dominates during the first few minutes of exercise. During endurance exercise red fibers dominate. Their aerobic glycolysis is increased and all endogenous and exogenous substrates are oxidized. Muscle and liver glycogen is mobilized and used up. Glucose uptake may increase up to 20-fold. Serum insulin decreases, indicating enhanced insulin sensitivity. After about 10 minutes' exercise, oxidation of FFA becomes more important and may increase to up to 50-fold of the basal level. Finally, energy metabolism is fueled mainly by FFA and β-hydroxybutyrate/acetoacetate. After strenuous exercise (e.g., marathon), plasma FFA may stay elevated and glucose uptake may remain reduced for several hours (“post-exercise insulin resistance”). A paradoxical increase in blood glucose is seen after short-term exhaustive exercise, which is the result of stress hormone release [106,107].
Increased insulin sensitivity during exercise is due to increased muscular blood flow with greater insulin delivery to muscle, opening of closed capillaries, which enhances the surface area for glucose uptake, and translocation of glucose transporters, mainly GLUT-4 [108]. Physical training stimulates GLUT-4 synthesis [109]. Enhanced insulin sensitivity vanishes in periods of physical inactivity. This occurs as early as after a few days of strict bed rest.
Clinical experience shows that in poorly controlled diabetic individuals insulin sensitivity is decreased. It improves when metabolic control is restored towards normal. This metabolic insulin resistance has been described by the term “glucose toxicity.” The mechanism of glucose toxicity is not fully understood. One explanation is increased synthesis of glucosamine, which could cause insulin resistance by inhibition of the translocation of GLUT-4 in muscle [110–112]. Glucosamine seems also to inhibit glucose-induced insulin secretion [110]. Thus, this metabolite would mimic both the major pathogenetic mechanisms in type 2 diabetes. However, since poor metabolic control is characterized by high plasma FFA levels, the aforementioned effects of plasma FFA on liver and muscle metabolism could also explain some signs of metabolic insulin resistance.
Insulin Secretion
Instead of postulating insulin resistance and peripheral underutilization of glucose as the primary defect, some investigators have proposed that impaired insulin secretion and impaired suppression of hepatic glucose production are the important determinants of glucose intolerance [102,113]. Gerich [114] based his view on the evaluation of insulin secretion after an oral glucose load. In subjects with impaired glucose tolerance, and even more in those with clinical N1DDM, early insulin secretion is reduced and late insulin secretion increased [115]. Defective early insulin release is responsible for impaired glucose tolerance, which on its part triggers late hyperinsulinemia. The suppression of hepatic glucose production is impaired [102,116], resulting in increased hepatic glucose output. Under steady-state conditions this is equal to increased glucose disposal. Indeed, forearm muscle glucose uptake is not impaired in person with impaired glucose tolerance [116]. From these observations, Gerich concluded that peripheral insulin resistance cannot be an important pathogenetic factor [114].
Hepatic glucose output is directly related to fasting plasma glucose, supporting the view that the liver plays a major role in fasting hyperglycemia. However, increased hepatic glucose output may not be a primary defect. As mentioned before, increased hepatic glucose output can be explained as a response to enhanced lipolysis, with the primary defect being ascribed to insulin resistance of the adipocyte.
Recently, in order to elucidate the sequence of events, body weight and body composition, insulin secretion, insulin action, and endogenous glucose output were continuously monitored in a longitudinal study over several years in Pima Indians in whom normal glucose tolerance progressed to diabetes [117]. Progression to impaired glucose tolerance was associated with an increase in body weight and fat mass and a decline in both early insulin response to a glucose stimulus and insulin-stimulated glucose disposal. Progression to diabetes was accompanied by progression of these two disorders and, in addition, by an increase in basal endogenous glucose output. Subjects who retained a normal glucose tolerance in spite of weight gain (nonprogressors) were insulin-resistant but improved their early insulin secretion. According to this study, the ability to improve early insulin secretion decides progression to diabetes. Increased endogenous glucose output is a later event in the development of type 2 diabetes [117].
Genes responsible for defects of early insulin secretion and insulin secretory capacity have not yet been identified. However, the familial nature of type 2 diabetes leaves little doubt that they play a role. On the other hand, secretory defects may also be acquired due to glucose toxicity or hyperlipacidemia [118]. Thus, there is evidence for primary genetic and secondary environmental influences on insulin secretion and insulin sensitivity, respectively.
Clinical Picture of Diabetes Mellitus
Acute Symptoms
Mild hyperglycemia usually does not cause symptoms and may not be noticed by the patient, but severe hyperglycemia will always cause clinical symptoms.
People with untreated diabetes develop progressive hyperglycemia. When the renal threshold for plasma glucose of about 7 mmol/l is surpassed, glucose is excreted with the urine. Glucosuria goes along with osmotic diuresis and results in large urine volume, thirst, exsiccosis, and electrolyte disorders. Together with these effects of insulin deficiency, electrolyte imbalance is accentuated by cellular loss and renal excretion of potassium. Protein synthesis is lowered and accelerated proteolysis results in protein loss from muscle and other tissues. Increased amino acid levels in blood may be utilized for energy metabolism and gluconeogenesis. Lipid storage is blocked, while lipolysis is increased. This results in the massive appearance of FFA in blood. They are in part incorporated into lipoproteins, thus inducing hyper- and dyslipidemia. FFA also swamp into the energy metabolism. This process is enhanced by elevated levels of plasma glucagon, which activates the enzyme carnitine-palmitoyltransferase (CPT-1) and the transport of long-chain fatty acids into the mitochondria. Here they compete with glucose for the oxidative chain, thus decreasing glucose oxidation. The supply of FFA is greater than the energy need. The FFA surplus is only degraded to the level of β-hydroxybutyrate and α-ketoglutarate, which may accumulate and cause ketoacidosis.
FFA also stimulate gluconeogenesis and hepatic glucose output, they modulate signal chains (e.g., PI-3 and IRS phosphorylation depressed. PKC activated), and contribute to metabolic insulin resistance (pages 6–8).
These disorders result in the classical symptoms of insulin deficiency: polyuria, thirst, polydipsia, exsiccosis, muscle wasting, loss of lipid stores, weight loss, polyphagia, fatigue, and nausea. At diagnosis, about 1% of the subjects have developed ketoacidosis with hyperventilation and eventual coma.
Type 1 Diabetes
Five phases
