chapter  8
78 Pages

Mitochondria in Diabetes Mellitus

Diabetes Mellitus ................................................................. 379 What Is Diabetes Mellitus? ........................................ 379 Types of Diabetes Mellitus ......................................... 380 Metabolic Syndrome and Diabetes Mellitus ............. 382 Complications of Diabetes Mellitus ........................... 383

Mitochondrial Abnormalities Precede the Appearance of Diabetes Mellitus ............................... 385 mtDNA Mutation in Diabetes Mellitus:

Insulin Secretion .............................................. 385 mtDNA Polymorphism and Type 2 Diabetes:

Insulin Resistance ............................................ 385 mtDNA Density in Diabetes: Insulin Resistance ..... 387 Mitochondrial Function and Insulin Resistance....... 391 Mitochondria-Related Gene Expression

Profile in Insulin Resistance ........................... 392 Mitochondrial Abnormalities in Diabetes-Prone

Animal Models .................................................. 394

Zucker Diabetic Fatty (ZDF) Rat .................... 394 Goto-Kakizaki (GK) Rat .................................. 395 Otsuka Long-Evans Tokushima Fatty

(OLETF) Rat ....................................... 396 Ob/Ob Mouse..................................................... 398

Mitochondria in the Malnutrition-Induced Rat: Thrifty Phenotype Hypothesis......................... 399

mtDNA Depletion Is Linked to Poor Glucose Utilization ......................................................... 402

Thrifty Phenotype, Thrifty Genotype, and Mitochondria ..................................................... 404

Improvement of Glucose Metabolism and Mitochondrial Function: Exercise .............................. 405 Exercise and Hexokinase II........................................ 405 Exercise and mtDNA Density .................................... 407 Mechanisms of mtDNA Increase Induced

by Exercise ........................................................ 408 Mechanisms of Increased Oxidative Stress in

Diabetes and Mitochondria ........................................ 408 Increased Oxidative Stress in Diabetes Mellitus ..... 408 Increased Oxidative Stress in Insulin Resistance.... 410 Glucose Stimulates Hydrogen Peroxide

Production ......................................................... 411 High Glucose Impairs Insulin Secretion and

Myocyte Function: Glucose Toxicity................ 413 Hyperglycemia Induces a Common mtDNA

Deletion in Vitro ............................................... 414 Nonesterified Fatty Acids Stimulate Hydrogen

Peroxide Production ......................................... 415 Insulin Acts on Mitochondria and Reduces

Free Radical Damage ....................................... 417 “Causal” Treatment of Diabetes................................. 419

Secondary Mitochondrial DNA Changes in Diabetes: Diabetic Complications ............................................... 420 Oxidative mtDNA Damage Is Linked to

Diabetic Complications .................................... 420 mtDNA Depletion in Diabetic Complications ........... 423 Abnormal Mitochondrial Function of Diabetes

Mellitus Exacerbates Insulin Deficiency ........ 423

NO and Vascular Complications of Diabetes ............ 425 Molecular Mechanisms of mtDNA Depletion............ 425

Whole-Body Energy Metabolism in Diabetes and Metabolic Syndrome.................................................... 428 Type 1 Diabetes........................................................... 428 Type 2 Diabetes........................................................... 428 Obesity ......................................................................... 430

Combination of Mitochondrial Hypothesis and Biological Allometric Scaling Law ............................. 431 Biological Allometric Scaling Law ............................. 431 Mitochondria of a Cell and Whole Body.................... 432 Heat Production, Body Temperature Control, and

Biological Scale ................................................. 433 Summary: New Paradigm for Understanding

Diabetes Mellitus ........................................................ 434 Acknowledgment .................................................................. 436 References............................................................................. 436

DIABETES MELLITUS

What Is Diabetes Mellitus?