Diabetic ketoacidosis and acute pancreatitis associated with antipsychotic drugs: report of a case

Introduction. Diabetic ketoacidosis (DKA) is a feature of type 1 diabetes mellitus, but it can develop in people with type 2 diabetes (T2DM) in the presence of precipitating factors. Antipsychotics have been associated with pancreatitis without DKA or hyperglycemia or acidosis with no evidence of pancreatitis. To our knowledge, there are few reports of patients who developed pancreatitis and DKA during treatment with antipsychotis. We present a case of a patient who developed such life-threatening conditions while on antipsychotics. Clinical case. A 53-years-old Caucasian woman (BMI 32.7 kg/m2) was transferred to our Unit from the ED where she was admitted for dyspnea and abdominal pain. She had T2DM, managed with diet, and bipolar disorder treated with mood stabilizers and antipsychotics (valproic acid, haloperidol, quetiapine). Initial lab results revealed hyperglycemia (446 mg/dl; HbA1c 118 mmol/mol) and metabolic acidosis (pH 7.0; HCO3- 5.3 mmol/l; 3-beta-hydroxy-butyrate O3 mmol/l; BEE K25 mmol/l). Patient received i.v. fluid and insulin therapy until DKA resolution, but clinical course was complicated by acute pancreatitis (amylase 550 U/l; lipase 1574 U/l). Abdomen CT showed moderate edematous acute pancreatitis, with no evidence of stones or bile duct dilatation. On admission and during the early phase of acute pancreatitis, triglycerides were modestly increased (365 mg/dl). Supportive care with i.v. fluids, bowel rest and pain control were mainstays of therapy. The patient became medically stable after 15 days of hospitalization. Before withdrawal insulin, metformin was introduced with maintenance of satisfactory glycemia (fasting 122 mg/dl; post-prandial 124 mg/dl). Antipsychotic medications were reviewed after psychiatric consultation. Discussion. We present a case of a T2DM patient who developed pancreatitis and life- threatening DKA while receiving antipsychotics, that may be the common denominator linking DKA and acute pancreatitis though the exact mechanisms responsible remain to be identified. As far as DKA is concerned, antipsychotics may have an isolated toxic effect on beta-cell resulting in relative hypoinsulinemia and hyperglucagonemia. Marked hypertriglyceridemia can trigger acute pancreatitis, but triglyceridemia were only moderately increased in our case. This suggest that in our patient pancreatitis may be the result of drug- mediated acinar-cell damage or idiosyncratic drug reaction. In summary, physicians should be aware of the possibility of life-threatening adverse effects in T2DM patients on antipsychotic treatment especially when in combination with mood stabilizers. These subjects should undergo careful monitoring as they may have inappropriate assessment of signs and symptoms

Plasma N-Acetylaspartate Is Related to Age, Obesity, and Glucose Metabolism: Effects of Antidiabetic Treatment and Bariatric Surgery

Background: N-acetylaspartate (NAA) is synthesized only by neurons and is involved in neuronal metabolism and axonal myelination. NAA is the strongest signal on brain magnetic resonance spectroscopy, and its concentration have been associated with cognitive dysfunction in neurodegenerative diseases, obesity, and type 2 diabetes (T2D). Materials and Methods: We explored the impact of obesity and T2D on circulating NAA as well as the impact of bariatric surgery and antidiabetic treatments. We developed an LC-MS method for the accurate measurements of fasting plasma NAA levels in 505 subjects (156 subjects with normal glucose tolerance, 24 subjects with impaired glucose tolerance, and 325 patients with T2D) to examine the associations of NAA with obesity and dysglycemia. To validate cross-sectional findings, plasma NAA was measured 6 months after Roux-en-Y Gastric Bypass (RYGB) in 55 morbidly obese subjects, and after 1 year of antidiabetic treatment (with dapagliflozin, exenatide, or dapagliflozin plus exenatide) in 192 T2D patients. Results: In the whole population, NAA was associated with age (r = 0.31, p < 0.0001) and BMI (r = −0.20, p < 0.0001). Independently of age and BMI, NAA was reciprocally related to HbA1c and fasting plasma glucose (partial r = −0.13, both p = 0.01). Surgically-induced weight loss raised NAA (by 18 nmol/L on average, p < 0.02). Glucose lowering treatment increased NAA in proportion to the drop in HbA1c (r = 0.31, p < 0.0001) regardless of the agent used. Conclusions: Circulating NAA concentrations are modulated by age, obesity, and glycemic control. Whether they may mark for the corresponding metabolic effects on brain function remains to be established by joint measurements of spectroscopic signal and cognitive function

Metabolic regulation of GLP-1 and PC1/3 in pancreatic α-cell line

Background and aims: An intra-islet incretin system has been recently suggested to operate through modulation of the expression and activity of proconvertase 1/3 and 2 (PC1/3, PC2) in pancreatic alpha-cell accounting for local release of GLP-1. Little is known, whether this alpha-cell activity can be affected by the metabolic alterations occurring in type 2 diabetes, such as hyperglycemia, hyperlipidemia or hyperglucagonemia. Materials and methods: AlphaTC1/6 cells from a mice pancreatic cell line were incubated in the presence of two glucose (G) concentration (5.5 and 16.7 mM) for 16 h with or without free fatty acid, IL6 or glucagon. GLP-1 secretion was measured by ELISA and expression of PC1/3 and PC2 by RT-PCR and western blot; cell viability was determined by MTT method, Reactive Oxygen Species generation (ROS) by H2DCFDA fluorescence and apoptosis by Annexin staining and Propidium Iodine (PI) fluorescence. Results: Upon 16.7G incubation, GLP-1 secretion (total and active) was significantly increased in parallel with a significant increment in PC1/3 expression, a slight increase in cell viability and ROS generation and by a decrement in PC2 expression with no change in cell apoptosis. When cells were incubated at 5.5mM glucose with FFA, also an increment in GLP-1 secretion and PC1/3 expression was observed together an increment in ROS generation, a decrement in cell viability, and a modest increment in apoptosis. When incubated with 16.7mM glucose with FFA, the increment in GLP-1 secretion was reduced to basal, accompanied by an increment in apoptosis and ROS generation. This was also observed with IL-6, but in this case, no modification in ROS generation or apoptosis was observed when compared to 16.7mM glucose. The presence of glucagon did not modify any of the parameters studied. Conclusion: These data suggest that under hyperglycemic, hyperlipidemia or inflammatory conditions, alpha cells can increase expression PC1/3 and activate GLP-1 secretion, which may contribute protecting both alpha and beta-cells from glucose and lipotoxicity, while this effect seems to be lost in the presence of both pathophysiological conditions

Impact of COVID-19 lockdown on glucose control of elderly people with type 2 diabetes in Italy

Aims: to evaluate the effect of home confinement related to COVID-19 lockdown on metabolic control in subjects with T2DM in Italy. Methods: we evaluated the metabolic profile of 304 individuals with T2DM (65% males; age 69 ± 9 years; diabetes duration 16 ± 10 years) attending our Diabetes Unit early at the end of lockdown period (June 8 to July 7, 2020) and compared it with the latest one recorded before lockdown. Results: There was no significant difference in fasting plasma glucose (8.6 ± 2.1 vs 8.8 ± 2.5 mmol/L; P = 0.353) and HbA1c (7.1 ± 0.9 vs 7.1 ± 0.9%; P = 0.600) before and after lockdown. Worsening of glycaemic control (i.e., ΔHbA1c ≥ 0.5%) occurred more frequently in older patients (32.2% in > 80 years vs 21.3% in 61-80 years vs 9.3% in < 60 years; P = 0.05) and in insulin users (28.8 vs 16.5%; P = 0.012). On multivariable analysis, age > 80 years (OR 4.62; 95%CI: 1.22-16.07) and insulin therapy (OR 1.96; 95%CI: 1.10-3.50) remained independently associated to worsening in glycaemic control. Conclusions: Home confinement related to COVID-19 lockdown did not exert a negative effect on glycaemic control in patients with T2DM. However, age and insulin therapy can identify patients at greatest risk of deterioration of glycaemic control

Cognitive Function and Brain Plasticity in Obese Patients—The Impact of Bariatric Surgery

Background and Aim: Obesity adversely affects brain function, but the effect of bariatric surgery on cognitive function is still poorly evaluated. We assessed metabolic parameters and cognitive function in obese patients before and after bariatric surgery (RYGB). Methods: A 75g OGTT was performed in 10 nondiabetic obese patients (BMI 46.0±5.4 kg/m2; age 43.6±10.5 years; HbA1c 43.3±4.6 mmol/mol) before and 6-months after RYGB for measurements of metabolic parameters. Mini Mental State Examination (MMSE) and Montreal Cognitive Assessment (MoCA) were administered; neuronal plasticity (NP) of the visual cortex was measured as change in ocular dominance after 120 min monocular deprivation. No subject with drugs or alcohol abuse, psychiatric illness, head injury, brain tumor, dementia, epilepsy, learning disorder, developmental disability, and impaired sensory function were included. Results: At baseline median MMSE score was 28.5 (range 25-30) and median MoCA score 26.5 (range 21-30), indicating early cognitive abnormalities (MoCA<26 points). Six months after RYGB, BMI decreased to 35.2±6.1 kg/m2 (p=0.004) and glucose tolerance did not change. HOMA-IR (from 5.1±2.3 to 1.6±1.1) and disposition index (from 3.3±4.6 to 35.0±41.0) all improved (p<0.05); post-OGTT GLP-1 increased from 5336.6±2262.6 to 11132.3±3412.2 pmol/lx120min (p<0.05) and fasting plasma leptin decreased from 80.0±46.7 to 13.1±6.6 pmol/l (p<0.008). NP increased from 0.03±0.1 to 0.11±0.14 (p<0.01). Cognitive performance improved in all subjects (MMSE: 30, range 28-30; MoCA: 28.5, range 24-30; both p=0.03 or less vs. baseline). There was no correlation between MoCA and metabolic changes though it was positively correlated with NP post-RYGB (p=0.04). Conclusion: Morbid obese subjects have subclinical cognitive impairments and brain plasticity alterations that significantly improve after RYGB. While no correlation was found between metabolic and hormonal changes, NP was positively associated with MoCA score

Bariatric surgery restores visual cortical plasticity in nondiabetic subjects with obesity

International audienceBackground/objectives Obesity leads to changes in synaptic plasticity. We aimed at investigating the impact of bariatric surgery (RYGB) on visual neural plasticity (NP) and its relationship with the main gut peptides, leptin, and brain-derived neurotrophic factor (BDNF).Subjects/methods NP was assessed testing binocular rivalry before and after 2 h of monocular deprivation (index of visual brain plasticity) in 15 subjects with obesity (age 42.3 ± 9.8 years; BMI 46.1 ± 4.9 kg/m 2) before and after RYGB. Gut peptides, leptin, and BDNF were obtained at baseline and 6 months after surgery in 13 subjects.Results A significant reduction in BMI (p < 0.001 vs. baseline) and a significant increase of disposition index (DI, p = 0.02 vs baseline) were observed after RYGB. Total and active GLP-1 release in response to glucose ingestion significantly increased after RYGB, while no changes occurred in VIP, GIP, and BDNF levels. Fasting leptin concentration was lower after RYGB (p = 0.001 vs. baseline). Following RYGB, NP was progressively restored (p < 0.002). NP was correlated with DI and fasting glucose at baseline (r = 0.75, p = 0.01; r = −0.7, p = 0.02; respectively), but not with BMI. A positive correlation between post-pre-RYGB changes in AUC active GLP−1 and NP was observed (r = 0.70, p < 0.01). Leptin was inversely correlated with NP 6 months after surgery (r = −0.63, p = 0.02). No correlation was observed between GIP, VIP, BDNF, and NP.Conclusions Visual plasticity is altered in subjects with obesity, and it can be restored after RYGB. The improvement may be mediated by amelioration of insulin sensitivity, increased GLP-1 levels, and reduced leptin levels

Effect of metabolic/hormonal pertubation on PC1/3 and PC2 expression.

<p>Cells were incubated for 16 h in the presence of 5.5mM or 16.7mM, in the additional presence of glucagon, FFA and IL-6, total mRNA and protein were extracted and PC1/3 and PC2 expression were determined by Real Time PCR using specific primers and SDS-PAGE and Western Blotting. Panel A: PC1/3 RNA, Panel B: PC1/3 protein, Panel C: PC2 RNA and Panel D: PC2 protein. Results are Times vs control (5.5mM glucose) and % of control (5.5mM glucose) and expressed as MEAN±SEM, n = 5–7. *p<0.05 compared to control; $p<0.05 compare to control (16.7mM glucose).</p

Effect of metabolic/hormonal pertubation on cell viability.

<p>Cells were incubated for 16 h in the presence of 5.5mM or 16.7mM, in the additional presence of glucagon, FFA and IL-6 and cell viability was determined by MTT method. Results are % of control (cells incubated in 5.5mM glucose) and expressed as MEAN±SEM, n = 4. *p<0.05 compared to 5.5mM glucose control; $p<0.05 compare to 16.7mM glucose control.</p

Effect of metabolic/hormonal pertubation on GLP-1 secretion.

<p>Cells were incubated for 16 h in the presence of 5.5mM or 16.7mM, in the additional presence of glucagon, FFA and IL-6; hormone secretion at medium was determined by ELISA method using specific kits. Panel A: GLP-1 Active, Panel B: GLP-1 Total and Panel C: Glucagon. Results are % of control (cells incubated in 5.5mM glucose) and expressed as MEAN±SEM, n = 4. *p<0.05 compared to 5.5mM glucose control; $p<0.05 compare to FFA (5.5mM glucose).</p