Causation of Type 2 Diabetes — The Gordian Knot Unravels
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《新英格兰医药杂志》
Type 2 diabetes has always been a snake in the grass, sneaking up on both those with the disease and their physicians. To whit, the term "mild diabetes" persists, even though the disease is a leading cause of premature death from cardiovascular causes, amputations, and blindness. Life expectancy is considerably worse after the diagnosis of type 2 diabetes than after the diagnosis of some types of cancer. Moreover, the incidence of this condition is currently increasing so rapidly that it has been referred to as a pandemic. Basic concepts of the causation of type 2 diabetes have changed little for more than two decades, and progress in this field has appeared to be as difficult as untying the Gordian knot of mythology. However, the article by Petersen and colleagues in this issue of the Journal (pages 664–671) brings a welcome new direction to the field.
Let us consider the insights of the past decade that formed the springboard for this apparent breakthrough. First, insulin resistance in muscle is the earliest detectable defect in persons in whom type 2 diabetes will later develop. Second, beta-cell function has to be abnormal before hyperglycemia develops. This decline in function begins an estimated 10 years before diabetes is diagnosed, at which time beta-cell function is typically about 30 percent of the normal level. The United Kingdom Prospective Diabetes Study confirmed that this inexorable decline in beta-cell function was the same irrespective of treatment with dietary interventions alone, sulfonylurea, metformin, or insulin.
A third observation of note allowed us to escape from the glucose-only view of diabetes. A remarkable excess accumulation of intracellular triglyceride in both muscle and liver has been demonstrated to occur in type 2 diabetes. Knowledge about substrate competition between lipid and glucose suggested that this lipid accumulation contributed to insulin resistance. Further studies strongly suggested that the increased intracellular lipid stores in muscle predate the clinical onset of type 2 diabetes by many years.
In the mid-1990s, troglitazone was shown to improve insulin sensitivity in humans by interacting with a nuclear receptor, the peroxisome-proliferator–activated receptor (PPAR). This drug improved glucose control in patients with type 2 diabetes, but the subsequent demonstration that troglitazone actually delayed the decline in beta-cell function and prevented the onset of type 2 diabetes in a high-risk population was exciting.1 No other drug had previously affected the natural history of the development of type 2 diabetes. Ensuing work has shown that the newer agents pioglitazone and rosiglitazone also appear to have the remarkable ability to protect the beta cell as well as improve insulin sensitivity. However, these drugs do not prevent the terminal decline in beta-cell function after the onset of symptomatic diabetes.
As a consequence, the biology of PPAR has been vigorously probed. A coactivator of the receptor, peroxisome-proliferator–activated receptor coactivator 1 (PGC-1), has been discovered, and a common polymorphism of PGC-1 has been identified in patients with type 2 diabetes in population-based studies.2 Overweight people with a family history of type 2 diabetes have decreased expression of PGC-1, even when glucose tolerance is still normal.3
Since PGC-1 is a transcriptional coactivator that is essential for the synthesis of the mitochondrial enzymes for the beta-oxidation of fatty acid, the relevance of an apparently unrelated line of research becomes clear. Studies of triglyceride accumulation in muscle led to the recognition of a diabetes-associated decrease in the activity of the enzymes that are responsible for lipid oxidation, a process located almost exclusively in mitochondria. Recent biopsy studies in patients with type 2 diabetes have shown that mitochondria have impaired oxidative capacity and are only 55 percent of their normal size.4
Petersen and colleagues report changes in mitochondrial function that potentially link the twin defects in muscle and beta-cell function in type 2 diabetes. They used the elegant technique of saturation-transfer magnetic resonance spectroscopy to measure the rates of ATP synthesis in vivo (see Figure). The rate of mitochondrial ATP synthesis in skeletal muscle was decreased by 30 percent in a group of young, lean, insulin-resistant offspring of parents with type 2 diabetes, as compared with a group of control subjects with normal insulin sensitivity who were matched for physical activity. The findings suggest that an inherited defect in mitochondrial oxidative phosphorylation could lead to lipid accumulation and hence underlie the insulin resistance in muscle. A similar inherited tendency might be postulated to explain the progressive decrease in beta-cell function.
Figure. The Use of Saturation-Transfer Magnetic Resonance Spectroscopy to Measure the Rates of ATP Synthesis in Muscle.
In this schematic of a phosphorus-31 magnetic resonance spectrum from human muscle, the area under each peak is proportional to the concentration of the particular compound. The generation of a spectrum such as that shown in Panel A depends on the parallel alignment of the magnetic axes of the atomic nuclei with the magnetic field. If the nuclei in one compound are knocked out of alignment by a radiofrequency pulse tuned to the characteristic frequency for, say, ATP, then the spectrum measured immediately afterward will look like that shown in Panel B. The phosphorus atoms of ATP have, in effect, been labeled by becoming invisible on magnetic resonance imaging, and a short-lived, endogenously derived tracer has been created. The subsequent movement of these "labeled" phosphorus atoms into other compounds can be tracked. Since there is a continuous interchange of phosphorus between ATP and inorganic phosphorus (Pi), with ATP synthesis and breakdown, the signal from the inorganic phosphorus peak will decrease within milliseconds (Panel C). The quantitation of the areas under the peaks permits the calculation of the rate of mitochondrial ATP synthesis. PCr denotes phosphocreatine.
Might this study represent a definitive breakthrough in our understanding of type 2 diabetes? The implication of recent observations, taken together, is that a moderate deficiency in the action of PGC-1 or related factors may underlie the mitochondrial dysfunction, as reflected in somewhat subnormal rates of lipid oxidation. This dysfunction could explain a steady tendency toward both weight gain and excess intraorgan lipid levels.
It is notable that the typical bioenergetic properties of mitochondria in type 2 diabetes are also present in obesity.4 We know that the population rates of diabetes are dependent on physical inactivity and adiposity, phenomena that can now be explained. Weight loss would be expected to offset the metabolic effects of the subtle mitochondrial defect. Similarly, physical exercise increases mitochondrial gene expression and oxidative capacity, possibly through increases in PGC-1 levels. Aging is associated with declining mitochondrial function and decreased rates of muscle ATP synthesis.5 Thus, separate influences of genetic and environmental factors increase the prevalence of type 2 diabetes with increasing age.
The same processes appear likely to affect the beta cell, as well as muscle. Mitochondria play a critical role in mediating glucose-induced insulin secretion, and islets that are exposed to increased lipid levels in vitro exhibit inhibition of insulin-gene expression. Indeed, a sudden and massive increase in islet triglyceride levels occurs just before the onset of hyperglycemia in some animal models of diabetes. The administration of troglitazone both decreases islet lipid levels and prevents the onset of diabetes.
A number of new hypotheses now unfold. Do obese, inactive people who retain normal glucose tolerance lack the susceptibility-related polymorphism of PGC-1? Do moderately overweight people in whom type 2 diabetes develops in early adult life have multiple genetic "hits" affecting pathways involving PGC-1? What is the dose–response relationship between the exercise-induced stimulation of mitochondrial activity and the prevention of diabetes? At what stage of incipient beta-cell failure will glitazones and other therapies that influence PPAR be most effective? Will this effect be magnified by concurrent therapy with fibrate drugs — now known to be agonists of peroxisome-proliferator–activated receptor (PPAR)?
Management of type 2 diabetes has always been centered on control of the body's energy economy — the attempt to achieve a negative calorie balance and the achievement of the optimal intake of carbohydrates and lipids. These latest studies permit us to peer into the powerhouse of the cell in order to bring causation and pathogenesis into sharper focus.
Dr. Taylor reports having received consulting and lecture fees and grant support from Eli Lilly and grant support from Takeda.
Source Information
From the University of Newcastle upon Tyne Medical School, Newcastle upon Tyne, United Kingdom.
References
Buchanan TA, Xiang AH, Peters RK, et al. Preservation of pancreatic beta-cell function and prevention of type 2 diabetes by pharmacological treatment of insulin resistance in high-risk Hispanic women. Diabetes 2002;51:2796-2803.
Ek J, Andersen G, Urhammer SA, et al. Mutation analysis of peroxisome proliferator-activated receptor-gamma coactivator-1 (PGC-1) and relationships of identified amino acid polymorphisms to Type II diabetes mellitus. Diabetologia 2001;44:2220-2226.
Patti ME, Butte AJ, Crunkhorn S, et al. Coordinated reduction of genes of oxidative metabolism in humans with insulin resistance and diabetes: potential role of PGC1 and NRF1. Proc Natl Acad Sci U S A 2003;100:8466-8471.
Kelley DE, He J, Menshikova EV, Ritov VB. Dysfunction of mitochondria in human skeletal muscle in type 2 diabetes. Diabetes 2002;51:2944-2950.
Petersen KF, Befroy D, Dufour S, et al. Mitochondrial dysfunction in the elderly: possible role in insulin resistance. Science 2003;300:1140-1142.(Roy Taylor, M.D.)
Let us consider the insights of the past decade that formed the springboard for this apparent breakthrough. First, insulin resistance in muscle is the earliest detectable defect in persons in whom type 2 diabetes will later develop. Second, beta-cell function has to be abnormal before hyperglycemia develops. This decline in function begins an estimated 10 years before diabetes is diagnosed, at which time beta-cell function is typically about 30 percent of the normal level. The United Kingdom Prospective Diabetes Study confirmed that this inexorable decline in beta-cell function was the same irrespective of treatment with dietary interventions alone, sulfonylurea, metformin, or insulin.
A third observation of note allowed us to escape from the glucose-only view of diabetes. A remarkable excess accumulation of intracellular triglyceride in both muscle and liver has been demonstrated to occur in type 2 diabetes. Knowledge about substrate competition between lipid and glucose suggested that this lipid accumulation contributed to insulin resistance. Further studies strongly suggested that the increased intracellular lipid stores in muscle predate the clinical onset of type 2 diabetes by many years.
In the mid-1990s, troglitazone was shown to improve insulin sensitivity in humans by interacting with a nuclear receptor, the peroxisome-proliferator–activated receptor (PPAR). This drug improved glucose control in patients with type 2 diabetes, but the subsequent demonstration that troglitazone actually delayed the decline in beta-cell function and prevented the onset of type 2 diabetes in a high-risk population was exciting.1 No other drug had previously affected the natural history of the development of type 2 diabetes. Ensuing work has shown that the newer agents pioglitazone and rosiglitazone also appear to have the remarkable ability to protect the beta cell as well as improve insulin sensitivity. However, these drugs do not prevent the terminal decline in beta-cell function after the onset of symptomatic diabetes.
As a consequence, the biology of PPAR has been vigorously probed. A coactivator of the receptor, peroxisome-proliferator–activated receptor coactivator 1 (PGC-1), has been discovered, and a common polymorphism of PGC-1 has been identified in patients with type 2 diabetes in population-based studies.2 Overweight people with a family history of type 2 diabetes have decreased expression of PGC-1, even when glucose tolerance is still normal.3
Since PGC-1 is a transcriptional coactivator that is essential for the synthesis of the mitochondrial enzymes for the beta-oxidation of fatty acid, the relevance of an apparently unrelated line of research becomes clear. Studies of triglyceride accumulation in muscle led to the recognition of a diabetes-associated decrease in the activity of the enzymes that are responsible for lipid oxidation, a process located almost exclusively in mitochondria. Recent biopsy studies in patients with type 2 diabetes have shown that mitochondria have impaired oxidative capacity and are only 55 percent of their normal size.4
Petersen and colleagues report changes in mitochondrial function that potentially link the twin defects in muscle and beta-cell function in type 2 diabetes. They used the elegant technique of saturation-transfer magnetic resonance spectroscopy to measure the rates of ATP synthesis in vivo (see Figure). The rate of mitochondrial ATP synthesis in skeletal muscle was decreased by 30 percent in a group of young, lean, insulin-resistant offspring of parents with type 2 diabetes, as compared with a group of control subjects with normal insulin sensitivity who were matched for physical activity. The findings suggest that an inherited defect in mitochondrial oxidative phosphorylation could lead to lipid accumulation and hence underlie the insulin resistance in muscle. A similar inherited tendency might be postulated to explain the progressive decrease in beta-cell function.
Figure. The Use of Saturation-Transfer Magnetic Resonance Spectroscopy to Measure the Rates of ATP Synthesis in Muscle.
In this schematic of a phosphorus-31 magnetic resonance spectrum from human muscle, the area under each peak is proportional to the concentration of the particular compound. The generation of a spectrum such as that shown in Panel A depends on the parallel alignment of the magnetic axes of the atomic nuclei with the magnetic field. If the nuclei in one compound are knocked out of alignment by a radiofrequency pulse tuned to the characteristic frequency for, say, ATP, then the spectrum measured immediately afterward will look like that shown in Panel B. The phosphorus atoms of ATP have, in effect, been labeled by becoming invisible on magnetic resonance imaging, and a short-lived, endogenously derived tracer has been created. The subsequent movement of these "labeled" phosphorus atoms into other compounds can be tracked. Since there is a continuous interchange of phosphorus between ATP and inorganic phosphorus (Pi), with ATP synthesis and breakdown, the signal from the inorganic phosphorus peak will decrease within milliseconds (Panel C). The quantitation of the areas under the peaks permits the calculation of the rate of mitochondrial ATP synthesis. PCr denotes phosphocreatine.
Might this study represent a definitive breakthrough in our understanding of type 2 diabetes? The implication of recent observations, taken together, is that a moderate deficiency in the action of PGC-1 or related factors may underlie the mitochondrial dysfunction, as reflected in somewhat subnormal rates of lipid oxidation. This dysfunction could explain a steady tendency toward both weight gain and excess intraorgan lipid levels.
It is notable that the typical bioenergetic properties of mitochondria in type 2 diabetes are also present in obesity.4 We know that the population rates of diabetes are dependent on physical inactivity and adiposity, phenomena that can now be explained. Weight loss would be expected to offset the metabolic effects of the subtle mitochondrial defect. Similarly, physical exercise increases mitochondrial gene expression and oxidative capacity, possibly through increases in PGC-1 levels. Aging is associated with declining mitochondrial function and decreased rates of muscle ATP synthesis.5 Thus, separate influences of genetic and environmental factors increase the prevalence of type 2 diabetes with increasing age.
The same processes appear likely to affect the beta cell, as well as muscle. Mitochondria play a critical role in mediating glucose-induced insulin secretion, and islets that are exposed to increased lipid levels in vitro exhibit inhibition of insulin-gene expression. Indeed, a sudden and massive increase in islet triglyceride levels occurs just before the onset of hyperglycemia in some animal models of diabetes. The administration of troglitazone both decreases islet lipid levels and prevents the onset of diabetes.
A number of new hypotheses now unfold. Do obese, inactive people who retain normal glucose tolerance lack the susceptibility-related polymorphism of PGC-1? Do moderately overweight people in whom type 2 diabetes develops in early adult life have multiple genetic "hits" affecting pathways involving PGC-1? What is the dose–response relationship between the exercise-induced stimulation of mitochondrial activity and the prevention of diabetes? At what stage of incipient beta-cell failure will glitazones and other therapies that influence PPAR be most effective? Will this effect be magnified by concurrent therapy with fibrate drugs — now known to be agonists of peroxisome-proliferator–activated receptor (PPAR)?
Management of type 2 diabetes has always been centered on control of the body's energy economy — the attempt to achieve a negative calorie balance and the achievement of the optimal intake of carbohydrates and lipids. These latest studies permit us to peer into the powerhouse of the cell in order to bring causation and pathogenesis into sharper focus.
Dr. Taylor reports having received consulting and lecture fees and grant support from Eli Lilly and grant support from Takeda.
Source Information
From the University of Newcastle upon Tyne Medical School, Newcastle upon Tyne, United Kingdom.
References
Buchanan TA, Xiang AH, Peters RK, et al. Preservation of pancreatic beta-cell function and prevention of type 2 diabetes by pharmacological treatment of insulin resistance in high-risk Hispanic women. Diabetes 2002;51:2796-2803.
Ek J, Andersen G, Urhammer SA, et al. Mutation analysis of peroxisome proliferator-activated receptor-gamma coactivator-1 (PGC-1) and relationships of identified amino acid polymorphisms to Type II diabetes mellitus. Diabetologia 2001;44:2220-2226.
Patti ME, Butte AJ, Crunkhorn S, et al. Coordinated reduction of genes of oxidative metabolism in humans with insulin resistance and diabetes: potential role of PGC1 and NRF1. Proc Natl Acad Sci U S A 2003;100:8466-8471.
Kelley DE, He J, Menshikova EV, Ritov VB. Dysfunction of mitochondria in human skeletal muscle in type 2 diabetes. Diabetes 2002;51:2944-2950.
Petersen KF, Befroy D, Dufour S, et al. Mitochondrial dysfunction in the elderly: possible role in insulin resistance. Science 2003;300:1140-1142.(Roy Taylor, M.D.)