Diabetic nephropathy has a significant impact on vitamin D status partially due to the role of kidney in maintaining renal uptake of 25-hydroxycholecalciferol (25D) and its subsequent activation to 1,25-dihydroxycholecalciferol (1,25D). We previously reported that feeding high-amylose maize (HAM), a rich source of resistant starch (RS), prevented excretion of 25D-vitamin D-binding protein (DBP) and albumin in Streptozotocin (STZ)-induced type 1 diabetic (T1D) rats. The objectives of the studies described in this dissertation were to: 1) determine if dietary RS could prevent excessive excretion of vitamin D metabolites and maintain serum 25D levels in Zucker diabetic fatty (ZDF) rats, a well characterized animal model of type 2 diabetes (T2D); 2) to conduct dose-response studies to evaluate the renoprotective effect of RS following the induction of T1D; and 3) to determine the impact of RS on cytokines and hormones involved in the inflammatory process and whether the renoprotective actions of RS can be achieved at a lower dose in ZDF rats.

In the first study described in this dissertation, Lean Zucker (n = 8) rats were fed a control diet (LC; AIN-93G diet with 550 g/kg of corn starch) and ZDF rats (n = 8/group) were fed either the control diet (DC) or RS diet (DRS; AIN-93G diet with 550 g/kg of HAM) for 6 weeks. RS attenuated hyperglycemia by 41% and prevented albuminuria. Additionally, urinary 25D and 1,25D in DRS were 90% and 97% lower, respectively, resulting in 41% greater serum 25D concentrations (P < 0.001) compared to DC rats. Along with the improved renal histopathologic scoring, our data suggest that dietary RS maintained vitamin D balance through its protection against diabetes-induced kidney damage.

In the second study described in this dissertation, we explored the possibility that RS would have a nephroprotective effect following T1D onset. Sprague Dawley (SD) rats (n = 8/ group), after induction of T1D with STZ, were fed with AIN-93G diet containing 550g/kg of corn starch (CS), 550 g/kg of high-amylose maize (HRS), 275 g/kg of high-amylose maize + 275 g/kg of corn starch (MRS), or 138 g/kg of high-amylose maize + 412 g/kg of corn starch (LRS) for 4 weeks. Vehicle-treated SD rats (n = 5) fed AIN-93G diet containing 550 g/kg of corn starch were served as non-diabetic control (NDC). Our results showed that RS, regardless of dose, did not improve fasting blood glucose levels in T1D rats compared to NDC rats. The overall growth rate in NDC rats was 1.7- to 3.3-fold greater than in T1D rats. In comparison with CS rats, MRS- and HRS-rats gained 52% and 72%, respectively, but body weight did not differ between LRS and CS rats. Though RS normalized growth pattern in T1D rats, no differences were observed in urinary albumin or 25D concentrations in these rats regardless of treatments. Despite the improvement of vitamin D status (~15 – 20% greater compared to NDC rats) in T1D rats, interleukin-6 (IL-6) was 9 – 31% greater compared to CS rats which was strongly correlated to hyperglycemia (r = 0.472, P = 0.02). Hence, the potential mechanism by which RS promotes kidney health and reduces inflammation could be contingent on glycemic status and thus future work should focus on a preventative approach with RS to maximize its beneficial effects in diabetes.

The objective of the third study included in this dissertation was to examine the mechanism underlying the RS-mediated effects on vitamin D balance of and whether lower intake of dietary RS would promote kidney health and vitamin D balance in ZDF rats. Here, lean Zucker rats (n=5) were used as our control group (LC) and fed a control diet (AIN-93G). For comparison to LC rats, ZDF rats (n = 5/group) were fed the control diet (DC), RS diet (HRS), or a diet containing 275 g/kg of high-amylose maize and 275 g/kg of corn starch (MRS) for 6 weeks. Fasting blood glucose concentrations and hemoglobin A1c% were not affected by HRS or MRS diet. Yet, insulin concentrations were 1.5-fold greater and HOMA-β% was 2-fold greater in HRS rats compared to DC rats, whereas these improvements were not observed in MRS-fed ZDF rats. Additionally, HRS rats, when compared to DC rats, exhibited a 20% increase in serum 25D concentrations and excretion of vitamin D metabolites was blunted. No differences were detected between MRS and DC rats with respect to vitamin D balance. Serum triglycerides were 50% lower and liver triglycerides were 2-fold greater in HRS rats when compared to DC rats. Circulating adiponectin concentrations were 77% greater and serum angiotensin II concentrations were 44% lower in HRS rats than in DC rats. No differences in circulating adiponectin and angiotensin II concentrations were observed in MRS compared to DC rats. Moreover, adiponectin concentrations were highly correlated with vitamin D status (r = 0.815, P < 0.001) and urinary creatinine output (r = 0.818, P < 0.001) and inversely correlated with urinary protein (r = -0.583, P = 0.02).

Collectively, though we showed that the effect of 20% RS on promoting kidney function and vitamin D homeostasis in ZDF rats may be influenced by circulating adiponectin concentrations, our studies indicate that a 50% reduction in dietary RS does not produce the same results. Nevertheless, the studies described in this dissertation indicate that HAM could be a part of dietary intervention strategies aiming to prevent or attenuate symptoms of diabetic nephropathy that are independent of blood glucose management. Because the level of dietary RS used in these studies would be difficult to translate to human feeding studies, future work should consider combination strategies with RS and other dietary compounds or medications for the prevention and/or management of diabetic nephropathy and its associated complications.