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Hypoglycemia in venlafaxine overdose: A hypothesis of increased glucose uptake

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Miran Brvar
Miran Brvar
Miran Brvar
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Gordana Kozelj at University of Ljubljana
Gordana Kozelj
Lucija Peterlin Mašič at University of Ljubljana
Lucija Peterlin Mašič
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Abstract

Antidepressant therapy is associated with disturbances in glucose homeostasis, and hypoglycemia is most pronounced in antidepressants with a high affinity for a serotonin reuptake transporter such as fluoxetine and sertraline [1, 2]. In the therapeutic use of venlafaxine, a dual-acting serotonin and norepinephrine reuptake inhibitor, no hypoglycemia has been demonstrated as yet. However, there are two case reports of severe hypoglycemia in venlafaxine overdose that were explained by increased insulin levels [3, 4]. In this case, we present prolonged hypoglycemia with normal insulin levels in venlafaxine overdose.A 42-year-old woman weighting 70 kg with a history of depression treated with venlafaxine was admitted to the Emergency Department 4 h following ingestion of 9.0 g of venlafaxine in a suicide attempt. On arrival, she was somnolent and had mydriasis, tremor and tachycardia. The initial serum glucose level was 2.6 mmol/L; all other laboratory results, including liver and kidney t ...
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LETTER TO THE EDITORS
Hypoglycemia in venlafaxine overdose: a hypothesis
of increased glucose uptake
Miran Brvar &Gordana Koželj &Lucija Peterlin Mašič
Received: 23 September 2014 / Accepted: 10 November 2014 /Published online: 20 November 2014
#Springer-Verlag Berlin Heidelberg 2014
Antidepressant therapy is associated with disturbances in glu-
cose homeostasis, and hypoglycemia is most pronounced in
antidepressants with a high affinity for a serotonin reuptake
transporter such as fluoxetine and sertraline [1,2]. In the
therapeutic use of venlafaxine, a dual-acting serotonin and
norepinephrine reuptake inhibitor, no hypoglycemia has been
demonstrated as yet. However, there are two case reports of
severe hypoglycemia in venlafaxine overdose that were ex-
plained by increased insulin levels [3,4]. In this case, we
present prolonged hypoglycemia with normal insulin levels
in venlafaxine overdose.
A 42-year-old woman weighting 70 kg with a history of
depression treated with venlafaxine was admitted to the
Emergency Department 4 h following ingestion of 9.0 g of
venlafaxine in a suicide attempt. On arrival, she was somno-
lent and had mydriasis, tremor and tachycardia. The initial
serum glucose level was 2.6 mmol/L; all other laboratory
results, including liver and kidney tests, were within normal
limits. Hypoglycemia was corrected with 50 ml of 50 %
glucose. Gastric lavage was performed and activated charcoal
was given. Immediately afterwards, she had a grand-mal
seizure. A continuous infusion of 10 % glucose was started
at 250 mL/h, and intermittent hypoglycemia (0.9–3.2 mmol/L)
with neurological signs requiring treatment with 50 ml of 50 %
glucose or 200 ml sugared tea were recorded seven times
during subsequent hospitalization, the last episode being de-
tected 40 h after venlafaxine ingestion (Table 1) while she was
still treated with glucose infusion. Plasma insulin and C-
peptide level measurement by immunoradiometric assays
were in normal ranges during episodes of hypoglycemia
(Table 1). A toxicology analysis of the serum by LC-MS/MS
revealed 14.7 mg/L of venlafaxine 14 h after ingestion (ther-
apeutic range 0.07–0.27 mg/L). Afterwards, serum
venlafaxine concentration decreased with a prolonged half-
life of 15 h (at 5 h therapeutic doses) (Table 1). No ethanol or
other medications were found.
It seems that in venlafaxine overdose with prolonged
normoinsulinemic hypoglycemia resistant to glucose therapy,
the increased rate of glucose uptake from the blood by the
peripheral tissues (e.g. increased glucose disposal rate) might
became clinically important because in this patient with nor-
mal insulin levels, prolonged hypoglycemia persisted, despite
a continuous glucose infusion of 6 mg/kg/min (e.g. 250 ml of
10 % glucose for 70 kg patient per hour). According to the
studies with the euglycemic glucose clamp technique, the
glucose disposal rate at an insulin concentration of 26 mU/L
is only around 3 mg/kg/min [5]. In a non-diabetic patient, a
glucose infusion of 6 mg/kg/min, as given to the presented
patient, should maintain eugylcemia at insulin levels as high
as 100 mU/L [5]. So hypoglycemia in patients with normal
insulin levels and a glucose infusion rate at twice the glucose
disposal rate could be explained only with increased glucose
uptake, probably due to venlafaxine in this case.
In venlafaxine overdose, the increased glucose uptake rate
might be associated with increased serotonin since in rats,
serotonin induces beta-endorphin release and stimulates mus-
cle glucose utilization through the activation of mu-opioid
receptors by the insulin-independent mechanism [6]. In
M. Brvar (*)
Centre for Clinical Toxicology and Pharmacology, Division of
Internal Medicine, University Medical Centre Ljubljana,
Zaloška cesta 7, Ljubljana, Slovenia
e-mail: miran.brvar@kclj.si
G. Koželj
Institute of Forensic Medicine, Faculty of Medicine,
University of Ljubljana, Korytkova 2, 1000 Ljubljana, Slovenia
e-mail: gordana.kozelj@mf.uni-lj.si
L. P. Mašič
Faculty of Pharmacy, University of Ljubljana,
Aškerčeva cesta 7, 1000 Ljubljana, Slovenia
e-mail: lucija.peterlinmasic@ffa.uni-lj.si
Eur J Clin Pharmacol (2015) 71:261–262
DOI 10.1007/s00228-014-1784-9
addition, increased glucose utilization (uptake) in peripheral
tissues and/or inhibition of hepatic gluconeogenesis in
venlafaxine overdose could also be mediated directly through
opioid pathways involving the mu-opioid receptors since
venlafaxine is structurally very similar to the mu-opioid re-
ceptor agonist tramadol, which is a known cause of hypogly-
cemia [7,8].
In conclusion, in venlafaxine overdose, hypoglycemia
should be ruled out and glucose monitored continuously since
hypoglycemia after venlafaxine overdose may last 48 h. It
would be interesting to consider the potential venlafaxine
increase of glucose uptake more precisely as this might influ-
ence the therapeutic approach in patients with diabetes and
depression which commonly goes together.
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Table 1 Serum glucose, plasma insulin, plasma C-peptide and serum venlafaxine levels following ingestion of 9.0 g venlafaxine
Time after ingestion (h)
41114172024323840424448
Serum glucose (mmol/L) (normal levels 3.6–6.1 mmol/L) 2.6 2.2 5.4 2.5 0.9 2.1 2.7 7.4 3.2 7.6 6.0 6.6
Plasma insulin (mE/L) (normal levels 2–29.1 mU/L) 23 26.1 7.6 17.1 3.2 5.7
Plasma C-peptide (nmol/L) (normal levels 0.3–2.4 nmol/L) 1.47 2.28 0.55 1.18 0.40 0.50
serum venlafaxine concentration (mg/L) (therapeutic range 0.07–0.27 mg/L) 14.7 12.5 11.6 8.7 6.7 4.6
262 Eur J Clin Pharmacol (2015) 71:261–262
... 5 Venlafaxine and tramadol are nearly identical in structure and share chemical properties, supporting a similar mech anism of causing hypoglycemia. 4 Hypoglycemia is a rare, underappreciated adverse effect of venlafaxine that should be considered and treated appropriately, particularly in overdose situations. References 1. Murphy L, Rasmussen J, Murphy NG. ...
... Several case reports describing venlafaxine-induced hypoglycemia have been published. [2][3][4] Although the exact mechanism is yet to be elucidated, it is postulated that hypoglycemia develops through μ-opioid receptormediated processes that reduce hepatic gluconeogenesis and increase peripheral glucose uptake and insulin sensitivity. 4 This rare adverse event is supported by the molecular similarity of venlafaxine to the analgesic tramadol, a more established and recognized cause of hypogly-cemia. ...
... [2][3][4] Although the exact mechanism is yet to be elucidated, it is postulated that hypoglycemia develops through μ-opioid receptormediated processes that reduce hepatic gluconeogenesis and increase peripheral glucose uptake and insulin sensitivity. 4 This rare adverse event is supported by the molecular similarity of venlafaxine to the analgesic tramadol, a more established and recognized cause of hypogly-cemia. 4,5 Animal models show that the administration of tramadol causes plasma glucose levels to drop because of enhanced peripheral glucose uptake and glycogen synthesis, reduced hepatic gluconeogenesis and increased hepatic insulin sensitivity. ...
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... In three clinical trials, duloxetine resulted in modest increases in fasting plasma glucose in patients with DPNP [25] Venlafaxine In three case reports, overdose of venlafaxine resulted in hypoglycemia [26][27][28] ...
... These results were also confirmed in animal studies; venlafaxine did not affect blood glucose levels in non-diabetic normal mice [93] . However, there were three case reports of hypoglycaemia in venlafaxine overdose [26,28] . ...
... These two cases showed that venlafaxine-induced hypoglycaemia was associated high levels of insulin secretion. However, in a recent case report, a non-diabetic patient with depression presented prolonged hypoglycaemia with normal insulin levels in venlafaxine overdose [28] . It seemed that high dose of venlafaxine increased glucose uptake and glucose usage in the peripheral tissues [28] . ...
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... SNRIs have an additional counter effect on glucose metabolism through the norepinephrine pathway, and were therefore thought to have no net effect on glucose metabolism [5]. Despite this, there have been limited case reports in Europe describing hypoglycemia in the context of overdose with venlafaxine, an SNRI [6][7][8]. While mechanisms have been proposed, the pathophysiology of this phenomenon is still poorly understood. ...
... A case-control study showed, when compared to benzodiazepines, primarily serotonergic antidepressants [5,10]. However, there have been three published case reports of hypoglycemia associated with venlafaxine overdose [6][7][8]. One of the three cases was treated with two 50 mcg subcutaneous octreotide injections to resolve the hypoglycemia at 24 hours post-ingestion [7], and the other two cases resolved without intervention at 30 and 40 hours post-ingestion respectively [6,8]. ...
... However, there have been three published case reports of hypoglycemia associated with venlafaxine overdose [6][7][8]. One of the three cases was treated with two 50 mcg subcutaneous octreotide injections to resolve the hypoglycemia at 24 hours post-ingestion [7], and the other two cases resolved without intervention at 30 and 40 hours post-ingestion respectively [6,8]. ...
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... In the literature, hypoglycemia associated with venlafaxine overdose has been reported in four cases. [2][3][4][5] In two of these four case reports, hypoglycemia was treated with the administration of two 50 µg subcutaneous octreotide injections. 4,5) In the other two cases, it was resolved without the administration of octreotide injections. ...
... 4,5) In the other two cases, it was resolved without the administration of octreotide injections. 2,3) In our case, the patient was treated with dextrose infusion, and thus, octreotide injection was not required. To the best of our knowledge, there are only two case reports on venlafaxine-related lactic acidosis in the literature. ...
Rare Adverse Events Associated with Venlafaxine Administration: Hypoglycemia and Lactic Acidosis
Article
Full-text available
  • Nov 2021
We report the first case of hypoglycemia and lactic acidosis caused by the therapeutic doses of venlafaxine. A 19-year-old female patient had presyncope and she was taking venlafaxine 75 mg once a day because of major depression for a week and she had no history of any other drug use or disease. The blood gas analysis revealed hypoglycemia and lactic acidosis. Patient was treated with dextrose infusion and oral diet. Although hypoglycemia and lactic acidosis have been reported in overdose of venlafaxine in the literature, these effects were observed in therapeutic doses.
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... 33,34 On the other hand, there are clinical reports that show venlafaxine intoxication was frequently followed by severe hypoglycemia. 35,36 Though further studies are necessary to establish a causal relationship between comorbid diabetes distress and depression disorders, the literature illuminated the idea of developing novel candidates that are effective for patients with major depression disorder and diabetes, from which, our research efforts of finding a new venlafaxine salt were encouraged. ...
Venlafaxine Caffeic Acid Salt: Synthesis, Structural Characterization, and Hypoglycemic Effect Analysis
Article
Full-text available
  • May 2021
Depression is a recurrent and chronic mental disorder requiring long-term treatment. Major depressive disorder is present in 15–20% of patients with type 1 or type 2 diabetes. Large-scale evidence revealed that depression and depressive symptoms are independent risk factors for the development of type 2 diabetes, and they may contribute to hyperglycemia and even accelerate the premature onset of diabetes complications. Venlafaxine is a clinical first-line antidepressant used for more than 30 years. Recently, clinical reports showed that venlafaxine overdose might cause hypoglycemia. Venlafaxine is insoluble and salt formation technology is the most appropriate method to improve the physicochemical properties and the pharmacokinetic profile of the drug. In the present work, the use of the solvent evaporation method, slurry, and the liquid-assisted grinding method resulted in the crystalline salt venlafaxine–caffeic acid (1:1). The compounds were characterized using a series of solid-state techniques, viz., powder X-ray diffraction, differential scanning calorimetry, thermogravimetric analysis, Fourier transform infrared spectroscopy, and solid-state nuclear magnetic resonance, and the crystal structure was determined by single-crystal X-ray diffraction. Besides, a comparative study of solubility, dissolution, and hypoglycemic activity of the parent drug and the new salt has been carried out. The tested venlafaxine–caffeic acid salt showed about 16-fold higher solubility than the pure drug. Moreover, the glucose consumption assay results showed that the novel salt possesses potent hypoglycemic activity in vitro, suggesting that it is a promising candidate effective for major depressive disorder patients with type 2 diabetes.
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Dose-related hypoglycemia in venlafaxine poisoning: a retrospective cohort study
Article
  • Nov 2022
Context Several case reports describe hypoglycemia in the context of venlafaxine overdose, while investigations at therapeutic dose suggested a neutral effect on glucose homeostasis. Studies on hypoglycemia in venlafaxine intoxication are lacking. Methods Single-center retrospective cohort study of non-diabetic patients presenting with a laboratory-confirmed antidepressant overdose to the department of clinical toxicology of a tertiary care hospital over a 12-year period. Our main goal was to investigate the association of hypoglycemia as the primary outcome with venlafaxine exposure using multiple logistic regression. Multi-drug exposures were included. We further aimed to describe the association of blood glucose (BG)/hypoglycemia with antidepressant dose, seizures and length of hospital stay. Results 525 antidepressant intoxications were included, 85 of which involved venlafaxine. Hypoglycemia occurred in 34.1% (29/85) of venlafaxine intoxications and in 10.7% (47/440) of non-venlafaxine antidepressant overdoses. Venlafaxine exposure was significantly associated with hypoglycemia (adjusted odds ratio (OR): 6.6, 95% confidence interval (CI): 3.5–12.6). Venlafaxine-associated hypoglycemia was mainly mild (BG: 51–70 mg/dL), in 75.8% of cases, to moderate (BG: 31–50 mg/dL), in 20.7%, with one case of severe hypoglycemia (BG: 30 mg/dL). BG was significantly inversely correlated with dose in the venlafaxine group (Spearman’s correlation coefficient: −0.47, p = 0.002) but not in other commonly prescribed antidepressants. Regardless of venlafaxine exposure, hypoglycemia was associated with seizures (adjusted OR: 5.3, 95% CI: 2.6–10.6) and with a 2.7 day increase in hospital length of stay (95% CI: 1.3–4.2). Conclusion A dose-related, mild to moderate hypoglycemia occurred in over one-third of venlafaxine poisonings. In overdose of other antidepressants, hypoglycemia was seen less frequently and without significant dose-dependency. Regardless of venlafaxine exposure, hypoglycemia was associated with seizures and prolonged length of stay, although these factors are likely primarily determined by other toxicities. BG monitoring in venlafaxine overdose should be considered.
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The association between antidepressant use and disturbances in glucose homeostasis: Evidence from spontaneous reports
Article
Full-text available
  • Jun 2008
  • EUR J CLIN PHARMACOL
Depression is common in patients with diabetes, and the use of antidepressants may impair glycaemic control. We assessed the association between antidepressant use and hyper- and hypoglycaemia. Based on spontaneous reports listed in the World Health Organization (WHO) Adverse Drug Reaction Database, a case-control study was conducted. The study base consisted of all adverse drug reactions (ADRs) ascribed to antidepressants, antipsychotics and benzodiazepines between 1969 and 2005. Cases were defined as reported ADRs classified as hyper- or hypoglycaemia and separated in different study populations. All other reports were considered as controls. Exposure to antidepressants was the primary determinant investigated. Benzodiazepines and antipsychotics were chosen as reference groups. Potential confounding factors, namely, age, gender, use of antidiabetic medication, use of hyper- or hypoglycaemia-inducing comedication and reporting year, were determined on the index date. Multivariate logistic regression was used to evaluate the strength of the association, which was expressed as reporting odds ratios (RORs) with 95% confidence intervals (95% CI). Overall, the use of antidepressants was associated with hyperglycaemia [ROR 1.52 (95% CI: 1.20-1.93)] and of hypoglycaemia [ROR 1.84 (95% CI: 1.40-2.42)]. The association with hyperglycaemia was most pronounced for antidepressants with affinity for the 5-HT(2c) receptor, histamine-(1) receptor and norepinephrinic (NE) reuptake transporter. The association with hypoglycaemia was most pronounced for antidepressants with affinity for the serotonin reuptake transporter. The results of this study strengthen the findings in individual case reports that the use of antidepressants is associated with disturbances in glucose homeostasis.
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Tramadol and hypoglycaemia: Comparison with other step 2 analgesic drugs
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The risk of hypoglycaemia with tramadol (TRM) is not well described. Our aim was to analyze spontaneous reports of hypoglycaemia registered in the French Pharmacovigilance database and to compare these data with two other step-2 analgesic drugs. Cases of hypoglycaemia associated with TRM, dextropropoxyphene (DXP) and codeine (COD) recorded between 1997 and November 2010 in the French pharmacovigilance database were compared. Seventy-two cases of hypoglycaemia associated with DXP and 43 with TRM were retained for evaluation (the single case reported with COD was not further considered). Most patients were elderly people with no significant difference in age between DXP- and TRM-treated patients (71.2 ± 21 vs. 69.4 ± 22.5 years). Hypoglycaemia occurred after a median of 4 and 5 days with DXP and TRM treatment, respectively. The mean lowest serum glucose concentration was 2.1 ± 0.9 mmol l−1 in the DXP group compared with 2.5 ± 1 mmol l−1 in the TRM group (P = 0.072). At least, one risk factor of hypoglycaemia was found in most patients, with no significant difference between groups (58.3% in the DXP group and 58.1% in the TRM group). In particular, 31.9% patients from the DXP group had diabetes compared with 41.8 % from the TRM group (P = 0.28) and 18% of DXP patients had renal insufficiency compared with 16.3% of TRM patients (P = 0.8). Our study confirms that TRM is associated with the occurrence of hypoglycaemia in elderly or predisposed patients, with characteristics similar to those previously reported with DXP.
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Hypoglycaemia: A little known effect of Venlafaxine overdose
Article
We report the case of a 39-year-old woman who presented with serotonin syndrome and hypoglycaemia likely due to intoxication with a very high dose of venlafaxine. This case of venlafaxine-associated hypoglycaemia was treated first by glucose perfusion, but despite large doses, hypoglycaemia recurred. Blood glucose normalized after injection of octreotide, eliminating the need for hypertonic glucose. Octreotide has been shown to decrease glucose requirements and the number of hypoglycaemic episodes in patients with sulfonylurea-induced hypoglycaemia but, to our knowledge, its ability to resolve hypoglycaemic episodes due to massive venlafaxine overdose has not yet been described.
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Study of antinociceptive activity of SSRI (fluoxetine and escitalopram) and atypical antidepressants (venlafaxine and mirtazepine) and their interaction with morphine and naloxone in mice
Article
  • Jul 2011
to study the probable site of antinociceptive action of SSRI (fluoxetine, escitalopram) and atypical antidepressants (mirtazapine, venlafaxine) and their interaction with morphine and naloxone. the study was conducted on albino mice (25-35 grams) of either sex. Different doses of morphine (0.5 and 1 mg/kg), fluoxetine (2, 5 and 10 mg/kg), venlafaxine (30, 40 and 50 mg/kg), mirtazapine (3, 5 and 7 mg/kg) and escitalopram (2.5, 5 and 10 mg/kg) were administered subcutaneously to obtain their subanalgesic doses using tail flick analgesiometer. Tail flick latencies were obtained at 15, 30, 60 and 120 min. after drug administration. Naloxone (1 mg/kg) was administered 10 minutes prior to test drug for testing antagonism. fluoxetine (5 and 10 mg/kg), mirtazapine (5 and 7 mg/kg) and venlafaxine (40 and 50 mg/kg) were found to have antinociceptive activity but not at lower doses. Escitalopram failed to show any antinociceptive activity at any of the doses used. The antinociceptive effect of all the drugs was antagonized by naloxone (1 mg/kg). Further, subanalgesic doses of fluoxetine, mirtazapine and venlafaxine showed analgesic activity with suboptimal dose of morphine (0.5 mg/kg). fluoxetine, mirtazapine and venlafaxine have antinociceptive activity whereas escitalopram doesn't; their site of action seems to be the same as that of opioid analgesics ('mue' receptors). However, other pathways (cholinergic, histaminic, noradrenergic, GABAergic) may be involved in mediation of their analgesic activity, deserving further elucidation. Results apparently show that these drugs may be useful in the management of pain as monotherapy or in combination with other opioids.
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Serotonin enhances β-endorphin secretion to lower plasma glucose in streptozotocin-induced diabetic rats
Article
  • Apr 2007
  • LIFE SCI
Although serotonin, serotonin uptake inhibitors and serotonin precursors (including tryptophan or 5-hydroxytryptophan) are known to have hypoglycemic action in rodents or human, it is not clear whether serotonin has hypoglycemic effect in streptozotocin-induced diabetic rats (STZ-diabetic rats). The aim of this study was to investigate the action of serotonin in regulating the plasma glucose STZ-diabetic rats. Plasma glucose, insulin, beta-endorphin and adrenaline were assessed after intraperitoneal administration of serotonin. Serotonin produced hypoglycemic effects without altering plasma insulin and adrenaline levels but increasing beta-endorphin level in STZ-diabetic rats. The glycogen content in soleus muscle was increased at 90 min after application of serotonin (0.3 mg/kg) in STZ-diabetic rats. Dihydroergotamine (non-selective 5-HT receptor blocker) and pimozide (5-HT(7) receptor blocker) abolished the hypoglycemic effect of serotonin in STZ-diabetic rats. Serotonin-induced hypoglycemic effect in association with the increase of beta-endorphin release was abolished in bilaterally adrenalectomized STZ-diabetic rats. In isolated adrenal gland of STZ-diabetic rats, the increase of beta-endorphin secretion in response to serotonin was reduced by either dihydroergotamine or pimozide. Pretreatment with naloxone (1.0 mg/kg, i.p.) prevented serotonin-induced plasma glucose lowering effect in STZ-diabetic rats. The results demonstrated that serotonin may activate 5-HT(7) receptor on rat adrenal gland to enhance of beta-endorphin secretion, which then stimulates the opioid receptor to increase peripheral glucose utilization, resulting in decreased plasma glucose levels in STZ-diabetic rats.
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Glucose dysregulation associated with antidepressant agents: An analysis of 17 published case reports
Article
  • Jun 2011
Although there are several case reports in literature linking use of antidepressants and disturbances in glucose control, it is difficult to identify risk factors for serious adverse drug events from individual case reports. The aim of this review is to provide a descriptive analysis of the demographic and clinical characteristics of published glucose dysregulation case reports following initiation of antidepressant agents. Published case reports of glucose dysregulation associated with antidepressants were accessed through PubMed (Medline), PsycINFO, and Web of Science (WOS) between January 1, 1970 and April 30, 2010. The following key words were used: antidepressant agents, glucose dysregulation, hypoglycemia, hyperglycemia, diabetes mellitus, and diabetic ketoacidosis. Case reports were excluded if glucose dysregulation occurred after a drug overdose/improper dosing or after the patient was prescribed drugs known to cause glucose disturbances in addition to antidepressant agents. Out of the 17 cases reports reviewed, nine (53%) were of hyperglycemia while eight (47%) were of hypoglycemia. Hyperglycemia was reported following treatment with clomipramine, fluvoxamine, imipramine, mianserin, mirtazapine, paroxetine, and sertraline. Hypoglycemia was reported following treatment with doxepine, fluoxetine, imipramine, nefazodone, nortriptyline, maprotiline, and sertraline. Fourteen out of the seventeen patients were female (82%) while ten had a history of diabetes mellitus (59%). The average age of the patients was 53.9 (SD = 17.5) years (range: 24-84 years). The time to onset of glucose dysregulation ranged from 4 days to 5 months after initiation of antidepressant therapy. More than two-thirds (68%) of the cases (n = 11) reported glucose control disturbances within 1 month of therapy. It is not clear from published case reports whether changes in glucose regulation, following antidepressant therapy initiation are due to antidepressants or changes in mood and lifestyle. Nonetheless, healthcare providers should be aware of the potential changes in glucose regulation especially in the first month of antidepressant therapy, and use appropriate clinical and laboratory monitoring to prevent serious adverse events in patients at risk.
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Insulin resistance and non-insulin-dependent diabetes mellitus: Cellular and molecular mechanisms
Article
  • May 1995
Non-insulin-dependent diabetes mellitus is a complex metabolic disorder that involves numerous biochemical abnormalities, a heterogenous clinical picture, and a polygenic hereditary component. The pathophysiologic state involves increased basal hepatic glucose production, decreased insulin-mediated glucose utilization in target tissues, and altered pancreatic function with decreased beta cell function and enhanced glucagon secretion. Prospective studies indicate that insulin resistance and hyperinsulinemia exist in the prediabetic state at a time when glucose tolerance is normal. When hyperglycemia supervenes, both insulin secretion and insulin-mediated glucose utilization are further compromised, mediated in part by sustained hyperglycemia itself. Insulin resistance may occur at any level in the biologic action of insulin, from initial binding to cell surface receptors to the phosphorylation cascade that is initiated by autophosphorylation of the insulin receptor. Receptors isolated from patients with non-insulin-dependent diabetes mellitus have compromised autophosphorylation-kinase activity when isolated from adipocytes, liver, erythrocytes, and skeletal muscle. The magnitude of the decrease in insulin receptor kinase activity is correlated with the degree of fasting hyperglycemia. However, the defect in insulin receptor kinase activity is normalized after weight reduction or other measures that reduce hyperglycemia, indicating the secondary nature of the defect. Clarification of the mechanisms underlying insulin resistance in non-insulin-dependent diabetes mellitus will lead to new treatment modalities for this disease.
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Slovenia e-mail: miran.brvar@kclj.si G. Koželj Institute of Forensic Medicine, Faculty of Medicine Korytkova 2, 1000 Ljubljana, Slovenia e-mail: gordana.kozelj@mf.uni-lj.si L. P. Mašič Faculty of Pharmacy
  • M Brvar
M. Brvar (*) Centre for Clinical Toxicology and Pharmacology, Division of Internal Medicine, University Medical Centre Ljubljana, Zaloška cesta 7, Ljubljana, Slovenia e-mail: miran.brvar@kclj.si G. Koželj Institute of Forensic Medicine, Faculty of Medicine, University of Ljubljana, Korytkova 2, 1000 Ljubljana, Slovenia e-mail: gordana.kozelj@mf.uni-lj.si L. P. Mašič Faculty of Pharmacy, University of Ljubljana, Aškerčeva cesta 7, 1000 Ljubljana, Slovenia e-mail: lucija.peterlinmasic@ffa.uni-lj.si Eur J Clin Pharmacol DOI 10.1007/s00228-014-1784-9 References
F rench As soci ation o f R egional Pharmacovigilance Centres (2013) Tramadol and hypoglycaemia: comparison with other step 2 analgesic drugs
  • 1063-1067
  • C Bourne
  • A Gouraud
  • A Daveluy
  • A Grandvuillemin
  • Descotes P J Auriche
Bourne C, Gouraud A, Daveluy A, Grandvuillemin A, Auriche P, Descotes J, Vial T, F rench As soci ation o f R egional Pharmacovigilance Centres (2013) Tramadol and hypoglycaemia: comparison with other step 2 analgesic drugs. Br J Clin Pharmacol 75:1063–1067. doi:10.1111/j.1365-2125.2012.04451.x