MD Maroof Alam

I am a Research Investigator in Metabolism, Endocrinology & Diabetes at the University of Michigan. My
research expertise is primarily in cell biology, molecular biology, and physiology with a focus on type 2 diabetes
(T2D). During my Ph.D. at AMU India, I studied protein glycation in diabetes, both in vitro and in vivo.
Thereafter, at the National Institute of Immunology, New Delhi, I explored the effect of Rifampicin and
Rifampicin-quinone in db/db mice, which protected from hyperglycemia-related complications during diabetes
without hepatic injury. I then joined Peter Arvan's group, initially as a postdoctoral fellow in 2019, to study
proinsulin folding-trafficking relationships in pancreatic beta cells using animal models and cultured beta-cell lines.
My research has highlighted proinsulin misfolding as a genetic predisposition to the development of diet-induced
diabetes. Indeed, proinsulin misfolding can be entirely subclinical, yet dramatic pathology emerges upon
switching the animals to a high-fat diet, which triggers rapid insulin deficiency. My long-term goal is to explore
various means to improve proinsulin folding and trafficking in order to improve insulin synthesis / secretion for
the prevention and treatment of diabetes.

My current research at the Brehm Center for Diabetes Research, University of Michigan, focuses on
identifying the events and factors contributing to proinsulin misfolding in pancreatic beta cells. Proinsulin, a
prohormone synthesized in beta cells, is the initial and essential step in insulin production. Misfolding of
proinsulin, whether due to INS-gene mutations or defective ER quality control, has been linked to ER stress, beta
cell dysfunction, and diabetes. We have studied mice expressing heterozygous (or homozygous) proinsulinR(B22)E knocked into the Ins2 locus. Neither females nor males bearing the heterozygous mutation developed
diabetes on standard chow but slight evidence of increased proinsulin misfolding in the endoplasmic reticulum is
demonstrable in isolated islets from the heterozygotes. However, males have indications of glucose intolerance,
and within a few weeks of exposure to a high-fat diet, they developed frank diabetes. Evidently, subthreshold
predisposition to proinsulin misfolding can go undetected but provides genetic susceptibility to diet-induced bcell failure. Furthermore, we are studying role of diet and pattern of feeding regime (intermittent fasting) in dietinduced diabetes R(B22)E-Het male mice. We observed that diabetes was reversed, and blood glucose levels
returned to normal without any weight loss. Additionally, the insulin content and serum insulin levels were higher
in the intermittent fasting group compared to the control group. Apart from this, we recently have shown (a
collaborative work) that defects in proinsulin folding can cause proinsulin accumulation in the endoplasmic
reticulum (ER), impaired anterograde proinsulin trafficking, perturbed ER homeostasis, diminished insulin
production, and β-cell dysfunction. We published our work, in Protein Science journal (DOI: 10.1002/pro.4949).
In addition to this research, I have collaborated on projects focused on: (1) The role of C22 (FICD inhibitor) in
proinsulin folding and trafficking for insulin biosynthesis. (2) Synaptotagmins (Syts) -7 and -9 are the most highly
expressed calcium sensing Syts, involved in insulin release, (3) INS gene mutations leading to proinsulin
misfolding, and (4) the role of ER chaperones and oxidoreductases in improving protein folding. Overall, my
ongoing research on the misfolding of the insulin precursor protein, proinsulin, is clinically relevant due to its
implications in diabetes pathogenesis.