Progressive elements in type 2 diabetes, studies on secondary failure and diabetic complications

Diabetes is a progressive disease with late complications, one of the most common being diabetic neuropathy (DN). DN can lead to serious complications and accounts for more hospitalization and higher costs than all other complications of diabetes combined. DN is amongst other connected to deteriorated glucose control, however no cure is available today. The prevalence and nature of peripheral DN in a Swedish type 2 diabetes (T2D) population is not known.

The aims of this thesis were to study complications in a representative population withT2D with focus on peripheral neuropathy (PN) and the associations between peripheral sensory neuropathy (PSN) and different aspects of metabolism. Moreover, the features of late complications and metabolism were studied in subjects with PSN in relation to coexistence or not of retinopathy. Since metabolic control is important for prevention of complications the effects of the length of intensive insulin treatment on beta-cell function in subjects with T2D and features of secondary failure. Special focus was on the IGF-axis in relation to complications, metabolism and weight in T2D.

Results: A geographically defined population with T2D, mean age 61.7 ± 7.2 years and diabetes duration 7.0 ± 5.7 years, were investigated regarding disease and late complications. We found despite good glucose control retinopathy in 29%, nephropathy in 22 %, cardiovascular disease in 62%, cerebrovascular lesions in 11% and peripheral vascular disease (PVD) in 26%. Peripheral neuropathy was most common (67%) and peripheral sensory neuropathy was closely connected to PVD, especially in subjects without retinopathy. This finding suggests that PVD should be carefully considered in subjects with PSN and especially when no retinopathy. Signs of peripheral autonomic neuropathy (PAN) were the most common DN and predicted foot ulceration at 5 year follow-up, which to our knowledge has not been reported previously. This underlines the necessity to include the signs of PAN in foot examination protocols. Serum IGFBP-1 levels were higher in subjects with peripheral sensory neuropathy. This has previously been reported in type 1 diabetes but to our knowledge not in T2D. This finding suggests that low bioactive IGF is associated with increased risk for peripheral DN and that this can be associated with beta cell failure. We also found that low IGF-II was associated with weight gain in normal weight T2D patients. Intensive insulin treatment rapidly improved glucose control and beta-cell function in a group of T2D patients with secondary failure but prolongation did not elicit further enhancement. Furthermore this effect was rapidly lost when subjects were switched to less intense treatment. Subjects with higher C-peptide levels were likely to improve beta-cell function more, suggesting that the effect depends on remaining beta-cell mass. However, improvement of glucose control was less in subjects with lower IGFBP-1 which suggests other causes for deteriorated glucose control in these subjects than insulin deficiency, while high IGFBP-1 levels could indicate true insulin deficiency. Thus, determination of IGFBP-1 may be useful in the choice of treatment in secondary failure.

In conclusion we found macro- and microvascular complications to be common in this representative T2D population. The prevalence of peripheral neuropathy was the most common complication. The standardized foot examination used could predict future foot ulcers, especially the presence of autonomic neuropathy. Peripheral neuropathy suggested concomitant PVD if retinopathy was not present. Low HDLc, male gender and high age were other independent risk factors for DN. The IGF system seems also to be important for the development of peripheral neuropathy. Intensive insulin treatment improved insulin secretion in those with preserved beta cell function but improved metabolic control only in those with high IGFBP-1 levels, suggestive of beta cell failure.

List of scientific papers

I. Kärvestedt L, Mårtensson E, Grill V, Elofsson S, v Wendt G, Hamsten A, Brismar K (2008). The prevalence of Peripheral Neuropathy in a population based study of patients with type 2 diabetes in Sweden. [Manuscript]

II. Kärvestedt L, Mårtensson E, Grill V, Elofsson S, v Wendt G, Hamsten A, Brismar K (2008). Peripheral sensory neuropathy associates with micro- or macroangiopathy. Results from a population based study of patients with type 2 diabetes in Sweden. [Accepted]
https://doi.org/10.2337/dc08-1250

III. Kärvestedt L, Andersson G, Efendic S, Grill V (2002). A rapid increase in beta-cell function by multiple insulin injections in type 2 diabetic patients is not further enhanced by prolonging treatment. J Intern Med. 251(4): 307-16.
https://doi.org/10.1046/j.1365-2796.2002.00956.x

IV. Heald AH, Kärvestedt L, Anderson SG, McLaughlin J, Knowles A, Wong L, Grill V, Cruickshank JK, White A, Gibson JM, Brismar K (2006). Low insulin-like growth factor-II levels predict weight gain in normal weight subjects with type 2 diabetes. Am J Med. 119(2): 167.e9-15.
https://doi.org/10.1016/j.amjmed.2005.08.001