Improved Glycemic Control in Moderate Altitude Type II Diabetic Residents

Introduction

Permanent altitude residents are chronically exposed to hypobaric and hypoxic conditions. Due to the low oxygen tension, they are hypoxemic and have low blood oxygen saturation (Sao₂). Chronic hypoxia is partially acclimatized by polycythemia, increased hematocrit, and the molecular interactions between hemoglobin and Mg-2,3-diphosphoglycerate (DPG), adenosine triphosphate (ATP), and chloride (Cl) (Mairbaurl et al., 1993). These interactions improve the oxygen availability in tissues, through the decreased affinity of hemoglobin to oxygen.

Healthy nondiabetic people, permanently living at high altitude appear to have lower blood glucose levels and decreased incidence of diabetes. In HA pregnant women, fasting C-peptide levels and β-cell function were similar to sea level pregnant women, whereas insulin and proinsulin were lower. Insulin sensitivity was higher and fasting plasma glucose was lower at high altitude (4370 m) than at sea level in the presence of similar insulin secretion (Krample et al., 2001). Also, after moderate altitude exposure, subjects suffering from metabolic syndrome had significant improvements in glycemic parameters where the glucose concentration was significantly lower compared to the basal values (Schobersberge et al., 2002). Living at moderate altitude (1500–2000 m) is well tolerated for the majority of diabetics. Beyond 2500 m, hypoxia-induced anorexia, side effects of medications, and the higher incidence of mountain sickness, can make diabetes control difficult (Thalmann et al., 2007).

Diabetic retinopathy is known as one of the major complications of long-standing uncontrolled diabetes mellitus. Although diabetic climbers going to high altitude may have an increasing risk for development of retinopathy (Leal et al., 2008), long-term residence at moderate altitude did not induce significant difference in retinopathy incidence (Sayarlioglu et al., 2005). Subsequently, glycemic control plays an important role in prevention of such complications. Several studies have investigated the risk of high altitude short-term residents such as mountains climbers. No studies, however, were undertaken at Assir province to investigate the effect of chronic altitude exposure on patients with pre-existing type II diabetes mellitus. Asir mountains extend along the western province of Kingdom of Saudi Arabia, where El Namas (2400 m) is considered one of the highest cities located onto these mountain series. In this report, type II diabetic permanent residents of this city were studied to investigate the glycemic control compared to diabetics living in normobaric conditions. The data presented in this work monitored blood glucose level, glycemic control, represented as HbA1c, hemoglobin concentration and HCT, in addition to Pao₂ and Sao₂ that are directly involved in hemoglobin–oxygen affinity and delivery of oxygen to tissues.

Materials and Methods

Patient population and grouping

This study included 34 type II diabetic patients and 34 nondiabetic healthy subjects aged 50.06±9.8 years, range: 28–70 years. Subjects were 64 male and 4 female. They were categorized into four groups (Table 1). Groups I and II (n=18, each) included diabetic patients and nondiabetic subjects, living at moderate altitude (El Namas city, 2400 m above the sea level, standard barometric pressure 577 mmHg (77 kPa) (Fig. 1). Diabetic patients of group I were randomly selected from diabetic outpatients, regularly monitored for blood glucose at El Namas General Hospital. Groups III and IV (n=16 each) included diabetic and nondiabetic patients, respectively, living at normobaric condition (300 m). Group III patients were randomly selected from outpatients monitored for diabetes enrolled at El-Magarda General Hospital. As diabetic patients (groups I and III) were selected from 2 hospitals belonging to the same governorate (Assir Department for Health Management), the same protocol of diabetes monitoring and laboratory techniques were applied. Also, diabetics were selected according to the history of the disease and the level of fasting blood glucose (>130 mg/dL), only patients diagnosed with DM between 5–10 years ago were included. Patients treated with insulin and those with extremely high fasting glucose level, which may predispose diabetic complications, were excluded. All patients were native Saudis, not practicing exercises and not suffering from kidney, heart, or chest complications; samples were taken under informed consent following applied ethical regulations.

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FIG. 1.

Barometric pressure and oxygen and carbon dioxide tensions at low (300 m) and high (2400 m) altitudes.

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Table 1.

Patients Groups, Number, Sex, and Age of Patients

		Sex (%)
Group (n)	Altitude (m)	Male	Female	Age Mean±SD (yrs)
Group I: altitude DM (n=18)	2400 m	17 (94.4%)	1 (5.6%)	56.8±5.56
Group II: altitude nondiabetics (n=18)	2400 m	16 (88.9%)	2 (11.1%)	49.8±6.9
Group III: LA DM (n=16)	300 m	16 (100%)	0 (0.0%)	55.4±5.8
Group IV: LA nondiabetics (n=16)	300 m	15 (93.7%)	1 (6.3%)	37.4±6.8

DM, diabetes mellitus; LA, low altitude.

Results

Fasting blood glucose levels in groups I, II, III, and IV were: 157.33±12.3, 84.0±6.2, 176.81±15.90, and 89±6.55 mg/dl, respectively. As expected, glucose concentrations in groups I and III (ranged 125–182 mg/dL and 158–213 mg/dL, respectively) were significantly higher than the corresponding nondiabetic patients living at the same altitude (group I vs. group II: p<0.001; group III vs. group IV: p<0.001) (Table 2). Also, the glucose concentration of diabetic patients in groups I (HA diabetics) was significantly lower than diabetic patients living at low altitude (group I vs. group III, p<0.001), where moderate altitude diabetic patients have 11% less glucose compared to low altitude diabetics.

Assessment of glycemic control revealed that diabetic patients in groups I and III had mean HbA1c of 8.68% (±0.79) and 9.3% (±1.02) and ranges 6.7%–9.8% and 7.9%–11%, respectively, whereas HbA1c was higher in diabetic patients compared to healthy subjects in both groups II and IV (p<0.001, p<0.001). Altitude diabetics (group I) showed slightly but significantly lower (P<0.05) HbA1c than diabetic patients at low altitude (group III) (Table 2).

Significant increase in both hemoglobin concentration and HCT was observed in groups I and II compared to groups III and IV (Table 2). Also, no differences in hemoglobin and HCT were observed between diabetics and nondiabetics living in the same altitude (group I vs. group II, p>0.05; group III vs. group IV, p>0.05).

Partial pressure of arterial oxygen (Pao₂) and oxygen saturation (Sao₂) in altitude groups (groups I and II) were significantly lower than low altitude patients in both groups III and IV (p<0.001 in both), whereas pH values were slightly increased in the altitude residents, where the pH of arterial blood ranged from 7.36–7.45 in altitude patients (groups I and II), mean±SD: 7.40±0.02 and 7.40±0.03 in group I and II, respectively. No significant difference was observed in pH values between normal and diabetic patients living at the same altitude (Table 3).

Discussion

Altitude illnesses usually occur at altitude over 1500 m and are caused primarily by hypoxia. Chronic high altitude-induced hypoxia may lead to retinal disorders, which are well known long-term complications of diabetes mellitus. Type II diabetics were randomly assigned from native nonathletic Saudis, permanently living at moderate altitude. Chronic exposure to hypoxic condition affected the glucose level and glycemic control in diabetic patients (group I). Glucose level of diabetics living at moderate altitude was lower than those living at low altitude (mean: 157.33±12.30 and 176.81±15.88 mg/dL, respectively; p<0.001), where the mean glucose level of altitude diabetic patients was 11.1% lower than diabetic patients living at low altitude (p<0.001). Chronic hypoxia may increase insulin sensitivity and insulin-stimulated glucose uptake (Gamboa et al., 2011). This may explain the reduction of glucose in group I.

Long-standing hyperglycemia leads to the formation of glycohemoglobin, which is formed when glucose, nonenzymaticaly and irreversibly, interacts with the amino groups of valine and lysine of the hemoglobin. (Bry et al., 2001). As the level of HbA_1c in the red blood cell depends on the blood circulating glucose concentration, measuring HbA1c provides a measurement of long-term glycemic control in diabetic patients (Yue et al., 1993). Diabetics permanently living at moderate altitude (group I) showed a better glycemic control, where their HbA1c was lower than the corresponding diabetic patients living at normoxic and normobaric conditions (group III). This is supported by some reports that indicated that high altitude could produce a beneficial effect on glucose tolerance, and high altitude possibly is a potential natural medicine for treatment of type II diabetes (Bry et al., 2001). Also, chronic hypoxia has increased insulin-stimulated glucose uptake in mouse soleus muscle (Gamboa et al., 2011) and improved insulin action in mountain climbers on a prolonged altitude expedition (Chen et al., 2010). In contrast, short-term exposure to altitude and the altitude level (moderate, high, or extremely high) change glucose homeostasis. Exercise at short-term exposure to high altitude, for instance, induces impairment in glycemic control in type 1 diabetics (Brubaker, 2005). Very high altitude (5000 m) largely affects the glycemic control in both type I and II, where it increased insulin requirements during exercise in type 1 diabetes (deMol et al., 2011).

Permanent living in hypoxic conditions is physiologically compensated by a marked increase in hemoglobin and HCT. Groups I and II had 11.8% and 10.4% higher hemoglobin concentrations compared to the corresponding groups living at normoxic condition, and a similar changing pattern was observed in HCT percent by Palmer (2011).

Arterial oxygen pressure (Pao₂), the amount of free oxygen dissolved in plasma, reflects the oxygen adequacy in the blood and determines the availability of oxygen to bind to hemoglobin. Pao₂ in patients living at altitude (groups I and II) was still in the normal range, however it was significantly lower than patients living at low altitude (Table 3). At altitude, in response to atmospheric hypoxia, chemoreceptors in the carotid body can detect the decrease of Pao₂ and stimulate the hypoxic ventilatory response. This causes hyperventilation, which results in increased Pao₂ and decreased Paco₂. Permanent stay at high altitude stabilizes the pH within normal range by bicarbonate excretion from the kidneys. This may explain the maintenance of normal levels of Pao₂ and pH in altitude groups, where both groups showed insignificant difference compared the corresponding groups living near the sea level (Table 3). Oxygen saturation (Sao₂) which is ratio between O₂Hb and HHb+O₂Hb represents how much oxygen is bound to hemoglobin. In addition to pH, Paco₂ and 2,3-DPG, Pao₂ is the most important determinants of Sao₂ and their relation represents the oxygen dissociation curve. The data obtained revealed that patients in groups living at moderate altitude had slightly lower Sao₂ compared to low altitude groups, and diabetes did not affect the saturation percent.

Factors decreasing hemoglobin–oxygen affinity shift the oxygen dissociation curve to the right. High altitude-related increase in glucose uptake and the increased insulin sensitivity will increase the level of cellular glycolytic intermediate 2,3-diphosphoglycerate (2,3-DPG). When it binds to hemoglobin, 2,3-DPG causes a molecular configuration in hemoglobin that lower its affinity with oxygen, subsequently improving tissue oxygenation (Farber et al., 1991).

In conclusion, the study supports the notion that moderate (not extreme) altitude living may improve glycemic control in type II diabetic patients compared to diabetics living at low altitude. The study is limited to native Saudis, nonathletic, permanently living at moderate altitude. More studies are needed to confirm these findings.