Reviews/Commentaries/ADA Statements REVIEW ARTICLE Lipids and Glucose in Type 2 Diabetes What is the cause and effect? 1 GUENTHER BODEN, MD viving times of famine would be increased 2 MARKKU LAAKSO, MD if they could maximize energy storage (as fat) during times of surplus food availabil- ity. The stored fat could then be used dur- ing periods of starvation. istorically, type 2 diabetes was con- If this had happened, our understanding Adipocytes take up and store FFAs. sidered to revolve around a glu- of the pathogenesis of type 2 diabetes may The two main types of adipose tissue are H cose-insulin axis. The foundations have developed along a different route subcutaneous and visceral adipose tissue. for this thinking were probably laid down and led us more quickly to our current About 80% of body fat is located in the by two momentous discoveries in diabe- awareness that obesity, or more accu- subcutaneous adipose tissue, and ϳ10% tes research. According to popular leg- rately, the products of excess adipose tis- is located in visceral adipose tissue (7). end, Oskar Minkowski noticed that urine sue, precede the perturbations of glucose The remainder is in various other loca- from his pancreatectomized dogs at- metabolism. tions, such as perirenal and peritoneal ad- tracted an inordinate number of flies. He It is now apparent that elevation of ipose tissue (7). is then alleged to have tasted the urine plasma free fatty acids (FFAs) plays a piv- The body uses its fat reserves during and noted its sweetness. From this ob- otal role in the development of type 2 di- periods of low energy intake, when FFAs servation came the supposition that the abetes by causing insulin resistance. Type are being released for other tissues to be pancreas produced a substance that con- 2 diabetes develops because pancreatic used as fuel. However, if plasma FFA lev- trolled sugar concentration, and diabetes ␤-cells eventually fail to produce enough els are elevated for more than a few hours, occurred in the absence of this substance. insulin to compensate for the ongoing in- they will cause insulin resistance (8). In The second landmark was the discovery sulin resistance. There is a tight associa- certain conditions, the FFA-induced in- by Frederick Banting that insulin was the tion between type 2 diabetes and sulin resistance has the beneficial effect of active element from the pancreas. As a dyslipidemia. The latter is characterized preserving carbohydrate for use by vital consequence of these two discoveries, the by raised small, dense LDL levels, ele- tissues, such as the central nervous sys- concept that the glucose-insulin relation- vated levels of triglycerides, and low lev- tem. This is the case during starvation and ship was the central element of fuel me- els of HDL. Individually, the latter two during the second half of pregnancy, tabolism gained a firm hold. Diabetes has factors increase the risk of cardiovascular when the insulin resistance of the mother since been considered to be a disorder disease, and the combination of the two is preserves glucose for the growing fetus. primarily associated with abnormal glu- a risk factor for cardiovascular heart dis- cose metabolism. This notion is given cre- ease that is at least as strong as a high level PATHOLOGICAL dence by the considerable amount of data of LDL cholesterol (2). Some (3,4) but not CONSEQUENCES OF FAT indicating that the chronic elevation of all (5) studies have demonstrated that ACCUMULATION plasma glucose causes many of the micro- increased levels of small, dense LDL are In contrast to its beneficial effects during vascular complications of diabetes. associated with an elevated risk of cardio- periods of starvation and gestation, dur- In 1992, McGarry (1) asked what vascular disease. ing prolonged periods of energy excess, would have happened if Minkowski had the FFA-induced insulin resistance be- lacked a sense of taste but had a good EVOLUTIONARY comes counterproductive because there is nose. If that had been the case, he may RATIONALE FOR FAT no need for preservation of carbohydrate have smelled acetone, and this may have ACCUMULATION for use by vital tissues. Under these con- led him to the conclusion that removal of According to the thrifty gene hypothesis ditions, glucose levels remain normal the pancreas affects fatty acid metabolism. (6), the probability of an individual sur- only as long as the basal and postprandial ●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●● secretion of insulin by the pancreas is From the 1Division of Endocrinology/Diabetes/Metabolism and the General Clinical Research Center, Tem- 2 sufficient to compensate for the insulin ple University Hospital, Philadelphia, Pennsylvania; and the Department of Medicine, University of Kuopio, resistance. Kuopio, Finland. Address correspondence and reprint requests to G. Boden, MD, Temple University Hospital, 3401 N. Broad St., Philadelphia, PA 19140. E-mail: [email protected]. INDUCTION OF INSULIN Received for publication 27 May 2004 and accepted in revised form 10 June 2004. G.B. and M.L. have received honoraria from AstraZeneca Pharmaceuticals. RESISTANCE BY FFAS Abbreviations: DAG, diacylglycerol; FFA, free fatty acid; IL, interleukin; IRS, insulin receptor substrate; The mechanisms by which elevated FFA NF, nuclear factor; NHANES III, Third National Health and Nutrition Examination Survey; PKC, protein levels result in insulin resistance have kinase C; PPAR, peroxisome proliferator–activated receptor; TNF, tumor necrosis factor; TZD, thiazo- been determined in skeletal muscle, lidinedione. A table elsewhere in this issue shows conventional and Syste`me International (SI) units and conversion where most insulin-stimulated glucose factors for many substances. uptake occurs. Formerly, it was believed © 2004 by the American Diabetes Association. that FFA production from overloaded fat DIABETES CARE, VOLUME 27, NUMBER 9, SEPTEMBER 2004 2253 Lipids, glucose, and type 2 diabetes Figure 1—Potential mechanism of FFA on insulin resistance and atherogenesis in hu- man muscle. The key initiating event is an increase in plasma FFA followed by in- creased uptake of FFA into muscle. This leads to intramyocellular accumulation of fatty acyl-CoA and DAG and activation of PKC (the ␤ II and ␦ isoforms). It is assumed that activation of PKC interrupts insulin sig- naling by serine phosphorylation of IRS-1, resulting in a decrease in tyrosine phosphor- ylation of IRS-1. At the same time, activation of PKC also leads to production of inflam- matory and proatherogenic proteins through activation of the I␬B-␣/NF-␬B pathway. The broken lines indicate that ac- tivation of PKC by reactive oxygen species (ROS) and activation of the I␬B-␣/NF-␬B pathway by ROS has not been demonstrated in human muscle but only in bovine aortic smooth muscle and endothelial cells (ref. 84). PI, phosphatidylinositol. cells disrupted glucose homeostasis via However, it is probably not the accumu- can cause insulin resistance is by increas- the Randle glucose–fatty acid cycle. First lation of fat in muscle cells that causes ing oxidative stress (26). Reactive oxygen described by Randle et al. (9) in 1963, the insulin resistance but rather the accumu- species can activate PKC and the NF-␬B hypothesis was that glucose uptake is re- lation of other metabolites, including di- pathway (Fig. 1) and thereby contribute duced when tissue energy needs are being acylglycerol (DAG), that occur at the same to insulin resistance (17,27). met by FFA oxidation. The oxidation of time (17). FFAs also affect the functioning of in- FFAs was thought to result in decreased DAG, which is an intermediate of tri- sulin in the liver and thus contribute to glucose oxidation and an increase in in- glyceride metabolism, is a potent activa- hepatic overproduction of glucose and to tracellular citrate levels, which would tor of protein kinase C (PKC) (18). In elevated circulating blood glucose levels decrease glycolysis and glucose uptake. In healthy volunteers, along with the rise in (28). The main role of insulin in the liver is vivo and in vitro studies have only par- intramyocellular levels of DAG, there was control of glucose production. The mecha- tially confirmed Randle’s hypothesis (8, a concomitant increase in PKC activity nism by which insulin acutely (within 1–2 10–12). For instance, insulin-stimulated (17). PKC is an enzyme that can phos- h) suppresses hepatic glucose production is glucose uptake has been found to proceed phorylate serine and threonine residues by inhibiting glycogenolysis (29). FFAs normally for several hours after maximal on both the insulin receptor (19,20) and produce insulin resistance in the liver by inhibition of carbohydrate oxidation by insulin receptor substrate (IRS)-1 (20, inhibiting the acute insulin suppression of fatty acids (8,11–13). 21). The latter two molecules are impor- glycogenolysis (30). Insulin also promotes It is now thought that FFAs induce tant for insulin signaling. Serine phos- hepatic uptake of FFAs and production of insulin resistance in human muscle at the phorylation of IRS-1 can lead to its de- intracellular triglycerides. Thus, insulin re- level of insulin-stimulated glucose trans- struction and to insulin resistance (22). sistance in the liver may contribute to ele- port or phosphorylation by impairing the A change in intracellular DAG levels vated plasma FFA levels. insulin-signaling pathway (Fig. 1) is also accompanied by activation of the An increase in visceral fat could also (13,14). In a study of nondiabetic men nuclear factor (NF)-␬B pathway (Fig. 1) cause insulin resistance by mechanisms and women, insulin resistance developed (17). NF-␬B has been linked to fatty acid– that do not directly involve FFAs (Fig. 1). 2–4 h after an acute elevation in plasma induced impairment of insulin action in Adipose tissue is a source of inflammatory FFA concentration and took a similar rodents (23,24). NF-␬B is also increas- mediators, such as tumor necrosis factor amount of time to disappear after plasma ingly recognized as playing a crucial role (TNF)-␣ (31) and interleukin (IL)-6 (32) FFA levels had returned to normal (8,15).