Resistance to Ketoacidosis Despite Severe Hyperglycemia in Thin Adult Diabetics
1982; King Faisal Specialist Hospital and Research Centre; Volume: 2; Issue: 3 Linguagem: Inglês
10.5144/0256-4947.1982.139
ISSN0975-4466
AutoresMichael Kingston, William R. Scales, Nicholas Woodhouse,
Tópico(s)Pancreatic function and diabetes
ResumoOriginal ArticlesResistance to Ketoacidosis Despite Severe Hyperglycemia in Thin Adult Diabetics Michael E. Kingston, MD FRCP William R. Scales, and PhD Nicholas J. Y. WoodhouseMB BS MRCP Michael E. Kingston * Chairman, Department of Medicine; King Faisal Specialist Hospital Research Centre Search for more papers by this author , William R. Scales † Chief Biochemist, Department of Pathology and Laboratory Medicine; King Faisal Specialist Hospital Research Centre Search for more papers by this author , and Nicholas J. Y. Woodhouse ‡ Endocrinologist, Department of Medicine, King Faisal Specialist Hospital Research Centre Search for more papers by this author Published Online:1 Jul 1982https://doi.org/10.5144/0256-4947.1982.139SectionsPDF ToolsAdd to favoritesDownload citationTrack citations ShareShare onFacebookTwitterLinked InRedditEmail AboutABSTRACTABSTRACTNinety-eight percent (217 of 221) adult Saudi Arabian out-patients referred to the medical clinics of King Faisal Specialist Hospital and Research Centre with random serum glucose >200 mg/dl during two years from 1978 to 1980 had noninsulin dependent diabetes; only four patients (two percent) had insulin dependent diabetes. Body weight was normal or below normal in 62 percent, and 77 percent were aged between 30 and 60 years. Microangiopathic complications were common but coronary and peripheral artery disease was rare. Liver disease was present in 25 percent.The random, highest serum glucose mean was 410 mg/dl. The blood levels of serum glucose (n =125), insulin (n = 108), C-peptide (n = 105), measured during fasting and 45 minutes after 50 grams of glucose taken orally were glucose 262 ± 153 (mean ± S.D.) and 396 ± 111 mg/dl, insulin 20 ± 18 and 32 ± 28 μu/ml, and C-peptide 2.8 ± 1.6 and 3.6 ± 1.9 ng/ml.Despite exposure to stress in 64 cases (sufficiently severe to warrant hospitalization) only two patients developed ketoacidosis, and four hyperglycemic (hyperosmolar) encephalopathy during the two-year follow-up period.Ten patients each had at least one episode of ketonuria without acidosis, and serum insulin measured in seven of these patients was below 13 μu/ml. Ketonuria did not develop in other patients with higher levels of serum insulin.Diabetes in Saudi Arabian adults is therefore characterized by well-tolerated hyperglycemia and resistance to ketoacidosis. Insulin secretion is reduced but is sufficient to prevent ketoacidosis. Atherosclerosis is rare; but liver disease is an important association.INTRODUCTIONDiabetes mellitus is a common disease in Saudi Arabia. A recent survey by Abu-Aisha, et al. reported a prevalence of 4.5 percent in 11 villages in the Sedair region.1 We were impressed by the apparent clinical differences between Saudi Arabian diabetics and those from Europe and North America. Many from Saudi Arabia were not obviously overweight, had severe hyperglycemia but rarely developed ketoacidosis. Although microvascular complications were common, coronary artery and peripheral vascular diseases were rare. We therefore undertook a study to confirm our initial observations and to explore the reason for the resistance to ketoacidosis. This paper presents our preliminary findings.SUBJECTS AND METHODSTwo hundred twenty-one consecutive diabetic patients (criteria for diagnosis, random serum glucose > 200 mg/ml) were seen by two of the authors during a two-year period, July 1978 to July 1980, in the general medical or endocrine clinics of the King Faisal Specialist Hospital and Research Centre. The primary reasons for referral were diabetes or its complications in 67 cases, suspected gastrointestinal disease in 55, and unexpected findings on biochemical screening in 95 cases. All patients were examined by the authors and over 90 percent were followed as out-patients during the two-year period. Attention was directed particularly to the presence or absence of peripheral pulses, limb reflexes and fundi, examined without dilatation. A routine biochemical profile using the SMAC-20™ blood analyzer, chest radiograph, hemogram, and urinalyses were done in all cases and electrocardiograms were done in 170 cases. The weights (W) and heights (H) of the patients without shoes and wearing examination gowns were expressed as the body mass index (BMI) = W/H2.2 Serum glucose, C-peptide and/or insulin were measured, when serum insulin measurements became available, in 125 consecutive, fasting patients 45 minutes after ingesting drinks each containing 50 grams of glucose. Patients who were taking insulin or had taken insulin for more than three months had C-peptide measurements but not insulin measurements and in some cases C-peptide measurements were omitted. Thus, 108 patients had insulin levels and 105 had C-peptide levels measured. Plasma glucagon before and 45 minutes after oral glucose was measured in 30 cases and glycosylated hemoglobin in 42 consecutive patients who had insulin determinations.In ambulant patients the tests were done in the morning after overnight fasting, but in 21 cases they were done shortly after hospitalization for infection or serious illness. We were unable to control rigorously the patients’ diets and activities prior to the glucose tolerance testing, but diuretics and oral hypoglycemic drugs were stopped ten days before, and patients taking corticosteroids were excluded. Sixty-four patients (stress cases) required hospitalization at presentation or during the two-year follow-up; 53 had infections severe enough to warrant hospitalization (pneumonia, septicemia, gangrene, osteomyelitis, severe tuberculosis, pyelonephritis); seven were admitted for operations and four for cardiac failure. Patients who had previously been prescribed insulin or oral hypoglycemics had stopped these drugs for over 24 hours prior to admission, as is common practice here.LABORATORY METHODSBlood specimens were collected by the vacucontainer method before and following a 50 gram glucose drink (0.33 g/cc). Serum glucose and glycosylated hemoglobin (Hemoglobin Quik Column Method of Helena Laboratory using a modified hemolysizing agent) were done the same day.3Serum for insulin and C-peptide, and blood for determining plasma glucagon (collected in tubes containing EDTA and proteinase inhibitor, 400 kallikrein inhibitor units/ml whole blood) were stored at — 20 °C and sent in dry ice to Bioscentia Laboratory, Frankfurt, Germany, where they were measured by radioimmunoassay.4–6 All samples were checked on arrival and unfrozen samples discarded. Each batch contained blood from at least one normal subject. The determinations listed above were therefore done on 14 normal subjects, which included seven laboratory technicians and seven Saudi Arabian medical students, aged 27 to 41 years. Laboratory quality controls for these determinations were as follows: glucose (X̄) = 311 mg/dl, coefficient of variation (cv) = 1.3%; insulin X = 9.8 μu/ml, cv = 16.3%; C-peptide X̄ = 1.5 ng/ml, cv = 20%; glucagon X̄ = 125 pg/ml, cv = 12%.RESULTSTwo hundred seventeen patients had noninsulin dependent diabetes mellitus (NIDDM), absence of ketoacidosis in the absence of stress, whereas only four patients had insulin dependent diabetes mellitus which developed before the age of 20 years in each case.2 The clinical data are shown in Table 1. Seventy-seven percent of our patients were between 30 and 60 years of age and 62 percent were normal weight or less. Only seven percent of patients took insulin regularly. There was an appreciable prevalence of microangiopathic complications including neuropathy (bilateral, symmetrical limb parasthesia, burning or numbness) in 71 cases (32 percent); ankle jerks were absent in 26 (three percent) and knee jerks in 13 (one percent); background retinopathy (>two microaneurysms seen on ophthalmoscopy with or without exudates) was present in 35 cases (17 percent) and of these eight had neovascularization. Proteinuria (> one g/day) occurred in 15 cases (six percent) and was associated with both peripheral neuropathy and retinopathy in 12 cases. Hypertension, blood pressure greater than 150/90 mmHg on more than two occasions, was present in 14 percent of patients with peripheral neuropathy and 53 percent of those with retinopathy, a significant difference (p>0.01, Chi square test). Twelve patients had gangrene in the feet despite the presence of dorsalis pedis and posterior tibial pulses in all.Table 1. Clinical data in diabetic subjects (standard deviation in brackets)Table 1. Clinical data in diabetic subjects (standard deviation in brackets)Seven patients were referred with primary diagnoses of cardiovascular disease, post-myocardial infarction in five cases, angina pectoris in one case, and occlusion at the abdominal aortic bifurcation in one case; diabetes was a secondary associated finding. Of the patients who did not present with cardiac failure and hypertension, only one had signs and symptoms or past history of coronary artery and peripheral vascular disease. One other patient had more than three of four peripheral pulses absent. Excluding patients with cardiac failure and hypertension, only five percent of this group (mean age 52 years) had minor electrocardiographic changes (ST-T segment changes, left axis deviation) and only one had abnormal Q waves. Biopsy-proven liver disease, chronic active hepatitis or cirrhosis, was present in 55 patients (25 percent).The biochemical results are shown in Table 2. The highest random glucose levels were >300 mg/100 ml in 69 percent and >400 mg/ml in 38 percent of our patients and the mean glycosylated hemoglobin in 42 consecutive patients was 15.1 percent. This was a positive correlation with the fasting serum glucose in these cases (r = 0.8, p<0.01). The mean serum cholesterol of the whole group of patients (201 mg/100 ml), although lower than the mean level found in North American normal subjects of the same age, was higher than the mean level (172 mg/100 ml) we observed in 150 healthy Saudi Arabian blood donors (not age or sex matched). The results of the basal and poststimulation hormone levels in general indicate that insulin levels in our patients were higher than those expected in juvenile diabetics but lower than those characteristic of obese diabetic patients.Table 2. Biochemical results in subjects with diabetes (mean ± standard deviation)Table 2. Biochemical results in subjects with diabetes (mean ± standard deviation)The mean plasma glucagon both before and after glucose stimulation were < 250 pg/ml in all except three cases. The correlation coefficients between the serum insulin and C-peptide were, fasting r = 0.58 and following glucose loading r = 0.62 (p 23 mMol/l, anion gap < 12) and only two had acidosis (serum bicarbonate 13 mMol/l and 20 mMol/l).Figure 1 shows the maximum levels of serum insulin attained in the glucose tolerance test in 108 of the subjects who had serum insulin levels measured. The serum insulin levels in the eight patients with ketonuria were all < 13 μu/ml and the two with acidosis had maximum insulin levels of 5.0 and 5.7 μu/ml. The poor correlation (r = –0.23, p = 13 μu/ml.Figure 1.: Serum insulin 45 minutes following 50 g glucose in 108 diabetic patients. Circles indicate patients who developed one or more episodes of ketonuria during follow-up. Correlation between serum insulin and serum glucose: r = −0.23 (p <0.25).Download FigureOnly four patients each developed one episode of mental aberration or coma due to severe hyperglycemia during observation period.Figure 2 shows the increase in serum insulin (Δ insulin) from the basal level following glucose loading in our subjects. There is a significant negative correlation (r = 0.49, p = < 0.01) between the fasting serum glucose and increase in serum insulin following glucose loading. The serum insulin rose less than 13 μu/ml in 39 of 41 patients with fasting serum glucose levels >250 mg/dl suggesting that the insulin output is near maximum when the plasma glucose level is greater than approximately 250 mg/dl.Figure 2.: Increase in serum insulin (Δ insulin) from the fasting level 45 minutes after 50 g glucose by mouth in 108 diabetic patients. Correlation between the fasting serum glucose and Δ insulin r = −0.49 (p 250 mg/100 ml) as suggested by our results. Although serum insulin reaches a peak at one and one-half to two hours in mildly diabetic subjects, little further increase in insulin secretion follows glucose challenge in severe diabetes.14–16 Our data suggest that ketonuria is inhibited in diabetics capable of achieving serum insulin levels > 13 μu/ml, even when stress occurs. It is important to question whether other factors could account for the resistance to ketosis despite severe hyperglycemia. Increased glucagon secretion was probably relatively unimportant because the plasma glucagon levels were much lower in our patients than in those reported with uncontrolled diabetes, and moderate elevation of plasma glucagon does not have an appreciable effect on counteracting the effects of insulin.17 Secondly, insulin sensitivity may have been greater than usual for maturity-onset diabetes because the majority of our patients were not obese, particularly those with severe diabetes. Finally, mild dehydration, a consequence of the desert climate, might diminish glucose excretion and thereby increase hyperglycemia, or the threshold for glucose reabsorption might be different in Saudi Arabians adapted to desert conditions. This is, at present, under investigation.It is widely, although not universally, held that diabetes predisposes to atherosclerosis despite the poor correlation between the severity of diabetes and the extent of atherosclerosis.18–24 This predisposition has been related to hyperglycemia per se and to elevated plasma lipids considered to be a consequence of hyperglycemia.18–21We saw an appreciable prevalence of microvascular complications and severe hyperglycemia, but despite this, symptoms or signs of coronary and peripheral artery disease only occurred in one of the 215 patients referred for reasons other than cardiovascular disease. Remarkably, only two patients had more than one of four pedal pulses absent and the pedal pulses were easily palable in all 12 patients with gangrene. Infection and gangrene of the feet, an important complication in our experience, therefore appears to be due to small vessel disease, poor foot hygiene or neuropathy. Electrocardiography done in 128 patients without hypertension or cardiac failure was normal in 95 percent and only one patient showed pathological Q waves, the others showed minor ST-T changes only.Our results therefore suggest that hyperglycemia by itself may be less important than nutritional factors in the etiology of atherosclerosis. Our observations have important implications for the treatment of diabetes in Saudi Arabia and perhaps for several other countries. The rarity of ketoacidosis and hyperglycemic (hyperosmolar) encephalopathy suggests that the indication for insulin or oral hypoglycemic therapy, in the absence of pregnancy and infection, depends on their effects in diminishing vascular complications or in improving symptoms such as nocturia. Large vessel disease was rare in our patients and evidence that microangiopathy is improved with insulin therapy is inconclusive at present.25The greater difficulty of achieving effective but safe insulin therapy in many of our patients, the unproven benefit and the ineffectiveness we noted of oral hypoglycemic drugs, and the problems in continuing therapy during religious festivals involving fasting, such as Ramadan, indicate that more rigorous selection of patients for treatment with insulin or oral hypoglycemic drugs is in order. Weight reduction, proper diet, and exercise, however, should be encouraged as they diminish insulin resistance and, perhaps lessen the severity of atherosclerosis.25–29 Hypertension, an important risk factor for retinopathy and nephropathy, should be vigorously treated. Patients should avoid smoking and should receive regular eye examinations, because early treatment of neovascularization and macular retinopathy can prevent deterioration of vision.30, 31 Special measures should be taken to prevent infection and gangrene of the feet in predisposed subjects. This includes comfortable, protective footwear, wearing woollen socks, softening of ketatin by olive oil application, and meticulous nail and skin hygiene. Such measures may be more important for ketosis-resistant diabetics than therapy with oral hypoglycemic drugs or insulin.ARTICLE REFERENCES:1. Abu-Aisha H, Al-Khatir A, Sinaidi A, et al.: "The epidemiology of diabetes mellitus in a rural community in central Saudi Arabia" . (Abstract 2.2.4) Abstracts of the 5th Saudi Medical Meeting. Riyadh, 1980, p 38. Google Scholar2. National Diabetes Data Group: "Classification of diabetes mellitus and other categories of glucose intolerance" . Diabetes 12: 10391979. Google Scholar3. Kynoch PAM, Lehmann H: "Rapid estimation (21/2; hours) of glycosylated haemoglobin for routine purposes" . Lancet 2: 161972. Google Scholar4. Wide L, Parath J: "Radioimmunoassay of proteins with the use of sephadex-coupled antibodies" . Biochem Biophys Acta 130: 2571966. Google Scholar5. Block MB, Make ME, Steiner DF, et al.: "Circulating C-peptide immunoreactivity studies in normals and diabetic patients" . Diabetes 21: 10131972. Google Scholar6. Shima K, Foà PP: "A double antibody assay for glucagon" . Clin Chim Acta 22: 511, 1968. Google Scholar7. Zuidema PJ: "Cirrhosis and disseminated calcification of the pancreas in patients with malnutrition" . Trop Geog Med 11: 701959. Google Scholar8. Hugh-Jones P: "Diabetes in Jamaica" . Lancet ii: 8911955. Google Scholar9. "Editorial: Diabetes, cyanide, and rat poison" . Lancet 2: 3411979. Google Scholar10. Brown PM, Tomkins CV, Juul S, et al.: "Mechanism of action of insulin in diabetic patients: a dose-related effect on glucose production and utilisation" . Br Med J 1(6122): 12391978. Google Scholar11. Parrilla R, Goodman MN, Toews CJ: "Effect of glucagon: insulin ratios on hepatic metabolism" . Diabetes 23(9): 7251974. Google Scholar12. Rabinowitz D, Liljenquist JE: "Glucose metabolism in intact man: the responsiveness of splanchnic and peripheral tissues to insulin" . Metabolism 27 (12 suppl 2): 18321978. Google Scholar13. Madsbad S, Alberti KG, Binder C, et al.: "Role of residual insulin secretion in protecting against ketoacidosis in insulin-dependent diabetes" . Br Med J 2(6200): 12571979. Google Scholar14. Seltzer HS, Allen EW, Herron AL, et al.: "Insulin secretion in response to glycemic stimulus: relation of delayed initial release to carbohydrate intolerance in mild diabetes mellitus" . J Clin Invest 46: 3231967. Google Scholar15. Perly M, Kipnis DM: "Plasma insulin response to glucose and tolbutamide of normal weight and obese diabetic and non-diabetic subjects" . Diabetes 15: 8671966. Google Scholar16. Genuth SM: "Plasma insulin and glucose profiles in normal, obese, and diabetic persons" . Ann Intern Med 78: 8121973. Google Scholar17. Clarke WL, Santiago JV, Kipnis DM: "The effect of hyperglucagonemia on blood glucose concentrations and on insulin requirements in insulin-requiring diabetes mellitus" . Diabetes 27(6): 6491978. Google Scholar18. Fuller JH, Shipley MJ, Rose G, et al.: "Coronary-heart-disease risk and impaired glucose tolerance. The Whitehall Study" . Lancet 1(8183): 13731980. Google Scholar19. Keen H, Rose GA, Pyke DA, et al.: "Blood-sugar and arterial disease" . Lancet 11: 5051965. Google Scholar20. Ostrander LD, Francis T, Hayner NS, et al.: "The relationship of cardiovascular disease to hyperglycemia" . Ann Intern Med 62: 11881965. Google Scholar21. Kannel WB, McGee DL: "Diabetes and cardiovascular disease. The Framingham Study" . JAMA 241(19): 20351979. Google Scholar22. Sosenko JM, Breslow JL, Miettinen OS, et al.: "Hyperglycemia and plasma lipid levels: a prospective study of young insulin-dependent diabetic patients" . N Engl J Med 302(12): 6501980. Google Scholar23. Vallance-Owen J, ed: Diabetes, Its Physiological and Biochemical Basis. Lancaster, MTP Press Ltd, 1975 p 125. Google Scholar24. Ždanov VS, Vihert AM: "Atherosclerosis and diabetes mellitus" . Bull World Health Organ 53: 5471976. Google Scholar25. Olefsky JM: "The insulin receptor: its role in insulin resistance of obesity and diabetes" . Diabetes 25(12): 11541976. Google Scholar26. Stanik S, Marcus R: "Insulin secretion improves following dietary control of plasma glucose in severely hyperglycemia obese patients" . Metabolism 29(4): 3461980. Google Scholar27. Richter EA, Ruderman NB, Schneider SH: "Diabetes and exercise" . Am J Med 70: 2011981. Google Scholar28. Beck-Nielsen H, Pedersen O, Sørensen NS: "Effects of dietary changes on cellular insulin binding and in vivo insulin sensitivity" . Metabolism 29(5): 4821980. Google Scholar29. Simpson HCR, Lousley S, Geekie M, et al.: "A high carbohydrate leguminous fibre diet improves all aspects of diabetes control" . Lancet 1: 11981. Google Scholar30. Knowler WC, Bennett PH, Ballintine EJ: "Increased incidence of retinopathy in diabetics with elevated blood pressure. A six-year follow-up study in Pima Indians" . New Engl J Med 302(12): 6451980. Google Scholar31. Rand LI: "Recent advances in diabetic retinopathy" . Am J Med 70: 5951981. Google Scholar32. Friedman EA, L’Esperance FA: "Diabetic renal-retinal syndrome. The prognosis improves (editorial)" . Arch Int Med 140(9): 11491980. Google Scholar Previous article Next article FiguresReferencesRelatedDetails Volume 2, Issue 3July 1982 Metrics History Published online1 July 1982 KeywordsAcidosisdiabetic Hyperglycemia Diabetes mellitusInformationCopyright © 1982, Annals of Saudi MedicinePDF download
Referência(s)