Deficit In Insulin Secretion Research Articles

Hyperglucagonemia precedes a decline in insulin secretion and causes hyperglycemia in chronically glucose-infused rats

Islet damage from glucose toxicity is implicated in the pathogenesis of type 2 diabetes, but the sequence of events leading to islet cell dysfunction and hyperglycemia remains unclear. To examine the early stages of islet pathology resulting from increased basal glucose loads, normal awake rats were infused with glucose continuously for 10 days. Plasma glucose and markers of islet and liver function were monitored throughout the infusion. After initial hyperglycemia, rats adapted to the infusion and maintained euglycemia for approximately 4 days. Continued infusion led to worsening hyperglycemia in just 5% of rats after 6 days, but 69% after 8 days and 89% after 10 days, despite unchanged basal and stimulated plasma insulin and C-peptide concentrations. In contrast, plasma glucagon concentrations increased fivefold. Endogenous glucose production (EGP) was appropriately suppressed after 4 days (2.8 ± 0.7 vs. 6.1 ± 0.4 mg·kg(-1)·min(-1) on day 0, P < 0.001) but tripled between days 4 and 8 (9.9 ± 1.7 mg·kg(-1)·min(-1), P < 0.01). Surprisingly, the increase in EGP was accompanied by increased mitochondrial phosphoenolpyruvate carboxykinase expression with appropriate suppression of the cytosolic isoform. Infusion of anti-glucagon antibodies normalized plasma glucose to levels identical to those on day 4 and ∼300 mg/dl lower than controls. This improved glycemia was associated with a 60% reduction in EGP. These data support the novel concept that glucose toxicity may first manifest as α-cell dysfunction prior to any measurable deficit in insulin secretion. Such hyperglucagonemia could lead to excessive glucose production overwhelming the capacity of the β-cell to maintain glucose homeostasis.

Do insulinotropic glucose-lowering drugs do more harm than good? The hypersecretion hypothesis revisited

Significant progress has been made in recent years in the characterisation of the signal pathways of beta cell dysfunction and death in the pathogenesis of type 2 diabetes. Glucolipotoxicity acts as an exogenous factor whereas oxidative stress and endoplasmic reticulum stress may result from the processes of signal recognition and stimulated secretion within the beta cell. The pharmacological stimulation of secretion may thus appear to be a double-edged sword: it counteracts hyperglycaemia, but may do so at the expense of beta cell mass. So, in the long run, insulinotropic glucose-lowering drugs might do more harm than good. However, much of this logic is derived by analogy from the long-held assumption that beta cell hypersecretion imposed by insulin resistance causes the absolute secretion deficit in the later course of type 2 diabetes. In this concept the beta cell has a secondary role and loss of beta cell mass is necessary for the manifestation of type 2 diabetes. Recent studies have shown that a secretion deficit can exist well before insulin resistance and that major genetic risk factors concern beta cell function. Also, the evidence for a beta cell toxic effect of insulinotropic drugs is currently inconclusive. Assuming that the insulin secretion deficit is of pathogenetic importance in a network with insulin resistance as an aggravating factor, an insulinotropic glucose-lowering drug may do more good than harm if it relieves the beta cell from the stress of glucose overstimulation and does so without inducing hypoglycaemia.

Medikamentöse Prävention des Diabetes mellitus Typ 2 – Wenn eine Lebensstiländerung nicht ausreicht ...

Already in the prediabetic state we find a deficit in insulin secretion and a decrease in insulin sensitivity typical for clinical type 2 diabetes. Furthermore in about 60 % comorbidities of the metabolic syndrome, increased levels of biomarkers of low grade inflammation and atherosclerotic vascular disease are present. Therefore the prevention of type 2 diabetes is an urgent task. This review presents an up-date of controlled medical prevention trials. So far evidence based data for the prevention of type 2 diabetes are only available for acarbose, metformin, rosiglitazone and pioglitazone with a safety profile in favour of acarbose and metformin. Acarbose in the STOP-NIDDM trial had in addition beneficial effects on incidence of newly diagnosed hypertension and cardiovascular events.

The Effects of the Pro12Ala Polymorphism of the Peroxisome Proliferator-Activated Receptor- 2 Gene on Glucose/Insulin Metabolism Interact With Prenatal Exposure to Famine

An adverse fetal environment may permanently modify the effects of specific genes on glucose tolerance, insulin secretion, and insulin sensitivity. In the present study, we assessed a possible interaction of the peroxisome proliferator-activated receptor (PPAR)-gamma2 Pro12Ala polymorphism with prenatal exposure to famine on glucose and insulin metabolism. We measured plasma glucose and insulin concentrations after an oral glucose tolerance test and determined the PPAR-gamma2 genotype among 675 term singletons born around the time of the 1944-1945 Dutch famine. A significant interaction effect between exposure to famine during midgestation and the PPAR-gamma2 Pro12Ala polymorphism was found on the prevalence of impaired glucose tolerance and type 2 diabetes. The Ala allele of the PPAR-gamma2 gene was associated with a higher prevalence of impaired glucose tolerance and type 2 diabetes but only in participants who had been prenatally exposed to famine during midgestation. Similar interactions were found for area under the curve for insulin and insulin increment ratio, which were lower for Ala carriers exposed to famine during midgestation. The effects of the PPAR-gamma2 Pro12Ala polymorphism on glucose and insulin metabolism may be modified by prenatal exposure to famine during midgestation. This is possibly due to a combined deficit in insulin secretion, as conferred by pancreatic beta-cell maldevelopment and carrier type of the Ala allele in the PPAR-gamma2 gene.

Proinflammatory Cytokines, Insulin Resistance, and Insulin Secretion in Chronic Hepatitis C patients

OBJECTIVE—The purpose of this study was to explore the initial pathogenic mechanisms of diabetes associated with hepatitis C virus (HCV) infection. RESEARCH DESIGN AND METHODS—Insulin resistance, proinflammatory cytokines, and β-cell function were evaluated in a case-control study. A total of 28 consecutive nondiabetic patients with chronic hepatitis C were included in the study (anti-HCV+). Fourteen patients with chronic hepatitis other than HCV infection served as the control group (anti-HCV−). Both groups were closely matched by the main clinical variables associated with insulin resistance and the degree of liver fibrosis. In addition, there were no differences between groups regarding hepatic insulin extraction measured by calculating the ratio between C-peptide and insulin. Serum levels of proinflammatory cytokines (tumor necrosis factor [TNF]-α, soluble TNF receptor [sTNFR] 1, soluble TNFR2, and interleukin-6) were measured by enzyme-linked immunosorbent assay. Insulin resistance (homeostasis model assessment [HOMA] of insulin resistance [HOMA-IR]) and insulin secretion at baseline (HOMA-β) and after various stimulus (oral glucose tolerance test, standard food intake, and intravenous glucagon) were determined by previously validated mathematic indexes. RESULTS—HOMA-IR was higher in anti-HCV+ than in anti-HCV− patients (4.35 ± 2.27 vs. 2.58 ± 1.74; P = 0.01). All the proinflammatory cytokines analyzed were significantly higher in anti-HCV+ patients than in anti-HCV− patients. In addition, sTNFR1 and sTNFR2 were directly correlated to HOMA-IR. HOMA-β as well as insulin and C-peptide responses after the intravenous glucagon test were significantly higher in anti-HCV+ patients than in anti-HC− patients. CONCLUSIONS—Insulin resistance mediated by proinflammatory cytokines, but not a deficit in insulin secretion, could be the primary pathogenic mechanism involved in the development of diabetes associated with HCV infection.

The Effects of the Pro12Ala Polymorphism of the Peroxisome Proliferator–Activated Receptor-γ2 Gene on Glucose/Insulin Metabolism Interact With Prenatal Exposure to Famine

OBJECTIVE—An adverse fetal environment may permanently modify the effects of specific genes on glucose tolerance, insulin secretion, and insulin sensitivity. In the present study, we assessed a possible interaction of the peroxisome proliferator–activated receptor (PPAR)-γ2 Pro12Ala polymorphism with prenatal exposure to famine on glucose and insulin metabolism. RESEARCH DESIGN AND METHODS—We measured plasma glucose and insulin concentrations after an oral glucose tolerance test and determined the PPAR-γ2 genotype among 675 term singletons born around the time of the 1944–1945 Dutch famine. RESULTS—A significant interaction effect between exposure to famine during midgestation and the PPAR-γ2 Pro12Ala polymorphism was found on the prevalence of impaired glucose tolerance and type 2 diabetes. The Ala allele of the PPAR-γ2 gene was associated with a higher prevalence of impaired glucose tolerance and type 2 diabetes but only in participants who had been prenatally exposed to famine during midgestation. Similar interactions were found for area under the curve for insulin and insulin increment ratio, which were lower for Ala carriers exposed to famine during midgestation. CONCLUSIONS—The effects of the PPAR-γ2 Pro12Ala polymorphism on glucose and insulin metabolism may be modified by prenatal exposure to famine during midgestation. This is possibly due to a combined deficit in insulin secretion, as conferred by pancreatic β-cell maldevelopment and carrier type of the Ala allele in the PPAR-γ2 gene.

Proinflammatory Cytokines, Insulin Resistance, and Insulin Secretion in Chronic Hepatitis C patients: A case-control study

The purpose of this study was to explore the initial pathogenic mechanisms of diabetes associated with hepatitis C virus (HCV) infection. Insulin resistance, proinflammatory cytokines, and beta-cell function were evaluated in a case-control study. A total of 28 consecutive nondiabetic patients with chronic hepatitis C were included in the study (anti-HCV+). Fourteen patients with chronic hepatitis other than HCV infection served as the control group (anti-HCV-). Both groups were closely matched by the main clinical variables associated with insulin resistance and the degree of liver fibrosis. In addition, there were no differences between groups regarding hepatic insulin extraction measured by calculating the ratio between C-peptide and insulin. Serum levels of proinflammatory cytokines (tumor necrosis factor [TNF]-alpha, soluble TNF receptor [sTNFR] 1, soluble TNFR2, and interleukin-6) were measured by enzyme-linked immunosorbent assay. Insulin resistance (homeostasis model assessment [HOMA] of insulin resistance [HOMA-IR]) and insulin secretion at baseline (HOMA-beta) and after various stimulus (oral glucose tolerance test, standard food intake, and intravenous glucagon) were determined by previously validated mathematic indexes. HOMA-IR was higher in anti-HCV+ than in anti-HCV- patients (4.35 +/- 2.27 vs. 2.58 +/- 1.74; P = 0.01). All the proinflammatory cytokines analyzed were significantly higher in anti-HCV+ patients than in anti-HCV- patients. In addition, sTNFR1 and sTNFR2 were directly correlated to HOMA-IR. HOMA-beta as well as insulin and C-peptide responses after the intravenous glucagon test were significantly higher in anti-HCV+ patients than in anti-HC- patients. Insulin resistance mediated by proinflammatory cytokines, but not a deficit in insulin secretion, could be the primary pathogenic mechanism involved in the development of diabetes associated with HCV infection.

Insulin Secretion and Sensitivity in Newly Diagnosed NIDDM Caucasians in the UK

Beta-cell secretion and insulin sensitivity was studied in healthy subjects and newly diagnosed Caucasian (Welsh) NIDDM patients. A standardized meal tolerance test (MTT) and frequent sampled intravenous glucose tolerance tests (FSIVGTT) were employed and the patients stratified according to fasting plasma glucose (FPG). A deficient early (first hour) post-prandial (MTT) insulin secretion was demonstrated in all NIDDM patients, deteriorating with increasing fasting hyperglycaemia. For the patient group fasting and post-prandial hyperproinsulinaemia was evident with diminishing post-prandial excursions as fasting hyperglycaemia increased. The early phase (0-10 min) insulin secretion to intravenous glucose (300 mg kg-1) was severely impaired in NIDDM patients. A shortlived paradoxical fall in plasma insulin concentrations was observed in those with FPG > 9 mmol l-1. Insulin sensitivity utilizing the insulin modified FSIVGTT demonstrated that all NIDDM patients had marked insulin insensitivity. Characteristic of the newly diagnosed previously untreated Caucasian NIDDM is a dysfunctional beta cell, resulting in a deficit in insulin secretion with relative hyperproinsulinaemia. The quantitative and qualitative secretory status of the beta cell decreases with increasing fasting hyperglycaemia. Insulin sensitivity is markedly reduced when FPG exceeds 7.0 mmol l-1 with little or no further discernible fall with deteriorating glycaemic control.

Bone mineral density measured by dual energy X-ray absorptiometry in patients with non-insulin-dependent diabetes mellitus

Because of the previous controversial findings in diabetic patients with older methodologies, we assessed bone mineral density (BMD) in 78 patients (38 males and 40 females) with non-insulin-dependent diabetes mellitus using dual energy x-ray absorptiometry (DEXA). BMD was measured in lumbar vertebrae (L 2–4). The BMD of each patient was calculated as the percentage of the mean value (%BMD) obtained from a healthy control group matched for sex and age. The %BMD of the patients with diabetes was about 100% for females and 96% for males, as compared with BMD of normal controls. The %BMD of the patients with diabetes was significantly correlated with body mass index and urinary C peptide level, and inversely correlated with age and duration of diabetes within 20 years. No relationships were found between %BMD and serum calcium, phosphorus, or glycosylated hemoglobin A 1C levels. These observations suggest that metabolic abnormalities associated with diabetes mellitus alter the BMD, and that such factors as duration of the disease and deficit in insulin secretion are risk factors for decreased BMD.