Hyperinsulinemia or Insulin Resistance: What Impacts the Progression of Alzheimer's Disease?

Type 2 diabetes mellitus (T2D), which is often accompanied by hyperinsulinemia and insulin resistance, is associated with an increased risk for developing mild cognitive impairment and Alzheimer's disease (AD); however, the underlying mechanisms for this association are still unclear. Recent findings have shown that hyperinsulinemia and insulin resistance can coexist or be independent events. This makes it imperative to determine the contribution of these individual conditions in impacting AD. This literature review highlights the recent developments of hyperinsulinemia and insulin resistance involvement in the progression and pathogenesis of AD.

Impaired insulin sensitivity is associated with worsening cognition in HIV-infected patients.

OBJECTIVE: To determine the association of insulin sensitivity and metabolic status with declining cognition in HIV-infected individuals. METHODS: We conducted targeted clinical and metabolic measures in longitudinal plasma samples obtained from HIV-infected patients enrolled in the Central Nervous System HIV Anti-Retroviral Therapy Effects Research Study (CHARTER). Findings were validated with plasma samples from the Multicenter AIDS Cohort Study (MACS). Patients were grouped according to longitudinally and serially assessed cognitive performance as having stably normal or declining cognition. RESULTS: Patients with declining cognition exhibited baseline hyperinsulinemia and elevated plasma c-peptide levels with normal c-peptide/insulin ratios, suggesting that insulin production was increased, but insulin clearance was normal. The association of hyperinsulinemia with worsening cognition was further supported by low high-density lipoprotein (HDL), high low-density lipoprotein/HDL ratio, and elevated cholesterol/HDL ratio compared to patients with stably normal cognition. CONCLUSIONS: These findings suggest that hyperinsulinemia and impaired insulin sensitivity are associated with cognitive decline in antiretroviral therapy-treated HIV-infected patients.

Cognitive, neurophysiologic and metabolic sequelae of previous hypoglycemic coma revealed by hyperinsulinemic-hypoglycemic clamp in type 1 diabetic patients.

To examine the relationship between electroencephalographic (EEG) activity and hypoglycemia unawareness, we investigated early parameters of vigilance and awareness of various symptom categories in response to hypoglycemia in intensively treated type 1 diabetic (T1DM) patients with different degrees of hypoglycemia unawareness. Hypoglycemia was induced with a hyperinsulinemic-hypoglycemic clamp in six T1DM patients with a history of hypoglycemia unawareness previous severe hypoglycemic coma (SH) and in six T1DM patients without (C) history of hypoglycemia unawareness previous severe hypoglycemic coma. Cognitive function tests (four choice reaction time), counterregulatory responses (adrenaline), and symptomatic responses were evaluated at euglycemia (90 mg/dl) and during step-wise plasma glucose reduction (68, 58 and 49 mg/dl). EEG activity was recorded continuously throughout the study and analyzed by spectral analysis. Cognitive function deteriorated significantly at a glucose threshold of 55 ± 1 mg/dl in both groups (p = ns) during hypoglycemia, while the glucose threshold for autonomic symptoms was significantly lower in SH patients than in C patients (49 ± 1 vs. 54 ± 1 mg/dl, p < 0.05, respectively). In SH patients, eye-closed resting EEG showed a correlation between the mean dominance frequency and plasma glucose (r = 0.62, p < 0.001). Theta relative power increased during controlled hypoglycemia compared to euglycemia (21.6 ± 6 vs. 15.5 ± 3% Hz p < 0.05) and was higher than in the C group (21.6 ± 6 vs. 13.8 ± 3%, p < 0.03). The cognitive task beta activity was lower in the SH group than in the C group (14.8 ± 3 Hz, vs. 22.6 ± 4 vs. p < 0.03). Controlled hypoglycemia elicits cognitive dysfunction in both C and SH patients; however, significant EEG alterations during hypoglycemia were detected mainly in patients with a history of hypoglycemia unawareness and previous severe hypoglycemic coma. These data suggest that prior episodes of hypoglycemic coma modulate brain electric activity.

A difficult case of recurrent hypoglycaemia: role of insulin assays in establishing the diagnosis.

BACKGROUND: Insulin assays are designed to detect endogenous insulin, however, insulin assays produced by different manufacturers may detect exogenous recombinant insulin, with varying degrees of cross-reactivity between different assays. We report a fascinating and difficult case of recurrent hypoglycaemia, where the final diagnosis was established with the help of insulin assays using different platforms. CASE REPORT: A 24-year-old female presented with recurrent hypoglycaemic episodes on a background of Type 1 diabetes mellitus and a completely resected synovial sarcoma of the right hip several years previously. She reported significant physical, sexual and emotional abuse leading to reduced appetite and weight loss. Despite withdrawing insulin therapy, she experienced profound hypoglycaemic episodes with detectable C-peptide and inappropriately elevated insulin levels, suggesting endogenous hyperinsulinaemic hypoglycaemia; however, localization studies were negative and finally she was found to have exogenous hyperinsulinaemia after discordant insulin levels were detected using two different insulin assays. The C-peptide level was elevated as a result of stimulation by parenteral dextrose and was suppressed after dextrose was ceased. Her Type 1 diabetes mellitus was fabricated and she had factitious hypoglycaemia. CONCLUSIONS: Factitious hypoglycemia is difficult to diagnose and treat. A low blood glucose level, suppressed C-peptide level and an inappropriately elevated insulin level is the classic finding. We were able to make a diagnosis in the present case after discordant insulin levels were detected on the two different insulin assays, signifying cross-reactivities of the recombinant insulin with the assays. A multidisciplinary team approach with psychiatric input is needed to treat such cases.

Intraoperative tight glucose control using hyperinsulinemic normoglycemia increases delirium after cardiac surgery.

BACKGROUND: Postoperative delirium is common in patients recovering from cardiac surgery. Tight glucose control has been shown to reduce mortality and morbidity. Therefore, the authors sought to determine the effect of tight intraoperative glucose control using a hyperinsulinemic-normoglycemic clamp approach on postoperative delirium in patients undergoing cardiac surgery. METHODS: The authors enrolled 198 adult patients having cardiac surgery in this randomized, double-blind, single-center trial. Patients were randomly assigned to either tight intraoperative glucose control with a hyperinsulinemic-normoglycemic clamp (target blood glucose, 80 to 110 mg/dl) or standard therapy (conventional insulin administration with blood glucose target, <150 mg/dl). Delirium was assessed using a comprehensive delirium battery. The authors considered patients to have experienced postoperative delirium when Confusion Assessment Method testing was positive at any assessment. A positive Confusion Assessment Method was defined by the presence of features 1 (acute onset and fluctuating course) and 2 (inattention) and either 3 (disorganized thinking) or 4 (altered consciousness). RESULTS: Patients randomized to tight glucose control were more likely to be diagnosed as being delirious than those assigned to routine glucose control (26 of 93 vs. 15 of 105; relative risk, 1.89; 95% CI, 1.06 to 3.37; P = 0.03), after adjusting for preoperative usage of calcium channel blocker and American Society of Anesthesiologist physical status. Delirium severity, among patients with delirium, was comparable with each glucose management strategy. CONCLUSION: Intraoperative hyperinsulinemic-normoglycemia augments the risk of delirium after cardiac surgery, but not its severity.

Diabetes mellitus and disturbances in brain connectivity: a bidirectional relationship?

Diabetes mellitus (DM) is associated with deficits across multiple cognitive domains. The observed impairments in cognitive function are hypothesized to be subserved by alterations in brain structure and function. Several lines of evidence indicate that alterations in glial integrity and function, as well as abnormal synchrony within brain circuits and associated networks, are observed in adults with DM. Microangiopathy and alterations in insulin homeostasis appear to be principal effector systems, although a unitary explanation subsuming the complex etiopathology of white matter in DM is unavailable. A contemporary model of disease pathophysiology for several mental disorders, including but not limited to mood disorders, posits abnormalities in the synchronization of cellular systems in circuits. The observation that similar abnormalities occur in diabetic populations provides the basis for hypothesizing the convergence of pathoetiological factors. Herein, we propose that abnormal structure, function and chemical composition as well as synchrony within and between circuits is an accompaniment of DM and is shared in common with several mental disorders.

Hyperinsulinemia, insulin resistance and cognitive decline in older cohort.

OBJECTIVE: Type 2 diabetes has been recently recognized as an important risk factor for cognitive decline of patients with Alzheimer's disease (AD). But the roles of hyperinsulinemia (HI) and insulin resistance (IR) in the development of AD are still controversial. This study was designed to evaluate whether HI or IR influenced the cognitive functions of older cohort. METHODS: The cognitive functions of 328 consecutive elderly patients were evaluated with a battery of cognitive rating scales. Their fasting blood glucose (FBG) and fasting insulin (FINS) were analyzed and IR was calculated with modified-Homa. The cognitive scores in different groups and the correlation of cognitive functions with HI or IR were analyzed. RESULTS: In our study, there were 180 participants with HI and 148 without HI, and 192 with IR and 136 without IR. The participants with HI showed worse cognitive functions than those without HI in MMSE, MOCA, CDR, orientation, delayed memory, and attention/calculation domains. Similarly, the elderly with IR had lower cognitive scores than those without IR in MMSE, MOCA, CDR, GDS, orientation, delayed memory, and attention/calculation domains. The insulin levels and Homa IR had negative correlation with the scores of MMSE and delayed memory, not only in the model 1 adjusted for FBG and diabetes history, but also in the model 2 adjusted for all nine demographic characteristics. CONCLUSION: HI and IR are important risk factors for cognitive decline of the elderly, especially for the dysfunctions in delayed memory domains.

Hyperinsulinemia and cognitive decline in a middle-aged cohort.

OBJECTIVE: Determining modifiable risks factors for cognitive decline and dementia are a public health priority as we seek to prevent dementia. Type 2 diabetes and related disorders such as hyperinsulinemia increase with aging and are increasing in the U.S. population. Our objective was to determine whether hyperinsulinemia is associated with cognitive decline among middle-aged adults without type 2 diabetes, dementia, or stroke in the Atherosclerosis Risk in Communities (ARIC) cohort. RESEARCH DESIGN AND METHODS: Middle-aged adults (aged 45-64 years at baseline) in the ARIC cohort had fasting insulin and glucose assessed between 1987 and 1989. Subjects with dementia, type 2 diabetes, or stroke at baseline were excluded from analysis. Three tests of cognitive function available at baseline and 6 years later were delayed word recall (DWR), digit symbol subtest (DSS), and first letter word fluency (WF). Cross-sectional comparisons and linear regression models were computed for cognitive tests at baseline and change in cognitive test scores to determine whether cognitive function was associated with two measures of insulin resistance, fasting insulin and homeostasis model assessment (HOMA). Linear regression models controlled for age, sex, race, marital status, education level, smoking status, alcohol use, depression, hypertension, and hyperlipidemia. RESULTS: In unadjusted and adjusted analyses, hyperinsulinemia based on fasting insulin and HOMA at baseline was associated with significantly lower baseline DWR, DSS, and WF scores and a greater decline over 6 years in DWR and WF. CONCLUSIONS: Insulin resistance is a potentially modifiable midlife risk factor for cognitive decline and dementia.

Hyperinsulinemia and risk of Alzheimer disease.

OBJECTIVE: To explore the association between fasting insulin levels and dementia. METHODS: Fasting insulin levels were measured from frozen sera using solid-phase chemiluminescent enzyme immunoassay in a sample of elderly subjects chosen at random from a cohort of persons aged 65 years and older from northern Manhattan. Dementia was diagnosed using standard methods. Neuropsychiatric testing was available on all subjects at each follow-up interval. RESULTS: A total of 683 subjects without prevalent dementia were followed for 3,691 person-years and 149 persons developed dementia (137 Alzheimer disease [AD], 6 dementia associated with stroke, 6 other). The risk of AD doubled in the 39% of the sample with hyperinsulinemia (HR = 2.1; 95% CI: 1.5, 2.9) and was highest in people without diabetes. The HR relating presence of hyperinsulinemia or diabetes in 50% of our sample to AD was 2.2 (95% CI: 1.5, 3.1). The risk of AD attributable to the presence of hyperinsulinemia or diabetes was 39%. The HR of AD for the highest quartile of insulin compared to the lowest was 1.7 (95% CI: 1.0, 2.7; p for trend = 0.009). Hyperinsulinemia was also related to a significant decline in memory-related cognitive scores, but not to decline in other cognitive domains. CONCLUSIONS: Hyperinsulinemia is associated with a higher risk of AD and decline in memory.

Glucose intolerance, hyperinsulinaemia and cognitive function in a general population of elderly men.

Cognitive impairment is highly prevalent among the elderly. Subjects with disturbed glucose metabolism may be at risk of impaired cognitive function, as these disturbances can influence cognition through atherosclerosis, thrombosis and hypertension. We therefore studied the cross-sectional association of cognitive function with hyperinsulinaemia, impaired glucose tolerance and diabetes mellitus in a population-based cohort of 462 men aged 69 to 89 years. Cognitive function was measured by the 30-point Mini-Mental State Examination. Results were expressed as the rate ratio (95% confidence interval) of the number of erroneous answers given on the Mini-Mental State Examination by the index compared to the reference group. Compared to subjects with normal glucose tolerance, known diabetic patients had a rate ratio of 1.23 (1.04-1.46), newly-diagnosed diabetic patients of 1.16 (0.91-1.48) and subjects with impaired glucose tolerance of 1.18 (0.98-1.41), after adjustment for confounding due to age, occupation and cigarette smoking (p-trend = 0.01). Non-diabetic subjects in the highest compared to the lowest quartile of the area under the insulin curve had a rate ratio of 1.24 (1.03-1.50), after adjustment for confounding (p-trend = 0.02). The results did not change appreciably when potentially mediating factors, including cardiovascular diseases and risk factors associated with the insulin resistance syndrome, were taken into account. These results suggest that diabetes, as well as impaired glucose tolerance and hyperinsulinaemia in non-diabetic subjects are associated with cognitive impairment.

Changes in mood during acute hypoglycemia in healthy participants.

Acute hypoglycemia provides a reproducible method of investigating the effect of biological changes induced during hypoglycemia on mood states. Hypoglycemia was induced twice using a hyperinsulinemic glucose clamp in 24 nondiabetic human participants; a euglycemic placebo control study was also performed. Serial changes in mood were assessed using the UWIST Mood Adjective Checklist before, during, and after 60 min of controlled hypoglycemia (2.5 mmol/l). Hypoglycemia induced a significant reduction in hedonic tone (p = .001), a significant increase in tense arousal (p < .0005), and a significant decline in energetic arousal (p = .01) in comparison with the euglycemia control study. Profound changes in mood were observed in nondiabetic participants during acute hypoglycemia, and a state called tense tiredness persisted for at least 30 min after restoration of euglycemia.

Essential hypertension and cognitive function. The role of hyperinsulinemia.

The relation between hypertension and cognitive function is not well established. Therefore, we examined cognitive function in a random sample of 744 nondiabetic elderly inhabitants of Kuopio, East Finland. Five brief neuropsychological tests known to be sensitive to cognitive impairment due to dementia--the Mini-Mental State Examination (MMSE), the Trail Making Test (TMT), the Buschke Selective Reminding Test (BSR), Russell's Adaptation of the Visual Reproduction Test (HVR), and the Verbal Fluency Test (VFT)--were used to evaluate cognitive function. The performance of the hypertensive group (n = 378) was impaired in almost all test items compared with that of the normotensive group (n = 366), but the difference between these two groups was statistically significant in 5 of 19 test items only. Moreover, within the hypertensive group, hyperinsulinemic (fasting plasma insulin > 17.9 mU/L) hypertensive subjects (n = 57) scored worse than normoinsulinemic hypertensive subjects (n = 321) in 16 of 19 test items and worse than the normotensive subjects in the same 16 of 19 test items. The difference between the hyperinsulinemic hypertensive and normotensive groups was significant in 11 test items that reflected complex cognitive function such as calculation, language, semantic memory, and problem solving. This difference in neuropsychological tests among the three study groups (normotensive, normoinsulinemic hypertensive, and hyperinsulinemic hypertensive subjects) persisted after adjustment for fasting plasma glucose, age, sex, and education in 3 test items measuring calculation, copying, and semantic memory. Thus, essential hypertension in the elderly is associated with an impairment in complex cognitive function.(ABSTRACT TRUNCATED AT 250 WORDS)

Familial hyperinsulinism: successful conservative management.

A large family in whom 4 of 13 children were affected with hyperinsulinism of variable severity is described. The oldest affected child required subtotal pancreatectomy to control the hypoglycemia, but the three younger children were managed successfully with prolonged conservative therapy with maintenance oral doses of diazoxide. The three affected school-age children in the family have deficits in the areas of visuomotor integration and short-term memory. The three youngest children have normal intelligence compared with four unaffected siblings; only the oldest child, who has undergone pancreatectomy, has low-average intelligence (IQ80). We conclude that in infants with persistent but asymptomatic hyperinsulinemic hypoglycemia every effort should be made to treat conservatively with antihypoglycemic agents such as diazoxide for as long as possible to allow for spontaneous remission and thereby avoid pancreatectomy.