Olfactory dysfunction in patients with type 2 diabetes mellitus.

BACKGROUND: diabetic complications and olfactory dysfunction (OD) in patients with type 2 diabetes mellitus (T2DM) seem related. This study aims to evaluate the prevalence of OD in T2DM patients and to analyze its relationship with diabetic complications. METHODS: 130 T2DM patients and 100 comparable controls were enrolled. Olfaction was evaluated using the Extended Smell Test (TDI) and the Italian brief Questionnaire of Olfactory Disorders - Brief-IT-QOD. T2DM patients were divided into: "Group 1", patients with no complications, and "Group 2", patients with at least one diabetic complication. Non-parametric tests were used. Machine learning algorithms were applied to explore which variables were most important in predicting the presence of OD in T2DM. RESULTS: The prevalence of OD was significantly higher in Group 2 than in controls (71.4% vs 30%) and in Group 1 (71.4% vs 43.3%). However, when comparing the TDI scores between Group 1 and 2 the only significant difference was found for the discrimination scale and not for the identification and threshold scales. Brief-IT-QOD scores were significantly higher in Group 2 than in controls. The Random Forest and variable importance algorithms highlighted the relevance of LDL, glycated hemoglobin, type of complication (macrovascular) and age in determining OD in T2DM. The last three variables were included in a nomogram for the prediction of OD risk in T2DM. CONCLUSIONS: T2DM patients with diabetic complications are more frequently affected by OD. Poor glycemic control, LDL values, age and presence of macrovascular complications are the more important factors in determining OD in T2DM patients.

L-Carnitine counteracts in vitro fructose-induced hepatic steatosis through targeting oxidative stress markers.

PURPOSE: Nonalcoholic fatty liver disease (NAFLD) is defined by excessive lipid accumulation in the liver and involves an ample spectrum of liver diseases, ranging from simple uncomplicated steatosis to cirrhosis and hepatocellular carcinoma. Accumulating evidence demonstrates that high fructose intake enhances NAFLD development and progression promoting inhibition of mitochondrial ß-oxidation of long-chain fatty acids and oxidative damages. L-Carnitine (LC), involved in ß-oxidation, has been used to reduce obesity caused by high-fat diet, which is beneficial to ameliorating fatty liver diseases. Moreover, in the recent years, various studies have established LC anti-oxidative proprieties. The objective of this study was to elucidate primarily the underlying anti-oxidative mechanisms of LC in an in vitro model of fructose-induced liver steatosis. METHODS: Human hepatoma HepG2 cells were maintained in medium supplemented with LC (5 mM LC) with or without 5 mM fructose (F) for 48 h and 72 h. In control cells, LC or F was not added to medium. Fat deposition, anti-oxidative, and mitochondrial homeostasis were investigated. RESULTS: LC supplementation decreased the intracellular lipid deposition enhancing AMPK activation. However, compound C (AMPK inhibitor-10 µM), significantly abolished LC benefits in F condition. Moreover, LC, increasing PGC1 α expression, ameliorates mitochondrial damage-F induced. Above all, LC reduced ROS production and simultaneously increased protein content of antioxidant factors, SOD2 and Nrf2. CONCLUSION: Our data seemed to show that LC attenuate fructose-mediated lipid accumulation through AMPK activation. Moreover, LC counteracts mitochondrial damages and reactive oxygen species production restoring antioxidant cellular machine. These findings provide new insights into LC role as an AMPK activator and anti-oxidative molecule in NAFLD.

Transmucosal oxygen tension of the clitoris: a new parameter for future investigations of the sexual, metabolic, and cardiovascular health of women.

BACKGROUND: Several studies suggested that abnormalities in tissue perfusion of external genitalia and vagina can lead to female sexual dysfunctions (FSDs) and can be associated to metabolic and cardiovascular risk factors. However, there are some technical difficulties in assessing these abnormalities. The measurement of oxygen partial pressure is a noninvasive method to measure oxygen partial pressure (pO2) at the skin surface to assess tissue perfusion. The aim of this study was to evaluate whether transmucosal oxygen tension (TmPO2) can be measured at the mucosal surface of clitoris and whether the measurements are reliable. METHODS: TmPO2 was measured in six young healthy women by using a device to measure transcutaneous pO2 on the skin and by choosing a small sensor, usually used for newborns. The identical procedure for the detection of pO2 at the skin surface was used. RESULTS: The mean value of TmPO2 was 42.3 mmHg (range: 24.1-53.4 mmHg). All the trend curves of the TmPO2 showed the same behavior: after a stabilization time, there was a stable pO2 (plateau phase) that corresponds to the TmPO2 of the clitoris. These curves had a similar trend to those recorded at the skin surface. CONCLUSIONS: TmPO2 can be easily measured at the mucosal surface of clitoris. Large epidemiological studies in healthy and unhealthy women and in women with FSD are needed to establish both the normal range of TmPO2 and the meaning that different values of TmPO2 can have on sexual and general health of the women.

Hungry brains: A meta-analytical review of brain activation imaging studies on food perception and appetite in obese individuals.

The dysregulation of food intake in chronic obesity has been explained by different theories. To assess their explanatory power, we meta-analyzed 22 brain-activation imaging studies. We found that obese individuals exhibit hyper-responsivity of the brain regions involved in taste and reward for food-related stimuli. Consistent with a Reward Surfeit Hypothesis, obese individuals exhibit a ventral striatum hyper-responsivity in response to pure tastes, particularly when fasting. Furthermore, we found that obese subjects display more frequent ventral striatal activation for visual food cues when satiated: this continued processing within the reward system, together with the aforementioned evidence, is compatible with the Incentive Sensitization Theory. On the other hand, we did not find univocal evidence in favor of a Reward Deficit Hypothesis nor for a systematic deficit of inhibitory cognitive control. We conclude that the available brain activation data on the dysregulated food intake and food-related behavior in chronic obesity can be best framed within an Incentive Sensitization Theory. Implications of these findings for a brain-based therapy of obesity are briefly discussed.

Ultrasound characterization of insulin induced lipohypertrophy in type 1 diabetes mellitus.

OBJECTIVE: Subcutaneous insulin absorption is one of the key factors affecting glycemic control in patients with diabetes mellitus under insulin therapy. Insulin-induced subcutaneous lipohypertrophy has been reported to impair insulin regular absorption and hence glycemic control. So far, lipohypertrophy diagnosis has only been clinical. This study aims at evaluating the possible role of ultrasound scan in the assessment of subcutaneous lipohypertrophy in patients affected by type 1 diabetes mellitus. METHODS: A pilot observational retrospective study was performed in 20 patients affected by type 1 diabetes mellitus. In these patients the areas with clinical evidence of lipohypertrophy dependent on the insulin injections were characterized by the presence of tissues that at the ultrasound scan resulted similar to fibrotic tissues (hyperechogenic) or to an interstitial edema or to fat tissues (hypoechogenic). It was utilized a multi frequency linear probe (6-18 MHz). The patients were advised to avoid insulin injections on the areas with lipohypertrophy scanned by the ultrasound and the HbA1c changes were evaluated 3 months later. RESULTS: The lipohypertrophic areas presented at least three different aspects upon ultrasound assessment: the iso-hyperechogenic one, with a predominant fibrotic component; the isoechogenic one, with "large tangles" fibrotic elements and the iso-hypoechogenic aspect with no fibrotic elements. When patients were advised to avoid insulin injections on areas with lipohypertrophy defined by ultrasound scan, 3 months after the first evaluation HbA1c had significantly improved (basal HbA1c 7.87 ± 0.56 versus 7.67 ± 0.52 3 months later, p = 0.029). No significant improvements of the HbA1c were found in the control matched group in which lipohypertrophy was only clinically valued through inspection and palpation. CONCLUSIONS: Ultrasound scan can help identify and characterize the lipohypertrophic areas and this might be useful to improve glycemic control.

Active Subjects With Autoimmune Type 1 Diabetes Have Better Metabolic Profiles Than Sedentary Controls.

Previous studies in humans with type 1 diabetes mellitus (T1D) and in nonobese diabetic mice have investigated the beneficial immunomodulatory potential of aerobic physical activity. Performing high volume of aerobic exercise may favorably regulate autoimmunity in diabetes. We tested whether increased physical activity is a self-sufficient positive factor in T1D subjects. During a 3-month observational period, active (six males; 40.5 ± 6.1 years; BMI: 24.5 ± 2.1) and sedentary (four males, three females; 35.9 ± 8.9 years; BMI: 25.7 ± 3.8) T1D individuals on insulin pump therapy were studied for metabolic, inflammatory, and autoimmune parameters. At baseline and at the end of a 3-month period, glycosylated hemoglobin (HbA1c), autoantibodies (anti-GAD, anti-ZnT8, anti-IA2, and ICA) and proinflammatory cytokines (IL-6 and TNF-α) were evaluated. During the third month of the period, physically active T1D patients showed a significant reduction in the average glucose levels (-9%, p = 0.025, by CGM) compared to the first month values, and even their hyperglycemic episodes (>180 mg/dl) diminished significantly (-24.2%, p = 0.032 vs. first month). Moreover, active T1D subjects exhibited an improved body composition with respect to sedentary controls. No significant changes were detected as to the autoimmune and inflammatory profiles. This study confirms the beneficial role of physical exercise associated with insulin pump therapy in order to improve metabolic control in individuals with T1D. These preliminary positive observations need to be challenged in a prolonged interventional follow-up.

PML-RARA-associated cooperating mutations belong to a transcriptional network that is deregulated in myeloid leukemias.

It has been shown that individual acute myeloid leukemia (AML) patients are characterized by one of few initiating DNA mutations and 5-10 cooperating mutations not yet defined among hundreds identified by massive sequencing of AML genomes. We report an in vivo insertional-mutagenesis screen for genes cooperating with one AML initiating mutations (PML-RARA, oncogene of acute promyelocytic leukemia, APL), which allowed identification of hundreds of genetic cooperators. The cooperators are mutated at low frequency in APL or AML patients but are always abnormally expressed in a cohort of 182 APLs and AMLs analyzed. These deregulations appear non-randomly distributed and present in all samples, regardless of their associated genomic mutations. Reverse-engineering approaches showed that these cooperators belong to a single transcriptional gene network, enriched in genes mutated in AMLs, where perturbation of single genes modifies expression of others. Their gene-ontology analysis showed enrichment of genes directly involved in cell proliferation control. Therefore, the pool of PML-RARA cooperating mutations appears large and heterogeneous, but functionally equivalent and deregulated in the majority of APLs and AMLs. Our data suggest that the high heterogeneity of DNA mutations in APLs and AMLs can be reduced to patterns of gene expression deregulation of a single 'mutated' gene network.

Proceedings of the inaugural International Summit for Medical Nutrition Education and Research.

Medical Nutrition Education (MNE) has been identified as an area with potential public health impact. Despite countries having distinctive education systems, barriers and facilitators to effective MNE are consistent across borders, demanding a common platform to initiate global programmes. A shared approach to supporting greater MNE is ideal to support countries to work together. In an effort to initiate this process, the Need for Nutrition Education/Innovation Programme group, in association with their strategic partners, hosted the inaugural International Summit on Medical Nutrition Education and Research on August 8, 2015 in Cambridge, UK. Speakers from the UK, the USA, Canada, Australia, New Zealand, Italy, and India provided insights into their respective countries including their education systems, inherent challenges, and potential solutions across two main themes: (1) Medical Nutrition Education, focused on best practice examples in competencies and assessment; and (2) Medical Nutrition Research, discussing how to translate nutrition research into education opportunities. The Summit identified shared needs across regions, showcased examples of transferrable strategies and identified opportunities for collaboration in nutrition education for healthcare (including medical) professionals. These proceedings highlight the key messages presented at the Summit and showcase opportunities for working together towards a common goal of improvement in MNE to improve public health at large.

The anti-inflammatory effects of exercise in the syndromic thread of diabetes and autoimmunity.

A unifying thread over the wide spectrum of diabetes might be the triggering of innate immunological and inflammatory pathways leading to insulin resistance, beta-cell dysfunction and beta-cell destruction: the hybrid features of type 1 and type 2 diabetes. In fact, hyperglycemia can arise from a deficit in insulin action, insulin secretion, or both. Regularly exercising at moderate intensity has been shown to efficiently and positively impact upon physiological imbalances caused by several morbid conditions. Even in different immunological dysfunctions, physical exercise has been prescribed as a complementary therapeutic strategy. In fact, as suggested by our observations, there is a putative inverse relationship between autoimmunity markers (GAD, IA) and exercise-derived energy expenditure in type 1 pre-diabetic subjects. Exercise also has been shown to maintain muscle mitochondrial function and thus ability to maintain fuel metabolism and islet cell function. An additional benefit is the enhancement of antioxidant defense system and thus reducing oxidative stress. Therefore, the purpose of this review is to address the importance of physical exercise in a broad range of metabolic disorders that set out a common milieu in which type 1 and type 2 diabetes could be identified as one extensive syndrome.

Ten years' evaluation of diet, anthropometry, and physical exercise adherence after islet allotransplantation.

Allogeneic islet transplantation (IT) provokes changes in metabolic responses and nutritional behaviors. The durability of these changes needs to be described as well as their impact on the recipients' lifestyle. The goal of this study was to investigate how islet transplantation influenced diet, exercise habits, and body composition during 10 years after IT. A retrospective study performed in 33 (14 males, 19 females) IT recipients used dietary, physical activity open- ended questionnaire and anthropometric measurements. Data were collected before transplantation, every 3 months up to the 18th and every 6 months thereafter. Data were grouped by gender and eras: pre-IT; 0-3 years; 4-6 years, and 7-10 years after IT. Reduction in body mass index (BMI) from pre-IT to 0-3 years was noted: 23.68 ± 2,18 kg/m(2) to 22.07 ± 2.94 kg/m(2) (P < .05). Increased values were observed from 0-3 years to 4-6 years in: waist circumference (WC) (76.68 ± 7.22 to 79.44 ± 7.58 cm), BMI (23,68 ± 2,18 to 22,75 ± 3,11 kg/m(2)) and weight (64.69 ± 11.98 to 67.43 ± 14 kg): (P < .03). WC increased continuously up to 7-10 years (86.33 ± 9.45 cm; P < .05). There was an average of 5.3 ± 5.6 h/wk of exercise during follow-up. From pre-IT to 0-3 years there was a 19% reduction in protein consumption (P < .05) and a 39% increase in calories from saturated fats (P < .05). A trend to reduce carbohydrates intake noted from pre-IT to 0-3 years was progressively inverted from then throughout 7-10 years (not significant). IT was associated with a significantly decreased BMI early on that it was not sustained. The subsequent weight gain and WC increase could be the result of chronic immunosuppressive therapy and/or voluntary change in eating habits. The increased consumption of carbohydrates could be related to an adaptation of a lifestyle or/and reintroduction of insulin after graft dysfunction. Active lifestyle might be result of the intensive clinical care after IT, concomitant awareness of the importance of routine physical exercise on blood glucose control, and diabetes management. Continuous follow-up of IT recipients is needed to better understand these changes and for comparison with subjects with type 1 diabetes mellitus.

Metabolic and hormonal responses to a single session of kumite (free non-contact fight) and kata (highly ritualized fight) in karate athletes.

BACKGROUND: Several studies report martial arts as a good model for investigating neuroendocrine responses to competitive fighting. However, little is known on the metabolic responses elicited by elite athletes during fighting. In particular, the metabolic picture in elite athletes of martial arts is little known. AIM: In the present study, our aim was to investigate the acute effects of a session of karate practice on the glucose-insulin system. SUBJECTS AND METHODS: Ten healthy individuals (6M/4F; BMI: 22.1 ± 0.7 kg/m(2); 21.9 ± 1.1 years, mean ± SE) who practice karate in national or international competitions were enrolled. All participants completed two experimental trials in a randomised-crossover fashion. A basal blood sample was collected from each athlete to assess plasma glucose, insulin, cortisol, testosterone and catecholamines, before karate training session. In two separate days, another blood sample was collected from each participants after 3 min of real fighting (kumite) and 3 min of ritualized simulation of combat (kata). RESULTS: In both trials, plasma glucose resulted to be higher at the end the of performance compared to the basal (p < 0.001 after kumite and p < 0.02 after kata). In contrast, insulin was similar in the basal and after physical activity in the two trials. Catecholamines were higher after kata and kumite sessions with respect to the basal values (p < 0.04) and, in particular, epinephrine post-kumite values were much greater than those measured after kata. CONCLUSIONS: Our results indicate that unlike performances of karate (kumite and kata) elicit different plasma glucose increases. In particular, we found that glucose and epinephrine concentrations increased more after kumite than after kata.

Different circulating ghrelin responses to isoglucidic snack food in healthy individuals.

The last decade has seen much debate on ghrelin as a potential target for treating obesity. Despite a close connection between snack food intake and obesity, snacking is controversially reviewed as a good habit in a healthy nutritional regimen. The aim of the study was to evaluate whether a different nutrient composition influences postprandial ghrelin levels and glucose increments induced by 6 isoglucidic snack food. 20 healthy individuals (10 M/10 F; BMI 23.1 ± 0.5; age 33 ± 0.67 years, mean and SE) from H San Raffaele Scientific Institute and Milan University were enrolled. The subjects underwent OGTT (50 g) and 6 isoglucidic test-meal loads to assess the ghrelin circulating levels and the area under glycemic curves induced by 6 commercial snacks. 3 h after hazelnut chocolate intake, ghrelin was significantly lower than with wafer chocolate intake (p<0.002). As a response to all snacks, the glycemic curves were not different even though hazelnut chocolate showed the lowest glycemic curve. Moreover, snack fat content was found to be inversely correlated to 3-h plasma ghrelin levels (p<0.0001; R (2)=0.77) and positively associated with satiety scores (p<0.02; R (2)=0.28). Also energy load was inversely correlated to 3-h plasma ghrelin (p<0.0001; R (2)=0.73). Our results indicate that snack food administered in equivalent glucidic loads elicits postprandial ghrelin suppression and satiety ratings in different ways. Further studies are needed to elucidate the role of ghrelin as hunger-hormone in the regulation of energy balance.

Insulin-mimetic action of conglutin-γ, a lupin seed protein, in mouse myoblasts.

BACKGROUND AND AIMS: Lupin seed is referred to as an antidiabetic product in traditional medicine. Conglutin-γ, a lupin seed glycoprotein, was found to cause a significant plasma glucose reduction when orally administered to rats in glucose overload trials. Conglutin-γ was identified as being responsible for the claimed biological activity, and the aim of this work was to envisage its hypothetical insulin-mimetic cellular mechanism of action. Insulin is responsible for proteosynthesis control through IRS/AKT/P70S6k/PHAS1 pathways modulation, glucose homeostasis through PKC/Flotillin-2/caveolin-3/Cbl activation and muscle differentiation/hypertrophy via muscle-specific MHC gene transcription control. METHODS AND RESULTS: To assess whether conglutin-γ modulates the same insulin-activated kinases, myoblastic C2C12 cells were incubated after 72 h of differentiation with 100 nM insulin or 0.5 mg/mL (∼10 µM) conglutin-γ. Metformin-stimulated cells were used as a positive control. The effect on the above mentioned pathways was evaluated after 5, 10, 20 and 30 min. In the control cells medium insulin, conglutin-γ and metformin were not added. We demonstrated that insulin or conglutin-γ cell stimulation resulted in the persistent activation of protein synthetic pathway kinases and increased glucose transport, glut4 translocation and muscle-specific gene transcription regulation. CONCLUSIONS: Our results indicate that conglutin-γ may regulate muscle energy metabolism, protein synthesis and MHC gene transcription through the modulation of the same insulin signalling pathway, suggesting the potential therapeutic use of this natural legume protein in the treatment of diabetes and other insulin-resistant conditions, as well as the potential conglutin-γ influence on muscle cells differentiation and regulation of muscle growth.

Elevated fasting plasma C-peptide occurs in non-diabetic individuals with fatty liver, irrespective of insulin resistance.

AIMS: Studies have pointed to insulin resistance as a pathogenic factor in fatty liver. Although pancreatic B-cell function is believed to be involved, its role is unclear. This study was undertaken to test whether fasting C-peptide, an index of fasting B-cell function, was related to intra-hepatic fat (IHF) content in non-diabetic humans. METHODS: We assessed, retrospectively, fasting plasma C-peptide concentration in 31 patients with fatty liver and 62 individuals without fatty liver. The IHF content was measured by proton magnetic resonance spectroscopy ((1)H-MRS), while insulin sensitivity was estimated based on fasting plasma glucose and insulin with the homestasis model assessment (HOMA) 2 method. RESULTS: Age, sex and body mass index (BMI) were not different between groups. Patients with fatty liver had higher fasting insulin (P < 0.01), C-peptide (P < 0.005) and lower insulin sensitivity (HOMA2-%S). Fasting insulin alone explained 14% of the IHF content variability (P < 0.001); inclusion of fasting C-peptide in multivariate regression explained up to 32% (P < 0.001). A subgroup analysis was performed by matching 1 : 1 for HOMA2-%S. These data were analysed by conditional logistic regression which showed that, when HOMA2-%S was matched between groups, fasting C-peptide remained the only significant predictor of fatty liver. CONCLUSIONS: Non-diabetic individuals with fatty liver are characterized by increased fasting plasma C-peptide concentration, irrespective of their insulin resistant state.

Effect of L-acetylcarnitine on body composition in HIV-related lipodystrophy.

This study examined the impact of L-acetylcarnitine treatment on metabolic parameters and body composition in patients with lipodystrophy syndrome secondary to antiretroviral treatment in human immunodeficiency virus (HIV) infection. A total of 9 HIV-1 infected patients with lipodystrophy syndrome (4F/5M, age 41+/-5 years, HIV duration 8+/-2 years, BMI 23.7+/-3.4 kg/m(2), on protease inhibitors and nucleoside analogue Reverse Transcriptase inhibitors) were evaluated before and after 8 months of therapy with L-acetylcarnitine (2 g/die) and 9 matched healthy subjects served as control subjects. In all patients fasting plasma glucose, insulin concentrations (for evaluation of surrogate indexes of insulin sensitivity), lipid profile, lipid oxidation (by indirect calorimetry), body composition (by DEXA), and intramyocellular triglyceride (IMCL) content of the calf muscles (by (1)H NMR spectroscopy) were assessed. After this therapy, in HIV-1 patients, the IMCL content of the soleus had significantly decreased (p=0.03). Plasma FFAs (0.79+/-0.31 to 0.64+/-0.25; p<0.05) and Respiratory Quotient (0.83+/-0.18 to 0.72+/-0.16; p<0.03) also decreased. Insulin sensitivity was significantly lower prior (HOMA-IS 0.56+/-0.30) and nonstatistically different than controls after therapy (0.72+/-0.49 vs. 0.78+/-0.42) whilst the percentage of fat in the legs increased (p=0.05). Eight months of L-acetylcarnitine treatment increased lipid oxidation, decreased intramyocellular triglyceride content, and induced a more physiological distribution of fat deposits.

Impaired left ventricular energy metabolism in patients with hypertrophic cardiomyopathy is related to the extension of fibrosis at delayed gadolinium-enhanced magnetic resonance imaging.

OBJECTIVE: Areas of intramyocardial late enhancement (LE) at delayed enhanced magnetic resonance imaging (DE-MRI) and reduction of myocardial phosphocreatine (PCr)/ATP-ratio at phosphorus magnetic resonance spectroscopy ((31)P-MRS) are both reported in hypertrophic cardiomyopathy (HCM) and indicate areas of increased interstitial myocardial space with fibrosis and impairment of myocardial energy metabolism, respectively. We sought to ascertain whether in HCM patients the abnormal features of left ventricular (LV) interstitial space revealed by DE-MRI correlated with impaired LV energy metabolism shown at (31)P-MRS. METHODS: 19 patients with HCM proved by histological analysis of multiple endomyocardial biopsies and with normal coronary arteries, underwent cardiac MRI including DE-MRI and (31)P-MRS. DE-MRI for detection and quantification of late enhancement (LE) and (31)P-MRS to assess the myocardial PCr/ATP-ratio were performed by means of a 1.5-T magnet. 19 healthy subjects, matched for gender and age were studied by (31)P-MRS as control group. RESULTS: LE areas in the LV wall were found in 17 out of 19 patients with an extension ranging from 0.8% to 19.5% of the LV-mass (mean value 7.6% (SD 5.6%). The PCr/ATP-ratio was lower in HCM patients than in control subjects (2.18 (0.41) vs 2.41 (0.30); p<0.05). LE% and PCr/ATP-ratio were inversely related (R = -0.57; p<0.05) and LE% was the stronger predictor of PCr/ATP-ratio by multivariate analysis. CONCLUSIONS: This study demonstrated that the known alteration of the PCr/ATP-ratio observed in HCM patients is correlated with the presence of fibrotic areas in the myocardium of the left ventricle.

Protein and glutamine kinetics during counter-regulatory failure in type 1 diabetes.

BACKGROUND AND AIMS: Healthy individuals counteract insulin-induced hypoglycaemia by increasing glutamine utilization but not proteolysis. Glucagon is important to this response because it increases glutamine uptake. In type 1 diabetes (T1DM) glucagon and epinephrine responses to hypoglycaemia are defective. We investigated whether glutamine and amino acid utilization during hypoglycaemia is altered in T1DM with defective counter-regulatory responses. METHODS AND RESULTS: Eight T1DM patients (duration of diabetes 14+/-4 years and therefore with presumed defective counter-regulatory response) and eight controls (CON) received a 3h hypoglycaemic hyperinsulinaemic (0.65mU/kg per min) clamp coupled to [6,6-(2)H(2)]glucose, [1-(13)C]leucine and [2-(15)N]glutamine to trace the relative kinetics. Post-absorptive plasma glucose and glucose uptake were increased in T1DM (9.09+/-0.99 vs 5.01+/-0.22mmol/l and 19.5+/-0.9 vs 12.6+/-0.8micromol/kg per min, p<0.01). During the clamp T1DM but not CON required exogenous glucose (4.4+/-1.7micromol/kg per min) to maintain the hypoglycaemic plateau because the endogenous glucose production was significantly suppressed (p<0.01). In T1DM the leucine and phenylalanine concentrations were less suppressed from basal (p<0.05) despite a similar insulin suppression of proteolysis (-16+/-2 vs -20+/-4%, p=ns) indicating a defective stimulation of leucine metabolic clearance from basal (+18+/-3% vs +55+/-9%, p<0.01). Glutamine concentration remained unchanged from basal (-7+/-3% vs -35+/-3%, p<0.01) and the clearance of glutamine was markedly defective in T1DM (+6+/-2%) in comparison with controls (+22+/-4%; p=0.02). CONCLUSIONS: In T1DM, the counter-regulatory failure to hypoglycaemia seems to be associated with a defective glutamine utilization. The failure to clear circulating amino acids, specifically glutamine, during hypoglycaemia may adversely affect gluconeogenesis.