Evidence of Gene-Gene Interaction and Age-at-Diagnosis Effects in Type 1 Diabetes

The common genetic loci that independently influence the risk of type 1 diabetes have largely been determined. Their interactions with age-at-diagnosis of type 1 diabetes, sex, or the major susceptibility locus, HLA class II, remain mostly unexplored. A large collection of more than 14,866 type 1 diabetes samples (6,750 British diabetic individuals and 8,116 affected family samples of European descent) were genotyped at 38 confirmed type 1 diabetes-associated non-HLA regions and used to test for interaction of association with age-at-diagnosis, sex, and HLA class II genotypes using regression models. The alleles that confer susceptibility to type 1 diabetes at interleukin-2 (IL-2), IL2/4q27 (rs2069763) and renalase, FAD-dependent amine oxidase (RNLS)/10q23.31 (rs10509540), were associated with a lower age-at-diagnosis (P = 4.6 × 10⁻⁶ and 2.5 × 10⁻⁵, respectively). For both loci, individuals carrying the susceptible homozygous genotype were, on average, 7.2 months younger at diagnosis than those carrying the protective homozygous genotypes. In addition to protein tyrosine phosphatase nonreceptor type 22 (PTPN22), evidence of statistical interaction between HLA class II genotypes and rs3087243 at cytotoxic T-lymphocyte antigen 4 (CTLA4)/2q33.2 was obtained (P = 7.90 × 10⁻⁵). No evidence of differential risk by sex was obtained at any loci (P ≥ 0.01). Statistical interaction effects can be detected in type 1 diabetes although they provide a relatively small contribution to our understanding of the familial clustering of the disease.Knowledge of the genetic architecture of type 1 diabetes has increased recently owing to large-scale genome-wide association (GWA) studies (1–3). Estimates of the contributions of the HLA region and numerous non-HLA loci across the genome now account for a sizeable proportion of familial clustering of the disorder (4–6). However, there remains substantial familial clustering that is not explained by the known loci (likely to be in excess of 40%) (4–6). Interactions between risk loci beyond that of a multiplicative model on the odds ratio (OR) scale (or additive on the log odds scale (7)) could account for some of the “missing heritability.” In addition, the existence of differential effects according to age-at-diagnosis and sex remains relatively unexplored.The HLA region on chromosome 6p21 is the major source of familial clustering in type 1 diabetes (4). HLA-DRB1 and HLA-DQB1 are associated with ORs in excess of 10 for susceptible genotypes (or less than 0.1 for protective genotypes) (8). The risk genotype HLA-DRB1*03/HLA-DRB1*04-HLA-DQB1*0302 (referred to as DR3/DR4-DQ302) with greatest effect has been shown to have the highest frequency in the individuals with youngest onset (9). An age-at-diagnosis interaction has also been reported for HLA-DRB1*04 (10) and the HLA class I alleles HLA-A*24 and HLA-B*39 (11,12).In contrast, reports of age-at-diagnosis interaction effects at non-HLA loci are contradictory, with positive reports largely confined to studies involving small sample sets (3,13–15). Similarly, reports of gene–gene interaction of type 1 diabetes–associated regions are also mainly conflicting (16–19), we presume due to inadequate sample sizes, with most positive reports likely to be false because the false-discovery rate would be high in these underpowered studies. The only convincing gene–gene interaction reported, is between a major non-HLA locus, protein tyrosine phosphatase nonreceptor type 22 (PTPN22) and DR3/DR4-DQ302 genotypes (20–23).The incidence of childhood type 1 diabetes is similar in males and females, unlike other autoimmune diseases such as Graves disease, celiac disease, or multiple sclerosis. Despite similar frequencies of childhood type 1 diabetes by sex, there have been reports of genetic risk factors differing between males and females (22,24).Given that most studies of gene–gene interaction, age-at-diagnosis effects, and sex effects on type 1 diabetes risk have not been addressed in sufficiently well-powered studies, the Type 1 Diabetes Genetics Consortium (T1DGC) has collected more than 16,000 type 1 diabetes–affected samples and tested them for interaction effects with sex and age-at-diagnosis at 38 non-HLA type 1 diabetes–associated regions (Supplementary Table 2). Gene–gene interaction was also tested between HLA class II and the 38 non-HLA loci. With this very large sample set, the study had at least 80% power to detect effects as small as an interaction OR = 1.12 for sex and 1.19 for interactions with age-at-diagnosis or HLA. These calculations assume a multiplicative (log additive) effects model, an OR = 1.15 for association with type 1 diabetes for the test locus and a minor allele frequency of 0.2 and α = 0.0004. In contrast, with 5,000 samples, which is twice as large as any other study testing for interaction effects in type 1 diabetes published to date, the study would only be powered at 80% to detect interaction effects larger than an OR = 1.3 with sex (with the same assumptions as above). For age-at-diagnosis interaction, an OR ≥ 1.37 could be detected; for HLA interaction, an OR ≥ 1.38 could be detected (Supplementary Figs. 1–6).     

Evidence That in Uncontrolled Diabetes,Hyperglucagonemia Is Required for Ketosis but Not for Increased Hepatic Glucose Production or Hyperglycemia

Several lines of evidence implicate excess glucagon secretion in the elevated rates of hepatic glucose production (HGP), hyperglycemia, and ketosis characteristic of uncontrolled insulin-deficient diabetes (uDM), but whether hyperglucagonemia is required for hyperglycemia in this setting is unknown. To address this question, adult male Wistar rats received either streptozotocin (STZ) to induce uDM (STZ-DM) or vehicle and remained nondiabetic. Four days later, animals received daily subcutaneous injections of either the synthetic GLP-1 receptor agonist liraglutide in a dose-escalating regimen to reverse hyperglucagonemia or its vehicle for 10 days. As expected, plasma glucagon levels were elevated in STZ-DM rats, and although liraglutide treatment lowered glucagon levels to those of nondiabetic controls, it failed to attenuate diabetic hyperglycemia, elevated rates of glucose appearance (Ra), or increased hepatic gluconeogenic gene expression. In contrast, it markedly reduced levels of both plasma ketone bodies and hepatic expression of the rate-limiting enzyme involved in ketone body production. To independently confirm this finding, in a separate study, treatment of STZ-DM rats with a glucagon-neutralizing antibody was sufficient to potently lower plasma ketone bodies but failed to normalize elevated levels of either blood glucose or Ra. These data suggest that in rats with uDM, hyperglucagonemia is required for ketosis but not for increased HGP or hyperglycemia.     

Spillover of Fatty Acids During Dietary Fat Storage in Type 2 Diabetes: Relationship to Body Fat Depots and Effects of Weight Loss

Spillover of lipoprotein lipase-generated fatty acids from chylomicrons into the plasma free fatty acid (FFA) pool is an important source of FFA and reflects inefficiency in dietary fat storage. We measured spillover in 13 people with type 2 diabetes using infusions of a [³H]triolein-labeled lipid emulsion and [U-¹³C]oleate during continuous feeding, before and after weight loss. Body fat was measured with dual energy X-ray absorptiometry and computed tomography. Participants lost ∼14% of body weight. There was an ∼38% decrease in meal-suppressed FFA concentration (P < 0.0001) and an ∼23% decrease in oleate flux (P = 0.007). Fractional spillover did not change (P = NS). At baseline, there was a strong negative correlation between spillover and leg fat (r = −0.79, P = 0.001) and a positive correlation with the trunk-to-leg fat ratio (R = 0.56, P = 0.047). These correlations disappeared after weight loss. Baseline leg fat (R = −0.61, P = 0.027) but not trunk fat (R = −0.27, P = 0.38) negatively predicted decreases in spillover with weight loss. These results indicate that spillover, a measure of inefficiency in dietary fat storage, is inversely associated with lower body fat in type 2 diabetes.Free fatty acids (FFAs) mediate insulin resistance (1,2), drive VLDL triglyceride synthesis in the liver (3), and play an important role in the pathogenesis of hypertension (4,5) and diabetes (6). Spillover of lipoprotein lipase (LPL)-generated fatty acids from chylomicrons into the plasma FFA pool is an important source of FFA (7–10) and reflects inefficiency in dietary fat storage. Previous work has shown that the amount of fat taken up in leg fat per gram of tissue increases as a function of leg fat mass, whereas it actually decreases as a function of visceral fat mass and does not change in upper body subcutaneous fat (11). However, it is not clear whether these findings reflect changes in rates of LPL-mediated meal fat hydrolysis, changes in fractional spillover, or both. We therefore undertook a study in people with type 2 diabetes to determine the effects of weight loss on spillover and to investigate potential associations between spillover and body fat depots.     

Effects of Prostaglandin F2α and Cisapride on Small Intestinal Activity During the Early Postoperative Period in Humans

2 α (PGF) and cisapride were investigated during the early postoperative period in 26 patients who underwent abdominal surgery. Records of intestinal motility were made using an infusion catheter. PGF, 0.4 μg/kg per minute, given intravenously over 60 min, and cisapride, 5 mg, given intraintestinally, were administered to 13 patients each, first immediately after the operation, and then after the migrating motor complexes (MMCs) had reappeared following a period of intestinal quiescence. The MMCs were reestablished within the first postoperative day. Both PGF and cisapride stimulated irregular, high-amplitude contractions; however, the MMCs reappeared following these induced contractions only if the drugs were administered just after the postoperative MMCs became evident. These prokinetic drugs did not affect gastrointestinal hormone concentrations, but induced contractile activity even in the early postoperative period. Although the findings of this study demonstrate that these drugs may be useful as prokinetic agents to promote recovery from postoperative ileus just after the reappearance of MMCs in the early postoperative period, their precise mode of action has not been established. (Received for publication on May 7, 1997; accepted on Nov. 6, 1997)     

Cost-Effectiveness of Aliskiren in Type 2 Diabetes,Hypertension, and Albuminuria

The Aliskiren in the Evaluation of Proteinuria in Diabetes (AVOID) trial demonstrated that adding aliskiren, an oral direct renin inhibitor, at a dosage of 300 mg/d to the highest approved dosage of losartan and optimal antihypertensive therapy reduces albuminuria over 6 mo among patients with type 2 diabetes, hypertension, and albuminuria. The cost-effectiveness of this therapy, however, is unknown. Here, we used a Markov model to project progression to ESRD, life years, quality-adjusted life years, and lifetime costs for aliskiren plus losartan versus losartan. We used data from the AVOID study and the Irbesartan in Diabetic Nephropathy Trial (IDNT) to estimate probabilities of progression of renal disease. We estimated probabilities of mortality for ESRD and other comorbidities using data from the US Renal Data System, US Vital Statistics, and published studies. We based pharmacy costs on wholesale acquisition costs and based costs of ESRD and transplantation on data from the US Renal Data System. We found that adding aliskiren to losartan increased time free of ESRD, life expectancy, and quality-adjusted life expectancy by 0.1772, 0.1021, and 0.0967 yr, respectively. Total expected lifetime health care costs increased by $2952, reflecting the higher pharmacy costs of aliskiren and losartan ($7769), which were partially offset by savings in costs of ESRD ($4860). We estimated the cost-effectiveness of aliskiren to be $30,500 per quality-adjusted life year gained. In conclusion, adding aliskiren to losartan and optimal therapy in patients with type 2 diabetes, hypertension, and albuminuria may be cost-effective from a US health care system perspective.Recent clinical trials have shown that reductions in albuminuria with agents that inhibit the renin-angiotensin-aldosterone system (RAAS; e.g., angiotensin-converting enzyme inhibitors or angiotensin receptor blockers), as defined by a urinary albumin-creatinine ratio (UACR) or urinary albumin excretion rate (UAER), can delay progression of renal disease in patients with hypertension and type 2 diabetes.^1–5 Albuminuria is associated with fatal and nonfatal cardiovascular events and progression toward ESRD,^1,2,6 and reductions in albuminuria have been widely used as surrogate markers of renoprotection.^7,8The Aliskiren in the Evaluation of Proteinuria in Diabetes (AVOID) trial was a multicenter, randomized, double-blind study to assess the efficacy and safety of adding aliskiren, an oral direct renin inhibitor, at a dosage of 300 mg/d to the highest approved dosage of losartan (100 mg/d) and optimal antihypertensive therapy in patients with type 2 diabetes, hypertension, and albuminuria.⁹ At the end of 6 mo of follow-up, aliskiren 300 mg/d significantly reduced mean UACR by 20% (P = 0.0009) and overnight UAER by 18% versus placebo (P = 0.009). Although the AVOID trial demonstrated that adjunctive treatment with aliskiren 300 mg/d reduces albuminuria during 6 mo in these patients, it did not examine the potential long-term clinical and economic consequences of such treatment.The objective of this study was to evaluate, from the US health care system perspective, the potential cost-effectiveness of lifetime treatment with aliskiren 300 mg/d plus losartan 100 mg/d and optimal antihypertensive therapy (aliskiren plus losartan) versus lifetime treatment with losartan 100 mg/d and optimal antihypertensive therapy alone (losartan only) in patients with type 2 diabetes, hypertension, and albuminuria. We evaluated cost-effectiveness using a Markov model (Figure 1).¹⁰ The initial distribution of the population across disease states and probabilities of progression from microalbuminuria (MA) and early overt nephropathy (EON) to advanced overt nephropathy (AON) were from the AVOID trial (11Open in a separate windowFigure 1.Markov state transition model. Ovals represent health states. Patients are assumed to transition among states every 6 mo on the basis of transition probabilities in

Interactions Among Glucose Delivery,Transport, and Phosphorylation That Underlie Skeletal Muscle Insulin Resistance in Obesity and Type 2 Diabetes: Studies With Dynamic PET Imaging

Dynamic positron emission tomography (PET) imaging was performed using sequential tracer injections ([¹⁵O]H₂O, [¹¹C]3-O-methylglucose [3-OMG], and [¹⁸F]fluorodeoxyglucose [FDG]) to quantify, respectively, skeletal muscle tissue perfusion (glucose delivery), kinetics of bidirectional glucose transport, and glucose phosphorylation to interrogate the individual contribution and interaction among these steps in muscle insulin resistance (IR) in type 2 diabetes (T2D). PET imaging was performed in normal weight nondiabetic subjects (NW) (n = 5), obese nondiabetic subjects (OB) (n = 6), and obese subjects with T2D (n = 7) during fasting conditions and separately during a 6-h euglycemic insulin infusion at 40 mU·m⁻²·min⁻¹. Tissue tracer activities were derived specifically within the soleus muscle with PET images and magnetic resonance imaging. During fasting, NW, OB, and T2D subjects had similar [¹¹C]3-OMG and [¹⁸F]FDG uptake despite group differences for tissue perfusion. During insulin-stimulated conditions, IR was clearly evident in T2D (P < 0.01), and [¹⁸F]FDG uptake by muscle was inversely correlated with systemic IR (P < 0.001). The increase in insulin-stimulated glucose transport was less (P < 0.01) in T2D (twofold) than in NW (sevenfold) or OB (sixfold) subjects. The fractional phosphorylation of [¹⁸F]FDG during insulin infusion was also significantly lower in T2D (P < 0.01). Dynamic triple-tracer PET imaging indicates that skeletal muscle IR in T2D involves a severe impairment of glucose transport and additional impairment in the efficiency of glucose phosphorylation.     

Effects of Differing Antecedent Increases of Plasma Cortisol on Counterregulatory Responses During Subsequent Exercise in Type 1 Diabetes

OBJECTIVE

Antecedent hypoglycemia can blunt neuroendocrine and autonomic nervous system responses to next-day exercise in type 1 diabetes. The aim of this study was to determine whether antecedent increase of plasma cortisol is a mechanism responsible for this finding.

RESEARCH DESIGN AND METHODS

For this study, 22 type 1 diabetic subjects (11 men and 11 women, age 27 ± 2 years, BMI 24 ± 1 kg/m², A1C 7.9 ± 0.2%) underwent four separate randomized 2-day protocols, with overnight normalization of blood glucose. Day 1 consisted of morning and afternoon 2-h hyperinsulinemic- (9 pmol · kg⁻¹ · min⁻¹) euglycemic clamps (5.1 mmol/l), hypoglycemic clamps (2.9 mmol/l), or euglycemic clamps with a physiologic low-dose intravenous infusion of cortisol to reproduce levels found during hypoglycemia or a high-dose infusion, which resulted in further twofold greater elevations of plasma cortisol. Day 2 consisted of 90-min euglycemic cycling exercise at 50% Vo_2max.

RESULTS

During exercise, glucose levels were equivalently clamped at 5.1 ± 0.1 mmol/l and insulin was allowed to fall to similar levels. Glucagon, growth hormone, epinephrine, norepinephrine, and pancreatic polypeptide responses during day 2 exercise were significantly blunted following antecedent hypoglycemia, low- and high-dose cortisol, compared with antecedent euglycemia. Endogenous glucose production and lipolysis were also significantly reduced following day 1 low- and high-dose cortisol.

CONCLUSIONS

Antecedent physiologic increases in cortisol (equivalent to levels occurring during hypoglycemia) resulted in blunted neuroendocrine, autonomic nervous system, and metabolic counterregulatory responses during subsequent exercise in subjects with type 1 diabetes. These data suggest that prior elevations of cortisol may play a role in the development of exercise-related counterregulatory failure in those with type 1 diabetes.The Diabetes Control and Complications Trial has definitively demonstrated that intensive glycemic control can reduce microvascular complications in those with type 1 diabetes (1). However, intensive therapy is associated with an increased incidence of hypoglycemia (2). Exercise is a cornerstone of diabetes management. It improves insulin sensitivity, helps in body weight maintenance, and lowers the risk of cardiovascular disease. Unfortunately, exercise is associated with an increased prevalence of hypoglycemia in patients with diabetes. Furthermore, fear of hypoglycemia results in a serious limitation to the widespread implementation of intensive glycemic control and exercise.Previous studies have shown that antecedent hypoglycemia can blunt neuroendocrine, autonomic nervous system (ANS), and metabolic counterregulatory responses to subsequent exercise (3,4). Reciprocally, antecedent exercise can also blunt homeostatic counterregulatory responses to subsequent hypoglycemia (5,6). Therefore, vicious cycles can be created in type 1 diabetes where an episode of hypoglycemia or exercise can downregulate counterregulatory responses to a subsequent episode of either stress, thereby increasing the risk for further hypoglycemia. However, the mechanisms responsible for exercise-associated counterregulatory failure are not known. Multiple studies have demonstrated that antecedent increases of corticosteroids can blunt subsequent ANS and neuroendocrine responses to a wide spectrum of differing antecedent stress (7–21). Previous studies have also demonstrated that pharmacologic antecedent increases of cortisol can blunt counterregulatory responses to subsequent hypoglycemia in normal subjects (a stress that defends against a falling plasma glucose with similar counterregulatory responses compared with exercise) (7–8). Although, the question of whether physiologic levels of cortisol can blunt counterregulatory responses to subsequent hypoglycemia is still undecided (15,22–24). However, studies specifically investigating the effects of prior elevations of corticosteroids on counterregulatory mechanisms during exercise are lacking. Furthermore, no study has investigated the mechanisms responsible for exercise-related counterregulatory failure in the clinically relevant group of those with type 1 diabetes.Therefore, the specific aim of this present study was to test the hypothesis that antecedent physiologic or pharmacologic elevations of cortisol could blunt counterregulatory responses during subsequent submaximal exercise in type 1 diabetic individuals. To test this hypothesis, hydrocortisone was administered intravenously on day 1 during hyperinsulinemic-euglycemic clamps and responses to subsequent euglycemic exercise were studied during the following day.     

系统性心理行为干预对2型糖尿病患者的影响

目的探讨系统性心理行为干预对2型糖尿病患者的影响。方法将87例2型糖尿病住院患者随机分为研究组（49例）与对照组（38例）。对照组仅进行常规药物治疗和糖尿病常规护理；研究组在此基础上进行系统性心理行为干预，其内容包括心理健康教育、个别心理咨询与家庭治疗、行为矫正和运动疗法等。两组患者分别于干预前、干预后3个月采用焦虑自评量表（SAS）、抑郁自评量表（SDS）评定患者焦虑、抑郁症状，并进行空腹血糖（FBG）厦糖化血红蛋白（HbAlc）、体重指数（BMI）、总体幸福感量表（GWB）的测评；分别计算两组的住院时间及总住院费用，比较两组患者出院3个月内与糖尿痛有关的再住院率。结果研究组干预前后SAS、SDS、FBG、HbAlc、BMI、GWB比较，差异有显著性意义（均P〈0．01）；对照组除BMI外。组内干预前后比较，差异有显著性意义（均P〈0.01）；干预后两组SAS、SDS、FBG、HbAlc、GWB比较，差异有显著性意义（P〈0．05，P〈0．01），而BMI之间比较，差异无显著性意义（P〉0．05）。研究组的住院时间、总住院费用较对照组显著减少（均P〈0．01）；干预3个月后研究组与糖尿病有关的再住院率显著低于对照组（P〈o．05）。结论系统性心理行为干预能显著改善2型糖尿病患者的抑郁、焦虑症状，保持血糖穗定，改善患者生活质量，缩短住院时间，减少住院成本和再住院率。     

系统性心理行为干预对2型糖尿病患者的影响

目的探讨系统性心理行为干预对2型糖尿病患者的影响.方法将87例2型糖尿病住院患者随机分为研究组(49例)与对照组(38例).对照组仅进行常规药物治疗和糖尿病常规护理;研究组在此基础上进行系统性心理行为干预,其内容包括心理健康教育、个别心理咨询与家庭治疗、行为矫正和运动疗法等.两组患者分别于干预前、干预后3个月采用焦虑自评量表(SAS)、抑郁自评量表(SDS)评定患者焦虑、抑郁症状,并进行空腹血糖(FBG)及糖化血红蛋白(HbA1c)、体重指数(BMI)、总体幸福感量表(GWB)的测评;分别计算两组的住院时间及总住院费用,比较两组患者出院3个月内与糖尿病有关的再住院率.结果研究组干预前后SAS、SDS、FBG、HbA1c、BMI、GWB比较,差异有显著性意义(均P<0.01);对照组除BMI外,组内干预前后比较,差异有显著性意义(均P<0.01);干预后两组SAS、SDS、FBG、HbA1c、GWB比较,差异有显著性意义(P<0.05,P<0.01),而BMI之间比较,差异无显著性意义(P>0.05).研究组的住院时间、总住院费用较对照组显著减少(均P<0.01);干预3个月后研究组与糖尿病有关的再住院率显著低于对照组(P<0.05).结论系统性心理行为干预能显著改善2型糖尿病患者的抑郁、焦虑症状,保持血糖稳定,改善患者生活质量,缩短住院时间,减少住院成本和再住院率.     

Effect of Liver Transplantation on Glucose Levels in Patients with Prediabetes or Type 2 Diabetes

Background

Liver transplantation (LT) may induce the occurrence of diabetes mellitus. It can be speculated, however, that the LT may have a beneficial effect on glucose metabolism. We therefore conducted a study to examine the changing trends in blood glucose levels before and after LT in patients with prediabetes or type 2 diabetes.

Methods

In this observational study, we enrolled 47 patients (38 prediabetes and 9 diabetes) who underwent LT. We compared the blood glucose levels between the pre-transplantation (24 months) and the post-transplantation (36 months) periods and analyzed the diverse factors affecting glucose levels.

Results

The glucose regulation worsened and insulin dose increased in patients with diabetes, which was notably seen during the steroid maintenance period. Following steroid withdrawal, however, there was a decrease in the insulin dose in 55.6% of the patients, and 33.3% of the patients converted from insulin to oral agents. Of the patients with prediabetes, 55.3% developed new-onset diabetes after transplantation (NODAT). However, 18.4% achieved a recovery of glucose levels to normal range. Of the 21 NODAT patients, 52.4% achieved a recovery of glucose level to the prediabetes range after steroid withdrawal. There was a significant correlation between the old age and the persistence of NODAT (P < .05).

Conclusions

LT may have a diverse effect on glycemia, which may lead to changes in glucose control methods. Therefore, glucose metabolism after LT may need to be differentiated by the underlying glucose disturbance status and the time after LT with or without steroid maintenance period.     

Short-term Effects of Sleeve Gastrectomy on Type 2 Diabetes Mellitus in Severely Obese Subjects

Background Data on the effectiveness of sleeve gastrectomy (SG) in improving or resolving type 2 diabetes mellitus (T2DM) are scarce. Methods A 4-month prospective study was conducted on the changes in glucose homeostasis in 35 severely obese T2DM subjects undergoing laparoscopic SG (LSG) and 50 subjects undergoing laparoscopic Roux-en-Y gastric bypass (LRYGBP), matched for DM duration, type of DM treatment, and glycemic control. Results At 4-months after surgery, LSG and LRYGBP operated subjects lost a similar amount of weight (respectively, 20.6 ± 0.7% and 21.0 ± 0.6%). T2DM had resolved respectively in 51.4% and 62.0% of the LSG and LRYGBP operated subjects (P = 0.332). A shorter preoperative DM duration (P < 0.05), a preoperative DM treatment not including pharmacological agents, and a better pre-surgical fasting plasma glucose (P < 0.01) or HbA1c (P < 0.01), were significantly associated with a better type 2 DM outcome in both surgical groups. Conclusions Our data show that LSG and LRYGBP result in a similar rate of type 2 DM resolution at 4-months after surgery. Moreover, our data suggest that mechanisms beyond weight loss may be implicated in DM resolution following LSG and LRYGBP.     

Strong Parent-of-Origin Effects in the Association of KCNQ1 Variants With Type 2 Diabetes in American Indians

Parent-of-origin effects were observed in an Icelandic population for several genetic variants associated with type 2 diabetes, including those in KLF14 (rs4731702), MOB2 (rs2334499), and KCNQ1 (rs2237892, rs231362). We analyzed parent-of-origin effects for these variants, along with two others in KCNQ1 identified in previous genome-wide association studies (rs2237895, rs2299620), in 7,351 Pima Indians from 4,549 nuclear families; 34% of participants had diabetes. In a subset of 287 normoglycemic individuals, acute insulin secretion was measured by an intravenous glucose tolerance test. Statistically significant (P < 0.05) parent-of-origin effects were seen for association with type 2 diabetes for all variants. The strongest effect was seen at rs2299620 in KCNQ1; the C allele was associated with increased diabetes when maternally derived (odds ratio [OR], 1.92; P = 4.1 × 10⁻¹²), but not when paternally derived (OR, 0.93; P = 0.47; P = 9.9 × 10⁻⁶ for difference in maternal and paternal effects). A maternally derived C allele also was associated with a 28% decrease in insulin secretion (P = 0.002). This study confirms parent-of-origin effects in the association with type 2 diabetes for variants in KLF14, MOB2, and KCNQ1. In Pima Indians, the effect of maternally derived KCNQ1 variants appears to be mediated through decreased insulin secretion and is particularly strong, accounting for 4% of the variance in liability to diabetes.Several single nucleotide polymorphisms (SNPs) reproducibly associated with type 2 diabetes recently have been identified (1–4). Many of these are in regions of the genome that are imprinted, and studies of an Icelandic population suggest that there are parent-of-origin effects at four of these variants (5); in other words, the extent of association with the risk allele depends on whether it is inherited from the mother or from the father. The SNPs for which parent-of-origin effects have been observed include one in KLF14 (rs4731702), one near MOB2 (rs2334499), and two independent SNPs in KCNQ1 (rs231362 and rs2237892) (5). The presence of parent-of-origin effects at these SNPs is consistent with imprinting and may have important implications for the mechanisms by which variants in or near these genes confer susceptibility to type 2 diabetes. However, for some of the SNPs, the current statistical evidence for parent-of-origin effects is modest. Furthermore, to our knowledge, these effects have not been replicated in other ethnic groups, nor have parent-of-origin effects been analyzed for metabolic traits that underlie the risk of type 2 diabetes, perhaps because few large studies have family data. In the current study, we have analyzed parent-of-origin effects at these SNPs in Pima Indians, an American Indian population in which the prevalence of type 2 diabetes is extraordinarily high (6) and in which family and detailed metabolic data were obtained.