Risk factors for mortality in Type II (non-insulin-dependent) diabetes: evidence of a role for neuropathy and a protective effect of HLA-DR4

Abstract

The prognosis of patients with Type II (non-insulindependent) diabetes mellitus is primarily determined by the presence of macro-and microangiopathy. There is, however, a large variation in the propensity for the patient to develop these devastating complications. While poor glycaemic control and duration of diabetes are strong predictors of microangiopathy [1], their role as predictors of macroangiopathy is less clear [2±6]. In Type II diabetes, clustering of the metabolic syndrome (hyperglycaemia, obesity, hyper- Diabetologia (1998) Summary To test the hypothesis that interaction between genetic, immunological, clinical and metabolic risk factors influences the outcome of Type II (noninsulin-dependent) diabetes mellitus, we examined which of the above factors present at baseline were associated with mortality in 134 Type II diabetic patients followed for 9 years. Thirty-eight patients (29 %) died during the follow-up period; the majority of whom (68 %) died from cardiovascular disease. At baseline, the deceased patients had higher HbA 1 c values (p = 0.002), higher LDL-triglycerides (p = 0.007), lower HDL-cholesterol (p = 0.007), higher non-esterified fatty acid (NEFA) concentrations (p = 0.014), and higher albumin excretion rate (p < 0.0001) than the patients who survived. In addition, the frequency of HLA-DR4 (21 vs 39 %, p = 0.048) and of parietal cell antibodies (5 vs 14 %, p = 0.016) were decreased in the deceased as compared to the living patients.Patients who died during follow-up also had more retinopathy (42 vs 16 %, p = 0.002), neuropathy (57 vs 23 %, p < 0.001), microalbuminuria (45 vs 6 %, p < 0.0001), coronary heart disease (50 vs 13 %, p < 0.0001), and peripheral vascular disease (27 vs 9 %, p = 0.005) at baseline than patients who survived. In a multiple logistic regression analysis macroangiopathy (p = 0.004), neuropathy (p = 0.007), HbA 1 c (p = 0.018) and albumin excretion rate (p = 0.016) were independent risk factors for death. In patients free of cardiovascular disease at baseline, conventional risk factors such as LDL-cholesterol (p = 0.005) and age (p = 0.003) were associated with subsequent development of cardiovascular disease. In conclusion, in addition to coexisting macroangiopathy, increased albumin excretion rate, poor glycaemic control and neuropathy are risk factors for cardiovascular mortality in patients with Type II diabetes. The presence of HLA-DR4 and signs of autoimmunity may be associated with decreased risk of cardiovascular disease.[ Diabetologia (1998

Type 1 and Type 2 Diabetes

“…Family history of type 1 diabetes was negatively associated with coronary artery disease in relatively young (Ͻ60 years of age) type 2 diabetic patients, and patients with such family history were leaner than those with family history for type 2 diabetes only (24). Also, type 2 diabetic patients with the type 1-associated HLA-DR4 allele had a lower cardiovascular mortality rate than DR4 Ϫ patients (25). Overall, the patients with mixed family history also had lower serum C-peptide concentrations, but this largely depended on the high frequency of circulating autoantibodies to GAD (GADAs) in this group, whereas the BMI and coronary artery disease association was present also in GADA Ϫ patients (24).…”

Vascular calcification and osteolysis in diabetic neuropathy?is RANK-L the missing link?

“…While there is evidence that this is true [45], it is difficult to dissect an effect of distal symmetrical neuropathy from a possible confounding effect on mortality from autonomic neuropathy and cardiac denervation [46], as well as from the effect of nephropathy. Given, however, that the vascular calcification associated with neuropathy would be characterised by widened pulse pressure, it is worth noting that widened pulse pressure has recently been shown to be an independent predictor of death in patients with renal failure [47,48].…”

High Levels of Nonesterified Fatty Acids Are Associated With Increased Familial Risk of Cardiovascular Disease

“…Finally, it was recently demonstrated that elevated NEFA levels predict CVD mortality in patients with type 2 diabetes. 34 The question remains of how high NEFA concentrations could promote CVD. High levels of NEFA could lead to increased concentrations of VLDL, small, dense LDL particles, and elevated apoB concentrations in plasma, all of which are associated with an increased risk of coronary heart disease 32 and stroke.…”

“…Support for this view comes from a recent prospective study showing elevated NEFA concentrations 10 years earlier in patients with type 2 diabetes who died of CVD. 34 …”