Improvements in Metabolic Control in Adults with Type 2 Diabetes Following Referral to a Diabetes Center, 2005–2010

Objective: We aimed to compare metabolic control in adults with diabetes in the general population to those newly referred to a diabetes center and after 1 year of specialty care.Methods: We performed a retrospective comparison of adults with diabetes aged ≥20 years data from the National Health and Nutrition Examination Survey (NHANES, n = 1,674) and a diabetes center (n = 3,128) from 2005–2010. NHANES participants represented the civilian, non-institutionalized U.S. population. Diabetes center referrals lived primarily around eastern Massachusetts. The proportion attaining targets for glycated hemoglobin A1c (A1c), blood pressure (BP), low-density lipoprotein (LDL) cholesterol, or all 3 (ABC control) and the proportion prescribed medications to lower A1c, BP, or cholesterol were evaluated.Results: Compared to the general sample, a smaller proportion of new diabetes center referrals had A1c <7% (<53 mmol/mol, 24% vs. 53%, P<.001), BP <130/80 mm Hg (38% vs. 50%, P<.001), and ABC control (5.6% vs. 17%, P<.001) but not LDL<100 mg/dL (<2.6 mmol/L, 54% vs. 53%, P = .65). After 1 year, more diabetes center referrals attained targets for A1c (40%), BP (38%), LDL (67%), and ABC control (15%) (P<.001 for all versus baseline). ABC control was not different between the general sample and diabetes center referrals at 1 year (P = .16). After 1 year, a greater percentage of diabetes center referrals compared to the general sample were prescribed medications to lower glucose (95% vs. 72%), BP (79% vs. 64%), and cholesterol (77% vs. 54%)(all P<.001).Conclusion: Compared to the general population, glycemic control was significantly worse for adults newly referred to the diabetes center. Within 1 year of specialty care, ABC control increased 270% in the setting of significant therapy escalation.Abbreviations:A1c = glycated hemoglobin A1cABC = composite of A1c, blood pressure, and cholesterolACEi = angiotensin-converting enzyme inhibitorARB = angiotensin receptor blockerBMI = body mass indexBP = blood pressureEHR = electronic health recordLDL = low-density lipoproteinNCHS = National Center for Health StatisticsNHANES = National Health and Nutrition Examination SurveyPCP = primary care provider     

Exposure to p,p′-DDE: A Risk Factor for Type 2 Diabetes

Background

Persistent organic pollutants (POPs), such as PCBs, DDT and dioxins have in several cross-sectional studies shown strong associations with type 2 diabetes mellitus. Reversed causality can however not be excluded. The aim of this case-control study was to evaluate whether POPs concentration is a risk factor for type 2 diabetes.

Methodology/Principal Findings

A case-control study was performed within a well-defined cohort of women, age 50–59 years, from the Southern part of Sweden. Biomarkers for POP exposure, 2,2′,4,4′,5,5′-hexachlorobiphenyl (CB-153) and 1,1-dichloro-2,2-bis (p-chlorophenyl)-ethylene (p,p′-DDE) were analyzed in stored serum samples, which were collected at the baseline examination when the cohort was established. For 107 out of the 371 cases, serum samples were stored at least three years before their type 2 diabetes was diagnosed. In this data set, CB-153 and p,p′-DDE were not associated with an increased risk to develop type 2 diabetes. However, when only the cases (n = 39) that were diagnosed more than six years after the baseline examination and their controls were studied, the women in the highest exposed quartile showed an increased risk to develop type 2 diabetes (OR of 1.6 [95% 0.61, 4.0] for CB-153 and 5.5 [95% CI 1.2, 25] for p,p′-DDE).

Conclusions/Significance

The results from the present case-control study, including a follow-up design, confirms that p,p′-DDE exposure can be a risk factor for type 2 diabetes.     

Do Variants Associated with Susceptibility to Pancreatic Cancer and Type 2 Diabetes Reciprocally Affect Risk?

ObjectivesAlthough type 2 diabetes mellitus is a known risk factor for pancreatic cancer, the existence of shared genetic susceptibility is largely unknown. We evaluated whether any reported genetic risk variants of either disease found by genome-wide association studies reciprocally confer susceptibility.MethodsData that were generated in previous genome-wide association studies (GENEVA Type 2 Diabetes; PanScan) were obtained through the National Institutes of Health database of Genotypes and Phenotypes (dbGaP). Using the PanScan datasets, we tested for association of 38 variants within 37 genomic regions known to be susceptibility factors for type 2 diabetes. We further examined whether type 2 diabetes variants predispose to pancreatic cancer risk stratified by diabetes status. Correspondingly, we examined the association of fourteen pancreatic cancer susceptibility variants within eight genomic regions in the GENEVA Type 2 Diabetes dataset.ResultsFour plausible associations of diabetes variants and pancreatic cancer risk were detected at a significance threshold of p = 0.05, and one pancreatic cancer susceptibility variant was associated with diabetes risk at threshold of p = 0.05, but none remained significant after correction for multiple comparisons.ConclusionCurrently identified GWAS susceptibility variants are unlikely to explain the potential shared genetic etiology between Type 2 diabetes and pancreatic cancer.     

Sglt-2 Inhibition Added to Glp-1 Agonist Therapy for Type 2 Diabetes: What is the Benefit?

Abbreviations:GLP-1 = glucagon-like peptide-1HbA1c = glycated hemoglobinRCT = randomized controlled trialSGLT-2 = sodium-glucose cotransporter type 2     

Type 2 Diabetes with Comorbid Depression in Relation to Cognitive Impairment: an Opportunity for Prevention?

Studies show poor glycemic control is associated with increased risk of dementia among patients with Type 2 diabetes, indicating potential for prevention of dementia with improved glycemia. Emerging evidence suggests that a relationship between short-term glycemic control and cognitive function exists in Type 2 diabetes. However, detailed mechanisms relating diabetic dementia are lacking, as other concurrent conditions, such as depression, may also increase the risk of dementia in Type 2 diabetes. We examined the effects of glycemic control and depression on cognitive function in 88 patients (mean age, 67 ± 4 years) whose A1c (glycosylated hemoglobin) levels, comorbid depression, mini-mental state examination (MMSE) scores were recorded at baseline. Seventeen patients had depression; 14 agreed on anti-depressants. In 6 months, 69 patients reached A1c goal of < 7% (A1c from 9.7 ± 0.8 to 6.4 ± 0.3) while cognition improved significantly (MMSE scored from 20.2 ± 3.5 to 26.2 ± 2.1, p < 0.05). Cognitive increment in controlled diabetes was more consistently observed if their underlying depression was effectively treated (n ? 14). Nineteen patients did not reach A1c goal of < 7% (A1c from 9.6 ± 0.9 to 8.9 ± 0.9) while cognitive increment was minimal (MMSE scored from 20.6 ± 4.9 to 21.3 ± 5.1, p > 0.05). Cognitive decrements were observed among depressed diabetics who refused anti-depressants. Multivariate analysis adjusted for age, education, alcohol use, and other variables yielded similar results. We found controlled glycemia and depression prevent cognitive decline. Further research into mechanisms of cognitive impairment in diabetes may allow us to challenge the concept of dementia in those patients as an irremediable disease.     

Direct Angiotensin II Type 2 Receptor Stimulation Ameliorates Insulin Resistance in Type 2 Diabetes Mice with PPARγ Activation

Objectives

The role of angiotensin II type 2 (AT₂) receptor stimulation in the pathogenesis of insulin resistance is still unclear. Therefore we examined the possibility that direct AT₂ receptor stimulation by compound 21 (C21) might contribute to possible insulin-sensitizing/anti-diabetic effects in type 2 diabetes (T2DM) with PPARγ activation, mainly focusing on adipose tissue.

Methods

T2DM mice, KK-Ay, were subjected to intraperitoneal injection of C21 and/or a PPARγ antagonist, GW9662 in drinking water for 2 weeks. Insulin resistance was evaluated by oral glucose tolerance test, insulin tolerance test, and uptake of 2-[³H] deoxy-D-glucose in white adipose tissue. Morphological changes of adipose tissues as well as adipocyte differentiation and inflammatory response were examined.

Results

Treatment with C21 ameliorated insulin resistance in KK-Ay mice without influencing blood pressure, at least partially through effects on the PPARγ pathway. C21 treatment increased serum adiponectin concentration and decreased TNF-α concentration; however, these effects were attenuated by PPARγ blockade by co-treatment with GW9662. Moreover, we observed that administration of C21 enhanced adipocyte differentiation and PPARγ DNA-binding activity, with a decrease in inflammation in white adipose tissue, whereas these effects of C21 were attenuated by co-treatment with GW9662. We also observed that administration of C21 restored β cell damage in diabetic pancreatic tissue.

Conclusion

The present study demonstrated that direct AT₂ receptor stimulation by C21 accompanied with PPARγ activation ameliorated insulin resistance in T2DM mice, at least partially due to improvement of adipocyte dysfunction and protection of pancreatic β cells.     

Can Newer Therapies Delay the Progression of Type 2 Diabetes Mellitus?

ObjectiveTo review the multifactorial and progressive nature of type 2 diabetes mellitus (T2DM), the consequences of its progression, and the potential of traditional and newer therapies to delay the progression of this disease.MethodsThe relevant literature is reviewed, and the mechanisms of action of novel agents for treatment of T2DM are discussed.ResultsThe global prevalence of diabetes has been increasing in recent decades, reaching near-epidemic proportions, and is projected to more than double by 2030. More than 90% of cases of diabetes in most countries consist of T2DM, but many individuals remain undiagnosed or are diagnosed only after their disease has progressed considerably. Inadequate glycemic control in a majority of patients with T2DM is due to the progressive nature of the disease, delay in initiating pharmacotherapy, and failure to intensify treatment more quickly in patients who do not achieve glycemic targets. Traditional oral therapies are usually effective at lowering hyperglycemia initially but do not prevent disease progression; thus, many patients ultimately require insulin. Furthermore, because most antidiabetic therapies are associated with weight gain or risk of hypoglycemia (or both), patients may not adhere to treatment recommendations.ConclusionA new therapeutic approach focuses on the use of the incretin hormone glucagon-like peptide-1. Analogues of this hormone delay the progression of β-cell dysfunction and promote β-cell regeneration in animal models. In clinical trials, they have been shown to improve glycemic control by increasing glucose-stimulated insulin secretion and suppressing glucagon secretion. At high concentrations, they also slow gastric emptying and increase satiety, which often promotes weight loss. Another approach is to inhibit the enzyme dipeptidyl-peptidase 4, which rapidly inactivates glucagon-like peptide- 1 and glucose-dependent insulinotropic polypeptide, thereby increasing endogenous incretin levels. (Endocr Pract. 2008;14:625-638)     

A Genomewide Search for Type 2 Diabetes–Susceptibility Genes in Indigenous Australians

The prevalence of type 2 diabetes among Australian residents is 7.5%; however, prevalence rates up to six times higher have been reported for indigenous Australian communities. Epidemiological evidence implicates genetic factors in the susceptibility of indigenous Australians to type 2 diabetes and supports the hypothesis of the "thrifty genotype," but, to date, the nature of the genetic predisposition is unknown. We have ascertained clinical details from a community of indigenous Australian descent in North Stradbroke Island, Queensland. In this population, the phenotype is characterized by severe insulin resistance. We have conducted a genomewide scan, at an average resolution of 10 cM, for type 2 diabetes-susceptibility genes in a large multigeneration pedigree from this community. Parametric linkage analysis undertaken using FASTLINK version 4.1p yielded a maximum two-point LOD score of +2.97 at marker D2S2345. Multipoint analysis yielded a peak LOD score of +3.9 <1 cM from marker D2S2345, with an 18-cM 3-LOD support interval. Secondary peak LOD scores were noted on chromosome 3 (+1.8 at recombination fraction [theta] 0.05, at marker D3S1311) and chromosome 8 (+1.77 at theta=0.0, at marker D8S549). These chromosomal regions are likely to harbor novel susceptibility genes for type 2 diabetes in the indigenous Australian population.     

A Syntenic Cross Species Aneuploidy Genetic Screen Links RCAN1 Expression to β-Cell Mitochondrial Dysfunction in Type 2 Diabetes

Type 2 diabetes (T2D) is a complex metabolic disease associated with obesity, insulin resistance and hypoinsulinemia due to pancreatic β-cell dysfunction. Reduced mitochondrial function is thought to be central to β-cell dysfunction. Mitochondrial dysfunction and reduced insulin secretion are also observed in β-cells of humans with the most common human genetic disorder, Down syndrome (DS, Trisomy 21). To identify regions of chromosome 21 that may be associated with perturbed glucose homeostasis we profiled the glycaemic status of different DS mouse models. The Ts65Dn and Dp16 DS mouse lines were hyperglycemic, while Tc1 and Ts1Rhr mice were not, providing us with a region of chromosome 21 containing genes that cause hyperglycemia. We then examined whether any of these genes were upregulated in a set of ~5,000 gene expression changes we had identified in a large gene expression analysis of human T2D β-cells. This approach produced a single gene, RCAN1, as a candidate gene linking hyperglycemia and functional changes in T2D β-cells. Further investigations demonstrated that RCAN1 methylation is reduced in human T2D islets at multiple sites, correlating with increased expression. RCAN1 protein expression was also increased in db/db mouse islets and in human and mouse islets exposed to high glucose. Mice overexpressing RCAN1 had reduced in vivo glucose-stimulated insulin secretion and their β-cells displayed mitochondrial dysfunction including hyperpolarised membrane potential, reduced oxidative phosphorylation and low ATP production. This lack of β-cell ATP had functional consequences by negatively affecting both glucose-stimulated membrane depolarisation and ATP-dependent insulin granule exocytosis. Thus, from amongst the myriad of gene expression changes occurring in T2D β-cells where we had little knowledge of which changes cause β-cell dysfunction, we applied a trisomy 21 screening approach which linked RCAN1 to β-cell mitochondrial dysfunction in T2D.     

Which Obesity Index Best Explains Prevalence Differences in Type 2 Diabetes Mellitus?

Objective: Obesity drives the diabetes epidemic. However, it is not known which obesity index best explains variations in type 2 diabetes mellitus prevalence across populations. Research Methods and Procedures: We analyzed three cross‐sectional studies from San Antonio, TX, (Mexican‐Americans and non‐Hispanic whites, n = 2839), Mexico City (n = 2233), and Spain (n = 2161) (age range, 35 to 64 years). We used the area under the receiver operating characteristic curve (AUC) to assess performance for identifying diabetic subjects and logistic regression analysis to examine differences in diabetes prevalence. Results: AUCs for waist circumference and BMI were similar in white subjects, but the AUC for waist circumference was greater in Mexican‐origin subjects (Mexican men, 0.594 vs. 0.549, p = 0.008; and women, 0.605 vs. 0.557, p = 0.002; Mexican‐American men, 0.648 vs. 0.600, p < 0.001; and women, 0.744 vs. 0.693, p < 0.001). The AUC for waist‐to‐height ratio tended to be greater than that for waist circumference, but statistical significance was demonstrated only in Mexican women (0.628 vs. 0.613, p = 0.044), Mexican‐American women (0.774 vs. 0.758, p < 0.001), and Spanish women (0.734 vs. 0.715, p = 0.039). No obesity index was consistently superior to the others for explaining differences in diabetes prevalence among populations. Conclusions: In white and Mexican‐origin men, waist circumference may be the preferred marker for identifying diabetic subjects on account of its simplicity; in women, waist‐to‐height ratio may be better. Differences in diabetes prevalence among these populations cannot be attributed to a single measure of obesity.     

Lymphocyte-Derived Exosomal MicroRNAs Promote Pancreatic β Cell Death and May Contribute to Type 1 Diabetes Development

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Integrated Model of Metabolism and Autoimmune Response in β-Cell Death and Progression to Type 1 Diabetes

Progression to type 1 diabetes is characterized by complex interactions of environmental, metabolic and immune system factors, involving both degenerative pathways leading to loss of pancreatic β-cells as well as protective pathways. The interplay between the degenerative and protective pathways may hold the key to disease outcomes, but no models have so far captured the two together. Here we propose a mathematical framework, an ordinary differential equation (ODE) model, which integrates metabolism and the immune system in early stages of disease process. We hypothesize that depending on the degree of regulation, autoimmunity may also play a protective role in the initial response to stressors. We assume that β-cell destruction follows two paths of loss: degenerative and autoimmune-induced loss. The two paths are mutually competing, leading to termination of the degenerative loss and further to elimination of the stress signal and the autoimmune response, and ultimately stopping the β-cell loss. The model describes well our observations from clinical and non-clinical studies and allows exploration of how the rate of β-cell loss depends on the amplitude and duration of autoimmune response.     

Can Data Science Inform Environmental Justice and Community Risk Screening for Type 2 Diabetes?

Background

Having the ability to scan the entire country for potential “hotspots” with increased risk of developing chronic diseases due to various environmental, demographic, and genetic susceptibility factors may inform risk management decisions and enable better environmental public health policies.

Objectives

Develop an approach for community-level risk screening focused on identifying potential genetic susceptibility hotpots.

Methods

Our approach combines analyses of phenotype-genotype data, genetic prevalence of single nucleotide polymorphisms, and census/geographic information to estimate census tract-level population attributable risks among various ethnicities and total population for the state of California.

Results

We estimate that the rs13266634 single nucleotide polymorphism, a type 2 diabetes susceptibility genotype, has a genetic prevalence of 56.3%, 47.4% and 37.0% in Mexican Mestizo, Caucasian, and Asian populations. Looking at the top quintile for total population attributable risk, 16 California counties have greater than 25% of their population living in hotspots of genetic susceptibility for developing type 2 diabetes due to this single genotypic susceptibility factor.

Conclusions

This study identified counties in California where large portions of the population may bear additional type 2 diabetes risk due to increased genetic prevalence of a susceptibility genotype. This type of screening can easily be extended to include information on environmental contaminants of interest and other related diseases, and potentially enables the rapid identification of potential environmental justice communities. Other potential uses of this approach include problem formulation in support of risk assessments, land use planning, and prioritization of site cleanup and remediation actions.     

Omitting Late-Night Eating May Cause Hypoglycemia in “Well Controlled” Basal Insulin-Treated Type 2 Diabetes

ObjectiveTo assess hypoglycemia caused by eating the last meal of the day earlier or its omission in “well controlled” type 2 diabetes mellitus patients treated with once-nightly basal insulin.MethodsPreviously basal insulin-titrated subjects (n = 20) (fasting plasma glucose, FPG, < 110 mg/dL and no self-reported hypoglycemia) underwent continuous glucose monitoring (CGM) during 3 consecutive eating conditions of 3 days each; (1) usual eating, (2) the last meal restricted to 18:00, and (3) 1 sequential meal omitted/day thereby creating a fasting day after transposing the 4-hour period after a meal with that when the meal was omitted. One 24-hour (00:00 to 00:00) period within each eating condition was selected for comparison.ResultsThe mean duration in all hypoglycemic ranges doubled (P = .0584 or greater) when the last meal was omitted or eaten at 18:09 ± 0:39 instead of 19:43 ± 1:01, the usual time for the subjects’ undisturbed eating. The mean duration of hypoglycemia was greatest between 00:00 to 06:00 compared to the 3 other 6-hour periods of the day.ConclusionsIncreased hypoglycemia occurs when the subject’s last meal is eaten earlier or omitted and may not be recognized because it occurs predominately during sleep. When titrating basal insulin from the morning FPG, considerations should be given to the effect of the last meal of the day and possible hypoglycemia between 00:00 and 06:00 to avoid excessive basal insulin treatment. (Endocr Pract. 2015;21:280-285)     

Polymorphisms within the Novel Type 2 Diabetes Risk Locus MTNR1B Determine β-Cell Function

Background

Very recently, a novel type 2 diabetes risk gene, i.e., MTNR1B, was identified and reported to affect fasting glycemia. Using our thoroughly phenotyped cohort of subjects at an increased risk for type 2 diabetes, we assessed the association of common genetic variation within the MTNR1B locus with obesity and prediabetes traits, namely impaired insulin secretion and insulin resistance.

Methodology/Principal Findings

We genotyped 1,578 non-diabetic subjects, metabolically characterized by oral glucose tolerance test, for five tagging single nucleotide polymorphisms (SNPs) covering 100% of common genetic variation (minor allele frequency >0.05) within the MTNR1B locus (rs10830962, rs4753426, rs12804291, rs10830963, rs3781638). In a subgroup (N = 513), insulin sensitivity was assessed by hyperinsulinemic-euglycemic clamp, and in a further subgroup (N = 301), glucose-stimulated insulin secretion was determined by intravenous glucose tolerance test. After appropriate adjustment for confounding variables and Bonferroni correction for multiple comparisons, none of the tagging SNPs was reliably associated with measures of adiposity. SNPs rs10830962, rs4753426, and rs10830963 were significantly associated with higher fasting plasma glucose concentrations (p<0.0001) and reduced OGTT- and IVGTT-induced insulin release (p≤0.0007 and p≤0.01, respectively). By contrast, SNP rs3781638 displayed significant association with lower fasting plasma glucose levels and increased OGTT-induced insulin release (p<0.0001 and p≤0.0002, respectively). Moreover, SNP rs3781638 revealed significant association with elevated fasting- and OGTT-derived insulin sensitivity (p≤0.0021). None of the MTNR1B tagging SNPs altered proinsulin-to-insulin conversion.

Conclusions/Significance

In conclusion, common genetic variation within MTNR1B determines glucose-stimulated insulin secretion and plasma glucose concentrations. Their impact on β-cell function might represent the prevailing pathomechanism how MTNR1B variants increase the type 2 diabetes risk.     

Ketosis-Prone Type 2 Diabetes: Effect of Hyperglycemia on β-Cell Function and Skeletal Muscle Insulin Signaling

ObjectiveTo determine the underlying mechanism for the severe and transient β-cell dysfunction and impaired insulin action in obese African American patients with ketosis-prone diabetes.MethodsThe effect of sustained hyperglycemia (glucotoxicity) and increased free fatty acids (lipotoxicity) on β-cell function was assessed by changes in insulin secretion during a 20-hour glucose (200 mg/m² per minute) and a 48-hour Intralipid (40 mL/h) infusion, respectively. Insulin-activated signaling pathways and pattern of Akt-1 and Akt-2 expression and insulin-stimulated phosphorylation were analyzed in skeletal muscle biopsy specimens. Studies were performed in an obese African American woman within 48 hours after resolution of diabetic ketoacidosis and 1 week after discontinuation of insulin treatment.ResultsDextrose infusion rapidly increased C-pep-tide levels from a baseline of 3.2 ng/mL to a mean of 7.1 ± 0.5 ng/mL during the first 8 hours of infusion; thereafter, C-peptide levels progressively declined. Lipid infusion was not associated with any deleterious effect on insulin and C-peptide secretion. Initial in vitro stimulation of muscle tissue with insulin resulted in a substantial and selectively decreased Akt-2 expression and insulin-stimulated phosphorylation on the serine residue. Improved metabolic control resulted in 70% greater Akt expression at near-normoglycemic remission in comparison with the period of hyperglycemia.ConclusionHyperglycemia, but not increased free fatty acid levels, led to progressive β-cell dysfunction and impaired insulin secretion. Hyperglycemia was also associated with diminished skeletal muscle Akt expression and phosphorylation in an African American woman with ketosis-prone diabetes, and this defect improved notably with aggressive insulin therapy. These results indicate the importance of glucose toxicity in the pathogenesis of keto-sis-prone diabetes in obese African American patients. (Endocr Pract. 2007;13:283-290)