Cardiac Complications

Diabetes mellitus (DM), both type 1 and type 2, affects many organ systems, particularly the heart, eyes, kidneys, and the peripheral and autonomic nervous systems. Also, macrosomia and birth complications occur more often in infants born to women with inadequately controlled diabetes mellitus.

Prevention of macrovascular complications depends on control of the major risk factors for cardiac disease, such as smoking, blood pressure, and blood lipid concentrations; blood glucose control has been less effective in controlled trials. For prevention of microvascular damage, glycemic control is essential, and control of blood pressure and other vascular parameters is also important.

1. Cardiac Complications¹

Cardiovascular disease (CVD) is the leading cause of mortality in individuals with diabetes. Morbidity due to CVD is also common. Control of cardiac risk factors is therefore critical. These include smoking, hypertension, and hyperlipidemia (see chapters on CHD, hypertension, and hyperlipidemia ).

Risk Factors

• Smoking.
• Hypertension.
• Hyperlipidemia.
• Obesity.
• Microalbuminuria.

Diagnosis

Patients with diabetes may have atypical presentations for CVD. Screening with electrocardiogram or cardiac stress tests may be appropriate in some patients.

Hypertension

Blood pressure control is particularly important for individuals with diabetes. The goal blood pressure should be less than 130/80 mmHg, and further lowering may be beneficial (see Hypertension ).

Hyperlipidemia

The goals for blood lipid concentrations are also somewhat different for patients with diabetes. LDL should be less than 100 mg/dl, and in certain patients (especially those with known CVD), the goal may be less than 70 mg/dl. In known cases of CVD, triglycerides should be less than 150, and HDL greater than 40 mg/dl. HDL greater than 50 mg/dl may be an appropriate goal for women (see Hyperlipidemia ).

Treatment

Dietary and behavioral modifications, including smoking cessation, regular exercise, and loss of excess weight, are critical for the prevention and management of cardiac complications in diabetes patients.

When further therapy is needed, specific medicines are usually helpful.

Aspirin therapy (75-325 mg/day) is recommended for most persons older than 30 years of age, particularly in the presence of additional cardiovascular risk factors or documented cardiovascular disease. Potential side effects, including bleeding, must be considered. Because of the risk of Reye's syndrome, aspirin therapy should not be instituted in patients under 21 years.

Hypertension

Hypertension in diabetes should be treated with an angiotensin-converting enzyme (ACE) inhibitor or angiotensin receptor blocker (ARB). Further drugs to lower blood pressure may be required. These include diuretics, beta blockers, and calcium channel blockers (see Hypertension).

Hyperlipidemia

Statins and fibrates are likely to be effective in reducing cardiovascular events, and other lipid-lowering therapies may also be tried in combination (see Hyperlipidemia ).

Nutritional Considerations

To reduce the risk of cardiac complications, the appropriate dietary changes are those that improve plasma lipid concentrations, reduce blood pressure, and control glycemia. These steps are discussed in detail in the chapters on coronary heart disease, hyperlipidemia, hypertension, and diabetes.

A substantial body of evidence suggests that a combination of a vegetarian diet, regular exercise, smoking cessation, and stress management yields greater improvements in indices of cardiovascular disease, compared with other regimens.^2,3 The Multicenter Lifestyle Demonstration Project, which included 440 patients with coronary artery disease, of whom 91 also had diabetes, showed that such a regimen is effective in individuals with diabetes, just as it is for those without diabetes.⁴ In a randomized, controlled trial of individuals with type 2 diabetes, a low-fat, vegan diet reduced LDL cholesterol concentrations by 21% and reduced triglycerides by 16% among participants whose lipid-lowering medications were held constant.⁵ The type of carbohydrate that predominates in the therapeutic diet may be clinically important. Diets high in refined carbohydrate may increase triglyceride concentrations for some individuals, but high-carbohydrate diets that are drawn from high-fiber and low-glycemic index foods appear to have the opposite result.⁶

A randomized controlled clinical trial of alpha-lipoic acid, administered at 800 mg/d for 4 months, showed improvements in symptoms of cardiac autonomic neuropathy.⁷ Further study with a larger number of individuals is required before this treatment can be recommended.

Eye Complications

Glaucoma and Cataracts

Glaucoma and cataracts may develop earlier in diabetes patients, compared with those without diabetes (see Glaucoma and Cataract ).

Retinopathy

In diabetes, pathologic changes in the retinal vasculature pose a major long-term threat to vision. In nonproliferative diabetic retinopathy, microaneurysms, small "dot and blot" hemorrhages, hard exudates (lipid material that can be toxic to the retina), and retinal infarcts known as "cotton wool spots" appear. These changes tend to concentrate in the macula, where they can blur and distort central vision.

In proliferative retinopathy (neovascularization), fragile, abnormal vessels grow into the vitreous, presumably in response to ischemia. Vitreous hemorrhage causes symptoms ranging from "floaters" to complete visual obscuration. Ultimately, tractional retinal detachment can result. Retinopathy is not painful. As a result, the condition can progress without its being detected by the patient.

Good blood glucose control, as indicated by a low hemoglobin A1c, can reduce the risk of ophthalmic involvement and slow its progression.^8-12 Similarly, blood pressure control is important, as poorly controlled hypertension increases the severity of retinopathy.^13-15

Risk Factors

• Poor blood glucose control.
• Hypertension.
• Duration of diabetes.
• Smoking.

Diagnosis

Retinopathy can be diagnosed by ophthalmoscopy with dilated pupils.

Use of a fundus lens at the slit lamp allows a stereoscopic view and facilitates diagnosis of macular edema.

In fluorescein angiography, an intravenous injection of fluorescein followed by serial photography of the fundus reveals leakage from microaneurysms, nonperfusion, and other useful information to guide therapy.

Treatment

For proliferative retinopathy, where vitreous hemorrhage appears likely, panretinal laser photocoagulation often stabilizes neovascularization or even causes it to regress.

When diabetic retinopathy causes clinically significant macular edema (defined by severity of leakage and proximity to the central macula), photocoagulation can slow progression.¹⁶ Individual microaneurysms can be obliterated, or a broader grid photocoagulated, if the leakage pattern is diffuse.

Nutritional Considerations

Nutritional interventions that improve control of blood glucose, blood pressure, and lipid concentrations may help prevent or slow ophthalmic complications.

Glaucoma

Most individuals with diabetes are known to be insulin resistant, and evidence indicates that 85% of persons with type 2 diabetes also have the metabolic syndrome.¹⁷ Both of these conditions are associated with elevated intraocular pressure, a well-known risk factor for glaucoma.¹⁸ Control of high blood pressure (a component of the metabolic syndrome) is also important in the care of glaucoma (see Glaucoma ). Dietary treatments that address these underlying conditions have not yet been found to prevent or treat glaucoma.

Cataract

Individuals with diabetes are at increased risk for cataract. However, no controlled clinical trials using nutrition therapies indicate that diet changes reduce this risk among individuals with diabetes. In the general population, a number of dietary factors are associated with lower cataract risk, including maintenance of ideal weight and normal lipid levels; high intake of antioxidant-containing foods; avoidance of alcohol; and avoidance of sources of galactose (ie, dairy products) (see Cataract ).

Retinopathy

Evidence indicates that control of blood glucose,^11,12 blood pressure,¹⁹ and blood cholesterol²⁰ reduces the onset and progression of diabetic retinopathy.A^21,22 A specific diet therapy suitable for prevention of retinopathy has not yet been established. However, evidence from the Diabetes Complications and Control Trial (DCCT) associated diets high in fat and low in fiber with progression of retinopathy,²³ suggesting that low-fat, high-fiber diets diet may have promise for reducing retinopathy risk.

Nephropathy

Diabetic nephropathy involves pathologic changes to the kidney vasculature. If uncontrolled, the disease progresses from microalbuminuria to macroalbuminuria and an elevated plasma creatinine concentration, and eventually to end-stage disease requiring dialysis or transplant. Pathogenesis involves hypertension, ischemia, hyperglycemia, and advanced glycosylation end products. Persistently elevated blood glucose, blood pressure, and cholesterol and triglyceride concentrations are associated with microalbuminuria.²⁴

Risk Factors

All individuals with diabetes are at risk for nephropathy. Pima Indians with type 2 diabetes have a particularly high susceptibility to nephropathy, with a 50% incidence after 20 years. However, Pimas living in the U.S. are at much higher risk, compared with Pimas in Mexico, suggesting that the risk among Pimas may be, in part, mediated by diet and lifestyle, rather than genetic factors. African Americans with type 2 DM appear to have more than 4 times the risk of end-stage renal disease, compared with Caucasians.²⁵ This may also be true for Native Americans and Mexican Americans.²⁶

Risk factors include:

• Family history of diabetes nephropathy.
• Poor blood glucose control.
• Concomitant hypertension.
• Elevated glomerular filtration rate.
• Dietary factors (see Nutritional Considerations below).

Other possible risk factors include obesity, increasing age, duration of DM, and smoking.

Diagnosis

Microalbuminuria, defined as a persistent loss of albumin in the urine of 30 to 299 mg/day, is the first indication of nephropathy. Macroalbuminuria is diagnosed when urinary albumin losses are ≥300 mg/day.

A random urine specimen with an albumin concentration of greater than 30 mg/L suggests microalbuminuria. False-negative or false-positive results may occur due to urine volume at time of collection.

A urine albumin/creatinine ratio with a value of 30 μg/mg or greater also suggests microalbuminuria.

Transient microalbuminuria may occur with hyperglycemia, exercise, heart failure, and febrile illness.

When screening suggests microalbuminuria, a repeat specimen (albumin/creatinine ratio) should be obtained after waiting at least 1 to 2 weeks. A standard urine test strip can usually detect macroalbuminuria (1+ or greater). Albumin-specific test strips can detect microalbuminuria. However, false-negatives and false-positives are possible when using test strips. Twenty-four hour urine samples are not required to make these diagnoses.

Treatment

Treatment recommendations for nephropathy are similar in type 1 and type 2 diabetes.

Glycemic control is essential for preventing further kidney damage.

Treatment with angiotensin-converting enzyme (ACE) inhibitors or/and angiotensin receptor blockers (ARBs) helps prevent the progression of microalbuminuria to more severe renal disease. This approach is especially important if hypertension is present, and target blood pressure to reduce vascular complications is less than 130/80 mmHg. Diltiazem, verapamil, and low-dose diuretics (because hypertension in diabetes is often volume dependent) may also be indicated.

Control of plasma cholesterol and triglyceride concentrations is important (see Hyperlipidemia for details on optimizing LDL, HDL, and triglycerides).

Weight loss is helpful, perhaps because of its beneficial effects on glucose, blood pressure, and lipid control.²⁷

Nutritional Considerations

Reducing saturated fat, cholesterol, and animal protein intake may reduce the risk for or progression of nephropathy. Elevated cholesterol is a risk factor for nephropathy28 and end-stage renal disease.²⁹ Cholesterol-lowering treatment was found to retard the progression of diabetic nephropathy.³⁰

Restriction of animal protein reduces the progression of diabetic nephropathy.³¹ Excessive intake of total protein and animal (not vegetable) protein has been shown to increase urinary albumin excretion.³² In short-term studies, proteinuria has been reduced through the use of vegetarian diets³³ and diets deriving protein primarily from soy and other plant sources.³⁴ These diets also facilitate blood pressure control,3 which further helps reduce diabetic nephropathy progression.³⁵

Dietary sodium restriction is indicated for a number of reasons, including prevention or treatment of microalbuminuria. It is also important because sodium excess may offset both the antihypertensive and antiproteinuric effects of renin-angiotensin system blocking drugs.³⁶

Neuropathy

Neuropathy is a particularly common diabetes complication, affecting approximately half of all diabetes patients. Distal symmetric polyneuropathy is the most common presentation. However, neuropathy can also involve the autonomic nervous system and individual nerves.

The disease may present with sensory loss, but also with paresthesia and dysesthesia in the affected areas. Pathogenesis may occur due to ischemia and metabolic factors, including advanced glycosylation end products. Progression is likely. If severe, neuropathy may lead to joint deformities and infections that ultimately require amputation.

Risk Factors

• Poor blood glucose control. Good glycemic control helps prevent neuropathy, and improvement of previously poor glycemic control can improve neuropathic symptoms.¹⁰
• Duration of diabetes.

Diagnosis

The presence of distal symmetric polyneuropathy can be assessed with simple clinical tests. Altered sensation, whether vibration (128 Hz tuning fork), pain (pin-prick), temperature, or pressure (10-g monofilament at dorsal aspect of great toe), or absence of ankle reflexes suggests neuropathy. The use of more than one test increases diagnostic accuracy.¹ Electrophysiologic studies such as nerve conduction tests can confirm the diagnosis.

The presence of autonomic neuropathy can be assessed by history and physical examination. Constipation, incontinence, erectile dysfunction, tachycardia, pupillary dysfunction, and orthostatic hypotension, among other abnormalities, suggest autonomic neuropathy.

Treatment

Diabetes neuropathy is best addressed through primary prevention, which requires tight glycemic control. In cases of pre-existing neuropathy, symptoms may improve with diet and lifestyle changes, as noted below.

In addition to optimized glycemic control, foot care is essential. Properly fitted shoes, foot hygiene, daily foot inspection (special mirrors can help patients who have mobility problems), regular nail care (without cutting nails too short), and immediate consultation with a health care provider whenever an abnormality occurs are all important.

Medications also may help alleviate pain symptoms of diabetes neuropathy. Examples include:

• Tricyclic antidepressants.
• Capsaicin cream.
• Anticonvulsants, such as carbamazepine and gabapentin. Phenytoin has shown inconsistent results, and other anticonvulsants are under study. Mexiletine may be substituted for carbamazepine, in consultation with a cardiologist, if pain persists. Pregabalin is structurally similar to gabapentin, but has a different mechanism of action.
• Duloxetine, a dual serotonin and norepinephrine reuptake inhibitor.

Medications may treat autonomic symptoms, such as erectile dysfunction, gastric abnormalities, and incontinence. These treatments usually improve quality of life, but do not alter the disease course. 

Nutritional Considerations

A combination of a vegetarian diet and exercise may have particular value in treating neuropathy. In a study of 21 individuals with painful neuropathy, symptoms completely disappeared in 17 and improved in the remainder using a vegan diet along with regular walking.³⁷ Evidence suggests that in addition to the effect of vegetarian diets on glycemic control, their effect on body weight, blood pressure, lipids, and blood rheology may be relevant to neuropathy.^38,39 Future clinical trials are needed to determine the value of dietary modifications for this condition.

In addition to the benefits of a diet and exercise regimen, some nutritional supplements have shown potential benefit. Alpha-lipoic acid, in both intravenous and oral forms (≥600 mg/day), appears to be safe and effective for improving symptoms of diabetic neuropathy in clinical trials.^40,41 Long-term safety and efficacy have yet to be established. Although an antioxidant action is presumed, alpha-lipoic acid also improves microcirculation.⁴² Other supplements under investigation for neuropathy treatment include gammalinolenic acid,^43,44 carnitine,^{45, 46} and magnesium.⁴⁷

Complications for the Newborn

Because of the insulin antagonist effect of pregnancy, some women develop DM only during pregnancy (gestational diabetes). Although gestational diabetes is not associated with an increase in congenital anomalies, it can cause other difficulties, such as macrosomia, birth trauma, and an increased risk of cesarean section.

Nutritional Considerations

Avoidance of complications requires good glycemic control before most women recognize that they are pregnant. Women with diabetes can be counseled to plan their pregnancies, so that good control can be in place early.

Control of blood glucose has been shown to prevent macrosomia. Complications of delivery, including shoulder dystocia, increase with newborns that are more than 4000 grams (macrosomic). Elevated glucose contributes to macrosomia, and control of blood sugar (eg, with insulin) reduces this risk.^{48, 49}

Orders

See Diabetes.

What to Tell the Family

The best way to prevent diabetes complications is through aggressive control of blood glucose and cardiovascular risk factors. Diet plays an important role, along with exercise and appropriate medications. Encouraging the entire family to adopt a healthy diet is important, not only to support dietary adherence by the patient, but also to reduce the family's risk of disease.

All diabetes patients should be screened yearly for retinopathy by an ophthalmologist and have lab work done to monitor for nephropathy. Neuropathy is most likely to be discovered by the patient, but the family can help monitor for blisters or calluses. Special shoes may be needed to prevent infections.

It is important for the family and patient to understand that because diabetes complications can greatly reduce quality of life, aggressive prevention and/or treatment is imperative.

References

1. American Diabetes Association. Standards of medical care in diabetes-2006. Diabetes Care. 2006;29:S4-S42.

2. Ornish D, Scherwitz LW, Billings JH, et al. Intensive lifestyle changes for reversal of coronary heart disease. JAMA. 1998;280:2001-2007.

3. Berkow SE, Barnard ND. Blood pressure regulation and vegetarian diets. Nutr Rev. 2005;63:1-8.

4. Pischke CR, Weidner G, Elliott-Eller M, et al. Comparison of coronary risk factors and quality of life in coronary artery disease patients with versus without diabetes mellitus. Am J Cardiol. 2006;97:1267-1273

5. Barnard ND, Cohen J, Jenkins DJ, et al. A low-fat, vegan diet improves glycemic control and cardiovascular risk factors in a randomized clinical trial in individuals with type 2 diabetes. Diabetes Care. 2006;29:1777-1783.                  

6. Jenkins DJ, Wolever TM, Kalmusky J, et al. Low-glycemic index diet in hyperlipidemia: use of traditional starchy foods. Am J Clin Nutr. 1987;46:66-71.

7. Ziegler D, Gries FA. Alpha-lipoic acid in the treatment of diabetic peripheral and cardiac autonomic neuropathy. Diabetes. 1997;46(suppl 2):S62-S66.

8. Klein R, Klein BEK, Moss SE, Davis MD, DeMets DL. Glycosylated hemoglobin predicts the incidence and progression of diabetic retinopathy. JAMA. 1988;260:2864-2871.

9. Reichard P, Nilsson B-Y, Rosenqvist U. The effect of long-term intensified insulin treatment on the development of microvascular complications of diabetes mellitus. N Engl J Med. 1993;329:304-309.

10. Diabetes Control and Complications Trial Research Group. The effect of intensive treatment of diabetes on the development and progression of long-term complications in insulin-dependent diabetes mellitus. N Engl J Med. 1993;329:977-986.

11. UK Prospective Diabetes Study (UKPDS) Group. Effect of intensive blood-glucose control with metformin on complications in overweight patients with type 2 diabetes (UKPDS 34). Lancet. 1998;352:854-865.

12. UK Prospective Diabetes Study (UKPDS) Group. Intensive blood-glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33). Lancet. 1998;352:837-853.

13. Knowler WC, Bennett PH, Ballintine EJ. Increased incidence of retinopathy in diabetics with elevated blood pressure. N Engl J Med. 1980;302:645-650.

14. Klein R, Klein BE, Moss SE, Davis MD, DeMets DL. Wisconsin Epidemiologic Study of Diabetic Retinopathy: III. Prevalence and risk of diabetic retinopathy when age at diagnosis is 30 or more years. Arch Ophthalmol. 1984;102:527-532.

15. Kohner EM, Aldington SJ, Stratton IM, et al. United Kingdom Prospective Diabetes Study, 30: Diabetic retinopathy at diagnosis of non-insulin-dependent diabetes mellitus and associated risk factors. Arch Ophthalmol. 1998;116:297-303.

16. Early Treatment Diabetic Retinopathy Study Research Group. Photocoagulation for diabetic macular edema. Arch Ophthalmol. 1985;103:1796-1806.

17. Alexander CM, Landsman PB, Teutsch SM, Haffner SM. 2003 NCEP-defined metabolic syndrome, diabetes, and prevalence of coronary heart disease among NHANES III participants age 50 years and older. Diabetes. 2003;52:1210-1214.

18. Oh SW, Lee S, Park C, Kim DJ. Elevated intraocular pressure is associated with insulin resistance and metabolic syndrome. Diabetes Metab Res Rev. 2005;21:434-440.

19. Mathews JP, Mathews D, Lavin MJ. The management of diabetic retinopathy.
Practitioner. 2004;248:34,38-40,42.

20. Chew EY, Klein ML, Ferris FL III, et al. Association of elevated serum lipid levels with retinal hard exudate in diabetic retinopathy. Early Treatment Diabetic Retinopathy Study (ETDRS) Report 22. Arch Ophthalmol. 1996;114:1079-1084.

21. Ohkubo Y, Kishikawa H, Araki E, et al. Intensive insulin therapy prevents the progression of diabetic microvascular complications in Japanese patients with non-insulin-dependent diabetes mellitus: a randomized prospective 6-year study. Diabetes Res Clin Pract. 1995;28:103-117.

22. Rowe S, MacLean CH, Shekelle PG. Preventing visual loss from chronic eye disease in primary care: scientific review. JAMA. 2004;291:1487-1495.

23. Cundiff DK, Nigg CR. Diet and diabetic retinopathy: insights from the Diabetes Control and Complications Trial (DCCT). MedGenMed. 2005;7:3.

24. Perkins BA, Ficociello LH, Silva KH, Finkelstein DM. Regression of microalbuminuria in type 1 diabetes. N Engl J Med. 2003;348:2285-2293.

25. Brancati FL, Whittle JC, Whelton PK, et al. The excess incidence of diabetic end-stage renal disease among blacks. A population-based study of potential explanatory factors. JAMA. 1992;268:3079-3084.

26. Smith SR, Svetkey LP, Dennis VW. Racial differences in the incidence and progression of renal diseases. Kidney Int. 1991;40:815-822.

27. Morales E, Valero MA, Leon M, Hernandez E, Praga M. Beneficial effects of weight loss in overweight patients with chronic proteinuric nephropathies.  Am J Kidney Dis. 2003;41:319-327.

28. Gall MA, Hougaard P, Borch-Johnsen K, Parving HH. Risk factors for development of incipient and overt diabetic nephropathy in patients with non-insulin dependent diabetes mellitus: prospective, observational study. BMJ. 1997;314:783-788.

29. Appel GB, Radhakrishnan J, Avram MM, et al. Analysis of metabolic parameters as predictors of risk in the RENAAL study. Diabetes Care. 2003;26:1402-1407.

30. Lam KS, Cheng IK, Janus ED, Pang RW. Cholesterol-lowering therapy may retard the progression of diabetic nephropathy. Diabetologia. 1995;38:604-609.

31. Pedrini MT, Levey AS, Lau J, Chalmers TC, Wang PH. The effects of dietary protein restriction on the progression of diabetic and non-diabetic renal disease: a meta-analysis. Ann Intern Med 1996;124:627-632.

32. Toeller M, Buyken A, Heitkamp G, et al. Protein intake and urinary albumin excretion rates in the EURODIAB IDDM Complications Study. Diabetologia. 1997;40:1219-1226.

33. Jibani MM, Bloodworth LL, Foden E, Griffiths KD, Galpin OP. Predominantly vegetarian diet in patients with incipient and early clinical diabetic nephropathy: effects on albumin excretion rate and nutritional status. Diabet Med. 1991;8:949-953.

34. Azadbakht L, Shakerhosseini R, Atabak S, Jamshidian M, Mehrabi Y, Esmaill-Zadeh A. Beneficiary effect of dietary soy protein on lowering plasma levels of lipid and improving kidney function in type II diabetes with nephropathy. Eur J Clin Nutr. 2003;57:1292-1294.

35. Parving HH, Hovind P. Microalbuminuria in type 1 and type 2 diabetes mellitus: evidence with angiotensin converting enzyme inhibitors and angiotensin II receptor blockers for treating early and preventing clinical nephropathy. Curr Hypertens Rep. 2002;4:387-393.

36. Weir MR. Dietary salt, blood pressure, and microalbuminuria. J Clin Hypertens (Greenwich). 2004;6(suppl 3):23-26.

37. Crane MG, Sample C. Regression of diabetic neuropathy with total vegetarian (vegan) diet. J Nutr Med. 1994;4:431-439.

38. McCarty MF. Favorable impact of a vegan diet with exercise on hemorheology: implications for control of diabetic neuropathy. Med Hypotheses. 2002;58:476-486.

39. Bansal V, Kalita J, Misra UK. Diabetic neuropathy. Postgrad Med J. 2006;82:95-100.

40. Ziegler D, Reljanovic M, Mehnert H, Gries FA. Normal ranges and reproducibility of statistical, geometric, frequency domain, and non-linear measures of 24-hour heart rate variability. Horm Metab Res. 1999;31:672-679.

41. Reljanovic M, Reichel G, Rett K, et al. Treatment of diabetic polyneuropathy with the antioxidant thioctic acid (alpha-lipoic acid): a two year multicenter randomized double-blind placebo-controlled trial (ALADIN II). Alpha Lipoic Acid in Diabetic Neuropathy. Free Radic Res. 1999;31:171-179.

42. Haak E, Usadel KH, Kusterer K, et al. Effects of alpha-lipoic acid on microcirculation in patients with peripheral diabetic neuropathy. Exp Clin Endocrinol Diabetes. 2000;108:168-174.

43. Keen H, Payan J, Allawi J, et al. Treatment of diabetic neuropathy with gamma-linolenic acid. The gamma-Linolenic Acid Multicenter Trial Group. Diabetes Care. 1993;16:8-15.

44. Horrobin DF. Essential fatty acids in the management of impaired nerve function in diabetes. Diabetes. 1997;46(suppl 2):S90-S93.

45. Sima AA, Calvani M, Mehra M, Amato A, and the Acetyl-L-Carnitine Study Group. Acetyl-L-carnitine improves pain, nerve regeneration, and vibratory perception in patients with chronic diabetic neuropathy: an analysis of two randomized placebo-controlled trials. Diabetes Care. 2005;28:89-94.

46. De Grandis D, Minardi C. Acetyl-L-carnitine (levacecarnine) in the treatment of diabetic neuropathy. A long-term, randomised, double-blind, placebo-controlled study. Drugs R D. 2002;3:223-231.

47. De Leeuw I, Engelen W, De Block C, Van Gaal L. Long term magnesium supplementation influences favourably the natural evolution of neuropathy in Mg-depleted type 1 diabetic patients (T1dm). Magnes Res. 2004;17:109-114.

48. Di Cianni G, Miccoli R, Volpe L, et al. Maternal triglyceride levels and newborn weight in pregnant women with normal glucose tolerance. Diabet Med. 2005;22:21-25.

49. Kitajima M, Oka S, Yasuhi I, Fukuda M, Rii Y, Ishimaru T. Maternal serum triglyceride at 24-32 weeks' gestation and newborn weight in nondiabetic women with positive diabetic screens. Obstet Gynecol. 2001;97:776-780.