Dr. Ralph Defronzo Interview

Dr. Ralph Defronzo Interview

Dr. Ralph Defronzo Interview

Dr. Ralph Defronzo Interview

Steve Freed, RPh, CDE from Diabetes in Control conducted a terrific interview with Ralph DeFronzo, MD, who is an endocrinologist and Deputy Director of the Texas Diabetes Institute.  Dr. DeFronzo has been a pioneer in conducting studies to elucidate the pathophysiology of type 2 diabetes mellitus, and in the evaluation of treatment strategies that address the underlying defects.  Dr. DeFronzo recently surpassed 750 publications and it is difficult to overstate his influence on the field of diabetology.  The full interview on video and a transcript may be obtained at www.diabetesincontrol.com and http://www.diabetesincontrol.com/dr-ralph-defronzo-full-transcript/.

Below is a summary of Dr. DeFronzo’s key points.

  1. Impaired fasting glucose (IFG) and impaired glucose tolerance (IGT) are two subtypes of prediabetes with different pathophysiologies:
    • IFG is characterized by hepatic insulin resistance and impaired first-phase insulin secretion;
    • IGT is characterized by skeletal muscle insulin resistance and impairment of second-phase insulin secretion.
  2. Progressive loss of pancreatic beta-cell function is the hallmark of progression from prediabetes to type 2 diabetes mellitus (T2D), and then to more severe T2D. Impairment of beta-cell response is due to a combination of dysfunction (hibernation) and loss of beta-cell mass.  This process can be arrested or slowed by drug therapies that have direct or indirect effects.
    • Direct effects – thiazolidinediones and GLP-1 agonists appear to have direct effects on the pancreas that help to preserve beta-cell mass, in part through reducing apoptosis.
    • Indirect effects – other drugs that lower glucose will reduce glucose toxicity, which, in turn, will improve beta-cell function and insulin sensitivity. DeFronzo believes that sulfonylureas should rarely be used and favors metformin and SGLT-2 inhibitors over other classes of glucose-lowering drugs.
  3. Recently published data support effects of three classes of hypoglycemic agents to reduce cardiovascular risk.
    • Pioglitazone (a thiazolidinedione) – the IRIS trial
    • SGLT-2 inhibitors – EMPA-REG Outcome and CANVAS
    • GLP-1 agonists – SUSTAIN-6 and LEADER
  4. DeFronzo advocates triple-therapy from early in the disease process (which can be costly) to address the underlying insulin resistance and arrest the progression of beta-cell impairment. This involves use of:
    • Pioglitazone (a thiazolidinedione),
    • A GLP-1 agonist,
    • Metformin or an SGLT-2 inhibitor.

Abbreviations:  CANVAS, Canagliflozin Cardiovascular Assessment Study; EMPA-REG, Empagliflozin Cardiovascular Outcome Event Trial in Type 2 Diabetes Mellitus Patients; GLP-1, glucagon-like peptide-1; IFG, impaired fasting glucose; IGT, impaired glucose tolerance; IRIS, Insulin Resistance Intervention after Stroke; LEADER, Liraglutide Effect and Action in Diabetes: Evaluation of Cardiovascular Outcome Results; SGLT-2, sodium-glucose cotransporter-2; SUSTAIN-6, Trial to Evaluate Cardiovascular and Other Long-term Outcomes with Semaglutide in Subjects with Type 2 Diabetes; T2D, type 2 diabetes mellitus.

Relevant references

Abdul-Ghani M, Migahid O, Megahed A, Adams J, Triplitt C, DeFronzo RA, Zirie M, Jayyousi A. Combination therapy with exenatide plus pioglitazone versus basal/bolus insulin in patients with poorly controlled type 2 diabetes on sulfonylurea plus metformin: The QATAR Study. Diabetes Care. 2017;40:325-331. Erratum: 2017 June 14 [Epub ahead of print].

DeFronzo RA. Banting Lecture. From the triumvirate to the ominous octet: A new paradigm for the treatment of type 2 diabetes mellitus. Diabetes. 2009;58:773-795.

Kaul S. Mitigating cardiovascular risk in type 2 diabetes with antidiabetes drugs: A review of principal cardiovascular outcome results of EMPA-REG OUTCOME, LEADER, and SUSTAIN-6 trials. Diabetes Care. 2017;40:821-831.

Neal B, Perkovic V, Mahaffey KW, de Zeeuw D, Fulcher G, Erondu N, Shaw W, Law G, Desai M, Matthews DR, for the CANVAS Program Collaborative Group. Canagliflozin and cardiovascular and renal events in type 2 diabetes. N Engl J Med. 2017 June 12 [Epub ahead of print].

 

Dr. Ralph Defronzo Interview

Replacing Refined Carbohydrates with Egg Protein and Unsaturated Fatty Acids Improves Insulin Sensitivity and the Cardiometabolic Profile

Replacing Refined Carbohydrates with Egg Protein

Replacing Refined Carbohydrates with Egg Protein and Unsaturated Fatty Acids Improves Insulin Sensitivity and the Cardiometabolic Profile

Replacing Refined Carbohydrates with Egg Protein and Unsaturated Fatty Acids Improves Insulin Sensitivity and the Cardiometabolic Profile

Consuming a healthful diet and participating in an adequate amount of physical activity are key tools for managing metabolic abnormalities that can increase risk for both cardiovascular disease and type 2 diabetes mellitus.  A growing body of evidence supports the view that a diet high in refined starches and added sugars exacerbates disturbances in carbohydrate (CHO) metabolism.  Replacement of these macronutrients with protein and/or unsaturated fatty acids (UFA) may help to improve the cardiometabolic risk factor profile.  The MB Clinical Research team conducted a trial to evaluate the effects of a combination of egg protein (Epro) and UFA, substituted for refined starches and added sugars, on insulin sensitivity and other cardiometabolic health markers in adults with elevated (≥150 mg/dL) triglycerides (TG).

Participants (11 men, 14 women) with elevated TG were randomly assigned to consume test foods prepared using Epro (~8% of energy) and UFA (~8% of energy) for the Epro/UFA condition, or using refined starch and sugar (~16% of energy) for the CHO condition.  Each diet was low in saturated fat and consumed for 3 weeks in a controlled feeding (all food provided) crossover trial, with a 2-week washout between diets.  Insulin sensitivity, assessed by the Matsuda insulin sensitivity index (MISI), increased 18.1 ± 8.7% from baseline during the Epro/UFA condition, compared to a change of -5.7 ± 6.2% during the CHO condition (p < 0.001). The disposition index, a measure of pancreatic beta-cell function, increased during the Epro/UFA condition compared to the CHO condition (net difference 40%, p = 0.042), and low-density lipoprotein (LDL) peak particle size increased during the Epro/UFA condition compared to the CHO condition (net difference 0.27 nm, p = 0.019).  TG and very low-density lipoprotein cholesterol (VLDL-C) levels were lowered more following the Epro/UFA (~16% differences, p < 0.002) versus the CHO diet condition.  LDL-C was lowered by 9-10% with both diets, compared with baseline, but the response did not differ between diets.

Comment:

Consumption of a low-saturated fat diet, where ~16% of energy from refined starches and added sugars was replaced with Epro and UFA, increased indices of insulin sensitivity and pancreatic beta-cell function, increased LDL peak particle size, and lowered fasting TG and VLDL-C levels in men and women with elevated TG.  The results of this study are consistent with a previous study by our group, where daily consumption of three servings of sugar-sweetened products reduced insulin sensitivity by 18% as assessed by HOMA2-%S compared to a habitual diet baseline, and three daily servings of dairy products produced no change.  Reductions in TG and VLDL-C may benefit cardiometabolic health, and are often accompanied by a shift toward larger, more buoyant LDL particles.  This shift, as observed in the current trial, may result in a less atherogenic LDL particle.  The findings from this trial support the Dietary Guidelines for Americans’ recommendations to limit intake of refined starches and added sugars, and to emphasize UFA intake as replacements for both dietary saturated fatty acids and refined CHO.

References:

Maki KC, Palacios OM, Lindner E, Nieman KM, Bell M, Sorce J. Replacement of refined starches and added sugars with egg protein and unsaturated fats increases insulin sensitivity and lowers triglycerides in overweight or obese adults with elevated triglycerides. J Nutr. 2017;May 17 [Epub ahead of print]

Maki KC, Nieman KM, Schild AL, Kaden VN, Lawless AL, Kelley KM, Rains TM. Sugar-sweetened product consumption alters glucose homeostasis compared with dairy product consumption in men and women at risk of type 2 diabetes mellitus. J Nutr. 2015; 145:459-466. Available at http://jn.nutrition.org/content/145/3/459.full.pdf+html.

U.S. Department of Health and Human Services and U.S. Department of Agriculture. 2015-2020 Dietary Guidelines for Americans 2015-2020. Eighth Edition. December 2015. Available at http://health.gov/dietaryguidelines/2015/guidelines/.

 

Replacing Refined Carbohydrates with Egg Protein