Type 2 Diabetes
Non-insulin-dependent diabetes and obesity are two metabolic disorders that are closely related because insulin resistance constitutes a common complication of excess weight and is the key element of non-insulin-dependent diabetes. A disrupted inflammatory response plays an essential role in insulin resistance (Grimble, 2002).
The inflammatory response constitutes an essential defence mechanism against pathogens. TNFa, IL-1 and IL-6 are the most important mediators involved in inflammation. Cytokine secretion induces metabolic changes to supply the immune system with nutritional elements from various body tissues to fight the pathogenic agent.
These metabolic changes include hyperlipidemia and increased gluconeogenesis.
The metabolic disruptions occur in cases of obesity, non-insulin-dependent diabetes and atherosclerosis. Cardiovascular mortality is 5 times higher in insulin resistant subjects than in the “normal” population (Muller-Wieland et al., 2001).
The deleterious effect of an exaggerated inflammatory response to insulin sensitivity is related to several concurrent factors (Fernandez-Real and Ricart; 1999):
• Presence of hereditary factors predisposing to insulin resistance
• Western lifestyle (diet high in carbohydrates and saturated fatty acids and low in vegetable fibre, and sedentary lifestyle)
• Predisposition to an intense inflammatory cytokine response
Chronic inflammatory response therefore triggers insulin resistance and not vice versa. From an evolutionary perspective, the benefits of an intense inflammatory response leading to eradication of the pathogenic agent and moderate resistance to insulin protecting against malnutrition are far more important than the long-term risks (e.g., atherosclerosis) related to underlying metabolic disorders. However, due to increasing longevity and adaptation to the western lifestyle, the deleterious effects of a strong chronic or repetitive inflammatory response become increasingly important in the medium and long term.
It is mostly NFa and other cytokines produced locally by the adipocytes, the striated muscle cells (paracrine and autocrine activity) and the cells of the immune system (systemic activity) that form the link between the inflammatory response and insulin resistance.
Pathophysiology of Type 2 Diabetes
Non-insulin-dependent diabetes has a multi-factorial pathology involving genetic predisposition, endocrine disorders and environmental factors such as obesity, malnutrition and sedentary lifestyle. Reduced synthesis of insulin and insulin resistance are necessary for the disease to clinically manifest. Type 2 diabetes takes many years to develop and is preceded by the progressive deterioration of glucose tolerance (Weyer et al.,1999). Glucose intolerance constitutes an intermediary stage between normal glucose metabolism and diabetes.
Reduced stimulation by insulin primarily of non-oxidative muscle metabolism of glucose (insulin resistance) represents a key element of Type 2 diabetes and is observed very early in the pre-diabetic stage. However, it is not clear if this metabolic anomaly represents a genetic deficit or if it develops secondarily following obesity. The genes potentially responsible are those involved in lipolysis regulation, lipase synthesis and the beta3-adrenergic receptor (Groop, 1999).
Several cytokines (TNFa, IL-1b and IL-6), hormones (growth factor and angiotensin), leptin and free fatty acids play a part in insulin resistance (Mooney et al., 2001). Insulin resistance a the cellular level is related to the reduced activity of the tyrosine kinase of the insulin receptor and reduced phosphorylation of target proteins such as insulin receptor substrates (IRS) through induction of SOCS-3. This modified form of IRS-1 has an inhibitory action. TNFa also interferes with transport by reducing the synthesis of the GLUT-4 carriers. These effects involve the production of H2O2. Oxidative stress related to an increased production of TNFa may play a role in inducing insulin resistance at an early stage of the disease.
TNFa is involved in insulin resistance in muscle and fat tissue. Obese Sprague-Dawley (S-D) rats that quickly develop insulin resistance during their lives by reducing muscular transport of glucose show increased muscle concentrations of TNFa. Administration of anti-TNFa IgG to S-D rats reduces insulin resistance and leads to reduced TNFa levels in muscle (Borst and Bagby, 2002). The same effect was observed in the fatty tissue of fa/fa obese rats (Hotamisligil et al., 1993)., 1993). In humans, elevated tissue levels of TNFa in adipocytes and muscles with an increased release into the blood circulation were observed in cases of obesity (Hotamisligil et al., 1995; Kern et al., 1995; Nilsson et al., 1998)., These TNFa plasma levels are relatively low and the question whether this circulating TNFa exerts a systemic biological effect or an effect on other organs currently remains unanswered. TNFa may be related to a soluble receptor that inhibits its biological activity (Engelberts et al., 1991); the systemic effects of TNFa produced by the fatty and muscle tissue would therefore be limited. However, the fraction of circulating TNFa observed in insulin-resistant subjects may reflect an inflammatory activation of the disease (Nilsson et al., 1998), and the plasma levels could increase to those in advanced stages of the disease, preceded by other metabolic changes (Zinman et al., 1999).
A detailed description of all the common TNFa effects on the two pathologies of Type 2 diabetes and obesity is given in the section dealing with obesity.
Food Intolerance and Type 2 Diabetes
Intestinal absorption of glucose and postprandial hyperglycemia increase in the early stage of glucose intolerance in an animal model for Type 2 diabetes (Fujita et al., 1998). This is a strain of obese rats with Type 2 diabetes exhibiting insulin resistance (Otsuka Long-Evans Tokushima Fatty rat (OLETF)). In these animals, with an anomaly of the intestinal mucous membrane, intestinal permeability is disrupted, and in fact, the D-Xylose test shows absorption increased by more than 50% compared to the control rat strain. In humans, intestinal permeability in subjects at risk for non-insulin-dependent diabetes has not yet been studied at this time.
Guidelines for measurement of dietary IgG anti-antigens by ImuPro 300
The measurement of dietary IgG anti-antigens is useful both as prevention and therapy. Apart from the local activity in adipocytes and striated muscle cells, exaggerated circulating levels of TNFa and other cytokines following a chronic inflammatory response in predisposed subjects cause insulin resistance, and subsequently, the development of Type 2 diabetes. Since the occurrence of food intolerance is high, this could constitute an inflammatory stimulus in a high number of cases. Food intolerance could also be secondary, following the systemic effect of TNFa produced in excessive quantities by one or more other inflammatory foci or in adipocytes or striated muscle cells, which may provoke or aggravate food intolerance, thereby creating a vicious cycle.
Proposed Indications:
Normoglycemic obese and non-obese subjects with a family history of Type 2 diabetes and asymptomatic subjects exhibiting glucose intolerance. The purpose of this indication is to slow down or prevent the development of insulin resistance and weight loss (see section on obesity) by an indirect anti-TNF& effect.
People with Type 2 diabetes. The expected effects are a partial reversal of insulin resistance and a slowing down of the disease progress, thus helping to reduce the risk of complications and postponing insulin therapy.
