The diabetes epidemic is now expected by the year 2050 to become a global pandemic with approx. 592 million affected in both the developed and developing world. The treatment of diabetes by insulin therapy has been the focus for many diabetics with the improvement and prevention of various diseases such as cardiovascular disease, kidney disease and neurodegeneration. The global nonalcoholic fatty liver disease (NAFLD) epidemic has now become of major concern to diabetes with critical interest in insulin therapy to reverse and stabilize autoimmune disease with relevance to NAFLD and the diabetes pandemic. Dietary components that activate anti-aging genes improve insulin therapy and should be assessed with specific amounts and doses of Indian spices consumed that may not interfere with insulin therapy and induce mitophagy in various diseases. Food quality, appetite control and core body temperature are critical to maintain insulin therapy with unhealthy diets linked to NAFLD and diabetes. Genomic medicine and dietary activators are essential to maintain insulin therapy and prevent toxic immune reactions with relevance to NAFLD and diabetes management.
- insulin therapy
- autoimmune disease
The diabetes epidemic is expected to affect approx. 592 people by the year 2035. The urgency to prevent the largest diabetes epidemic in history has now assessed multiple risk factors involved with induction of Type 3 diabetes connected to various chronic diseases. Insulin resistance and brain aging now indicate neuron vulnerability to mitophagy associated with the diabetes pandemic expected in 2050 [1, 2]. Diabetes and its connections autoimmunity  have become important to mitophagy, metabolic disease with relevance to the nonalcoholic fatty liver disease (NAFLD) epidemic.
An association between various genes and the immune system [4, 5] has been proposed to be involved with the regulation of life-span in various species. Immune gene activation has been associated with brain aging  with the critical involvement of inflammation in the development of neuro-degeneration. Autoimmune disease, drugs and immunosenescence are related to the chronic disease epidemic with uncontrolled release of inflammatory cytokines such as tumor necrosis factor α and interleukin-6 [7, 8]. Major interests to determine human longevity require the assessment of nutrition and diet with relevance to the control of inflammatory cytokines that are associated with age-related changes in the immune system and the induction of diabetes, NAFLD and neurodegeneration.
Appetite control with relevance to immuno-metabolism has become critical to the treatment of NAFLD. The major defect in global chronic disease is autoimmune disease with defective adipose tissue and liver interaction involved with the release of inflammatory cytokines and adipo-cytokines relevant to toxic immune reactions that involve the pancreas, brain, heart, thyroid, kidneys and reproductive organs. Appetite control and autoimmune disease are connected to anti-aging genes with relevance to irreversible programmed cell death in various cells and tissues. Immune competence changes over a human’s life span with a process known as immunosenescence [9, 10]. In man multiple theories of aging have been proposed with the immune theory of aging that involve abnormal inflammatory responses that contribute to the induction of chronic diseases .
In various communities in the developing and developed world the understanding of the ingestion of a healthy diet and hepatic fat metabolism has become of critical importance to the treatment diabetes that is now linked to various organ diseases. In the world  transition to healthy diets has become urgent to prevent insulin resistance, autoimmune disease and NAFLD. The liver is the major organ for the metabolism of dietary fat and after consumption of a meal in healthy individuals the fat is rapidly metabolized by the mitochondria in the liver.
A diet rich in fat and sugar that lead to fat deposition in the liver can be referred to as liver steatosis. The defect in the liver fatty acid metabolism is possibly related to mitochondrial dysfunction and a careful calorie controlled diet may reverse liver steatosis. As mitochondrial apoptosis occurs steatohepatitis may be associated with liver inflammation. Steatohepatitis may induce NAFLD that may then progress to severe inflammation and liver cirrhosis. In obesity and diabetes the metabolism of a fat meal by the liver is defective with associated hyperglycemia and hyperinsulinemia. Food restriction  and appetite control are vital to the treatment of NAFLD with hepatic fat metabolism connected to insulin resistance, autoimmune disease and mitophagy .
2. Diabetes and pathogenetic loop complications
Insulin treatment in diabetes has provided information that approx. 30% of patients are involved with insulin treatment or plan to start insulin with insulin regimens  associated with various insulin doses and failure of oral anti-diabetic medications. Type 2 diabetes mellitus is characterized by hyperglycemia, insulin resistance, and impairment of insulin secretion . The impairment of insulin secretion is related to hyperglycemia, high serum low-density lipoprotein cholesterol concentrations and low serum high-density lipoprotein cholesterol concentrations with relevance to cardiovascular disease . The relative importance of impaired insulin release and insulin resistance in the pathogenesis of Type 2 diabetes has been evaluated and may be connected to NAFLD. NAFLD may be connected to autoimmune disease and mitophagy associated with impairment in insulin secretion and cardiovascular disease [18, 19, 20]. In Type 1 diabetes the use of insulin therapy has been assessed with the critical importance to reduce hyperglycemia, severe hypoglycemia and the development of long-term complications [21, 22, 23]. Insulin therapy should be carefully evaluated in Type 1 and Type 2 diabetes with relevance to reduction in plasma glucose levels . Interference in hepatic glucose production [24, 25] or interference with increased glucose uptake by the liver may be sensitive to repression of glucose related genes associated with the induction of glucolipotoxicity, NAFLD and insulin resistance. Exercise and insulin therapy  may reduce glucolipotoxicity and NAFLD but with the aging process the pathogenetic loop [27, 28, 29, 30, 31, 32] that involve hyperglycemia, hypercholesterolemia and hyperinsulinemia may be associated with autoimmune disease, mitophagy and programmed cell death of various cells and tissues [18, 19, 20]. The role of diet, lifestyle, stress, sleep and circadian disorders  may inactivate the anti-aging gene Sirtuin 1 (Sirt 1) with relevance to insulin therapy and induction of NAFLD associated with the pathogenetic loop (Figure 1) and uncontrolled inflammation of cells and tissues [18, 19, 20].
3. Anti-aging genes, mitochondrial apoptosis and programmed cell death
Insulin resistance is involved early in alterations of nuclear, subcellular and cell membrane function that lead to cell transformation without reversible changes with accelerated cell apoptosis . In 2050 the predicted global diabetes pandemic [1, 2] has accelerated scientific research to determine the identification of novel genomic pathways such as the anti-aging gene Sirt 1 that may provide new knowledge with relevance to accelerated cell apoptosis and inactivated insulin therapy. In Type 2 diabetes and Type 1 diabetes various genes and genetic loci have been reported to be involved in the development of diabetes . Novel genes  have been identified that are involved with autoimmune disease [18, 19, 36, 37] and glucolipotoxicity with irreversible immune complications relevant to NAFLD, diabetes  and the pathogenetic loop. The discovery of the anti-aging gene Sirt 1 now has become important to the treatment of diabetes with insulin therapy in Type 1 and Type 2 diabetes connected to Sirt 1 activation in the pancreas with relevance to insulin release  with Sirt 1 associated with mitochondrial biogenesis (Figure 1) and cell survival in various tissues [38, 39]. The inactivation of Sirt 1  in humans leads to the pathogenetic loop in diabetes and implicates nutritional and environmental factors in the induction of programmed cell death.
Sirt 1 is a nicotinamide adenine dinucleotide (NAD+) dependent class III histone deacetylase (HDAC) that targets transcription factors such as p 53 to adapt gene expression to metabolic activity and the deacetylation of nuclear receptors indicate its critical involvement in insulin resistance and autoimmune disease . In situ hybridization analysis has localized the human Sirt 1 gene to chromosome 10q21.3 . Calorie restriction is essential for Sirt 1 transcriptional regulation with other factors such as diet and lifestyle critical for the prevention of insulin resistance and NAFLD. Sirt 1 is an acute phase protein involved with neuron proliferation  and its regulation of the suprachiasmatic nucleus is involved with control of the circadian rhythm . The circadian rhythm and immune system are closely connected to the immune response. Nutritional interventions that are controlled by the consumption of a low calorie diet indicate the maintenance of connections between Sirt 1 and other anti-aging genes such as Klotho, p66shc (longevity protein) and FOXO1/FOXO3a that are connected to programmed cell death . Sirt 1 and transcriptional regulation of anti-aging genes are critical to mitophagy (Figure 1) and neurodegenerative disease with accelerated brain aging connected to NAFLD and diabetes [19, 36].
4. Insulin therapy and Indian spices with relevance to NAFLD and diabetes
The connections between NAFLD and diabetes have become of central importance to the expected diabetes pandemic by the year 2050 [1, 2]. NAFLD in diabetic individuals may completely inactivate insulin therapy with defective insulin dose regimens and failure of oral anti-diabetic medications. The defect in the liver fatty acid metabolism is possibly related to mitochondrial dysfunction associated with severe liver inflammation and steatohepatitis that may induce NAFLD that may then progress to severe inflammation (NASH) and liver cirrhosis. Insulin therapy has been used to improve liver function but with NAFLD, high dose insulin therapy may be unsuccessful with liver inflammation [40, 41, 42] associated with uncontrolled hyperglycemia and mitochondrial apoptosis (Figure 2). Insulin therapy with insulin dose and oral anti-diabetic medications should be re-evaluated to improve hepatocyte mitochondrial biogenesis with relevance to reversal of liver disease connected to hyperglycemia and NAFLD in various Type 1, Type 2 and Type 3 [35, 39] diabetics.
The connections between Sirt 1 and insulin resistance have accelerated in recent years with Sirt 1 as a calorie sensitive gene is now implicated in insulin resistance and to the important to glucose dependent insulin secretion with protection of pancreatic β-cell mass [43, 44, 45, 46]. Sirt 1 may be involved in silencing insulin resistance by regulation of specific proteins involved in insulin action . Anti-inflammatory actions in adipocytes involve Sirt 1 repression and inflammation [48, 49] associated with the adipose-liver defect [49, 50] and the induction of NAFLD. Sirt 1 dysfunction in the brain leads to systemic insulin resistance  with close links to Type 3 diabetes and NAFLD [52, 53]. In Sirt 1 knockout mice increased adipose tissue mass has been connected to NAFLD . The expression of Sirt 1 protein has a molecular weight (Mol Wt) of 81 kda with Mol Wt variation (81–110 kda). Insulin therapy to prevent NAFLD requires insulin dose/antidiabetic medication calculation to release the Sirt 1 acute phase protein [18, 37]. Sirt 1 is essential to prevent inflammation and Sirt 1 inactivation may induce NAFLD that may corrupt pancreas function. Insulin therapy and plasma Sirt 1 levels may allow mitochondrial biogenesis to be assessed with relevance to therapeutic glucose control in Type 1, 2 and 3 diabetics. It is unclear if inactivation of insulin therapy is associated with mitophagy and the induction of NAFLD and various organ diseases . Appetite control [13, 18] is now critical to the maintenance of mitochondrial biogenesis and insulin therapy with overeating  connected to inactivation of insulin therapy and linked to the severity of the diabetic condition.
Indian spices have become important as a diabetes technology  with Indian spices such as curcumin and cinnamon associated with glucose control in diabetics (Figure 2). The event of insulin therapy as the primary therapy in diabetes technology has raised concern with relevance to the consumption of Indian spices as a secondary technology . Indian spices consumed over many years are not cleared from the body and may bind to cells and receptors with excess Indian spices that may associate with insulin receptors related to altered insulin actions and inactivated insulin therapy. In normal individuals consumption of cinnamon and curcumin may inactivate the biological activity of insulin [54, 55] with Indian spices as the secondary treatment for glucose control in the brain and the periphery. Drugs such as anti-obese drugs  and novel drugs  are now of critical importance to NAFLD and insulin therapy. Insulin therapy and the use of various therapeutic drugs in diabetes have been linked to the treatment of organ dysfunction [35, 57, 58, 59] in diabetes. The use of Indian spices should be reassessed in various populations to prevent interference with drug/insulin therapy (Figure 2) or with caffeine effects  relevant to the treatment of NAFLD and diabetes. The mixing of spices such as curcumin, turmeric and black pepper in coffee should be discouraged and may contribute to the transcriptional dysregulation of Sirt 1 and induction of mitochondrial apoptosis relevant to diabetes and the pathogenetic loop [27, 28, 29, 30, 31, 32].
5. Genomic medicine and Sirt 1 activators reverse immune reactions in global chronic disease
Genomic medicine in the treatment of cardiovascular disease and diabetes [19, 37] has now accelerated in various communities. Peripheral nutrition is essential early to prevent neurodegeneration (Type 3 diabetes) that lead to uncontrolled peripheral glucose homeostasis. Type 3 diabetes is associated with suprachiasmatic nucleus defects with the abnormal maintenance of brain and whole body glucose metabolism in various species and man . Nutritional therapy in diabetics now need to involve the use of Sirt 1 activators  to prevent the effects of various Sirt 1 inhibitors that accumulate in the blood plasma that repress Sirt 1 expression in cells and tissues. A dose of 4 g/day of phosphatidylinositol  is essential with insulin therapy to prevent hyperglycemia, NAFLD and other neurodegenerative diseases. Sirt 1 inhibitors such as excess palmitic acid (cream, cheese), alcohol and drugs (suramin and sirtinol) should be carefully controlled to prevent inactivation of insulin therapy. Sirt 1 activators such as pyruvic acid, leucine and magnesium are critical with relevance to insulin therapy. Diabetic individuals with Indian spice consumption (Figure 3) over years need to be carefully evaluated with relevance to plasma Sirt 1 inhibitors, xenobiotics , caffeine content , drug therapy, bacterial lipopolysaccharides (LPS) and mycotoxins  that may interfere with insulin/oral medication therapy. The importance of genomic medicine may indicate that the immune system may malfunction  early with relevance to poor nutrition of food quality with irreversible organ disease manifestations. Biotherapy and the immune system [37, 61] may be critical to insulin therapy and connected to insulin resistance and NAFLD. Appetite control and essential food components  may be essential to maintain the immune system with autoimmune disease associated with appetite dysregulation and poor food quality. Specific mitochondrial nutrients  with insulin therapy need to be consumed to prevent severe mitophagy and organ disease.
Food quality with relevance to stroke, synaptic plasticity and neurological diseases has become important to diabetic individuals with essential maintenance and prevention of brain diseases by insulin therapy. Unhealthy diets that contain LPS, mycotoxins and xenobiotics can induce NAFLD with inactivation of insulin therapy. In the developing world increased plasma LPS levels (Figure 3) have raised concern with relevance to induction of metabolic and neurodegenerative diseases [66, 67]. Antibiotic resistance with relevance to antimicrobial drug use should be carefully controlled to prevent excessive release of LPS from the debris of gram negative bacteria . Food preparation should be carefully assessed to prevent end products such as LPS and patulin that may persist in contaminated food [63, 69]. LPS and patulin may inactivate Sirt 1  with relevance to insulin resistance and NAFLD. Xenobiotics  in air, food and water may inactivate insulin therapy (Figure 3) with increased xenobiotic levels associated with mitochondrial apoptosis.
Core body temperature (Figure 3) and insulin therapy are closely connected and dysregulation of core body temperature may induce NAFLD. The discovery of the heat shock gene Sirt 1  has indicated that careful body temperature control is critical to prevent autoimmune disease and mitochondrial apoptosis. Sirt 1 and its inactivation are associated with increased heat shock protein 70 with relevance to natural killer cell activation and mitochondrial apoptosis. Nutritional therapy and core body temperature are essential to maintain insulin therapy in diabetics with relevance to mitophagy and programmed cell death. The event of heat shock protein 70 disturbances may lead to kidney injury  and associated with chronic kidney disease and neurodegeneration in diabetes.
6. Novel biomarkers and insulin therapy may reverse NAFLD and diabetes
The analysis of various plasma biomarkers with insulin therapy  has become of major interest to NAFLD development, therapeutic strategies [73, 74, 75, 76, 77] and diabetes research. Essential measurements of plasma Sirt 1 and heat shock protein levels need to be determined to indicate core body temperature defects with relevance to inactivation of insulin therapy. Tissue analysis of anti-aging genes [18, 33, 54] need to be conducted to determine the role of insulin therapy with relevance to reversal of NAFLD [18, 33, 35, 49, 55, 68, 69] with connections to inflammation and metabolic diseases. Plasma assays of inflammatory cytokines such as tumor necrosis factor alpha, interleukin-1 and interleukin-6 [10, 11] need to be assayed with effective insulin therapy. The major limitation with insulin therapy is to correlate the dose of insulin injected with plasma biomarkers  that maintain mitochondrial biogenesis associated with the prevention of NAFLD (Figure 4). The use of antimicrobials  with insulin therapy should be carefully controlled to prevent increased release of gram negative bacteria LPS end products that may interfere with glucose homeostasis and induce NAFLD. Plasma LPS should be measured with antimicrobial use in individuals on insulin therapy. The connections between the antimicrobial activity, immune system and nitric oxide homeostasis involve Sirt 1 and connected to toxic immune reactions .
The geriatric population in many communities is associated with insulin resistance, Sirt 1 repression and nuclear-mitochondria defects relevant to NAFLD. Sirt 1 measurement in the plasma, cytoplasm and nucleus are essential to determine the relevance of insulin therapy and mitochondrial apoptosis when compared to the validity of various diagnostic tests and plasma analytic measurements. In many biomarker laboratories the comprehensive assessment of various biomarkers may not be correlated with insulin therapy with mitophagy the inevitable cellular defect in geriatric individuals. Analysis of plasma biomarkers (Figure 4) and tissue samples may indicate a primary autoimmune reaction related to a defective nuclear-mitochondria interaction.
Insulin therapy and its use should be carefully revised with relevance to conventional plasma tests that do not indicate cellular mitophagy and toxic immune reactions associated with diabetes [81, 82]. Previous studies [83, 84] with the assessment of the role of insulin on cytokines, lymphocytes and macrophages do not assess Sirt 1’s role in toxic immune reactions and mitophagy. Recent studies have shown that molecular lipid biomarkers from lipidomic analysis [85, 86, 87, 88] may determine diabetes severity. The role of insulin therapy with relevance to lipidomic biomarkers may integrate routine plasma biomarker testing with relevance to cellular Sirt 1 expression and plasma Sirt 1 analysis (Figure 4).
Insulin treatment has been evaluated in diabetes but the global NAFLD epidemic that is expected to reach between 20 and 30% of the worldwide communities will now be connected to diabetes pandemic and the pathogenetic loop. Insulin therapy has been assessed with relevance to improvement in inflammatory conditions but the defect in the anti-aging gene Sirt 1 and diabetic mitophagy still persists with the induction of NAFLD and various organ diseases. Insulin therapy with Indian spice consumption requires reassessment to avoid over-consumption of Indian spices that may inactivate insulin therapy and mitochondrial biogenesis. Food quality, appetite control and core body temperature are critical to maintain insulin therapy with unhealthy diets linked to NAFLD and diabetes. Genomic medicine and Sirt 1 activators are essential to maintain insulin therapy in the developing world with toxic immune reactions important to NAFLD. Insulin therapy may not reverse the nuclear-mitochondria defect that is relevant to global organ disease and various plasma biomarkers.
This work was supported by grants from Edith Cowan University, the McCusker Alzheimer’s Research Foundation and the National Health and Medical Research Council.
|NAFLD||nonalcoholic fatty liver disease|
|Sirt 1||Sirtuin 1|