Despite extreme insulin resistance, patients with primary defects at the level of the insulin receptor (generalized insulin resistance) did not manifest metabolic dyslipidemia. This was true in people with loss-of-function mutations in the insulin receptor and in those with severe insulin resistance due to inhibitory insulin receptor antibodies, effectively representing a naturally occurring model of acquired and reversible insulin receptor dysfunction in adult life. These data are consistent with similar observations by Musso et al. in a smaller number of patients (9
). It even appears to be true in those patients in whom insulin receptor–mediated insulin resistance progresses to overt type 2 diabetes mellitus, where one might expect hyperglycemia to promote lipogenesis via carbohydrate response element binding protein (CHREBP) (20
). Despite higher plasma FFA and glucose levels and massively increased plasma insulin levels, liver fat measurements were normal in the patients we studied with insulin receptor mutations. Theoretically, this could be a result of either reduced hepatic lipogenesis or increased oxidation or excretion of liver TGs. While it is not currently possible to measure hepatic fat oxidation directly in vivo in humans, plasma ketone levels were unremarkable in these patients (data not shown), and they are not prone to develop ketoacidosis in the prediabetic state. We did not measure VLDL turnover but did document surprisingly normal rates of de novo lipogenesis and low VLDL TG/cholesterol ratios in 4 patients with insulin receptor mutations. Although the data (Figure D) suggest that de novo lipogenesis may be modestly increased in patients with INSR
mutations, the magnitude of this change (~2-fold) is still remarkably small in comparison with the huge increases in plasma insulin (~30-fold). A small increase in hepatic lipogenesis is consistent with a degree of residual insulin signaling capacity of the mutant insulin receptors. Collectively, these observations suggest that reduced liver fat synthesis plays a key role in the protection from dyslipidemia observed in patients with insulin receptoropathy.
These data are consistent with the concept of selective postreceptor hepatic insulin resistance (partial insulin resistance) in the highly prevalent form of insulin resistance (5
). We were also able to extend these human observations by studying 2 patients with AKT2
mutations. We have previously demonstrated hepatic insulin resistance with respect to gluconeogenesis in one of these subjects (18
), in whom we have now also demonstrated increased hepatic lipogenesis. One interpretation of these data is that the signaling pathway responsible for insulin activation of SREBP1c diverges from the insulin receptor/IRS/PI3K/AKT2/FOXO1 pathway proximal to AKT2 activation. Recently published observations in mice indicate that the specificity of insulin signaling in the liver lies downstream of IRS1 and IRS2 (21
) and suggest that the insulin SREBP1c/lipogenic pathway diverges from the canonical pathway after IRS but before AKT2. This is consistent with the observations by Taniguchi et al. (24
) in liver-specific PI3K knockout mice that reconstitution of the defect in these mice with an adenoviral construct expressing constitutively active PKCλ significantly increased SREBP1c expression (5- to 6-fold), whereas overexpression of a constitutively active Akt isoform had no discernible effect on SREBP1c expression. Alternatively, the lipogenic pathway might divert from the canonical pathway before IRS1/2. A caveat to this interpretation of our data is suggested by the observation that one of the patients with an AKT2
loss-of-function mutation had clinical evidence of femorogluteal lipodystrophy and had slightly more visceral adipose tissue (VAT) than her insulin receptoropathy counterparts (Table and Figure ). It remains possible, therefore, that altered AKT2 activity in adipose tissue contributes to the severe dyslipidemia in these patients.
Our observations concur with some of those of Biddinger et al. (8
), who noted similar changes in liver TG and VLDL composition in LIRKO mice. However, those authors suggested that LIRKO mice were highly susceptible to hypercholesterolemia and atherosclerotic vascular disease when challenged with an atherogenic diet. “Atherogenic” mouse diets are similar to “Western” human diets, so one might expect patients with insulin receptor signaling defects to manifest similar abnormalities. Our data do not suggest that hypercholesterolemia is common in patients with insulin receptor defects. In our view this is in keeping with predominantly independent genetic and environmental regulation of cholesterol metabolism in humans.
It is also important to remember that our patients, unlike the LIRKO mice, have impaired insulin receptor function in all tissues and so may exhibit indirect hepatic effects of insulin receptor dysfunction in sites such as adipose tissue. For example, patients with insulin receptoropathy have significantly higher plasma adiponectin levels than is seen in other forms of severe insulin resistance, and indeed many have extreme hyperadiponectinemia (25
). Adiponectin receptors are expressed in the liver, which is thought to be a key target for adiponectin action, and one recent study suggested that adiponectin lowers plasma TG levels by increasing VLDL catabolism, primarily in muscle (26
). The possibility thus arises that high levels of adiponectin may contribute to the difference in lipid profile between patients with insulin receptoropathy and those with other forms of insulin resistance. While we cannot formally exclude this possibility, the 4 patients we studied in detail all had adiponectin levels within the healthy population range. Furthermore, we were able to show reduced hepatic lipogenesis and VLDL TG/ cholesterol levels in patients with insulin receptor mutations, implicating TG synthesis and thus VLDL production.
A significant body of work in vitro and a more limited number of in vivo observations have led to the suggestion that the dominant effect of insulin on VLDL synthesis and secretion is on APOB metabolism, with insulin suppressing VLDL production by enhancing APOB degradation (27
). If this were true in patients with primary insulin receptoropathy, one might expect these patients to manifest high VLDL production rates and a tendency toward hypertriglyceridemia, which is not what we have observed. This discrepancy probably reflects differences between the experimental paradigms used and the difficulty inherent in modeling a complex in vivo phenomenon. Interestingly, our findings are exactly in line with previous work in type 1 diabetes showing that VLDL TG content is lowered in well-controlled type 1 diabetes in euglycemic conditions (effectively a state of relative hepatic insulinopenia), with moreover no discernible difference in APOB kinetics in this situation (29
). They are also consistent with data suggesting that VLDL production rates are strongly linked with liver fat content (30
The level at which insulin signaling is impaired in pandemic insulin resistance remains unclear (31
). While substantial heterogeneity is very likely, our observations suggest that the presence of metabolic dyslipidemia indicates that the signaling defect is, at least in the liver, at a postreceptor level. De novo lipogenesis is already known to be increased in obese patients with fatty liver (32
) and in lean insulin-resistant diabetic offspring (1
). Our observations in patients with partial lipodystrophy suggest that here too, the defect in insulin action probably occurs at a postreceptor level. Given the strong correlations between hypertriglyceridemia, fatty liver, and insulin resistance, we suggest that postreceptor hepatic insulin resistance (partial insulin resistance) is likely to be present in most forms of human insulin resistance.
In summary, by studying patients with rare, molecularly defined defects in the insulin signaling pathway, we provide human evidence supporting the notion that metabolic dyslipidemia and hepatic steatosis are the results of selective postreceptor hepatic insulin resistance in humans.