**2.1.1 Protein**

22 Type 1 Diabetes – Complications, Pathogenesis, and Alternative Treatments

times higher for people with type 1 diabetes (Soedamah-Muthu SS et al. 2006). The major microvascular complications are diabetic nephropathy, diabetic neuropathy and diabetic retinopathy (American Diabetes Association (ADA) 2010). Of the patients with type 1 diabetes approximately 29% develop persistent microalbuminuria (urinary albumin excretion rate between 30 and 300 mg/24 h) after 20 years. Of these 29%, 34% progressed further to persistent macroalbuminuria (urinary albumin excretion rate > 300 mg/24 h). Persistent microalbuminuria is a risk factor for the development of diabetic nephropathy. Microalbuminuria can be seen as an early marker of diabetic kidney disease (Hovind P 2004). Also retinopathy is a common microvascular complication. The 25-year cumulative incidences of any visual impairment and severe visual impairment are 13% and 3%, respectively. Diabetic retinopathy is an important cause of visual impairment (Klein R et al. 2010). Finally the high incidence of lower extremity amputations also stresses how serious the complications of type 1 diabetes are. The overall 25-year incidence of lower extremity amputations is 10.1% in 943 American type 1 diabetic patients (Sahakyan K et al. 2011). These complications account for the major morbidity and mortality associated with type 1

In type 1 diabetes, special attention is paid to balancing the insulin dose with episodes of activity and the quantity and timing of food intake to prevent acute episodes of hypoglycaemia and hyperglycaemia (Franz MJ et al. 2003). This is important because these acute complications can lead to a coma, but also because a high blood glucose concentration (glycosylated hemoglobin (HbA1c) ≥ 7%) in people with diabetes increases the risk for macrovascular as well as microvascular complications. Other risk factors for these chronic complications are smoking, obesity, physical inactivity, high blood pressure and high cholesterol levels. Also people with a longer history of diabetes have a higher risk (National Institute for Public Health and the Environment (RIVM) 2007). Furthermore it is important to realise that the microvascular complications lie on the pathway between diabetes and cardiovascular disease. Nephropathy for example is an important risk factor for

Recent studies have shown that people with type 1 diabetes eat a more atherosclerosisprone diet. This includes a high intake of energy from saturated fat and a low intake of fiber, fruits and vegetables, which could increase the risk of the development of atherosclerosis. An atherogenic diet may contribute to the risk of cardiovascular disease (Øverby NC et al. 2006; Snell-Bergeon JK et al. 2009). It has been demonstrated that 80%-90% of type 2 diabetes and coronary heart disease cases can be prevented by healthy lifestyle behavior with a focus on healthy diet and exercise.(Stampfer et al. 2000; Hu et al. 2001; Yusuf et al. 2004) These studies suggest that there could be a potential role for diet in type 1 diabetes to

There are more studies suggesting that diet (including alcohol) can play an important role in treating the complications of diabetes (Franz MJ et al. 2003; Franz et al. 2010). Several studies have reviewed nutritional recommendations for people with diabetes (Franz MJ et al. 2003; Toeller M July 2010). But most of these recommendations combine both type 1 as well as type 2 diabetes. Furthermore they are general and not always specific for the different type of complications. An overview of the relationship between diet (including alcohol) and complications in type 1 diabetic patients is lacking. Also the effect of lifestyle (including physical activity and dietary patterns) on complications is still not elucidated for type 1 diabetic patients. Lack of physical activity together with an atherogenic diet could enhance

diabetes, so it is very important to treat them (Daneman D 2006).

cardiovascular disease in people with type 1 diabetes (Jensen T et al. 1987).

development of complications especially in high risk type 1 diabetic patients.

reduce the risk of cardiovascular disease.

Of the thirteen studies that reported an association between protein and nephropathy there were three cross-sectional studies (Toeller M et al. 1997; Riley MD& Dwyer T 1998; O'Hayon BE et al. 2000), one case control study (Möllsten AV et al. 2001), two cohort studies (Jibani MM et al. 1991; Barsotti G et al. 1998), six randomized controlled trials (Brouhard BH& LaGrone L 1990; Zeller K et al. 1991; Dullaart RP et al. 1993; Raal FJ et al. 1994; Hansen HP et al. 1999; Hansen HP et al. 2002) and a pilot study (Percheron C et al. 1995). These will be discussed in the following paragraphs by study design.

The three cross-sectional studies were not consistent in their conclusions on the effect of protein on diabetic nephropathy. O'Hayon et al. (O'Hayon BE et al. 2000) failed to show a significant relationship between dietary protein intake and markers of early nephropathy, other than creatinine clearance. Toeller et al. (Toeller M et al. 1997) found a significant relationship between dietary protein intake and urinary albumin excretion rate (AER). A higher AER was particularly found in people consuming more than 20% of their dietary food energy as protein. Riley et al. (Riley MD& Dwyer T 1998) even found the opposite, a decreased prevalence of microalbuminuria at high relative intakes of protein.

In the case-control study (Möllsten AV et al. 2001) total protein intake was not associated with the presence of microalbuminuria, but a diet including a high amount of fish protein seemed to decrease the risk. Furthermore they could not confirm an association between a high total animal protein intake and having microalbuminuria. In contrast to this finding , Jibani et al. (Jibani MM et al. 1991) found in their cohort study that a predominantly vegetarian diet (low in animal protein) may have an important beneficial effect on diabetic nephropathy without the need for a heavily restricted total protein intake. But they were not able to determine if the reduction in total protein intake rather than the reduction in the fraction of animal origin was primarily responsible for the fall in the fractional albumin clearance. Another (Barsotti G et al. 1998) cohort study showed that a low protein diet has a protective effect on the residual renal function in type 1 diabetic patients.

Diet, Lifestyle and Chronic Complications in Type 1 Diabetic Patients 25

\* after adjustment for MAP (mean arterial pressure) and diabetes duratio

CC: creatinine clearance

Table 1. Randomized controlled trials; protein and diabetic nephropathy

n

GFR: glomerular filtration rate; LPD: low protein diet; UPD: usual protein diet; LPLP: low protein, low phosphorus; IC: iothalamate clearance;

In conclusion, these studies were not consistent in their conclusions on the effect of protein restriction on type 1 diabetic nephropathy. Furthermore there is not enough evidence for recommendations about the preferred type of dietary protein.

Of the six randomized controlled trials reporting an association between protein and nephropathy (**Table 1**), four have reported a decline in glomerular filtration rate (GFR) during the low protein diet (protein intake of approximately 0.8 g/kg/day) (Brouhard BH& LaGrone L 1990; Dullaart RP et al. 1993; Hansen HP et al. 1999; Hansen HP et al. 2002). In one of these four this decline was greater in the low protein diet group than in the usual protein diet group, but this difference was not significant (Hansen HP et al. 1999). In two studies this decline was greater in the usual protein diet group than in the low protein group (Brouhard BH& LaGrone L 1990; Hansen HP et al. 2002). Among these 2 studies, one (Brouhard BH& LaGrone L 1990) found a decline that was significantly greater in the usual protein group. Another study showed a decline in GFR in the low protein diet group, but did not directly compare this with the usual protein group (Dullaart RP et al. 1993). Only one study(Raal FJ et al. 1994) reported an increase in GFR during the low protein diet, but this increase was not significant. Zeller et al. (Zeller K et al. 1991) used iothalamate clearance and creatinine clearance to assess renal function. The rates of decline in both iothalamate and creatinine clearence were significantly slower in the patients in the study-diet group than in those in the control-diet group.

Five trials reported an effect of protein on albuminuria (Brouhard BH& LaGrone L 1990; Dullaart RP et al. 1993; Raal FJ et al. 1994; Hansen HP et al. 1999; Hansen HP et al. 2002). In three of these five trials there was a decline in albuminuria in the low protein diet group as well as in the usual protein diet group (Dullaart RP et al. 1993; Hansen HP et al. 1999; Hansen HP et al. 2002). Two of these three showed a significant greater decline in albuminuria in the low protein diet group than in the usual protein diet group (Dullaart RP et al. 1993; Hansen HP et al. 1999). The other two trials showed a decline in albuminuria in the low protein diet group and an increase in the usual diet protein group (Brouhard BH& LaGrone L 1990; Raal FJ et al. 1994). One of these (Brouhard BH& LaGrone L 1990) found a significant difference between the diet groups. Furthermore, another (pilot) study (Percheron C et al. 1995) also found a decline in albuminuria and in creatinine clearance. They conclude that moderately (protein intake of approximately 1.2 g/kg/day) rather than severely protein restricted diets (protein intake of approximately 0.8 g/kg/day) should be recommended, because of the lack of compliance with severely protein restricted diets. The only trial (Hansen HP et al. 2002) that determined the effect of dietary protein restriction on survival and progression to end stage renal disease (ESRD) in diabetic nephropathy reported a relative risk of 0.23 (95% CI: 0.07-0.72) for ESRD in patients assigned to a lowprotein diet compared with patients assigned to a usual protein diet.

In conclusion, protein restriction (protein intake of approximately 0.8 g/kg/day, **Table 1**) had a positive significant effect on albuminuria, but no effect on GFR was found.

#### **2.1.2 Carbohydrate**

Two cross-sectional studies (Watts GF et al. 1988; Riley MD& Dwyer T 1998) examined the association between carbohydrates and nephropathy. In one study (Watts GF et al. 1988) type 1 diabetic patients with microalbuminuria consumed a significantly smaller percentage of total energy as carbohydrate compared with patients with normal albumin excretion. In the other study (Riley MD& Dwyer T 1998) no significant association between energy adjusted carbohydrate intake and microalbuminuria was found. This could be due to their


\* after adjustment for MAP (mean arterial pressure) and diabetes duration

GFR: glomerular filtration rate; LPD: low protein diet; UPD: usual protein diet; LPLP: low protein, low phosphorus; IC: iothalamate clearance; CC: creatinine clearance 

Table 1. Randomized controlled trials; protein and diabetic nephropathy

24 Type 1 Diabetes – Complications, Pathogenesis, and Alternative Treatments

In conclusion, these studies were not consistent in their conclusions on the effect of protein restriction on type 1 diabetic nephropathy. Furthermore there is not enough evidence for

Of the six randomized controlled trials reporting an association between protein and nephropathy (**Table 1**), four have reported a decline in glomerular filtration rate (GFR) during the low protein diet (protein intake of approximately 0.8 g/kg/day) (Brouhard BH& LaGrone L 1990; Dullaart RP et al. 1993; Hansen HP et al. 1999; Hansen HP et al. 2002). In one of these four this decline was greater in the low protein diet group than in the usual protein diet group, but this difference was not significant (Hansen HP et al. 1999). In two studies this decline was greater in the usual protein diet group than in the low protein group (Brouhard BH& LaGrone L 1990; Hansen HP et al. 2002). Among these 2 studies, one (Brouhard BH& LaGrone L 1990) found a decline that was significantly greater in the usual protein group. Another study showed a decline in GFR in the low protein diet group, but did not directly compare this with the usual protein group (Dullaart RP et al. 1993). Only one study(Raal FJ et al. 1994) reported an increase in GFR during the low protein diet, but this increase was not significant. Zeller et al. (Zeller K et al. 1991) used iothalamate clearance and creatinine clearance to assess renal function. The rates of decline in both iothalamate and creatinine clearence were significantly slower in the patients in the study-diet group

Five trials reported an effect of protein on albuminuria (Brouhard BH& LaGrone L 1990; Dullaart RP et al. 1993; Raal FJ et al. 1994; Hansen HP et al. 1999; Hansen HP et al. 2002). In three of these five trials there was a decline in albuminuria in the low protein diet group as well as in the usual protein diet group (Dullaart RP et al. 1993; Hansen HP et al. 1999; Hansen HP et al. 2002). Two of these three showed a significant greater decline in albuminuria in the low protein diet group than in the usual protein diet group (Dullaart RP et al. 1993; Hansen HP et al. 1999). The other two trials showed a decline in albuminuria in the low protein diet group and an increase in the usual diet protein group (Brouhard BH& LaGrone L 1990; Raal FJ et al. 1994). One of these (Brouhard BH& LaGrone L 1990) found a significant difference between the diet groups. Furthermore, another (pilot) study (Percheron C et al. 1995) also found a decline in albuminuria and in creatinine clearance. They conclude that moderately (protein intake of approximately 1.2 g/kg/day) rather than severely protein restricted diets (protein intake of approximately 0.8 g/kg/day) should be recommended, because of the lack of compliance with severely protein restricted diets. The only trial (Hansen HP et al. 2002) that determined the effect of dietary protein restriction on survival and progression to end stage renal disease (ESRD) in diabetic nephropathy reported a relative risk of 0.23 (95% CI: 0.07-0.72) for ESRD in patients assigned to a low-

In conclusion, protein restriction (protein intake of approximately 0.8 g/kg/day, **Table 1**)

Two cross-sectional studies (Watts GF et al. 1988; Riley MD& Dwyer T 1998) examined the association between carbohydrates and nephropathy. In one study (Watts GF et al. 1988) type 1 diabetic patients with microalbuminuria consumed a significantly smaller percentage of total energy as carbohydrate compared with patients with normal albumin excretion. In the other study (Riley MD& Dwyer T 1998) no significant association between energy adjusted carbohydrate intake and microalbuminuria was found. This could be due to their

had a positive significant effect on albuminuria, but no effect on GFR was found.

protein diet compared with patients assigned to a usual protein diet.

recommendations about the preferred type of dietary protein.

than in those in the control-diet group.

**2.1.2 Carbohydrate** 

Diet, Lifestyle and Chronic Complications in Type 1 Diabetic Patients 27

There were no prospective studies on physical activity and type 1 diabetic nephropathy. One cross-sectional study (Kriska AM et al. 1991) found the lowest occurrence of diabetic nephropathy in people being 7+ hours a week physically active (sports and leisure physical

Only two studies reported results for the association between macronutrients and type 1 diabetic retinopathy. Furthermore two studies reported an association between alcohol consumption and diabetic retinopathy and one study reported an association between physical activity and diabetic retinopathy. No studies were found examining the effect of

In post-hoc analyses (Cundiff DK& Nigg CR 2005) a positive association between total dietary fat, saturated fat and MUFA with retinopathy progression and retinopathy risk factors (mean arterial pressure, LDL/HDL cholesterol ratio, serum triglycerides, HbA1c, body mass index, and insulin utilization) was found. Furthermore, a negative association between carbohydrates and dietary fiber with retinopathy progression and risk factors was found. In addition to this, another cross-sectional study(Toeller M et al. 1999 1) reported a higher intake of cholesterol, total fat and saturated fat in Eastern Europe compared to Southern or North-Western Europe. They also found more frequent acute and chronic complications (including retinopathy) in Eastern European people. As with nephropathy, they could not conclude if this was due to the high intake of cholesterol, total fat and/or

In conclusion there is limited research on the effect of diet on diabetic retinopathy. The results of the post hoc analyses should be interpreted carefully, since it is a retrospective

In cross-sectional analyses of the EURODIAB Prospective Complications Study (Beulens et al. 2008) moderate alcohol consumers (30-70 g alcohol per week) had a lower risk of diabetic proliferative retinopathy, with an odds ratio of 0.60 (95% CI: 0.37-0.99). This association was most pronounced for the consumption of wine. Another cross-sectional study (Moss SE et al. 1992) examined whether alcohol consumption was associated with type 1 diabetic retinopathy. They found that moderate alcohol consumption was inversely associated with the prevalence of retinopathy (OR=0.49, 95% CI: 0.27-0.92) in patients with type 1

One cross-sectional study (Kriska AM et al. 1991) examined the relationship between physical activity and the occurrence of retinopathy in type 1 diabetic patients. They found no association between physical activity (sports and leisure physical activity) and

glycaemic index/glycaemic load on retinopathy in type 1 diabetic patients.

analysis which can generate hypotheses but not prove them.

**2.1.5 Physical activity** 

**3.1 Macronutrients** 

saturated fat.

**3.1.2 Alcohol** 

diabetes.

**3.1.3 Physical activity** 

occurrence of retinopathy.

**3. Diet, lifestyle and retinopathy** 

activity).

study design (cross-sectional), due to a substantial measurement error in the food frequency questionnaires (FFQs) and due to the low response rate (61.2%) for participation.

### **2.1.3 Fat/cholesterol**

Four cross-sectional studies reported an association between fat and/or cholesterol and nephropathy (Watts GF et al. 1988; Bouhanick B 1995; Riley MD& Dwyer T 1998; Toeller M et al. 1999 1). One study (Riley MD& Dwyer T 1998) found no significant association between energy adjusted monounsaturated fat intake or energy adjusted polyunsaturated fat intake and microalbuminuria, but reported a positive association between usual dietary saturated fat intake and microalbuminuria. Another study (Watts GF et al. 1988) found a significant positive association between total fat intake and microalbuminuria. Another study (Bouhanick B 1995) examined the relationship between fat intake and glomerular hyperfiltration (GFR > 173 ml/min/1.73m2), a marker for diabetic nephropathy, in type 1 diabetic patients. They found that excess fat intake may contribute to hyperfiltration in type 1 diabetic patients. Finally the fourth study(Toeller M et al. 1999 1) found a higher intake of cholesterol, total fat and saturated fat in Eastern Europe compared to Southern or North-Western Europe. They also found more frequent acute and chronic complications (including nephropathy) in Eastern Europe people. Since it was a cross-sectional study they could not conclude if this was due to the high intake of cholesterol, total fat and/or saturated fat.

These cross-sectional studies show that there seems to be a detrimental effect of total dietary fat intake as well as saturated fat intake on type 1 diabetic nephropathy. No association between energy adjusted MUFA and energy adjusted PUFA and microalbuminuria was found.

In a case-control study (Möllsten AV et al. 2001), no association between total fat intake and microalbuminuria was found. In a prospective study (Cárdenas C et al. 2004) a progression of nephropathy with greater saturated fatty acid (SFA) consumption and lesser polyunsaturated fatty acid consumption (PUFA) was demonstrated. Specifically with higher SFA-to-PUFA and SFA-to-MUFA ratios. Another prospective cohort study (Lee CC et al. 2010) found an association between PUFA and microalbuminuria. They found that dietary n-3 PUFAs (eicosapentaenoic acid and docosahexaenoic acid) are inversely associated with the degree but not with the incidence of albuminuria in type 1 diabetes (Lee CC et al. 2010).

In conclusion these prospective studies are consistent with the cross-sectional studies about the detrimental effect of saturated fat on type 1 diabetic nephropathy. The effect of total fat intake on nephropathy is still not elucidated. The cross-sectional study of Watts et al. (Watts GF et al. 1988) and the case control study of Möllsten et al. (Möllsten AV et al. 2001) were in contrast with each other. Also the effect of PUFAs on nephropathy is still doubtful, but there seems to be an inverse association between n-3 PUFAs and the degree of albuminuria.

#### **2.1.4 Alcohol**

In the EURODIAB Prospective Complications Study (Beulens et al. 2008) the association between alcohol and nephropathy was analysed cross-sectionally. They found that moderate alcohol consumers (30-70 g alcohol per week) had a lower risk of diabetic nephropathy, with an odds ratio of 0.36 (95% CI: 0.18-0.71). This association was most pronounced for the consumption of wine.
