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PubMed2004

Is parity associated with earlier diagnosis of type 2 diabetes?

AIM: Whether parity promotes the development of diabetes has been a subject of controversy. Earlier population studies have produced discrepant findings. The aim of the current study was to investigate this question by examining the relationship between parity and the age of diagnosis of diabetes. METHODS: A retrospective analysis from a diabetes database was conducted. Data for 2102 women with type 2 diabetes (T2DM), including date of birth, age at diagnosis, parity, body mass index (BMI), and family history were extracted. A multivariate linear regression model was applied to ascertain if there was an association between parity and the age of diagnosis of diabetes. RESULTS: With correction for the year of birth, there was a significant association between parity and the age of diagnosis of diabetes (beta = -0.25 +/- 0.08, P = 0.002, where beta is the regression coefficient). That is, for an increase in parity by one, the age of diagnosis decreased by 0.25 years. When further adjustments were made for the other variables in the data set, the effect on the overall cohort disappeared, but it persisted in subjects born before 1950 (beta = -0.17 +/- 0.1, P = 0.09), or with a parity >5 (beta = -0.60 +/- 0.25, P = 0.02). CONCLUSIONS: There is an association between parity and the age of diagnosis of diabetes, suggesting that pregnancy may promote the development of diabetes. However, the magnitude of the effect is small, and unlikely to be of great clinical significance in society today.

Aged↗
PubMed2005

Anticardiolipin and anti-beta2 glycoprotein I antibody concentrations in patients with type 2 diabetes mellitus.

Anticardiolipin and anti-beta2 glycoprotein I antibodies are associated with an increased tendency to thrombosis by various mechanisms. This study aimed to evaluate the association between micro and macrovascular complications of diabetes and anticardiolipin and anti-beta2 glycoprotein I antibodies. Forty-six patients with type 2 diabetes mellitus (T2DM) were studied. Twenty-one patients had coronary artery disease as a macrovascular complication. Twenty-five age and sex matched healthy subjects formed a control group. Anticardiolipin IgM, IgG, anti-beta2 glycoprotein IgM and IgG antibody levels were studied in both patient and control groups. Diabetic patients with ischaemic heart disease had significantly higher titres of anticardiolipin IgG antibody than patients without ischaemic heart disease (P < 0.001). However, none of these patients had an anticardiolipin IgG antibody level higher than 20 GPL, which is accepted as a clinically significant value, so this association may not be clinically important. There was no association with the microvascular complications. There was also no significant association between anti-beta2 glycoprotein I antibodies in type 2 diabetic patients and micro and macrovascular complications. Anticardiolipin and anti-beta2 glycoprotein I antibodies do not have a major role in the pathogenesis of diabetic complications in type 2 diabetic patients. Prospective studies of large populations are needed to explore this association further.

Aged↗
PubMed2005

Basal production of nitric oxide (NO) and non-NO vasodilators in the forearm microcirculation in Type 2 diabetes: associations with blood pressure and HDL cholesterol.

We examined basal forearm microcirculatory blood flow (FBF) using venous occlusive strain-gauge plethysmography in 47 middle-aged men and women [55+/-1 years] with Type 2 diabetes and 15 age-matched healthy individuals [52+/-3 years], all receiving aspirin. Blood flow was also measured following infusion of N(G)-monomethyl-L-arginine into the brachial artery to inhibit basal NO release (FBF+L-NMMA). Acetylcholine (ACh) and sodium nitroprusside (SNP) were administered to assess endothelium-dependent and endothelium-independent functions. Compared with controls, diabetic subjects had significantly lower vasodilatory responses to ACh and SNP (p<0.05 for each). Basal FBF and FBF+L-NMMA were increased in diabetic subjects compared with controls (2.4+/-0.2 ml/100ml/min versus 1.7+/-0.2 ml/100ml/min, p=0.02 and 1.9+/-0.1 ml/100ml/min versus 1.2+0.1 ml/100ml/min, p=0.01, respectively) whereas the change in FBF following L-NMMA was greater in the controls (-27% versus -19%, p=0.05). Amongst the diabetic subjects, pulse pressure and HDL cholesterol were independent predictors of FBF (b=0.04+/-0.01, adjusted r2=0.21 and p=0.001, and b=3.3+/-1.2, adjusted r2=0.12 and p=0.007, respectively) and FBF+L-NMMA (b=0.03+/-0.01, adjusted r2=0.20, p=0.002 and b=2.1+/-0.9, adjusted r2=0.09 and p=0.02, respectively). Diastolic blood pressure predicted the change in FBF with L-NMMA (b=-1.02+/-0.32, adjusted r2=0.20 and p=0.003). Our findings suggest that well controlled T2DM patients have impaired agonist-mediated vasodilatation of the forearm resistance arteries that is associated with impaired basal release of nitric oxide but an increase in the release of non-NO vasodilators. The latter may be a compensatory response to increased arterial stiffness and may be facilitated by an effect of HDL.

Acetylcholine↗
PubMed2006

Evaluation of the superiority of insulin glargine as basal insulin replacement by continuous glucose monitoring system.

To evaluate the superiority of insulin glargine as basal insulin replacement by continuous glucose monitoring system (CGMS). Twenty-four patients with type 2 diabetes mellitus (T2DM) whose blood glucose was not well controlled with sulphanylureas were enrolled. At first, they were treated with extended-release glipizide (glucotrol XL) 5mg/d before breakfast for 2 weeks, then randomized to combination treatment with glargine (16 patients) or NPH (8 patients) and treated for 12 weeks. CGMS were carried in the second week after treatment with glucotrol XL, and in the 12th week after combination treatment. The data of CGMS showed: (1) When FPG were well controlled in both groups (glargine group versus NPH group: 6.0+/-1.0 mmol/L versus 5.8+/-1.3 mmol/L), the blood glucose level at 3:00 a.m. (5.1+/-0.9 mmol/L versus 4.2+/-0.8 mmol/L) were higher (P<0.05), TPG< or =3.0 mmol/L at night were lower (2.56+/-1.79 versus 5.88+/-1.96), and the rate of nocturnal hypoglycemia (1/16 versus 4/8) were less (P=0.028) in glargine group than those in NPH group. (2) CGMS showed that the daily blood glucose profile excursion were more smoother in glargine group than those in NPH group. In conclusion, it was confirmed with CGMS that compared with traditionally basal insulin replacement with NPH, the combination treatment with glargine injection at bedtime may be predominant for stabilizing the daily blood glucose profile excursion and decreasing the nocturnal hypoglycemia events incidence. So glargine may be a more ideal basal insulin replacement than NPH.

Blood Glucose↗
PubMed2006

Antioxidant and antiplatelet effects of rosuvastatin in a hamster model of prediabetes.

The objectives of this study were to determine the relationships among Type II diabetes (T2DM)-dependent elevations in platelet-derived reactive oxygen species (ROS), platelet-surface protein disulfide isomerase (psPDI) NO-releasing activity, and platelet aggregation and to evaluate the efficacy of rosuvastatin in normalizing these parameters in primary cells derived from a hamster model of prediabetic insulin resistance induced by fructose feeding. Platelets from rosuvastatin-treated non-fructose-fed (NFF) and fructose-fed (FF) hamsters were analyzed for aggregability and psPDI-denitrosation activity. Platelets from NFF animals treated with xanthine/xanthine oxidase (X/XO) were assessed for the same parameters and primary aortic endothelial cells (AEC) cultivated with a range of [rosuvastatin] +/- mevalonate were analyzed for ROS production. Platelets from FF hamsters displayed statistically significant enhanced ROS production, diminished psPDI-mediated NO-releasing activity, and hyperaggregability. Suggestively, platelets from NFF animals treated with X/XO displayed characteristics similar to platelets from FF animals. Rosuvastatin elicited a normalizing effect on all parameters measured in platelets from FF animals. Further, ROS production in primary AEC from FF animals could be blunted to that of NFF animals by concentrations of rosuvastatin in the range of those achieved in the bloodstream. Diminished psPDI-dependent NO-releasing activity and increased initial aggregation rates of FF platelets may result from elevated vascular ROS production under conditions of insulin resistance. Normalization of ROS production and platelet aggregation by rosuvastatin indicates its potential use as a vasculoprotective agent.

Animals↗
PubMedDate not supplied

Diabetes treatments have differential effects on nontraditional cardiovascular risk factors.

OBJECTIVE: The aim of this study was to determine the effect of basal insulin, alone or with a sensitizer, or a combination of oral agents on nontraditional risk factors for cardiovascular disease (CVD). RESEARCH DESIGN AND METHODS: We randomized 57 patients with T2DM to either (1) continuous subcutaneous basal Lispro insulin at a single rate using an insulin pump (basal insulin) or (2) basal insulin and oral pioglitazone 30 mg daily (basal insulin +Pio) or (3) a sulfonylurea and metformin (SU+M). We measured glycosylated hemoglobin (HbA1c), plasma high-sensitivity C-reactive protein (hs-CRP), plasminogen activator inhibitor-1 (PAI-1), 8-epi-prostaglandin F2 alpha (PGF2alpha), serum lipoprotein (a) [Lp (a)], and lipoprotein profile at baseline and after 20 weeks of treatment. RESULTS: HbA1c decreased by >or=2% (P<.001) and to comparable levels (P=NS) in all groups. Despite improved glycemia, hsCRP did not change in any group, whereas plasma PAI-1 fell with basal insulin +Pio (P<.02) and SU+M (P<.01). PGF2alpha declined with basal insulin (P<.02) and SU+M (P<.001). High-density lipoprotein cholesterol (HDL-C) increased only with basal insulin +Pio (18.2%, P<.05). Lp (a) increased with basal insulin therapy alone (P<.01). Data were pooled from all groups to determine the overall effect of glycemic control-there was a significant (P<.001) decline in HbA1c, PAI-1, and PGF2alpha and an increase in HDL-C (P<.001). There was no correlation between HbA1c reduction and changes in these parameters. CONCLUSIONS: We conclude that excellent glycemic control per se does not impact nontraditional risk factors for CVD equally, but various diabetes medications have different effects on these risk factors. These findings may have implications for making appropriate therapeutic choices for patients with Type 2 diabetes, although larger studies with more appropriate treatment comparisons may be necessary.

C-Reactive Protein↗
PubMed2004

Triple genetic variation in the HNF-4alpha gene is associated with early-onset type 2 diabetes mellitus in a philippino family.

Maturity-onset diabetes of the young-type 1 (MODY1) is a form of monogenic type 2 diabetes mellitus (T2DM) with long-term complications due to mutations in the HNF-4alpha gene. The HNF-4alpha gene is involved in hepatic differentiation and expression of genes regulating glucose transport, glycolysis, and lipid metabolism. The abnormal glucose-stimulated insulin secretion in MODY1 subjects may be due to reduced glucose transport and glycolysis. To date, 14 mutations in the HNF-4alpha gene have been identified as a cause of either MODY1 or late-onset type 2 diabetes. So far, no screening has been performed in subjects from the Philippines. We recruited a Philippino family with autosomal dominant early-onset type 2 diabetes and screened the proband for mutations in the genes for HNF-1alpha, GCK, HNF-4alpha, IPF-1, HNF-6, and NGN3. We identified a new missense mutation in exon 5 (V199I) of the HNF-4alpha gene and 2 new single-nucleotide substitutions in intron 4, IVS4-nt4 (G --> A) and IVS4-nt20 (C --> T), all cosegregating with diabetes in the 3 affected available siblings. These variations were not present in 100 normal healthy subjects. Bioinformatic analysis suggests that these variations in the whole, and overall the IVS4-nt4 variation located at splicing site, may affect the splicing potential of intron 4. We have biochemically and clinically characterized the Philippine-1 family. We suggest that the V199I missense mutation located in the ligand binding/dimerization domain of HNF-4alpha contributes to type 2 diabetes in the Philippine-1 family. The intron variations may contribute susceptibility to diabetes.

Adult↗
PubMed2006

Hypothalamic-pituitary-adrenal activity in type 2 diabetes mellitus: role of autonomic imbalance.

Symptomatic diabetic neuropathy has been found to be associated with hypothalamus-pituitary-adrenal (HPA) axis hyperfunction, but no data are available about HPA activity in diabetic patients with asymptomatic autonomic imbalance. To evaluate HPA axis activity in patients with type 2 diabetes mellitus (T2DM) in relation to the presence or the absence of subclinical parasympathetic or sympathetic neuronal dysfunction, we performed an observational study on 59 consecutive type 2 diabetic patients without chronic complications and/or symptoms of neuropathy or hypercortisolism. The following were measured: serum cortisol at 08:00 am and at midnight (F8 and F24, respectively), post-dexamethasone suppression cortisol, 24-hour urinary free cortisol (UFC), and morning corticotropin (ACTH). Deep-breathing (DB) and LS (LS) autonomic tests were performed to assess the parasympathetic function; postural hypotension test was performed to evaluate sympathetic activity. Patients were subdivided into 4 groups: subjects with parasympathetic failure (group A), sympathetic failure (group B), both para- and sympathetic failure (group C), and without autonomic failure (group D). Hypothalamus-pituitary-adrenal activity was increased in group A compared with group D (UFC, 48.6 +/- 21.4 vs 21.6 +/- 9.8 microg/24 h, P < .0001; ACTH, 27.0 +/- 8.6 vs 15.7 +/- 5.7 pg/dL, P < .01; F8, 20.4 +/- 4.5 vs 13.6 +/- 3.8 microg/dL, P < .05; post-dexamethasone suppression cortisol, 1.2 +/- 0.4 vs 0.8 +/- 0.6 microg/dL, P < .05, respectively) and group B (UFC, 26.3 +/- 11.0 microg/24 h, P < .0001; ACTH, 19.9 +/- 8.0 pg/dL, P < .05). Regression analysis showed that UFC levels were significantly associated with the deep-breathing test (beta = -0.40, P = .004) and tended to be associated with the lying-to-standing test (beta = -0.26, P = .065), whereas body mass index, glycated hemoglobin, and duration of disease were not. Type 2 diabetic patients with asymptomatic parasympathetic derangement have increased activity of HPA axis, related to the degree of the neuronal dysfunction.

Adrenal Cortex Hormones↗
PubMed2026

Acute Stevia Consumption does not Alter Endocrine Responses in Individuals with Normal Weight, Overweight, and Type 2 Diabetes Mellitus.

BACKGROUND: Stevia is a plant-based non-nutritive sweetener. Acute effects of stevia ingestion on glycemia and hormonal responses have not been fully investigated. OBJECTIVE: This objective of this study was to evaluate the acute effects of beverages containing stevia alone and in combination with glucose on glycemic, hormonal, and appetite responses. METHODS: This study evaluated three cohorts of n=23 individuals with either normal weight (NW), overweight (OW), or type 2 diabetes mellitus (T2DM) for which each individual completed four test conditions in a randomized sequence crossover study design. The four test conditions were beverages containing stevia (75.6 mg steviol equivalents), water, glucose (30 g), and stevia+glucose (30 g glucose+75.6 mg steviol equivalents). Blood samples were collected before and for 180 min after beverage consumption. Assessments included net area under the curve (niAUC) and incremental maximal concentration values for plasma glucose, insulin, glucose-dependent insulinotropic polypeptide (GIP), glucagon-like peptide-1, glucagon, and PYY. Appetite was assessed with visual-analog scale questions and energy consumption during an ad libitum meal. RESULTS: Responses to the stevia beverage did not differ significantly from those for water alone, and stevia + glucose did not differ significantly from glucose alone for any of the three groups. CONCLUSION: Acute stevia consumption did not materially alter responses for glycemia or hormones involved in glucose and appetite regulation, appetite ratings, or energy intake at a subsequent meal. Clinical Trial Registry number and website where it was obtained: Clinical Trials.gov Identifier: NCT05287906. Study Details | NCT05287906 | A Trial to Assess Steviol Glycosides on Acute Appetite Hormone Release | ClinicalTrials.gov.

Appetite↗
PubMed2006

The role of PPARs in the microvascular dysfunction in diabetes.

There is a major defect in skin blood flow (SkBF) in people with type 2 diabetes (T2DM). This defect is associated with relatively normal nitric oxide (NO) production in the skin. The abnormal blood flow cosegregates with hypertension, dyslipidemia, abnormal fatty acid composition, a proinflammatory state, and insulin resistance. Since these covariates are an integral part of the insulin resistance syndrome, we examined the effects of the thiazoledindiones (TZDs) as insulin sensitizers for their ability to correct the abnormal blood flow. The PPARgamma rosiglitazone improved NO production to normal levels, but had a small effect on SKBF. In contrast, pioglitazone had a small effect on skin neurovascular function but a dramatic effect on reducing nitrosative stress. These effects do not appear to be due to the insulin sensitizing properties of these compounds but are associated with a reduction in indices of inflammation, hemodilution, and are likely to be due to one of the many "vascular" effects of TZDs. The role of inflammation in the disordered neurovascular function in diabetes cannot be underplayed and the possible contribution of PPARalpha agonists to alter the inflammatory state needs to be explored further. Since blood flow regulation is mediated by mechanisms other than NO, such as prostaglandins and endothelial derived hyperpolarizing factor, which, in turn, are compromised by the inflammatory state, we anticipate that activation of both the PPARgamma as well as PPARalpha should ameliorate the disordered blood flow in type 2 diabetes. While it now appears that the PPARs may have a major role to play in protection from macrovascular disease, their contribution to amelioration of the microvascular defects in type 2 diabetes has fallen short of spectacular success. In this respect, the combinations of PPARalpha, PPARbeta and PPARgamma may better serve the unique requirements for improving the microvascular defect in diabetes.

Animals↗
PubMed2003

Effect of thiazolidinediones on glucose and fatty acid metabolism in patients with type 2 diabetes.

The current study aimed to compare the effects of treatment (2 months) with thiazolidinediones (TZDs) and placebo on glucose and fat metabolism in patients with type 2 diabetes (T2DM) in a crossover design. Eight patients received placebo (2 months) followed by TZD (2 months). Two-stage (1.5 and 6.0 pmol/kg min) hyperinsulinemic-euglycemic clamps were performed in all 8 patients pre- and post-placebo and post-TZD (post-placebo = pre-TZD). We determined rates of glucose disappearance (G(Rd)), glycolysis (GLS), glycogen synthesis (GS) (all with 3-(3)H glucose), carbohydrate (CHO) oxidation (indirect calorimetry), endogenous glucose production (EGP), free fatty acid (FFA) release ((2)H(5) glycerol), and oxidation (indirect calorimetry) and re-esterification, as well as plasma adiponectin and leptin concentrations, and fat cell size and number (determined in upper thigh biopsy samples). Placebo treatment had no effects on any of the measured parameters. TZD treatment improved insulin-stimulated glucose uptake (ISGU) from 17.1 to 26.4 micromol/kg min (P <.01) and insulin-stimulated GS from 4.8 to 13.4 micromol/kg min (P < 0.03), potentiated insulin-induced suppression of lipolysis from 4.3 to 2.3 micromol/kg min (P <.03) and FFA re-esterification from 1.9 to 1.0 micromol/kg min (P <.02), increased plasma adiponectin levels from 2.7 to 7.2 microg/mL (P <.05), and decreased plasma leptin levels from 30.8 to 23.4 ng/mL (P <.02). In addition, TZD tended to increase the number of small adipocytes (<50 microm) in subcutaneous adipose tissue. We conclude that TZDs have multiple actions and that many, but perhaps not all, can be accounted for by their action on adipose tissue.

Adipocytes↗
PubMed2006

Hypoglycemia in diabetes: pathophysiological mechanisms and diurnal variation.

Iatrogenic hypoglycemia, the limiting factor in the glycemic management of diabetes, causes recurrent morbidity (and sometimes death), precludes maintenance of euglycemia over a lifetime of diabetes and causes a vicious cycle of recurrent hypoglycemia. In insulin deficient - T1DM and advanced T2DM - diabetes hypoglycemia is the result of the interplay of therapeutic insulin excess and compromised physiological (defective glucose counterregulation) and behavioral (hypoglycemia unawareness) defenses against falling plasma glucose concentrations. The concept of hypoglycemia-associated autonomic failure (HAAF) in diabetes posits that recent antecedent hypoglycemia causes both defective glucose counterregulation (by reducing epinephrine responses in the setting of absent insulin and glucagon responses) and hypoglycemia unawareness (by reducing sympathoadrenal and the resulting neurogenic symptom responses) and thus a vicious cycle of recurrent hypoglycemia. The clinical impact of HAAF-including its reversal by avoidance of hypoglycemia-is well established, but its mechanisms are largely unknown. Loss of the glucagon response, a key feature of defective glucose counterregulation, is plausibly attributed to insulin deficiency, specifically loss of the decrement in intraislet insulin that normally signals glucagon secretion as glucose levels fall. Reduced neurogenic symptoms, a key feature of hypoglycemia unawareness, are largely the result of reduced sympathetic neural responses to falling glucose levels. The mechanism(s) by which hypoglycemia shifts the glycemic thresholds for sympathoadrenal activation to lower plasma glucose concentrations, the key feature of both components of HAAF, is not known. It does not appear to be the result of the release of a systemic mediator such as cortisol or epinephrine during antecedent hypoglycemia or of increased blood-to-brain glucose transport. It is likely the result of an as yet to be identified alteration of brain metabolism. While the research focus has been largely on the hypothalamus, hypoglycemia is known to activate widespread brain regions including the medial prefrontal cortex. The possibility of post-hypoglycemic brain glycogen supercompensation has also been raised. Finally, a unifying mechanism of HAAF would need to incorporate the effects of sleep and antecedent exercise which produce a phenomenon similar to hypoglycemia induced HAAF.

Animals↗
PubMed2003

Mortality in diabetes: a retrospective analysis from a tertiary care hospital in North India.

Cause(s) of death in patients with diabetes mellitus (DM) admitted to a tertiary care hospital in North India was analysed from classified information in patients' death records and case file. Of the 306652 total admissions from 1991 to 1999, 21584 patients died (7.04%), 592 of whom (355 men and 237 women) had DM (2.7%). Information from 92 patients with diabetes could not be retrieved and six patients with hyperglycemia of short duration (two with gestational DM, three with post-transplant diabetes and one with stress hyperglycemia) were excluded. Of the 494 patients, 456 (92.3%) had T2DM and 38 (7.7%) had T1DM. Four hundred and forty patients had diabetes related mortality: infections (230, 46.5%), cardiovascular events (86, 17.4%), chronic renal failure (CRF) (48, 9.7%), stroke (30, 6%), diabetic ketoacidosis (DKA) (15, 3%), hyperosmolar coma (11, 2.2%), and hypoglycemia (5, 1%), while others (54 patients) had diabetes unrelated deaths. Cause of death could not be ascertained in six patients (1.2%). Death was attributed to a single cause in 301 (60.9%), to two causes in 175 (35.4%) and to three or more causes in 12 (2.4%) patients. Analysis of the cause of death in DM versus hospital in-patients in general, showed infection (P<0.02), coronary artery disease (CAD) (P<0.001), and CRF (P<0.001) to be more frequent in diabetes.

Adult↗
PubMed2003

Nucleotide variation, haplotype structure, and association with end-stage renal disease of the human interleukin-1 gene cluster.

A dense gene-based SNP map was constructed across a 360-kb region containing the interleukin-1 gene cluster (IL1A, IL1B, and IL1RN), focusing on IL1RN. In total, 95 polymorphisms were confirmed or identified primarily by direct sequencing. Polymorphisms were precisely mapped to completed BAC and genomic sequences spanning this region. The polymorphisms were typed in 443 case-control subjects from Caucasian and African American groups. Consecutive pair-wise marker linkage disequilibrium was not strictly correlated with distance and ranged from D'=0.0079 to 1.000 and D'=0.0521 to 1.0000 in Caucasians and African Americans, respectively. Single markers and haplotypes in IL1 cluster genes were evaluated for association with end-stage renal disease (ESRD). Eleven SNPs show some evidence of association with ESRD, with the strongest associations in two IL1A variants, one SNP, rs1516792-3, in intron 5 (p=0.0015) and a 4-bp insertion/deletion within the 3'UTR, rs16347-2 (p=0.0024), among African Americans with non-T2DM-associated ESRD.

Black or African American↗
PubMed2000

PPAR gamma and the treatment of insulin resistance.

Numerous studies across several population groups have indicated that insulin resistance plays a central role in the development of type 2 diabetes mellitus (T2DM). Moreover, this disorder is also strongly associated with other metabolic syndromes, including hypertension, dyslipidemias and polycystic ovarian syndrome (PCOS). Recent advances have demonstrated that pharmacological agents of the thiazolidinedione class can reverse insulin resistance and profoundly improve many of these associated symptoms. These effects have been documented in a variety of genetic and acquired animal models of insulin resistance, as well as in numerous clinical trials in patients with insulin resistance. These compounds appear to enhance insulin action by modulating the activity of the nuclear receptor peroxisome proliferator-activated receptor (PPAR) gamma. This activation results in changes in the expression of a number of genes that are critically involved in glucose and lipid metabolism, as well as in insulin signal transduction. While precise events that occur downstream from PPAR gamma modulation remain uncertain, new insights are emerging from knockout studies in mice and the identification of genetic variants in humans. These findings indicate that there is still much to learn about the molecular biology and physiology of these interesting receptors, and that research in this area can lead to more effective and safer drugs to treat insulin resistance and associated syndromes.

Animals↗
PubMed2000

GLUT4 and company: SNAREing roles in insulin-regulated glucose uptake.

The primary physiological role of insulin is in glucose homeostasis. This is accomplished through the inhibition of gluconeogenesis in the liver and the stimulation of glucose uptake into insulin-sensitive tissues, such as adipose tissue, skeletal muscle and cardiac muscle. The ability of insulin to stimulate glucose uptake relies on a complex signaling cascade that leads to the translocation of glucose transporter protein 4 (GLUT4) from an intracellular compartment to the plasma membrane, which results in increased glucose uptake. Defects in the ability of insulin to regulate this key metabolic event can lead to insulin resistance and non-insulin-dependent type 2 diabetes mellitus (T2DM). To design effective treatments for diabetes, there have been major efforts to understand the insulin-regulated mechanisms that govern glucose uptake. These have involved defining the components of the insulin signaling network and identifying the molecular machinery that is used to translocate GLUT4.

Animals↗
PubMed2003

The adipocyte in insulin resistance: key molecules and the impact of the thiazolidinediones.

Globally, the prevalence of obesity is escalating, and insulin resistance resulting from increased (predominantly visceral) adipose tissue mass has been identified as a key factor that could drive parallel rises in type 2 diabetes mellitus (T2DM) prevalence. Correlations between these global epidemics have encouraged investigation into potential molecular links between the related impairments in lipid and glucose homeostasis. This article reviews factors released from adipose tissue that could contribute to the development of insulin resistance and beta-cell dysfunction, including tumour necrosis factor alpha (TNF-alpha), free fatty acids (FFAs), adiponectin, resistin and leptin. It also considers whether agonists of the peroxisome proliferator-activated receptor gamma, which is abundant in adipose tissue, might have an important impact on factors associated with adipocyte metabolism. For example, the thiazolidinediones, a class of oral anti-diabetic agents that reduce insulin resistance and improve beta-cell function, might mediate these effects by regulating adipocyte-derived factors, in particular TNF-alpha and FFAs.

Adipocytes↗
PubMed2003

The search for type 2 diabetes genes.

Type 2 diabetes (T2DM) is a serious disease with severe complications. Around one in 10 people alive today suffer from type 2 diabetes or are destined to develop it before they die. Inheritance plays an important role in the cause of type 2 diabetes. A considerable amount of research is devoted to defining the genes involved in the aetiology of this widespread disease. This information is crucial if we are to improve our methods of preventing and treating diabetes. Over the last 25 years there have been considerable advances in our understanding of the genetics of diabetes. Important discoveries have been made in dissecting the genes involved in rare monogenic forms of type 2 diabetes which has become a paradigm for genetic studies of type 2 diabetes. This review focuses on the main approaches currently adopted and our current understanding of the genes involved in susceptibility to type 2 diabetes.

Diabetes Mellitus, Type 2↗