Pathobiology of Remission of Type 2 Diabetes

Greater than 30 million people have diabetes. Over time diabetic patients need more and more
medications and develop numerous medical complications. Remission of Type 2 Diabetes (T2DM)
would have profound effects on people with diabetes with respect to overall health
improvement (insulin sensitivity(Si), cardiovascular risk factors(CVR), inflammation markers
(IC)), reduction of retinopathy, nephropathy, neuropathy and reduction in medical costs.
Methods to accomplish this have not yet been determined, however, it is generally accepted
that non-drug methods to treat T2DM is the most cost effective and have the fewest side
effects. The primary risk factor for T2DM is obesity. Our randomized clinical trials
comparing the effects of High Protein (HP) vs High Carbohydrate (HC) weight loss diets in
obese, prediabetic(IGT) women and men where all foods were provided daily for 6 months(mo)
showed that while both diet groups had similar weight loss, 100% of HP diet subjects had
remission from IGT to Normal Glucose Tolerance(NGT), but only 33% of HC diet group had
remission. Also, the HP diet provided greater improvement in Si, CVR, IC, and an increase in
% lean body mass (LBM) compared to the HC diet demonstrating that weight loss is not the only
factor involved in remission. Based on these findings, we now propose to investigate effects
of HP and HC weight loss diets in Newly Diagnosed T2DM (NT2DM) women and men for 6 mo. Our
long term goal is to establish a weight loss diet plan for remission of NT2DM which would be
adaptable for use in physicians' clinics and metabolomics predictors for assess-ment of
remission. The overall objective of this study is to determine if remission of NT2DM can be
induced by dietary manipulation using a HP diet and the pathobiology of this remission. We
hypothesize that NT2DM subjects will have remission to NGT on the HP diet when they are
provided the food and daily menus for compliance. The rationale is the HP diet is palatable
for subjects to continue after the 6 mo study and stay in remission using diet plans we
provide. We will compare the effects of the HP vs HC diet on remission. Specific aims of this
study are to determine the effects of the HP and HC diets on NT2DM obese subjects in a 6 mo
feeding study and determine: (a)remission of NT2DM to NGT, (b)weight loss and LBM
preservation, (c)improvements in metabolic markers, CVRs, IC, epigenetic DNA methylation
changes and pathways involved with remission and metabolomic markers to establish predictive
markers of remission of NT2DM. This study is innovative in that we propose to use a
non-pharmaceutical means (HP diet) for remission of T2DM diabetes and weight loss and
determine the pathobiology involved in improvement in metabolic and CVRs by interrogating the
samples with emerging technologies. The proposed research is significant because if we can
demonstrate the HP diet cause remission of NT2DM to NGT along with other metabolic
improvements, it would be a significant improvement in health risk and medical cost to
subjects

Inclusion Criteria:

i) Age range 20 yrs to 50 yrs; ii) BMI > 30 kg/m2 to 55kg/m2; iii). Fasting blood glucose
>126 mg/dl and 2 hour glucose >200 mg/dl determined by OGTT; iv). HbA1c > 6.5 % to ≤10%.

Exclusion Criteria:

i) Proteinuria or elevated serum creatinine (>1.5 mg/dl); ii) Surgical or premature
menopause; iii) liver disease or abnormal liver function tests; iv) T2DM of greater than 2
yrs; v) Thyroid disease with abnormal TSH; vi) Weight > 350 lbs, (due to fit on DXA); vii)
Triglycerides>400 mg/dl or LDL cholesterol >160 mg/dl; viii) SBP>145, DBP>100 mm of Hg; ix)
on medications known to effect lipid or glucose metabolism; x) Pregnancy or become pregnant
in next 6 mo; xi) Weight loss >10% of body weight in last 6 mo; xii)History of cancer <5
yrs or undergoing active treatment; xiii) smoking, xiv)alcohol abuse; xv) having CPAP
treatment. xvi)Subjects with HbA1c >10% will be referred to an endocrinologist for
pharmacological treatment.