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About one in four Veterans lives with type 2 diabetes (T2D) , and nationwide, only 50% of Veterans meet the ADA glycemic target of A1c Disclosure A.L.Mckenzie: Employee; Virta Health Corp., Stock/Shareholder; Virta Health Corp. M.Vantieghem: Employee; Virta Health Corp., Stock/Shareholder; Virta Health Corp. B.Fell: Employee; Virta Health Corp., Stock/Shareholder; Virta Health Corp. R.E.Ratner: Employee; Virta Health Corp.

Lifestyle interventions for type 2 diabetes (T2D) typically have poor retention, and drop out is often assumed to indicate treatment failure. A partnership between the Veterans Health Administration and Virta Health allows Veterans with T2D to enroll in Virta's clinic, which provides carbohydrate restricted nutrition therapy via continuous remote care. We sought to assess change in clinical outcomes upon clinic departure using medical record data. Percent change in clinical outcomes on a per patient basis from enrollment to time of departure were assessed with one sample t tests. Among 677 enrolled Veterans, 270 (40.0%) departed the clinic within 2 years (283±184 days in treatment; enrollment: age 58±9y, 13% female, 235±47 lb, 179±86 mg/dl glucose, 2.3±0.9 T2D medications) . Weight was significantly reduced at time of departure in all groups initiating nutrition therapy (p0.05) despite lower mean glucose which occurred concurrent with medication deprescription in most groups (p Disclosure B.Fell: Employee; Virta Health Corp., Stock/Shareholder; Virta Health Corp. M.Vantieghem: Employee; Virta Health Corp., Stock/Shareholder; Virta Health Corp. A.L.Mckenzie: Employee; Virta Health Corp., Stock/Shareholder; Virta Health Corp. R.E.Ratner: Employee; Virta Health Corp.

Background: We previously reported 1- and 2-year effectiveness of a VLCI via CRC. Here we assess the long term effectiveness of the treatment via achievement of A1c ≤6.5%, Research Design and Methods: Patients with T2D who initially enrolled in a 2-year non-randomized, controlled clinical trial and received a VLCI via CRC were offered 3 additional years of prospective follow-up. Of the 200 patients completing 2 years, 169 (84.5%) consented to extend; 122 (72.2%) were retained at 5 years. Among those who extended, McNemar's test was used to assess the change in percent of patients meeting glycemic targets from baseline to 5 years among completers and on an intent-to-treat basis. Results: At 5 years, the percent of completing patients meeting glycemic goals improved across all defined targets (Table 1) . Of completing patients, 20% achieved diabetes remission, while 32.5% achieved an A1c Conclusions: One fifth of completing patients achieved the international consensus criteria for diabetes remission at 5 years, which is unique among lifestyle interventions. The proportion of people at A1c goal increased, suggesting the VLCI delivered via CRC may be an effective, long-term strategy to improve population health. Disclosure B.M.Volk: Employee; Virta Health Corp., Stock/Shareholder; Virta Health Corp. S.Hallberg: Advisory Panel; Atkins Nutritionals Inc., Employee; Virta Health Corp., Stock/Shareholder; Virta Health Corp. A.L.Mckenzie: Employee; Virta Health Corp., Stock/Shareholder; Virta Health Corp. S.J.Athinarayanan: Employee; Virta Health Corp. M.Vantieghem: Employee; Virta Health Corp., Stock/Shareholder; Virta Health Corp. R.N.Adams: Employee; Virta Health Corp. C.G.P.Roberts: Employee; Virta Health Corp., Stock/Shareholder; Virta Health Corp. R.E.Ratner: Employee; Virta Health Corp. J.Volek: Advisory Panel; Abbott Diagnostics, Simply Good Foods, Stock/Shareholder; Virta Health Corp. S.Phinney: Employee; Virta Health Corp.

Objective: We previously reported long term effectiveness of a very low carbohydrate intervention including nutritional ketosis (VLCI) delivered via continuous remote care (CRC) for improving weight and glycemia at 2 years in people with type 2 diabetes (T2D) . We assessed 5-year changes to determine if the intervention is sustainable, durable, and effective over a longer period of time. Research Design and Methods: Patients with T2D who were initially enrolled in a 2 year non-randomized, controlled clinical trial received a CRC emphasizing a VLCI. These patients were offered to continue for an additional 3 years of prospective follow-up. Of the 200 patients completing 2 years, 169 (84.5%) patients consented to the extension and 122 (72.2%) were retained at 5 years. Among those who extended, baseline versus 5 year differences in weight and glycemic outcomes were assessed using linear mixed effects models in an intent-to-treat analysis. P-values were adjusted using Holm-Bonferroni correction. Results: At five years, there were persistent improvements in weight from 116.4 to 107.6 kg (-8.8 kg, 95%CI [-11.0, -6.6]) , fasting insulin from 25.8 to 24.5 mIU/L (-7.9 mIU/L, 95%CI [-10.0, -5.8]) , and HOMA-IR from 9.1 to 6.6 (-2.5, 95%CI [-3.5, -1.5]) (all adjusted p-values Conclusions: Over 5 years follow-up, the VLCI with CRC showed excellent retention, sustained clinically significant weight loss, and stable glycemic control with reduced dependency on antidiabetes medications. Disclosure S.J.Athinarayanan: Employee; Virta Health Corp. S.Phinney: Employee; Virta Health Corp. M.Vantieghem: Employee; Virta Health Corp., Stock/Shareholder; Virta Health Corp. A.L.Mckenzie: Employee; Virta Health Corp., Stock/Shareholder; Virta Health Corp. S.Hallberg: Advisory Panel; Atkins Nutritionals Inc., Employee; Virta Health Corp., Stock/Shareholder; Virta Health Corp. C.G.P.Roberts: Employee; Virta Health Corp., Stock/Shareholder; Virta Health Corp. B.M.Volk: Employee; Virta Health Corp., Stock/Shareholder; Virta Health Corp. R.N.Adams: Employee; Virta Health Corp. R.E.Ratner: Employee; Virta Health Corp. J.Volek: Advisory Panel; Abbott Diagnostics, Simply Good Foods, Stock/Shareholder; Virta Health Corp.

Type 2 diabetes (T2D) affects about one in four Veterans, a rate nearly three times the general population, and diabetes medications and supplies constitute about one quarter of these Veterans’ pharmacy spend. The Veterans Health Administration partnered with Virta Health to provide carbohydrate restricted nutrition therapy via a continuous remote care model to Veterans in a pilot program. Five-month outcomes demonstrated significant reductions in HbA1c, BMI, diabetes medications and cost, and outpatient visits, but long term sustainability in this population is unknown. This retrospective, real-world, longitudinal analysis assessed the 1- and 2-year effects of the treatment on glycemia, diabetes medications, and body weight using medical record data. Veterans retained at least two years at time of analysis were included (n=254, 58.5% of 434 eligible enrolled, 60±8 years, 12% female) . With initiation of nutritional intervention, glycemia fell necessitating medication titration and elimination to prevent hypoglycemia. The number of diabetes medications prescribed to each person significantly decreased from 2.4±0.9 to 1.3±0.9 and 1.6±0.8 at one and two years, respectively (ps Disclosure A.L.Mckenzie: Employee; Virta Health Corp., Stock/Shareholder; Virta Health Corp. M.Vantieghem: Employee; Virta Health Corp., Stock/Shareholder; Virta Health Corp. B.Fell: Employee; Virta Health Corp., Stock/Shareholder; Virta Health Corp. R.E.Ratner: Employee; Virta Health Corp.

Type 2 Diabetes (T2D) affects one in four Veterans and often occurs with dyslipidemia, chronic kidney disease, and nonalcoholic fatty liver disease (NAFLD) . In a pilot program, the Veterans Health Administration partnered with Virta Health to provide carbohydrate restricted nutrition therapy via continuous remote care to Veterans to reverse T2D by reducing glucose and dependence on medication, as demonstrated in prior research. This retrospective analysis assessed the 1- and 2-year effects on lipids and renal and hepatic markers in a real-world sample of Veterans with T2D using medical record data. Changes in metabolic markers from enrollment to 1- and 2-years (E, 1y, 2y) were assessed with paired t-tests with Holm-Bonferroni correction for multiple comparisons. Veterans retained at least two years at time of analysis were included (n=254, 58.5% of 434 eligible enrolled, 60±8 years, 12% female) . HDL-C (E: 42±16, 1y: 46±12, 2y: 44±11 mg/dl; ps Disclosure M.Vantieghem: Employee; Virta Health Corp., Stock/Shareholder; Virta Health Corp. A.L.Mckenzie: Employee; Virta Health Corp., Stock/Shareholder; Virta Health Corp. R.E.Ratner: Employee; Virta Health Corp.

Objective: To address the long-term effectiveness of VLCI for T2D, we report changes in lipids, inflammatory, hepatic, and renal markers at 5y. Research Design and Methods: Of the 200 subjects with T2D reaching 2-years in a non-randomized, controlled trial of CRC emphasizing VLCI, 169 (84.5%) consented to 3-year extension and 122 (61%) completed 5y. Metabolic changes from baseline (BL) to 5y were assessed with linear mixed effect models as an intent-to-treat analysis (n=169) . Holm-Bonferroni adjusted p-values are Results: At 5y, there were significant changes in HDLc from 43.0 mg/dl to 50.6 mg/dl (+17.7%) , apoA-I from 146.9 mg/dl to 153.5 mg/dl (+4.5%) , and no changes in Total Cholesterol, LDLc, apoB. There were marginal improvements in non-HDLc from 139.2 mg/dl to 128.9 mg/dl (-7.4%, unadjusted p-value Conclusions: People with T2D following VLCI for 5y show improvements in diabetic dyslipidemia and inflammation. Notably, there is no change in LDLc. There is no significant deterioration in liver and renal labs, although regression from CKD3 to 2 is possible with a VLCI and warrants further investigation. Disclosure C.G.Roberts: Employee; Virta Health Corp., Stock/Shareholder; Virta Health Corp. S.Phinney: Employee; Virta Health Corp. S.Hallberg: Advisory Panel; Atkins Nutritionals Inc., Employee; Virta Health Corp., Stock/Shareholder; Virta Health Corp. S.J.Athinarayanan: Employee; Virta Health Corp. M.Vantieghem: Employee; Virta Health Corp., Stock/Shareholder; Virta Health Corp. A.L.Mckenzie: Employee; Virta Health Corp., Stock/Shareholder; Virta Health Corp. B.M.Volk: Employee; Virta Health Corp., Stock/Shareholder; Virta Health Corp. R.N.Adams: Employee; Virta Health Corp. B.Fell: Employee; Virta Health Corp., Stock/Shareholder; Virta Health Corp. R.E.Ratner: Employee; Virta Health Corp. J.Volek: Advisory Panel; Abbott Diagnostics, Simply Good Foods, Stock/Shareholder; Virta Health Corp.

Type 2 diabetes (T2D) and obesity are risk factors for severe COVID-19 infection and death. A medically supervised ketogenic diet (MSKD) can quickly reduce weight and glycemia, so we assessed the incidence of reported COVID-19, its severity, and factors associated with hospitalization in our geographically diverse, US-based, ambulatory population following initiation of a MSKD for T2D. Data were obtained from medical records and from surveys sent to T2D patients who self-reported COVID-19 diagnosis; 47.8% (294/614) responses and one known COVID-related death yielded a sample of 295 (50% male, 54±9 years, across 41 US states). We observed low reported rates of hospitalization (10.9%), ventilation (2.0%), and death (0.3%) relative to national reports. Weight and BMI did not differ by hospitalization status (Table 1), yet greater percent weight loss following initiation of MSKD was associated with reduced hospitalization after accounting for age, baseline weight, and days on MSKD (OR = 1.08, P = 0.03). Nutritional therapies, such as MSKD, that elicit rapid, significant weight loss may favorably impact hospitalization for and COVID-19 severity in patients with T2D. Disclosure B. M. Volk: Employee; Self; Virta Health Corp., Virta Health Corp. C. G. P. Roberts: Employee; Self; Virta Health Corp., Stock/Shareholder; Self; Virta Health Corp. M. Vantieghem: Employee; Self; Virta Health Corp., Stock/Shareholder; Self; Virta Health Corp. A. L. Mckenzie: Employee; Self; Virta Health Corp., Stock/Shareholder; Self; Virta Health Corp. P. George: Advisory Panel; Self; Altavant, United Therapeutics, Consultant; Self; United Therapeutics, Research Support; Self; Janssen Pharmaceuticals, Inc., Speaker’s Bureau; Self; Bayer U. S., Janssen Pharmaceuticals, Inc. S. J. Athinarayanan: Employee; Self; Virta Health Corp. R. N. Adams: Employee; Self; Virta Health Corp., Stock/Shareholder; Self; Virta Health Corp. S. Phinney: Stock/Shareholder; Self; Beyond Obesity LLC, Virta Health Corp. R. E. Ratner: Employee; Self; Virta Health Corp.

Very low carbohydrate diets (VLCD) can reduce weight and often target nutritional ketosis (NK). This analysis assessed the relationship between NK (mean blood beta-hydroxybutyrate, BHB) and weight loss during the first 90 days in 6283 patients treated via a continuous remote care model. Daily medical record weight and fingerstick BHB data obtained from patients with BMI ≥ 25 kg/m2 and type 2 diabetes or prediabetes counseled to target NK for 90 days were included. Linear regression and receiver operating characteristic curve analyses were performed. Clinically significant weight loss (≥5%, CSWL) was achieved by 63.0% (3958/6283) of patients (6.6±4.7% body weight loss at 90 days). Mean BHB over 90 days was a significant predictor of weight change (F=982, R2=0.135, P 1 mM higher likelihood of achieving CSWL within 90 days of initiating a VLCD. A therapeutic target for BHB may be > 0.5-0.7 mM, and likelihood of CSWL increases with higher mean BHB. Future analyses should explore means by which the relationship can be further refined and the impact of longer therapy duration. Disclosure A. L. Mckenzie: Employee; Self; Virta Health Corp., Stock/Shareholder; Self; Virta Health Corp. S. J. Athinarayanan: Employee; Self; Virta Health Corp. R. N. Adams: Employee; Self; Virta Health Corp., Stock/Shareholder; Self; Virta Health Corp. B. M. Volk: Employee; Self; Virta Health Corp., Virta Health Corp. S. Phinney: Stock/Shareholder; Self; Beyond Obesity LLC, Virta Health Corp. R. E. Ratner: Employee; Self; Virta Health Corp.

From 27–29 October 2014, more than 100 people gathered in Chicago, IL, to participate in a research symposium titled “Diabetes and the Microbiome,” jointly sponsored by the American Diabetes Association and JDRF. The conference brought together international scholars and trainees from multiple disciplines, including microbiology, bioinformatics, endocrinology, metabolism, and immunology, to share the current understanding of host-microbe interactions and their influences on diabetes and metabolism. Notably, this gathering was the first to assemble specialists with distinct expertise in type 1 diabetes, type 2 diabetes, immunology, and microbiology with the goal of discussing and defining potential pathophysiologies linking the microbiome and diabetes. In addition to reviewing existing evidence in the field, speakers presented their own original research to provide a comprehensive view of the current understanding of the topics under discussion. Presentations and discussions throughout the conference reflected a number of important concepts. The microbiota in any host represent a complex ecosystem with a high degree of interindividual variability. Different microbial communities, comprising bacteria, archaea, viruses, and fungi, occupy separate niches in and on the human body. Individually and collectively, these microbes provide benefits to the host—including nutrient harvest from food and protection against pathogens. They are dynamically regulated by both host genes and the environment, and they critically influence both physiology and lifelong health. The objective of the symposium was to discuss the relationship between the host and the microbiome—the combination of microbiota and their biomolecular environment and ecology—specifically with regard to metabolic and immunological systems and to define the critical research needed to understand and potentially target the microbiome in the prevention and treatment of diabetes. In this report, we present meeting highlights in the following areas: 1) relationships between diabetes and the microbiome, 2) bioinformatic tools, resources, and study design considerations, 3) microbial programming of the immune system, 4) the microbiome and energy balance, 5) interventions, and 6) limitations, unanswered questions, and resource and policy needs.

The American Diabetes Association, JDRF, the European Association for the Study of Diabetes, and the American Association of Clinical Endocrinologists convened a research symposium, “The Differentiation of Diabetes by Pathophysiology, Natural History and Prognosis” on 10–12 October 2015. International experts in genetics, immunology, metabolism, endocrinology, and systems biology discussed genetic and environmental determinants of type 1 and type 2 diabetes risk and progression, as well as complications. The participants debated how to determine appropriate therapeutic approaches based on disease pathophysiology and stage and defined remaining research gaps hindering a personalized medical approach for diabetes to drive the field to address these gaps. The authors recommend a structure for data stratification to define the phenotypes and genotypes of subtypes of diabetes that will facilitate individualized treatment.

On 26–28 April 2013, the American Diabetes Association convened an international group of experts in Washington, DC, for a research symposium titled “Biologic Responses to Weight Loss and Weight Regain.” The speakers addressed the following topics: 1 ) developmental processes and the prevention of weight gain, 2 ) behavioral management approaches to weight loss, 3 ) distinctions between the physiological mechanisms of weight loss and weight maintenance and the implications for treatment, 4 ) the role of exercise in weight loss and maintenance, 5 ) the physiological mechanisms and effectiveness of bariatric surgery, and 6 ) pharmacological approaches to weight loss and maintenance. Both scientific and clinical perspectives were provided. The meeting concluded with an open session in which all the participants discussed emerging areas of investigation as well as unmet research needs. This discussion resulted in a series of recommendations for future research directions (Table 1). This Perspective article consists of summaries of the symposium sessions, by topic. View this table: Table 1 Recommendations for research questions regarding biologic responses to weight loss and weight regain The rapid increase in the prevalence of childhood obesity has drawn attention to early life influences that may, in part, explain the increased susceptibility to weight gain for individuals and populations. This session featured investigators examining gestational factors and events early in intra- and extrauterine development that may predispose individuals to obesity later in life, such as the programming of the body weight “set point.” These investigations may uncover developmental stages where behavioral or clinical interventions could be implemented to prevent or minimize excessive weight gain. A propensity toward obesity may begin in utero. Over 40 studies have found a U-shaped relationship between birth weight and the risk for a variety of illnesses, including obesity, type 2 diabetes, and cardiovascular disease, with both high and low birth weights associated with greater risk. Susan Ozanne …

We examined the metabolic characteristics that attend the development of type 2 diabetes (T2DM) in 441 impaired glucose tolerance (IGT) subjects who participated in the ACT NOW Study and had complete end-of-study metabolic measurements. Subjects were randomized to receive pioglitazone (PGZ; 45 mg/day) or placebo and were observed for a median of 2.4 years. Indices of insulin sensitivity (Matsuda index [MI]), insulin secretion (IS)/insulin resistance (IR; ΔI0–120/ΔG0–120, ΔIS rate [ISR]0–120/ΔG0–120), and β-cell function (ΔI/ΔG × MI and ΔISR/ΔG × MI) were calculated from plasma glucose, insulin, and C-peptide concentrations during oral glucose tolerance tests at baseline and study end. Diabetes developed in 45 placebo-treated vs. 15 PGZ-treated subjects (odds ratio [OR] 0.28 [95% CI 0.15–0.49]; P < 0.0001); 48% of PGZ-treated subjects reverted to normal glucose tolerance (NGT) versus 28% of placebo-treated subjects (P < 0.005). Higher final glucose tolerance status (NGT > IGT > T2DM) was associated with improvements in insulin sensitivity (OR 0.61 [95% CI 0.54–0.80]), IS (OR 0.61 [95% CI 0.50–0.75]), and β-cell function (ln IS/IR index and ln ISR/IR index) (OR 0.26 [95% CI 0.19–0.37]; all P < 0.0001). Of the factors measured, improved β-cell function was most closely associated with final glucose tolerance status.

Controversy persists about whether hyperinsulinemia and hyperproinsulinemia are independent risk markers for coronary atherosclerosis. A common limitation of most previous studies has been imprecise categorization of disease status in normal and coronary artery disease (CAD) groups. We assessed the relationship of pancreatic β-cell secretory products and premature CAD in a casecontrol study of 134 nondiabetic subjects, aged ≤55 years old, carefully defined for CAD status by catheterization and/or thallium stress studies. Case patients comprised 66 patients with premature CAD, and control subjects (non-CAD group) included 68 patients without CAD but with traditional CAD risk factors and chest pain and/or abnormal electrocardiograms but normal catheterization and/or thallium stress studies. In addition to the CAD and non-CAD group comparison, both groups were compared with a reference group of 27 mixed lean and obese control volunteers. All CAD and non-CAD patients had a 3-h 75-g oral glucose tolerance test with measurement of fasting and post-glucose load immunoreactive insulin (IRI), specific insulin (INS), proinsulin-like material (PI), and C-peptide. Increased fasting insulin and fasting proinsulin levels both were statistically significantly associated with higher odds of being in either the premature CAD and the non-CAD groups when compared with the reference group in a polychotomous logistic regression model (odds ratio of at least 1.20 for a 20% increase in each β-cell secretory product in both comparisons, P ≤ 0.05). However, increased pancreatic β-cell secretory hormone levels did not show a statistically significant relative risk for being in the premature CAD group when compared with the non-CAD group. After adjustment for BMI, all statistically significant associations disappeared for IRI, INS, and PI when the odds favoring being in the CAD and non-CAD groups were compared versus the reference group. Furthermore, the odds of being in the premature CAD and non-CAD groups when compared with the reference group were not significantly associated to the ratio of PI to insulin and C-peptide. Thus, although there is a statistically significant association between the odds of having premature CAD with elevated insulin and proinsulin levels compared with the reference group, these findings are equally common in subjects with traditional CAD risk factors without detectable CAD. Furthermore, the association of higher insulin and proinsulin levels with the likelihood of a patient having or not having CAD disappears after adjustment for BMI, suggesting that insulin and proinsulin are not independent risk markers but are primarily dependent on obesity.

Cutaneous insulin allergy remains a clinical problem despite the use of highly purified human insulins. We used in vitro lymphocyte-transformation studies to examine the reactivity of various insulin formulations in diabetic patients with (n = 4) and without (n = 8) cutaneous allergies. Nonspecific response to concanavalin A demonstrated a >40-fold response in both groups. Control patients did not respond to the addition of commercial insulin preparations (stimulation index [SI]