Response of the alternative complement pathway to an oral fat load in first-degree relatives of subjects with type II diabetes

Abstract

OBJECTIVE:To investigate levels of components of the alternative pathway of complement, and of two activation products, ASP and Bb, in persons ranging in insulin resistance both fasting and following the consumption of a high-fat, low-carbohydrate meal. SUBJECTS: Healthy controls (n ¼ 17) and normoglycaemic first-degree relatives of patients with type II diabetes (n ¼ 15). MEASUREMENTS: All subjects had normal glucose tolerance. Blood was collected for the measurement of plasma glucose, insulin, triglycerides and free fatty acids. Body composition was assessed with dual energy X-ray absorptiometry (DEXA) and whole-body insulin sensitivity with a euglycaemic, hyperinsulinaemic clamp. Basal and postprandial values over 6 h were determined for plasma C3, B, D, Bb and ASP. Basal levels of C1q, C4 and CRP were also determined. RESULTS: Controls did not differ significantly from the relatives of patients with type II diabetes for any metabolic parameter except in their degree of insulin resistance and central fat (kg). Across all subjects, basal levels of C3, but no other complement protein, were correlated with insulin resistance. Native complement proteins, but not ASP or Bb, were correlated with body mass index and the amount (kg) of central fat. Basal levels of C3 and factor B were significantly higher in the relatives group, whereas factor D and the classical pathway proteins C1q and C4 did not differ between the two groups. Postprandially, levels of factor D were significantly reduced in both groups. ASP levels also fell postprandially, the decline achieving significance in the relatives group. CONCLUSIONS: Elevated levels of C3 and factor B in the diabetic relatives group may have resulted from increased synthesis by adipose tissue. There was no evidence of alternative pathway activation in response to a fat meal in terms of ASP or Bb production, or significant consumption of C3 and factor B. These data do not support an essential requirement of the hypothesis that ASP is produced in response to the intake of fat.

Weight gain in relation to plasma levels of complement factor 3: results from a population-based cohort study

“…Cross-sectional studies have shown that obesity is associated with elevated plasma levels of C3 [4,[6][7][8][9][10], but the causal and temporal relations of this association have been unclear. The present study showed that C3 was strongly associated both with weight at baseline and weight at follow-up.…”

“…Individuals who are overweight or obese generally have raised concentrations of C3 and C4 [4][5][6][7][8][9][10], and it has been reported that C3 levels decrease after weight loss [6,7]. The proteolytic fragment of C3, acylation-stimulating protein (ASP), is a paracrine metabolic factor that stimulates the uptake of glucose and fat storage in human adipose tissue [11][12][13][14].…”

Complement C3 Is a Risk Factor for the Development of Diabetes

“…The synthesis of these proteins is increased in response to inflammation and infection but at a slower rate than for traditional acute phase proteins (1,2). Both C3 and C4 have shown substantial correlations with obesity (3)(4)(5)(6), and high gene expression of these complement components has been reported in omental adipose tissue in obese men (3). High C3 levels have been reported in subjects with diabetes and insulin resistance (6 -9).…”

Circulating glucagon is associated with inflammatory mediators in metabolically compromised subjects

“…Levels of CFB and C3 were also higher in subjects with insulin resistance and other features of the metabolic syndrome (25). CFB is produced by adipose tissue where they likely influence the production of the anaphylatoxin C3a and its carboxypeptidase B-anaphylatoxic-inactivated derivative C3adesArg (ASP).…”

“…The activation of the alternative pathway of the complement system could be a link between obesity and obesity-related metabolic disorders since CFB is expressed by adipose tissue and upregulated in obese and/or IGT subjects (23)(24)(25). CFB may influence the production of acylation-stimulating protein (ASP), which could play an important role in the regulation of fatty acid uptake and triglycerides formation (26).…”