c-peptide and Cognition-Disorders

With the changes of life style, diabetes and its complications have become a major cause of morbidity and mortality. It is reasonable to anticipate a continued rise in the incidence of diabetes and its complications along with the aging of the population, increase in adult obesity rate, and other risk factors. Diabetic encephalopathy is one of the severe microvascular complications of diabetes, characterized by impaired cognitive functions, and electrophysiological, neurochemical, and structural abnormalities. It may involve direct neuronal damage caused by intracellular glucose. However, the pathogenesis of this disease is complex and its diagnosis is not very clear. Previous researches have suggested that chronic metabolic alterations, vascular changes, and neuronal apoptosis may play important roles in neuronal loss and damaged cognitive functions. Multiple factors are responsible for neuronal apoptosis, such as disturbed insulin growth factor (IGF) system, hyperglycemia, and the aging process. Recent data suggest that insulin/C-peptide deficiency may exert a primary and key effect in diabetic encephalopathy. Administration of C-peptide partially improves the condition of the IGF system in the brain and prevents neuronal apoptosis in the hippocampus of diabetic patients. Those findings provide a basis for application of C-peptide as a potentially effective therapy for diabetes and diabetic encephalopathy.

Topics: Animals; Brain Diseases; C-Peptide; Cognition Disorders; Diabetes Complications; Humans; Risk Factors; Stroke

In this review we will describe the interaction between insulin and C-peptide which enhances and attenuates insulin-signaling functions. We will describe how replenishment of C-peptide prevents and reverses the early metabolic abnormalities in type 1 diabetic polyneuropathy, such as Na(+)/K(+)-ATPase activity and endoneurial vascular NO release, resulting in prevention and reversal of early nerve dysfunction. The effects on expression of neurotrophic factors and their receptors, mediated by corrections of early gene responses and transcription factors, have downstream beneficial effects on cytoskeletal protein mRNAs and protein expression. Similar effects probably underlie corrections of cell adhesive molecules. The end-effects are prevention and reversal of myelinated and unmyelinated axonal degeneration, atrophy, and loss. Similarly, progressive degeneration of the node and paranode is prevented and repaired by C-peptide replacement with normalization of the molecular constituents of these functionally important structures. Cognitive dysfunction is now recognized as a complication of type 1 diabetes. Experimentally it is linked to impaired synaptic plasticity and eventually apoptotic neuronal loss caused by impaired insulin action and neurotrophic support. C-peptide replacement partially prevents hippocampal neuronal apoptosis and cognitive deficits. It is therefore becoming increasingly clear that C-peptide has major functions in supporting insulin action with a multitude of beneficial effects on diabetic polyneuropathy and primary diabetic encephalopathy in type 1 diabetes.

Topics: Animals; Brain Diseases, Metabolic; C-Peptide; Cognition Disorders; Diabetes Complications; Diabetes Mellitus, Type 1; Diabetic Neuropathies; Gene Expression Regulation; Humans; Insulin; Signal Transduction

Diabetic polyneuropathy (DPN) occurs more frequently in type 1 diabetes resulting in a more severe DPN. The differences in DPN between the two types of diabetes are due to differences in the availability of insulin and C-peptide. Insulin and C-peptide provide gene regulatory effects on neurotrophic factors with effects on axonal cytoskeletal proteins and nerve fiber integrity. A significant abnormality in type 1 DPN is nodal degeneration. In the type 1 BB/Wor-rat, C-peptide replacement corrects metabolic abnormalities ameliorating the acute nerve conduction defect. It corrects abnormalities of neurotrophic factors and the expression of neuroskeletal proteins with improvements of axonal size and function. C-peptide corrects the expression of nodal adhesive molecules with prevention and repair of the functionally significant nodal degeneration. Cognitive dysfunction is a recognized complication of type 1 diabetes, and is associated with impaired neurotrophic support and apoptotic neuronal loss. C-peptide prevents hippocampal apoptosis and cognitive deficits. It is therefore clear that substitution of C-peptide in type 1 diabetes has a multitude of effects on DPN and cognitive dysfunction. Here the effects of C-peptide replenishment will be extensively described as they pertain to DPN and diabetic encephalopathy, underpinning its beneficial effects on neurological complications in type 1 diabetes.

Topics: Animals; Brain Diseases; C-Peptide; Cognition Disorders; Diabetes Mellitus, Type 1; Diabetic Neuropathies; Hyperalgesia; Rats; Rats, Inbred BB

Type 2 diabetes has been associated with diminished late-life cognition; less is known about relations of insulin levels and insulin secretion to cognitive change among persons without diabetes. We examined prospectively relations of fasting insulin levels and insulin secretion to cognitive decline among healthy, community-dwelling older men without diabetes.. Fasting plasma insulin and C-peptide (insulin secretion) levels were measured in 1,353 nondiabetic men, aged 60-92 years (mean = 71.3 years), in the Physicians' Health Study II, who participated in cognitive testing an average of 3.3 years later. Two assessments were administered 2 years apart (range = 1.5-4.0 years) using telephone-based tests (general cognition, verbal memory and category fluency). Primary outcomes were the Telephone Interview for Cognitive Status (TICS), global cognition (averaging all tests) and verbal memory (averaging 4 verbal tests). Multivariable linear regression models were used to estimate the relations of insulin and C-peptide to cognitive decline.. Higher fasting insulin was associated with a greater decline on all tests, after adjustment. Findings were statistically significant for the TICS and category fluency, e.g. the multivariable-adjusted mean difference (95% CI) in decline for men with the highest versus lowest insulin levels was -0.62 (-1.15, -0.09) points on the TICS (p for trend = 0.04); this difference was similar to that between men 7 years apart in age. Similarly, there was a greater decline across all tests with increasing C-peptide, but the findings were statistically significant only for the global score (p for trend = 0.03).. Higher fasting insulin and greater insulin secretion in older men may be related to overall cognitive decline, even in the absence of diabetes.

Topics: Aged; Aged, 80 and over; Aging; C-Peptide; Cognition; Cognition Disorders; Fasting; Health Status; Health Surveys; Humans; Insulin; Interviews as Topic; Linear Models; Male; Middle Aged; Neuropsychological Tests; Radioimmunoassay; Reference Values; Surveys and Questionnaires

To test whether cognitive function is impaired in early states of diabetes and to identify possible risk factors for cognitive impairment.. A cross-sectional analysis within the German Diabetes Study included patients with type 1 or type 2 diabetes within the first year after diagnosis or five years after study inclusion and metabolically healthy individuals. Participants underwent comprehensive metabolic phenotyping and testing of different domains of cognitive function. Linear regression models were used to compare cognition test outcomes and to test associations between cognitive function and possible influencing factors within the groups.. In participants with recently diagnosed diabetes, verbal memory was poorer in patients with type 2 diabetes (. Verbal memory is impaired in individuals with recently diagnosed type 2 diabetes and likely associated with higher body mass. This trial is registered with the trial registration number NCT01055093.

Topics: Adult; Aged; Biomarkers; Blood Glucose; Body Mass Index; C-Peptide; Cognition; Cognition Disorders; Cross-Sectional Studies; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Female; Germany; Glycated Hemoglobin; Humans; Intelligence; Male; Memory; Middle Aged; Obesity; Prognosis; Prospective Studies; Risk Factors; Sex Factors; Time Factors; Verbal Behavior

This study aims to investigate whether altered baseline brain activity exists in type 2 diabetes mellitus (T2DM) patients using resting-state functional magnetic resonance imaging (rs-fMRI) and whether abnormal neural activity in the middle temporal gyrus (MTG) is correlated with cognitive function.. T2DM patients (n=28) were compared with nondiabetic age-, sex-, and education-matched control subjects (n=29) using rs-fMRI. We computed the amplitude of low-frequency fluctuations (ALFF) of fMRI signals to measure spontaneous neuronal activity and detect the relationship between rs-fMRI information and clinical data.. Compared with healthy controls, T2DM patients had significantly decreased ALFF values in the bilateral middle temporal gyrus, left fusiform gyrus, left middle occipital gyrus, right inferior occipital gyrus; and increased ALFF values in both the bilateral cerebellum posterior lobe and right cerebellum culmen. Moreover, we found an inverse correlation between the ALFF values in the MTG and both the HbA1c (r=-0.451, p=0.016) and the score of Trail Making Test-B (r=-0.420, p=0.026) in the patient group. On the other hand, C-peptide level and pancreatic β-cell function had a positive correlation (r=0.429, p=0.023; r=0.453, p=0.016, respectively) with the ALFF value in the middle temporal gyrus.. The present study confirms that T2DM patients have altered ALFF in many brain regions, which is associated with poor neurocognitive performances, severity of consistent hyperglycemic state and impaired β-cell function. ALFF disturbance in MTG may play a central role in cognitive decline associated with T2DM and serve as reference for future clinical diagnosis.

Topics: Aged; Blood Glucose; Brain; Brain Mapping; C-Peptide; Case-Control Studies; Cognition Disorders; Diabetes Mellitus, Type 2; Female; Glycated Hemoglobin; Humans; Magnetic Resonance Imaging; Male; Middle Aged; Neuropsychological Tests; Temporal Lobe

Insulin degradation pathways may be related to Alzheimer's disease pathology. In preliminary analyses, we considered the relation of combined lower insulin secretion (c-peptide) and higher insulin--possibly a phenotype for impaired insulin degradation--to cognitive decline.. Fasting plasma c-peptide and insulin were measured in 1,187 non-diabetic Nurses' Health Study participants (mean age = 64 years). Cognitive testing began 10 years later. Participants completed three repeated assessments (over an average span of 4.4 years) of verbal memory, a strong predictor of Alzheimer disease development. C-peptide and insulin distributions were dichotomized at their medians to create four cross-tabulated categories. Multivariable linear mixed effects models were used to relate c-peptide/insulin categories to cognitive decline.. Compared to the lower c-peptide/lower insulin group, women with lower c-peptide/higher insulin had a significantly faster rate of verbal memory decline: the mean difference was -0.05 units/year (95% CI -0.09,-0.01). This mean difference was similar to that which we found for women 5 years apart in age, indicating that having a profile of lower c-peptide/higher insulin appeared cognitively equivalent to aging by five years on tests of verbal memory. For women with higher c-peptide/higher insulin, the estimated mean difference in decline compared to those in the lower c-peptide/lower insulin group was statistically significant, but slightly lower, at -0.04 units/year (95% CI: -0.07,-0.02).. These preliminary analyses of a possible phenotype of impaired insulin degradation provide supportive evidence that deficits in insulin degradation may be related to late-life verbal memory decline.

Topics: Aged; Aging; Alzheimer Disease; C-Peptide; Cognition; Cognition Disorders; Female; Humans; Insulin; Male; Memory; Middle Aged; Multivariate Analysis; Phenotype

Both type 2 diabetes and hyperinsulinemia have been related to diminished cognition. To address independent effects of increasing mid-life insulin secretion on late-life cognition, we prospectively examined the relation of plasma C-peptide levels to cognitive decline in a large sample of older women without diabetes or stroke.. Plasma C-peptide levels were measured in 1187 "young-old" women (mean age=64 years) without diabetes in the Nurses' Health Study. Cognitive decline was assessed approximately 10 years later. Three repeated cognitive batteries were administered over an average of 4.4 years using telephone-based tests of general cognition, verbal memory, category fluency, and attention. Primary outcomes were general cognition (measured by the Telephone interview for Cognitive Status [TICS], as well as a global score averaging all tests) and a verbal memory score averaging four tests of word-list and paragraph recall. Linear mixed effects models were used to compute associations between C-peptide levels and rates of cognitive decline.. Higher C-peptide levels were associated with faster decline in global cognition and verbal memory. Compared to those in the lowest C-peptide quartile, multivariable-adjusted mean differences (95% CI) in rates of decline for women in the highest quartile were -0.03 (-0.06,-0.00) units/year for the global score, and -0.05 (-0.09,-0.02) units/year for verbal memory. Each one standard-deviation increase in C-peptide was associated with significantly faster decline on the TICS (p-trend=0.05), global score (p-trend=0.04) and verbal memory (p-trend=0.006).. Higher levels of insulin secretion in those without diabetes may be related to decline in general cognition and verbal memory.

Topics: Adult; Aging; C-Peptide; Cognition; Cognition Disorders; Cohort Studies; Diabetes Mellitus; Female; Humans; Linear Models; Middle Aged; Prospective Studies; Reference Values; Residence Characteristics; United States

To determine whether systematic evaluation of cognitive function by the Mini-Mental State Examination (MMSE) allows the objective detection and documentation of cognitive deterioration in patients referred for evaluation of suspected hypoglycaemic disorders by the 72-h fast.. Prospective case series.. In 50 patients referred for evaluation of suspected hypoglycaemic disorders, the MMSE score (maximum 30 points) was assessed at the start and at the end of the fast.. The fast was terminated before 72 h in 14 patients because they developed neuroglycopenic symptoms due to hypoglycaemic disorders. Their MMSE score fell from a median of 29 points (range 20-30) at the beginning to 17 points (range 0-24) at the termination of the fast. The score dropped by > or =6 points in all patients with hypoglycaemic disorders. Median (range) plasma glucose concentration at the end of the fast was 2.1 (1.1-2.5) mmol/l. Thirty-six individuals developed no neuroglycopenic symptoms throughout the 72-h fast, their MMSE score remained between 27 and 30 throughout the fast and their median plasma glucose concentration dropped to 2.9 (2-3.6) mmol/l.. Systematic evaluation of cognitive function by the MMSE at the beginning and at the termination of the fast allows objective determination and documentation of the deterioration of the cognitive state in patients with hypoglycaemic disorders. A decline in the cognitive performance by > or =6 points in the MMSE score rather than a distinct plasma glucose concentration should be used as the criterion to terminate the prolonged fast before 72 h.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Blood Glucose; C-Peptide; Cognition; Cognition Disorders; Fasting; Female; Humans; Hypoglycemia; Insulin; Male; Middle Aged; Prospective Studies; Time Factors

Primary diabetic encephalopathy is a recently recognized late complication of diabetes resulting in a progressive decline in cognitive faculties. In the spontaneously type 1 diabetic BB/Wor rat, we recently demonstrated that cognitive impairment was associated with hippocampal apoptotic neuronal loss. Here, we demonstrate that replacement of proinsulin C-peptide in this insulinopenic model significantly prevented spatial learning and memory deficits and hippocampal neuronal loss. C-peptide replacement prevented oxidative stress-, endoplasmic reticulum-, nerve growth factor receptor p75-, and poly(ADP-ribose) polymerase-related apoptotic activities. It partially ameliorated apoptotic stresses mediated via impaired insulin and IGF activities. These findings were associated with the prevention of increased expression of Bax and active caspase 3 and the frequency of caspase 3-positive neurons. The results show that several partially interrelated apoptotic mechanisms are involved in primary encephalopathy and suggest that impaired insulinomimetic action by C-peptide plays a prominent role in cognitive dysfunction and hippocampal apoptosis in type 1 diabetes. Although these abnormalities were not fully prevented by C-peptide replacement, the findings suggest that this regime will substantially prevent cognitive decline in the type 1 diabetic population.

Topics: Animals; Apoptosis; C-Peptide; Caspase 12; Caspases; Cognition; Cognition Disorders; Diabetes Mellitus, Type 1; Disease Models, Animal; Hippocampus; Male; Maze Learning; Polymerase Chain Reaction; Prediabetic State; Rats; Rats, Inbred BB

Topics: Adult; Angiography; Blood Glucose; C-Peptide; Cognition Disorders; Diagnosis, Differential; Female; Glucose Tolerance Test; Humans; Hyperinsulinism; Hypoglycemia; Insulinoma; Male; Middle Aged; Pancreatectomy; Pancreatic Neoplasms; Splenectomy; Syncope; Tomography, X-Ray Computed

To assess the relative roles of insulin and hypoglycaemia on induction of neuroendocrine responses, symptoms and deterioration of cognitive function (12 cognitive tests) during progressive decreases in plasma glucose, and to quantitate glycaemic thresholds, 22 normal, non-diabetic subjects (11 males, 11 females) were studied on four occasions: prolonged fast (n = 8, saline euglycaemia study, SA-EU), stepped hypoglycaemia (plasma glucose plateaus of 4.3, 3.7, 3 and 2.3 mmol/l) or euglycaemia during insulin infusion at 1 and 2 mU.kg-1.min-1 (n = 22, high-insulin hypoglycaemia and euglycaemia studies, HI-INS-HYPO and HI-INS-EU, respectively), and stepped hypoglycaemia during infusion of insulin at 0.35 mU.kg-1.min-1 (n = 9, low-insulin hypoglycaemia study, LO-INS-HYPO). Insulin per se (SA-EU vs HI-INS-EU), suppressed plasma glucagon (approximately 20%) and pancreatic polypeptide (approximately 30%), whereas it increased plasma noradrenaline (approximately 10%, p < 0.05). Hypoglycaemia per se (HI-INS-HYPO vs HI-INS-EU) induced responses of counterregulatory hormones (CR-HORM), symptoms and deteriorated cognitive function. With the exception of suppression of endogenous insulin secretion, which had the lowest glycaemic threshold of 4.44 +/- 0.06 mmol/l, pancreatic polypeptide, glucagon, growth hormone, adrenaline and cortisol had similar glycaemic thresholds (approximately 3.8-3.6 mmol/l); noradrenaline (3.1 +/- 0.0 mmol/l), autonomic (3.05 +/- 0.06 mmol/l) and neuroglycopenic (3.05 +/- 0.05 mmol/l) symptoms had higher thresholds. All 12 tests of cognitive function deteriorated at a glycaemic threshold of 2.45 +/- 0.06 mmol/l, but 7 out of 12 tests were already abnormal at a glycaemic threshold of 2.89 +/- 0.06 mmol/l. Although all CR-HORM had a similar glycaemic threshold, the lag time of response (the time required for a given parameter to increase) of glucagon (15 +/- 1 min) and growth hormone (14 +/- 3 min) was shorter than adrenaline (19 +/- 3 min) and cortisol (39 +/- 4 min) (p < 0.05). With the exception of glucagon (which was suppressed) and noradrenaline (which was stimulated), insulin per se (HI-INS-HYPO vs LO-INS-HYPO) did not affect the responses of CR-HORM, and did not influence the symptoms or the cognitive function during hypoglycaemia. Despite lower responses of glucagon, adrenaline and growth hormone (but not thresholds) in females than males, females were less insulin sensitive than males during stepped hypoglycaemia.

Topics: Adult; Autonomic Nervous System; Blood Glucose; C-Peptide; Cognition; Cognition Disorders; Epinephrine; Female; Glucagon; Glucose Clamp Technique; Growth Hormone; Hormones; Humans; Hydrocortisone; Hypoglycemia; Insulin; Insulin Secretion; Male; Norepinephrine; Pancreatic Polypeptide; Reference Values; Sex Factors; Time Factors