David M. Pober

Pyruvate kinase M2 activation may protect against the progression of diabetic glomerular pathology and mitochondrial dysfunction

Diabetic nephropathy (DN) is a major cause of end-stage renal disease, and therapeutic options for preventing its progression are limited. To identify novel therapeutic strategies, we studied protective factors for DN using proteomics on glomeruli from individuals with extreme duration of diabetes (ł50 years) without DN and those with histologic signs of DN. Enzymes in the glycolytic, sorbitol, methylglyoxal and mitochondrial pathways were elevated in individuals without DN. In particular, pyruvate kinase M2 (PKM2) expression and activity were upregulated. Mechanistically, we showed that hyperglycemia and diabetes decreased PKM2 tetramer formation and activity by sulfenylation in mouse glomeruli and cultured podocytes. Pkm-knockdown immortalized mouse podocytes had higher levels of toxic glucose metabolites, mitochondrial dysfunction and apoptosis. Podocyte-specific Pkm2-knockout (KO) mice with diabetes developed worse albuminuria and glomerular pathology. Conversely, we found that pharmacological activation of PKM2 by a small-molecule PKM2 activator, TEPP-46, reversed hyperglycemia-induced elevation in toxic glucose metabolites and mitochondrial dysfunction, partially by increasing glycolytic flux and PGC-1α mRNA in cultured podocytes. In intervention studies using DBA2/J and Nos3 (eNos) KO mouse models of diabetes, TEPP-46 treatment reversed metabolic abnormalities, mitochondrial dysfunction and kidney pathology. Thus, PKM2 activation may protect against DN by increasing glucose metabolic flux, inhibiting the production of toxic glucose metabolites and inducing mitochondrial biogenesis to restore mitochondrial function.

Association of Glycemic Control With Reduced Risk for Large-Vessel Disease After More Than 50 Years of Type 1 Diabetes

Context Previously we demonstrated, in individuals who have had type 1 diabetes (T1D) for 50 or more years (Medalists), that glycemic control was unrelated to diabetic complications, with the exception of cardiovascular disease (CVD), contrary to what has been documented in registry-based studies. Objective The purpose of this study is to validate these initial findings and identify contributors to mortality on an individual basis in a large cohort. Design Cross-sectional and longitudinal study. Setting Joslin Diabetes Center (JDC), Boston, Massachusetts. Patients 50-year Medalists presenting to JDC for study participation. Interventions None. Main Outcomes Measures Microvascular and macrovascular complications of diabetes and mortality. Results Glycemic control was not significantly associated with small-vessel complications in Medalists but was associated with CVD in the overall cohort, yet with varying effect by tertile of cohort duration. CVD was the largest contributor to mortality, whereas hemoglobin A1c was not an independent predictor of mortality either overall or substantially by diagnosis interval. Additionally, exercise mitigated mortality risk imparted by CVD. Conclusions Few large populations with long duration of (T1D) have been available to examine the effects of long-term exposure to hyperglycemia. These data indicate that an association of glycemic control, complications, and mortality may change in an older population with T1D. These results suggest that careful control is still warranted in older populations with T1D.

Improving patients’ home cooking – A case series of participation in a remote culinary coaching program

This case series describes and examines the outcomes of a remote culinary coaching program aimed at improving nutrition through home cooking. Participants (n = 4) improved attitudes about the perceived ease of home cooking (p < 0.01) and self-efficacy to perform various culinary skills (p = 0.02); and also improved in confidence to continue online learning of culinary skills and consume healthier food. We believe this program might be a viable response to the need for effective and scalable health-related culinary interventions.

Exogenous Insulin Infusion Can Decrease Atherosclerosis in Diabetic Rodents by Improving Lipids, Inflammation, and Endothelial Function

Objective— The objective of this study is to evaluate whether exogenously induced hyperinsulinemia may increase the development of atherosclerosis. Approach and Results— Hyperinsulinemia, induced by exogenous insulin implantation in high-fat fed (60% fat HFD) apolipoprotein E–deficient mice (ApoE−/−) mice, exhibited insulin resistance, hyperglycemia, and hyperinsulinemia. Atherosclerosis was measured by the accumulation of fat, macrophage, and extracellular matrix in the aorta. After 8 weeks on HFD, ApoE−/− mice were subcutaneously implanted with control (sham) or insulin pellet, and phlorizin, a sodium glucose cotransporters inhibitor (1/2)inhibitor, for additional 8 weeks. Intraperitoneal glucose tolerance test showed that plasma glucose levels were lower and insulin and IGF-1 (insulin-like growth factor-1) levels were 5.3- and 3.3-fold higher, respectively, in insulin-implanted compared with sham-treated ApoE−/− mice. Plasma triglyceride, cholesterol, and lipoprotein levels were decreased in mice with insulin implant, in parallel with increased lipoprotein lipase activities. Atherosclerotic plaque by en face and complexity staining showed significant reductions of fat deposits and expressions of vascular adhesion molecule-1, tumor necrosis factor-&agr;, interleukin 6, and macrophages in arterial wall while exhibiting increased activation of pAKT and endothelial nitric oxide synthase (P<0.05) comparing insulin-implanted versus sham HFD ApoE−/− mice. No differences were observed in atherosclerotic plaques between phlorizin-treated and sham HFD ApoE−/− mice, except phlorizin significantly lowered plasma glucose and glycated hemoglobin levels while increased glucosuria. Endothelial function was improved only by insulin treatment through endothelial nitric oxide synthase/nitric oxide activations and reduced proinflammatory (M1) and increased anti-inflammatory (M2) macrophages, which were inhibited by endothelial nitric oxide synthase inhibitor. Conclusions— Exogenous insulin decreased atherosclerosis by lowering inflammatory cytokines, macrophages, and plasma lipids in HFD-induced hyperlipidemia, insulin resistant and mildly diabetic ApoE−/− mice.

Impact of Diabetes-Specific Nutritional Formulas versus Oatmeal on Postprandial Glucose, Insulin, GLP-1 and Postprandial Lipidemia

Diabetes-specific nutritional formulas (DSNFs) are frequently used as part of medical nutrition therapy for patients with diabetes. This study aims to evaluate postprandial (PP) effects of 2 DSNFs; Glucerna (GL) and Ultra Glucose Control (UGC) versus oatmeal (OM) on glucose, insulin, glucagon-like peptide-1 (GLP-1), free fatty acids (FFA) and triglycerides (TG). After an overnight fast, 22 overweight/obese patients with type 2 diabetes were given 200 kcal of each of the three meals on three separate days in random order. Blood samples were collected at baseline and at 30, 60, 90, 120, 180 and 240 min. Glucose area under the curve (AUC0–240) after GL and UGC was lower than OM (p < 0.001 for both). Insulin positive AUC0–120 after UGC was higher than after OM (p = 0.02). GLP-1 AUC0–120 and AUC0–240 after GL and UGC was higher than after OM (p < 0.001 for both). FFA and TG levels were not different between meals. Intake of DSNFs improves PP glucose for 4 h in comparison to oatmeal of similar caloric level. This is achieved by either direct stimulation of insulin secretion or indirectly by stimulating GLP-1 secretion. The difference between their effects is probably related to their unique blends of amino acids, carbohydrates and fat.

Differential Association of Microvascular Attributions With Cardiovascular Disease in Patients With Long Duration of Type 1 Diabetes

OBJECTIVE Independent association of chronic kidney disease (CKD) and proliferative diabetic retinopathy (PDR) with cardiovascular disease (CVD) has not been established. In the Joslin 50-Year Medalist study, characterizing individuals with type 1 diabetes for 50 years or more, we examined the associations of CKD and PDR with CVD, which was validated by another cohort with type 1 diabetes from Finland. RESEARCH DESIGN AND METHODS This cross-sectional study characterized U.S. residents (n = 762) with type 1 diabetes of 50 years or longer (Medalists) at a single site by questionnaire, clinical, ophthalmic, and laboratory studies. A replication cohort (n = 675) from the longitudinal Finnish Diabetic Nephropathy Study (FinnDiane) was used. CKD and PDR were defined as estimated glomerular filtration rate <45 mL/min/1.73 m2 (CKD stage 3b) and according to the Early Treatment Diabetic Retinopathy Study (ETDRS) protocol, respectively. CVD was based on questionnaires and/or hospital discharge registers. Associations of CVD status with CKD and PDR were analyzed by multivariable logistic regression. RESULTS CVD prevalence in the Medalists with CKD and without PDR (+CKD/−PDR) (n = 30) and CVD prevalence in the −CKD/+PDR group (n = 339) were half the prevalence in the +CKD/+PDR group (n = 66) (34.5% and 42.8% vs. 68.2%, P = 0.002). PDR status was independently associated with CVD (odds ratio 0.21 [95% CI 0.08–0.58], P = 0.003) in patients with CKD. Among the Finnish cohort, a trend toward a lower prevalence of CVD in the +CKD/−PDR group (n = 21) compared with the +CKD/+PDR group (n = 170) (19.1% vs. 37.1%, P = 0.10) was also observed. CONCLUSIONS Absence of PDR in people with type 1 diabetes and CKD was associated with a decreased prevalence of CVD, suggesting that common protective factors for PDR and CVD may exist.

Metabolic Effects of Betaine: A Randomized Clinical Trial of Betaine Supplementation in Prediabetes.

Context Plasma betaine correlates with insulin sensitivity in humans. Betaine supplementation improves metabolic effects in mice fed a high-fat diet. Objective To assess metabolic effects of oral betaine in obese participants with prediabetes. Design A 12-week, parallel arm, randomized, double-masked, placebo-controlled trial. Setting University-affiliated hospital. Participants and Interventions Persons with obesity and prediabetes (N = 27) were randomly assigned to receive betaine 3300 mg orally twice daily for 10 days, then 4950 mg twice daily for 12 weeks, or placebo. Main Outcome Measures Changes from baseline in insulin sensitivity, glycemia, hepatic fat, and endothelial function. Results There was a 16.5-fold increase in plasma dimethylglycine [dimethylglycine (DMG); P < 0.0001] levels, but modest 1.3- and 1.5-fold increases in downstream serine and methionine levels, respectively, in the betaine vs placebo arm. Betaine tended to reduce fasting glucose levels (P = 0.08 vs placebo) but had no other effect on glycemia. Insulin area under curve after oral glucose was reduced for betaine treatment compared with placebo (P = 0.038). Insulin sensitivity, assessed by euglycemic hyperinsulinemic clamp, was not improved. Serum total cholesterol levels increased after betaine treatment compared with placebo (P = 0.032). There were no differences in change in intrahepatic triglyceride or endothelial function between groups. Conclusion DMG accumulation supports DMG dehydrogenase as rate limiting for betaine metabolism in persons with prediabetes. Betaine had little metabolic effect. Additional studies may elucidate mechanisms contributing to differences between preclinical and human responses to betaine, and whether supplementation of metabolites downstream of DMG improves metabolism.

Innovation in medical education: a culinary coaching tele-nutrition training program

ABSTRACT Background: Nutrition medical education training programs that are focused on home cooking are emerging. Objective: This short communication describes the first synchronous tele-nutrition medical education training program using a novel Culinary Coaching (CC) model. Design: Seven health coaches were trained and each coach delivered CC programs to four patients (28 total). Evaluations included:1) two questionnaires before, immediately after, and six months post training program; and 2) one questionnaire after each patient program. Results: CC training significantly improved coaches’ attitudes about and confidence to deliver CC from pre-program means of 3.61 and 3.65 (out of 5), respectively, to post-program means, 3.77 (p<0.01) and 3.86 (p<0.05), respectively, and remained higher 6 months after the training program (3.93, p<0.01; 3.93, p<0.05). Health coaches described a high usage of CC principles and tools through the patient programs. Conclusions: This early evidence suggests that the CC model can be successfully expanded to health coaches, thus improving nutritional care.

Cognitive Function Deficits Associated With Long-Duration Type 1 Diabetes and Vascular Complications

OBJECTIVE Patients with type 1 diabetes now live long enough to experience cognitive decline. During middle age, they show mild cognitive deficits, but it is unknown whether severity increases with aging or whether cognitive profiles are similar to those of age-matched peers with and without diabetes. RESEARCH DESIGN AND METHODS We tested and compared cognition in 82 individuals with 50 or more years of type 1 diabetes (Medalists), 31 age-matched individuals with type 2 diabetes, and 30 age-matched control subjects without diabetes. Medical histories and biospecimens were collected. We also evaluated the association of complications with cognition in Medalists only. RESULTS Compared with control subjects, both individuals with type 1 diabetes and individuals with type 2 diabetes performed worse on immediate and delayed recall (P ≤ 0.002) and psychomotor speed in both hands (P ≤ 0.01) and showed a trend toward worse executive function (P = 0.05). In Medalists, cardiovascular disease was associated with decreased executive function and proliferative diabetic retinopathy with slower psychomotor speed. CONCLUSIONS Both patients with type 1 and patients with type 2 diabetes showed overall worse cognition than control subjects. Further, in Medalists, a relationship between complications and cognition was seen. Although both groups with diabetes showed similar deficit patterns, the underlying mechanisms may be different. Now that patients with type 1 diabetes are living longer, efforts should be made to evaluate cognition and to identify modifying behaviors to slow decline.

Protection from Severe Periodontal Disease among People with Type 1 Diabetes with Duration of 50 Years or Longer

Periodontal disease (PD) is more common and severe in people with diabetes than the general population. The presence of severe PD is correlated with decreased survival, since it can potentially affect glycemic control and severity of complications in people with diabetes. We have reported that Medalists (people with T1DM of 50 years or longer duration) may have endogenous protective factors for the development of diabetic nephropathy (DN) and retinopathy (DR). This study assessed the prevalence of PD in the Medalist cohort and correlated it to the known risk factors of PD and diabetic complications. Severity of PD was defined in a subset (n=170) of Medalists with comparable characteristics of the whole cohort, according to the AAP criteria. The prevalence of severe PD was dramatically decreased in Medalists (13.5%) compared with other studies of people with diabetes of similar age, approximately 33%. Clinical parameters, such as male gender, chronological age, age at diagnosis, and total insulin dose were correlated positively with severity of PD (p=0.04, 0.01, 0.03, and 0.02, respectively), while duration of disease, hemoglobin A1c, BMI, and lipid profiles did not exhibit any correlation. Interestingly, detectible plasma C-peptide levels correlated inversely with severity of PD (p=0.04). Systemic inflammatory markers, such as plasma IL-6, clearly correlated positively with the severity of PD (p=0.01). Serum antibody titer against Porphyromonas gingivalis (Pg), a known pathogen of PD, trended with severity of PD (p=0.08). Amongst the various complications, only the prevalence of CVD correlated positively with severity of PD (p=0.02). These results suggest that Medalists are protected from severe PD even with hyperglycemia. The endogenous protective factors for PD could be similar to those for CVD, possibly related to endogenously produced insulin to neutralize the chronic inflammation caused by residual infection with Pg in the gingival tissues. Disclosure T. Shinjo: None. A. Ishikado: Employee; Self; Sunstar Inc.. Employee; Spouse/Partner; Sunstar Inc.. H. Hasturk: None. L.J. Tinsley: None. D.M. Pober: None. I. Wu: None. T.E. Van Dyke: None. R.J. Genco: None. G.L. King: Research Support; Self; Sanofi-Aventis.