Lactic Acidosis in Diabetes

Lactic acidosis is occasionally responsible for metabolic acidosis in diabetics. It may occur in the presence of normal blood levels of the ketone bodies, and such cases are often described as having “non-ketotic diabetic acidosis.” Lactic acid may contribute to the metabolic acidosis in patients with true diabetic ketoacidosis, but the blood lactate concentrations in these patients are not usually very high. In some patients the ketoacidosis is replaced by a lactic acidosis during treatment. This usually occurs in association with a serious underlying disorder and is associated with a poor prognosis. A transient increase in blood lactate concentration was in fact observed in most patients after the beginning of treatment, but the significance of this finding is uncertain.     

Lactic acidosis and ketoacidosis: biochemical and clinical implications.

A case of lactic acidosis presented the opportunity for review of the association between lactic acidosis and ketoacidosis. The diagnosis of lactic acidosis or the combination of lactic acidosis and ketoacidosis is established clinically by the detection of a metabolic acidosis of the "unmeasured anion gap" type in the absence of significant renal failure, poison intake or a strongly positive clinical test for ketones. Before treatment can be planned the biochemical basis of lactic acidosis and ketoacidosis must be understood -- especially the fact that lactic acidosis is not a single disease entity but has many possible causes. Among important considerations is the relation between the blood concentrations of bicarbonate and organic acid anions. After recovery from metabolic acidosis of the unmeasured anion gap type, metabolic alkalosis is common. Decreased bicarbonate excretion plays an important role in the pathogenesis of the latter and may be the result of potassium or chloride loss, or both. The deficits, if present, should be corrected with appropriate therapy.     

Renal tubular acidosis during therapy for diabetic ketoacidosis.

A young woman presented with typical diabetic ketoacidosis. Five hours after insulin had been given hyperchloremic metabolic acidosis developed. This could not be attributed to gastrointestinal loss of bacarbonate, ingestion of HCI or carbonic anhydrase inhibitor, or the administered fluids and electrolytes. The combination of hyperchloremic metabolic acidosis and a urine pH of 5.6 during acidemia prompted specific studies that established the presence of disorders of renal acidification. A transient defect of hydrogen ion secretion in the distal nephron was suggested by the decrease in urine-blood Pco-2 gradient after administration of sodium bicarbonate. Proximal renal tubular acidosis was indicated by the reduced bicarbonate threshold that persisted for approximately 7 weeks.     

Hypothermia: a complication of diabetic ketoacidosis.

During 1969-77, 20 episodes of severe hypothermia occurred in 19 diabetic patients in Nottingham. Thirteen were associated with ketotic hyperosmolar coma, two with lactic acidosis, and one with hypoglycaemia, while in four there was no loss of diabetic control. Ketoacidosis accounted for 11.8% of all admissions for severe accidental hypothermia and was a commoner cause than hypothyroidism (8%). Patients with ketoacidosis were younger and developed hypothermia as often during the summer as during the winter. The metabolic disturbance was characteristic, with severe acidosis (mean pH 7.04), a high blood glucose concentration (mean 56.6 mmol/l; 1020 mg/100 ml), and high plasma osmolality (mean 379.7 mmol (mosmol)/kg). Eight of the 13 episodes proved fatal. Hypothermia may aggravate ketoacidosis and complicate treatment and should be sought in all patients with severe diabetic coma.     

Somatostatin and insulin infusion in the management of diabetic ketoacidosis

The effect of low-dose insulin infusion (4.8 U/h) in diabetic ketoacidosis was compared to that of low-dose insulin infusion (4.8 U/h) plus somatostatin (500 microgram/h IV). Treatment with insulin only in 20 patients caused normalization of blood glucose levels within 6 hours and resolution of ketoacidosis within 5 hours. During insulin plus somatostatin infusion in 7 patients, blood glucose levels returned to normal within 4 hours and acidosis was reduced within 3 hours. Correction of acidosis is the most important problem in diabetic ketoacidosis: in the severest cases cardiovascular and cerebral complications may ensue. The data presented show that addition of somatostatin to treatment with low doses of insulin reduces and resolves acidosis in a shorter time while plasma levels of glucagon and GH were concomitantly reduced.     

Targeting acidity in cancer and diabetes

While cancer is commonly described as “a disease of the genes”, it is also a disease of metabolism. Indeed, carcinogenesis and malignancy are highly associated with metabolic re-programming, and there is clinical evidence that interrupting a cancer's metabolic program can improve patients' outcomes. Notably, many of the metabolic adaptations observed in cancer are similar to the same perturbations observed in diabetic patients. For example, metformin is commonly used to reduce hyperglycemia in diabetic patients, and has been demonstrated to reduce cancer incidence. Treatment with PI3K inhibitors can induce hyperinsulinemia, which can blunt therapeutic efficacy if unchecked. While commonalities between metabolism in cancer and diabetes have been extensively reviewed, here we examine a less explored and emergent convergence between diabetic and cancer metabolism: the generation of lactic acid and subsequent acidification of the surrounding microenvironment. Extracellular lactic acidosis is integral in disease manifestation and is a negative prognostic in both disease states. In tumors, this results in important sequela for cancer progression including increased invasion and metastasis, as well as inhibition of immune surveillance. In diabetes, acidosis impacts the ability of insulin to bind to its receptor, leading to peripheral resistance and an exacerbation of symptoms. Thus, acidosis may be a relevant therapeutic target, and we describe three approaches for targeting: buffers, nanomedicine, and proton pump inhibitors.     

Diabetes and abdominal surgery: the mutual risks

The patient with diabetes represents to the surgeon a particular challenge in the management of acute abdominal problems. In addition to their ongoing and potential metabolic problems, diabetics have specific difficulty in their ability to handle infections and heal wounds. The present report reviews the general principles in the peri-operative management of diabetics and discusses the implications in the diabetic of several specific clinical problems. In view of the known accelerated atherosclerosis associated with diabetes, the risks of anesthesia and surgery must be assessed in the context of the coronary, cerebral, visceral, and peripheral vascular status. Infections in diabetics (potential or established) must be treated aggressively and promptly. Acidosis in the diabetic with abdominal pain must be considered both a metabolic problem and a possible secondary manifestation of an intra-abdominal process. In view of these challenges, the need for careful, anticipatory management of the diabetic patient facing major abdominal surgery is clear.     

Diabetic Ketoacidosis—A Review of Cases at a University Medical Center

Twenty-five cases of diabetic ketoacidosis were studied retrospectively with respect to clinical characteristics and results of therapy. In this series (as with all 88 patients admitted in the last five years with a diagnosis of diabetic ketoacidosis) there were no deaths. Infection was found to be the most common precipitating event, documented by physical findings and cultures in one-third of these cases.In about two-thirds of the cases, electrocardiograms which were read as abnormal on admission reverted to normal after therapy.In all patients serum potassium levels decreased from admission values; one patient became symptomatically hypokalemic.Low serum potassium levels on admission and early vigorous bicarbonate therapy are emphasized as major predisposing factors of symptomatic hypokalemia. None of the patients had overt hyperosmolar coma, lactic acidosis or cerebral edema during therapy.     

Diabetic ketoacidosis in a community of suburban Osaka. Analysis of 39 episodes of ketoacidosis and related conditions

Thirty-nine episodes of hyperglycemia and disturbance of acid-base equilibrium were classified according to the result of nitroprusside test for serum (or urine) ketones, serum electrolytes, glucose, lactate, beta-hydroxybutyrate and arterial blood pH and gas analysis into the following 6 groups; (1) diabetic ketoacidosis (DKA), (2) mild DKA, (3) DKA with mixed acid-base disturbance, (4) DKA with lactic acidosis, (5) lactic acidosis with mild ketonemia, (6) lactic acidosis. Their clinical manifestations, laboratory findings, insulin and i.v. fluid requirement in the early phase of therapy were surveyed and compared with those reported from Western countries. The fundamental problems of groups (1) to (4) were hyperglycemia and acid-base disturbance. Groups (5) and (6) were characterized by underlying serious medical illness, accompanied by lactic acidosis and hyperglycemia. All patients in groups (1) to (4) recovered but 7 of 10 patients in groups (5) and (6) died within the first 7 days. DKA with or without lactic acidosis and lactic acidosis with or without mild ketonemia appeared as two separate conditions from the standpoint of management and prognosis and were differentiated only by nitroprusside test for serum ketones. DKA with lactic acidosis and DKA without it could not be differentiated by routine blood chemistries and therapy for the two did not differ so that they were thought to be in the same spectrum of metabolic alteration.     

Intra-abdominal Cryptococcosis by Cryptococcus gattii: Case Report and Review

Although abdominal cryptococcomas and visceral cryptococcal lymphadenitis as part of disseminated fungal infection have been reported mostly in HIV-infected patients, localized intra-abdominal involvement due to Cryptococcus gattii has not been previously described in non-HIV-infected patients. In general, a smaller proportion of cryptococcosis is caused by C. gattii. We report here on a type II diabetic HIV-negative patient who presented with a localized intra-abdominal cryptococcal mass due to C. gattii. In addition, we review the general aspects of intra-abdominal and gastrointestinal involvement by Cryptococcus neoformans in the literature and discuss the importance of identifying the C. neoformans varieties and C. gattii in routine laboratories.     

General screening for celiac disease is advisable in children with type 1 diabetes.

The association between celiac disease (CD) and diabetes mellitus type 1 is well known. Only about one-third of all patients with CD are diagnosed in childhood as a result of typical gastrointestinal symptoms or growth retardation. To evaluate the feasibility of CD screening in diabetic children, we tested autoantibodies to tissue transglutaminase (tTGA) in all children with type 1 diabetes from our pediatric department during a 12-month period. In antibody-positive cases, we analyzed the clinical presentation and offered a duodenal biopsy to confirm the diagnosis and grade the severity of the inflammatory process. Of 205 children, 13 (6.3 %) were tTGA-positive. In seven of eight children who agreed to perform a biopsy, CD typical histological signs were detected (Marsh 1: n = 1, Marsh 3: n = 6). In three patients with confirmed disease, symptoms (iron deficiency, recurrent abdominal pain) remained undiscovered up to time of screening (latent form); in four, the disease was asymptomatic (silent form). Since clinical symptoms are mostly mild or absent in spite of severe signs of duodenal inflammation, we recommend tTGA screening in all diabetic children. This strategy may allow the identification of patients in an early stage in respect of prevention of long-term complications.     

The status of metformin in Canada.

During the 1970s two biguanide drugs, phenformin and metformin, were used to control hyperglycemia. Phenformin was phased out of the Canadian market because it carried an unacceptable risk of causing lactic acidosis, but metformin remains available. All documented cases of lactic acidosis associated with metformin administration, which are rare, have occurred abroad in patients who were taking the drug in spite of having contraindications to its use. The two drugs are metabolized differently, phenformin being deactivated and concentrated in the liver, and metformin being excreted rapidly, unchanged, by the kidneys. In properly selected diabetic patients therapeutic doses of metformin do not raise the blood levels of intermediary metabolites enough to induce ketoacidosis or lactic acidosis. The safety of the drug is supported by the clinical experience over about 56,000 patient-years in Canada.     

<Emphasis Type="Italic">Rhizopus arrhizus</Emphasis> Invasive Infection due to Self-Inflicted Scratch Injuries in a Diabetic Patient with Non-ketotic Acidosis

Mucormycosis is a rare infection caused by members included in the subphylum Mucoromycotina. Characterized by the histopathological hallmark of angioinvasion, these infections affect most often patients with certain underlying conditions carrying immunosuppression (haematological neoplasias, diabetic ketoacidosis and other forms of acidosis, and iron overload) or immunocompetent patients with traumatic mucocutaneous barriers breakdown and direct inoculation of the mould. A case is presented in which a rare underlying condition (non-ketotic acidosis) and a rare cause of cutaneous injuries collide. Prognosis, treatment options and management decisions are described thoroughly.     

Renal enzymes during experimental diabetes mellitus in the rat. Role of insulin, carbohydrate metabolism, and ketoacidosis

The activities of various ammoniagenic, gluconeogenic, and glycolytic enzymes were measured in the renal cortex and also in the liver of rats made diabetic with streptozotocin. Five groups of animals were studied: normal, normoglycemic diabetic (insulin therapy), hyperglycemic, ketoacidotic, and ammonium chloride treated rats. Glutaminase I, glutamate dehydrogenase, glutamine synthetase, phosphoenolpyruvate carboxykinase (PEPCK), hexokinase, phosphofructokinase, fructose-1,6-diphosphatase, malate dehydrogenase, malic enzyme, and lactate dehydrogenase were measured. Renal glutaminase I activity rose during ketoacidosis and ammonium chloride acidosis. Glutamate dehydrogenase in the kidney rose only in ammonium chloride treated animals. Glutamine synthetase showed no particular variation. PEPCK rose in diabetic hyperglycemic animals and more so during ketoacidosis and ammonium chloride acidosis. It also rose in the liver of the diabetic animals. Hexokinase activity in the kidney rose in diabetic insulin-treated normoglycemic rats and also during ketoacidosis. The same pattern was observed in the liver of these diabetic rats. Renal and hepatic phosphofructokinase activities were elevated in all groups of experimental animals. Fructose-1,6-diphosphatase and malate dehydrogenase did not vary significantly in the kidney and the liver. Malic enzyme was lower in the kidney and liver of the hyperglycemic diabetic animals and also in the liver of the ketoacidotic rats. Lactate dehydrogenase fell slightly in the liver of diabetic hyperglycemic and NH4Cl acidotic animals. The present study indicates that glutaminase I is associated with the first step of increased renal ammoniagenesis during ketoacidosis. PEPCK activity is influenced both by hyperglycemia and ketoacidosis, acidosis playing an additional role. Insulin appears to prevent renal gluconeogenesis and to favour glycolysis. The latter would seem to remain operative in hyperglycemic and ketoacidotic diabetic animals.     

Cerebral Syndromes of Diabetes Mellitus

Three labile diabetic patients had recurring episodes of altered sensorium. Each had severe cerebrovascular disease with superimposed metabolic derangements, including ketoacidosis, hyperglycemia without ketosis, mild uremia, and possibly cerebral edema. Two of the patients were examined postmortem. Severe leptomeningeal scarring, basal ganglial calcification and destruction of small intracerebral vessels without evidence of large vessel atherosclerosis were found unexpectedly in one patient, a rare occurrence in this country although recently reported from Europe. The other patient had large vessel atherosclerosis only.The clinical expression of the vascular disease was modified by concurrent abnormalities and reflected the sum total of the complexities which coexisted. The pathophysiology of the unconscious state necessarily depends on the inciting factors. Ketoacidotic coma is associated with depressed cerebral oxygen consumption. Spinal fluid pH is usually maintained during ketosis but is sometimes lowered inadvertently during bicarbonate therapy, with resultant coma. Other variables influencing the clinical expression, with or without ketosis, would include, among others, blood viscosity alterations, rapid decrements in blood sugar, and existing degrees of lactic acidosis.The increasing life-span of the juvenile diabetics, favorably influenced by improved management and recently by hemodialysis, may uncover vascular complications heretofore rarely seen and create additional diagnostic and therapeutic enigmas.     

The possible role of the gut neuroendocrine system in diabetes gastroenteropathy

Gastrointestinal symptoms such as nausea and vomiting, heartburn, abdominal pain, diarrhoea, constipation and faecal incontinence are common in patients with diabetes. Diabetes gastroenteropathy is a clinically relevant problem. In addition to the increased morbidity it causes, it results in severely impaired metabolic control, which in turn increases the risk of hyper-/hypoglycaemia. Moreover, the poorly controlled blood glucose level increases the risk of secondary diabetes complications, namely, retinopathy, nephropathy, neuropathy and cardiovascular affection. Gastrointestinal symptoms may also cause malnutrition in patients with diabetes, which, together with the disturbed immune defence in diabetes, may cause intercurrent infections. Gastrointestinal symptoms in patients with diabetes are attributed to disturbed gastrointestinal motility. Gastrointestinal dysmotility in diabetes is believed to be caused by autonomic neuropathy and/or hyperglycaemia. The neuroendocrine system of the gut secretes peptides/amines that play an important role in regulating gastrointestinal motility. It is conceivable, therefore, to assume that a disturbance in this regulatory system may contribute to the pathogenesis of gastrointestinal complications in diabetes. The present review gives an updated overview of the abnormalities in the gastrointestinal neuroendocrine system in diabetes, speculates upon the possible role of these abnormalities in the pathogenesis of diabetes gastroenteropathy and, finally, predicts the possible clinical implications of these findings.     

Plasma amino acid levels in hyperosmolar nonketotic diabetic coma

The plasma amino acid levels in five patients with hyperosmolar nonketotic diabetic coma and in seven normal subjects were analysed. In the patients with hyperosmolar nonketotic diabetic coma, total amino acids were generally low, especially, the concentrations and the molar ratios of arginine, taurine and serine were significantly low, and ornithine decreased only at the concentration. The level of phenylalanine increased both at the concentration and the molar ratio, and tyrosine did only at the molar ratio. The significance of such changes in the plasma is discussed in relation to diabetic ketoacidosis or lactic acidosis.     

Venous Serum Bicarbonate Concentration Predicts Arterial pH in Adults with Diabetic Ketoacidosis

ObjectiveThe initial assessment of metabolic acidosis in subjects with diabetic ketoacidosis (DKA) is arterial blood gas analysis. This process is expensive, painful, and technically difficult. Furthermore, blood gas analysis may not be available in some facilities, especially in developing countries where DKA-associated morbidity and mortality remain high. Therefore, we investigated the utility of venous bicarbonate concentration obtained from a basic metabolic panel in predicting arterial pH in adults with DKA.MethodsWe performed a retrospective analysis of clinical and biochemical data of 396 adults admitted to 2 community teaching hospitals with DKA. We determined the correlation between arterial pH and venous serum parameters. Using multiple logistic regression, we obtained a predictive formula for arterial pH from serum venous bicarbonate level.ResultsThe patient population was 59.0% male and had a mean age of 36.7 ± 13.3 years. We derived that arterial pH = 6.97 + (0.0163 × bicarbonate), and by applying this equation, we determined that serum venous bicarbonate concentration of ≤ 20.6 mEq/L predicted arterial pH ≤ 7.3 with over 95% sensitivity and 92% accuracy.ConclusionVenous serum bicarbonate obtained from the basic metabolic panel is an affordable and reliable way of estimating arterial pH in adults with DKA. Validation of this formula in a prospective study would offer a more accessible means of estimating metabolic acidosis in adults with DKA, especially in developing countries where DKA incidence and mortality remain high. (Endocr Pract. 2014;20:201-206)     

Effect of metabolic alkalosis on respiratory function in patients with chronic obstructive lung disease.

Eleven instances of a mixed acid-base disorder consisting of chronic respiratory acidosis and metabolic alkalosis were recognized in eight patients with chronic obstructive lung disease and carbon dioxide retention. Correction of the metabolic alkalosis led to substantial improvement in blood gas values and clinical symptoms. Patients with mixed chronic respiratory acidosis and metabolic alkalosis constitute a common subgroup of patients with chronic obstructive lung disease and carbon dioxide retention; these patients benefit from correction of the metabolic alkalosis.