The Diabetes Syndrome – A Collection of Conditions with Common, Interrelated Pathophysiologic Mechanisms

Figures & data

Table 1 Targets and Potential Utility of Diabetes Therapies in Conditions of the Diabetes Syndrome

DM Therapy	Effect on “Egregious Eleven” (Mechanisms of Hyperglycemia)											Potential Utility in Diabetes Syndrome Conditions
	Islet Regulation			Insulin Resistance			Brain (↑ Appetite, ↓Morning Dopamine Surge, ↑ Sympathetic Tone)	Colon/Biome (Abnormal Microbiome, Possible ↓ GLP-1 Secretion)	Immune Dysreg/Inflammation	Stomach/Small Intestine (↑Rate of Glucose Absorption)	Kidney (↑Glucose Re-Absorption)
	β-Cell (↓Function, Mass; ↓ Insulin, ↓Amylin)	Incretin Defect	α-Cell (↓ Glucagon)	Liver (↑ Glucose Production)	Adipose (↑ Lipolysis)	Muscle (↓ Peripheral Insulin Uptake)
TZDs	✔			✔	✔	✔			✔			Cancer
												Dementia
												Psoriasis
												ASCVD
												NAFLD/NASH
Metformin				✔				✔				Cancer
												Dementia
												ASCVD
												NAFLD/NASH
GLP-1 RAs	✔	✔	✔	✔	✔	✔	✔		✔	✔		Cancer
												Dementia
												ASCVD
												NAFLD/NASH
DPP-4 inhibitors	✔	✔	✔						✔			Dementia
												NAFLD/NASH
SGLT-2 inhibitors	✔			✔	✔	✔			✔		✔	ASCVD
												NAFLD/NASH
Dopamine D2 agonist	✔	✔		✔	✔	✔	✔		✔			ASCVD
Immune modulators*	✔								✔			Psoriasis

Note: *Used but not approved for DM.

Abbreviations: ASCVD, atherosclerotic cardiovascular disease; DM, diabetes mellitus; DPP, dipeptidyl peptidase; GLP, glucagon-like protein; NAFLD, nonalcoholic fatty liver disease; NASH, nonalcoholic steatohepatitis; RA, receptor agonist; SGLT, sodium-glucose cotransporters; TZD, thiazolidinediones.

Figure 1 Overlapping pathophysiologic mechanisms that lead to the diabetes syndrome.

Notes: Insulin resistance, its complications, and other conditions arise from common pathophysiologies. Metabolic syndrome, obesity, and PCOS, etc, can be viewed as phenotypes related to genes and epigenetic changes associated with IR. Insulin resistance along with inflammation increase the risk of β-cell dysfunction as well as the Diabetes Syndrome. *Traditional DM complications include retinopathy, nephropathy, neuropathy-tissues that do not require insulin to get glucose into cells.

Abbreviations: AGE, advanced glycosylation end products; ASCVD, atherosclerotic cardiovascular disease; DM, diabetes mellitus; DNA, deoxynucleic acid; HDL, high density lipoprotein; IR, insulin resistance; MS, metabolic syndrome; NAFLD, nonalcoholic fatty liver disease; NASH, nonalcoholic steatohepatitis; PCOS, polycystic ovary disease.