Decreased effect of insulin to stimulate skeletal muscle blood flow in obese man. A novel mechanism for insulin resistance.

Abstract

Obesity is characterized by decreased rates of skeletal muscle insulin-mediated glucose uptake (IMGU). Since IMGU equals the product of the arteriovenous glucose difference (AVGd) across muscle and blood flow into muscle, reduced blood flow and/or tissue activity (AVGd) can lead to decreased IMGU. To examine this issue, we studied six lean (weight 68±3 kg, mean±SEM) and six obese (94±3 kg) men. The insulin doseresponse curves for whole body and leg IMGU were constructed using the euglycemic clamp and leg balance techniques over a large range of serum insulin concentrations. In lean and obese subjects, whole body IMGU, AVGd, blood flow, and leg IMGU increased in a dose dependent fashion and maximal rates of all parameters were reduced in obese subjects compared to lean subjects. The dose-response curves for whole body IMGU, leg IMGU, and AVGd were right-shifted in obese subjects with an ED50 two-to threefold higher than that of lean subjects for each parameter. Leg blood flow increased approximately twofold from basal 2.7±0.2 to 4.4±0.2 dl/min in lean, P < 0.01, and from 2.5±0.3 to 4.4±0.4 dl/min in obese subjects, P < 0.01. The ED50 for insulin's effect to increase leg blood flow was about fourfold higher for obese (957 pmol/liter) than lean subjects (266 pmol/liter), P < 0.01. Therefore, decreased insulin sensitivity in human obesity is not only due to

Role of insulin resistance in the pathogenesis of NIDDM

“…Insulin also increases blood flow but this effect of insulin differs from stimulation of glucose extraction in two important ways. First, stimulation of blood flow requires higher, supraphysiological plasma insulin concentrations than stimulation of glucose extraction [68,69], (Fig. 6).…”

“…6). Second, the response of blood flow to insulin is gradual and reaches maximum after several hours of insulin stimulation, while glucose extraction is maximal within 30 to 90 min [68,69]. Based on this physiological knowledge, one may predict that variation in insulin action in normal subjects is more likely to be attributable to blood flow at supraphysiological than physiological insulin concentrations while differences in glucose extraction distinguish between sensitive and insensitive individuals under physiological conditions.…”

“…Abundant experimental evidence indicates that this indeed is the case. Thus, defects in insulin action on blood flow have been described in both obese subjects [68], and patients with IDDM [70], NIDDM [71] and essential hypertension [72], when glucose uptake has been measured during high-dose insulin infusions lasting up to 9 h. On the other hand, during short-term insulin infusions lasting 2-3 h, defects in glucose uptake are due to defects in glucose extraction in obese subjects [40], and patients with IDDM [73], NIDDM [74,75] and essential hypertension [76].…”

Direct vasodilator effects of physiological hyperinsulin‐aemia in human skeletal muscle

“…Until now very little attention has been given to the time course of the insulin-induced vasodilator effect, which may be an important clue with respect to the controversial observations in the literature. From data o f Laakso et a l [1], it is obvious that the vasodilator effect of systemic insulin infusion (physiological plasm a insulin concentrations) is not maximal until 3 h o f infusion, and that after 30 and 60 min, respectively, only approximately 10% and approximately 30% of the maximum effect has been reached. Recently, even slower increases in blood flow in response to insulin have been reported [13,14].…”

Arterial stiffness and type 2 diabetes: dietary modulation after a single meal?

“…8 However, the vasodilator effects of insulin in patients with type 2 diabetes (in the presence of obesity) are often impaired. 10 Importantly, patients who participated in the current study were lean (average body mass index: 23.3) and there were no apparent correlations found between changes in insulin and glucose, and changes in baBWV, AI or CAVI. 8 Although these results argue against the contribution of insulin in lower postprandial vascular stiffness, it may be important in future studies to determine the relationship(s) between postprandial blood pressure, insulin and vascular stiffness in diabetes and patients at risk for type 2 diabetes (pre-diabetes).…”