Insulin Sensitivity of Suppression of Endogenous Glucose Production Is the Single Most Important Determinant of Glucose Tolerance

Abstract

Hyperglycemia results from an imbalance between endocrine pancreatic function and hepatic and extrahepatic insulin sensitivity. We studied 57 well-matched Swedish men with normal glucose tolerance (NGT), impaired glucose tolerance (IGT), or mild diabetes. Oral glucose tolerance and insulin release were assessed during an oral glucose tolerance test (OGTT). Insulin sensitivity and glucose turnover were determined during a two-step euglycemic insulin clamp (infusion 0.25 and 1.0 mU ⅐ kg -1 ⅐ min -1). High-performance liquid chromatography-purified [6-3 H]glucose was used as a tracer. During low-insulin infusion, the rate of endogenous glucose production (EGP) decreased more in subjects with NGT than in subjects with IGT N ormal glucose tolerance (NGT) is mainly a function of the interplay between insulin sensitivity (muscle, liver, and adipocytes) and endocrine pancreatic function (1-3). This is evident from studies showing that insulin resistance (comparable with what is found in type 2 diabetes) with ensuing hyperinsulinemia is prevalent in ϳ25% of individuals with NGT (4), whereas subjects that are characterized by a low insulin response maintain NGT by exhibiting increased extrahepatic insulin sensitivity (5). The pathogenesis of glucose intolerance is often complex and includes both decreased insulin release and decreased insulin sensitivity. Accordingly, it has long been debated whether impaired insulin secretion or decreased insulin sensitivity in liver and/or extrahepatic tissues or a combination thereof is the primary defect. The results from several longitudinal studies that aimed to evaluate these components are contradictory and limited by the fact that insulin release and peripheral insulin sensitivity were often not assessed simultaneously (6 -10).Whereas there is ample evidence that fasting blood glucose levels are mainly determined by the rate of endogenous glucose production (EGP) (2,11), which mechanisms regulate variability in postprandial glycemia is less clear. Thus, the relative changes in the rates of glucose appearance and disappearance after a mixed meal or an oral glucose load are determined by islet ␤-and ␣-cell responsiveness, hepatic and extrahepatic insulin sensitivity, glucose effectiveness, etc. (12-14). The aim of the present study was to evaluate the impact of insulin sensitivity on suppression of EGP versus insulin sensitivity in muscle versus insulin release to the variation in OGTT. For that purpose, we studied 57 well-matched middle-aged Swedish men with either normal, impaired, or decreased OGTT. EGP and glucose uptake were determined during a twostep hyperinsulinemic-euglycemic clamp with a matchedstep tracer infusion (MSTI) technique (15,16). In this study, under these experimental conditions, the hepatic glucose production accounted for ϳ95% of the rate of EGP (17). Insulin response was evaluated during OGTT. RESEARCH DESIGN AND METHODSA total of 57 Swedish men who had NGT (n ϭ 31), impaired glucose tolerance (IGT) (n ϭ 12), or mild diabetes (n ϭ 14) were recruited and i...

Marked differences in the IGF system that are associated with migration in comparable populations of Gujaratis living in Sandwell, UK, and Gujarat, India

“…The finding of a negative association between circulating IGF-I and fasting/2-h glucose (Tables 5 and 6) is intriguing in the light of our previous results showing that low circulating IGF-I was predictive of higher 2-h glucose at the 5-year follow-up [6]. Fasting blood glucose levels are mainly determined by the rate of endogenous glucose production [38]. Postprandial changes in glucose concentrations, however, are related to numerous factors, including glucose uptake by skeletal muscle and peripheral insulin sensitivity, as well as by the rate of endogenous glucose production [38,39].…”

“…Fasting blood glucose levels are mainly determined by the rate of endogenous glucose production [38]. Postprandial changes in glucose concentrations, however, are related to numerous factors, including glucose uptake by skeletal muscle and peripheral insulin sensitivity, as well as by the rate of endogenous glucose production [38,39]. Given the relative paucity of hepatic IGF-I receptors [40], our observation is consistent with IGF-I mainly influencing peripheral glucose uptake in the postprandial state, either directly or indirectly via its effects on the action of insulin to dispose of glucose.…”

Parallel manifestation of insulin resistance and beta cell decompensation is compatible with a common defect in Type 2 diabetes

“…Indeed, the fasting NEFA concentrations correlated with the fasting insulin levels (r=0.263; p<0.0005). A recent study by Bavenholm et al on a smaller group of middle-aged Swedish men reported that suppression of EGP was the single most important determinant of glucose intolerance, explaining 55% of variance in the 2-hour glucose values [43]. Our data are not inconsistent with these findings, although our study was not really designed to assess suppression of EGP during the clamp, as we employed a rather high insulin infusion rate (1 mU·kg −1 ·min −1 ) compared to that used in the study by …”

A novel functional polymorphism (?336A/G) in the promoter of the partitioning-defective protein-6? gene is associated with increased glucose tolerance and lower concentrations of serum non-esterified fatty acids

“…Nevertheless, it may be speculated that Par6α specifically plays a role in liver. The results of a previous study suggest that basal and 2-h glycaemia are largely influenced by basal and insulinsuppressed hepatic glucose production, both of which are measurements of hepatic insulin sensitivity [20]. However, it has also been shown that IGT primarily results from the reduced suppression of hepatic glucose output due to abnormal pancreatic islet function [21].…”