Summary
Using primed-continuous 3-3H-glucose infusion, basal glucose production rate has been reported to be 140% higher than normal or almost normal in hyperglycaemic patients with Type 2 (non-insulin-dependent) diabetes mellitus. To determine whether these markedly different results could be due to the mode of priming: fixed or adjusted, or the mode of calculation: steady state or non-steady state equations, we studied 11 patients with Type 2 diabetes (fasting plasma glucose 8–20 mmol/l). For 6 h 3-3H-glucose (0.40 μCi/min) was infused preceded by a priming dose of 40 μCi (fixed priming), or 40 μCi · plasma glucose (mmol/l)·5−1 (adjusted priming). In diabetic patients the plasma glucose concentration was not constant but declined 0.52±0.07 mmol·l−1· h−1. Furthermore, the rate of fall was correlated to the fasting plasma glucose concentration (r=0.90, p<0.01). Thus, the fasting state was not a steady state condition. Using adjusted priming a constant tracer steady state level was obtained within 60 min. In contrast, using fixed priming tracer steady state was not reached within 6 h. The initial tracer level was far below, and increased in time towards the steady state level observed after adjusted priming. Consequently, using Steele's equations after fixed priming, glucose production rates calculated after 90–120 min were overestimated in proportion to fasting hyperglycaemia. In conclusion: The fasting state in patients with Type 2 diabetes is not a steady state condition. Adjusted priming seems most appropriate in Type 2 diabetes. By estimating glucose production 2 h after fixed priming or assuming steady state conditions, most previous studies may have overestimated basal glucose production in Type 2 diabetes in proportion to fasting hyperglycaemia.
Article PDF
Similar content being viewed by others
References
Olefsky JM (1985) Pathogenesis of insulin resistance and hyperglycemia in non-insulin-dependent diabetes mellitus. Am J Med 79 [Suppl 3B]: 1–7
Scarlett JA, Gray RS, Griffin J, Olefsky JM, Kolterman OG (1982) Insulin treatment reverses the insulin resistance of type II diabetes mellitus. Diabetes Care 5: 353–363
Revers RR, Fink R, Griffin J, Olefsky JM, Kolterman OG (1984) Influence of hyperglycemia on insulin's in vivo effects in type II diabetes. J Clin Invest 73: 664–672
Garvey WT, Olefsky JM, Griffin J, Hamman RF, Kolterman OG (1985) The effect of insulin treatment on insulin secretion and insulin action in type II diabetes mellitus. Diabetes 34: 222–234
Henry RR, Scheaffer L, Olefsky JM (1985) Glycemic effects of intensive caloric restriction and isocaloric refeeding in non-insulin dependent diabetes mellitus. J Clin Endocrinol Metab 61: 917–925
Kolterman OG, Gray RS, Shapiro G, Scarlett JA, Griffin J, Olefsky JM (1984) The acute and chronic effects of sulfonylurea therapy in type II diabetic subjects. Diabetes 33: 346–354
Kolterman OG, Gray RS, Griffin J, Burstein P, Insel J, Scarlett JA, Olefsky JM (1981) Receptor and postreceptor defects contribute to the insulin resistance in non-insulin-dependent diabetes mellitus. J Clin Invest 68: 957–969
Henry RR, Wallace P, Olefsky JM (1986) Effects of weight loss on mechanisms of hyperglycemia in obese non-insulin-dependent diabetes mellitus. Diabetes 35: 990–998
Osei K, Falko JM, O'Dorisio TM, Fields PG, Bossetti B (1986) Gastric inhibitory polypeptide responses and glucose turnover rates after natural meals in type II diabetic patients. J Clin Endocrinol Metab 62: 325–330
Bogardus C, Lillioja S, Howard BV, Reaven G, Mott D (1984) Relationships between insulin secretion, insulin action, and fasting plasma glucose concentration in non-diabetic and non-insulin-dependent diabetic subjects. J Clin Invest 74: 1238–1246
Firth RG, Bell PM, Marsh HM, Hansen I, Rizza RA (1986) Post-prandial hyperglycemia in patients with non-insulin-dependent diabetes mellitus. Role of hepatic and extrahepatic tissues. J Clin Invest 77: 1525–1532
Golay A, Swislocki ALM, Chen Y-DI, Reaven GM (1987) Relationships between plasma-free fatty acid concentration, endogenous glucose production, and fasting hyperglycemia in normal and non-insulin-dependent diabetic individuals. Metabolism 36: 692–696
Baron AD, Schaeffer L, Shragg P, Kolterman OG (1987) Role of hyperglucagonemia in maintenance of increased rates of hepatic glucose output in type II diabetics. Diabetes 36: 274–283
Osei K, Holland GC (1987) Clinical correlates of basal hepatic glucose output and metabolic clearance rate of glucose using glucose-C-peptide-body mass indexes in ambulatory type 2 diabetic patients. Diab Res 5: 181–187
Firth R, Bell P, Marsh M, Rizza RA (1987) Effects of tolazamide and exogenous insulin on pattern of postprandial carbohydrate metabolism in patients with non-insulin-dependent diabetes mellitus. Diabetes 36: 1130–1138
Firth RG, Bell PM, Rizza RA (1986) Effects of tolazamide and exogenous insulin on insulin action in patients with non-insulin-dependent diabetes mellitus. N Engl J Med 314: 1280–1286
Nankervis A, Proietto J, Aitken P, Harewood M, Alford F (1982) Differential effects of insulin therapy on hepatic and peripheral insulin sensitivity in Type 2 (non-insulin-dependent) diabetes. Diabetologia 23: 320–325
Campbell PJ, Mandarino LJ, Gerich JE (1988) Quantification of the relative impairment in actions of insulin on hepatic glucose production and peripheral glucose uptake in non-insulin-dependent diabetes mellitus. Metabolism 37: 15–21
DeFronzo RA, Ferrannini E, Simonson DC (1989) Fasting hyperglycemia in non-insulin-dependent diabetes mellitus. Contribution of excessive hepatic glucose production and impaired tissue glucose uptake. Metabolism 38: 387–395
DeFronzo RA, Gunnarson R, Björkman O, Olsson M, Wahren J (1985) Effects of insulin on peripheral and splanchnic glucose metabolism in non-insulin-dependent (type II) diabetes mellitus. J Clin Invest 76: 149–155
DeFronzo RA, Simonson D, Ferrannini E (1982) Hepatic and peripheral insulin resistance: a common feature of Type 2 (non-insulin-dependent) and Type 1 (insulin-dependent) diabetes mellitus. Diabetologia 23: 313–319
Ferrannini E, Simonson DC, Katz LD, Reichard G, Bevilacqua S, Barrett EJ, Olsson M, DeFronzo RA (1988) The disposal of an oral glucose load in patients with non-insulin-dependent diabetes. Metabolism 37: 79–85
Simonson DC, Ferrannini E, Bevilacqua S, Smith D, Barrett E, Carlson R, DeFronzo RA (1984) Mechanism of improvement in glucose metabolism after chronic glyburide therapy. Diabetes 33: 838–845
Hother-Nielsen O, Schmitz O, Andersen PH, Pedersen O, Beck-Nielsen H (1988) In vivo action of glibenclamide in obese subjects with mild type 2 (non-insulin dependent) diabetes. Diabetes Res 8: 63–70
Hother-Nielsen O, Schmitz O, Bak J, Beck-Nielsen H (1987) Enhanced hepatic insulin sensitivity, but peripheral insulin resistance in patients with Type 1 (insulin-dependent) diabetes. Diabetologia 30: 834–840
McGuire EAH, Helderman JH, Tobin JD, Andres R, Berman M (1976) Effects of arterial versus venous sampling on analysis of glucose kinetics in man. J Appl Physiol 41: 565–573
Frayn KN (1983) Calculation of substrate oxidation rates in vivo from gaseous exchange. J Appl Physiol 55: 628–634
Ferrannini E (1988) The theoretical basis of indirect calorimetry: a review. Metabolism 37: 287–301
Andersen I, Hannibal S (1983) Analytical and economical optimization of a glucose method with immobilized enzymes. J Automatic Chem 5: 188–192
Heding LG (1966) A simplified insulin radioimmunoassay method. In: Donato L (ed) Labelled proteins in tracer studies. European atomic energy community, Brussels, pp 345–350
Heding LG (1975) Radioimmunological determination of human C-peptide in serum. Diabetologia 11: 541–548
Ørskov H, Thomsen HG, Yde H (1968) Wick chromatography for rapid and reliable immunoassay of insulin, glucagon and growth hormone. Nature 219: 193–195
Ferrannini E, Del Prato S, DeFronzo RA (1986) Glucose kinetics. Tracer methods. In: Clarke WL, Larner J, Pohl SL (eds) Methods in diabetes research, Vol 2. John Wiley, New York Chichester Brisbane Toronto Singapore, pp 107–141
Katz J (1979) Use of isotopes for the study of glucose metabolism in vivo. In: Kornberg NL (ed) Techniques in metabolic research, B207. Elsevier, Amsterdam, pp 1–22
Shipley RA, Clark RE (1972) Tracer methods for in vivo kinetics. Theory and applications. Academic Press, New York, pp 145–162
Steele R (1959) Influence of glucose loading and of injected insulin on hepatic glucose output. Ann NY Acad Sci 82: 420–430
DeBodo R, Steele R, Altszuler N, Dunn A, Bishop J (1963) On the hormonal regulation of carbohydrate metabolism: studies with C14-glucose. Recent Progr Horm Res 19: 445–488
Shipley RA, Clark RE (1972) Tracer methods for in vivo kinetics. Theory and applications. Academic Press, New York, pp 163–175
Wolfe RR (1984) Tracers in metabolic research: radioisotope and stable isotope/mass spectrometry methods. Laboratory and research methods in biology and medicine, Vol 9. Alan R Liss, New York
Cowan JS, Hetenyi S (1971) Glucoregulatory responses in normal and diabetic dogs recorded by a new tracer method. Metabolism 20: 360–372
Finegood DT, Bergman RN (1983) Optimal segments: a method for smoothing tracer data to calculate metabolic fluxes. Am J Physiol 244: E472-E479
Glauber H, Wallace P, Brechtel G (1987) Effects of fasting on plasma glucose and prolonged tracer measurement of hepatic glucose output in NIDDM. Diabetes 36: 1187–1194
Hother-Nielsen O, Schmitz O, Andersen PH, Beck-Nielsen H, Pedersen O (1989) Metformin improves peripheral but not hepatic insulin action in obese patients with type II diabetes. Acta Endocrinol (Copenh) 120: 257–265
Chen Y-DI, Jeng C-Y, Hollenbeck CB, Wu M-S, Reaven GM (1988) Relationship between plasma glucose and insulin concentration, glucose production, and glucose disposal in normal subjects and patients with non-insulin-dependent diabetes. J Clin Invest 82: 21–25
Chen Y-DI, Swislocki ALM, Jeng C-Y, Juang J-H, Reaven GM (1988) Effect of time on measurement of hepatic glucose production. J Clin Endocrinol Metab 67: 1084–1088
Radziuk J, Lickley HLA (1985) The metabolic clearance of glucose: measurement and meaning. Diabetologia 28: 315–322
Author information
Authors and Affiliations
Rights and permissions
About this article
Cite this article
Hother-Nielsen, O., Beck-Nielsen, H. On the determination of basal glucose production rate in patients with Type 2 (non-insulin-dependent) diabetes mellitus using primed-continuous 3-3H-glucose infusion. Diabetologia 33, 603–610 (1990). https://doi.org/10.1007/BF00400204
Received:
Revised:
Issue Date:
DOI: https://doi.org/10.1007/BF00400204