Normal insulin receptors in mitochondrial myopathies with ophthalmoplegia

Seven patients with histologically proven mitochondrial myopathy with ophthalmoplegia (OMM), 6 of them nondiabetic, 1 affected by diabetes mellitus (DM), were submitted to a study of glucose tolerance and of insulin receptors on peripheral mononuclear cells and cultured skin fibroblasts. The diabetic patient, who had the typical features of the Kearns-Sayre syndrome (KSS) and deleted muscle mitochondrial DNA (mtDNA) presented a low insulin secretion rate under physiological stimuli (intravenous glucose and glucagon) whereas the insulin receptor parameters were found normal. The other patients showed a normal glucose tolerance and normal insulin receptors. Our data support the hypothesis that insulin receptors are not involved in the pathogenesis of DM associated with mitochondrial encephalomyopathies, in contrast to other neuromuscular inherited disorders. The clinical and biological features of DM presented by our KSS patient show normal insulin receptor parameters in spite of a defective insulin secretion, possibly depending on mitochondrial dysfunction.     

Overexpression of p35 in Min6 pancreatic beta cells induces a stressed neuron-like apoptosis

Cdk5 activity has been implicated in brain development and the regulation of many neuronal processes. Recently, the expression of p35 and Cdk5 activity has been reported in pancreatic beta cells. Decreased Cdk5 activity enhanced glucose-stimulated insulin secretion. This suggests that Cdk5 may play an important role in the regulation of insulin secretion. To further understand how Cdk5 regulates insulin secretion in glucose-stimulated pancreatic β cells, we first confirmed the presence of a low level of p35 in pancreatic Min6 cells. Next, in a time-course experiment in high glucose (25 mM) we showed that endogenous p35 increased gradually accompanied by a 3-fold increase in Cdk5 activity by 16 h. Insulin secretion, however, doubled after 2 h followed by progressive downregulation, negatively correlated with Cdk5 activity. On the other hand, overexpression of p35 in these cells resulted in more than a three-fold increase in Cdk5 activity within 2 h coupled to a 50% reduction in insulin secretion in both high and low (3 mM) glucose. Most significantly, cells overexpressing p35, treated with high glucose for 4 h, showed induction of p25, the p35-derived truncated fragment which hyperactivates Cdk5 in neurons. As a result, insulin secretion was inhibited and cells became apoptotic. Roscovitine or co-infection of dominant negative Cdk5 (dnCdk5) with p35 increased insulin secretion and inhibited apoptosis. These results suggest that the model for deregulation and hyperactivation of Cdk5 in neurodegeneration may apply to the pathology seen in type 2 diabetes (T2DM). It is consistent with the view that Alzheimer's disease and T2DM are linked metabolically and pathologically by Cdk5 in a number of ways.     

Elevated FGF 21 in myotonic dystrophy type 1 and mitochondrial diseases

Introduction: Human fibroblast growth factor 21 (FGF21) is a regulator of lipid and glucose metabolism. It is expressed in skeletal muscle and may be a sensitive and specific marker for mitochondrial diseases and other neuromuscular disorders. Methods: Serum FGF21 levels were determined in 71 human samples. Thirty patients with mitochondrial disease, 16 patients with myotonic dystrophy type 1 (DM1), 5 patients with facioscapulohumeral dystrophy, and 20 healthy controls were enrolled. Results Serum FGF21 levels were significantly elevated in patients with progressive external ophthalmoplegia and DM1 compared with patients with facioscapulohumeral dystrophy, other types of mitochondrial diseases, and controls. In the mitochondrial disorder group, serum FGF21 levels were related to the number of ragged blue fibers. Significant insulin resistance was found in DM1 that might be responsible for FGF21 elevation. Conclusions FGF21 elevation may be associated with certain types of mitochondrial disease, and it is influenced by insulin resistance. Muscle Nerve 55 : 564–569, 2017     

Insulin,but not proinsulin C-peptide,enhances platelet fibrinogen binding in vitro in Type 1 diabetes mellitus patients and healthy subjects

INTRODUCTION: Insulin treatment is essential in Type 1 diabetes mellitus (DM). However, previous studies have shown complex effects of insulin on platelet function. Proinsulin C-peptide has shown beneficial effects in Type 1 DM, but it is not known if it can affect platelet activation. We thus investigated how insulin, C-peptide, and their combination influence platelets from DM patients and healthy subjects. MATERIALS AND METHODS: Hirudinized blood from patients (n = 10) and healthy subjects (n = 10) was preincubated in the absence or presence of insulin (10 and 100 microU/ml), C-peptide (0.3, 1, and 10 nM), or the combination (1 nM C-peptide + 100 microU/ml insulin or 10 nM C-peptide + 100 microU/ml insulin) and further incubated without or with 10(-6) M ADP. Platelet activation was monitored by platelet fibrinogen binding and P-selectin expression using whole blood flow cytometry. Data are presented as binding index (BI), which integrates the percentage of activated cells and their mean fluorescence intensity. RESULTS: Insulin enhanced ADP-induced platelet fibrinogen binding in both Type 1 DM patients and healthy subjects. For example, ADP-stimulated platelet fibrinogen BI increased from 4.25 +/- 0.74 to 8.63 +/- 2.00 with 10 microU/ml insulin (P < .05) in Type 1 DM patients. However, insulin did not increase platelet P-selectin expression. Proinsulin C-peptide did not influence platelet fibrinogen binding or P-selectin expression in either Type 1 DM patients or healthy subjects. The combination of C-peptide and insulin had similar effects as insulin alone. CONCLUSIONS: Insulin at physiological concentrations enhances platelet fibrinogen binding in both Type 1 DM patients and healthy subjects, whilst C-peptide does not influence platelet activation.     

Novel nervous and multi-system regenerative therapeutic strategies for diabetes mellitus with mTOR

Throughout the globe,diabetes mellitus(DM) is increasing in incidence with limited therapies presently available to prevent or resolve the significant complications of this disorder.DM impacts multiple organs and affects all components of the central and peripheral nervous systems that can range from dementia to diabetic neuropathy.The mechanistic target of rapamycin(m TOR) is a promising agent for the development of novel regenerative strategies for the treatment of DM.m TOR and its related signaling pathways impact multiple metabolic parameters that include cellular metabolic homeostasis,insulin resistance,insulin secretion,stem cell proliferation and differentiation,pancreatic β-cell function,and programmed cell death with apoptosis and autophagy.m TOR is central element for the protein complexes m TOR Complex 1(m TORC1) and m TOR Complex 2(m TORC2) and is a critical component for a number of signaling pathways that involve phosphoinositide 3-kinase(PI 3-K),protein kinase B(Akt),AMP activated protein kinase(AMPK),silent mating type information regulation 2 homolog 1(Saccharomyces cerevisiae)(SIRT1),Wnt1 inducible signaling pathway protein 1(WISP1),and growth factors.As a result,m TOR represents an exciting target to offer new clinical avenues for the treatment of DM and the complications of this disease.Future studies directed to elucidate the delicate balance m TOR holds over cellular metabolism and the impact of its broad signaling pathways should foster the translation of these targets into effective clinical regimens for DM.     

Glucose metabolism alterations in Friedreich's ataxia

We have characterized the abnormalities of glucose metabolism associated with Friedreich's ataxia (FA) by studying plasma glucose, insulin, growth hormone (GH), and glucagon before and after an oral glucose tolerance test (OGTT), an IV glucose load, and an IV arginine load, in 21 patients and in controls. Twelve patients were normotolerant (NT) to glucose, five glucose-intolerant (IT), and four diabetic (DM). Insulin secretion of IT patients was increased and delayed during OGTT. Interestingly, the insulin release during arginine load was significantly decreased in NT and IT as well as in DM patients. The GH response to OGTT was altered in IT patients. Plasma glucagon after an arginine load was significantly higher in patients than in controls. The results indicate that FA is associated with insulin resistance, beta-cell deficiency, and type I diabetes. These alterations might be genetically linked or metabolically related to the primary defect in FA. Their interplay or independent effects are responsible for abnormalities of glucose metabolism in FA.     

Limited Alzheimer-type neurodegeneration in experimental obesity and type 2 diabetes mellitus

Alzheimer's disease (AD) is associated with brain insulin resistance and insulin deficiency, whereas Type 2 diabetes mellitus (T2DM) is associated with peripheral insulin resistance. This study assesses the degree to which T2DM causes AD-type neurodegeneration. In a C57BL/6 mouse model of obesity and T2DM, we characterized the histopathology, gene expression, and insulin and insulin-like growth factor (IGF)-receptor binding in temporal lobe. High fat diet (HFD) feeding for 16 weeks doubled mean body weight, caused T2DM, and marginally reduced mean brain weight. These effects were associated with significantly increased levels of tau, IGF-I receptor, insulin receptor substrate-1 (IRS-1), IRS-4, ubiquitin, glial fibrillary acidic protein, and 4-hydroxynonenol, and decreased expression of beta-actin. HFD feeding also caused brain insulin resistance manifested by reduced BMAX for insulin receptor binding, and modestly increased brain insulin gene expression. However, HFD-fed mouse brains did not exhibit AD histopathology, increases in amyloid-beta or phospho-tau, or impairments in IGF signaling or acetylcholine homeostasis. Obesity and T2DM cause brain atrophy with insulin resistance, oxidative stress, and cytoskeleton degradation, but the absence of many features that typify AD suggests that obesity and T2DM may contribute to, but are not sufficient to cause AD.     

A case of myasthenia gravis accompanied by large thymoma and anti-GAD antibody]

A 61-year-old woman had repeated episodes of muscle weakness of face, neck and limbs for 18 years. She was diagnosed as having myasthenia gravis (MG) by the positive anti-acetylcholine receptor antibody and findings of electromyogram. Simultaneously, she was noticed to have diabetes mellitus with high titers of anti-glutamic acid decarboxylase (GAD) antibody. Magnetic resonance imaging showed a large thymoma. In spite of the improvement of MG after thymectomy, the insulin secretion slowly exacerbated during next two years. The clinical course of her disease was characteristic as slowly progressive insulin dependent diabetes mellitus (SPIDDM). She continued to have positive autoantibody against beta-cell of pancreas. Recently, anti-GAD antibody is detected in patients with SPIDDM and stiffman syndrome (SS) in high rate, and it is closely associated with the cause of these syndromes. The patient did not reveal the symptoms of SS. From the clinical course, MG and SPIDDM in this patient may be caused by a common underlying autoimmune abnormality resulting from the long presence of the thymoma. MG and SPIDDM may be derived from organ-specific autoimmunopathy from the defect of self-tolerance.     

Therapy Insight: type 2 diabetes mellitus and the risk of late-onset Alzheimer's disease

A number of well-designed epidemiological studies have linked type 2 diabetes mellitus (T2DM) with an increased risk of Alzheimer's disease (AD). Several mechanisms could help to explain this proposed link, including insulin and insulin resistance, inflammatory cytokines, and oxidative stress. Obesity or physical inactivity might also influence AD through effects on hypertension, insulin sensitivity or inflammation. Typical AD pathology, such as amyloid-beta deposits, might be exacerbated by insulin dysregulation, T2DM itself, or microvascular disease that is a consequence of T2DM. T2DM patients are not routinely evaluated for cognitive outcomes, and cognitive impairment in T2DM is rarely treated. Similarly, AD patients are not routinely evaluated for T2DM or hyperinsulinemia. Current treatments for AD have only modest benefits, and several drugs that target metabolic and inflammatory pathways are being evaluated, most notably the statins, which reduce LDL and inflammation but might not influence amyloid- deposition, an important precursor for AD. Although some evidence supports a potentially important role for peroxisome proliferative activated receptor agonists such as glitazones, at present there are no published randomized clinical trials in AD patients of any drugs that target insulin or insulin resistance. Clinical implications of the T2DM-AD link include cognitive evaluations of patients with T2DM, and potential benefits for such patients through treatment with statins or diabetes drugs that target insulin.     

The link between iron,metabolic syndrome,and Alzheimer’s disease

Both Alzheimer’s disease (AD), the most common form of dementia, and type-2 diabetes mellitus (T2DM), a disease associated with metabolic syndrome (MetS), affect a great number of the world population and both have increased prevalence with age. Recently, many studies demonstrated that pre-diabetes, MetS, and T2DM are risk factors in the development of AD and have many common mechanisms. The main focus of studies is the insulin resistance outcome found both in MetS as well as in brains of AD subjects. However, oxidative stress (OS)-related mechanisms, which are well known to be involved in AD, including mitochondrial dysfunction, elevated iron concentration, reactive oxygen species (ROS), and stress-related enzyme or proteins (e.g. heme oxygenase-1, transferrin, etc.), have not been elucidated in MetS or T2DM brains although OS and iron are involved in the degeneration of the pancreatic islet β cells. Therefore, this review sets to cover the current literature regarding OS and iron in MetS and T2DM and the similarities to mechanisms in AD both in human subjects as well as in animal models.     

A case of mitochondrial myopathy, encephalopathy, lactic acidosis and stroke-like episodes (MELAS), showing temporary improvement during the treatment with eicosapentaenoic acid ethyl ester]

We report a 67-year-old man with mitochondrial myopathy, encephalopathy, lactic acidosis and stroke-like episodes (MELAS), successfully treated with eicosapentaenoic acid ethyl ester (EPA-E) for about eight months. He showed bilateral auditory disturbance and slowly progressive gait ataxia at age 50 during treatment of diabetes mellitus (DM) with subcutaneous injection of insulin since age 29. At age 58 he manifested an acute hemiparesis of right extremities for one week with no abnormal findings on neuroradiological examinations. A permanent pacemaker was implanted at age 61 to treat frequent syncopal attacks due to complete atrioventricular block. On admission to our hospital, neurological examinations revealed dementia, auditory disturbance, severe cerebellar ataxia and mild atrophy of proximal muscles with systemic hyporeflexia. Based on a point mutation in position 3243 of mitochondrial DNA, he was diagnosed as having MELAS with severe DM, auditory disturbance and cardiac conduction block. After initiation of treatment with EPA-E at a dose of 2,700 mg/day he showed temporarily an improvement in auditory disturbance, blood glucose control and cerebellar ataxia. In objective evaluations for cerebellar ataxia, we could find significant decreases in times for 20 m walking and heel-knee patting in the ninth month, and in time for tracing of a whirl from the third to the ninth month, compared with those before treatment of EPA-E (p < 0.0001). Because EPA-E is taken into mitochondrial membranes and activates electron transmission enzyme complexes, it might be a candidate for therapy of mitochondrial encephalomyopathy, including MELAS.     

Differential impact of diabetes and hypertension in the brain: adverse effects in grey matter

Diabetes mellitus types 1 and 2 (DM1 and DM2) and/or hypertension (HTN) can contribute to cognitive decline, cerebral atrophy and white matter abnormalities in humans. Adult rat models of streptozotocin-induced DM1 and genetic strains of DM2 and HTN were used to investigate relative contributions of DM and HTN for alterations in cerebral structure and function as well as insulin receptor biology using cognitive testing, magnetic resonance imaging (MRI), and histological and molecular methods. The effects of DM1 or DM2 were generally similar. DM was associated with earlier onset of cognitive impairment than with HTN alone. DM was independently correlated with brain atrophy, whereas HTN had minimal effects on brain volume. The combination of DM and HTN led to identifiable mild hippocampal neuronal loss while either DM or HTN led to synaptic loss. Only DM led to downregulation of the insulin receptor pathways' activation. In contrast, only HTN was associated with vascular luminal reduction and restricted cerebral perfusion on MRI. The impacts of DM and HTN in the brain differ, while their separate contributions can lead to some additive adverse effects within rodent brain grey matter.     

A cross-sectional study for glucose intolerance of myotonic dystrophy

We made a cross-sectional study to analyze glucose intolerance of myotonic dystrophy type 1 (DM1) with several examination including oral glucose tolerance test (OGTT), insulin tolerance test (ITT) and adiponectin. Ninety-five DM1 patients participated in this study. Health examination data from general people were used as controls. In DM1, homeostasis model assessment-insulin resistance (HOMA-IR) was higher than control even in the lowest fasting blood sugar (FBS) stage (<80 mg/dl) and insulin sensitivity assessed by ITT was low regardless of their FBS. Insulinogenic index of DM1 was positively correlated to HOMA-IR. Insulinogenic index and sum of IRI in OGTT were markedly elevated in the lowest FBS stage and declined along with elevation of FBS. Consequently, as many as 13.3% of DM1 patients with 90-110 mg/dl of FBS exhibited DM pattern, while only 1.9% in control. Adiponectin was higher in DM1 than control. Although age correlated with adiponectin in both control and DM1, its impact was stronger in DM1. DM1 predisposes insulin resistance and compensatory hyperinsulinemia exist even in patients with low FBS. We should pay attention to glucose intolerance of DM1 patients earlier than that of the general population. It seemed that 90 mg/dl of FBS is an important index as an indication of careful managements.     

Insulin and glucagon secretion in the rat: effects of gastrin releasing peptide

Immunoreactive gastrin releasing peptide (GRP) has been shown to occur in intrapancreatic nerve fibers, and to be released from the perfused porcine pancreas during electrical vagal activation. Hence, it could be anticipated that GRP may be of functional importance for the neural control of islet hormone secretion. Therefore, we investigated the effects of intravenous infusion of GRP on basal and stimulated insulin and glucagon secretion in vivo in the rat. We found that GRP, at 4.3 or 17 pmol/min, increased basal plasma concentrations of both insulin and glucagon and induced hyperglycemia. Furthermore, GRP (1.1 or 4.3 pmol/min) potentiated the plasma insulin response to glucose (7 mg/min). In contrast, the peptide (at 4.3 pmol/min) inhibited the insulin response to arginine (8.5 mg/min). Moreover, GRP increased the plasma glucagon levels during infusion of both arginine and glucose. In summary, in the rat GRP 1) stimulates basal insulin and glucagon secretion, 2) potentiates glucose-stimulated insulin secretion, 3) inhibits arginine-stimulated insulin secretion, 4) potentiates arginine-stimulated glucagon secretion, 5) counteracts the glucose-induced suppression of glucagon secretion, and 6) induces hyperglycemia. Though this study can not establish the mechanisms or physiological importance of these effects, we conclude that the intrapancreatic neuropeptide GRP has the capability to affect both insulin and glucagon secretion in vivo in the rat.     

Valproic acid modulates islet cell insulin secretion: a possible mechanism of weight gain in epilepsy patients

A significant weight gain in the course of treatment of epilepsy with valproic acid (VPA) was described in several clinical studies. We recently demonstrated that postprandial insulin levels are increased in patients with VPA therapy. This possible modulation of pancreatic insulin secretion by VPA could be due to the structure of VPA as a fatty acid derivative and thus to direct stimulation of pancreatic insulin secretion or competition with free fatty acids (FFA) for albumin binding. In order to investigate the effect of VPA on insulin secretion in pancreatic islet cells we performed in vitro experiments with islets from pancreases of multiorgan donors. After preparation, the incubation with valproate caused a time and dose-dependent increase of insulin concentration in the cell supernatant. This could also be demonstrated with the control drug, lorazepam, a benzodiazepine, but not with mirtazepin and phenytoin. It can be speculated that an increase in pancreatic insulin secretion under chronic VPA treatment enhances appetite and energy storage and is related to the observed weight gain.     

Oxidative stress biology and cell injury during type 1 and type 2 diabetes mellitus

Diabetes mellitus (DM) affects approximately 170 million individuals worldwide and is expected to alter the lives of at least 366 million individuals within a future span of 25 years. Of even greater concern is the premise that these projections are underestimated since they assume obesity levels will remain constant. Type 1 insulin-dependent DM accounts for only 5-10 percent of all diabetics but represents a highly significant health concern, since this disorder begins early in life and leads to long-term complications. In contrast, Type 2 DM is recognized as the etiology of over 80 percent of all diabetics and is dramatically increasing in incidence as a result of changes in human behavior and increased body mass index. Yet, the pathological consequences of these disorders that involve the both the neuronal and vascular systems are intimately linked through the pathways that mediate oxidative stress. Here we highlight some of the relevant oxidative pathways that determine insulin resistance through reactive oxygen species, mitochondrial dysfunction, uncoupling proteins, and endoplasmic reticulum stress. These pathways are ultimately linked to protein kinase B (Akt) and the insulin signaling pathways that determine the initial onset of glucose intolerance and the subsequent course to apoptotic cell injury. Through the elucidation of these targets, improvement in current strategies as well as the development of future clinical applications can move forward for both the prevention and treatment of Type 1 and Type 2 DM.     

A case of left dorsomedial thalamic infarction with unilateral schizophrenia-like auditory hallucinations]

We report a case of a right-handed, 73-year-old woman with auditory hallucinations lateralized to the right ear. A brain MRI revealed a small infarction in the left dorsomedial nucleus (DM) of the thalamus. The patient did not have either psychiatric or neurological prior history, and had otherwise been treated for ischemic heart disease, hypertension, and hyperlipidemia for 10 years. Two months prior to admission, she had become forgetful, and had lost her wallet several times. She concurrently began to experience auditory hallucinations in which she heard the voices of her acquaintances, or "the gods". She frequently monologized and wandered about outside following the contents of the hallucinations. Therefore, she was admitted to our institution. On admission, no apparent abnormalities were revealed by physical examinations or blood analyses. She was alert and had no aphasic symptoms. Except for memory disturbances, no neurological symptoms, including no hearing loss, were found. A brain MRI showed a small localized infarction in the left DM, but EEG findings were normal. The patient had prominent anterograde memory deficits: she hardly remembered what she had done the very same day, or the names of the doctor and hospital. She also demonstrated a retrograde amnesia of the past decade or two: she showed difficulty recalling either personal history or social events that occurred during this era. Wechsler Adult Intelligence Scale-Revised (WAIS-R) revealed a total IQ of 75 (verbal IQ 77; performance IQ 77). The verbal hallucinations continued with frequent occurrence even after admission. They included voices telling her about misfortunes, such as death or sickness, of her relatives. These turned into threats and commands, such as "I'm gonna kill ya. I attack you from behind. You, do not eat!" In addition, she occasionally experienced "third person auditory hallucination", in which several men were discussing the plan to kill her. As is characteristic of this type of case, the hallucinations always appeared in only her right ear. They did not occur in the other modalities (e.g. as a visual one). She was convinced that the hallucinations were real and looked frightened while they were happening. Whereas the anterograde amnesia continued for 6 months after admission, the retrograde amnesia gradually improved within 2 or 3 months after admission, although a partial amnesia on the past decade eventually turned out to persistent. On the other hand, the hallucinations did not ameliorate satisfactorily with risperidone (3-6 mg/day), but on augmentation with olanzapine (5-20 mg/day), they lessened gradually and almost disappeared within 6 months. She also slowly developed symptoms similar to those of frontal lobe syndrome, i.e., aspontaneity and apathy. In conclusion, our case indicates the importance of DM on memory function. It is noteworthy that schizophrenia-like hallucinations developed in the case. Localized neuronal deficits evoked by infarction in the left DM probably caused the schizophrenia-like hallucinations; the lateralization phenomenon further indicates the involvement of specific neuronal mechanisms in the mediation of the hallucinations. According to the knowledge of the functional anatomy of the DM and the lateralization phenomenon of auditory hallucinations, it is possible that the neuronal loop, comprised of the prefrontal cortex and thalamus, designated as "basal ganglia-thalamocortical circuits", in addition to the left temporal cortex, plays an important role in the development of the hallucinations in this case. This possibility might also shed light on the neurological basis of schizophrenia.     

DPP4‐inhibitor improves neuronal insulin receptor function,brain mitochondrial function and cognitive function in rats with insulin resistance induced by high‐fat diet consumption

High‐fat diet (HFD) consumption has been demonstrated to cause peripheral and neuronal insulin resistance, and brain mitochondrial dysfunction in rats. Although the dipeptidyl peptidase‐4 inhibitor, vildagliptin, is known to improve peripheral insulin sensitivity, its effects on neuronal insulin resistance and brain mitochondrial dysfunction caused by a HFD are unknown. We tested the hypothesis that vildagliptin prevents neuronal insulin resistance, brain mitochondrial dysfunction, learning and memory deficit caused by HFD. Male rats were divided into two groups to receive either a HFD or normal diet (ND) for 12 weeks, after which rats in each group were fed with either vildagliptin (3 mg/kg/day) or vehicle for 21 days. The cognitive function was tested by the Morris Water Maze prior to brain removal for studying neuronal insulin receptor (IR) and brain mitochondrial function. In HFD rats, neuronal insulin resistance and brain mitochondrial dysfunction were demonstrated, with impaired learning and memory. Vildagliptin prevented neuronal insulin resistance by restoring insulin‐induced long‐term depression and neuronal IR phosphorylation, IRS‐1 phosphorylation and Akt/PKB‐ser phosphorylation. It also improved brain mitochondrial dysfunction and cognitive function. Vildagliptin effectively restored neuronal IR function, increased glucagon‐like‐peptide 1 levels and prevented brain mitochondrial dysfunction, thus attenuating the impaired cognitive function caused by HFD.     

The Response of Glucose-Excited Neurones in the Ventromedial Hypothalamus to Decreased Glucose is Enhanced in a Murine Model of Type 2 Diabetes Mellitus

Obesity and type 2 diabetes mellitus (T2DM) are associated with dysfunctional insulin signalling and impaired central glucose sensing. Glucose sensing neurones reside in key areas of the brain involved in glucose and energy homeostasis (e.g. ventromedial hypothalamus; VMH). We have recently shown that insulin attenuates the ability of glucose-excited (GE) neurones to sense decreased glucose. We hypothesise that this effect of insulin on VMH GE neurones is impaired during T2DM when insulin signalling is dysfunctional. To test our hypotheses, we used whole cell patch clamp recording techniques to evaluate the effects of insulin on VMH GE neurones in brain slices from wild-type and diabetic ( db/db ) mice. The effects of decreasing glucose from 2.5 to 0.1 m m on VMH GE neurones were similar in wild-type and db/db mice. However, decreasing glucose from 2.5 to 0.5 m m decreased the action potential frequency, membrane potential and input resistance of VMH GE neurones to a significantly greater extent in db/db versus wild-type mice. Furthermore, insulin (5 n m ) blunted the effects of decreased glucose in wild-type, but not db/db mice. These differences in both glucose and insulin sensitivity between wild-type and db/db mice were completely ameliorated by the insulin sensitiser, Compound 2 (300 n m ). These data are consistent with our hypothesis that impaired insulin signalling in T2DM sensitises VMH GE neurones to decreased glucose.     

C-Peptide and its correlation to parameters of insulin resistance in the metabolic syndrome

The progress of metabolic syndrome (MetS) continues with the onset of type-2 diabetes mellitus (Type-2 DM) along with linkage to other disorders such as neurodegenerative, especially Alzheimer's disease (AD), via oxidative stress and low grade systemic inflammatory process. Type-2 DM and AD are health disorders of priority research. The treatment for an individual suffering with Type- 2 DM and/or AD requires monitoring by clinicians. The aim of this study was to investigate the role of C-peptide and its correlation to insulin resistance, body mass index (BMI), β cell function, insulin sensitivity, lipid profile and hemoglobin A1c (HbA1c). The study was designed to include 96 Type-2 DM individuals from India. 58.3% males and 41.7% females were selected and fasting blood samples were collected for estimation of fasting C-peptide, fasting blood sugar (FBS), postprandial blood sugar (PPBS), HbA1c and lipid profile. Analysis was done on Hitachi912 and Elecsys 2010 using Roche reagents and standard controls. Anthropometries to calculate BMI and β cell function, insulin sensitivity, and insulin resistance were obtained. The statistical tool ANOVA, followed by calculation of p-value and r ? value were applied for investigating correlation of C-peptide levels to those of high density lipoprotein-C (HDL-C), low density lipoprotein-C (LDL-C), triglycerides (TGL), HbA1c, β cell function, insulin sensitivity and insulin resistance. Highly significant positive correlations were observed in different quantiles of C-peptide levels to the studied parameters of MetS, BMI and % β cell function. Lower HDL-C level was found to be significantly related to higher C-peptide levels. Similarly, TGL and C-peptide levels displayed a significant positive correlation. A significant negative correlation was observed between C-peptide quantiles and % sensitivity. Thus, insulin resistance showed a positive correlation until the fourth quantile. No significant correlation was observed between C-peptide and HbA1c levels. This study demonstrates that assessment of C-peptide levels is a useful tool to monitor the progress of MetS among patients suffering from Type-2 DM and AD, as these disorders are intertwined to each other by common metabolic pathways. Assessment of C-peptide levels, along with HDL-C levels, in patients can be used to monitor insulin resistance.