Type 2 Diabetes Impairs Splanchnic Uptake of Glucose but Does Not Alter Intestinal Glucose Absorption During Enteral Glucose Feeding

Abstract

We have previously reported that splanchnic glucose uptake, hepatic glycogen synthesis, and hepatic glucokinase activity are decreased in people with type 2 diabetes during intravenous glucose infusion. To determine whether these defects are also present during more physiological enteral glucose administration, we studied 11 diabetic and 14 nondiabetic volunteers using a combined organ catheterization-tracer infusion technique. Glucose was infused into the duodenum at a rate of 22 mol ⅐ kg ؊1 ⅐ min ؊1 while supplemental glucose was given intravenously to clamp glucose at ϳ10 mmol/l in both groups. Endogenous hormone secretion was inhibited with somatostatin, and insulin was infused to maintain plasma concentrations at ϳ300 pmol/l (i.e., twofold higher than our previous experiments). Total body glucose disappearance, splanchnic, and leg glucose extractions were markedly lower (P < 0.01) in the diabetic subjects than in the nondiabetic subjects. UDP-glucose flux, a measure of glycogen synthesis, was ϳ35% lower (P < 0.02) in the diabetic subjects than in the nondiabetic subjects. This was entirely accounted for by a decrease (P < 0.01) in the contribution of extracellular glucose because the contribution of the indirect pathway to hepatic glycogen synthesis was similar between groups. Neither endogenous and splanchnic glucose productions nor rates of appearance of the intraduodenally infused glucose in the portal vein differed between groups. In summary, both muscle and splanchnic glucose uptake are impaired in type 2 diabetes during enteral glucose administration. The defect in splanchnic glucose uptake appears to be due to decreased uptake of extracellular glucose, implying decreased glucokinase activity. Thus, abnormal hepatic and muscle (but not gut) glucose metabolism are likely to contribute to postprandial hyperglycemia in people with type 2 diabetes. Diabetes 50:1351-1362, 2001

Effects of Free Fatty Acids and Glycerol on Splanchnic Glucose Metabolism and Insulin Extraction in Nondiabetic Humans

“…If so, this would imply that the inhibitory effects of FFAs on splanchnic glucose uptake are likely to be of little significance under the conditions of daily living because insulin concentrations are rarely, if ever, elevated in the absence of a concomitant increase in glucose concentration. Furthermore, the current data indicate that the decrease in both splanchnic glucose uptake and uptake of extracellular glucose that we have previously observed under similar conditions in people with type 2 diabetes is unlikely to be caused by the higher FFAs that were present in those individuals during the study (1,2). On the other hand, because the present experiments examined the effects of a transient (ϳ8 h) elevation of FFAs, it remains possible that a more chronic elevation alone or in association with hepatic steatosis may have a more marked effect on hepatic glucose uptake and glycogen synthesis.…”

“…Volunteers were moved to an intervention radiology suite at ϳ0800, where femoral arterial, femoral venous and hepatic venous catheters were placed as previously described (1,2 ; Genentech, South San Francisco, CA) were started and continued until study end at 1400. A glucose infusion was also begun at 1000 and the rate adjusted to maintain plasma glucose concentrations ϳ8.3 mmol/l over the next 4 h. To minimize the change in plasma glucose specific activity, all infused glucose contained [3-3 H]glucose.…”

“…A glucose infusion was also begun at 1000 and the rate adjusted to maintain plasma glucose concentrations ϳ8.3 mmol/l over the next 4 h. To minimize the change in plasma glucose specific activity, all infused glucose contained [3-3 H]glucose. In addition, the "basal" [3-3 H]glucose infusion was reduced in a pattern (50% from 0 to 30 min, 43% from 31 to 60 min, 31% from 61 to 90 min, 23% from 91 to 120 min, 19% from 121 to 150 min, 15% from 151 to 180 min, and 12% from 211 to 240 min) designed to mimic the anticipated pattern of change in glucose production (1,2).…”

Insulin:Carbohydrate Ratio—Part of the Story

“…9 These processes include but are not limited to (a) rates of carbohydrate absorption from the gastrointestinal tract, 10 which in turn depend on rates of gastric emptying 11 ; (b) insulin and glucagon concentrations in the portal vein [12][13][14][15] ; (c) net postprandial hepatic glucose uptake (storing meal-derived glucose as glycogen) 16 ; (d) rates of hepatic glucose production 17 ; and (e) net peripheral glucose uptake. 6 From the carbohydrate absorption standpoint, an important and often neglected factor that has profound effects on postprandial plasma glucose concentrations is the meal macronutrient content.…”

“…[27][28][29] Moreover, the extent to which systemic appearance of meal carbohydrates is a function of the grams of carbohydrates ingested minus the grams of ingested carbohydrates stored in the liver as glycogen, abnormalities in hepatic glycogen synthesis due to deficiencies in hepatic glucokinase activity, 16,17,30 and/or reduced glucose transport into the hepatocytes could also influence postprandial glucose concentrations by increasing the net release of meal carbohydrates into the systemic circulation. Although hepatic glycogen content in individuals with poorly controlled type 1 diabetes has been shown to be reduced, putatively because of a defect in functional hepatic glucokinase activity, 31 the role of a high-fat meal on glucokinase activity and/or hepatic glucose uptake is as yet unexplored in type 1 diabetes, although in individuals without diabetes elevated levels of free fatty acids did not alter hepatic glucose uptake.…”