Bell, P. M.

To determine whether therapy with exogenous insulin or sulfonylureas results in a postprandial pattern of carbohydrate metabolism in patients with non-insulin-dependent diabetes mellitus (NIDDM) that resembles that in nondiabetic individuals, we employed a dual-isotope technique combined with forearm catheterization to examine meal disposition in NIDDM patients, before and after 3 mo of therapy with tolazamide and after 3 mo of therapy with exogenous insulin, with a randomized crossover design. Results were compared with those observed in nondiabetic subjects. Although both forms of therapy improved chronic glycemic control (glycosylated hemoglobin concentration went from 9.6 ± 0.7 to 7.6 ± 0.5 and 7.1 ± 0.2%, respectively, P <.01), exogenous insulin resulted in a lower postprandial glycemic response than tolazamide (P <.001). Both agents comparably increased (P <.01) fasting and integrated postprandial insulin concentrations. However, the initial rate of postprandial increase was greater with exogenous insulin (P <.05). Tolazamide (P <.05) but not exogenous insulin increased postprandial C-peptide concentrations. However, tolazamide did not improve the deficient early insulin release. Both agents (P <.05) lowered postabsorptive hepatic glucose release (from 2.8 ± 0.3 to 2.3 ± 0.2 mg · kg−1 · min−1), but not to normal rates (1.8 ± 0.1 mg · kg−1 · min−1). Endogenous glucose release after carbohydrate ingestion was lowered (P <.001) by insulin (from 633 ± 52 to 460 ± 41 mg kg−1 7 h−1) but not by tolazamide (625 ± 62 mg · kg−1 · 7 h−1) to rates observed in nondiabetic subjects (470 ± 32 mg · kg−1 · 7 h−1). Unmetabolized meal glucose reaching the systemic circulation did not differ before or after therapy with either insulin or tolazamide. Total postprandial glucose uptake was not changed by tolazamide (1308 ± 85 mg kg−1 · 7 h−1) but was lowered (P <.01) by exogenous insulin (from 1269 ± 57 to 1088 ± 67 mg · kg−1 · 7 h−1) to normal rates (1023 ± 64 mg kg−1 7 h−1). Forearm glucose uptakedid not differ among any group. We conclude that, although tolazamide and exogenous insulin, as administered in this study, both improve carbohydrate tolerance, therapy with exogenous insulin results in a pattern of postprandial carbohydrate metabolism that more closely approximates that observed in nondiabetic subjects.

Studies with tritiated isotopes of glucose have demonstrated that hyperglycemia per se stimulates glucos utilization and suppresses glucose production in humans. These conclusions rely on the assumption that tritiated glucose provides an accurate measure of glucose turnover. However, if in the presence of hyperglycemia the isotope either loses its label during “futile” cycling or retains its label during cycling through glycogen, then this assumption is not valid. To examine this question, glucose utilization and glucose production rates were measuredin nine normal subjects with a simultaneous infusion of [23H]glucose, an isotope that may undergo futile cycling but does not cycle through glycogen; [614C]glucose, an isotope that may cycle through glycogen but does not futile cycle; and [33H]glucose, an isotope that can both undergo futile cycling and cycle through glycogen. In the postabsorptive state at plasma glucose concentration of 95 mg dl−1, glucose turnover determined with [614C]glucose (2.3 ±0.1 mg kg−1 min−1) was greater than that determined with [33H]glucose (2.1 ± 0.1 mg kg−1 min−1 P = 0.002) and slightly less than that determined with [23H]glucose (2.7 ± 0.2 mg kg−1 min−1 P = 0.08). Plasma glucose was then raised from 95 to 135 to 175 mg dl−1 while insulin secretion was inhibited, and circulating insulin, glucagon, and growth hormone concentrations were maintained constant by infusion of these hormones and somatostatin. Glucose production and utilization rates determined with [614C]-glucose continued to be less than those determined with [23H]glucose and greater than those seen with [33H]glucose. However, the decrements in glucose production and increments in glucose utilization were identical with all isotopes. Glucagon was then infused at a high rate to stimulate endogenous glucose release. This resulted in a significant (P < 0.05) increase in both [614C]- and [33H]- but not [23H]giucose, indicating release of the former two isotopes from glycogen. This resulted in a significantly lower (P < 0.04) estimate of glucose production and utilization during the glucagon infusion determined with [614C]- and [33H]glucose compared with that determined with [23H]glucose. Thus, whereas neither [23H]- nor [33H]glucose precisely reflect glucose turnover measured by [614C]glucose, all three isotopes provide an equivalent assessment of the effects of hyperglycemia on glucose production and utilization in humans. However, release of either [614C]- or [33H]glucose from glycogen may result in an underestimate Of glucose turnover.