nearly 100% of the ingested available glucose appearing in the Vd. This extends the suggestion by Cobelli, et al. that in diabetics, there is no first pass hepatic GL uptake; the majority of available GL appears in the extracellular space. This present analysis shows the same phenomenon in patients with impaired glucose tolerance as compared to normal. This simple calculation works nicely and reproducibly when available carbohydrate is administered alone. A more complex additional calculation must be used when mixed diets of protein and/or fat are added to CHO. Varghese used radioisotope techniques to determine that gluconeogenesis and glycogenolysis were within normal limits in both groups. Elevated prediabetic glucose combined curves were explained by reduced GL disposal. This present analysis uniquely demonstrates 1) first pass hepatic GL uptake is minimal in prediabetic as well as diabetic patients as an additional contribution to elevated postprandial letter GL values. 2) an alternative method to CC for assessing insulin need. 3) further calculation is needed to assess glucose appearance from mixed diets. patients. When applied to a separate study by Wolpert, et al. Type 1 patients on a high CHO low fat, low protein diet exhibited the same phenomenon with nearly 100% of the ingested available glucose appearing in the Vd. This extends the suggestion by Cobelli, et al. that in diabetics, there is no first pass hepatic GL uptake; the majority of available GL appears in the extracellular space. This present analysis shows the same phenomenon in patients with impaired glucose tolerance as compared to normal. This simple calculation works nicely and reproducibly when available carbohydrate is administered alone. A more complex additional calculation must be used when mixed diets of protein and/or fat are added to CHO. Varghese used radioisotope techniques to determine that gluconeogenesis and glycogenolysis were within normal limits in both groups. Elevated prediabetic glucose combined curves were explained by reduced GL disposal. This present analysis uniquely demonstrates 1) first pass hepatic GL uptake is minimal in prediabetic as well as diabetic patients as an additional contribution to elevated postprandial plasma GL values. 2) an alternative method to CC for assessing insulin need. 3) further calculation is needed to assess glucose appearance from mixed diets.