Perspectives in Circulation Today

Diabetes Control, Complications of hyperglycemia, NICE-Sugar Study and Wound Healing

. Glycosylation: The glycosylation process is perhaps the cause of diabetic complications most commonly recognized by the clinician because of the availability of the glycohemoglobin determination. So what, it might be asked of the clinician, if the A1C is elevated? First, the glycosylation process makes polymers of sugar and proteins. Proteins in the red cell membranes and the hemoglobin molecules themselves may be bound together making the red cell (rbc) stiff and its passage through the capillary bed more difficult. The rbc has a diameter close to that of the capillary and normally tumbles and twists stirring up its hemoglobin facilitating oxygen and carbon dioxide transfer as it traverses the capillary. Hemoglobin polymers are not easily stirred and the increased capillary pressure needed to push the rbc on it way can force macromolecules into the small nutrition channels in the capillary wall where they can be trapped causing thickening of the capillary membrane. The “so what” as regards the glycosylated rbc: stiff cells, decreased gas transfer, increased capillary perfusion pressure and thickened capillary membranes throughout the body. The glycohemoglobin determination may be regarded as a tissue biopsy and a model for potential complications in other tissues. Collagen in skin, tendon and muscles are likewise glycosylated as are components of enzymes. Schachter in his foreword of Reid et al’s book on protein glycosylation points out that oligosaccharides covalently bound to proteins are highly branched polymers with multiple potential linkages: the anomeric carbon of one sugar can be linked in either an alpha or beta linkage to hydroxyls at carbon positions 2,3,4 or 6 of the typical hexose pyranose ring structure resulting in a possible 1x1012 linear or branched isomers versus only 4.7x104 for a hexapeptide. Clearly the glycosylation process is capable of immense mischief. Thus, glycosylated lipoproteins may be recognized as foreign by scavenger cells in the vessel wall where they may be phagocytized and accumulate giving in time first a foam cell and later a plaque. The function of glycosylated platelets and leukocytes is compromised. Blood viscosity is increased. Fibrinolysis is diminished. Stiffness of the great vessels promotes systolic hypertension which together with the atherosclerosis and glycosylation of myocardial proteins decreases myocardial compliance and results in cardiomyopathy. Testa et al(1996) point out that the ambient level of HbA1c and fructosamine is related both to the rate of production (hyperglycemia) and clearance by scavenging mechanisms. The latter, however, likely differ significantly between structural advanced glycosylation end products (AGE) in muscle, tendons etc and glycosylated proteins in the serum. To the degree the clearance of glycosylated products in the serum and tissues differ, the harm that may be associated with elevations in glycohemoglobin and hyperglycemia may be underestimated. How soon after the onset of hyperglycemia are detrimental effects seen? Rodriguez-Mañas et al (2003) in their streptozotocin-induced diabetic rats found impairment of endothelium-dependent relaxations occurred after 2 weeks of untreated diabetes and recovered after three weeks of insulin treatment, the time course correlating more with the changes in glycosylated hemoglobin then serum glucose of serum AGE. Turke et al (1999) found progressive increases in AGE-content of the aorta and tendons of rats with hyperglycemia of 4, 12 and 20 weeks duration with a very good exponential correlation with the mean levels of glycosylated hemoglobin. The advanced glycosylation process was retarded and reduced in intensity by attempts at glycemic control but not abolished.

Hyperglycemia and Wound Healing: The above might be expected to affect wound healing. Recent literature has specifically examined the means whereby hyperglycemia decreases wound healing and the results of various therapies on healing and inflammatory markers. Velander et al (2008) studied the question as to whether the detrimental effect of hyperglycemia was due to a high concentration of glucose in the wound itself or in tissues at least somewhat remote from the surface of the wound; they found that application of glucose to the wound itself had no detrimental effect, a happy finding for those recommending the application of honey to wounds today. Rosa et al (2008) found specific cytokines (IL-1alpha, IL-4, and IL-6) are acutely elevated during hyperglycemia in children with T1DM, and these elevations persist for hours after hyperglycemia has been corrected. D’Souza (2009) noted that hyperglycemia regulates RUNX2 transcription factor activation and cellular wound healing through the aldose reductase polyol pathway; RUNX2 is diminished in diabetic animals resulting in less endothelial cell migration, proliferation and angiogenesis. Tsai et al (2009) noted no beneficial effect of lower extremity bypass surgery on inflammatory reaction and endothelial dysfunction in type 2 diabetic patients. Breen et al (2008) in stereological studies found that the alloxan-treated rabbits (a model for noncontractile wounds) had more inflammatory cells and fibroblasts at 14 days along with a reduction the length density of blood vessels , representing a greater radial diffusion distance between vessels and a less efficient network for nutrient exchange. Brem et al (2007) found that advanced age and diabetes acted synergistically in impairing wound healing in their mouse studies and concluded early and aggressive intervention was warranted for elderly patients with diabetic foot ulcers.

Relative hypoxia normally plays a pivotal role in regulation of all the critical processes involved in tissue repair and hypoxia-inducible factor (HIF) 1alpha is the critical transcription factor that regulates adaptive responses to hypoxia. Botusan et al (2008) showed that hyperglycemia affects both HIF-1alpha stability and activation, resulting in suppression of expression of HIF-1 target genes essential for wound healing both in vitro and in vivo. (They did not describe how hyperbaric treatments affects this system.) Lin HI, Chu SJ et al (2008) did study the combined effect of hyperglycemia and hyperbaric treatments on fibroblasts in vitro; they found that high concentrations of glucose in the media inhibited cell proliferation and enhanced cell death. Daily hyperbaric treatments likewise reduced cell proliferation and increased cell death in normal cultured fibroblasts. The combination of hyperglycemia and hyperbaric treatments had synergistic detrimental effects. In lieu of summarizing the many other articles that document the detrimental effects of hyperglycemia on wound healing, the reader is referred to the titles below of other interesting and relevant studies. That by Litchfield et al, for example, suggests that antioxidant therapy may have a limited role in preventing the complications of the glycosylation process. The work of Tan et al points to the benefits of tea and harm of soft drinks.

Table 1
Other References Docummenting the Harm of Hyperglycemia

Stress, the ICU and the Cortisone glucose tolerance test: Conn and Fajans pretreated relatives of diabetics with 50mg cortisone acetate (62.5 mg for those over 160 pounds) both 8 and a half and 2 hours before their standard glucose tolerance test (1.75 gms glucose/kg ideal body weight) in an attempt to identify diabetes before the standard glucose tolerance became abnormal (Ann N.Y Acad. Sci 82:208, 1959). The cortisone raised the venous blood sugar 0-20 mg/dl in normal subjects, 20-60 mg//dl in latent diabetics and in excess of 60 mg//dl in overt diabetics. The elevation in blood sugar may be likened to that produced by the various stresses of illness seen in the intensive care unit. Thus an admission glucose value over 180 mg/dl has been said to predict undiagnosed diabetes rather than stress hyperglycemia among patients with an acute MI (Malmberg et al 1995)(Malmberg & Ryden 1988). The presence of diabetes and/or hyperglycemia has been noted in many studies to increase the risk of death and postoperative infection in patients admitted to the Intensive Care Unit. Stress can also been associated with hypoglycemia especially in patients with limited caloric intake. Indeed, caloric intake is a common factor controlling the ambient blood glucose level. As there is an upper limit for glucose uptake in the tissues in the presence of greatly elevated serum levels, one common cause of marked hyperglycemia and insulin resistance in the ICU is the intravenous administration of hypertonic glucose solutions as part of a hyperalimentation program. In such patients, the cure is not more insulin but less intravenous glucose. Various algorithms are commonly utilized to regulate intravenous insulin administration with the unfortunate production of an increased incidence of hypoglycemia. Thus, in one arm an insulin/saline intravenous may be running while in the other antibiotics or high-calorie solutions (perhaps one moment lipids, protein or carbohydrate solutions). Little wonder swings in blood glucose may be produced. In practice, the postoperative diabetic may be easily controlled by giving 20% of their usual total insulin dose subcutaneously as long-acting insulin (Ultralente or Lantus) to meet their fasting insulin needs and adding 8-12 units of regular insulin to each liter of 5% G/W they receive. Such patients commonly run blood glucose levels in the 100-160 mg/dl range. When 12-15 units are added per liter of 5% G/W, the glucose commonly runs in the70-110 range(Dillon: Handbook of Endocrinology 1980). The stability results from the concomitant administration of reasonable amounts of both glucose and insulin. All programs especially in obtunded patients require close bedside monitoring.

The Nice-Sugar Study and the University Group Diabetes Program Phenformin Study: Both studies purport to show that mortality is increased in one by tight control of blood sugar in the intensive care unit and in the other by usage of Phenformin in type 2 diabetics. The above dissertation on the complications of hyperglycemia would seem to make the results of the Nice-Sugar study unexpected. Likewise, previous studies showing that phenformin decreased the hyperinsulinism of obesity, lowered cholesterol, promoted weight reduction and has a significant fibrinolytic action seemed to make the results of the UGDP study unexpected. Both studies have had an impact on the therapeutic actions of clinicians… and perhaps wrongly. Secretary of Health Califano, a lay person and a lawyer, perhaps responding to the clamor of Ralph Nader, declared Phenformin to be a public hazard (lactic acidosis) and removed it from our market. It took over twenty years before metformin was allowed back in US pharmacies. Pursuit of the Nice-Sugar tight control goal (glucose levels of 81-108 mg/dl) was associated with an increased incidence of both severe hypoglycemia and death (the two not necessarily related). In both studies, no glycohemoglobin data was presented to help evaluate the burden of glycosylated products the patients may have suffered from previous hyperglycemia. In both studies minor differences in baseline risk factors did not seem to explain the data. The patients in the tight control group of the Nice-Sugar Study did have significant increases in the percentage of patients treated with insulin (97.2% vs 69%), the units administered per day (50.2 vs 16,9) and the percentage of patients treated with corticosteroids 34.6 vs 31.7%). They also had minor increases in the use of mechanical ventilation and renal replacement therapy, in a history of type 1 diabetes and usage of insulin, and in the presence of sepsis at randomization. In an independent analysis of the phenformin data by Dillon, the data of the phenformin patients and control patients was pooled and the relationship of the baseline data to death was analyzed. It was found that death was significantly associated with age over 55 (P<0.001) and that in the patients over 55, it was associated with blood pressure over 145 (P<0.05), creatinine >1.0 (P<0.05) and the combination creatinine >1.0 and cholesterol>250mg/dl (P<0.02). The phenformin group had both more young patients and patients over age 55, but about the same average age as the control group. When the population at risk of death (age >55) was compared in the phenformin group versus their controls, it was found that the phenformin group had greater numbers of patients with a relative weight >1.2 (P<0.02), cholesterol>=250mg/dl (P<0.05) and a combination of hypertension, obesity and hypercholesterolemia (P<0.01)(Dillon, Handbook of Endocrinology 1980). Such an analysis of the Nice-Sugar data would be interesting. In any event, the conclusions of the Nice-Sugar investigators and their reviewers, should not be considered in the long term treatment of insulin-dependent diabetics and those diabetics with non-healing wounds. In the latter, the clinician should aim for the best control possible considering the individual situation of the patient and his/her ability to reliably test their sugar, take their insulin and follow a proper diet.

The Efect of Circulator Boot Therapy on the Complications of hyperglycemia: Our Case History library (http://www.circulatorboot.com/casehistory/csemenu1.html) provides illustrative cases of most of the complications of diabetes: retinopathy, nephropathy, neuropathy, acute neuritis, arteriosclerotic heart disease,congestive heart failure, necrotizing cellulitis and osteomyelitis. These patients were benefitted although treated largely as outpatients and commonly in spite of their inability to comply with their prescribed diet and insulin programs. The means whereby these benefits were achieved might be a subject of clinical research. Stimulation of various endothelial humoral factors (nitric oxide, prostacyclin, vascular endothelial growth factors, fibrinolysins and more?), improved cardiac function, improved blood flow to the nerves and other tissues, all may be involved. The effect of pumping on tissue AGE products might be considered. Hopefully, some of our boot clinics will investigate these issues.

Perspectives in Circulation Today

Volume 4, Number 5