Production and metabolic clearance of glucose under basal conditions in Type II (non-insulin-dependent) diabetes mellitus

Abstract

The relative importance of glucose over-production and inadequate peripheral removal in the postabsorptive (fasting) hyperglycaemia of Type II (non-insulin dependent) diabetes mellitus has produced diverse estimates. Some studies show that a strong correlation exists between fasting glucose concentrations and its production over a wide range of glycaemia, suggesting a causative role for excessive glucose output in hyperglycaemia [1,8]. Other measurements, however, show almost no correlation between glucose production rates and concentrations [9±14], Diabetologia (2001) AbstractAims/hypothesis. The pathogenesis of fasting hyperglycaemia in Type II (non-insulin-dependent) diabetes mellitus has yet to be clarified. Rates of glucose production (R a ), utilization and metabolic clearance rate were therefore measured during an extended fast, in control subjects and in Type II diabetic patients. Methods. Nine subjects with newly-diagnosed or diettreated diabetes and seven control subjects matched for age and weight (BMI 36.0 2.4 and 35.3 3.1 kg/ m 2 respectively) underwent an overnight fast followed by a 10-h unprimed infusion of [6-3 H]glucose. Plasma tracer concentrations were fitted by a singlecompartment model. Results. The metabolic clearance rate was near-constant [61.7 + 2.4 ml/(min-m 2 )] in diabetic patients and [75.5 3.3 ml/(min-m 2 )] in control subjects (p < 0.05). It was correlated to the glucose concentrations both at t = 0 (r = ±0.752, p = 0.0008) and t = 10 h (r = ±0.675, p = 0.004). The calculated volume of distribution was 17.3 1.4 l (18.2 % weight, diabetes), 19.6 2.4 l (18.4 % weight, control). Glycaemia fell from 10.7 0.8 mmol/l to 6.5 0.3 mmol/l by 10 h (p < 0.05) in diabetes and from 5.6 0.6 to 4.8 0.1 mmol/l in control subjects (p < 0.05). The rate of glucose production decreased in parallel, from 563 33 to 363 23 mmol/(min-m 2 ) (p < 0.05) in diabetes from 419 20 to 347 32 mmol/(min-m 2 ) in control subjects. Initial R a was higher in diabetic patients than in control subjects (p < 0.05) and was highly correlated to glycaemia (r = 0.836, p = 0.0001). By 10 h, R a had converged in diabetic patients and control subjects and all correlation with glycaemia was lost (r = 0.0017, p = 0.95). Conclusions/interpretation. In relatively early diabetes, the more ªlabileº portion of fasting hyperglycaemia, which subsequently decreased, was closely related to the simultaneously decreasing R a . The 25 % increase in glucose concentrations which persisted as stabilized R a , resulted from about a 20 % lower metabolic clearance rate. [Diabetologia (2001) 44: 983± 991]

Glucagon-Like Peptide-1 Gene Therapy in Obese Diabetic Mice Results in Long-Term Cure of Diabetes by Improving Insulin Sensitivity and Reducing Hepatic Gluconeogenesis

“…Elevated hepatic glucose production, due to increased gluconeogenesis, glycogenolysis, or both, is associated with the pathogenesis of type 2 diabetes (38,39). We found that basal hepatic glucose production was significantly decreased by rAd-GLP-1 treatment.…”

Homeostastic Model Assessment and Insulin Sensitivity/Resistance

“…Should such adjustments be useful, the estimates of S I /S IN can be achieved on a population basis, which is the recommended venue for HOMA use. Interestingly, also, when morning fasting glucose levels are elevated as in type 2 diabetes, this appears to correspond to a high EGP, which declines during the day to near-normal rates (30). Glycemia decreases correspondingly.…”

Diurnal rhythm in endogenous glucose production is a major contributor to fasting hyperglycaemia in type 2 diabetes. Suprachiasmatic deficit or limit cycle behaviour?

“…They were admitted to the clinical investigation area at 12:00 h (day 1). Unprimed infusions of [U- 13 C]glucose and [3][4][5][6][7][8][9][10][11][12][13][14] C]lactate were initiated at 14.00 h. Sleep was again monitored during the night. The study continued until 14.00 h on day 2.…”

“…The resolution of this issue was based on the following observations: (1) glycaemia in type 2 diabetes is never constant, and so the assumption of a steady state could lead to quantitative inaccuracies [7,9]; and (2) EGP is elevated in the morning by 30-50% and decreases to near-normal rates by afternoon [4,7,8]. This results in a high degree of correlation between elevated glycaemia and EGP early in the morning and its dissipation by mid-afternoon [7,8]. The time of its determination is therefore critical to the conclusions drawn, as is the methodology used.…”

“…The time of its determination is therefore critical to the conclusions drawn, as is the methodology used. The metabolic clearance rate (MCR) of glucose, however, remains constant throughout the day and is decreased in type 2 diabetes [7]. It therefore accounts for the baseline elevation in glycaemia that persists throughout the day [7,9].…”