MODY 2 causado por mutaciones en la glucoquinasa: una aproximación a nivel molecular / MODY 2 caused by glucokinase mutations: a molecular approach

La diabetes MODY 2 es un tipo de diabetes monogénica producida por una mutación en la enzima glucoquinasa, generando un fenotipo hiperglicémico. Para posibles fines terapéuticos o de diagnóstico, se debe conocer esta proteína, una enzima monomérica de la familia de las hexoquinasas, encargadas de convertir glucosa en glucosa-6-fosfato, el primer paso de la glicolisis. La glucoquinasa se caracteriza por sus propiedades cinéticas únicas: tiene una afinidad mucho menor por el sustrato que las demás hexoquinasas y no es inhibida por su producto. Se encuentra principalmente en páncreas e hígado (ßGK y LGK, respectivamente), donde como sensor regula los distintos estados metabólicos de estos tejidos, y controla la glicemia a nivel sistémico. Las formas ßGK y LGK se diferencian a nivel transcripcional, pues el gen posee dos promotores distintos, específicos para cada tejido. A nivel hormonal, la actividad de esta enzima es regulada selectivamente de manera tejido-específica por glucosa, insulina y otras proteínas reguladoras. La isoforma hepática puede ser secuestrada hacia el núcleo por la proteína reguladora de glucoquinasa (GKRP, por su sigla en inglés). La principal característica de la enzima glucoquinasa es su inusual regulación alostérica, propiedad que le permite adoptar dos conformaciones principales, una cerrada (activa) y otra súper-abierta (inactiva). Se han desarrollado distintas drogas activadoras de glucoquinasa, las cuales se unen al sitio alostérico de la enzima y estabilizan a la proteína en su estado cerrado. En esta revisión se describen las características estructurales y propiedades regulatorias que posee la enzima glucoquinasa, relacionándolas con su rol en el desarrollo de la diabetes MODY 2. También se profundiza en las implicancias moleculares de algunas mutaciones descritas que originan MODY 2, y se abordan los efectos de moléculas activadoras de glucoquinasa.

Diabetes MODY 2 or GCK-MODY is a type of monogenic diabetes produced by a mutation in the glucokinase enzyme, generating a hyperglycemic phenotype. This protein, a monomeric enzyme of the hexokinase family, is responsible for converting glucose into glucose-6-phosphate, the first step of glycolysis. Glucokinase is characterized by its unique kinetic properties: it has a much lower affinity for its substrate than other hexokinases and is not inhibited by its product. It is found mainly in pancreas (ßGK) and liver (LGK), where it acts as a sensor regulating the different metabolic states of these tissues, and ultimately, controlling systemic glycemia. The two forms ßGK and LGK differ at a transcriptional level, because the gene presents two different tissue-specific promoters. The activity of glucokinase in liver and pancreas is regulated by glucose, insulin and other regulatory proteins. The liver isoform can be sequestered to the nucleus by the glucokinase regulatory protein (GKRP). The main characteristic of the enzyme is its unusual allosteric regulation, a property that allows the protein to adopt a closed (active) conformation, and a super-open (inactive) conformation. Different glucokinase activating drugs have been developed, which bind to the allosteric site of the enzyme and stabilize glucokinase in its closed state. This review describes the structural and regulatory properties of the glucokinase enzyme, and its role in the development of MODY 2 diabetes. The molecular implications of some mutations that originate MODY 2 are also described, and the effects of glucokinase activating molecules are addressed.

Cetoacidosis normoglicémica en paciente embarazada con neumonía por COVID-19. Reporte de un caso clínico / Euglycaemic ketoacidosis in a pregnant woman with COVID-19 pneumonia. A case report

RESUMEN Introducción: La cetoacidosis en el embarazo es una emergencia médica que requiere tratamiento en Unidad de Cuidados Intensivos debido a su asociación con morbimortalidad maternofetal. Las gestantes pueden presentar una forma atípica del cuadro llamada cetoacidosis normoglicémica, siendo muy infrecuente en pacientes sin antecedente de diabetes. Caso Clínico: Se presenta una gestante cursando tercer trimestre de embarazo, sin antecedente de diabetes, ingresada en Unidad de Paciente Crítico debido a neumonía por COVID-19 y acidosis metabólica con anión gap aumentado. Se realizó diagnóstico de cetoacidosis normoglicémica posterior al ingreso, iniciándose tratamiento intensivo de trastorno ácido-base con buena evolución. Conclusión: La infección por SARS-CoV-2 puede causar cetoacidosis normoglicémicas en embarazadas no diabéticas; se requiere una alta sospecha clínica para realizar el diagnóstico y tratamiento oportuno.

ABSTRACT Introduction: Ketoacidosis in pregnancy is a medical emergency that requires treatment in an intensive care unit due to its association with maternal-fetal morbimortality. Pregnant women may present an atypical form of the condition called normoglycemic ketoacidosis, being very rare in patients with no history of diabetes. Clinical Case: We present a pregnant woman in the third trimester of pregnancy, without history of diabetes, admitted to a critical patient unit due to COVID-19 pneumonia and metabolic acidosis with an increased anion gap. A diagnosis of normoglycemic ketoacidosis was made after admission, and intensive treatment of acid-base disorder was initiated, with good evolution. Conclusion: SARS-CoV-2 infection can cause normoglycemic ketoacidosis in non-diabetic pregnant women; is required a high clinical suspicion to make the diagnosis and appropriate treatment.

Diabetes mellitus asociada a pancreatitis autoinmune: caso clínico / Autoimmune pancreatitis associated with diabetes mellitus: report of one case

Autoimmune pancreatitis is uncommon, responds to steroids and is usually associated with diabetes mellitus. We report a 73 year-old male who, two months after a diagnosis of diabetes mellitus, presented with obstructive jaundice and weight loss. Abdominal magnetic resonance imaging was suggestive of an autoimmune pancreatitis and serum IgG4 was 339 mg/dl (normal range 3-201). The patient was treated with prednisone 40 mg/day with a good clinical and laboratory response. During outpatient care, the dose of prednisone was tapered.

Hallazgo de una nueva mutación en una familia chilena con diabetes monogénica: caso clínico / Finding of a new mutation in a Chilean family with monogenic diabetes: report of one case

We report a 21 years old woman, without offspring, with diabetes mellitus diagnosed at 17 years of age, without ketosis or weight loss. Her body mass index was 18 kg/m2. Her C peptide was normal (2.3 ng/ml) and diabetes mellitus type 1 autoantibodies were negative. A monogenic diabetes Maturity Onset Diabetes of the Young (MODY) was proposed. Her family study disclosed a diabetic father and a brother with altered fasting glucose levels. The University of Exeter score for MODY yielded a 75.5% probability of MODY2. In the genetic-molecular study of the glucokinase gene (MODY2), the patient had a mutation at position 1343 of exon 10, corresponding to a heterozygous substitution of guanine by adenine (1343 G >A). The same mutation was found in her father and brother. This mutation is different from those previously described in the literature. The described change determines that a glycine is replaced by aspartic at amino acid 448 of the enzyme (non-synonymous substitution). The diagnosis of MODY2 was therefore confirmed in the patient and her father. The mutation was inherited by paternal line.

Programa de transición: una intervención para adolescentes con diabetes tipo 1: estudio de casos y controles / Transition program: an intervention for adolescents with type 1 diabetes: cases and controls study

Introduction: The transition programs (TP) are planned interventions with specific aims which support type 1 diabetes adolescents in their process to emigrate from a pediatric care system to an adult care system. Objective: To evaluate the effectiveness of a TP in type 1 diabetes adolescents. Subjects and Method: This study was performed in 20 adolescents: 10 in TP and 10 controls (no TP) attended in an adult care system in a traditional way. The applied program included: coordination of attention dates, administrative supervision of the cases, and integral health team attention: physician every three months, psychologist with psychosocial follow-up every three months, nutricionist and university nurse according to the case necessities. After a year of the TP implementation the indicators of adherence were evaluated: continuity of care, regular medical appointments, physician/adolescent relationship, psychosocial follow-up, and to maintain or improve the HbA1c. The statistical analysis of variables comparison was performed with Kwallis Test o Mann-Whitney Test, in STATA 12.0 program. Results: At comparing groups, it was found that the intervened adolescents presented a major frequency of: continuity of diabetes care, regular medical appointments, physician/adolescent relationship and psychosocial follow-up (p < 0,01); the indicator of maintaining or improving the HbA1c was better in the patients with TP (60 percent vs 30 percent) yet not significant. Conclusion: In type 1 diabetes adolescents, with the applied TP we get better indicators of adherence to the diabetes treatment

Experiencia con insulina degludec en pacientes diabéticos Tipo 1 del Hospital San Juan de Dios Santiago / Experience with degludec insulin in Type 1 diabetic patients at the San Juan de Dios Hospital

OBJECTIVE: To study the efficacy and safety of degludec insulin in Type 1 diabetic patients. PATIENTS AND METHOD: In a prospective study, 230 type 1 diabetics patients, average aged 34 years age and 14 years of diagnosis of diabetes and treated with two doses of insulin glargine U-100, were changed to degludec. Patients had glycosylated hemoglobins (HbA1c) greater than 10 percent. Results were recorded at 3 and 6 months with parameters clinical, biochemical, insulin requirements per kilogram of weight (U/kg/wt) and hypoglycemia. Capillary glycemia was evaluated three times a day and the dose of insulin degludec every two weeks. The statistical analysis used was average and rank, standard deviation, normal Swilk test, categorical Chi2 and continuous ANOVA or Kwallis, and p < 0.05. A psychological survey was conducted to evaluate satisfaction with the new treatment. RESULTS: Fasting blood glucose decreased from 253 (range 243-270) at 180 mg/dl (172-240) at 3 months and at 156 (137-180) at 6 months after the change insulin (p < 0.05). HbA1c, initially 10.6 percent (10.4-12.2) decreased to 8.7 percent (9.3-10.1) and 8.3 percent (8.7-9.7) at 3 and 6 months, respectively (p < 0.05). There was a decrease in basal insulin requirements from 0.7 to 0.4 U/kg/60 percent reduction in hypoglycaemia; both mild and moderate and severe. Isolated nocturnal hypoglycaemias were recorded in only 4 patients in this group. CONCLUSION: Six months of treatment with degludec insulin reduces fasting blood glucose, glycosylated hemoglobin and hypoglycemia, both mild and moderate severe and nocturnal, which makes this new ultra-long acting basal insulin a safe and effective tool for the management of type 1 diabetics patients

Cetoacidosis diabética normoglicémica en el embarazo: caso clínico / Normoglycemic diabetic ketoacidosis in pregnancy: report of one case

Normoglycemic diabetic ketoacidosis should be suspected in pregnant women presenting nausea, vomiting, abdominal pain and anorexia. We report a 39 years old woman with a 32 weeks pregnancy who sought emergency care due to hyperemesis. She was hospitalized with the following diagnoses: pregnancy hypertension syndrome, gestational diabetes, morbid obesity and poor prenatal control. The evaluation of the feto-placental unit showed perception of fetal movements, non-reactive non-stress baseline record and a biophysical profile of 6/8. Fetal maturation was initiated. Laboratory tests showed a metabolic acidosis, a low pH, an increased Gap anion, elevated ketonemia and a blood glucose of 172 mg/dl. A diagnosis of normoglycemic diabetic ketoacidosis was formulated and treatment with hydration and regular insulin according to capillary blood glucose levels was started. An emergency caesarean section was performed. The newborn weighed 2.650 kg, had a length of 46 cm, was large for gestational age, had an Apgar score of 2.7, had perinatal asphyxia, convulsive syndrome and a possible congenital cardiopathy. Once the ketoacidosis was resolved during the immediate puerperium, slow acting insulin was initiated.

Disfunción sexual en la mujer diabética pre y postmenopáusica / Sexual dysfunction in women with diabetes in pre and postmenopausic state

Objective: female sexual dysfunction (FSD) in diabetic women, is a topic poorly studied. The aim of this study is to determine the prevalence of FSD in typ1 1 and typ2 diabetic patients (T1D and T2D) compared with non diabetic controls. Patients and Method: interview under written consent 24 diabetic patients attended at Diabetes Unit of the San Juan de Dios Hospital and 24 healthy controls. Inclusion criteria: diagnosis of diabetes mellitus over one year, age 18-75 years old and stable partner for over a year. Exclusion criteria: antidepressants treatment. The validated survey by Rosen et al. was applied. Female Sexual Function Index (FSFI), of 19 questions that assess 6 areas of sexual function: desire, lubrication, excitement, orgasm, satisfaction and pain. A total score of 26.55 or less diagnosed DSF. In diabetic patients the metabolic control, lipid profile, creatinine and glycated hemoglobin A1c (HbA1c) was recorded. Statistical analysis was performed using median, range and Mann Whitney test. Percentages of sexual dysfunction was analysed by chi². It was considered significant at p < 0.05. Results: the results of the FSFI survey were divided and related to menopause. In premenopausal diabetic group (n = 11), the average score was 31.1 versus 32.5 in controls (NS) and in postmenopausal diabetic group (n = 13) the average score was 23,1 versus 28,5 (p = 0.05). The overall frequency of DSF in premenopausal diabetic women was 27.3 percent and 6.3 percent in controls (NS), in postmenopausal reached 69.2 percent and25.0 percent in controls (p = 0.01 ). Conclusion: in diabetic patients sexual dysfunction was more frequent than in controls; in premenopausal women the most affected area is the excitement and in postmenopausal women was lubrication.

Diabetes Mellitus tipo 2 con tendencia a la cetosis: Caso clínico / Ketosis prone type 2 diabetes (KPD)

Ketosis prone type 2 diabetes (KPD) is presently a well-defined clinical entity, characterized by a debut with severe hyperglycemia and ketoacidosis similar to the presenting form of Type 1 diabetes mellitus (DM1). However, it appears in subjects with Type 2 diabetes mellitus (DM2) phenotype. This situation is caused by an acute, reversible dysfunction of the beta cell in individuals with insulin resistance. Once the acute stage subsides, patients behave as having a DM2 and do not require insulin treatment. They should be kept on a diet and oral hypoglycemic drugs due to their susceptibility to have recurrent acute ketotic decompensations.

Metformina asociada a insulinoterapia en pacientes diabéticos tipo 1 / Metformin associated with insulin therapy in type 1 diabetic patients

In patients with diabetes type 1 (T1D) glycemic control remains suboptimal, despite the availability of new insulin analogues and continuous infusion systems. Metformin may be a complementary therapy regarding to intensified insulin therapy since a significant percentage of T1D have insulin resistance (IR). Objective: To analyze the clinical, anthropometric and metabolic effects of the combination of metformin to insulin therapy in T1D patients. Subjects and Method: 34 T1D patients, 15 men and 19 women, mean age 41 years (range 20-64) metformin 850 mg / day was associated for 6 months (group 1) and retrospectively evaluated 18 T1D, 9 men and 9 women, age average 34 years (range 17-58), who received metformin for 36 months (group 2). It was recorded before and after treatment with metformin: nutritional status, waist circumference, index waist / hip, glucose fasting, glycosylated hemoglobin (HbA1c), HDL cholesterol, triglycerides, systolic and diastolic blood pressure (BP), glucose uptake (UG) and insulin dose (U/kg). Statistical analyses. Clinical and biochemical parameters were expressed as median, range or percentage (percent). For the statistical significance were used chi2and Fisher exact and Mann Whitney test; and was established as significant at p <0.05. Results: In group 1 significantly decreased waist circumference in men and women and improved fasting glucose, HbA1c, systolic blood pressure and triglycerides. In group 2, waist circumference and systolic blood pressure was also reduced. Conclusion: In T1D patients with clinical signs of IR the association of metformin to insulin therapy may be useful.

Alteraciones hematológicas en la diabetes mellitus / Blood disorders in diabetes mellitus

Although it has been treated in a limited way the relationship between diabetes and hematopoietic system, there is evidence demonstrating thedeleterious effect of hyperglycemia on the three cell lines: red blood cells, white cells and platelets. Different forms of anemia associated with hyperglycemia are analyzed and erythrocyte alterations observed in diabetes. In chronic decompensated patients have been demonstrated alterationsof monocytes, lymphocytes and polymorphonuclear particularly, with decreased chemotaxis, adherence, phagocytosis and opsonization. Hyperglycemia determines a prothrombotic state by platelet hyperreactivity, which is a marker of inflammation...

Diabéticos tipo 1 portadores de síndrome metabólico: cuantificación de la resistencia a la insulina / Type 1 diabetics patients carriers of metabolic syndrome: quantification of insulin resistance

The presence of insulin resistance (IR) has been indirectly assessed in Type 1 Diabetics (T1DM) through the detection of Metabolic Syndrome (MS), by applying criteria for Type 2 Diabetics(T2DM). In the EDC study (the Pittsburg Epidemiology of Diabetes Complications) a formula applicable to T1DM was validated, quantifying IR through the glucose uptake (GU) employing the usual clinical and laboratory parameters, in patients with HbA1c < 11.4 percent. Objectives: To determine in T1DM whether there exists a relationship between the presence of MS according to the Modified NCEP/ATPIII criteria and IR quantification through assessment of the glucose uptake or GU. Patients and Method: The modified NCEP/ATPIII criteria were applied to 150 T1DM patients, and those with more than 3 altered parameters were classified as MS carriers. IR was quantified through the glucose uptake (GU), applying the formula for Estimated Glucose Disposal Rate (GDR-EDC). Results: 26.6 percent of the T1DM (40 patients) complied with the modified NCEP/ATPIII criteria. When the formula for GU was applied (31 patient), 90.3 percent of the T1DM showed insulin resistance (GU value < 8.77). And when applied to 124 patients (T1DM with and without MS and HbA1c < 11,4 percent) 75 percent showed IR...

Estudio del control metabólico en pacientes diabéticos en hemodiálisis crónica: hemoglobina glicosilada, fructosamina y glicemias capilares / Study of metabolic control in diabetic patients on chronic hemodialysis: glycated hemoglobin, fructosamine and capillary glycemia

Background: In conditions that may change red blood cell survival, such as hemodialysis, the accuracy of A1c glycosylated hemoglobin (HbA1c) to assess metabolic control can be hampered. Other glycosylated proteins such as fructosamine, could accomplish the role of HbA1c. Aim: To assess if HbA1c is a good metabolic control parameter in diabetic patients on chronic hemodialysis. To compare fructosamine, HbA1c and serial capillary glucose levels in the same patients. Material and Methods: Patients on hemodialysis three times per week were studied. Twenty one subjects with diabetes mellitus and 10 non-diabetic patients were included (70 percent were male). During a period of 14 days, fasting and post prandial capillary glucose levels were measured. Venous glucose, HbA1c and fructosamine were measured at the onset and completion of the monitoring period. Results: Diabetic patients were older than their non-diabetic counterparts (65 and 47 years respectively, p < 0.04). In diabetic and non-diabetic patients respectively, capillary blood glucose levels were 161 +/- 22 and 104 +/- 51 mg/dl, HbA1c levels were 6.8 +/- 1.2 and 5.4 +/- 0.4 percent and fructosamine levels were 282.0 +/- 126.6 and 154.6 +/- 73 umol/L. In all patients there was a positive correlation between blood glucose, HbA1c (r = 0.78 p < 0.01) and fructosamine (r = 0.52, p 0.02). There was a positive correlation between mean capillary glucose, HbA1c (r = 0.77, p < 0.01) and fructosamine (r = 0.69, p < 0.02). Among diabetic patients, the correlation coefficients between mean capillary glucose levels, HbA1c and fructosamine levels were 0.67 (p < 0.01) and 0.51 (NS), respectively. Conclusions: Among diabetic patients on hemodialysis fructosamine levels are not a better indicator of metabolic control than HbA1c.

Hemoglobina glicosilada A1c como criterio diagnóstico de diabetes y pre-diabetes / Glycosylated hemoglobin as a diagnostic criterion for diabetes and pre diabetes

The clinical usefulness of A1c glycosylated hemoglobin (A1c), in the metabolic control of diabetic patients is well known and the goal is to achieve values below 7 percent to prevent the appearance of microangiopathic complications. Standardized measurement methods are required to obtain trustful values. The proposal of the American Diabetes Association to accept A1c as a diagnostic criterion for diabetes and as a means to identify subjects at risk of developing the disease is currently being discussed. The establishment of universal cutoff points has been hindered by the fact that factors such as ethnic influence on glycosylation may modify values of A1c. The use of A1c as an alternative to blood glucose measured during fasting ad after a 75 g glucose load, will not be possible without standardizing measurement methods and performing studies to validate it as a diagnostic method in different populations, including Chileans.

Microalbuminuria como elemento de predicción de nefropatía y riesgo cardiovascular en pacientes diabéticos / Microalbuminuria as predictor of nephropathy and cardiovascular risk factor among diabetic patients

Microalbuminuria, defined as urinary excretion of albumin in the range of 30-300 mg/g creatinine, affects 20-30 percent of the type 2 diabetic (DM2) patients and 30-40 percent of type 1 diabetic (DM1) patients who, without intervention, progress to macroalbuminuria at rates of 5 and 7.5 percent per year, respectively. Hyperglycemia, by activating different metabolic pathways and the renin-angiotensin-aldosterone system, determines an increase in reactive oxygen species (ROS) which finally causes endothelial dysfunction. Albuminuria reflects a generalized endothelial dysfunction, that is related to cardiovascular disease in diabetic patients. Therefore, microalbuminuria becomes a predictor of renal damage, a coronary risk factor and a predictor of cardiovascular diseases. Several studies have demonstrated that progression of albuminuria can be prevented in normotensive and hypertensive DM1 and DM2 patients with the use of an inhibitor of angiotensin converting enzyme II or an antagonist of the angiotensin II receptor. These measures also provide cardiovascular protection in diabetic patients, an effect that is independent of the hypotensive action of the drug. In microalbuminuric diabetic patients, treatment should be oriented to diminish or avoid progression of microalbuminuria, and to maintain blood pressure, glucose and lipids within the recommended limits to avoid vascular and renal damage.

Cistatina C y adiponectina en pacientes diabéticos tipo 2 coronarios y no coronarios / Cystatin C and adiponectin in diabetics with and without coronary artery disease

Background: Patients with type 2 diabetes have a high incidence of coronary artery disease, which is even higher among those with renal failure. A serum level of cystatin C are used to assess renal function and is a potential cardiovascular risk factor. Adiponectin is an anti-atherogenic factor. Aim: To measure cystatin C and adiponectin in type 2 diabetic patients with and without coronary artery disease. Material and methods: Nine diabetic patients with coronary artery disease aged 76± 10 years, 20 diabetics without coronary artery disease aged 61 ±5 years and 20 non diabetic subjects aged 57±10 years, were studied. Results: Serum levels of cystatin C (mg/L) were 1.5 (range 0.89-219), 0.81 (range 0.71-1.08) and 0.68 mg/L (range 055-0.75) in diabetics with and without coronary artery disease and controls, respectively (p <0.0001). No differences in adiponectin between groups and no association between cystatin C and adiponectin, were observed. No association between both parameters and body mass index orglycosilated hemoglobin Ale was observed. Cystatin C had a positive correlation with serum creatinine (r =0.57p <0.001). Conclusions: Diabetics with coronary artery disease have higher levels of cystatin C, that are closely correlated with serum creatinine levels.

Nuevas perspectivas en la genética de la diabetes mellitus tipo 2 y sus complicaciones crónicas / New perspectives in the genetics of diabetes mellitus and its complications

This review describes the advances in the knowledge about the genetic aspects of common chronic complications of diabetes with prognostic significance, such as diabetic nephropathy and cardiovascular diseases. It is well known that the genetic factors responsible for chronic complications are different from those that cause diabetes mellitus. Until recently, the studies were limited to the analysis of individual genes associated or related to multifactorial diseases. However at the present time the "genome wide association studies" lead to a great advance in knowledge. The analysis of genetic variations or polymorphisms allows the understanding of human individuality and the predisposition towards certain diseases. A new research field appeared in 2004, when small messenger RNAs, called microRNA related to diabetes mellitus and its chronic complications, were identified. The function of these RNAs is to regulate several target genes. These affect insulin secretion and action and genes related to microangiopathic and specific macroangiopahic complications. This new knowledge will identify new genes related to the disease and will allow the development of therapeutic strategies devised according to individual susceptibility towards specific chronic complication.

Gluco-lipotoxicidad y sus implicancias en la diabetes mellitus tipo 2 / Glycolipotoxicity and it implications in diabetes mellitus type 2

Se entiende por glucotoxicidad a los daños estructurales y funcionales debidos a la hiperglicemia crónica, que se producen en la célula beta y en los tejidos periféricos donde actúa la insulina; alteraciones que se traducen en una menor secreción y acción de la hormona (insulinorresistencia). La lipotoxicidad se relacionea con daños similares a consecuencia de altos niveles de ácidos grasos libres(AGL), productos del catabolismo de los triglicéridos. Debido a que la elevación permanente de la glucosa y de los AGL interactúan y tiene los mismos efectos deletéreos, se ha acuñado el término de gluco-lipotoxicidad, cuya importancia radica en que sería uno de los factores implicados en la patogénesis de la diabetes tipo 2(DM 2) y en la evolución de ésta al fracaso secundario a las drogas hipoglicemiantes orales. En la actualidad se acepta que la DM 2 se desarrolla en etapas: resistencia a la insulina con normoglicemia, intolerancia a la glucosa y diabetes clínica. Dado que los dos primeros períodos son reversibles, y que el déficit de secreción insulínica es parte de la historia natural de la DM 2, el controlar las glicemias elevadas y la lipólisis exagerada(gluco-lipotoxicidad), permitiría revertir o enlentecer estos procesos