Type 2 Diabetes: Etiology and Reversibility

Roy Taylor, MD, FRCP

Disclosures

Diabetes Care. 2013;36(4):1047-1055. 

In This Article

New Perspectives on Insulin Resistance

Muscle

Whole-body insulin resistance is the earliest predictor of type 2 diabetes onset, and this mainly reflects muscle insulin resistance.[26] However, careful separation of the contributions of muscle and liver have shown that early improvement in control of fasting plasma glucose level is associated only with improvement in liver insulin sensitivity.[20,21] It is clear that the resumption of normal or near-normal diurnal blood glucose control does not require improvement in muscle insulin sensitivity. Although this finding may at first appear surprising, it is supported by a wide range of earlier observations. Mice totally lacking in skeletal muscle insulin receptors do not develop diabetes.[27] Humans who have the PPP1R3A genetic variant of muscle glycogen synthase cannot store glycogen in muscle after meals but are not necessarily hyperglycemic.[28] Many normoglycemic individuals maintain normal blood glucose levels with a degree of muscle insulin resistance identical to those with type 2 diabetes.[29]

Although a defect in mitochondrial function is associated with extremes of insulin resistance in skeletal muscle,[30] this does not appear to be relevant to the etiology of type 2 diabetes. No defect is present in early type 2 diabetes but rather is directly related to ambient plasma glucose concentration.[31] Observed rates of mitochondrial ATP production can be modified by increasing or decreasing plasma fatty acid concentration.[32,33] Additionally, the onset of insulin stimulation of mitochondrial ATP synthesis is slow, gradually increasing over 2 h, and quite distinct from the acute onset of insulin's metabolic effects.[34] Although it remains possible that secondary mitochondrial effects of hyperglycemia and excess fatty acids exist, there is no evidence for a primary mitochondrial defect underlying type 2 diabetes.

The physiologic importance of muscle insulin resistance is likely to operate over a period of many years. The presence of long-standing muscle insulin resistance will not of itself cause blood glucose levels to rise, but raised plasma insulin levels will expedite accumulation of liver fat by stimulation of de novo lipogenesis.[26]

Liver

Evidence linking hepatic insulin sensitivity to intraorgan triglyceride content has been steadily accumulating. In insulin-treated type 2 diabetes, insulin dose correlates with the extent of fatty liver,[35] and in turn, this is associated with insulin sensitivity to suppression of hepatic glucose production.[36] Decreasing the fat content of liver is associated with improvement in insulin suppression of glucose production and, thereby, with improvement in fasting plasma glucose.[20,23]

Storage of liver fat can only occur when daily calorie intake exceeds expenditure. Sucrose overfeeding for 3 weeks has been shown to cause a 30% increase in liver fat content.[37] The associated metabolic stress on hepatocytes was reflected by a simultaneous 30% rise in serum alanine aminotransferase (ALT) levels, and both liver fat and serum ALT returned to normal levels during a subsequent hypocaloric diet. Superimposed upon a positive calorie balance, the extent of portal vein hyperinsulinemia determines how rapidly conversion of excess sugars to fatty acid occurs in the liver. In groups of both obese and nonobese subjects, it was found that those with higher plasma insulin levels have markedly increased rates of hepatic de novo lipogenesis.[2,38,39] Conversely, in type 1 diabetes the relatively low insulin concentration in the portal vein (as a consequence of insulin injection into subcutaneous tissue) is associated with subnormal liver fat content.[40] Initiation of subcutaneous insulin therapy in type 2 diabetes brings about a decrease in portal insulin delivery by suppression of pancreatic insulin secretion and, hence, a decrease in liver fat.[41] Hypocaloric diet,[42] physical activity,[43] or thiazolidinedione use[23,44] each reduces insulin secretion and decreases liver fat content. Newly synthesized triacylglycerol in the liver will be either oxidized, exported, or stored as hepatic triacylglycerol. Because transport of fatty acid into mitochondria for oxidation is inhibited by the malonyl-CoA produced during de novo lipogenesis, newly synthesized triacylglycerol is preferentially directed toward storage or export. Hence, hepatic fat content and plasma VLDL triacylglycerol levels are increased.

Within the hepatocyte, fatty acids can only be derived from de novo lipogenesis, uptake of nonesterified fatty acid and LDL, or lipolysis of intracellular triacylglycerol. The fatty acid pool may be oxidized for energy or may be combined with glycerol to form mono-, di-, and then triacylglycerols. It is possible that a lower ability to oxidize fat within the hepatocyte could be one of several susceptibility factors for the accumulation of liver fat.[45] Excess diacylglycerol has a profound effect on activating protein kinase C epsilon type (PKCε), which inhibits the signaling pathway from the insulin receptor to insulin receptor substrate 1 (IRS-1), the first postreceptor step in intracellular insulin action.[46] Thus, under circumstances of chronic energy excess, a raised level of intracellular diacylglycerol specifically prevents normal insulin action, and hepatic glucose production fails to be controlled (Fig. 4). High-fat feeding of rodents brings about raised levels of diacylglycerol, PKCε activation, and insulin resistance. However, if fatty acids are preferentially oxidized rather than esterified to diacylglycerol, then PKCε activation is prevented, and hepatic insulin sensitivity is maintained. The molecular specificity of this mechanism has been confirmed by use of antisense oligonucleotide to PKCε, which prevents hepatic insulin resistance despite raised diacylglycerol levels during high-fat feeding.[47] In obese humans, intrahepatic diacylglycerol concentration has been shown to correlate with hepatic insulin sensitivity.[48,49] Additionally, the presence of excess fatty acids promotes ceramide synthesis by esterification with sphingosine. Ceramides cause sequestration of Akt2 and activation of gluconeogenic enzymes (Fig. 4), although no relationship with in vivo insulin resistance could be demonstrated in humans.[49] However, the described intracellular regulatory roles of diacylglycerol and ceramide are consistent with the in vivo observations of hepatic steatosis and control of hepatic glucose production.[20,21]

Figure 4.

Mechanism of interaction between excess amounts of fatty acids, diacylglycerol, and ceramide and insulin action within the hepatocyte. Diacylglycerol activates PKCε and inhibits activation of IRS-1 by the insulin receptor. Ceramides cause sequestration of Akt2 by PKCζ and inhibit insulin control of gluconeogenesis. These mechanisms have recently been reviewed.99 FFA, free-fatty acid; TG, triacylglycerol.

Fasting plasma glucose concentration depends entirely on the fasting rate of hepatic glucose production and, hence, on its sensitivity to suppression by insulin. Hepatic insulin sensitivity cannot be inferred from observed postprandial change in hepatic glycogen concentration because glucose transport into the hepatocyte is not rate limiting, unlike in muscle, and hyperglycemia itself drives the process of glycogen synthesis irrespective of insulin action. Indeed, postprandial glycogen storage in liver has been shown to be moderately impaired in type 2 diabetes[50] compared with the marked impairment in skeletal muscle.[51]

Although a close relationship exists among raised liver fat levels, insulin resistance, and raised liver enzyme levels,[52] high levels of liver fat are not inevitably associated with hepatic insulin resistance. This is analogous to the discordance observed in the muscle of trained athletes in whom raised intramyocellular triacylglycerol is associated with high insulin sensitivity.[53] This relationship is also seen in muscle of mice overexpressing the enzyme DGAT-1, which rapidly esterifies diacylglycerol to metabolically inert triacylglycerol.[54] In both circumstances, raised intracellular triacylglycerol stores coexist with normal insulin sensitivity. When a variant of PNPLA3 was described as determining increased hepatic fat levels, it appeared that a major factor underlying nonalcoholic fatty liver disease and insulin resistance was identified.[55] However, this relatively rare genetic variant is not associated with hepatic insulin resistance.[56] Because the responsible G allele of PNPLA3 is believed to code for a lipase that is ineffective in triacylglycerol hydrolysis, it appears that diacylglycerol and fatty acids are sequestered as inert triacylglycerol, preventing any inhibitory effect on insulin signaling.

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